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AU2003303144A1 - Compositions and methods for the diagnosis and treatment of tumor - Google Patents

Compositions and methods for the diagnosis and treatment of tumor Download PDF

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AU2003303144A1
AU2003303144A1 AU2003303144A AU2003303144A AU2003303144A1 AU 2003303144 A1 AU2003303144 A1 AU 2003303144A1 AU 2003303144 A AU2003303144 A AU 2003303144A AU 2003303144 A AU2003303144 A AU 2003303144A AU 2003303144 A1 AU2003303144 A1 AU 2003303144A1
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Thomas D. Wu
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    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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Description

WO 2004/060270 PCT/US2003/029126 COMPOSITIONS AND METHODS FOR THE DIAGNOSIS AND TREATMENT OF TUMOR FIELD OF THE INVENTION The present invention is directed to compositions of matter useful for the diagnosis and treatment of tumor in mammals and to methods of using those compositions of matter for the same. 5 BACKGROUND OF THE INVENTION Malignant tumors (cancers) are the second leading cause of death in the United States, after heart disease (Boring et al., CA Cancel J. Clin. 43:7 (1993)). Cancer is characterized by the increase in the number of abnormal, or neoplastic, cells derived from a normal tissue which proliferate to form a tumor mass, the 10 invasion of adjacent tissues by these neoplastic tumor cells, and the generation of malignant cells which eventually spread via the blood or lymphatic system to regional lymph nodes and to distant sites via a process called metastasis. In a cancerous state, a cell proliferates under conditions in which normal cells would not grow. Cancer manifests itself in a wide variety of forms, characterized by different degrees of invasiveness and aggressiveness. 15 In attempts to discover effective cellular targets for cancer diagnosis and therapy, researchers have sought to identify transmembrane or otherwise membrane-associated polypeptides that are specifically expressed on the surface of one or more particular type(s) of cancer cell as compared to on one or more normal non cancerous cell(s). Often, such membrane-associated polypeptides are more abundantly expressed on the surface of the cancer cells as compared to on the surface of the non-cancerous cells. The identification of such tumor 20 associated cell surface antigen polypeptides has given rise to the ability to specifically target cancer cells for destruction via antibody-based therapies. In this regard, it is noted that antibody-based therapy has proved very effective in the treatment of certain cancers. For example, HERCEPTIN@ and RITUXAN* (both from Genentech Inc., South San Francisco, California) are antibodies that have been used successfully to treat breast cancer and non-Hodgkin's lymphoma, respectively. More specifically, HERCEPTINo is a recombinant 25 DNA-derived humanized monoclonal antibody that selectively binds to the extracellular domain of the human epidermal growth factor receptor 2 (HER2) proto-oncogene. HER2 protein overexpression is observed in 25-30% of primary breast cancers. RITUXAN* is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. Both these antibodies are recombinantly produced in CHO cells. 30 In other attempts to discover effective cellular targets for cancer diagnosis and therapy, researchers have sought to identify (1) non-membrane-associated polypeptides that are specifically produced by one or more particular type(s) of cancer cell(s) as compared to by one or more particular type(s) of non-cancerous normal cell(s), (2) polypeptides that are produced by cancer cells at an expression level that is significantly higher than that of one or more normal non-cancerous cell(s), or (3) polypeptides whose expression is specifically limited 1 WO 2004/060270 PCT/US2003/029126 to only a single (or very limited number of different) tissue type(s) in both the cancerous and non-cancerous state (e.g., normal prostate and prostate tumor tissue). Such polypeptides may remain intracellularly located or may be secreted by the cancer cell. Moreover, such polypeptides may be expressed not by the cancer cell itself, but rather by cells which produce and/or secrete polypeptides having a potentiating or growth-enhancing effect on cancer cells. Such secreted polypeptides are often proteins that provide cancer cells with a growth advantage 5 over normal cells and include such things as, for example, angiogenic factors, cellular adhesion factors, growth factors, and the like. Identification of antagonists of such non-membrane associated polypeptides would be expected to serve as effective therapeutic agents for the treatment of such cancers. Furthermore, identification of the expression pattern of such polypeptides would be useful for the diagnosis of particular cancers in mammals. 10 As described above, genes upregulated in tumor cells provide attractive anti-cancer therapeutic targets. Although the general underlying mechanism for increased expression in tumor is often not known, tumor-specific upregulation of some genes can be attributed to abberant DNA amplification, a common phenomenon in many tumors. The availability of the human genome sequences and over 4-million expressed sequence tags (ESTs) in the public database has made it possible not only to construct a general transcriptome 15 map, but also to perform large-scale analyses of differential gene expression in normal and tumor tissues. Using a computational method described herein, we have found non-random regions of clusters of genes along various chromosomes that exhibit increased expression in ten tumor types, and these genomic regions often correspond to tumor amplicons experimentally demonstrated by other methods. Thus, we herein describe the genome-wide identification of chromosomal regions with increased tumor expression, regions that represent potential tumor 20 amplicons. There is a great need for additional diagnostic and therapeutic agents capable of detecting the presence of tumor in a mammal and for effectively inhibiting neoplastic cell growth, respectively. Accordingly, it is an objective of the present invention to identify: (1) cell membrane-associated polypeptides that are more abundantly expressed on one or more type(s) of cancer cell(s) as compared to on normal cells or on other 25 different cancer cells, (2) non-membrane-associated polypeptides that are specifically produced by one or more particular type(s) of cancer cell(s) (or by other cells that produce polypeptides having a potentiating effect on the growth of cancer cells) as compared to by one or more particular type(s) of non-cancerous normal cell(s), (3) non-membrane-associated polypeptides that are produced by cancer cells at an expression level that is significantly higher than that of one or more normal non-cancerous cell(s), or (4) polypeptides whose expression 30 is specifically limited to only a single (or very limited number of different) tissue type(s) in both a cancerous and non-cancerous state (e.g., normal prostate and prostate tumor tissue), and to use those polypeptides, and their encoding nucleic acids, to produce compositions of matter useful in the therapeutic treatment and diagnostic detection of cancer in mammals. It is also an objective of the present invention to identify cell membrane associated, secreted or intracellular polypeptides whose expression is limited to a single or very limited number 35 of tissues, and to use those polypeptides, and their encoding nucleic acids, to produce compositions of matter useful in the therapeutic treatment and diagnostic detection of cancer in mammals. 2 WO 2004/060270 PCT/US2003/029126 SUMMARY OF THE INVENTION A. Embodiments In the present specification, Applicants describe for the first time the identification of non-random regions of clusters of genes along various chromosomes that exhibit significantly increased expression in one or more tumor types as compared to normal tissues of the same tissue type. These non-randon chromosomal 5 regions appear to be regions of chromosomal DNA that are amplified in tumor cells yet not amplified in normal cells of the same tissue type, thereby resulting in tumor-specific overexpression of the genes located within the amplicons as compared to the expression level in normal tissue. Moreover, Applicants describe for the first time the identification of various cellular polypeptides (and their encoding nucleic acids or fragments thereof) which are expressed to a greater degree on the surface of or 10 by one or more types of cancer cell(s) as compared to on the surface of or by one or more types of normal non cancer cells. Alternatively, such polypeptides are expressed by cells which produce and/or secrete polypeptides having a potentiating or growth-enhancing effect on cancer cells. Again alternatively, such polypeptides may not be overexpressed by tumor cells as compared to normal cells of the same tissue type, but rather may be specifically expressed by both tumor cells and normal cells of only a single or very limited number of tissue 15 types (preferably tissues which are not essential for life, e.g., prostate, etc.). All of the above polypeptides are herein referred to as Tumor-associated Antigenic Target polypeptides ("TAT" polypeptides) and are expected to serve as effective targets for cancer therapy and diagnosis in mammals. Accordingly, in one embodiment of the present invention, the invention provides an isolated nucleic acid molecule having a nucleotide sequence that encodes a tumor-associated antigenic target polypeptide or 20 fragment thereof (a "TAT" polypeptide). In certain aspects, the isolated nucleic acid molecule comprises a nucleotide sequence having at least about 80% nucleic acid sequence identity, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% nucleic acid sequence identity, to (a) a DNA molecule encoding a full-length TAT polypeptide having an amino acid sequence as disclosed 25 herein, a TAT polypeptide amino acid sequence lacking the signal peptide as disclosed herein, an extracellular domain of a transmembrane TAT polypeptide, with or without the signal peptide, as disclosed herein or any other specifically defined fragment of a full-length TAT polypeptide amino acid sequence as disclosed herein, or (b) the complement of the DNA molecule of (a). In other aspects, the isolated nucleic acid molecule comprises a nucleotide sequence having at least 30 about 80% nucleic acid sequence identity, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% nucleic acid sequence identity, to (a) a DNA molecule comprising the coding sequence of a full-length TAT polypeptide cDNA as disclosed herein, the coding sequence of a TAT polypeptide lacking the signal peptide as disclosed herein, the coding sequence of an extracellular domain of a transmembrane TAT polypeptide, with or without the signal peptide, 35 as disclosed herein or the coding sequence of any other specifically defined fragment of the full-length TAT polypeptide amino acid sequence as disclosed herein, or (b) the complement of the DNA molecule of (a). In further aspects, the invention concerns an isolated nucleic acid molecule comprising a nucleotide 3 WO 2004/060270 PCT/US2003/029126 sequence having at least about 80% nucleic acid sequence identity, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% nucleic acid sequence identity, to (a) a DNA molecule that encodes the same mature polypeptide encoded by the full-length coding region of any of the human protein cDNAs deposited with the ATCC as disclosed herein, or (b) the complement of the DNA molecule of (a). 5 Another aspect of the invention provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding a TAT polypeptide which is either transmembrane domain-deleted or transmembrane domain inactivated, or is complementary to such encoding nucleotide sequence, wherein the transmembrane domain(s) of such polypeptide(s) are disclosed herein. Therefore, soluble extracellular domains of the herein described TAT polypeptides are contemplated. 10 In other aspects, the present invention is directed to isolated nucleic acid molecules which hybridize to (a) a nucleotide sequence encoding a TAT polypeptide having a full-length amino acid sequence as disclosed herein, a TAT polypeptide amino acid sequence lacking the signal peptide as disclosed herein, an extracellular domain of a transmembrane TAT polypeptide, with or without the signal peptide, as disclosed herein or any other specifically defined fragment of a full-length TAT polypeptide amino acid sequence as disclosed herein, 15 or (b) the complement of the nucleotide sequence of (a). In this regard, an embodiment of the present invention is directed to fragments of a full-length TAT polypeptide coding sequence (or any of the amplified chromosomal regions shown in Appendicies B through J), or the complement thereof, as disclosed herein, that may find use as, for example, hybridization probes useful as, for example, diagnostic probes, antisense oligofiucleotide probes, or for encoding fragments of a full-length TAT polypeptide that may optionally encode a polypeptide 20 comprising a binding site for an anti-TAT polypeptide antibody, a TAT binding oligopeptide or other small organic molecule that binds to a TAT polypeptide. Such nucleic acid fragments are usually at least about 5 nucleotides in length, alternatively at least about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 25 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 nucleotides in length, wherein in this context the term "about" means the referenced nucleotide sequence length plus or minus 10% of that referenced length. 30 It is noted that novel fragments of a TAT polypeptide-encoding nucleotide sequence may be determined in a routine manner by aligning the TAT polypeptide-encoding nucleotide sequence with other known nucleotide sequences using any of a number of well known sequence alignment programs and determining which TAT polypeptide-encoding nucleotide sequence fragment(s) are novel. All of such novel fragments of TAT polypeptide-encoding nucleotide sequences are contemplated herein. Also contemplated are the TAT 35 polypeptide fragments encoded by these nucleotide molecule fragments, preferably those TAT polypeptide fragments that comprise a binding site for an anti-TAT antibody, a TAT binding oligopeptide or other small organic molecule that binds to a TAT polypeptide. 4 WO 2004/060270 PCT/US2003/029126 In another embodiment, the invention provides isolated TAT polypeptides encoded by any of the isolated nucleic acid sequences hereinabove identified. In a certain aspect, the invention concerns an isolated TAT polypeptide, comprising an amino acid sequence having at least about 80% amino acid sequence identity, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino 5 acid sequence identity, to a TAT polypeptide having a full-length amino acid sequence as disclosed herein, a TAT polypeptide amino acid sequence lacking the signal peptide as disclosed herein, an extracellular domain of a transmembrane TAT polypeptide protein, with or without the signal peptide, as disclosed herein, an amino acid sequence encoded by any of the nucleic acid sequences disclosed herein or any other specifically defined fragment of a full-length TAT polypeptide amino acid sequence as disclosed herein. 10 In a further aspect, the invention concerns an isolated TAT polypeptide comprising an amino acid sequence having at least about 80% amino acid sequence identity, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity, to an amino acid sequence encoded by any of the human protein cDNAs deposited with the ATCC as disclosed herein. 15 In a specific aspect, the invention provides an isolated TAT polypeptide without the N-terminal signal sequence and/or without the initiating methionine and is encoded by a nucleotide sequence that encodes such an amino acid sequence as hereinbefore described. Processes for producing the same are also herein described, wherein those processes comprise culturing a host cell comprising a vector which comprises the appropriate encoding nucleic acid molecule under conditions suitable for expression of the TAT polypeptide and recovering 20 the TAT polypeptide from the cell culture. Another aspect of the invention provides an isolated TAT polypeptide which is either transmembrane domain-deleted or transmembrane domain-inactivated. Processes for producing the same are also herein described, wherein those processes comprise culturing a host cell comprising a vector which comprises the appropriate encoding nucleic acid molecule under conditions suitable for expression of the TAT polypeptide and 25 recovering the TAT polypeptide from the cell culture. In other embodiments of the present invention, the invention provides vectors comprising DNA encoding any of the herein described polypeptides. Host cells comprising any such vector are also provided. By way of example, the host cells may be CHO cells, E. coli cells, or yeast cells. A process for producing any of the herein described polypeptides is further provided and comprises culturing host cells under conditions 30 suitable for expression of the desired polypeptide and recovering the desired polypeptide from the cell culture. In other embodiments, the invention provides isolated chimeric polypeptides comprising any of the herein described TAT polypeptides fused to a heterologous (non-TAT) polypeptide. Example of such chimeric molecules comprise any of the herein described TAT polypeptides fused to a heterologous polypeptide such as, for example, an epitope tag sequence or a Fc region of an immunoglobulin. 35 In another embodiment, the invention provides an antibody which binds, preferably specifically, to any of the above or below described polypeptides. Optionally, the antibody is a monoclonal antibody, antibody fragment, chimeric antibody, humanized antibody, single-chain antibody or antibody that competitively inhibits 5 WO 2004/060270 PCT/US2003/029126 the binding of an anti-TAT polypeptide antibody to its respective antigenic epitope. Antibodies of the present invention may optionally be conjugated to a growth inhibitory agent or cytotoxic agent such as a toxin, including, for example, a maytansinoid or calicheamicin, an antibiotic, a radioactive isotope, a nucleolytic enzyme, or the like. The antibodies of the present invention may optionally be produced in CHO cells or bacterial cells and preferably induce death of a cell to which they bind. For diagnostic purposes, the antibodies 5 of the present invention may be detectably labeled, attached to a solid support, or the like. In other embodiments of the present invention, the invention provides vectors comprising DNA encoding any of the herein described antibodies. Host cell comprising any such vector are also provided. By way of example, the host cells may be CHO cells, E. coli cells, or yeast cells. A process for producing any of the herein described antibodies is further provided and comprises culturing host cells under conditions suitable 10 for expression of the desired antibody and recovering the desired antibody from the cell culture. In another embodiment, the invention provides oligopeptides ("TAT binding oligopeptides") which bind, preferably specifically, to any of the above or below described TAT polypeptides. Optionally, the TAT binding oligopeptides of the present invention may be conjugated to a growth inhibitory agent or cytotoxic agent such as a toxin, including, for example, a maytansinoid or calicheamicin, an antibiotic, a radioactive isotope, 15 a nucleolytic enzyme, or the like. The TAT binding oligopeptides of the present invention may optionally be produced in CHO cells or bacterial cells and preferably induce death of a cell to which they bind. For diagnostic purposes, the TAT binding oligopeptides of the present invention may be detectably labeled, attached to a solid support, or the like. In other embodiments of the present invention, the invention provides vectors comprising DNA 20 encoding any of the herein described TAT binding oligopeptides. Host cell comprising any such vector are also provided. By way of example, the host cells may be CHO cells, E. coli cells, or yeast cells. A process for producing any of the herein described TAT binding oligopeptides is further provided and comprises culturing host cells under conditions suitable for expression of the desired oligopeptide and recovering the desired oligopeptide from the cell culture. 25 In another embodiment, the invention provides small organic molecules ("TAT binding organic molecules") which bind, preferably specifically, to any of the above or below described TAT polypeptides. Optionally, the TAT binding organic molecules of the present invention may be conjugated to a growth inhibitory agent or cytotoxic agent such as a toxin, including, for example, a maytansinoid or calicheamicin, an antibiotic, a radioactive isotope, a nucleolytic enzyme, or the like. The TAT binding organic molecules of 30 the present invention preferably induce death of a cell to which they bind. For diagnostic purposes, the TAT binding organic molecules of the present invention may be detectably labeled, attached to a solid support, or the like. In a still further embodiment, the invention concerns a composition of matter comprising a TAT polypeptide as described herein, a chimeric TAT polypeptide as described herein, an anti-TAT antibody as 35 described herein, a TAT binding oligopeptide as described herein, or a TAT binding organic molecule as described herein, in combination with a carrier. Optionally, the carrier is a pharmaceutically acceptable carrier. 6 WO 2004/060270 PCT/US2003/029126 In yet another embodiment, the invention concerns an article of manufacture comprising a container and a composition of matter contained within the container, wherein the composition of matter may comprise a TAT polypeptide as described herein, a chimeric TAT polypeptide as described herein, an anti-TAT antibody as described herein, a TAT binding oligopeptide as described herein, or a TAT binding organic molecule as described herein. The article may further optionally comprise a label affixed to the container, or a package 5 insert included with the container, that refers to the use of the composition of matter for the therapeutic treatment or diagnostic detection of a tumor. Another embodiment of the present invention is directed to the use of a TAT polypeptide as described herein, a chimeric TAT polypeptide as described herein, an anti-TAT polypeptide antibody as described herein, a TAT binding oligopeptide as described herein, or a TAT binding organic molecule as described herein, for 10 the preparation of a medicament useful in the treatment of a condition which is responsive to the TAT polypeptide, chimeric TAT polypeptide, anti-TAT polypeptide antibody, TAT binding oligopeptide, or TAT binding organic molecule. B. Additional Embodiments Another embodiment of the present invention is directed to a method for inhibiting the growth of a cell 15 that expresses a TAT polypeptide, wherein the method comprises contacting the cell with an antibody, an oligopeptide or a small organic molecule that binds to the TAT polypeptide, and wherein the binding of the antibody, oligopeptide or organic molecule to the TAT polypeptide causes inhibition of the growth of the cell expressing the TAT polypeptide. In preferred embodiments, the cell is a cancer cell and binding of the antibody, oligopeptide or organic molecule to the TAT polypeptide causes death of the cell expressing the TAT 20 polypeptide. Optionally, the antibody is a monoclonal antibody, antibody fragment, chimeric antibody, humanized antibody, or single-chain antibody. Antibodies, TAT binding oligopeptides and TAT binding organic molecules employed in the methods of the present invention may optionally be conjugated to a growth inhibitory agent or cytotoxic agent such as a toxin, including, for example, a maytansinoid or calicheamicin, an antibiotic, a radioactive isotope, a nucleolytic enzyme, or the like. The antibodies and TAT binding oligopeptides 25 employed in the methods of the present invention may optionally be produced in CHO cells or bacterial cells. Yet another embodiment of the present invention is directed to a method of therapeutically treating a mammal having a cancerous tumor comprising cells that express a TAT polypeptide, wherein the method comprises administering to the mammal a therapeutically effective amount of an antibody, an oligopeptide or a small organic molecule that binds to the TAT polypeptide, thereby resulting in the effective therapeutic 30 treatment of the tumor. Optionally, the antibody is a monoclonal antibody, antibody fragment, chimeric antibody, humanized antibody, or single-chain antibody. Antibodies, TAT binding oligopeptides and TAT binding organic molecules employed in the methods of the present invention may optionally be conjugated to a growth inhibitory agent or cytotoxic agent such as a toxin, including, for example, a maytansinoid or calicheamicin, an antibiotic, a radioactive isotope, a nucleolytic enzyme, or the like. The antibodies and 35 oligopeptides employed in the methods of the present invention may optionally be produced in CHO cells or bacterial cells. 7 WO 2004/060270 PCT/US2003/029126 Yet another embodiment of the present invention is directed to a method of determining the presence of a TAT polypeptide in a sample suspected of containing the TAT polypeptide, wherein the method comprises exposing the sample to an antibody, oligopeptide or small organic molecule that binds to the TAT polypeptide and determining binding of the antibody, oligopeptide or organic molecule to the TAT polypeptide in the sample, wherein the presence of such binding is indicative of the presence of the TAT polypeptide in the sample. 5 Optionally, the sample may contain cells (which may be cancer cells) suspected of expressing the TAT polypeptide. The antibody, TAT binding oligopeptide or TAT binding organic molecule employed in the method may optionally be detectably labeled, attached to a solid support, or the like. A further embodiment of the present invention is directed to a method of diagnosing the presence of a tumor in a mammal, wherein the method comprises detecting the level of expression of a gene encoding a 10 TAT polypeptide (a) in a test sample of tissue cells obtained from said mammal, and (b) in a control sample of known normal non-cancerous cells of the same tissue origin or type, wherein a higher level of expression of the TAT polypeptide in the test sample, as compared to the control sample, is indicative of the presence of tumor in the mammal from which the test sample was obtained. Another embodiment of the present invention is directed to a method of diagnosing the presence of a 15 tumor in a mammal, wherein the method comprises (a) contacting a test sample comprising tissue cells obtained from the mammal with an antibody, oligopeptide or small organic molecule that binds to a TAT polypeptide and (b) detecting the formation of a complex between the antibody, oligopeptide or small organic molecule and the TAT polypeptide in the test sample, wherein the formation of a complex is indicative of the presence of a tumor in the mammal. Optionally, the antibody, TAT binding oligopeptide or TAT binding organic molecule 20 employed is detectably labeled, attached to a solid support, or the like, and/or the test sample of tissue cells is obtained from an individual suspected of having a cancerous tumor. Yet another embodiment of the present invention is directed to a method for treating or preventing a cell proliferative disorder associated with altered, preferably increased, expression or activity of a TAT polypeptide, the method comprising administering to a subject in need of such treatment an effective amount 25 of an antagonist of a TAT polypeptide. Preferably, the cell proliferative disorder is cancer and the antagonist of the TAT polypeptide is an anti-TAT polypeptide antibody, TAT binding oligopeptide, TAT binding organic molecule or antisense oligonucleotide. Effective treatment or prevention of the cell proliferative disorder may be a result of direct killing or growth inhibition of cells that express a TAT polypeptide or by antagonizing the cell growth potentiating activity of a TAT polypeptide. 30 Yet another embodiment of the present invention is directed to a method of binding an antibody, oligopeptide or small organic molecule to a cell that expresses a TAT polypeptide, wherein the method comprises contacting a cell that expresses a TAT polypeptide with said antibody, oligopeptide or small organic molecule under conditions which are suitable for binding of the antibody, oligopeptide or small organic molecule to said TAT polypeptide and allowing binding therebetween. 35 Other embodiments of the present invention are directed to the use of (a) a TAT polypeptide, (b) a nucleic acid encoding a TAT polypeptide or a vector or host cell comprising that nucleic acid, (c) an anti-TAT polypeptide antibody, (d) a TAT-binding oligopeptide, or (e) a TAT-binding small organic molecule in the 8 WO 2004/060270 PCT/US2003/029126 preparation of a medicament useful for (i) the therapeutic treatment or diagnostic detection of a cancer or tumor, or (ii) the therapeutic treatment or prevention of a cell proliferative disorder. Another embodiment of the present invention is directed to a method for inhibiting the growth of a cancer cell, wherein the growth of said cancer cell is at least in part dependent upon the growth potentiating effect(s) of a TAT polypeptide (wherein the TAT polypeptide may be expressed either by the cancer cell itself 5 or a cell that produces polypeptide(s) that have a growth potentiating effect on cancer cells), wherein the method comprises contacting the TAT polypeptide with an antibody, an oligopeptide or a small organic molecule that binds to the TAT polypeptide, thereby antagonizing the growth-potentiating activity of the TAT polypeptide and, in turn, inhibiting the growth of the cancer cell. Preferably the growth of the cancer cell is completely inhibited. Even more preferably, binding of the antibody, oligopeptide or small organic molecule to the TAT polypeptide 10 induces the death of the cancer cell. Optionally, the antibody is a monoclonal antibody, antibody fragment, chimeric antibody, humanized antibody, or single-chain antibody. Antibodies, TAT binding oligopeptides and TAT binding organic molecules employed in the methods of the present invention may optionally be conjugated to a growth inhibitory agent or cytotoxic agent such as a toxin, including, for example, a maytansinoid or calicheamicin, an antibiotic, a radioactive isotope, a nucleolytic enzyme, or the like. The antibodies and TAT 15 binding oligopeptides employed in the methods of the present invention may optionally be produced in CHO cells or bacterial cells. Yet another embodiment of the present invention is directed to a method of therapeutically treating a tumor in a mammal, wherein the growth of said tumor is at least in part dependent upon the growth potentiating effect(s) of a TAT polypeptide, wherein the method comprises administering to the mammal a therapeutically 20 effective amount of an antibody, an oligopeptide or a small organic molecule that binds to the TAT polypeptide, thereby antagonizing the growth potentiating activity of said TAT polypeptide and resulting in the effective therapeutic treatment of the tumor. Optionally, the antibody is a monoclonal antibody, antibody fragment, chimeric antibody, humanized antibody, or single-chain antibody. Antibodies, TAT binding oligopeptides and TAT binding organic molecules employed in the methods of the present invention may optionally be conjugated 25 to a growth inhibitory agent or cytotoxic agent such as a toxin, including, for example, a maytansinoid or calicheamicin, an antibiotic, a radioactive isotope, a nucleolytic enzyme, or the like. The antibodies and oligopeptides employed in the methods of the present invention may optionally be produced in CHO cells or bacterial cells. Yet further embodiments of the present invention will be evident to the skilled artisan upon a reading 30 of the present specification. BRIEF DESCRIPTION OF THE DRAWINGS In the list of figures for the present application, specific cDNA sequences which are overexpressed in certain tumor tissues as compared to their normal tissue counterparts are individually identified with a specific alphanumerical designation. These cDNA sequences are expressed from genes that are located within amplified 35 chromosomal regions in tumor cells that are identified as described in Example 1 below. If start and/or stop codons have been identified in a cDNA sequence shown in the attached figures, they are shown in bold and underlined font. 9 WO 2004/060270 PCT/US2003/029126 List of Figures Figure 1: NM005973.3 Figure 55: XM-08657 1.1 Figure 2: XM_044077.3 Figure 56: NM-0 18973.2 Figure 3: XM-056380.2 Figure 57: NM.018845.1 Figure 4: XM_044080.2 Figure 58: XM 13377.1 Figure 5: XM-044083.5 Figure 59: NM004952.2 Figure 6: NM-001878.2 Figure 60A-B: XMvL1l56l.10 Figure 7: XM-017040.3 Figure 61: XM 17201.1 Figure 8: NM-021948.2 Figure 62: XMJ-36744.6 Figure 9: NM-021817.1 Figure 63: NMA30898.1 Figure 10: XML086573.1 Figure 64: NM -006694.1 Figure 11: XM-097656.1 Figure 65: NMAJ02870.1 Figure 12: XM.D59219.2 Figure 66: NM001030.2 Figure 13: NM005920.1 Figure 67: XM.036829.6 Figure 14: NM-006365.1 Figure 68: NM-015449.1 Figure 15: XM_059216.5 Figure 69: NM014847.1 Figure 16: XM..044127.8- Figure 70: NM-06118.2 Figure 17: XM053245.6 Figure 71: XMA14855.1 Figure 18: NM_032323.1 Figure 72: NM1J80429.1 Figure 19A-B: XM-044148.3 Figure 73A-B: XMv036933.7 Figure 20: NML248974l Figure 74: XM036934.4 Figure 21: NM00722L1 Figure 75: X.1L87710.2 Figure 22A-B: XM_044155.1 Figure 76: W-004181 Figure 23: XMi-86562.1 Figure 77: XM467726.1 Figure 24: NM.022367.1 Figure 78: NM-021727.2 Figure 25: NM005572.1 Figure 79: NM004265.2 Figure 26: XM..044166.3 Figure S0A-B: NM013402.3 Figure 27: XMJ353243.1 Figure 81: NM-004111.4 Figure 28: XM017041.3 Figure 82: NMvL14206.1 Figure 29: XM_044128.6 Figure 83A-B: NM013279.1 Figure 30: NMO03145.2 Figure 84A-B: XMA67769.1 Figure 31A-B: XI-044172.7 Figure 85: XM043146.5 Figure 32A-B: XM_010715.2 Figure 86: XM.043151.7 Figure 33: XM44108.3 Figure 87: XM.090000.4 Figure 34: NM032292.1 Figure 88: XM'048286.6 Figure 35: NM_017710.1 Figure 89: NM016404.1 Figure 36: NM033657.1 Figure 90: XMA 13225.1 Figure 37: NM.018253.1 Figure 91: NM1304322.2 Figure 38: NMAJ18 116.1 Figure 92: XM 13222.1 Figure 39A-C: NM-018489.1 Figure 93: XM113221.1 Figure 40: XM-11513.3 Figure 94: XM4-15027.1 Figure 41: NM-014328.1 Figure 95: NM-014067.2 Figure 42: NM.002004.1 Figure 96: XM-05379 1.1 Figure 43A-B: XM_-086565.1 Figure 97: XM -006111.8 Figure 44: NMA103993.1 Figure 98: XM011988.9 Figure 45: NM _005698.2 Figure 99: XM049178.6 Figure 46: NM.006589.1 Figure 100: NM032344.1 Figure 47: XM_084078.4 Figure 101: NM-031472.1 Figure 48: XM-086567.1 Figure 102: XM1337808.4 Figure 49: XM.086552.4 Figure 103: NM-004074.1 Figure 50: NM..007112.1 Figure 104: Xlvl017481.6 Figure 51: XM.053256.7 Figure 105: NM017670.1 Figure 52: XM.089386.1 Figure 106: XMv043159.1 Figure 53: NM025058.1 Figure 107: XM113223.t Figure 54: XM-114144.1 Figure 108: NM-003942.1 10 WO 2004/060270 PCT/US2003/029126 Figure 109A-B: XM-045649.4 Figure 165: XOA166795.1 Figure 110: NM.A05825.2 Figure 166A-B: NM018312.2 Figure 111: NMA-05609.1 Figure 167: NM 001876.1 Figure 112: XM.045642.3 Figure 168: XM166196.1 Figure 113: XM_006533.7 Figure 169: XM165600.1 Figure 114: XM006532.9 Figure 170: XM166195.1 Figure 115: XM1D45613.6 Figure 171: XMA67784.1 Figure 116A-B: XM_045612.4 Figure 172: XMA69223.1 Figure 117: NM1J06244.1 Figure 173: NM005171.l Figure 118: XMLI13224.1 Figure 174: NM014033.1 Figure 119: XM045498.5 Figure 175A-B: NM0308O9.1 Figure 120: XM.045499.3 Figure 176: NM015416.1 Figure 121: NM-i01997.2 Figure 177: XM04961.4 Figure 122: NM-014205.1 Figure 178: XM..51166.6 Figure 123: XM045525.7 Figure 179: XMAI90501.4 Figure 124: NMA113265.2 Figure 180: XMAJ96620.4 Figure 125: XM006529.8 Figure 181: XMAI1l481.7 Figure 126: XM_053787.6 Figure 182: XMJJ49148.2 Figure 127: XM037756.2 Figure 183: XMA 13726.1 Figure 128: XM_165896.1 Figure 184: XM1112230.1 Figure 129: XM-084617.4 Figure 185: NMAIO6I21.2 Figure 130: XM45533.3 Figure 186: XM062616.1 Figure 131: XM_057307.6 Figure 187: XMAD49141.1 Figure 132: NMAJ01667.1 Figure 188: XM096612A Figure 133: NMA38456.1 Figure 189: NM-021934.1 Figure 134: XMA15029.1 Figure 190: XM-083884.1 Figure 135: XM115031.1 Figure 191A-B:XM007464.3 Figure 136: XM1084702.4 Figure 192: NM-006925.1 Figure 137: XM_037764.6 Figure 193: NM-022137.1 Figure 138: XMJJ53796.5 Figure 194: XM085065.4 Figure 139: NM.D02689.2 Figure 195: XM165656.1 Figure 140: NM1J06268.2 Figure 196: NMAI32330.1 Figure 141: XM166932.1 Figure 197: NM001043.1 Figure 142A-D: XMA167804.1 Figure 198: NMA100978.2 Figure 143: XM 166931.1 Figure 199: NM017748.2 Figure 144: XM_166235.1 Figure 200A-B: XM -008145.3 Figure 145: XM_166236.1 Figure 201: NMI002795.1 Figure 146: NM_006842.1 Figure 202: XM -008147.3 Figure 147: XM -167811.1 Figure 203: XMA 13893.1 Figure 148: NM_000852.2 Figure 204: NM 005937.1 Figure 149: NMA0O7103.2 Figure 205A-B: XMD85541.1 Figure 150: NM005851.2 Figure 206: NMA118530.1 Figure 151: XM_165598.1 Figure 207: NMAM6471.1 Figure 152: XMA65599.1 Figure 208: XMvL58830.3 Figure 153: XM166194.1 Figure 209: NMJ17040.1 Figure 154: XM_166793.1 Figure 210: NM.002809.1 Figure 155: XM_165594.1 Figure 211: XM049860.3 Figure 156: XM166190.1 Figure 212A-B: NM -007359.2 Figure 157: NM002496.1 Figure 213: Xlvi 13939.1 Figure 158: NM_006019.2 Figure 214: M1J08586.5 Figure 159: XM_165601.1 Figure 215: XMA 17071.1 Figure 160: XMJI89954.4 Figure 216: XM-13329.1 Figure 161: NMJJ17635.1 Figure 217: XM -083987.2 Figure 162: NM_016028.2 Figure 218: NMA-00422.1 Figure 163: NMi322338.1 Figure 219: XMAJ08579.4 Figure 164A-B: NM-002335-1 Figure 220: NM002276.1 Fiue16:X -169.
WO 2004/060270 PCT/US2003/029126 Figure 221: NM_002275.1 Figure 277: 1MM179834.1 Figure 222: NM_002274.1 Figure 278: NMJJ01319.4 Figure 223: NMAJ02277.2 Figure 279: NM-017797.2 Figure 224: NM100526.3 Figure 280: NM-017572.1 Figure 225A-B: XM.041843.2 Figure 281: XM1-59021.3 Figure 226: XM -042009.4 Figure 282: XM -053871.4 Figure 227: XM-065166.2 Figure 283A-B: NM-03938.2 Figure 228: XM_085978.1 Figure 284A-B: XM-046822.2 Figure 229: XM-042012.2 Figure 285: NM1-0l8049.1 Figure 230: NM-004359.1 Figure 286: NM1-07165.1 Figure 231: XM -042018.1 Figure 287: XM1-09274.1 Figure 232: XM-l14018.1 Figure 288: NM -004152.1 Figure 233: XM -042027.1 Figure 289: XMv036985.3 Figure 234A-B: XM._086110.1 Figure 290: NM1)12458.1 Figure 235: NM_017876.1 Figure 291: NM1)32737.1 Figure 236: XM1)55711.3 Figure 292: XM086115.1 Figure 237: NM-D02579.1 Figure 293: XM030485.3 Figure 238: XM1-92044.2 Figure 294: XAJ86123.2 Figure 239: NM _002819.2 Figure 295: XMJ-46934.3 Figure 240: NM-024888.1 Figure 296: NM1J03021.2 Figure 241: XIL086035.2 Figure 297: XMAJ55686-3 Figure 242: XM-137560.3 Figure 298A-B: XM-i55457.2 Figure 243: NMJ38774.1 Figure 299A-B: XM086121.2 Figure 244: NM-005224.1 Figure 300: XM1)86120.2 Figure 245: XM037565.1 Figure 301: )52643.2 Figure 246: NM1-33420.1 Figure 302: NM-024760.1 Figure 247: XM -092042.2 Figure 303: XM-D09222.6 Figure 248: XM1-37572.2 Figure 304: XM1-52629.4 Figure 249A-B: XM _037574.3 Figure 305: NM-003775.1 Figure 250: XM.D09279.6 Figure 306: XM-009220.4 Figure 251: NM 002085.1 Figure 307: XM-072009.2 Figure 252A-B: XM-009277.5 Figure 308: XM052661.3 Figure 253: XM_012913.4 Figure 309: XM1)86124.1 Figure 254: NM_001687.1 Figure 310: XM097426.1 Figure 255: XM028067.2 Figure 311: NM.005597.1 Figure 256: XAM1)28064.3 Figure 312: XM-096112.2 Figure 257: XMJJ86023.2 Figure 313: NM1)16263.1 Figure 258A-B: XM _028060.4 Figure 314: XMA 13988.1 Figure 259: XM1)72012.3 Figure 315: NM -024292.1 Figure 260: NM-024407.2 Figure 316: NM-006221.1 Figure 261: NM..000156.4 Figure 317: NM1-58164.1 Figure 262: NM1)18959.1 Figure 318A-B: XM1)09025.9 Figure 263: NM 01018.2 Figure 319: NM1)18381.1 Figure 264A-D: XM _047577.3 Figure 320: XM -097282.1 Figure 265: XM1)86101.1 Figure 321: XM1)49490.1 Figure 266: XM1-86102.1 Figure 322: NM1)20230.1 Figure 267: NM_138393.1 Figure 323: NM1)02566.1 Figure 268: XM_059051.2 Figure 324: NMJ-03755.1 Figure 269: XM.-047583.1 Figure 325A-B: NM1)01379.1 Figure 270: XM1-47584.2 Figure 326: XM1)49502. Figure 271: NM1)06830.2 Figure 327: M1)49518.1 Figure 272A-B: XM.047600.2 Figure 328: NM-022377.1 Figure 273A-B: XM -030721.1 Figure 329: XM-008895.2 Figure 274: NM1)31918.1 Figure 330: XM1)91913.4 Figure 275: XMA03282.1 Figure 331: NM80665.1 Figure 276: NM-031213.1 Figure 332: M058946.5 12 WO 2004/060270 PCT/US2003/029126 Figure 333: NM -002162.2 Figure 389: NM3-32332.1 Figure 334A-B: XM308893.4 Figure 390: NMA301930.2 Figure 335: NM..007065.2 Figure 391: NMA-32301.1 Figure 336A-B: XM-008891.7 Figure 392: XM-D09068.6 Figure 337: XM -49561.1 Figure 393: NM -324038.1 Figure 338: NM_032885.1 Figure 394: XM3-32041.2 Figure 339: XM-D17204.1 Figure 395: XM3309065.5 Figure 340: NM _001800.2 Figure 396: NM3-02229.1 Figure 341: NM -005498.3 Figure 397: XM3-09063.3 Figure 342: XM3308887.6 Figure 398: NM3-06397.1 Figure 343: XM3-85862.4 Figure 399: NM 031429.1 Figure 344: NM-012218.1 Figure 400A-B: XM-032034.2 Figure 345: XM.084014.1 Figure 401: NM3301375.1 Figure 346: NM 331209.1 Figure 402: NMJ-00159.1 Figure 347A-B: XM-032710.6 Figure 403: NM-004461.1 Figure 348: NM_006858.1 Figure 404: XM3332020.1 Figure 349: XM_032719.3 Figure 405: NMA-05053.2 Figure 350: NM_024029.2 Figure 406: CNA-85916.4 Figure 351: XM_032724.2 Figure 407: XMA357080.2 Figure 352A-B: NM-003072.1 Figure 408: XMA17130.1 Figure 353A-B: XMJ309082.1 Figure 409: NM3-17722.1 Figure 354: XM3385924.4 Figure 410: NM3352876.1 Figure 355: XM3385920.1 Figure 411: NM -003765.1 Figure 356A-B: XM-071996.2 Figure 412: XMv-051364.2 Figure 357: XMJ332773.1 Figure 413: NM3-04647.1 Figure 358: XM _058975.5 Figure 414: NM -033256.1 Figure 359: XM_032774.1 Figure 415: XM3-32281.4 Figure 360: NM3D00121.2 Figure 416: XM3-32285.3 Figure 361: XM3-32782.2 Figure 417: NM 002812.1 Figure 362: XM-I32783.1 Figure 418: 3385987.1 Figure 363: XM-057075.3 Figure 419A-E: XM -029455.3 Figure 364: NM_138783.1 Figure 420: NM3-07181.1 Figure 365: NM -16581.2 Figure 421: XM13-29450.1 Figure 366: XM.032792.1 Figure 422: NM3-04924.2 Figure 367: NM3332377.1 Figure 423: X-085989.2 Figure 368: XM _113989.1 Figure 424: )l115619.1 Figure 369: XM_015697.3 Figure 425: )1-009149.3 Figure 370: XM.064931.1 Figure 426: XM-056602.1 Figure 371: XM_032822.2 Figure 427: XM-008904.4 Figure 372: XM.064934.1 Figure 428: NM3301533.1 Figure 373: XM3364935.5 Figure 429: NM3312237.2 Figure 374: XM3332820.1 Figure 430: NM 3302503.1 Figure 375: XM3332812.1 Figure 431: NM.117827.2 Figure 376A-B: XM_091968.4 Figure 432: NM-321107.1 Figure 377A-B: XM -032811.1 Figure 433: NM3-24907.4 Figure 378: XM3391967.1 Figure 434: XM-059045.1 Figure 379: XM_032810.1 Figure 435A-B: NM-305884.2 Figure 380: XM_032799.5 Figure 436: XMA03270.1 Figure 381: XM009075.7 Figure 437: XM -046088.1 Figure 382: XM_085912.1 Figure 438: NM-018028.1 Figure 383: XM3385915.4 Figure 439: XM3346090.2 Figure 384: XM.064940.1 Figure 440: XM167529.1 Figure 385: XM.091959.1 Figure 441: XM 086004.2 Figure 386A-B: XM -032674.1 Figure 442: XM3-97361.2 Figure387: XM3310156.7 Figure 443: NM3-03407.1 Figure 388: NM3016145.1 Figure 444: XM3-46114.3 13 WO 2004/060270 PCT/US2003/029126 Figure 445: NM -01020.2 Figure 501: NM 033142-1 Figure 446A-B: NM -003169.2 Figure 502: NM-033183.1 Figure 447: XM -053074.4 Figure 503: NM -033043.1 Figure 448: NM016941.1 Figure 504: NMv033377.1 Figure 449: NM-04714.1 Figure 505: NM1)33378.1 Figure 450: NM1)01436.2 Figure 506: NM100894.2 Figure 451: XM016410.2 Figure 507: NL006666.1 Figure 452A-C: XM..096107.1 Figure 508: XM114024.1 Figure 453: XM -012860.4 Figure 509: NM-000146.2 Figure 454: NM1-06503.1 Figure 510: XM1)85957.1 Figure 455: XM1)42665.2 Figure 511: NM1)04324.1 Figure 456: XM1)85999.1 Figure 512: NM1)06184.2 Figure 457: XM-009203.6 Figure 513: XM1-09097.4 Figure 458: XM)059053.5 Figure 514: NM1-20904.1 Figure 459: XM058994.3 Figure 515: NM-016246.1 Figure 460A-B: XM _046390.3 Figure 516: NMJ001190.1 Figure 461: NMD016440.1 Figure 517: NM 00051 .1 Figure 462: XM -17132.1 Figure 518: XM1-09103.5 Figure 463: XM_053106.1 Figure 519: NM -01217.2 Figure 464: NM-012068.2 Figure 520: XM1)49974.5 Figure 465: XM -085927.2 Figure 521: NM1-20126.2 Figure 466: XM_084023.1 Figure 522: NM -000979.2 Figure 467: XM 016217.6 Figure 523KB: XMvL55866.4 Figure 468: XMA 14025.1 Figure 524: XM -049963.
4 Figure 469: XMD008985.6 Figure 525: NM-013348.1 Figure 470: NM-017432.1 Figure 526: NMv031485.1 Figure 471: XMD046344.2 Figure 527KB: XM-009108.3 Figure 472: NM 130973.1 Figure 528: NM-D06801.1 Figure 473: NMD-25129.2 Figure 529: XM.012808.5 Figure 474: NM -)14203.2 Figure 530: NM.001425.1 Figure 475: XM.085934.1 Figure 531A-B: XM1)49938.3 Figure 476: XM_058992.3 Figure 532: XM1)09118.9 Figure 477: XMA 17134.1 Figure 533: Xl 155864.4 Figure 478: NM1)01536.1 Figure 534: XM113344.1 Figure 479: XMA65432.1 Figure 535: XM1)46419.3 Figure 480: NM -01571.1 Figure 536: NM-D02691.1 Figure 48 IA-B: XM _046313.2 Figure 537: XM -056286.2 Figure 482: NM_006270.2 Figure 538: XM1-58990.5 Figure 483A-B: XM _046305.2 Figure 539: XM119305.1 Figure 484: NM-000951.1 Figure 540: NM138334.1 Figure 485: NM-015953.2 Figure 541: XM -058984.2 Figure 486: XM1)57199.3 Figure 542: XM1-91981.4 Figure 487: XM 027904.5 Figure 543: NM-132298-1 Figure 488: XM_084026.2 Figure 544A-B: XM1)53166-6 Figure 489: NM-012423.2 Figure 545: NM 002975.t Figure 490: XM1-58991.3 Figure 546: NM032712.1 Figure 491: NM1)17916.1 Figure 547: )M085958.1 Figure 492: NM1-20309.1 Figure 548: NM1)01648.1 Figure 493: NM -014419.1 Figure 549: XM1)55658-3 Figure 494: NM_003598.1 Figure 550: NM1)07196.1 Figure 495: NM-001774.1 Figure 551: )09004.4 Figure 496A-B: XM..057188.1 Figure 552: XMvL31105.1 Figure 497A-B: XM..027883.2 Figure 553: XM1-91891.4 Figure 498: NM..018111.1 Figure554: NM -01985.1 Figure 499: NM.022165.1 Figure 555A-B: NM1)13336.2 Figure 500: XM-085942-2 Figure 556: M067264.4 14 WO 2004/060270 PCT/US2003/029126 Figure 557: XM114309.1 Figure 613A-B: NM006709.2 Figure 558: XM-084111.4 Figure 614: NM-000434.1 Figure 559A-B: NM3004117.2 Figure 615: NM -005346.2 Figure 560: XM 166419.1 Figure 616: NMA005345.3 Figure 561:'NM307104.3 Figure 617: XM -166348.1 Figure 562: NM-021922.1 Figure 618: NMA021177.1 Figure 563: XM_165760.1 Figure 619A-B: NM006295.1 Figure 564: NMA-22047.1 Figure 620: NM025259.1 Figure 565: XM_166333.1 Figure 621: NM-i01288.3 Figure 566A-C: XM-166407.1 Figure 622: NM-013974.1 Figure 567: NM-015921.1 Figure 623: NMA021160.1 Figure 568: NMf-24165.1 Figure 624: NM'101320.2 Figure 569: XMA-58039.4 Figure 625: NMJ)33177.2 Figure 570: XM_-087990.2 Figure 626: XM165712.1 Figure 571: XM165743.1 Figure 627A-B: NM1J04639.2 Figure 572: XM_016857.3 'Figure 628A-B: NM 80686.1 Figure 573: NM_001350.1 Figure 629: NM 004847.2 Figure 574: NM-005453.3 Figure 630: XM166454.1 Figure 575: XM.165795.1 Figure 631: XM165823.1 Figure 576: NM004761.1 Figure 632: XM165771.1 Figure 577: NM014260.1 Figure 633: NMA-04640.3 Figure 578: NM_005452.3 Figure 634: NMA-05931.1 Figure 579: NM.003782.2 Figure 635: XM165832.1 Figure 580: NM-022551.2 Figure 636: XM165765.1 Figure 581: NMM80564.1 Figure 637: XM -087945.1 Figure 582: NM_002931.2 Figure 638: XMA6638 1 Figure 583: XM.165747.1 Figure 639: XM166395.1 Figure 584: NM -021976.1 Figure 640: XM 168104.1 Figure 585A-B: XM-165696.1 Figure 641: XM165720.1 Figure 586: XM A65807.1 Figure 642: XM 166401.1 Figure 587: XM_165698.1 Figure 643: NMA-01517.1 Figure 588: XM165808.1 Figure 644A-B: XMv165738.1 Figure 589A-B: XM..165770.1 Figure 645: NM-003897.2 Figure 590: NMA06120.2 Figure 646: NM1-05803.2 Figure 591: XM_165798.1 Figure 647: Xv07939.2 Figure 592: NM -000593.3 Figure 648A-B: XM165734.1 Figure 593: NMI004159.1 Figure 649: XM166353.1 Figure 594A-B: XM -165824.1 Figure 650A-B: XM166376.1 Figure 595: NMJ-22555.3 Figure 651: XM165782.1 Figure 596: XM165717.1 Figure 652: XM166409.1 Figure 597: XM166480.1 Figure 653: XM166398.1 Figure 598A-B: XMA65775.1 Figure 654: NM014046.2 Figure 599: NM-022107.1 Figure 655A-B: XM165799.1 Figure 600: XM165801.1 Figure 656: NMJJO109O.1 Figure 601: NM.006913.1 Figure 657: NM025263.1 Figure 602: XM165705.1 Figure 658: X166361.1 Figure 603: NM_004381.2 Figure 659: XMA69719.1 Figure 604A-D: NM.019105.2 Figure 660: XMi165764.1 Figure 605: NM.000500.3 Figure 661: XM-165758.1 Figure 606A-B: NM-000592.3 Figure 662: )31-069477.2 Figure 607: NM-032454.1 Figure 663: NM.024839.1 Figure 608: NM-005510.1 Figure 664: XM166388.1 Figure 609A-B: NM_006929.2 Figure 665: NM -003449.2 Figure 610: NMJ-02904.3 Figure 666: NM1125236.1 Figure 611: NM-01710.2 Figure 667: NM1-21959.1 Figure 612: NM 000063.2 Figure 668: NM014596.2 15 WO 2004/060270 PCT/US2003/029126 Figure 669: XMi87978.2 Figure 725: NM 005698.2 Figure 670: XM365809.1 Figure 726: NM006589.1 Figure 671: XI_087971.2 Figure 727: X34J84078.4 Figure 672: XMA_67122.1 Figure 728: XM086567.1 Figure 673: NM-002127.2 Figure 729: XM 086552.4 Figure 674: NM_018950.1 Figure 730: NM007112.1 Figure 675: XMA65803.1 Figure 731: X11 fJ53256.7 Figure 676: XM166392.1 Figure 732: XM 14144.1 Figure 677A-B: XM-165818.1 Figure 733: 1086571.1 Figure 678: XMJ-015516.4 Figure 734: NMv-018973.2 Figure 679A-B: XM -013042.3 Figure 735: NM018845.1 Figure 680: NMJ31206.1 Figure 736: XM-113377.1 Figure 681: XMAI88628.1 Figure 737A-B: XM-010561.10 Figure 682: XMvL093050.1 Figure 738: Xlv-117201.1 Figure 683: XMA002013.6 Figure 739: X14-036744.6 Figure 684: XMAI86138.1 Figure 740: NM130898.1 Figure 685: NM.000969.2 Figure 741: NMv006694.1 Figure 686: XM.059930.5 Figure 742: NM-002870-1 Figure 687: XMAJ05541.2 Figure 743: NM001O3O.2 Figure 688A-B: NM_014784.1 Figure 744: XM036829.6 Figure 689: NM -005973.3 Figure 745: NM015449.1 Figure 690: XM.044077.3 Figure 746: NM.D14847.1 Figure 691: XML056380.2 Figure 747: NM.-006118.2 Figure 692: XML44083.5 Figure 748A-B: XMAJ36933.7 Figure 693: NM001878.2 Figure 749: XMAJ36934. Figure 694: XM017040.3 Figure 750: XM1J55737.4 Figure 695: XMA386573.1 Figure 751: NL017582.2 Figure 696: XML097656.1 Figure 752A-B: )DA 036845.4 Figure 697: XI059219.2 Figure 753: NM-006556.2 Figure 698: NM.005920.1 Figure 754: NM.020524.2 Figure 699: XM_044127.8 Figure 755: XM -034083.2 Figure 700: XM-053245.6 Figure 756: XMv-034082.4 Figure 701A-B: XM -044148.3 Figure 757: NM -001826.1 Figure 702: NM-007221.1 Figure 758: NM-025207.1 Figure 703A-B: XM-044155.1 Figure 759: XM-054121.6 Figure 704: NM -022367.1 Figure 760: NM-003815.2 Figure 705: NM..005572.1 Figure 761: NM 002802.1 Figure.706: XM.044166.3 Figure 762A-B: Xv029368.3 Figure 707: XM-053243.1 Figure 763: XM -058677.2 Figure 708: XM-017041.3 Figure 764: NM.006888.1 Figure 709: XM -044128.6 Figure 765: XM-085175.1 Figure 710: NM-003145.2 Figure 766: XIvI.096813.I Figure 711A-B: XM_-044172.7 Figure 767: Xtv017823.4 Figure 712A-B: XM_010715.2 Figure 768: NMAO647O.2 Figure 713: NM-006912.1 Figure 769: X3.D51763.3 Figure 714: NM_-025174.1 Figure 770: XM.085726.1 Figure 715: NM-032292.1 Figure 771: XM.058899.3 Figure 716: NM.017710.1 Figure 772: NM.017775.1 Figure 717: NM.033657.1 Figure 773A-C: XM037176.2 Figure 718: NMAJ18253.1 Figure 774: XM113908.1 Figure 719: NM.018116.1 Figure 775: NM-018955.1 Figure 720: XM.017056.2 Figure 776: NM-016113.2 Figure 721A-C: NM.018489.1 Figure 777: XM-058900.2 Figure 722: NM.014328.1 Figure 778: XM-097213.2 Figure 723: NM-002004.1 Figure 779: XMA-39911.1 Figure 724: NM6003993.1 Figure 780: XM.091689.2 16 WO 2004/060270 PCT/US2003/029126 Figure 781: XM -039921.3 Figure 837: NMA115414.2 Figure 782: XM -012549.7 Figure 838A-B: XM-009398.4 Figure 783: NM020201.1 Figure 839A-B: NM-003624.1 Figure 784: NM 003653.1 Figure 840A-B: XM032278.5 Figure 785: XM-0 12695.4 Figure 841: NM_033256.1 Figure 786: XM -117042.1 Figure 842: XM.032281.4 Figure 787: NM032339.1 Figure 843: XM.D85984.2 Figure 788A-B: NM_004448.1 Figure 844: XM032285.3 Figure 789: NM 033419.1 Figure 845: NM_004823.1 Figure 790: NM_006804.1 Figure 846: NM02812.1 Figure 791: NMJ-32192.1 Figure 847: XM.029450.1 Figure 792A-B: XI-083956.2 Figure 848: NM.D04924.2 Figure 793A-B: XM..016544.3 Figure 849: XMJ85989.2 Figure 794: NM.032875.1 Figure 850: NM_006149.2 Figure 795: XML029046.2 Figure 851: XMAJ08904.4 Figure 796: XM.091460.1 Figure 852: NM1D01533.1 Figure 797: NM-0O0981.2 Figure 853: NM_012237.2 Figure 798A-B: NM-020405.2 Figure 854: NM002503.1 Figure 799: XM091455.1 Figure 855: NM_017827.2 Figure 800A-B: XM-008150.7 Figure 856: NM_021107.1 Figure 801: NM_000978.2 Figure 857: NM1324907.4 Figure 802: NM.017748.2 Figure 858: XM-059045.1 Figure 803A-B: XM-008145.3 Figure 859A-B: NMJ305884.2 Figure 804: NM002795.1 Figure 860: NM018028.1 Figure 805: XM008147.3 Figure 861: XM4L046090.2 Figure 806: XMA 13893.1 Figure 862: XM_167529.1 Figure 807: NM005937.1 Figure 863: XM2L086004.2 Figure 808: NM_018530.1 Figure 864: XM097361.2 Figure 809: NMiJ16471.1 Figure 865: NM-003407.1 Figure 810: XM-058830.3 Figure 866: XM46114.3 Figure 811: XM-117040.1 Figure 867: NMAJ01020.2 Figure 812: NM.002809.1 Figure 868A-B: NM-003169.2 Figure 813: XML049860.3 Figure 869: XM _053074.4 Figure 814A-B: NM -007359.2 Figure 870: NM_001436.2 Figure 815: XM.113939.1 Figure 871: XM -016410.2 Figure 816: XMA 13329.1 Figure 872: XM-012860.4 Figure 817: XM-083987.2 Figure 873: NM_006503.1 Figure 818: XML064591.1 Figure 874: XM_-114180.1 Figure 819: NMJJ22751.1 Figure 875: NM.033197.1 Figure 820: XM -015755.1 Figure 876: XM.-015893.3 Figure 821: XM.D97232.2 Figure 877A-B: XM.-047042.2 Figure 822A-B: XM _046103.4 Figure 878: XM.D56253.3 Figure 823: XMJD46099.1 Figure 879: NM.032819.2 Figure 824: NM..0 14649.1 Figure 880: XM-059282.3 Figure 825: NM-006012.1 Figure 881: NM-016732.1 Figure 826: NM.032306.1 Figure 882: NM_003908.1 Figure 827: NM-J02096.1 Figure 883: XM012928.4 Figure 828: NM.003685.1 Figure 884: NM-000687.1 Figure 829: XM044564.5 Figure 885: NM031483.1 Figure 830: XMID09015.1 Figure 886: XM.047136.1 Figure 831: NM003811.1 Figure 887: XM.041350.4 Figure 832A-B: XM_009010.4 Figure 888: XM.041363.7 Figure 833: XM.044591.4 Figure 889: XM116065.1 Figure 834: NM.004240.1 Figure 890: XM-076414.5 Figure 835: XM-044619.3 Figure 891: XM_116066.1 Figure 836: XM-044608.2 Figure 892: XM.093546.4 17 WO 2004/060270 PCT/US2003/029126 Figure 893: NM018130.1 Figure 949A-C: NM-022455- 2 Figure 894: NM1)80652.1 Figure 950: NM-DO2O11.2 Figure 895: XM087289.1 Figure 951: XM1-55292.1 Figure 896: XM_084114.4 Figure 952: NM-012279.1 Figure 897A-B: XM-048265.5 Figure 953: NM1)16290-1 Figure 898: NM1)04593.1 Figure 954: Xv -030295.3 Figure 899: XMI13406.1 Figure 955: Xlv155226.2 Figure 900: XM 111160.5 Figure 956A-B: NM-014901.1 Figure 901: XM-114399.1 Figure 957A-B: XM1-30257.3 Figure 902: NM -007100.1 Figure 958: NM-016391.2 Figure 903: NM-002477.1 Figure 959: XM1-55224.3 Figure 904:'NM -032219.1 Figure 960: XM 113453.1 Figure 905: NM.006527.2 Figure 961: NM -003093.1 Figure 906: NM.138385.1 Figure 962: NM1-24294.1 Figure 907: NM-D06342.1 Figure 963: NM 112391.1 Figure 908A-B: NM..012318.1 Figure 964: XMA68084.1 Figure 909A-C: NM .133334.1 Figure 965: XW -166344.1 Figure 910: XM{35378.2 Figure 966: XM166459.1 Figure 911: XM -14423.1 Figure 967: XM1-43240.1 Figure 912: XM1-68272.1 Figure 968: XM1)55002.1 Figure 913: NM_024751.1 Figure 969: NM133645.1 Figure 914: NM_020395.1 Figure 970: XMJ397453.2 Figure 915: XM_059633.5 Figure 971: XM1-29228.1 Figure 916: XM114424.1 Figure 972: NM1)12434.1 Figure 917: XM-042321.4 Figure 973: XM168627.1 Figure 918A-B: XN-042301.2 Figure 974: NM1-24653.1 Figure 919: XM-017641.3 Figure 975: M168574.1 Figure 920: NM1)30782.1 Figure 976: NM1306234.2 Figure 921: XM_049512.2 Figure 977: XM168603.1 Figure 922: XM1)49510.3 Figure 978: NM1)32958.1 Figure 923A-B: XM_049508.3 Figure 979: XM168560.1 Figure 924: XMI21103.1 Figure 980: NM -006989.1 Figure 925A-B: NM-007030.1 Figure 981: XM168558.1 Figure 926: XMJ -16422.1 Figure 982: XM168635.1 Figure 927: XM 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NM1)14380-1 Figure 948: NM-130781.1 Figure 1004: XM43643.1 18 WO 2004/060270 PCT/US2003/029126 Figure 1005: NM032621.1 Figure 1061: )M-046934.3 Figure 1006: XM-034430.2 Figure 1062: NMAI03021.2 Figure 1007: NM-018476.2 Figure 1063: XM.052629.4 Figure 1008: NM-004359.1 Figure 1064: XM.D72009.2 Figure 1009: XM_042018.1 Figure 1065: XM.D52661.3 Figure 1010: XM'-114018.1 Figure 1066: NM005597.1 Figure 1011A-B: Xvl086110.1 Figure 1067: NM016263.1 Figure 1012: NM..017876.1 Figure 1068: X1M059026.2 Figure 1013: XM-055711.3 Figure 1069: NMA06339.1 Figure 1014: XM-092044.2 Figure 1070A-B: XML047620.2 Figure 1015: NM-002819.2 Figure 1071: XM059027.1 Figure 1016: XM_037560.3 Figure 1072: NMAJ01348.1 Figure 1017: NM-138774.1 Figure 1073: NMA)01961.1 Figure 1018: NM_005224.1 Figure 1074: NMAJ15898.1 Figure 1019: XM_037564.1 Figure 1075: XM-016871.6 Figure 1020: XM.097386.2 Figure 1076: NMJJ16539.1 Figure 1021: XM-037565.1 Figure 1077: NM018074.1 Figure 1022: NM_033420.1 Figure 1078: NM024333.1 Figure 1023: XM-092042.2 Figure 1079: NM 017720.1 Figure 1024: XM-037572.2 Figure 1080: XM031841.3 Figure 1025: XM-009279.6 Figure 1081: NM.003025.1 Figure 1026: NM-002085.1 Figure 1082: XMA384031.1 Figure 1027A-B: XM -009277.5 Figure 1083: NM025241.1 Figure 1028: XM..012913.4 Figure 1084: XMv059013.3 Figure 1029: NM-001687.1 Figure 1085: XMfl59012.2 Figure 1030: XM-028067.2 Figure 1086: XL035638.5 Figure 1031: XM_028064.3 Figure 1087A-B: XM035636.3 Figure 1032: XM-086023.2 Figure 1088&-B: XM-035635.2 Figure 1033: NM.024407.2 Figure 1089: XM035634.2 Figure 1034: NM_018959.1 Figure 1090: XMJ112862.3 Figure 1035: NM-001018.2 Figure 1091: XM065020.1 Figure 1036A-D: XM_047577.3 Figure 1092A-B: XMv035627.2 Figure 1037: XM-086102.1 Figure 1093A-B: XNL035625.5 Figure 1038: XM.047584.2 Figure 1094: XM1J32281.4 Figure 1039: NM_006830.2 Figure 1095: XML5984.2 Figure 1040A-B: Xl.030721.1 Figure 1096: XM1J32285.3 Figure 1041: NM031918.1 Figure 1097: NMJJ02812.1 Figure 1042: XM_103282.1 Figure 1098: XM085987.1 Figure 1043: NM_031213.1 Figure 1099A-E: XM-029455.3 Figure 1044: NM_079834.1 Figure 1101: XMJD29450.1 Figure 1045: NM-001319.4 Figure 1101: NM-004924.2 Figure 1046: NM_017797.2 Figure 1102: XAJ08904.4 Figure 1047: NM.017572.1 Figure 1103: NMAJOI533.1 Figure 1048: XM_059021.3 Figure 1104: NMv012237.2 Figure 1049A-B: NM..003938.2 Figure 1105: NMv017827.2 Figure 1050A-B: XM-046822.2 Figure 1106: NMv021107.1 Figure 1051: NM -018049.1 Figure 1107: NM024907.4 Figure 1052: NM-007165.1 Figure 1108: XM059045.1 Figure 1053: NM.004152.1 Figure 1109A-B: NM.005884.2 Figure 1054: NM-016199.1 Figure 1110: XM009225.5 Figure 1055: NM-012458.1 Figure 1111: XMJ346090.2 Figure 1056: NM-032737.1 Figure 1112: XM167529.1 Figure 1057: XM.086115.1 Figure 1113: XM086004.2 Figure 1058: XM_030485.3 Figure 1114: XM -097361.2 Figure 1059: XM_046934.3 Figure 1115: NM-003407.1 Figure 1060: NM003021.2 Figure 1116: XM-04634.3 19 WO 2004/060270 PCT/US2003/029126 Figure 1117: NM_001020.2 Figure 1173: XM-001468.5 Figure 11 18A-B: NM-003169.2 Figure 1174: XMA047841.5 Figure 1119: XM-053074.4 Figure 1175A-B: XM.097444.4 Figure 1120: NM-001436.2 Figure 1176: XML047874.5 Figure 1121A-C: XIM 096107.1 Figure 1177A-B: XM-047883.4 Figure 1122: XM-012860.4 Figure 1178: NM002796.1 Figure 1123: NM-006503.1 Figure 1179: NM003944.2 Figure 1124A-B: XL-092019.1 Figure 1180: XM_086144.1 Figure 1125: XM_009203.6 Figure 1181: NM_002651.1 Figure 1126: XM-059053.5 Figure 1182: NM-002810.1 Figure 1127: XM-047409.3 Figure 1183: XM044077.3 Figure 1128: NM-000713.1 Figure 1184: XM056380.2 Figure 1129: XM-047376.6 Figure 1185: XM_044080.2 Figure 1130A-B: XM-047374.5 Figure 1186: XM86573.1 Figure 1131: NM-004756.1 Figure 1187: XM1159223.2 Figure 1132: XM-059052.5 Figure 1188: XM-f44127.8 Figure 1133: NM-004596.1 Figure 1189: XM.D53245.6 Figure 1134A-B: NM-017555.1 Figure 1190A-B: XM-044148.3 Figure 1135: NM_030622.4 Figure 1191A-B: XM-044155.1 Figure 1136A-B: XM_015505.1 Figure 1192: XMvL86562.1 Figure 1137: XM-030914.1 Figure 1193: NMAJ05572.1 Figure 1138: NM-052848.1 Figure 1194: XMA117041.3 Figure 1139: XM_008912.1 Figure 1195: XMA-44128.6 Figure 1140: XM-085882.1 Figure 1196: NM003145.2 Figure 1141: XM_030901.1 Figure 1197A-B: XM-010715.2 Figure 1142: NM.018035.1 Figure 1198: NM1I25174.1 Figure 1143: XM-085874.1 Figure 1199: NMI032292.1 Figure 1144: XM009171.3 Figure 1200: NM_017710.1 Figure 1145: XM-115603.1 Figure 1201: NM-033657.1 Figure 1146: NM-001022.2 Figure 1202: NMA18253.1 Figure 1147: NM3004706.2 Figure 1203: NM018 116.1 Figure 1148: NM-006423.1 Figure 1204A-C: NM_018489.1 Figure 1149: NM-022752.1 Figure 1205: NM-002004.1 Figure 1150: NM-006494.1 Figure 1206: NM000298.1 Figure 1151A-B: XM -29883.4 Figure 1207: NM_003993.1 Figure 1152: XM-041978.3 Figure 1208: NM_005698.2 Figure 1153: XM..017591.4 Figure 1209: NMi306589.1 Figure 1154: NM_006058.1 Figure 1210: XM114144.1 Figure 1155: NM-002084.2 Figure 1211: NMfl18845.1 Figure 1156: XM_117396.1 Figure 1212: XM. 13377.1 Figure 1157: NM018047.1 Figure 1213A-B: XM010561.10 Figure 1158A-B: NM-307286.1 Figure 1214: XM 117201.1 Figure 1159: XM_.042547.3 Figure 1215: XML36744.6 Figure 1160: NM._05617.2 Figure 1216: NMAI06694.1 Figure 1161: XM-003937.5 Figure 1217: NM.002870.1 Figure 1162A-B: NMJJ00176.1 Figure 1218: NM_001030.2 Figure 1163: XM-059214.2 Figure 1219: XM036829.6 Figure 1164: XM-046349.5 Figure 1220: NMAI15449.1 Figure 1165: XM.089375.4 Figure 1221: NM-014847.1 Figure 1166: XMA096141.1 Figure 1222: NM 006118.2 Figure 1167: NM_015911.1 Figure 1223: XMD36934.4 Figure 1168: NM006516.1 Figure 1224: NM017582.2 Figure 1169: XM-086543.4 Figure 1225A-B: XM-036845.4 Figure 1170: NM-006824.1 Figure 1226: NMJ19058.1 Figure 1171: NM-001255.1 Figure 1227: XML058400.5 Figure 1172: NM_005620.1 Figure 1228: XM045140.5 20 WO 2004/060270 PCT/US2003/029126 Figure 1229: XM-050993.5 Figure 1285: XM_037764.6 Figure 1230A-B: XNM058343.5 Figure 1286: NM-002689.2 Figure 1231: XM-058602.2 Figure 1287: NM.006268.2 Figure 1232A-B: XNM-031866.1 Figure 1288A-D: XM-167804.1 Figure 1233: NM_024541.1 Figure 1289: XM.166235.1 Figure 1234A-B: NM.015062.1 Figure 1290: XM-166236.1 Figure 1235A-B: XM -031890.2 Figure 1291: NM-006842.1 Figure 1236A-B: NM.004193.1 Figure 1292: NMA)00852.2 Figure 1237: XM-031926.6 Figure 1293: NM_-007103.2 Figure 1238: NMA_024040.1 Figure 1294: XMA133227.7 Figure 1239: XM_031949.5 Figure 1295: NM.001734.1 Figure 1240A-B: NM-016169.2 Figure 1296: NMJJ05768.3 Figure 1241: NM_030912.1 Figure 1297: NM_006331.1 Figure 1242: XM-011921.3 Figure 1298: NM3J07273.2 Figure 1243: XML058359.5 Figure 1299: NM.80549.1 Figure 1244: XM_058365.1 Figure 1300: NM-138425.1 Figure 1245: NM -005566.1 Figure 1301A-B: XM_4032588.5 Figure 1246: NM.-006292.2 Figure 1302: NMA100365.2 Figure 1247: XIA 115081.1 Figure 1303: XM1)32614.1 Figure 1248: XM087710.2 Figure 1304: NMI)31299.2 Figure 1249: NM-004183.1 Figure 1305: XM_006966.2 Figure 1250: XM_167726.1 Figure 1306: XM-165910.1 Figure 1251: NM-021727.2 Figure 1307: NM_016319.1 Figure 1252: NM-004265.2 Figure 1308: XM1)33223.5 Figure 1253A-B: NM _013402.3 Figure 1309: NM-005439.1 Figure 1254: NM-014206.1 Figure 1310A-B: NM.001273.1 Figure 1255: XM -043146.5 Figure 1311: XM_033253.4 Figure 1256: XM -043151.7 Figure 1312: NM.002046.2 Figure 1257: XM 048286.6 Figure 1313: XM033263.3 Figure 1258: NM_016404.1 Figure 1314A-B: XM_006958.7 Figure 1259: NM_004322.2 Figure 1315: NM.016497.2 Figure 1260: XM_011988.9 Figure 1316: NM1)18009.1 Figure 1261: XM _037808.4 Figure 1317: NM1J02342.1 Figure 1262: NM_004074.1 Figure 1318: NM701065.1 Figure 1263: XM-043159.1 Figure 1319A-B: XM_027198-1 Figure 1264: XM-113223.1 Figure 1320: XM_012272.3 Figure 1265: NM..003942.1 Figure 1321A-B: XM-056481.4 Figure 1266: NM..005825.2 Figure 1322: NM -024056.1 Figure 1267: NM-005609.1 Figure 1323: NM_001659.1 Figure 1268: XM_045642.3 Figure 1324: XMA184866.2 Figure 1269: XM-006533.7 Figure 1325: XM_006826.2 Figure 1270: XM-006532.9 Figure 1326: XM.028662.3 Figure 1271: XM-045613.6 Figure 1327: NMI131157.1 Figure 1272A-B: XM.045612.4 Figure 1328: NMA106163.1 Figure 1273: XM.113224.1 Figure 1329: NM1)16057.1 Figure 1274: XM-045498.5 Figure 1330: XMA.006800.3 Figure 1275: XM-045499.3 Figure 1331: NM.005016.2 Figure 1276: NM..001997.2 Figure 1332: XM -113707.1 Figure 1277: XM_045525.7 Figure 1333A-B: NM-032656.1 Figure 1278: NM..013265.2 Figure 1334: XMA115274.6 Figure 1279: XM..037756.2 Figure 1335: XMA155013.4 Figure 1280: XM 384617.4 Figure 1336: XM-113715.1 Figure 1281: XM-045533.3 Figure 1337: XM84832.4 Figure 1282: XM_057307.6 Figure 1338A-C: XM-045602.2 Figure 1283: NM -001667.1 Figure 1339A-B: XM031617.1 Figure 1284: XM.084702.4 Figure 1340: NMA107223.1 21 WO 2004/060270 PCT/US2003/029126 Figure 1341A-B: XM.031612.5 Figure 1397: XMl 13934.1 Figure 1342: NM-003134.1 Figure 1398: XM.-165421.1 Figure 1343: XM 113826.1 Figure 1399: NM-015343.1 Figure 1344: XM.031561.3 Figure 1400: XM113325.1 Figure 1345: NM-002225.2 Figure 1401: XM_165422.1 Figure 1346: XM_031555.3 Figure 1402: XMA 13931.1 Figure 1347: NM..018145.1 Figure 1403: XM_085689.2 Figure 1348: NM-005258.2 Figure 1404: XM.036659.1 Figure 1349: NM_032850.1 Figure 1405A-B: XM-113334.1 Figure 1350: XM-031510.4 Figure 1406: NM001254.2 Figure 1351: NM.024111.1 Figure 1407: XM.036465.1 Figure 1352: XM.085313.4 Figure 1408: XM.055061.1 Figure 1353: XM..113821.1 Figure 1409A-B: XM-036462.1 Figure 1354: NM _016359.1 Figure 1410: XM.083975.1 Figure 1355: NM.-007364.1 Figure 1411: XM_008290.2 Figure 1356: XM_091042.1 Figure 1412: XM_048654.3 Figure 1357: XM_044593.1 Figure 1413A-B: X1M.008633.4 Figure 1358: NM-006791.1 Figure 1414: NM.025197.1 Figure 1359: XM_060042.5 Figure 1415: NM2002087.1 Figure 1360: XM_085445.2 Figure 1416: NM.016016.1 Figure 1361: XM-058781.3 Figure 1417: NM.014233.1 Figure 1362: XM_113876.1 Figure 1418: XMD12642.4 Figure 1363: XM _117027.1 Figure 1419: NMA-53047.1 Figure 1364: XM_165927.1 Figure 1420: XM.097133.2 Figure 1365: XM.053402.2 Figure 1421: NM_032484.1 Figure 1366A-B: XM -055195.2 Figure 1422: XM.045901.4 Figure 1367: XM. 13291.1 Figure 1423: XM058850.3 Figure 1368: NM-000418.1 Figure 1424: NM.032376.1 Figure 1369: XM113874,1 Figure 1425: XM.091544.2 Figure 1370: XM_102377.2 Figure 1426: XM-045950.3 Figure 1371: XM-008441.5 Figure 1427: XM.032808.2 Figure 1372A-B: XM -13932.1 Figure 1428: XMA 15461.1 Figure 1373: NM_003809.1 Figure 1429A-B: XM_008393.3 Figure 1374A-B: XM_018453.3 Figure 1430: XM.032852.1 Figure 1375: NM-001416.1 Figure 1431: XM.064317.1 Figure 1376: XM._008237.3 Figure 1432: XM 13918.1 Figure 1377: NM._004870.1 Figure 1433: NM.000263.1 Figure 1378: XM-008234.3 Figure 1434: NML025233.1 Figure 1379: NM.-133491.1 Figure 1435: XM-032817.4 Figure 1380: NM.001040.2 Figure 1436: XM.085635.1 Figure 1381: XM.-008679.2 Figure 1437: XM.091549.2 Figure 1382: XM_008231.2 Figure 1438: XM.032781.1 Figure 1383: NM_025099.1 Figure 1439: NM.000151.1 Figure 1384: NM_032354.1 Figure 1440: XM113917.1 Figure 1385A-B: XM 034028.1 Figure 1441: XM017557.6 Figure 1386: XM_113328.1 Figure 1442: XM_032766.1 Figure 1387: XM-113929.1 Figure 1443: NM 003766.2 Figure 1388: NM.001970.2 Figure 1444: NM 014019.1 Figure 1389: NM_004217.1 Figure 1445: NM_032353.1 Figure 1390: NM-017622.1 Figure 1446: XM.008401.5 Figure 1391: XM-165941.1 Figure 1447: XM 108402.1 Figure 1392: NM..021210.1 Figure 1448: NM_017595.2 Figure 1393: XM -113928.1 Figure 1449: XM -116844.1 Figure 1394: XM_097077.1 Figure 1450: XM_085636.2 Figure 1395: XM-167528.1 Figure 1451: NM_000988.2 Figure 1396: NM-001307.1 Figure 1452: XM_008559.1 22 WO 2004/060270 PCT/US2003/029126 Figure 1453: XM- 15480.1 Figure 1509: NM_007165.1 Figure 1454: NM_005831.2 Figure 1510: NM.004152.1 Figure 1455: XM -117061.1 Figure 1511: XM.085870.1 Figure 1456: XM_113318.1 Figure 1512: NMfl18381.1 Figure 1457: XM-113319.1 Figure 1513: XM _049490.1 Figure 1458: XM-030444.5 Figure 1514: NM1120230.1 Figure 1459: XM..008459.3 Figure 1515: NM_003755.1 Figure 1460: NM-005324.1 Figure 1516A-B: NM_001379.1 Figure 1461: XM-054344.2 Figure 1517: XM-049502.1 Figure 1462: NM..002766.1 Figure 1518: XM_049518.1 Figure 1463: XM_046481.1 Figure 1519: XM.058946.5 Figure 1464: XM_097197.2 Figure 1520A-B: XM-008893.4 Figure 1465: XMI097193.2 Figure 1521: NM.007065.2 Figure 1466: XM-083988.1 Figure 1522A-B: XM -008891.7 Figure 1467: NM..004309.2 Figure 1523: XMAJ49561.1 Figure 1468: XMv-046472.1 Figure 1524: XM085862.4 Figure 1469: NM-016286.1 Figure 1525: NM_012218.1 Figure 1470: NM_004127.3 Figure 1526: XM084014.1 Figure 1471: NM -022156.1 Figure 1527: NM-031209.1 Figure 1472A-C: XMA-113943.1 Figure 1528A-B: XM_032710.6 Figure 1473: XM-042018.1 Figure 1529: XML032719.3 Figure 1474: XM_-114018.1 Figure 1530: NM _024029.2 Figure 1475A-B: XM_.086110.1 Figure 1531A-B: NM_003072.1 Figure 1476: NM-017876.1 Figure 1532A-B: XM_009082.1 Figure 1477: XM-055711.3 Figure 1533: XM085924.4 Figure 1478: NM-002819.2 Figure 1534: XM009085.7 Figure 1479: NM-024888.1 Figure 1535: XM_032773.1 Figure 1480: XM1_037560.3 Figure 1536: XM032782.2 Figure 1481: NM -138774.1 Figure 1537: NM.032377.1 Figure 1482: XM 037565.1 Figure 1538: NMA01611.2 Figure 1483: NM-033420.1 Figure 1539: XM 113989.1 Figure 1484: XM.092042.2 Figure 1540: XM..05697.3 Figure 1485: XM.037572.2 Figure 1541: XIM032812.1 Figure 1486A-B: XM -037574.3 Figure 1542: NM-01436.2 Figure 1487: XM-009279.6 Figure 1543: XM-012860:4 Figure 1488: NM_002085.1 Figure 1544: NMfl06503.1 Figure 1489: NM -001687.1 Figure 1545: XM_042665.2 Figure 1490: XM.028064.3 Figure 1546: XM047409.3 Figure 1491A-B: XM-028060.4 Figure 1547: NM000713.1 Figure 1492: XM.072012.3 Figure 1548: XM.047376.6 Figure 1493: NM.-000156.4 Figure 1549A-B: XM.047374.5 Figure 1494: NM_018959.1 Figure 1550: XM 059052.5 Figure 1495: NM-001018.2 Figure 1551: NMf004596.1 Figure 1496: XM-086101.1 Figure 1552: XM149920.1 Figure 1497: XM..086102.1 Figure 1553: XM_055859.2 Figure 1498: NM-138393.1 Figure 1554: XM _008860.6 Figure 1499: XM-047584.2 Figure 1555: XM.097339.1 Figure 1500: NM-006830.2 Figure 1556: XM.055856.5 Figure 1501A-B: XM.047600.2 Figure 1557: XM009036.3 Figure 1502A-B: XM_030721.1 Figure 1558A-B: XM.028253.1 Figure 1503: NM_031918.1 Figure 1559: XM.009039.1 Figure 1504: NM_079834.1 Figure 1560A-B: XM_085943.4 Figure 1505: NM_001319.4 Figure 1561: XM.D28263.1 Figure 1506: NM_017797.2 Figure 1562: XM_085928.1 Figure 1507: NM-017572.1 Figure 1563: NMA313403.1 Figure 1508A-B: NM-003938.2 Figure 1564: NMAI01743.3 23 WO 2004/060270 PCT/US2003/029126 Figure 1565: NM.017432.1 Figure 1621A-B: NM014808.1 Figure 1566: XM_046344.2 Figure 1622A-B: XM-117274.1 Figure 1567: NM-025129.2 Figure 1623: XMAJ02742.4 Figure 1568: NM_014203.2 Figure 1624: NM_023083.1 Figure 1569: NM-001536.1 Figure 1625: NM_018226.2 Figure 1570A-B: XM-046305.2 Figure 1626: XMM09622.5 Figure 1571: NM-015953.2 Figure 1627A-B: XM-009682.3 Figure 1572: XM-084026.2 Figure 1628: NM00801.2 Figure 1573: NM-012423.2 Figure 1629: NMAJ03091.1 Figure 1574: NM.017916.1 Figure 1630: NMAI52881.1 Figure 1575: NM-018111.1 Figure 1631: NM.006899.1 Figure 1576: NM_022165.1 Figure 1632: NM-i22760.2 Figure 1577: XI-085942.2 Figure 1633A-B: NM-002836.2 Figure 1578: NM-006666.1 Figure 1634: XM_045394.1 Figure 1579: NM-000146.2 Figure 1635: NMAJ30811.2 Figure 1580: NM-004324.1 Figure 1636: NMAJ16732.1 Figure 1581: NM-006184.2 Figure 1637: NM_003908.1 Figure 1582: XM-009097.4 Figure 1638: NM000687.1 Figure 1583: NM_000979.2 Figure 1639: NM1314183.1 Figure 1584: XI-049963.4 Figure 1640: NM-080476.1 Figure 1585: NM-031485.1 Figure 1641: XM-086728.1 Figure 1586: NM-006801.1 Figure 1642A-C: XM-047155.2 Figure 1587: XM-012808.5 Figure 1643: NMJJ18677.1 Figure 1588: NM-001425.1 Figure 1644: NM_000178.1 Figure 1589: XMv-091973.1 Figure 1645: NM.015638.1 Figure 1590A-B: XM_049938.3 Figure 1646: NM-018217.1 Figure 1591: XM-009118.9 Figure 1647: NM-D06404.1 Figure 1592: NM-021103.1 Figure 1648: NM-002212.1 Figure 1593: XM_086920.1 Figure 1649: NM_018244.1 Figure 1594: XM'-056742.2 Figure 1650A-C: NM-007186.1 Figure 1595: XM-034215.3 Figure 1651: NMAJ15966.1 Figure 1596: XM-086916.1 Figure 1652: NM1103915.1 Figure 1597: XI-002568.8 Figure 1653: XM_033090.4 Figure 1598: N1vL001747.1 Figure 1654: NM03776.1 Figure 1599: NM-005911.2 Figure 1655: XM_059313.2 Figure 1600: XM-050962.4 Figure 1656: XMfl55490.4 Figure 1601: NM_012100.1 Figure 1657: NMfl03504.2 Figure 1602: XM-050638.2 Figure 1658: NMJJ02688.2 Figure 1603: NM-002601.1 Figure 1659: XM.058918.2 Figure 1604: NM_022730.1 Figure 1660: NM.024627.2 Figure 1605: XMI-054226.4 Figure 1661A-B: NM_005877,2 Figure 1606A-B: NM-024085.1 Figure 1662: NM_012429.1 Figure 1607: XM..050885.1 Figure 1663: NM_016498.1 Figure 1608: XM_058098.3 Figure 1664: NM_004861.1 Figure 1609: XM..087157.1 Figure 1665: NM_014303.1 Figure 1610: XM..058100.3 Figure 1666: XM-114209.1 Figure 1611: XM-065804.1 Figure 1667: NMfl03661.1 Figure 1612: NM_000784.2 Figure 1668A-B: NM_002473.1 Figure 1613A-B: XM-002591.7 Figure 1669: NM003753.1 Figure 1614: NM-004328.2 Figure 1670: XMI009973.3 Figure 1615: XM_010866.6 Figure 1671: XM..009974.4 Figure 1616: XM-1 17275.1 Figure 1672: NM138797.1 Figure 1617: NM-002712.1 Figure 1673: NMAJ16091.1 Figure 1618: NM.018635.1 Figure 1674: NM1J12407.1 Figure 1619A-B: XM-042326.3 Figure 1675: NMAJ12264.2 Figure 1620: NM_004404.1 Figure 1676: NM_001894.1 24 WO 2004/060270 PCT/US2003/029126 Figure 1677: NM_006855.2 Figure 1733A-B: XNM-018223.6 Figure 1678: NM006386.2 Figure 1734: NM.D00481.1 Figure 1679: NM-015373.1 Figure 1735: NM-032316.1 Figure 1680: NM..020243.2 Figure 1736: XM-114367.1 Figure 1681: NM-014876.1 Figure 1737A-B: NM-005777.1 Figure 1682A-B: XM_039332.3 Figure 1738: NM005778.1 Figure 1683: XM-039339.5 Figure 1739: NM_006841.1 Figure 1684: XM_114199.1 Figure 1740: XM'L041507.1 Figure 1685: NM_021822.1 Figure 1741: NMI04636.1 Figure 1686A-B: XM-009997.2 Figure 1742: NM.0O7312.2 Figure 1687: NM-000967.2 Figure 1743: NMJJ33158.1 Figure 1688: XM-010000.3 Figure 1744: XM.D16345.5 Figure 1689: XM_010003.4 Figure 1745: XM.116479.1 Figure 1690: XMA-039372.4 Figure 1746: NMAJ02887.2 Figure 1691: NM.000026.1 Figure 1747: XMAJ47992.2 Figure 1692: NM-015705.1 Figure 1748: XM114453.1 Figure 1693: XM-039410.1 Figure 1749: XM165484.1 Figure 1694: NM_003932.2 Figure 1750: XM.030771.4 Figure 1695: NM_014248.1 Figure 1751: NMD019057.1 Figure 1696: XM-086844.1 Figure 1752: XMA)30777.2 Figure 1697A-C: XN.010013.4 Figure 1753: XM030782.2 Figure 1698: NM-002883.1 Figure 1754: XM.003735.6 Figure 1699: NM-017590.1 Figure 1755: XM.003736.4 Figure 1700: NM-016272.1 Figure 1756: NMi300505.2 Figure 1701: NM-001098.1 Figure 1757: NMJJ06816.1 Figure 1702A-B: XM-039448.4 Figure 1758: NM013237.1 Figure 1703: NM_002676.1 Figure 1759: NM130781.1 Figure 1704: XM-039495.2 Figure 1760: NM-002011.2 Figure 1705: NMA_001469.2 Figure 1761: NMA007355.2 Figure 1706: NM-005008.1 Figure 1762: XM.165772.1 Figure 1707A-B: NM 004599.1 Figure 1763: XM_168123.1 Figure 1708: NM_024053.1 Figure 1764: XM166457.1 Figure 1709A-B: XM -010024.3 Figure 1765: NMD018135.2 Figure 1710: NM_002490.2 Figure 1766: XM-166428.1 Figure 1711: XM..040050.3 Figure 1767: XM166334.1 Figure 1712: XM_040066.3 Figure 1768A-B: XM-166340.1 Figure 1713: XM-066334.1 Figure 1769: XM-87960.1 Figure 1714: XM_013015.3 Figure 1770: XM166404.1 Figure 1715: XM.040084.1 Figure 1771: NM015388.1 Figure 1716A-B: XM-084084.1 Figure 1772: NM 080604.1 Figure 1717: XM-010029.3 Figure 1773A-C: XM.165735.1 Figure 1718: XM_051518.6 Figure 1774: XM165754.1 Figure 1719: NM-003365.1 Figure 1775: NM006443.1 Figure 1720A-C: XM -030109.5 Figure 1776A-B: XM.166408.1 Figure 1721: XM_030062.4 Figure 1777A-B: NM-003131.1 Figure 1722: XM -003288.8 Figure 1778A-B: NM_002821.2 Figure 1723: XM-084122.1 Figure 1779: NM138343.1 Figure 1724: XM_047561.3 Figure 1780: XM465729.1 Figure 1725: XM-116853.1 Figure,1781A-B: XM.A165732.1 Figure 1726A-B: XM -114325.1 Figure 1782: XM..166425.1 Figure 1727A-B: XM-113405.1 Figure 1783: NM.014623.1 Figure 1728A-B: XM-028610.2 Figure 1784: NM.006245.1 Figure 1729: NM-013334.2 Figure 1785: XM165830.1 Figure 1730: NM-022064.1 Figure 1786: NM.018960.1 Figure 1731: NM-020998.1 Figure 1787: NM.005510.1 Figure 1732: XM002828.6 Figure 1788: NM-001710.2 25 WO 2004/060270 PCT/US2003/029126 Figure 1789: NM_000063.2 Figure 1845: XM-088338.1 Figure 1790A-B: NM.006709.2 Figure 1846: XM-040574.5 Figure 1791: NM_000434.1 Figure 1847: XML49247.2 Figure 1792: NM-005346.2 Figure 1848: XM058968.2 Figure 1793: NM.005345.3 Figure 1849: NM024736.2 Figure 1794A-B: NM-006295.1 Figure 1850A-B: XM-005044.7 Figure 1795: NM_001288.3 Figure 1851: NM-D03313.2 Figure 1796: NM-013974.1 Figure 1852: NM032862.1 Figure 1797: NM-021160.1 Figure 1853: XM_059915.5 Figure 1798: NM_001320.2 Figure 1854A-B: XM_114611.1 Figure 1799: NM-033177.2 Figure 1855: XML114613.1 Figure 1800: XM-165719.1 Figure 1856: XM035368.4 Figure 1801A-B: NM-004639.2 Figure 1857: NM-024531.1 Figure 1802A-B: NM-080686.1 Figure 1858: XM-113532.1 Figure 1803: NM-004847.2 Figure 1859: NMJ316458.2 Figure 1804: XM-165771.1 Figure 1860: NM032687.1 Figure 1805: NM-004640.3 Figure 1861: XMi35370.1 Figure 1806: NM.-005931.1 Figure 1862: XM_035341.1 Figure 1807: XM165832.1 Figure 1863: NM.033301.1 Figure 1808: XM-165765.1 Figure 1864: XM098796.1 Figure 1809: XM-087945.1 Figure 1865: XMA59998.5 Figure 1810: XM-166381.1 Figure 1866: NM-013442.1 Figure 1811: XM_165720.1 Figure 1867: XMf)48461.3 Figure 1812: NM-001517.1 Figure 1868A-B: XM_048462.3 Figure 1813A-B: XM-165738.1 Figure 1869: XM_114661.1 Figure 1814: NM_003897.2 Figure 1870: XM048479.1 Figure 1815: NM_005803.2 Figure 1871: NM_003289.1 Figure 1816: XM-087939.2 Figure 1872A-C: NM_006289.2 Figure 1817A-B: XM-165734.1 Figure 1873: XM1J48513.1 Figure 1818: XMA-166353.1 Figure 1874: XM.048518.6 Figure 1819A-B: XM-166376.1 Figure 1875: NM00907.1 Figure 1820: XM-165782.1 Figure 1876: XM005397.5 Figure 1821: NM_014046.2 Figure 1877: XM048539.1 Figure 1822: NM.001090.1 Figure 1878: NM_007268.1 Figure 1823: NM_025263.1 Figure 1879: XM015516.4 Figure 1824: XM.166361.1 Figure 1880A-B: XM-013042.3, Figure 1825: XM-165764.1 Figure 1881A-B: XM..001466.8 Figure 1826: XM-165758.1 Figure 1882: XMA)46565.1 Figure 1827: XM_069477.2 Figure 1883: NMAI24602.1 Figure 1828: NM-024839.1 Figure 1884: XMAJ56881.6 Figure 1829: NM-003449.2 Figure 1885: XMiJ86536.4 Figure 1830: NM..021959.1 Figure 1886: NM2004073.1 Figure 1831: NM.014596.2 Figure 1887: XM.046557.1 Figure 1832: XM-165809.1 Figure 1888: NM.001012.1 Figure 1833: XM..087971.2 Figure 1889: XM_046551.2 Figure 1834: XM.167122.1 Figure 1890: NM_024587.1 Figure 1835: XM-166392.1 Figure 1891: NM018150.1 Figure 1836: XM-167128.1 Figure 1892: XMA 17668.1 Figure 1837: XM.166357.1 Figure 1893: XM_086370.4 Figure 1838: NM_001069.1 Figure 1894: XM.001605.9 Figure 1839: NM-004332.1 Figure 1895: NM.005727.1 Figure 1840: NM-000904.1 Figure 1896A-B: XM.027983.5 Figure 1841: NM-004568.2 Figure 1897: XM.086324.2 Figure 1842: NM.030666.2 Figure 1898: NM016486.1 Figure 1843: NM.020135.2 Figure 1899: XM4-055818.6 Figure 1844: NM-004156.1 Figure 1900: XM.086537.4 26 WO 2004/060270 PCT/US2003/029126 Figure 1901: XM-032391.2 Figure 1957: NMAI06589.1 Figure 1902: NM-006066.1 Figure 1958: XM.084078.4 Figure 1903: NM-002574.1 Figure 1959: XMA386567.1 Figure 1904: XM_032397.1 Figure 1960: NM086552A Figure 1905: NM-025077.1 Figure 1961: NM-DO7112.1 Figure 1906: NM-012222.1 Figure 1962: XMJ53256.7 Figure 1907: NM-032756.1 Figure 1963: XM114144.1 Figure 1908: XM -114085.1 Figure 1964: XMA186571.1 Figure 1909: NM-006369.1 Figure 1965: NMAJ18845.1 Figure 1910: XM.097553.1 Figure 1966: XMA13377.1 Figure 1911: XM-059133.5 Figure 1967A-B: XM -010561.10 Figure 1912A-B: NM-014784.1 Figure 1968: MA 17201.1 Figure 1913: NM_003975.1 Figure 1969: XM1O36744.6 Figure 1914: NM.005973.3 Figure 1970: NMA30898.1 Figure 1915: XM-044077.3 Figure 1971: NMAJ06694.1 Figure 1916: XM-056380.2 Figure 1972: NMJJ02870.1 Figure 1917: XM044080.2 Figure 1973: NM001030.2 Figure 1918: XM-044083.5 Figure 1974: XMAJ36829.6 Figure 1919: NM-001878.2 Figure 1975: NM-015449.1 Figure 1920: XM.017040.3 Figure 1976: NMv014847.1 Figure 1921: NM.021948.2 Figure 1977: NMVLO6118.2 Figure 1922: XM-086573.1 Figure 1978A-B: XM#036933.7 Figure 1923: XM_097656.1 Figure 1979: XMv036934.4 Figure 1924: XM-059219.2 Figure 1980: XM055737.4 Figure 1925: NM_005920.1 Figure 1981A-B: XM060121.4 Figure 1926: XM_044127.8 Figure 1982: NM.017582.2 Figure 1927: XM_053245.6 Figure 1983: NMiJ00748.1 Figure 1928A-B: XM.044148.3 Figure 1984A-B: XM-036845.4 Figure 1929: NMA_024897.1 Figure 1985: 04-017789.1 Figure 1930: NM-007221.1 Figure 1986: NM053052.1 Figure 193 1A-B: XM _044155.1 Figure 1987: XMv052974.5 Figure 1932: XM _086562.1 Figure 1988: NM.033445.1 Figure 1933: NM_022367.1 Figure 1989: XMAJ47499.4 Figure 1934: NM-005572.1 Figure 1990: NM1100858.2 Figure 1935: XM-044166.3 Figure 1991: XM±59233,2 Figure 1936: XM.053243.1 Figure 1992: NMAI24319.1 Figure 1937: XM-0 17041.3 Figure 1993: XMAJ47545.6 Figure 1938: XM-044128.6 Figure 1994A-B: XMv056884.3 Figure 1939: NM..003145.2 Figure 1995: XMv048859.6 Figure 1940A-B: XM_044172.7 Figure 1996: NMJJ03739.3 Figure 1941A-B: XM-010715.2 Figure 1997: XMfl60976.1 Figure 1942: NM_006912.1 Figure 1998: NM-001818.1 Figure 1943: NM_032292.1 Figure 1999: XM165554.1 Figure 1944: NM..017710.1 Figure 2000: XMA65555.1 Figure 1945: NM_033657.1 Figure 2001: NM001494.2 Figure 1946: NM_018253.1 Figure 2002: XM166138.1 Figure 1947: NM-018116.1 Figure 2003: XMJ66136.1 Figure 1948A-C: NM-018489.1 Figure 2004: NMAJO2189.1 Figure 1949: XMW011513.3 Figure 2005: NM-fl0417.1 Figure 1950: NM..014328.1 Figure 2006: NM.032905.1 Figure 1951: NM002004.1 Figure 2007A-B: NM-035380.1 Figure 1952: NM-000298.1 Figure 2008: XMv004330.4 Figure 1953: XM-097660.1 Figure 2009: XM-006297.4 Figure 1954A-B: XM-086565.1 Figure 2010: NMAJ03646.1 Figure 1955: NM003993.1 Figure 201 lA-B: XN'037205.4 Figure 1956: NM-005698.2 Figure 2012: XM_ 13677.1 27 WO 2004/060270 PCT/US2003/029126 Figure 2013: XM -113678.1 Figure 2069: XM045498.5 Figure 2014: NM -014342.1 Figure 2070: XNI 045499.3 Figure 2015: NM -004551.1 Figure 2071: NM1301997.2 Figure 2016: NM_006560.1 Figure 2072: CM-045525.7 Figure 2017: XM-096467.1 Figure 2073: NM013265.2 Figure 20 1SA-B: XM _096466.4 Figure 2074: XML106529.8 Figure 2019: XM_006170.4 Figure 2075: XM1353787.6 Figure 2020: XM -037173.8 Figure 2076: XM-037756.2 Figure 2021: XM-006167.10 Figure 2077: XM.165896.1 Figure 2022A-B: NM-003682.2 Figure 2078: XM-084617.4 Figure 2023: NM-005693.1 Figure 2079: XM045533.3 Figure 2024: NM-006lO.1 Figure 2080: xA1.57307.6 Figure 2025: NM-000107.1 Figure 2081: NM-01667.1 Figure 2026: XM-089966.1 Figure 2082: NM 138456.1 Figure 2027: NM_016223.2 Figure 2083: XML-15031. Figure 2028: XM-037147.6 Figure 2084: XM1-84702.4 Figure 2029: NM_024113.1 Figure 2085: XM4-037764.6 Figure 2030: XM-113679.1 Figure 2086: Xl053796.5 Figure 203 1A-B: XM-035037.1 Figure 2087: NM-002689.2 Figure 2032: XM-087710.2 Figure 2088: NM1306268.2 Figure 2033: XM.167726.1 Figure 2089A-D: XA67804.1 Figure 2034: NM-021727.2 Figure 2090: XM-6693 1.1 Figure 2035: NM 004265.2 Figure 2091: XM166235.1 Figure 2036A-B: NM _013402.3 Figure 2092: XM166236.1 Figure 2037: NM_004111.4 Figure 2093: NM1-06842.1 Figure 2038: NM014206.1 Figure 2094: NM-000852.2 Figure 2039A-B: NM_013279.1 Figure 2095: NMII07103.2 Figure 2040: XM _043146.5 Figure 2096: XM166192.1 Figure 2041: XM -043151.7 Figure 2097: NM005851.2 Figure 2042: XM-048286.6 Figure 2098: XM165598.1 Figure 2043: NM-016404.1 Figure 2099: WM165599.1 Figure 2044: XM -113225.1 Figure 2100: XM166194.1 Figure 2045: NM-004322.2 Figure 2101: XM166190.1 Figure 2046: XM -113675.1 Figure 2102: NM1-02496.1 Figure 2047: XM _113222.1 Figure 2103: NM -006019.2 Figure 2048: NM-014067.2 Figure 2104: NM1301734.1 Figure 2049: XM..011988.9 Figure 2105: NM1305768.3 Figure 2050: XM-049178.6 Figure 2106: NM.007273.2 Figure 2051: NM-032344.1 Figure 2107: M.080549.1 Figure 2052: NM_031472.1 Figure 2108: NM138425.1 Figure 2053: XM-037808.4 Figure 2109A-B: XM032588.5 Figure 2054: NM..004074.1 Figure 2110: NM.001975.2 Figure 2055: XM.0 17481.6 Figure 2111: NM -006992.1 Figure 2056: NM-017670.1 Figure 2112: NM-032641.1 Figure 2057: XM043159.1 Figurb 2113: NM 100365.2 Figure 2058: XM-113223.1 Figure 2114: XM1-32614.1 Figure 2059A-B: NM_032251.1 Figure 2115: NM031299.2 Figure 2060: NM-003942.1 Figure 2116: NM1-02075.1 Figure 2061: XM-045642.3 Figure 2117: NM-014262.1 Figure 2062: XM..006533.7 Figure 2118: NM-019858.1 Figure 2063: XM..006532.9 Figure 2119: M165910.1 Figure 2064: XM -113676.1 Figure 2120: XM 15192.1 Figure 2065: XM_045613.6 Figure 2121: XM006980.5 Figure 2066A-B: XM -045612.4 Figure 2122: NM-016319.1 Figure 2067: NM_006244.1 Figure 2123: XM 033223.5 Figure 2068: XM -1 13224.1 Figure 2124: NM 405439.1 28 WO 2004/060270 PCT/US2003/029126 Figure 2125A-B: NM-001273.1 Figure 2181: XMA90768.1 Figure 2126: XM033253.4 Figure 2182: XMJ13768.1 Figure 2127: NM..015438.1 Figure 2183: XMv-090765.1 Figure 2128: NM_002046.2 Figure 2184: XM_ 15247.1 Figure 2129: XM-033263.3 Figure 2185: XMA_15248.1 Figure 2130A-B: XM.006958.7 Figure 2186: XMA)90762.1 Figure 2131: NM-016497.2 Figure 2187: XM063217.1 Figure 2132: NM.016830.1 Figure 2188: XMA _15249.1 Figure 2133: NM.001242.1 Figure 2189: XM-90758.1 Figure 2134. XM..115193.1 Figure 2190: XMA_15250.1 Figure 2135: NM_002342.1 Figure 2191: XM.090754.1 Figure 2136: NM-001038.1 Figure 2192: XM-035014.1 Figure 2137: NM..001065.1 Figure 2193: XM-113770.1 Figure 2138: XM-033313.1 Figure 2194: XMA-88587.4 Figure 2139: XM-016640.2 Figure 2195: XM.-027520.2 Figure 2140: XM096146.2 Figure 2196: NM.006428.1 Figure 2141A-B: XM -090334.1 Figure 2197: XM-027469.2 Figure 2142A-B: XM _084841.1 Figure 2198: NMA-05009.1 Figure 2143: NM-017822.1 Figure 2199: NM-020664.1 Figure 2144: XI-084860.4 Figure 2200A-B: NM_005632.1 Figure 2145A-B: XM_028817.4 Figure 2201: XM_027458.2 Figure 2146: XM-028766.2 Figure 2202: NM_021168.1 Figure 2147: XM -006784.6 Figure 2203: XM -85422.1 Figure 2148: NM_014470.1 Figure 2204: NM_138418.1 Figure 2149A-E: XM -028760.3 Figure 2205: XM- 13865.1 Figure 2150: NM..002733.1 Figure 2206: NM-138769.1 Figure 2151: XM084866.2 Figure 2207: XM_-083939.1 Figure 2152: XM..006826.2 Figure 2208: NM_032259.1 Figure 2153: XM_028662.3 Figure 2209: XM -85426.1 Figure 2154: XM-029373.2 Figure 2210: NM_024042.1 Figure 2155A-B: NM-018319.2 Figure 2211: XM 085413.1 Figure 2156: NM 022054.2 Figure 2212: NM-023933.1 Figure 2157: NM-002802.1 Figure 2213: XM.058770.1 Figure 2158: XM..058677.2 Figure 2214: NM058192.1 Figure 2159: NM-006888.1 Figure 2215: XMA_027412.3 Figure 2160: XM_-113759.1 Figure 2216: XM -018104.2 Figure 2161: NM -006427.2 Figure 2217: XM.007786.7 Figure 2162: NM-005163.1 Figure 2218A-B: NM-003933.3 Figure 2163: XM -113760.1 Figure 2219: XM_057058.3 Figure 2164: XM..059346.3 Figure 2220: NM_032520.1 Figure 2165A-B: XM-032235.5 Figure 2221: XM4- 117025.1 Figure 2166: XM-053817.4 Figure 2222: NM.024023.1 Figure 2167: XM058640.5 Figure 2223: XI.058733.3 Figure 2168: NM-025100.1 Figure 2224A-B: NM_001287.2 Figure 2169: NM_017955.1 Figure 2225: NM-016111.1 Figure 2170A-B: XM-085103.4 Figure 2226A-B: XM-034563.2 Figure 2171A-B: XI.029340.6 Figure 2227: XM-018018.2 Figure 2172A-B: XM..029344.6 Figure 2228A-B: XM.034570.2 Figure 2173: XM_029342.5 Figure 2229: XMA034571.2 Figure 2174: XM 088588.4 Figure 2230A-B: NM-015133.1 Figure 2175: XM-060012.4 Figure 2231: XM_034586.3 Figure 2176: XM..115237.1 Figure 2232: NM.023936.1 Figure 2177: XM-115238.1 Figure 2233A-B: XM-113869.1 Figure 2178: XM..090772.4 Figure 2234: XM_034588.4 Figure 2179: XM..115242.1 Figure 2235: XM.034590.1 Figure 2180: XM..085093.1 Figure 2236: NM.005326.2 29 WO 2004/060270 PCT/US2003/029126 Figure 2237: NM_031208.1 Figure 2293: XM-058781.3 Figure 2238: NM-016332.1 Figure 2294: XM -113876.1 Figure 2239: NM_004548.1 Figure 2295: XM -117027.1 Figure 2240: NM.002952.2 Figure 2296: XM-165927.1 Figure 2241: NM-006453.2 Figure 2297: XM_053402.2 Figure 2242: XM-058762.1 Figure 2298A-B: XM_055195.2 Figure 2243: NM-004209.2 Figure 2299: XM_1 1329 1.1 Figure 2244A-B: XM_034481.4 Figure 2300: XM036884.4 Figure 2245: X1VL028899.4 Figure 2301: XM_115423.1 Figure 2246: NM-002528.3 Figure 2302: NM-003955.1 Figure 2247A-B: XM_028893.3 Figure 2303A-B: XM-008142.6 Figure 2248: NM_032271.1 Figure 2304: XM-i51959.3 Figure 2249A-B: XM_028883.4 Figure 2305A-B: XM_051961.3 Figure 2250: XM-028881.5 Figure 2306A-B: XM-115424.1 Figure 2251: XM_096977.1 Figure 2307: XM.113890.1 Figure 2252: XM_083938.2 Figure 2308: XML017578.6 Figure 2253: XM-028848.3 Figure 2309A-B: XM-054999.1 Figure 2254: NM-006711.2 Figure 2310: XM4J08137.1 Figure 2255: XM-102343.1 Figure 2311: XM165933.1 Figure 2256A-B: XM.028843.2 Figure 2312: XM-036173.3 Figure 2257: NM_017810.1 Figure 2313: XM058817.3 Figure 2258: NM.003450.1 Figure 2314: XM008136.3 Figure 2259: NM_005741.1 Figure 2315A-B: XM.. 13302.1 Figure 2260: NM_003454.1 Figure 2316: XM113301.1 Figure 2261: XM_036493.2 Figure 2317: NM_006456.1 Figure 2262: NM-003456.1 Figure 2318: XM.036780.3 Figure 2263: XM-064033.1 Figure 2319: XM-091450.1 'Figure 2264: NM_004221.2 Figure 2320A-B: XM-036784.4 Figure 2265: NM-024339.1 Figure 2321: XM -058813.3 Figure 2266: NM-017885.1 Figure 2322: XM_036785.2 Figure 2267: NM_016639.1 Figure 2323: XMA397043.2 Figure 2268: NM-021195.2 Figure 2324A-B: XM-037262.2 Figure 2269: NM_020982.1 Figure 2325: XM85717.1 Figure 2270: NM-004203.1 Figure 2326: NM001168.1 Figure 2271: XM-058784.3 Figure 2327: XM-037196.3 Figure 2272: NM..032296.1 Figure 2328: XM_-037195.2 Figure 2273: XM-054962.3 Figure 2329: XM_085533.2 Figure 2274: NM_022119.1 Figure 2330: XM_085706.1 Figure 2275: XM_058782.2 Figure 233 1A-B: XM-027039.2 Figure 2276: NM_007108.1 Figure 2332: XIM-045104.3 Figure 2277A-C: XM_036528.3 Figure 2333: NM138793.1 Figure 2278A-B: XM -113289.1 Figure 2334A-B: XM_085716.2 Figure 2279: NM-025108.1 Figure 2335: NM-020649.1 Figure 2280: XM..113290.1 Figure 2336: XM115432.1 Figure 2281: XM-016980.4 Figure 2337A-C: XM-008617.3 Figure 2282: XM-058783.3 Figure 2338: XM-113945.1 Figure 2283: NM..002613.1 Figure 2339: XM.012718.2 Figure 2284A-C: XM -165411.1 Figure 2340: XM..046776.3 Figure 2285: XM_017975.4 Figure 2341: XM_119086.1 Figure 2286: XM..115389.1 Figure 2342: XM.096098.1 Figure 2287: NM_024793.1 Figure 2343: XM.046486.2 Figure 2288A-B: XM-036660.2 Figure 2344: XM_085712.2 Figure 2289: NM-016292.1 Figure 2345: XM-046481.1 Figure 2290A-C: NM-004380.1 Figure 2346: XMf-97197.2 Figure 2291A-B: XM.036671.1 Figure 2347: XM097193.2 Figure 2292: XM..085445.2 Figure 2348: XM_008591.4 30 WO 2004/060270 PCT/US2003/029126 Figure 2349: NM-004309.2 Figure 2405: XM -072012.3 Figure 2350: XM -046472.1 Figure 2406: NM-024407.2 Figure 2351: XM-097191.2 Figure 2407: NM-000156.4 Figure 2352: XM 113331.1 Figure 2408: NM _018959.1 Figure 2353: NM-016286.1 Figure 2409: NM_-001018.2 Figure 2354: XM_113942.1 Figure 2410A-D: XM-047577.3 Figure 2355: NM-004127.3 Figure 2411: XIM_086101.1 Figure 2356: NM-022156.1 Figure 2412: XM _086102.1 Figure 2357A-C: XM..113943.1 Figure 2413: NM-138393.1 Figure 2358: XM..113330.1 Figure 2414: XM_047583.1 Figure 2359: XM -117076.1 Figure 2415: XM-047584,2 Figure 2360: NM-006822.1 Figure 2416: NM-006830.2 Figure 2361: XM-085666.2 Figure 2417A-B: XM -047600.2 Figure 2362: XM-085559.2 Figure 2418: NM-031918.1 Figure 2363: NM_004514.1 Figure 2419: NM.031213.1 Figure 2364: XM-113303.1 Figure 2420: NM 079834.1 Figure 2365: XMA17043.1 Figure 2421: NM138422.1 Figure 2366: NM-031968.1 Figure 2422: NM -01319.4 Figure 2367: XM..083958.2 Figure 2423: NM_017797.2 Figure 2368: NM_022158.1 Figure 2424: NM -017572.1 Figure 2369A-B: NM-005993.2 Figure 2425: XM.D59021.3 Figure 2370: XM_165954.1 Figure 2426A-B: NM_003938.2 Figure 2371: XM-041678.4 Figure 2427A-B: XM-046822.2 Figure 2372: NM_-003244.1 Figure 2428: NM-018049.1 Figure 2373: NM-003712.1 Figure 2429: NM.007165.1 Figure 2374A-B: XM-041843.2 Figure 2430: NM004152.1 Figure 2375: NM..016585.1 Figure 2431: NM-016199.1 Figure 2376: XM-042009.4 Figure 2432: XM_036985.3 Figure 2377: XMA-042012.2 Figure 2433: NMD12458.1 Figure 2378: NM-004359.1 Figure 2434: NM -032737.1 Figure 2379: XM042018.1 Figure 2435: XMi386115.1 Figure 2380: XM -114018.1 Figure 2436: XM-030485.3 Figure 2381A-B: XM-086110.1 Figure 2437: XM_046934.3 Figure 2382: NM-017876.1 Figure 2438: NM.003021.2 Figure 2383: XM'-055711.3 Figure 2439: XM1-55686.3 Figure 2384: NM..002579.1 Figure 2440: NM1)24760.1 Figure 2385: XM-059034.1 Figure 2441: XM -009222.6 Figure 2386: NM-002819.2 Figure 2442: XM-052629.4 Figure 2387: NM.001972.1 Figure 2443: XM.009220.4 Figure 2388: XM037560.3 Figure 2444: XM_072009.2 Figure 2389: NM-138774.1 Figure 2445: XM1-52661.3 Figure 2390: XM_037565.1 Figure 2446: NMA305597.1 Figure 2391: NM-033420.1 Figure 2447: XM-96112.2 Figure 2392: XM.-D92042.2 Figure 2448: NM-.016263.1 Figure 2393: XM-037572.2 Figure 2449: XM-0 12867.3 Figure 2394A-B: XM4-055173.2 Figure 2450: NM-006339.1 Figure 2395A-B: XM-037574.3 Figure 2451: XM-114002.1 Figure 2396: XM-009279.6 Figure 2452A-B: XI_047620.2 Figure 2397: NM _002085.1 Figure 2453: NM_014428.1 Figure 2398A-B: XM -009277.5 Figure 2454: NM-004886.1 Figure 2399: XM..012913.4 Figure 2455: XM_059027.1 Figure 2400: NM -001687.1 Figure 2456: XM..056421.2 Figure 2401: XM..028067.2 Figure 2457A-B: XM-031917.1 Figure 2402: XM_-028064.3 Figure 2458: NMJJ01348.1 Figure 2403: XM -092031.1 Figure 2459: NM1)01961.1 Figure 2404A-B: XM-028060.4 Figure 2460: NM015898.1 31 WO 2004/060270 PCT/US2003/029126 Figure 2461: XM-016871.6 Figure 2517: XMA-55230.3 Figure 2462: NM-016539.1 Figure 2518: NM-015683.1 Figure 2463: NM_018074.1 Figure 2519: XM1-12179.5 Figure 2464: NM -024333.1 Figure 2520A-B: XM-038150.2 Figure 2465: NM_017720.1 Figure 2521A-B: XM1J09293.5 Figure 2466: XM-031841.3 Figure 2522: XM D38146.4 Figure 2467: NM_003025.1 Figure 2523: NMJ-32683.1 Figure 2468: XM-08403 1.1 Figure 2524: NM.002866.1 Figure 2469: NM_025241.1 Figure 2525A-B: XML-038114.4 Figure 2470: XM_059013.3 Figure 2526: XM-065046.1 Figure 2471: XM..092023.1 Figure 2527A-B: XM-086040.1 Figure 2472: NM..052972.1 Figure 2528: XM1J84038.1 Figure 2473: XM.059012.2 Figure 2529: XMD92046.1 Figure 2474: XM_035638.5 Figure 2530: NMA12321.1 Figure 2475: XM-010156.7 Figure 2531: NM -031425.1 Figure 2476: NM-016145.1 Figure 2532: XM.038098.1 Figure 2477: NM-032332.1 Figure 2533: NM.032627.1 Figure 2478: NM_001930.2 Figure 2534: XM_114004.1 Figure 2479: NM-032301.1 Figure 2535: NM006532.1 Figure 2480: XM -009068.6 Figure 2536: NM.012181.2 Figure 2481: NM-024038.1 Figure 2537: NM.024069.1 Figure 2482: XM-032041.2 Figure 2538: NMI003333.2 Figure 2483: XM-009065.5 Figure 2539: NM-J17967.1 Figure 2484: NM -002229.1 Figure 2540A-B: NM-002911.2 Figure 2485: XM..009063.3 Figure 2541: NM.007263.1 Figure 2486: NM_006397.1 Figure 2542: NM-19070.1 Figure 2487: NM-001375.1 Figure 2543: NM-004838.1 Figure 2488: NM-000159.1 Figure 2544: XM -097399.1 Figure 2489: NM_004461.1 Figure 2545A-B: XM-086055.2 Figure 2490: XM.032020.1 Figure 2546: NM.D33415.2 Figure 2491: NM-005053.2 Figure 2547: XMJ-009330.7 Figure 2492: XM..085916.4 Figure 2548: NM-005919.1 Figure 2493: XM-057080.2 Figure 2549: XM.86049.1 Figure 2494: XM_117130.1 Figure 2550: NM.-003721.2 Figure 2495: NM-017722.1 Figure 2551: XM _072027.3 Figure 2496: NM_-003765.1 Figure 2552: XMA14009.1 Figure 2497: XM-051364.2 Figure 2553A-B: XM-048457.1 Figure 2498: NM105234.2 Figure 2554: XM. .14008.1 Figure 2499: NM1-014173.1 Figure 2555: NM-015965.2 Figure 2500: XM..065157.1 Figure 2556: XMJ113176.3 Figure 2501: XM-050617.1 Figure 2557: NM..004647.1 Figure 2502: NM-023937.1 Figure 2558: XM.032281.4 Figure 2503: NM-024050.1 Figure 2559: XM 085984.2 Figure 2504A-B: XML050644.1 Figure 2560: XM .032285.3 Figure 2505: XM_114020.1 Figure 2561: NM_004823.1 Figure 2506: NM _031310.1 Figure 2562: NM _002812.1 Figure 2507: NM..004335.2 Figure 2563: XM.056604.3 Figure 2508: XM..050660.3 Figure 2564A-E: XM-029455.3 Figure 2509: XM-056925.1 Figure 2565: XM -029450.1 Figure 2510: NM-012088.1 Figure 2566: NM -004924.2 Figure 2511: XM_0L17615.5 Figure 2567: XM -085989.2 Figure 2512A-B: XM_038604.3 Figure 2568: XMA 15619.1 Figure 2513: NM -0 18174.2 Figure 2569: NM1106149.2 Figure 2514: XM..038598.3 Figure 2570: XM_008904.4 Figure 2515A-B: XM -038595.4 Figure 2571: NM.001533.1 Figure 2516: NM..000980.2 Figure 2572: NM_012237.2 32 WO 2004/060270 PCT/US2003/029126 Figure 2573: NM-002503.1 Figure 2629: XM-113346.1 Figure 2574: NM-017827.2 Figure 2630: XM 15603.1 Figure 2575: NM 021107.1 Figure 2631: NMA00I122.2 Figure 2576A-B: NM.005884.2 Figure 2632: NMAJ04706.2 Figure 2577: XM-092066.1 Figure 2633: NM006423.1 Figure 2578: XM-009225.5 Figure 2634: NM0227521 Figure 2579: NM-018028.1 Figure 2635: NM133328.1 Figure 2580: XM-046090.2 Figure 2636A-B: XM-057401.6 Figure 2581: XM-167529.1 Figure 2637: NM-006494.1 Figure 2582: XM..086004.2 Figure 2638: XM-064875.2 Figure 2583: XM.-097361.2 Figure 2639A-B: NM-015125.2 Figure 2584: NM_003407.1 Figure 2640: NM-002573.2 Figure 2585: XM -046114.3 Figure 2641: NM019108.1 Figure 2586: NM-001020.2 Figure 2642: NMv002659.1 Figure 2587A-B: NM _003169.2 Figure 2643: XM -059019.3 Figure 2588: XM-053074.4 Figure 2644: NM-024327.1 Figure 2589: NM -016941.1 Figure 2645: XMJI59018.3 Figure 2590: NM-004714.1 Figure 2646: XM-009200.3 Figure 2591: NM_001436.2 Figure 2647: XAJ86014.2 Figure 2592: XM-016410.2 Figure 2648: NMAY14297.1 Figure 2593A-C: XM_096107.1 Figure 2649: NMAJ14400.1 Figure 2594: XM_012860.4 Figure 2650: XM-113353.1 Figure 2595: NM-006503.1 Figure 2651: NM -003009.1 Figure 2596: XM-042665.2 Figure 2652: NMv-049920.1 Figure 2597: XM009203.6 Figure 2653: XMJ55859.2 Figure 2598: XM-059053.5 Figure 2654: XM-064954.1 Figure 2599: XM-047409.3 Figure 2655: XM1)08860.6 Figure 2600: NM-013376.1 Figure 2656: XM-055856.5 Figure 2601: NM-013368.2 Figure 2657: XM-085929.4 Figure 2602: NM000713.1 Figure 2658: XM.D09036.3 Figure 2603: XM047376.6 Figure 2659: NM.017854.1 Figure 2604A-B: XM -047374.5 Figure 2660A-B: XM-085943.4 Figure 2605: XM)097289.1 Figure 2661: XM .028263.1 Figure 2606: NM_004756.1 Figure 2662: XMJ-85928.1 Figure 2607: NM .. 024876.1 Figure 2663: NM -13403.1 Figure 2608: NM-025194.1 Figure 2664: NM 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Figure 2684: NM014203.2 33 WO 2004/060270 PCTIUS2003/029126 Figure 2685: XM-085934.1 Figure 2741: XM_-035920.4 Figure 2686: NM_001536.1 Figure 2742: NM_-032701.1 Figure 2687: XM_165432.1 Figure 2743: XM-008906.2 Figure 2688: NM_001571.1 Figure'2744: NM_000991.2 Figure 2689A-B: XM_046313.2 Figure 2745: NM_014501.1 Figure 2690: NM-006270.2 Figure 2746: NM013333.1 Figure 2691A-B: XM_046305.2 Figure 2747: NM-007279.1 Figure 2692: NM-015953.2 Figure 2748: NM.D16535.1 Figure 2693: XM:.057199.3 Figure 2749: XM.D97308.1 Figure 2694: XML027904.5 Figure 2750: XM.034409.2 Figure 2695: XM-084026.2 Figure 2751: XM_034377.3 Figure 2696: NM_012423.2 Figure 2752: XM_058964.2 Figure 2697: XM_-058991.3 Figure 2753: NM_024710.1 Figure 2698: NM-017916.1 Figure 2754: XM085842.1 Figure 2699: NM-020309.1 Figure 2755: XM -084011.1 Figure 2700: XM..085941.2 Figure 2756: NM-003969.1 Figure 2701: NM..003598.1 Figure 2757: NM.014453.1 Figure 2702: NM-001774.1 Figure 2758: NM-005762.2 Figure 2703A-B: XM 057188.1 Figure 2759: NM018337.1 Figure 2704A-B: XM_027883.2 Figure 2760: NM 003091.1 Figure 2705: NM_018111.1 Figure 2761: NM_05288 1.1 Figure 2706: NM-022165.1 Figure 2762: XM-044914.1 Figure 2707: XM_085942.2 Figure 2763: XM _044915.5 Figure 2708: NM_006179.2 Figure 2764: NM _006899.1 Figure 2709: NM -006666.1 Figure 2765: NM -022760.2 Figure 2710: XM,-1 14024.1 Figure 2766A-B: NM-002836.2 Figure 2711: NM -000146.2 Figure 2767: NM.030811.2 Figure 2712: NM-004324.1 Figure 2768: NM-D21826.1 Figure 2713: NM.-006184.2 Figure 2769A-B: XM-009582.2 Figure 2714: XM -009097.4 Figure 2770: NM -023935.1 Figure 2715: NM.-020904.1 Figure 2771: XM -045418.2 Figure 2716: NM..001190.1 Figure 2772: XM1-86711.1 Figure 2717: NM-017805.1 Figure 2773A-C: XM_045431.3 Figure 2718: NM_000511.1 Figure 2774: XM086708.1 Figure 2719: XM-009103.5 Figure 2775: NM_052970.2 Figure 2720: XM _049974.5 Figure 2776: NM-017874.1 Figure 2721: NM-020126.2 Figure 2777: XM_045451.2 Figure 2722: NM..000979.2 Figure 2778: XM 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Figure 2853: NM.D53004.1 Figure 2798: NM -018677.1 Figure 2854: XMfJ58918.2 Figure 2799: NM -000178.1 Figure 2855: XM.097833.1 Figure 2800A-B: XM4-047196.4 Figure 2856: NM_024627.2 Figure 2801: NM-015638.1 Figure 2857: NM006440.1 Figure 2802: NM018217.1 Figure 2858: NM1-00754.2 Figure 2803: NM-006404.1 Figure 2859: XM.033800.1 Figure 2804: XMv-086729.1 Figure 2860: XM34059310.3 Figure 2805: XM-072161.3 Figure 2861: NM022727.2 Figure 2806: NM-002212.1 Figure 2862: NM-i02882.2 Figure 2807: NM_018244.1 Figure 2863: XM.033828.2 Figure 2808: NM-000557.2 Figure 2864: NM.023004.2 Figure 2809A-C: NM_007186.1 Figure 2865: NM-033257.2 Figure 2810: NM-015966.1 Figure 2866: XM-036729.1 Figure 2811: NM-024777.1 Figure 2867A-B: XM-036730.3 Figure 2812: NM-003915.1 Figure 2868: NM_032775.1 Figure 2813A-B: XM.047271.2 Figure 2869: XM 186814.2 Figure 2814: XM-047273.2 Figure 2870: XM318295.2 Figure 2815: XM -113380.1 Figure 2871: XM-097875.1 Figure 2816: NM-004902.1 Figure 2872: XM86876.2 Figure 2817: XM-092776.1 Figure 2873: NMA302650.1 Figure 2818A-B: XM.165988.1 Figure 2874: XM-09850.5 Figure 2819: NM-000100.2 Figure 2875: NM.004782.2 Figure 2820: XM-035999.3 Figure 2876: NM-D05207.1 Figure 2821: NM_020132.1 Figure 2877: XM -097841.1 Figure 2822: NM-031487.1 Figure 2878A-B: XM_009853.5 Figure 2823A-B: XM-009794.5 Figure 2879: NM.030573.1 Figure 2824: XM-036011.2 Figure 2880: XM_054591.3 Figure 2825: NMA-04649.1 Figure 2881: XM03689 1.1 Figure 2826: XM-036042.5 Figure 2882: XM_036892.3 Figure 2827: NMJ104928.1 Figure 2883: XM.104587.2 Figure 2828: XI..114196.1 Figure 2884: XM_086827.1 Figure 2829: XM.036087.1 Figure 2885A-B: XMa-059324.1 Figure 2830: XM -009805.6 Figure 2886: XM -096155.2 Figure 2831: NM_004339.2 Figure 2887: XM.009885.6 Figure 2832: XM_036107.2 Figure 2888: XM.086855.2 Figure 2833: X1M-092854.1 Figure 2889: XM396156.2 Figure 2834: XM-086781.1 Figure 2890: XMM86824.2 Figure 2835A-B: NM -001112.1 Figure 2891: XM-167540.1 Figure 2836A-B: XM..036175.3 Figure 2892: NM..003347.1 Figure 2837: XM 033017.3 Figure 2893: XM_097886.2 Figure 2838: XML057166.4 Figure 2894: NM.022044.1 Figure 2839: XM -086807.2 Figure 2895: NM.014337.1 Figure 2840: XM_167538.1 Figure 2896: XM_059326.3 Figure 2841A-B: XM _086802.1 Figure 2897A-B: XM-097870.1 Figure 2842: NM_005675.2 Figure 2898: XM -036967.3 Figure 2843A-B: XM_033048.3 Figure 2899A-B: NM-014634.1 Figure 2844: NM_022719.1 Figure 2900: XMD37882.3 Figure 2845: XM0033090.4 Figure 2901: NM_-005080.2 Figure 2846A-B: XM 033096.4 Figure 2902A-B: XM037887.3 Figure 2847: NM-003776.1 Figure 2903: NMA-012265.1 Figure 2848: XM..055490.4 Figure 2904: NM-005243.1 Figure 2849: NM_003504.2 Figure 2905: NM_006478.2 Figure 2850: NM.003277.1 Figure 2906A-B: XM009905.7 Figure 2851: NM-002688.2 Figure 2907A-B: XM037942.2 Figure 2852: NM-080647.1 Figure 2908A-B: XM-037945.4 35 WO 2004/060270 PCT/US2003/029126 Figure 2909: XM-037947.1 Figure 2965: XM329078.5 Figure 2910: NM -000268.1 Figure 2966: NM -005787.1 Figure 2911: XM 392894.2 Figure 2967: NM1-3233 1.1 Figure 2912: NM..019103.1 Figure 2968: NMiJ02754.2 Figure 2913: NM-013387.1 Figure 2969A-B: NM_001315.1 Figure 2914: NM032204.2 Figure 2970A-B: NM-003137.2 Figure 2915A-B: NM -021090.1 Figure 2971A-B: NM.004117.2 Figure 2916: XM-066291.1 Figure 2972: XM166419.1 Figure 2917A-B: XM 309915.6 Figure 2973: NM-007104.3 Figure 2918: NM-020530.2 Figure 2974: XMA65760.1 Figure 2919: NM-031937.1 Figure 2975: NM -022047.1 Figure 2920A-B: NM -005877.2 Figure 2976: XM166399.1 Figure 2921: XM -117224.1 Figure 2977A-B: NM1-30900.1 Figure 2922: NM-016498.1 Figure 2978: NM031443.1 Figure 2923: NM-014303.1 Figure 2979: XMJ68417.1 Figure 2924: NM-000355.1 Figure 2980: NM312412.2 Figure 2925: XM-086838.1 Figure 2981: NM}321130.1 Figure 2926: XM-086863.1 Figure 2982: NM.-31449.1 Figure 2927: XM-097857.1 Figure 2983A-B: XM-165877.1 Figure 2928A-B: NM -014941.1 Figure 2984: XM166556.1 Figure 2929: NM1317903.1 Figure 2985: NM1319082.1 Figure 2930: NM-134269.1 Figure 2986A-B: NM1315332.1 Figure 2931: NM 380430.1 Figure 2987: XM315258.2 Figure 2932: XM-018516.4 Figure 2988: XM166566.1 Figure 2933A-B: NM -016733.1 Figure 2989: XM165870.1 Figure 2934A-B: NM -014323.2 Figure 2990: NM 100162.2 Figure 2935: NM-304147.1 Figure 2991: XMJ65863.1 Figure 2936A-B: NM -019843.2 Figure 2992: NM3306230.1 Figure 2937A-B: XM-038520.4 Figure 2993A-B: XM-165882.1 Figure 2938: NM -014338.2 Figure 2994: XM165867.1 Figure 2939: XM-097868.1 Figure 2995: XM165883.1 Figure 2940A-B: NM -014662.1 Figure 2996: NM-014063.2 Figure 2941: XM-056165.2 Figure 2997: XM168433.1 Figure 2942: XM-318539.4 Figure 2998: NM.315983.2 Figure 2943: NM 1020839.1 Figure 2999A-B: XM-166557.1 Figure 2944: XMa -114334.1 Figure 3000: NM3332014.1 Figure 2945: XM-059521.2 Figure 3001: XM1355774.3 Figure 2946: XM -047503.3 Figure 3002: XM1350586.1 Figure 2947: XM 347502.5 Figure 3003: XM J14560.1 Figure 2948: XM3-087349.4 Figure 3004A-B: XM-018359.5 Figure 2949: XM-084126.4 Figure 3005: XM3350607.1 Figure 2950: NM-002295.2 Figure 3006: XM388246.1 Figure 2951: XM-076414.5 Figure 3007: XM3388240.1 Figure 2952: XM-116066.1 Figure 3008: XM3342927.3 Figure 2953: XM 393546.4 Figure 3009: NM3318044.1 Figure 2954: XM-114314.1 Figure 3010A-B: NM-032408.1 Figure 2955: XM-093423.1 Figure 3011: NM-301707.2 Figure 2956A-B: XM-002914.6 Figure 3012: NMJ332988.1 Figure 2957: XM-029136.5 Figure 3013: NMA332951.1 Figure 2958: XM-087324.4 Figure 3014: NM3332317.1 Figure 2959: NM-006232.2 Figure 3015: NMJ117528.1 Figure 2960A-B: XM-029131.5 Figure 3016: NM.004603.1 Figure 2961A-B: XM-029132.6 Figure 3017: NM-331295.1 Figure 2962A-B: XM-029104.4 Figure 3018: NM3301306.1 Figure 2963: XM-084120.1 Figure 3019: XM.057966.2 Figure 2964: XM 098130.1 Figure 3020: NM.000501.1 36 WO 2004/060270 PCT/US2003/029126 Figure 3021: NM-002314.2 Figure 3077: NM-016458.2 Figure 3022: NM022170.1 Figure 3078: XMJJ35348.3 Figure 3023: NM-022040.2 Figure 3079: XM -17492.1 Figure 3024: XM-004901.3 Figure 3080: XMJJ35373.6 Figure 3025: XM-095287.2 Figure 3081: NM -032687.1 Figure 3026: XM-088090.2 Figure 3082: XM.035350.1 Figure 3027: XM-168472.1 Figure 3083: XM.035370.1 Figure 3028: XM-088228.1 Figure 3084: NM -030580.1 Figure 3029: XM-049100.4 Figure 3085: NM-033301.1 Figure 3030: NM-018991.1 Figure 3086: XMA370951.2 Figure 3031: XM-034751.1 Figure 3087: XM.070950.1 Figure 3032A-B: XM-167500.1 Figure 3088: XM -114679.1 Figure 3033: NM-005395.1 Figure 3089: XM -14678.1 Figure 3034A-B: XM-167504.1 Figure 3090: XM 114677.1 Figure 3035: XM-167498.1 Figure 3091: XMJ-59637.5 Figure 3036: XM_168454.1 Figure 3092: NM.000368.1 Figure 3037: NM-031925.1 Figure 3093: NM-018956.2 Figure 3038: XM-167499.1 Figure 3094: XM-027836.1 Figure 3039: NM-005918.1 Figure 3095: NM1J22779.7 Figure 3040: XM-170385.1 Figure 3096A-B: XM-033355.1 Figure 3041: NM-001540.2 Figure 3097: NM-014285.2 Figure 3042A-B: XM-168538.1 Figure 3098: XM.033327.2 Figure 3043: NM_080744.1 Figure 3099: NM-254012.1 Figure 3044: NM-007155.1 Figure 3100: XMA-95887.1 Figure 3045: XM-050377.4 Figure 3101: NM.001807.1 Figure 3046: NM_012230.1 Figure 3102: NM-0 1808.1 Figure 3047: XM-170389.1 Figure 3103: NM-006753.2 Figure 3048A-B: XM-170390.1 Figure 3104: XMAJ35103.4 Figure 3049: XM-168447.1 Figure 3105: NM-000972.2 Figure 3050: XM-088067.2 Figure 3106: NMII03172.2 Figure 3051: XM -051298.5 Figure 3107: NM-017503.2 Figure 3052: XM -088370.4 Figure 3108: NMJ-33161.2 Figure 3053: XM-088374.4 Figure 3109: NMJ-20385.1 Figure 3054: NM_052963.1 Figure 3110: NM-017586.1 Figure 3055: NM-138465.1 Figure 3111: NM-017585.2 Figure 3056A-B: XM.088298.4 Figure 3112: XMfl39282.2 Figure 3057: XM-049247.2 Figure 3113: NM-019056.2 Figure 3058: XM-058968.2 Figure 3114A-B: NM-005676.2 Figure 3059: XM-088299.1 Figure 3115A-B: NM-303334.1 Figure 3060: NM -024736.2 Figure 3116: NM-033018.1 Figure 3061: NM-003313.2 Figure 3117: XM.010378.4 Figure 3062: NM -023078.1 Figure 3118: XM.033888.3 Figure 3063: XM -117487.1 Figure 3119: XM.055758.3 Figure 3064: XM-049226.6 Figure 3120: XM-033884.2 Figure 3065A-B: NM-013432.2 Figure 3121: NM133499.1 Figure 3066: NM.016208.1 Figure 3122: XM.033878.1 Figure 3067: XM-005146.8 Figure 3123: XM.033862.1 Figure 3068: XM-016270.8 Figure 3124: XM.039450.1 Figure 3069: NM-38431.1 Figure 3125: NM-002436.2 Figure 3070A-B: XM-113533.1 Figure 3126: NM1301363.2 Figure 3071A-B: XM-114611.1 Figure 3127A-B: NM-080612.1 Figure 3072: XM-114613.1 Figure 3128: NM.003639.1 Figure 3073: XM-035368.4 Figure 3129: XM..049337.1 Figure 3074: NM_-024531.1 Figure 3130: NM.021806.1 Figure 3075: NM-024555.2 Figure 3131: NM014235.1 Figure 3076: XM-13532.1 Figure 3132: NM-006014.1 37 WO 2004/060270 PCT/US2003/029126 Figure 3133A-B: XM -010150.3 Figure 3189: NM033657.1 Figure 3134: NMj_004699.1 Figure 3190: NM18253.1 Figure 3135: XM-010152.4 Figure 3191: NMA318116.1 Figure 3136: NM-001183.2 Figure 3192A-C: NMA318489.1 Figure 3137: XM _010154.1 Figure 3193: NMA314328.1 Figure 3138: XM048420.1 Figure 3194: NMAJO2004.1 Figure 3139: NM-006013.2 Figure 3195: NM003993.1 Figure 3140: XM_048410.1 Figure 3196: NM.005698.2 Figure 3141A-C: XM -048404.2 Figure 3197: NM-006589.1 Figure 3142A-C: NM-004992.2 Figure 3198: W-086567.1 Figure 3143: NM...00 1569.2 Figure 3199: XMI086552.4 Figure 3144: NM-003492.1 Figure 3200: NMAJO7112.1 Figure 3145A-C: XM-048390.3 Figure 3201: XM-053256.7 Figure 3146: NM_003491.1 Figure 3202: XM114144.1 Figure 3147: NM_-001666.1 Figure 3203: NM1J18845.1 Figure 3148A-B: NM-000425.2 Figure 3204: XMv113377.1 Figure 3149: NM_006280.1 Figure 3205: NM-004952.2 Figure 3150: NM-004135.1 Figure 3206A-B: XM01056110 Figure 3151: NM-014370.1 Figure 3207: XM036744.6 Figure 3152A-B: NM_000033.2 Figure 3208: NM006694.1 Figure 3153: NM-005745.3 Figure 3209: NMAI02870.1 Figure 3154A-B: XM _048315.1 Figure 3210: NM -001030.2 Figure 3155: XM.042155.3 Figure 3211: XM -036829.6 Figure 3156A-B: XM-042154.3 Figure 3212: NM015449.1 Figure 3157: XM-042153.4 Figure 3213: NMAJ14847.1 Figure 3158: NM_007205.2 Figure 3214: NM-06118.2 Figure 3159: XM-059930.5 Figure 3215: XMv036934.4 Figure 3160A-B: NM_014784.1 Figure 3216: NM017582.2 Figure 3161: NM-003975.1 Figure 3217A-B: XM036845.4 Figure 3162: NM-005973.3 Figure 3218: XMA 67879.1 Figure 3163: XM-044077.3 Figure 3219: XM 167437.1 Figure 3164: XM_056380.2 Figure 3220: XM167871.1 Figure 3165: XM -044080.2 Figure 3221: XMJ729347.7 Figure 3166: XM044083.5 Figure 3222A-B: W-167880.1 Figure 3167: NM -001878.2 Figure 3223: XM054856.2 Figure 3168: XM..017040.3 Figure 3224A-B: XM-035380.1 Figure 3169: XM..086573.1 Figure 3225: W004330.4 Figure 3170: XM_097656.1 Figure 3226: XM006296.1 Figure 3171: XM_059219.2 Figure 3227: W-006297.4 Figure 3172: NM-005920.1 Figure 3228: NM003646.1 Figure 3173: XM-044127.8 Figure 3229A-B: XM-037205.4 Figure 3174: XM-053245.6 Figure 3230: XM113678.1 Figure 3175A-B: XM..044148.3 Figure 3231: NM.014342.1 Figure 3176: NM_024897.1 Figure 3232: NMi-0455 1.1 Figure 3177: NM.007221.1 Figure 3233: XM-f37142.5 Figure 3178A-B: XM 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2 Figure 3249: XM-043151.7 Figure 3305: XMl65601.1 Figure 3250: XM-048286.6 Figure 3306: Nv017635.1 Figure 3251: NM..016404.1 Figure 3307: NM-016028.2 Figure 3252: NM-004322.2 Figure 3308: NM.022338.1 Figure 3253: XM -113222.1 Figure 3309A-B: NM-002335.l Figure 3254: NM_014067.2 Figure 3310A-B: NM.018312.2 Figure 3255: XM-011988.9 Figure 3311: XM 165597.1 Figure 3256: XM_049178.6 Figure 3312A-B: XM-006936A Figure 3257: NM-032344.1 Figure 3313A-B: XM006925.6 Figure 3258: NM-031472.1 Figure 3314: 1-096630.1 Figure 3259: XM_037808.4 Figure 3315: NM.002355.2 Figure 3260: NM-004074.1 Figure 3316: XMv051166.6 Figure 3261: XM_017481.6 Figure 3317: XM-096620.4 Figure 3262: NM_017670.1 Figure 3318: XM.015481.7 Figure 3263: XMA-043159.1 Figure 3319: X1YL049148.2 Figure 3264: XM-113223.1 Figure 3320: XMJ 13726.1 Figure 3265: NM-003942.1 Figure 3321: XA4I-049141.1 Figure 3266: NM1-005825.2 Figure 3322: XM-096612.4 Figure 3267: NM-005609.1 Figure 3323: NM021934.1 Figure 3268: XM -045642.3 Figure 3324: XM-083884.1 Figure 3269: XM-006533.7 Figure 3325: NM007210.2 Figure 3270: XM -006532.9 Figure 3326: NM016293.1 Figure 3271: XM_045613.6 Figure 3327: NM-020467.2 Figure 3272A-B: XM-045612.4 Figure 3328: NM0022721 Figure 3273: XM_113224.1 Figure 3329: XM.D58525.5 Figure 3274: XM-045498.5 Figure 3330: NM-D02273.1 Figure 3275: XM 045499.3 Figure 3331: NMAI00224-1 Figure 3276: NM-001997.2 Figure 3332: XW029728.3 Figure 3277: XM_045525.7 Figure 3333: NM015989.2 Figure 3278: NM-013265.2 Figure 3334: XM015468.1 Figure 3279: XM-006529.8 Figure 3335: XM0M2162.4 Figure 3280: XM_053787.6 Figure 3336: NMAJ02178.1 Figure 3281: XM-037756.2 Figure 3337A-B: XM029631.2 Figure 3282: XM -084716.1 Figure 3338: NM.018507.1 Figure 3283: XM -084617.4 Figure 3339: XMA371646.5 Figure 3284: XM-045533.3 Figure 3340: NM -015665.1 Figure 3285: NM -001667.1 Figure 3341: XM012212.3 Figure 3286: NM-138456.1 Figure 3342: XM028598.1 Figure 3287: XMA-115031.1 Figure 3343A-B: NMAT20898.1 Figure 3288: XM -037764.6 Figure 3344: XM-028621-1 Figure 3289: NM -002689.2 Figure 3345: XMAI28619.1 Figure 3290: NM -006268.2 Figure 3346: NL058555.2 Figure 3291A-D: XM167804.1 Figure 3347: NM-014311.1 Figure 3292: XM-166931.1 Figure 3348: XMIf396606.2 Figure 3293: XM-166235.1 Figure 3349: XM-084873.2 Figure 3294: XMI-166236.1 Figure 3350: NM.018457.1 Figure 3295: NM.006842.1 Figure 3351: NM-00l92O.2 Figure 3296: NM-000852.2 Figure 3352: NM-002345.1 Figure 3297: NM..007103.2 Figure 3353: XM167518-1 Figure 3298: NM 005851.2 Figure 3354A-B: XM.031617.1 Figure 3299: XM.165598.1 Figure 3355: NM.007223-1 Figure 3300: XM-165599-1 Figure 3356A-B: XM.031612.5 39 WO 2004/060270 PCT/US2003/029126 Figure 3357: NM_003134.1 Figure 3413: XMJ-57150.3 Figure 3358: XM-1 13826.1 Figure 3414: XMJ358739.2 Figure 3359A-B: XM -085310.1 Figure 3415A-B: XM-028359.3 Figure 3360: XM_031561.3 Figure 3416: XI_085327.2 Figure 3361: NM.002225.2 Figure 3417: NM_000485.1 Figure 3362A-B: NM _014952.1 Figure 3418: XML-07803.3 Figure 3363: NM_130468.1 Figure 3419: NM016209.1 Figure 3364: XM..031555.3 Figure 3420A-B: NM_005187.3 Figure 3365: XM-031554.6 Figure 3421: XI.007909.2 Figure 3366: XM-031515.4 Figure 3422: NML024043.1 Figure 3367: NM-018145.1 Figure 3423: NM..017702.1 Figure 3368: NM-005258.2 Figure 3424: XM.047436.2 Figure 3369: NM_018163.1 Figure 3425: NM..002386.1 Figure 3370: NM.032850.1 Figure 3426: NM.D14972.1 Figure 3371: XM -031510.4 Figure 3427: XM.D47462.4 Figure 3372: NM_133639.2 Figure 3428A-B: NM-000135.1 Figure 3373: NM-080432.1 Figure 3429A-B: XM_047520.3 Figure 3374: NM.-024111.1 Figure 3430: XM.012545.6 Figure 3375A-B: NM_032196.1 Figure 3431: XM-047525.4 Figure 3376: XMA-113821.1 Figure 3432: NMAJ33251.1 Figure 3377: XM-031641.3 Figure 3433: NM_003119.1 Figure 3378: NM-016359.1 Figure 3434: XM085409.2 Figure 3379: XM-031645.1 Figure 3435: XM_085408.2 Figure 3380A-B: XM._031646.3 Figure 3436: XMA 13861.1 Figure 3381A-B: XM031674.5 Figure 3437: XM1 17012.1 Figure 3382A-B: XM.007545.3 Figure 3438: XML058830.3 Figure 3383: XM_091159.1 Figure 3439: NM002809.1 Figure 3384A-C: XM-031689.6 Figure 3440: XM1149860.3 Figure 3385: NM-005090.1 Figure 3441A-B: NM-007359.2 Figure 3386: XM-031718.4 Figure 3442: XM-113939.1 Figure 3387A-B: XM_031720.6 Figure 3443: XM_008586.5 Figure 3388: NM-015497.1 Figure 3444: XM113329.1 Figure 3389A-B: XM-085314.4 Figure 3445: XMAI83987.2 Figure 3390A-C: NM_022473.1 Figure 3446: NM.000422.1 Figure 3391: NM_003825.2 Figure 3447: XMA)08579.4 Figure 3392: XM..015963.6 Figure 3448: NM002276.1 Figure 3393A-B: NM-033238.1 Figure 3449: NM-002275.1 Figure 3394: NM_004809.2 Figure 3450: NM..02274.1 Figure 3395: XM-0 12425.7 Figure 3451: NM..000526.3 Figure 3396: NM_005545.1 Figure 3452: NM.000526.3 Figure 3397: NM.032907.1 Figure 3453: XM..049982.1 Figure 3398: XM-058699.5 Figure 3454: XM-085732.2 Figure 3399: XM_ 15295.1 Figure 3455: XM049972.4 Figure 3400: NM-016645.1 Figure 3456: NM.003079.2 Figure 3401: NM 306384.2 Figure 3457: XM -049959.1 Figure 3402A-B: XM.044533.6 Figure 3458: XM.049935.2 Figure 3403: XM-011655.9 Figure 3459: XMJ49937.1 Figure 3404A-C: XM.054900.6 Figure 3460A-B: XM-113334.1 Figure 3405: XM-035835.4 Figure 3461: NMJJ00964.1 Figure 3406: NM-032162.1 Figure 3462: NM.001254.2 Figure 3407A-B: XM.040592.3 Figure 3463: XM.085731.2 Figure 3408A-B: XM..091193.2 Figure 3464: NM.006455.1 Figure 3409: XM..085325.1 Figure 3465: XM.036465.1 Figure 3410: XM..008040.7 Figure 3466: XM-055061.1 Figure 3411: XM..054590.1 Figure 3467A-B: XML036462.1 Figure 3412: NM.002461.1 Figure 3468: XM.083975.1 40 WO 2004/060270 PCT/US2003/029126 Figure 3469: XM-008290.2 Figure 3525: NM-0O4309.2 Figure 3470: XM-048654.3 Figure 3526: XM146472.1 Figure 3471A-B: XM_008633.4 Figure 3527: NM1016286.1 Figure 3472: XM-008632.5 Figure 3528: XM A 13942.1 Figure 3473: NM_025197.1 Figure 3529: NMA0O4127.3 Figure 3474: NM._024320.1 Figure 3530: NM-022156.1 Figure 3475: XM -054038.4 Figure 3531A-C: XM.113943.1 Figure 3476: XM._058883.1 Figure 3532: XM113330.1 Figure 3477A-B: NM-0 14726.1 Figure 3533: XM_ 17076.1 Figure 3478A-B: NM-002265.3 Figure 3534: XM_113940.1 Figure 3479: NM-002145.1 Figure 3535: NM.006822.1 Figure 3480: XM -00856L1 Figure 3536: XMIL085666.2 Figure 3481: XM-008560.6 Figure 3537: XM085559.2 Figure 3482: XM-008559.1 Figure 3538: NM-004514.1 Figure 3483: NM-024017.2 Figure 3539: XML113303.1 Figure 3484: XM -115480.1 Figure 3540: XM_-117043.1 Figure 3485: NM-005831.2 Figure 3541: X1L 18938.1 Figure 3486: XM -113318.1 Figure 3542: NM-i31968.1 Figure 3487: XM -113319.1 Figure 3543: XM_083958.2 Figure 3488: XM -030444.5 Figure 3544A-B: NM-005993.2 Figure 3489: XM -08459.3 Figure 3545: XM.-42018.1 Figure 3490A-B: XM.-012651.5 Figure 3546: XMA14018.1 Figure 3491A-B: XM -008154.4 Figure 3547: NMD017876.1 Figure 3492A-B: XM.-008142.6 Figure 3548: XM 55711.3 Figure 3493: XM-051959.3 Figure 3549: NM1-02579.1 Figure 3494A-B: XM_051961.3 Figure 3550: XMJJ59034.1 Figure 3495: XM -113890.1 Figure 3551: NM_002819.2 Figure 3496: XM-017578.6 Figure 3552: NM-024888.1 Figure 3497: XM_165933.1 Figure 3553: XM 37560.3 Figure 3498: XI-036173.3 Figure 3554: NM138774.1 Figure 3499: XM_058817.3 Figure 3555: XM 37565.1 Figure 3500A-B: XMA- 13302.1 Figure 3556: NMAI33420.1 Figure 3501: XM-113301.1 Figure 3557: XM 92042.2 Figure 3502: NM_006456.1 Figure 3558: XM-037572.2 Figure 3503: XM-036780.3 Figure 3559A-B: XM-037574.3 Figure 3504: XM_091450.1 Figure 3560: XM.009279.6 Figure 3505A-B: XM-036784.4 Figure 3561: NM.002085.1 Figure 3506: XM-058813.3 Figure 3562A-B: XM.-009277.5 Figure 3507: XM_036785.2 Figure 3563: XM_012913.4 Figure 3508: XM3-097043.2 Figure 3564: NM-J01687.1 Figure 3509A-B: XM-037262.2 Figure 3565: XM_028067.2 Figure 3510A-B: XM4-083990.2 Figure 3566: XM-028064.3 Figure 3511: NM..001168.1 Figure 3567A-B: XM_028060.4 Figure 3512: XM_037196.3 Figure 3568: XM -072012.3 Figure 3513: XM-037195.2 Figure 3569: NM-024407.2 Figure 3514: XM..085533.2 Figure 3570: NM.000156.4 Figure 3515: XM -113945.1 Figure 3571: XM119329.1 Figure 3516: XM _012718.2 Figure 3572: NM-018959.1 Figure 3517: XM.046776.3 Figure 3573: NM..001018.2 Figure 3518: XM_096098.1 Figure 3574A-D: XM_047577.3 Figure 3519: XM-085712.2 Figure 3575: XM_086102.1 Figure 3520: XM_085711.1 Figure 3576: NM138393.1 Figure 3521: XM.046481.1 Figure 3577: XM.047584.2 Figure 3522: XM.097197.2 Figure 3578: NM.006830.2 Figure 3523: XM-097193.2 Figure 3579A-B: XM_047600.2 Figure 3524: XM..008591.4 Figure 3580A-B: XM_030721.1 41 WO 2004/060270 PCT/US2003/029126 Figure 3581: NM-031918.1 Figure 3637A-C: XM_008854.7 Figure 3582: NM -031213.1 Figure 3638: NMAJ05234.2 Figure 3583: NM -079834.1 Figure 3639: NM-014173.1 Figure 3584: NM-001319.4 Figure 3640: XM-050617.1 Figure 3585: NMJ117797.2 Figure 3641: NMJ323937.1 Figure 3586: NM_017572.1 Figure 3642: NMJ124050.1 Figure 3587: XM-059021.3 Figure 3643: NM-031310.1 Figure 3588A-B: NM -003938.2 Figure 3644: NMJ104335.2 Figure 3589A-B: XM-046822.2 Figure 3645: XM050660.3 Figure 3590: NM..018049.1 Figure 3646: XML056925.1 Figure 3591: NM_007165.1 Figure 3647: NM112088.1 Figure 3592: NM-004152.1 Figure 3648: XM1)17615.5 Figure 3593: NM_016199.1 Figure 3649: NM118174.2 Figure 3594: XM036985.3 Figure 3650: XM.038598.3 Figure 3595: NM-012458.1 Figure 3651: NMA100980.2 Figure 3596: NM_032737.1 Figure 3652: XM -055230.3 Figure 3597: XM-086115.1 Figure 3653: NMA315683.1 Figure 3598: XM _030485.3 Figure 3654: XM-12179.5 Figure 3599: XM-086123.2 Figure 3655A-B: XM-009293.5 Figure 3600: XMJ146934.3 Figure 3656: XMA138146.4 Figure 3601: NM-003021.2 Figure 3657: NMA)32683.1 Figure 3602: XM-055686.3 Figure 3658A-B: XM -086040.1 Figure 3603A-B: XM -086121.2 Figure 3659A-B: XMv-038109.3 Figure 3604: XM-052629.4 Figure 3660: XMJJ92046.1 Figure 3605: XMA-052629.4 Figure 3661: NMA112321.1 Figure 3606: XMA_052661.3 Figure 3662: XM -038098.1 Figure 3607: NM-005597.1 Figure 3663: NMA132627.1 Figure 3608: NM-016263.1 Figure 3664: XM -114004.1 Figure 3609 XMA012867.3 Figure 3665: NM006532.1 Figure 3610: NM_006339.1 Figure 3666: NM012181.2 Figure 3611: XM -114002.1 Figure 3667: NM -024069.1 Figure 3612A-B: XM.047620.2 Figure 3668: NM -003333.2 Figure 3613: NM_-004886.1 Figure 3669: NM-017967.1 Figure 3614: XM_-059027.1 Figure 3670: NM-012109.1 Figure 3615: NM-001348.1 Figure 3671: NM -018316.1 Figure 3616: NM-001961.1 Figure 3672: NM025021.1 Figure 3617: NM-016149.1 Figure 3673: XM -009336.3 Figure 3618: X1-016871.6 Figure 3674A-B: NM-002911.2 Figure 3619: NM-016539.1 Figure 3675: NM-021267.1 Figure 3620: NM-005755.2 Figure 3676: NM 107263.1 Figure 3621: XM -031841.3 Figure 3677: NMA-019070.1 Figure 3622: NM.003025.1 Figure 3678: NM -004838.1 Figure 3623: XM-.08403 1.1 Figure 3679A-B: XM-086055.2 Figure 3624: NM-025241.1 Figure 3680: NM -033415.2 Figure 3625: XM..059013.3 Figure 3681: XM -309330.7 Figure 3626: XM059012.2 Figure 3682: NM.005919.1 Figure 3627: XM-035638.5 Figure 3683: NM-003721.2 Figure 3628A-B: XM_035636.3 Figure 3684: XMA-72027.3 Figure 3629A-B: XM-035635.2 Figure 3685: XM -114009.1 Figure 3630: XM_035634.2 Figure 3686A-B: XML048457.1 Figure 3631: XMI-012862.3 Figure 3687: XM.114008.1 Figure 3632A-B: XI-035627.2 Figure 3688: NMJJ15965.2 Figure 3633A-B: XM..035625.5 Figure 3689: NM1)16573.1 Figure 3634A-B: XM-050561.6 Figure 3690: NM 120410.1 Figure 3635A-B: XM-008930.4 Figure 3691: NMA104647.1 Figure 3636: XM-050564.2 Figure 3692: NM133256.1 42 WO 2004/060270 PCT/US2003/029126 Figure 3693: XM-032281.4 Figure 3749A-B: XM.015505.1 Figure 3694: XM-085984.2 Figure 3750: XMJJ30914.1 Figure 3695: XM-032285.3 Figure 3751: NM1352848.1 Figure 3696: NM-004823.1 Figure 3752: XM_008912.1 Figure 3697: NM-002812.1 Figure 3753: XM1385882.1 Figure 3698: XM-085985.1 Figure 3754: NM1320158.1 Figure 3699: X-v085987.1 Figure 3755: NM1318035.1 Figure 3700A-E: XM3-029455.3 Figure 3756: XM-085874.1 Figure 3701: XM-029450.1 Figure 3757: XM-309170:3 Figure 3702: NM-004924.2 Figure 3758: XM.012777.2 Figure 3703: XM-085989.2 Figure 3759: XM-113346.1 Figure 3704: XM_115619.1 Figure 3760: XM- 15603.1 Figure 3705: NM-006149.2 Figure 3761( NM -D01022.2 Figure 3706: XM-008904.4 Figure 3762: NM1301783.1 Figure 3707: NM-001533.1 Figure 3763: NM 304706.2 Figure 3708: XM..059046.3 Figure 3764: NM-006423.1 Figure 3709: NM_012237.2 Figure 3765: NML022752.1 Figure 3710: NM _002503.1 Figure 3766: NM-133328.1 Figure 3711: NM_017827.2 Figure 3767A-B: XM-057401.6 Figure 3712: NM _021107.1 Figure 3768: NMJI06494.1 Figure 3713: NM-024907.4 Figure 3769A-B: NML015125.2 Figure 3714: XM-059045.1 Figure 3770: NM 302573.2 Figure 3715A-B: NM-005884.2 Figure 3771A-B: XM..029883.4 Figure 3716: XNM-092067.1 Figure 3772A-B: NM-005357.1 Figure 3717: XM-009225.5 Figure 3773: XM-058945.2 Figure 3718: NM .018028.1 Figure 3774: XMl 13980.1 Figure 3719: XM..046090.2 Figure 3775: XM1354350.3 Figure 3720: XM.167529.1 Figure 3776: XM_1 13354.1 Figure 3721: XM_086004.2 Figure 3777: NMJ103425.1 Figure 3722: XM-097361.2 Figure 3778: XM -092027.1 Figure 3723: NM_003407.1 Figure 3779: NMJ-002250.1 Figure 3724: XM.046114.3 Figure 3780: NM1319108.1 Figure 3725: NM.001020.2 Figure 3781: NMi102659.1 Figure 3726A-B: NM-003169.2 Figure 3782: XM59019.3 Figure 3727: XM-053074.4 Figure 3783: XMJ)09200.3 Figure 3728: NM-016941.1 Figure 3784: XM..086014.2 Figure 3729: XM-072007.2 Figure 3785: NMA14297.1 Figure 3730: NM.004714.1 Figure 3786: XMJ149015.4 Figure 3731: NM-001436.2 Figure 3787: NMA114400.1 Figure 3732: XM-016410.2 Figure 3788: NMA03009.1 Figure 3733: XM-012860.4 Figure 3789: XMA-49920.1 Figure 3734: NM_006503.1 Figure 3790: XMvL-55859.2 Figure 3735: XM-042665.2 Figure 3791A-B: XM-009125.1 Figure 3736: NM-024877.1 Figure 3792: XMA008860.6 Figure 3737: XM-009203.6 Figure 3793: XM0-55856.5 Figure 3738: XM-047409.3 Figure 3794: XMA185929.4 Figure 3739: NM.013376.1 Figure 3795A-B: NM.014681.2 Figure 3740: NM..000713.1 Figure 3796: XM-084025.1 Figure 3741: XM-047376.6 Figure 3797: XM-009036.3 Figure 3742A-B: XM_047374.5 Figure 3798A-B: XM_028253.1 Figure 3743: NM-004756.1 Figure 3799: NM017854.1 Figure 3744: NM-024876.1 Figure 3800A-B: XM.085943.4 Figure 3745: NM-025194.1 Figure 3801: XM.D28263.1 Figure 3746: XM-059052.5 Figure 3802: XM -85928.1 Figure 3747: NM-004596.1 Figure 3803: NM.013403.1 Figure 3748A-B: NM-017555.1 Figure 3804: NM-016457.2 43 WO 2004/060270 PCT/US2003/029126 Figure 3805: NM-001743.3 Figure 3861A-B: XM_046313.2 Figure 3806: XM009126.2 Figure 3862: NM_006270.2 Figure 3807: NM..032040.1 Figure 3863A-B: XM_046305.2 Figure 3808: NM-006247.2 Figure 3864: NM-015953.2 Figure 3809: NM-002516.1 Figure 3865: XM_027904.5 Figure 3810: XM-064921.1 Figure 3866: XM084026.2 Figure 3811: XM-051330.4 Figure 3867: NM012423.2 Figure 3812: XM-051332.1 Figure 3868: XM-027899.5 Figure 3813A-B: NM-004819.1 Figure 3869: XM058991.3 Figure 3814: XM..027569.1 Figure 3870: NMAJ17916.1 Figure 3815: XMA327572.1 Figure 3871: NM1J03598.1 Figure 3816: NM-004597.3 Figure 3872: NM001774.1 Figure 3817: NM-000164.1 Figure 3873A-B: XM-057188.1 Figure 3818: XM-097338.4 Figure 3874A-B: XM_027883.2 Figure 3819: NM-012155.1 Figure 3875: NMA-22165.1 Figure 3820: NM-025136.1 Figure 3876: XM85942.2 Figure 3821: XM-085848.1 Figure 3877: NM006666.1 Figure 3822: NM-003370.1 Figure 3878: XMl 14024.1 Figure 3823: NM_005619.1 Figure 3879: NM_000146.2 Figure 3824A-B: XM-009143.2 Figure 3880: NMfl04324.1 Figure 3825: NM_001983.1 Figure 3881: NMM06184.2 Figure 3826: NM_012099.1 Figure 3882: XM-009097.4 Figure 3827: XM-030918.4 Figure 3883: NM 120904.1 Figure 3828: N1vL000400.1 Figure 3884: NM_001190.1 Figure 3829: X1VL030967.5 Figure 3885: XMAJ49974.5 Figure 3830A-B: NM_031417.1 Figure 3886: NM1)20126.2 Figure 3831: NM-024108.1 Figure 3887: NM1)00979.2 Figure 3832: XM_-091899.4 Figure 3888: XM09112.4 Figure 3833: NM-007056.1 Figure 3889: XM_049964.2 Figure 3834: XM_-008848.4 Figure 3890: XMi049963.4 Figure 3835: NM_001294.1 Figure 3891: NM031485.1 Figure 3836: NM_000041.1 Figure 3892: NMAJ06801.1 Figure 3837: NM-006114.1 Figure 3893: XMA312808.5 Figure 3838: NMA02856.1 Figure 3894: NMJJ01425.1 Figure 3839: NM-005581.1 Figure 3895A-B: XM-049938.3 Figure 3840: NM-012116.2 Figure 3896: XM1-09118.9 Figure 3841: XM..008851.7 Figure 3897: XM1)55864.4 Figure 3842: NM-006505.2 Figure 3898: XMA 13344.1 Figure 3843: XM..165962.1 Figure 3899: XMiJ46419.3 Figure 3844: NM-016440.1 Figure 3900: NM1)02691.1 Figure 3845: NMAJ12068.2 Figure 3901: XM_056286.2 Figure 3846: XM-085927.2 Figure 3902: XM_058990.5 Figure 3847: XM-084023.1 Figure 3903: NM.138334.1 Figure 3848: XM-016217.6 Figure 3904: XM1)91981.4 Figure 3849: X ..114025.1 Figure 3905: NM.002975.1 Figure 3850: XM008985.6 Figure 3906: NM-032712.1 Figure 3851: NM-017432.1 Figure 3907: NM-002257.1 Figure 3852: XM-046344.2 Figure 3908: NMAJ05046.1 Figure 3853: NM-030973.1 Figure 3909: XM_009004.4 Figure 3854: NM_025129.2 Figure 3910: XM-091941.1 Figure 3855: NM..014203.2 Figure 3911: NMA38373.1 Figure 3856: NM-021733.1 Figure 3912: NM-D04542.1 Figure 3857: XM-085934.1 Figure 3913: NM-015629.1 Figure 3858: NM-001536.1 Figure 3914A-B: XM-008958.5 Figure 3859: XM-165432.1 Figure 3915: XM1085896.4 Figure 3860: NM-00157 1.1 Figure 3916: XMJJ50236.6 44 WO 2004/060270 PCT/US2003/029126 Figure 3917: XM_085899.4 Figure 3973A-B: NM-005877.2 Figure 3918: Xl050589.5 Figure 3974: NM_-0 12429.1 Figure 3919: XM -114013.1 Figure 3975: NM_016498.1 Figure 3920: XM-059321.2 Figure 3976: NMfl14303.1 Figure 3921: XM-050582.4 Figure 3977: NM00355.1 Figure 3922: XM -017977.4 Figure 3978: XM-086863.1 Figure 3923: XM-055900.2 Figure 3979A-B: NM_014941.1 Figure 3924: XM_-044313.4 Figure 3980: NMI117903.1 Figure 3925: XM_059049.2 Figure 3981: NM-134269.1 Figure 3926: NM_138412.1 Figure 3982: NM080430.1 Figure 3927: XM-009161.8 Figure 3983: XM_018516.4 Figure 3928: XM..092006.2 Figure 3984A-B: NM 016733.1 Figure 3929: NM-003283.1 Figure 3985: NM-f52880.1 Figure 3930: NM-000363.1 Figure 3986A-B: XM038605.4 Figure 3931: XM-012840.2 Figure 3987: NM.005488.1 Figure 3932A-B: NM-014931.1 Figure 3988: NM002133.1 Figure 3933: XM_035919.2 Figure 3989: XL009947.4 Figure 3934: NM-032701.1 Figure 3990: NM030641.1 Figure 3935: XM-058948.3 Figure 3991: XMJJ86858.2 Figure 3936: NM_000991.2 Figure 3992: NM_014309.1 Figure 3937: NM-014501.1 Figure 3993: NM-030882.1 Figure 3938: NM-013333.1 Figure 3994: NMI003661.1 Figure 3939: NM_007279.1 Figure 3995A-B: NM-002473.1 Figure 3940: NM_013301.1 Figure 3996: NM.012473.1 Figure 3941: NML016535.1 Figure 3997: XM- 14207.1 Figure 3942: NM-016202.1 Figure 3998: NMJJ03753.1 Figure 3943: XM-091947.4 Figure 3999: NM006860.2 Figure 3944: XM_-113986.1 Figure 4000: NM-D03312.2 Figure 3945: XM-034377.3 Figure 4001: NMA21126.2 Figure 3946: NM-024710.1 Figure 4002: XM-086817.1 Figure 3947: NM-003650.2 Figure 4003: NM-32468 1.1 Figure 3948: XM-042765.3 Figure 4004: NM031910.1 Figure 3949: XM-042770.2 Figure 4005: XMAJ84086.1 Figure 3950: NM_-001247.1 Figure 4006: NMAI02405.1 Figure 3951A-B: XM_009436.7 Figure 4007A-B: NM-014550.2 Figure 3952: XM-042805.4 Figure 4008: XM_009967.4 Figure 3953: XML086723.1 Figure 4009: NM-013365.2 Figure 3954A-B: XM-042806.3 Figure 4010: NM_018957.2 Figure 3955A-B: XI-042807.3 Figure 4011: NMfl20315.2 Figure 3956: NM.006115.2 Figure 4012: NM-002305.2 Figure 3957: BAA20895.1 Figure 4013: NM1324313.1 Figure 3958: BAA20024.1 Figure 4014: NMJJ07032.2 Figure 3959: BAA20026.1 Figure 4015: XM_-009973.3 Figure 3960: BAA20028.1 Figure 4016: NM-138797.1 Figure 3961: BAA20016.1 Figure 4017: NMA016091.1 Figure 3962A-B: XMa-037060.4 Figure 4018A-B: XMJ339236.3 Figure 3963: NM-006478.2 Figure 4019: NMAJ32561.1 Figure 3964A-B: XM_037945.4 Figure 4020: NM -021974.2 Figure 3965: XM-037947.1 Figure 4021: NM012407.1 Figure 3966: NMJ-00268.1 Figure 4022: NM.012323.1 Figure 3967: NM -019103.1 Figure 4023: NM_012264.2 Figure 3968: NM-013387.1 Figure 4024: NMAI01894.1 Figure 3969: NM-032204.2 Figure 4025: XM-086859.2 Figure 3970: XM..066291. 1 Figure 4026: NM106855.2 Figure 3971A-B: XM.009915.6 Figure 4027: NM_000026. 1 Figure 3972: NM..031937.1 Figure 4028: NM_015705.1 45 WO 2004/060270 PCT/US2003/029126 Figure 4029A-B: NM_020831.1 Figure 4085: NM_007312.2 Figure 4030: NM-003932.2 Figure 4086: NM_033158.1 Figure 4031: NM-022098.1 Figure 4087: NM_007275.1 Figure 4032: NM-014248.1 Figure 4088: NM-007182.3 Figure 4033: XM-086844.1 Figure 4089: NMO07022.1 Figure 4034A-C: XM -010013.4 Figure 4090: NM-007024.2 Figure 4035: XM- 14201.1 Figure 4091: NM-016210.1 Figure 4036: NM-002883.1 Figure 4092A-B: XM-040930.2 Figure 4037: NM_017590.1 Figure 4093: NM104635.2 Figure 4038: NM _003216.1 Figure 4094: XMJJ76414.5 Figure 4039: NM_-001098.1 Figure 4095: XM093546.4 Figure 4040A-B: XM-039448.4 Figure 4096: NMfl18130.1 Figure 4041: NM-002676.1 Figure 4097A-B: NM-013336.2 Figure 4042: XM..039495.2 Figure 4098: XMJI-67264.4 Figure 4043: NM_001469.2 Figure 4099: XM- 14309.1 Figure 4044: NM.005008.1 Figure 4100: XM -084111.4 Figure 4045: NM-024821.1 Figure 4101: XM.030286.7 Figure 4046A-B: NM-004599.1 Figure 4102: XMa 13397.1 Figure 4047: NM-024053.1 Figure 4103: XM055551.3 Figure 4048A-B: XM _010024.3 Figure 4104: XMi-96203.4 Figure 4049A-B: NM-014966.2 Figure 4105: NM.-024047.2 Figure 4050: XM-010953.4 Figure 4106: NMf-16245.1 Figure 4051: NM.005793.1 Figure 4107A-C: XM-018009.5 Figure 4052A-B: XMA-051491.5 Figure 4108: XM -084158.1 Figure 4053: NM..024661.1 Figure 4109A-C: NM-080685.1 Figure 4054: NM-015933.1 Figure 4110: XMvL32759.2 Figure 4055: NM_130384.1 Figure 4111A-E: XM-041971.4 Figure 4056: XM_003301.5 Figure 4112: XM.041974.3 Figure 4057: XM.051518.6 Figure 4113: XM-041978.3 Figure 4058: NM-022911.2 Figure 4114: XM -041981.3 Figure 4059: NM..003365.1 Figure 4115: XMJO 17591.4 Figure 4060A-C: XM -030109.5 Figure 4116: NMf-06058.1 Figure 4061: XM -030060.1 Figure 4117: NM002084.2 Figure 4062: NM-004157.1 Figure 4118: XMJ 17396.1 Figure 4063: XM..003288.8 Figure 4119: XM041993.1 Figure 4064: XM_084122.1 Figure 4120: NMA318047.1 Figure 4065: XM-047561.3 Figure 4121A-B: NM-007286.1 Figure 4066: XM- 16853.1 Figure 4122: NM-005617.2 Figure 4067A-B: XM -114325.1 Figure 4123: XM.003937.5 Figure 4068A-B: XM-113405.1 Figure 4124A-B: NM_000176.1 Figure 4069A-B: XM-028610.2 Figure 4125: XM059676.2 Figure 4070: XM-002828.6 Figure 4126: NMI006913.1 Figure 407 IA-E: XM..002829.6 Figure 4127: NM -022110.2 Figure 4072A-B:_XM-018223.6 Figure 4128A-B: NM_000592.3 Figure 4073: NM-022171.1 Figure 4129: NM 032454.1 Figure 4074: NM-000481.1 Figure 4130: NMI-05510.1 Figure 4075A-B: XM-01 1068.7 Figure 413 1A-B: NM-006929.2 Figure 4076: NM-032355.1 Figure 4132: NM4-02904.3 Figure 4077A-B: NM-005777.1 Figure 4133: NM-001710.2 Figure 4078: NM_005778.1 Figure 4134A-B: NM-006709.2 Figure 4079: XM_041509.1 Figure 4135: NM-025257.1 Figure 4080: XM-041507.1 Figure 4136: NM -000434.1 Figure 4081: NM_004636.1 Figure 4137: NM005346.2 Figure 4082: NM.006764.1 Figure 4138: NM005345.3 Figure 4083: NM-003549.2 Figure 4139: XM-66348.1 Figure 4084: NM..012191.1 Figure 4140: NM-021177.1 46 WO 2004/060270 PCT/US2003/029126 Figure 4141A-B: NM-006295.1 Figure 4197: NM006854.2 Figure 4142: NM-001288.3 Figure 4198: NM17756.1 Figure 4143: NM-013974.1 Figure 4199: NM-018106.1 Figure 4144: NM-021160.1 Figure 4200: NM -24067.1 Figure 4145: NM-001320.2 Figure 4201: XM-055724.4 Figure 4146: NM-033177.2 Figure 4202: XMA65859.1 Figure 4147: XM-165712.1 Figure 4203: XvI055725.1 Figure 4148A-B: NM-004639.2 Figure 4204: XM-030750.5 Figure 4149A-B: NM-080686.1 Figure 4205: XM 13547.1 Figure 4150: NM-002341.1 Figure 4206: XM -05 1298.5 Figure 4151: XM-165771.1 Figure 4207: XM1388370.4 Figure 4152: NM-004640.3 Figure 4208: XM.-030743.7 Figure 4153: NM-00593 1.1 Figure 4209: NM.052963.1 Figure 4154: XM.,165832.1 Figure 4210: XMA 13534.1 Figure 4155: XM-165765.1 Figure 4211: NM138465.1 Figure 4156: XM -087945.1 Figure 4212A-B: X34-088298.4 Figure 4157: XM_166381.1 Figure 4213: XM049247.2 Figure 4158: NM-080870.1 Figure 4214: XM058968.2 Figure 4159A-B: XM.167116.1 Figure 4215: XMv088299.1 Figure 4160: XM.-66401.1 Figure 4216: NMI024736.2 Figure 4161: NM-001517.1 Figure 4217: NM003313.2 Figure 4162A-B: XM-165738.1 Figure 4218: NMA723078.1 Figure 4163: NM -003897.2 Figure 4219: NM032862,1 Figure 4164: NM_005803.2 Figure 4220: XMJ17487.1 Figure 4165: XM -087939.2 Figure 4221: XMv-049226.6 Figure 4166A-B: XM -165734.1 Figure 4222: NM016208.1 Figure 4167: XM_166353.1 Figure 4223: XM-0O5146.8 Figure 4168A-B: XM.166376.1 Figure 4224: XM-016270.8 Figure 4169: XM.165782.1 Figure 4225A-B: NM.004260.1 Figure 4170: XM-166409.1 Figure 4226A-B: XM 13533.1 Figure 4171: NM_014046.2 Figure 4227: XMJ-59915,5 Figure 4172A-B: XM-165799.1 Figure 4228: XM -114613.1 Figure 4173: NM-001090.1 Figure 4229: XMA135368.4 Figure 4174: XM-166361.1 Figure 4230: NMA-2453 I.1 Figure 4175: XMv-165764.1 Figure 4231: NM1-24555.2 Figure 4176: XM-165758.1 Figure 4232: XMJ 13532.1 Figure 4177: NM_003449.2 Figure 4233: XMi-35348.3 Figure 4178: NM...025236.1 Figure 4234: XN117492.1 Figure 4179: NM-021959.1 Figure 4235: XM-114612.1 Figure 4180: NM..014596.2 Figure 4236: UMA035373.6 Figure 4181: XM-165809.1 Figure 4237: NM.032687.1 Figure 4182: XV-167122.1 Figure 4238: XMD35350.1 Figure 4183: NM_018950.1 Figure 4239: XM1135341.1 .Figure 4184: XM-166392.1 Figure 4240: NM.D33301.1 Figure 4185: XM-167128.1 Figure 4241: NM -003416.1 Figure 4186: XM_166550.1 Figure 4242: NM-li4066.2 Figure 4187: NM-001101I. Figure 4243: XM -059913.5 Figure 4188: NM.003088.1 Figure 4244: NMJI01539.1 Figure 4189: NM-019011.2 Figure 4245: NMA18225.1 Figure 4190: XM-165858.1 Figure 4246A-B: XMvL36235.1 Figure 4191: NM..000535.2 Figure 4247: NM.004323.2 Figure 4192: NM006303.2 Figure 4248: NM016410,2 Figure 4193A-B: NM-014413.2 Figure 4249A-B: XM-036219.5 Figure 4194: NM -032706.1 Figure 4250: X1N4 -005543.8 Figure 4195: NM.006908.2 Figure 425 lA-B: NM-022917.2 Figure 4196: XM-166545.1 Figure 4252: XM 18105545.4 47 WO 2004/060270 PCT/US2003/029126 Figure 4253: NM_017811.1 Figure 4309: NM1-03492.1 Figure 4254A-B: XM..036125.2 Figure 43 1OA-C: XM_048390.3 Figure 4255: XM_036284.5 Figure 4311: NM-00349 1.1 Figure 4256: XM-084277.1 Figure 4312: N100 1666.1 Figure 4257: NM..00 1161.1 Figure 4313: NM_000054.2 Figure 4258: NM_001161.1 Figure 4314A-B: NM.000425.2 Figure 4259: XM-088504.1 Figure 4315: NM -006280.1 Figure 4260: NM-024348.1 Figure 4316: NM -004135.1 Figure 4261: NM_005866.1 Figure 4317A-B: NM_000033.2 Figure 4262: NM.000155.1 Figure 4318: NM_005745.3 Figure 4263: NM..002989.1 Figure 4319A-B: XM -048315.1 Figure 4264: XM..071063.2 Figure 4320: XM1)42155.3 Figure 4265: XM-016894.3 Figure 4321: XM1)42153.4 Figure 4266: XM-059998.5 Figure 4322: NM1)07205.2 Figure 4267: NM -004629.1 Figure 4323: NM_018196.1 Figure 4268: NM -032634.1 Figure 4324: NM..001289.3 Figure 4269: NM-013442.1 Figure 4325: XM1-60045.2 Figure 4270: NM-025182.1 Figure 4326: XM1-84297.2 Figure 427 1A-B: XM -005627.7 Figure 4327: XM -01472.4 Figure 4272: XM-048461.3 Figure 4328A-C: XM84-055481.5 Figure 4273A-B: XM -048462.3 Figure 4329: XM_044474.1 Figure 4274: XM-114661.1 Figure 4330: XM_001710.5 Figure 4275: XM_048479.1 Figure 4331: XMAJ55482.1 Figure 4276: NM-001216.1 Figure 4332: XM _114894.1 Figure 4277: NM..003289.1 Figure 4333A-B: NM_014000.1 Figure 4278A-C: NM .006289.2 Figure 4334: XM1)11882.8 Figure 4279: XM-048513.1 Figure 4335: XM-117912.1 Figure 4280: XM_048518.6 Figure 4336: XM1)89438.4 Figure 4281A-B: XM_005394.2 Figure 4337: NM1-33022.1 Figure 4282: NM..000907.1 Figure 4338A-B: NM -007055.1 Figure 4283: XM_005397.5 Figure 4339: XM -096398.1 Figure 4284: NM..032593.1 Figure 4340: XM 111913.3 Figure 4285: XM-048539.1 Figure 4341A-B: XM-005895.7 Figure 4286A-B: NM _021111.1 Figure 4342: NM -003375.1 Figure 4287: NM_007096.1 Figure 4343: XM1-58351.5 Figure 4288A-B: XM -045037.1 Figure 4344: NM 032772.1 Figure 4289A-B: XM -045035.1 Figure 4345: XM -046668.4 Figure 4290: NM-002436.2 Figure 4346: XM1-46674.4 Figure 4291: NM_001363.2 Figure 4347: XM 1)16625.4 Figure 4292: NM.003639.1 Figure 4348: XMA-02674.7 Figure 4293: XM -049337.1 Figure 4349: NM -032775.1 Figure 4294: NM-021806.1 Figure 4350: XM-018295.2 Figure 4295: NM-019848.2 Figure 4351: NM_032262.1 Figure 4296: NM.0 14235.1 Figure 4352: NM.002650.1 Figure 4297: NM_006014.1 Figure 4353: NM1-04782.2 Figure 4298A-B: XM-010150.3 Figure 4354: XM1-97841.1 Figure 4299: NM-004699.1 Figure 4355: NM 1)30573.1 Figure 4300: XM_010152.4 Figure 4356A-B: XM_059324.1 Figure 4301: NM -001183.2 Figure 4357: XM_096155.2 Figure 4302: XM-010154.1 Figure 4358: XM1)96156.2 Figure 4303: XM_.048420.1 Figure 4359: XM1)86824.2 Figure 4304: NM.006013.2 Figure 4360: XM-114202.1 Figure 4305: XM..048410.1 Figure 4361: XM_167540.1 Figure 4306A-C: XM..048404.2 Figure 4362: NM1)03347.1 Figure 4307A-C: NM-004992.2 Figure 4363: XM1)97886.2 Figure 4308: NM -001569.2 Figure 4364: NM.022044.1 48 WO 2004/060270 PCT/US2003/029126 Figure 4365: NM -014337.1 Figure 4421: XM165474.1 Figure 4366: XM 059326.3 Figure 4422: XM_168338.1 Figure 4367A-B: XM-097870.1 Figure 4423: NM015610.1 Figure 4368: NM _015705.1 Figure 4424A-B: XM-166549.1 Figure 4369A-B: NM-020831.1 Figure 4425: XM_166550.1 Figure 4370: XM_039410.1 Figure 4426: NMfl01101.2 Figure 4371: NM -003932.2 Figure 4427: NM-D03088.1 Figure 4372: NM-022098.1 Figure 4428: XM165858.1 Figure 4373: XM -086848.1 Figure 4429: NM_-000535.2 Figure 4374: NM-014248.1 Figure 4430: NM_006303.2 Figure 4375: XM_086844.1 Figure 4431A-B: NM-014413.2 Figure 4376A-C: XM -010013.4 Figure 4432: NM_-032706.1 Figure 4377: XM _114201.1 Figure 4433: NM -006908.2 Figure 4378: NM-002883.1 Figure 4434: XM166545.1 Figure 4379: NM -017590.1 Figure 4435: NM -006854.2 Figure 4380: NM -003216.1 Figure 4436: NM_017756.1 Figure 4381: NM -016272.1 Figure 4437:,NM-018106.1 Figure 4382: NM -032758.1 Figure 4438: XM-166538.1 Figure 4383: NM -001098.1 Figure 4439: XMAI37224.3 Figure 4384A-B: XM-039448.4 Figure 4440: XM-165859.1 Figure 4385: NM-002676.1 Figure 4441: XM_167302.1 Figure 4386: NM-001469.2 Figure 4442: XM-055725.1 Figure 4387: NM_005008.1 Figure 4443: XM_167304.1 Figure 4388: XM-039501.2 Figure 4444: X1166521.1 Figure 4389: NM-024588.1 Figure 4445: XM-166512.1 Figure 4390: NM-024821.1 Figure 4446: NMJ)19059.1 Figure 4391A-B: NM-004599.1 Figure 4447: XM167279.1 Figure 4392: NM-024053.1 Figure 4448: XM.D88260.1 Figure 4393A-B: XM -010024.3 Figure 4449: NM -003406.1 Figure 4394: NM -033318.1 Figure 4450: XM.-011657.3 Figure 4395: NM -002490.2 Figure 4451: NM.002568.1 Figure 4396: XML040050.3 Figure 4452: XM_035046.2 Figure 4397: XM_040066.3 Figure 4453: XM.L070950.1 Figure 4398: XM-013015.3 Figure 4454: XM_114679.1 Figure 4399: NM.014509.2 Figure 4455: XM_114678.1 Figure 4400A-B: XMv -084084.1 Figure 4456: XMl 14677.1 Figure 4401: XM-010029.3 Figure 4457: XM_)59637.5 Figure 4402: XM-076414.5 Figure 4458: NM_032360.1 Figure 4403: XM..116066.1 Figure 4459: XM-114109.1 Figure 4404: XM -093546.4 Figure 4460: NM -002826.2 Figure 4405: XM -116067.1 Figure 4461A-D: XM-113370.1 Figure 4406: XM_ 16069.1 Figure 4462: NM1)19852.1 Figure 4407: NM-018130.1 Figure 4463A-B: NM1)14828.1 Figure 4408: XM..051902.4 Figure 4464A-B: XM_033511.6 Figure 4409: XM -116410.1 Figure 4465A-B: NM..007192.2 Figure 4410: XML098401.1 Figure 4466: XM-0 12376.6 Figure 4411A-B: XM -027156.3 Figure 4467: XM_-085105.1 Figure 4412A-B: NM_006999.2 Figure 4468: NM-016423.1 Figure 4413: NM-138809.1 Figure 4469: XMI-033553.6 Figure 4414: XM..052313.5 Figure 4470: NM_022734.1 Figure 4415: XM-059691.3 Figure 4471: XM.-033595.6 Figure 4416: XM-003862.5 Figure 4472: NM.002937.2 Figure 4417: XM-057492.4 Figure 4473: NM -001145.1 Figure 4418: XM-016170.6 Figure 4474: XMJ-07491.3 Figure 4419: XM-030424.3 Figure 4475: XMA-34238.5 Figure 4420A-B: XM -113451.1 Figure 4476: NM.-00 1641.2 49 WO 2004/060270 PCT/US2003/029126 Figure 4477: NM _0 17807.1 Figure 4533A-B: XM-058343.5 Figure 4478: NM_005484.2 Figure 4534: XMi-58602.2 Figure 4479: NM-021178.1 Figure 4535: XM_016640.2 Figure 4480: XM-015893.3 Figure 4536: XM_096146.2 Figure 4481: NM_003098.2 Figure 4537A-B: XM_090334.1 Figure 4482A-B: XM-047042.2 Figure 4538A-B: XM-084841.1 Figure 4483: XM-056253.3 Figure 4539: NM-022496.1 Figure 4484: XM-097772.1 Figure 4540A-B: XM -113724.1 Figure 4485: XM_059282.3 Figure 4541: XM_052542.1 Figure 4486: NM -0 16732.1 Figure 4542: NM-003348.1 Figure 4487: NM-003908.1 Figure 4543A-B: NM-019094.1 Figure 4488: NM_000687.1 Figure 4544: NM-003877.2 Figure 4489: XM-047136.1 Figure 4545: XM-012219.4 Figure 4490: NM...014183.1 Figure 4546A-B: XM-040952.1 Figure 4491: NM-032514.1 Figure 4547: XM -116948.1 Figure 4492: NM-080476.1 Figure 4548: NM -005348.1 Figure 4493: XM_086728.1 Figure 4549: XM_016985.2 Figure 4494A-C: XM -047155.2 Figure 4550: XMI12448.9 Figure 4495: NM-052830.1 Figure 4551: NM-014736.1 Figure 4496: NM-018677.1 Figure 4552: NM -000942.2 Figure 4497: NM-000178.1 Figure 4553: XM) 42248.1 Figure 4498: NM -015638.1 Figure 4554: NM1-32231.2 Figure 4499: NM -018217.1 Figure 4555: NM .002789.2 Figure 4500: NM .006404.1 Figure 4556: XM -113812.1 Figure 4501: XM _086729.1 Figure 4557: XM_091100.1 Figure 4502: XM-072161.3 Figure 4558: XM _047970.6 Figure 4503: NM-002212.1 Figure 4559: NM-012170.1 Figure 4504: NM -0 18244.1 Figure 4560: NM -00126.1 Figure 4505A-C: NM-007186.1 Figure 4561A-C: XM-037176.2 Figure 4506: NM-015966.1 Figure 4562: NM-004278.1 Figure 4507: XM -016061.3 Figure 4563: NM1118955.1 Figure 4508: NM-003915.1 Figure 4564: XM.058900.2 Figure 4509A-B: XM-047271.2 Figure 4565: NM-016428.1 Figure 4510: XM-047273.2 Figure 4566: NMJ-02634.2 Figure 4511: XM_ 13380.1 Figure 4567: XM-011118.7 Figure 4512: NM_004902.1 Figure 4568: NM -003563.1 Figure 4513: XM-092776.1 Figure 4569: NM1-05827.1 Figure 4514: NM _016436. 2 Figure 4570: NM.030802.1 Figure 4515: NM-016558.2 Figure 4571: NM_007067.1 Figure 4516A-B: XM -047295.1 Figure 4572: XM-165954.1 Figure 4517: XM -114076.1 Figure 4573: XM_041678.4 Figure 4518: XM-086357.1 Figure 4574: NM.003244.1 Figure 4519: NM-000975.2 Figure 4575: XM-167362.1 Figure 4520: NM-003198.1 Figure 4576: XM_064591.1 Figure 4521: NM_007260.2 Figure 4577: XM-015755.1 Figure 4522: NM-000191.1 Figure 4578: XM-097232.2 Figure 4523: NM _017761.2 Figure 4579: NM _022081.2 Figure 4524: NM_054016.1 Figure 4580: XM_037840.4 Figure 4525: XM-086375.1 Figure 4581: NM1t2143.1 Figure 4526: XM-006290.5 Figure 4582: NM1-03595.1 Figure 4527: NM-019084,1 Figure 4583: XM1)86821.1 Figure 4528A-B: XM..005681.1 Figure 4584: XM1)92888.1 Figure 4529: XM..089514.1 Figure 4585: XM1-57492.4 Figure 4530: NM.013314.1 Figure 4586: XM1)16170.6 Figure 4531: XM1-55459.3 Figure 4587: XM -030424.3 Figure 4532: XM-050993.5 Figure 4588A-B: XM-113451.1 50 WO 2004/060270 PCT/US2003/029126 Figure 4589: XM-165474.1 Figure 4606: NM -022170.1 Figure 4590: XM-055002.1 Figure 4607: NM 322040.2 Figure 4591: NM-133645.1 Figure 4608: XM-04901.3 Figure 4592: XM-097453.2 Figure 4609A-B: NM-003388.3 Figure 4593: XM-029228,1 Figure 4610: NM016328.1 Figure 4594: XM_059745.3 Figure 4611A-B: NM-032999.1 Figure 4595: NM-004906.1 Figure 4612: XM -113540.1 Figure 4596: XM_087871.1 Figure 4613: NMA-015941.1 Figure 4597: XM-033912.1 Figure 4614: NM_-006330.2 Figure 4598: XM -033910.1 Figure 4615: NM_014175.1 Figure 4599: NM-014161.1 Figure 4616: NM.005648.2 Figure 4600A-C: XM-004237.5 Figure 4617: NM000971.2 Figure 4601: XM-166521.1 Figure 4618: XM-88311.2 Figure 4602: XM.166512.1 Figure 4619A-B: NM -014393.1 Figure 4603: XM-167279,1 Figure 4620: NM.003406.1 Figure 4604A-B: NM -032581.2 Figure 4621: XML011657.3 Figure 4605: NM-002314.2 Figure 4622: NM_002568.1 51 WO 2004/060270 PCT/US2003/029126 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS I. Definitions The terms "TAT polypeptide" and "TAT" as used herein and when immediately followed by a numerical designation, refer to various polypeptides, wherein the complete designation (i.e.,TAT/number) refers to specific polypeptide sequences as described herein. The terms "TAT/number polypeptide" and 5 "TAT/number" wherein the term "number" is provided as an actual numerical designation as used herein encompass native sequence polypeptides, polypeptide variants and fragments of native sequence polypeptides and polypeptide variants (which are further defined herein). The TAT polypeptides described herein may be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods. The term "TAT polypeptide" refers to each individual TAT/number 10 polypeptide disclosed herein. All disclosures in this specification which refer to the "TAT polypeptide" refer to each of the polypeptides individually as well as jointly. For example, descriptions of the preparation of, purification of, derivation of, formation of antibodies to or against, formation of TAT binding oligopeptidez to or against, formation of TAT binding organic molecules to or against, administration of, compositions containing, treatment of a disease with, etc., pertain to each polypeptide of the invention individually. The term 15 "TAT polypeptide" also includes variants of the TAT/number polypeptides disclosed herein. A "native sequence TAT polypeptide" comprises a polypeptide having the same amino acid sequence as the corresponding TAT polypeptide derived from nature. Such native sequence TAT polypeptides can be isolated from nature or can be produced by recombinant or synthetic means. The term "native sequence TAT polypeptide" specifically encompasses naturally-occurring truncated or secreted forms of the specific TAT 20 polypeptide (e.g., an extracellular domain sequence), naturally-occurring variant forms (e.g., alternatively spliced forms) and naturally-occurring allelic variants of the polypeptide. In certain embodiments of the invention, the native sequence TAT polypeptides disclosed herein are mature or full-length native sequence polypeptides comprising the full-length amino acids -sequences shown in the accompanying figures. Start and stop codons (if indicated) are shown in bold font and underlined in the figures. Nucleic acid residues indicated 25 as "N" in the accompanying figures are any nucleic acid residue. However, while the TAT polypeptides disclosed in the accompanying figures are shown to begin with methionine residues designated herein as amino acid position 1 in the figures, it is conceivable and possible that other methionine residues located either upstream or downstream from the amino acid position 1 in the figures may be employed as the starting amino acid residue for the TAT polypeptides. 30 The TAT polypeptide "extracellular domain" or "ECD" refers to a form of the TAT polypeptide which is essentially free of the transmembrane and cytoplasmic domains. Ordinarily, a TAT polypeptide ECD will have less than 1 % of such transmembrane and/or cytoplasmic domains and preferably, will have less than 0.5 % of such domains. It will be understood that any transmembrane domains identified for the TAT polypeptides of the present invention are identified pursuant to criteria routinely employed in the art for identifying that type 35 of hydrophobic domain. The exact boundaries of a transmembrane domain may vary but most likely by no more than about 5 amino acids at either end of the domain as initially identified herein. Optionally, therefore, an extracellular domain of a TAT polypeptide may contain from about 5 or fewer amino acids on either side of the 52 WO 2004/060270 PCT/US2003/029126 transmembrane domain/extracellular domain boundary as identified in the Examples or specification and such polypeptides, with or without the associated signal peptide, and nucleic acid encoding them, are contemplated by the present invention. The approximate location of the "signal peptides" of the various TAT polypeptides disclosed herein may be shown in the present specification and/or the accompanying figures. It is noted, however, that the C 5 terminal boundary of a signal peptide may vary, but most likely by no more than about 5 amino acids on either side of the signal peptide C-terminal boundary as initially identified herein, wherein the C-terminal boundary of the signal peptide may be identified pursuant to criteria routinely employed in the art for identifying that type of amino acid sequence element (e.g., Nielsen et al., Prot. Eng. 10:1-6 (1997) and von Heinje et al., Nucl. Acids. Res. 14:4683-4690 (1986)). Moreover, it is also recognized that, in some cases, cleavage of a signal 10 sequence from a secreted polypeptide is not entirely uniform, resulting in more than one secreted species. These mature polypeptides, where the signal peptide is cleaved within no more than about 5 amino acids on either side of the C-terminal boundary of the signal peptide as identified herein, and the polynucleotides encoding them, are contemplated by the present invention. "TAT polypeptide variant" means a TAT polypeptide, preferably an active TAT polypeptide, as defined 15 herein having at least about 80% amino acid sequence identity with a fall-length native sequence TAT polypeptide sequence as disclosed herein, a TAT polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a TAT polypeptide, with or without the signal peptide, as disclosed herein or any other fragment of a full-length TAT polypeptide sequence as disclosed herein (such as those encoded by a nucleic acid that represents only a portion of the complete coding sequence for a full-length TAT polypeptide). 20 Such TAT polypeptide variants include, for instance, TAT polypeptides wherein one or more amino acid residues are added, or deleted, at the N- or C-terminus of the full-length native amino acid sequence. Ordinarily, a TAT polypeptide variant will have at least about 80% amino acid sequence identity, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity, to a full-length native sequence TAT polypeptide sequence 25 as disclosed herein, a TAT polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a TAT polypeptide, with or without the signal peptide, as disclosed herein or any other specifically defined fragment of a full-length TAT polypeptide sequence as disclosed herein. Ordinarily, TAT variant polypeptides are at least about 10 amino acids in length, alternatively at least about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 30 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600 amino acids in length, or more. Optionally, TAT variant polypeptides will have no more than one conservative amino acid substitution as compared to the native TAT polypeptide sequence, alternatively no more than 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitution as compared to the native TAT polypeptide sequence. 35 "Percent (%) amino acid sequence identity" with respect to the TAT polypeptide sequences identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific TAT polypeptide sequence, after aligning the sequences and introducing gaps, 53 WO 2004/060270 PCT/US2003/029126 if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms 5 needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2, wherein the complete source code for the ALIGN-2 program is provided in Table 1 below. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc. and the source code shown in Table 1 below has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 10 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available through Genentech, Inc., South San Francisco, California or may be compiled from the source code provided in Table 1 below. The ALIGN-2 program should be compiled for use on a UNIX operating system, preferably digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. 15 In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 20 100 times the fraction X/Y where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid 25 sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. As examples of % amino acid sequence identity calculations using this method, Tables 2 and 3 demonstrate how to calculate the % amino acid sequence identity of the amino acid sequence designated "Comparison Protein" to the amino acid sequence designated "TAT", wherein "TAT" represents the amino acid sequence of a hypothetical TAT polypeptide of interest, "Comparison Protein" represents the amino acid 30 sequence of apolypeptide against which the "TAT" polypeptide of interest is being compared, and "X, "Y" and "Z" each represent different hypothetical amino acid residues. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program. "TAT variant polynucleotide" or "TAT variant nucleic acid sequence" means a nucleic acid molecule 35 which encodes a TAT polypeptide, preferably an active TAT polypeptide, as defined herein and which has at least about 80% nucleic acid sequence identity with a nucleotide acid sequence encoding a full-length native sequence TAT polypeptide sequence as disclosed herein, a full-length native sequence TAT polypeptide sequence 54 WO 2004/060270 PCT/US2003/029126 lacking the signal peptide as disclosed herein, an extracellular domain of a TAT polypeptide, with or without the signal peptide, as disclosed herein or any other fragment of a full-length TAT polypeptide sequence as disclosed herein (such as those encoded by a nucleic acid that represents only a portion of the complete coding sequence for a full-length TAT polypeptide). Ordinarily, a TAT variant polynucleotide will have at least about 80% nucleic acid sequence identity, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 5 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% nucleic acid sequence identity with a nucleic acid sequence encoding a full-length native sequence TAT polypeptide sequence as disclosed herein, a full-length native sequence TAT polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a TAT polypeptide, with or without the signal sequence, as disclosed herein or any other fragment of a full-length TAT polypeptide sequence as disclosed herein. Variants do not encompass the native 10 nucleotide sequence. Ordinarily, TAT variant polynucleotides are at least about 5 nucleotides in length, alternatively at least about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 15 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 nucleotides in length, wherein in this context the term "about" means the referenced nucleotide sequence length plus or minus 10% of that referenced length. 20 "Percent (%) nucleic acid sequence identity" with respect to TAT-encoding nucleic acid sequences identified herein is defined as the percentage of nucleotides in a candidate sequence that are identical with the nucleotides in the TAT nucleic acid sequence of interest, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, 25 using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. For purposes herein, however, % nucleic acid sequence identity values are generated using the sequence comparison computer program ALIGN-2, wherein the complete source code for the ALIGN-2 program is provided in Table 1 below. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc. and the source code shown in Table I below has been filed with user documentation in the 30 U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available through Genentech, Inc., South San Francisco, California or may be compiled from the source code provided in Table 1 below. The ALIGN-2 program should be compiled for use on a UNIX operating system, preferably digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. 35 In situations where ALIGN-2 is employed for nucleic acid sequence comparisons, the % nucleic acid sequence identity of a given nucleic acid sequence C to, with, or against a given nucleic acid sequence D (which can alternatively be phrased as a given nucleic acid sequence C that has or comprises a certain % nucleic acid 55 WO 2004/060270 PCT/US2003/029126 sequence identity to, with, or against a given nucleic acid sequence D) is calculated as follows: 100 times the fraction W/Z where W is the number of nucleotides scored as identical matches by the sequence alignment program ALIGN-2 5 in that program's alignment of C and D, and where Z is the total number of nucleotides in D. It will be appreciated that where the length of nucleic acid sequence C is not equal to the length of nucleic acid sequence D, the % nucleic acid sequence identity of C to D will not equal the % nucleic acid sequence identity of D to C. As examples of % nucleic acid sequence identity calculations, Tables 4 and 5, demonstrate how to calculate the % nucleic acid sequence identity of the nucleic acid sequence designated "Comparison DNA" to the nucleic 10 acid sequence designated "TAT-DNA", wherein "TAT-DNA" represents a hypothetical TAT-encoding nucleic acid sequence of interest, "Comparison DNA" represents the nucleotide sequence of a nucleic acid molecule against which the "TAT-DNA" nucleic acid molecule of interest is being compared, and "N", "L" and "V" each represent different hypothetical nucleotides. Unless specifically stated otherwise, all % nucleic acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 15 computer program. In other embodiments, TAT variant polynucleotides are nucleic acid molecules that encode a TAT polypeptide and which are capable of hybridizing, preferably under stringent hybridization and wash conditions, to nucleotide sequences encoding a full-length TAT polypeptide as disclosed herein. TAT variant polypeptides may be those that are encoded by a TAT variant polynucleotide. 20 The term "full-length coding region" when used in reference to a nucleic acid encoding a TAT polypeptide refers to the sequence of nucleotides which encode the full-length TAT polypeptide of the invention (which is often shown between start and stop codons, inclusive thereof, in the accompanying figures). The term "full-length coding region" when used in reference to an ATCC deposited nucleic acid refers to the TAT polypeptide-encoding portion of the cDNA that is inserted into the vector deposited with the ATCC (which is 25 often shown between start and stop codons, inclusive thereof, in the accompanying figures). "Isolated, " when used to describe the various TAT polypeptides disclosed herein, means polypeptide that has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would typically interfere with diagnostic 30 or therapeutic uses for the polypeptide, and may include enzymes, hormones, and other proteinaceous or non proteinaceous solutes. In preferred embodiments, the polypeptide will be purified (1) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain. Isolated polypeptide includes polypeptiddn situ within recombinant cells, since at least 35 one component of the TAT polypeptide natural environment will not be present. Ordinarily, however, isolated polypeptide will be prepared by at least one purification step. 56 WO 2004/060270 PCT/US2003/029126 An "isolated" TAT polypeptide-encoding nucleic acid or other polypeptide-encoding nucleic acid is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the natural source of the polypeptide-encoding nucleic acid. An isolated polypeptide-encoding nucleic acid molecule is other than in the form or setting in which it is found in nature. Isolated polypeptide-encoding nucleic acid molecules therefore are distinguished from the specific polypeptide 5 encoding nucleic acid molecule as it exists in natural cells. However, an isolated polypeptide-encoding nucleic acid molecule includes polypeptide-encoding nucleic acid molecules contained in cells that ordinarily express the polypeptide where, for example, the nucleic acid molecule is in a chromosomal location different from that of natural cells. The term "control sequences" refers to DNA sequences necessary for the expression of an operably 10 linked coding sequence in a particular host organism. The control sequences that are suitable for prokaryotes, for example, include a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers. Nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is operably linked to DNA for a 15 polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally, "operably linked" means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is 20 accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice. "Stringency" of hybridization reactions is readily determinable by one of ordinary skill in the art, and generally is an empirical calculation dependent upon probe length, washing temperature, and salt concentration. In general, longer probes require higher temperatures for proper annealing, while shorter probes need lower 25 temperatures. Hybridization generally depends on the ability of denatured DNA to reanneal when complementary strands are present in an environment below their melting temperature. The higher the degree of desired homology between the probe and hybridizable sequence, the higher the relative temperature which can be used. As a result, it follows that higher relative temperatures would tend to make the reaction conditions more stringent, while lower temperatures less so. For additional details and explanation of stringency of 30 hybridization reactions, see Ausubel et al., Current Protocols in Molecular Biology Wiley Interscience Publishers, (1995). "Stringent conditions" or "high stringency conditions", as defined herein, may be identified by those that: (1) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0. 1% sodium dodecyl sulfate at 50'C; (2) employ during hybridization a 35 denaturing agent, such as formamide, for example, 50% (vlv) formamide with 0.1% bovine serum alburnin/0.1% Ficoll0.1 % polyvinylpyrrolidone/50mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42*C; or (3) overnight hybridization in a solution that employs 50% 57 WO 2004/060270 PCT/US2003/029126 formamide, 5 x SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5 x Denhardt's solution, sonicated salmon sperm DNA (50 pg/ml), 0.1% SDS, and 10% dextran sulfate at 42*C, with a 10 minute wash at 42*C in 0.2 x SSC (sodium chloride/sodium citrate) followed by a 10 minute high-stringency wash consisting of 0.1 x SSC containing EDTA at 55"C. "Moderately stringent conditions" may be identified as described by Sambrook et al., Molecular 5 Cloning: A Laboratory Manual New York: Cold Spring Harbor Press, 1989, and include the use of washing solution and hybridization conditions (e.g., temperature, ionic strength and %SDS) less stringent that those described above. An example of moderately stringent conditions is overnight incubation at 37*C in a solution comprising: 20% formamide, 5 x SSC (150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5 x Denhardt's solution, 10% dextran sulfate, and 20 mg/ml denatured sheared salmon sperm DNA, 10 followed by washing the filters in 1 x SSC at about 37-50*C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc. as necessary to accommodate factors such as probe length and the like. The term "epitope tagged" when used herein refers to a chimeric polypeptide comprising a TAT polypeptide or anti-TAT antibody fused to a "tag polypeptide". The tag polypeptide has enough residues to provide an epitope against which an antibody can be made, yet is short enough such that it does not interfere 15 with activity of the polypeptide to which it is fused. The tag polypeptide preferably also is fairly unique so that the antibody does not substantially cross-react with other epitopes. Suitable tag polypeptides generally have at least six amino acid residues and usually between about 8 and 50 amino acid residues (preferably, between about 10 and 20 amino acid residues). "Active" or "activity" for the purposes herein refers to form(s) of a TAT polypeptide which retain a 20 biological and/or an immunological activity of native or naturally-occurring TAT, wherein "biological" activity refers to a biological function (either inhibitory or stimulatory) caused by a native or naturally-occurring TAT other than the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring TAT and an "immunological" activity refers to the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring TAT. 25 The term "antagonist" is used in the broadest sense, and includes any molecule that partially or fully blocks, inhibits, or neutralizes a biological activity of a native TAT polypeptide disclosed herein. In a similar manner, the term "agonist" is used in the broadest sense and includes any molecule that mimics a biological activity of a native TAT polypeptide disclosed herein. Suitable agonist or antagonist molecules specifically 30 include agonist or antagonist antibodies or antibody fragments, fragments or amino acid sequence variants of native TAT polypeptides, peptides, antisense oligonucleotides, small organic molecules, etc. Methods for identifying agonists or antagonists of a TAT polypeptide may comprise contacting a TAT polypeptide with a candidate agonist or antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the TAT polypeptide. 35 "Treating" or "treatment" or "alleviation" refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder. Those in need of treatment include those already with the disorder as well as those prone to have 58 WO 2004/060270 PCT/US2003/029126 the disorder or those in whom the disorder is to be prevented. A subject or mammal is successfully "treated" for a TAT polypeptide-expressing cancer if, after receiving a therapeutic amount of an anti-TAT antibody, TAT binding oligopeptide or TAT binding organic molecule according to the methods of the present invention, the patient shows observable and/or measurable reduction in or absence of one or more of the following: reduction in the number of cancer cells or absence of the cancer cells; reduction in the tumor size; inhibition (i.e., slow 5 to some extent and preferably stop) of cancer cell infiltration into peripheral organs including the spread of cancer into soft tissue and bone; inhibition (i.e., slow to some extent and preferably stop) of tumor metastasis; inhibition, to some extent, of tumor growth; and/or relief to some extent, one or more of the symptoms associated with the specific cancer; reduced morbidity and mortality, and improvement in quality of life issues. To the extent the anti-TAT antibody or TAT binding oligopeptide may prevent growth and/or kill existing cancer 10 cells, it may be cytostatic and/or cytotoxic. Reduction of these signs or symptoms may also be felt by the patient. The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and/or determining the response rate (RR). 15 Metastasis can be determined by staging tests and by bone scan and tests for calcium level and other enzymes to determine spread to the bone. CT scans can also be done to look for spread to the pelvis and lymph nodes in the area. Chest X-rays and measurement of liver enzyme levels by known methods are used to look for metastasis to the lungs and liver, respectively. Other routine methods for monitoring the disease include transrectal ultrasonography (TRUS) and transrectal needle biopsy (TRNB). 20 For bladder cancer, which is a more localized cancer, methods to determine progress of disease include urinary cytologic evaluation by cystoscopy, monitoring for presence of blood in the urine, visualization of the urothelial tract by sonography or an intravenous pyelogram, computed tomography (CT) and magnetic resonance imaging (MRI). The presence of distant metastases can be assessed by CT of the abdomen, chest x-rays, or radionuclide imaging of the skeleton. 25 "Chronic" administration refers to administration of the agent(s) in a continuous mode as opposed to an acute mode, so as to maintain the initial therapeutic effect (activity) for an extended period of time. "Intermittent" administration is treatment that is not consecutively done without interruption, but rather is cyclic in nature. "Mammal" for purposes of the treatment of, alleviating the symptoms of or diagnosis of a cancer refers 30 to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc. Preferably, the mammal is human. Administration "in combination with" one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order. "Carriers" as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers which 35 are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including 59 WO 2004/060270 PCT/US2003/029126 ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt forming counterions such as sodium; and/or nonionic surfactants such as TWEEN*, polyethylene glycol (PEG), 5 and PLURONICS*. By "solid phase" or "solid support" is meant a non-aqueous matrix to which an antibody, TAT binding oligopeptide or TAT binding organic molecule of the present invention can adhere or attach. Examples of solid phases encompassed herein include those formed partially or entirely of glass (e.g., controlled pore glass), polysaccharides (e.g., agarose), polyacrylamides, polystyrene, polyvinyl alcohol and silicones. In certain 10 embodiments, depending on the context, the solid phase can comprise the well of an assay plate; in others it is a purification column (e.g., an affinity chromatography column). This term also includes a discontinuous solid phase of discrete particles, such as those described in U.S. Patent No. 4,275,149. A "liposome" is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as a TAT polypeptide, an antibody thereto or a TAT binding 15 oligopeptide) to a mammal. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes. A "small" molecule or "small" organic molecule is defined herein to have a molecular weight below about 500 Daltons. An "effective amount" of a polypeptide, antibody, TAT binding oligopeptide, TAT binding organic 20 molecule or an agonist or antagonist thereof as disclosed herein is an amount sufficient to carry out a specifically stated purpose. An "effective amount" may be determined empirically and in a routine manner, in relation to the stated purpose. The term "therapeutically effective amount" refers to an amount of an antibody, polypeptide, TAT 25 binding oligopeptide, TAT binding organic molecule or other drug effective to "treat" a disease or disorder in a subject or mammal. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated 30 with the cancer. See the definition herein of "treating". To the extent the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. A "growth inhibitory amount" of an anti-TAT antibody, TAT polypeptide, TAT binding oligopeptide or TAT binding organic molecule is an amount capable of inhibiting the growth of a cell, especially tumor, e.g., cancer cell, either in vitro or in vivo. A "growth inhibitory amount" of an anti-TAT antibody, TAT 35 polypeptide, TAT binding oligopeptide or TAT binding organic molecule for purposes of inhibiting neoplastic cell growth may be determined empirically and in a routine manner. 60 WO 2004/060270 PCT/US2003/029126 A "cytotoxic amount" of an anti-TAT antibody, TAT polypeptide, TAT binding oligopeptide or TAT binding organic molecule is an amount capable of causing the destruction of a cell, especially tumor, e.g., cancer cell, either in vitro or in vivo. A "cytotoxic amount" of an anti-TAT antibody, TAT polypeptide, TAT binding oligopeptide or TAT binding organic molecule for purposes of inhibiting neoplastic cell growth may be determined empirically and in a routine manner. 5 The term "antibody" is used in the broadest sense and specifically covers, for example, single anti-TAT monoclonal antibodies (including agonist, antagonist, and neutralizing antibodies), anti-TAT antibody compositions with polyepitopic specificity, polyclonal antibodies, single chain anti-TAT antibodies, and fragments of anti-TAT antibodies (see below) as long as they exhibit the desired biological or immunological activity. The term "immunoglobulin" (Ig) is used interchangeable with antibody herein. 10 An "isolated antibody" is one which has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In preferred embodiments, the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 15 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step. 20 The basic 4-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains (an IgM antibody consists of 5 of the basic heterotetramer unit along with an additional polypeptide called J chain, and therefore contain 10 antigen binding sites, while secreted IgA antibodies can polymerize to form polyvalent assemblages comprising 2-5 of the basic 4-chain units along with J chain). In the case of IgGs, the 4-chain unit is generally about 150,000 daltons. Each L chain is linked to 25 a H chain by one covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also has regularly spaced intrachain disulfide bridges. Each H chain has at the N-terminus, a variable domain (V H) followed by three constant domains (C.) for each of the a and y chains and four CH domains for i and e isotypes. Each L chain has at the N-terminus, a variable domain (VL) followed by a constant domain (C) at its other end. The V is aligned with 30 the V, and the C, is aligned with the first constant domain of the heavy chain (C Hl). Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains. The pairing of a V, and VL together forms a single antigen-binding site. For the structure and properties of the different classes of antibodies, see, e.g., Basic and Clinical Immunoloay, 8th edition, Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6. 35 The L chain from any vertebrate'species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains (CH), immunoglobulins can be assigned to different 61 WO 2004/060270 PCT/US2003/029126 classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, having heavy chains designated a, 6, E, y, and p, respectively. The y and a classes are further divided into subclasses on the basis of relatively minor differences in CH sequence and function, e.g., humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgAl, and IgA2. The term "variable " refers to the fact that certain segments of the variable domains differ extensively 5 in sequence among antibodies. The V domain mediates antigen binding and define specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed across the 110-amino acid span of the variable domains- Instead, the V regions consist of relatively invariant stretches called framework regions (FRs) of 15-30 amino acids separated by shorter regions of extreme variability called "hypervariable regions" that are each 9-12 amino acids long. The variable domains of native heavy and light chains each 10 comprise four FRs, largely adopting a P-sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases forming part of, the O-sheet structure. The hypervariable regions in each chain are held together in close proximity by the FRs and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Proteins of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. 15 (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody dependent cellular cytotoxicity (ADCC). The term "hypervariable region" when used herein refers to the amino acid residues of an antibody which are responsible for antigen-binding. The hypervariable region generally comprises amino acid residues from a "complementarity determining region" or "CDR" (e.g. around about residues 24-34 (Li), 50-56 (L2) 20 and 89-97 (L3) in the VL, and around about 1-35 (HI), 50-65 (H2) and 95-102 (H3) in the V H; Kabat et al., Sequences of Proteins of Immunological Interest 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)) and/or those residues from a "hypervariable loop" (e.g. residues 26-32 (LI), 50-52 (L2) and 91-96 (L3) in the VL, and 26-32 (HI), 53-55 (H2) and 96-101 (H3) in the VH; Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). 25 The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations which include different antibodies directed against different determinants (epitopes), each 30 monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they may be synthesized uncontaminated by other antibodies. The modifier "monoclonal" is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies useful in the present invention may be prepared by the hybridoma methodology first described by Kohler et al., Nature 256:495 (1975), or may be made using 35 recombinant DNA methods in bacterial, eukaryotic animal or plant cells (see, e.g., U.S. Patent No. 4,816,567). The "monoclonal antibodies" may also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature 352:624-628 (1991) and Marks et al., J. Mol. Biol. 222:581-597 (1991), for 62 WO 2004/060270 PCT/US2003/029126 example. The monoclonal antibodies herein include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to 5 another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (see U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA. 81:685 1 6855 (1984)). Chimeric antibodies of interest herein include "primatized" antibodies comprising variable domain antigen-binding sequences derived from a non-human primate (e.g. Old World Monkey, Ape etc), and human constant region sequences. 10 An "intact" antibody is one which comprises an antigen-binding site as well as a C, and at least heavy chain constant domains, CH, CH2 and CH3. The constant domains may be native sequence constant domains (e.g. human native sequence constant domains) or amino acid sequence variant thereof. Preferably, the intact antibody has one or more effector functions. "Antibody fragments" comprise a portion of an intact antibody, preferably the antigen binding or 15 variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab') 2, and Fv fragments; diabodies; linear antibodies (see U.S. Patent No. 5,641,870, Example 2; Zapata et al., Protein Eng. 8(10): 1057-1062 [1995]); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" 20 fragments, and a residual "Fc" fragment, a designation reflecting the ability to crystallize readily. The Fab fragment consists of an entire L chain along with the variable region domain of the H chain (Vn), and the first constant domain of one heavy chain (C,1). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab') fragment which roughly corresponds to two disulfide linked Fab fragments having divalent antigen-binding activity and 25 is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having additional few residues at the carboxy terminus of the CH1 domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known. 30 The Fc fragment comprises the carboxy-terminal portions of both H chains held together by disulfides. The effector functions of antibodies are determined by sequences in the Fc region, which region is also the part recognized by Fe receptors (FcR) found on certain types of cells. "Fv" is the minimum antibody fragment which contains a complete antigen-recognition and -binding site. This fragment consists of a dimer of one heavy- and one light-chain variable region domain in tight, non 35 covalent association. From the folding of these two domains emanate six hypervariable loops (3 loops each from the H and L chain) that contribute the amino acid residues for antigen binding and confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three 63 WO 2004/060270 PCT/US2003/029126 CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site. "Single-chain Fv" also abbreviated as "sFv" or "scFv" are antibody fragments that comprise the VH and VL antibody domains connected into a single polypeptide chain. Preferably, the sFv polypeptide farther comprises a polypeptide linker between the V H and VL domains which enables the sFv to form the desired 5 structure for antigen binding. For a review of sFv, see Plucktiun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994); Borrebaeck 1995, infra. The term "diabodies" refers to small antibody fragments prepared by constructing sFv fragments (see preceding paragraph) with short linkers (about 5-10 residues) between the VH and VL domains such that inter 10 chain but not intra-chain pairing of the V domains is achieved, resulting in a bivalent fragment, i.e., fragment having two antigen-binding sites. Bispecific diabodies are heterodimers of two "crossover" sFv fragments in which the VH and VL domains of the two antibodies are present on different polypeptide chains. Diabodies are described more fully in, for example, EP 404,097; WO 93/11161; and Hollinger et al., Proc. Nati. Acad. Sci. USA, 90:6444-6448 (1993). 15 "Humanized" forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. For the most part, humanized antibodies are human inununoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having the desired antibody specificity, affinity, and capability. In some instances, 20 framework region (FR) residues of the human inmmunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipientantibody or in the donor antibody. These modifications are made to further refine antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin 25 and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). A "species-dependent antibody," e.g., a mammalian anti-human IgE antibody, is an antibody which 30 has a stronger binding affinity for an antigen from a first mammalian species than it has for a homologue of that antigen from a second mammalian species. Normally, the species-dependent antibody "bind specifically" to a human antigen (i.e., has a binding affinity (Kd) value of no more than about 1 x 10- M, preferably no more than about 1 x 108 and most preferably no more than about 1 x 10 - M) but has a binding affinity for a homologue of the antigen from a second non-human mammalian species which is at least about 50 fold, or at 35 least about 500 fold, or at least about 1000 fold, weaker than its binding affinity for the human antigen. The species-dependent antibody can be of any of the various types of antibodies as defined above, but preferably is a humanized or human antibody. 64 WO 2004/060270 PCT/US2003/029126 A "TAT binding oligopeptide" is an oligopeptide that binds, preferably specifically, to a TAT polypeptide as described herein. TAT binding oligopeptides may be chemically synthesized using known oligopeptide synthesis methodology or may be prepared and purified using recombinant technology. TAT binding oligopeptides are usually at least about 5 amino acids in length, alternatively at least about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 5 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 amino acids in length or more, wherein such oligopeptides that are capable of binding, preferably specifically, to a TAT polypeptide as described herein. TAT binding oligopeptides may be identified without undue experimentation using well known techniques. In this regard, it is noted that techniques 10 for screening oligopeptide libraries for oligopeptides that are capable of specifically binding to a polypeptide target are well known in the art (see, e.g., U.S. Patent Nos. 5,556,762, 5,750,373, 4,708,871, 4,833,092, 5,223,409, 5,403,484, 5,571,689, 5,663,143; PCT Publication Nos. WO 84/03506 and W084/03564; Geysen et al., Proc. Nat. Acad. Sci. U.S.A., 81:3998-4002 (1984); Geysen et al., Proc. Natl. Acad. Sci. U.S.A., 82:178-182 (1985); Geysen et al., in Synthetic Peptides as Antigens, 130-149 (1986); Geysen et al., J. 15 Immunol. Meth., 102:259-274 (1987); Schoofs et al., J. Immunol., 140:611-616 (1988), Cwirla, S. E. et al. (1990) Proc. Nat. Acad. Sci. USA, 87:6378; Lowman, H.B. et al. (1991) Biochemistry, 30:10832; Clackson, T. et al. (1991) Nature, 352: 624; Marks, J. D. et al. (1991), J. Mol. Biol., 222:581; Kang, A.S. et al. (1991) Proc. Natl. Acad. Sci. USA, 88:8363, and Smith, G. P. (1991) Current Opin. Biotechnol., 2:668). A "TAT binding organic molecule" is an organic molecule other than an oligopeptide or antibody as 20 defined herein that binds, preferably specifically, to a TAT polypeptide as described herein. TAT binding organic molecules may be identified and chemically synthesized using known methodology (see, e.g., PCT Publication Nos. WOOO/00823 and WOOO/39585). TAT binding organic molecules are usually less than about 2000 daltons in size, alternatively less than about 1500, 750, 500, 250 or 200 daltons in size, wherein such organic molecules that are capable of binding, preferably specifically, to a TAT polypeptide as described herein 25 may be identified without undue experimentation using well known techniques. In this regard, it is noted that techniques for screening organic molecule libraries for molecules that are capable of binding to a polypeptide target are well known in the art (see, e.g., PCT Publication Nos. WOOO/00823 and W00/39585). An antibody, oligopeptide or other organic molecule "which binds" an antigen of interest, e.g. a tumor associated polypeptide antigen target, is one that binds the antigen with sufficient affinity such that the antibody, 30 oligopeptide or other organic molecule is useful as a diagnostic and/or therapeutic agent in targeting a cell or tissue expressing the antigen, and does not significantly cross-react with other proteins. In such embodiments, the extent of binding of the antibody, oligopeptide or other organic molecule to a "non-target" protein will be less than about 10% of the binding of the antibody, oligopeptide or other organic molecule to its particular target protein as determined by fluorescence activated cell sorting (FACS) analysis or radioimmunoprecipitation (RIA). 35 With regard to the binding of an antibody, oligopeptide or other organic molecule to a target molecule, the term "specific binding" or "specifically binds to" or is "specific for" a particular polypeptide or an epitope on a particular polypeptide target means binding that is measurably different from a non-specific interaction. Specific 65 WO 2004/060270 PCT/US2003/029126 binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by excess unlabeled target. The term "specific binding" or 5 "specifically binds to" or is "specific for" a particular polypeptide or an epitope on a particular polypeptide target as used herein can be exhibited, for example, by a molecule having a Kd for the target of at least about I0 M, alternatively at least about 10- M, alternatively at least about 10-6 M, alternatively at least about 10-7 M, alternatively at least about 10-8 M, alternatively at least about 10- M, alternatively at least about 10-' M, alternatively at least about 10~" M, alternatively at least about 102 M, or greater. In one embodiment, the term 10 "specific binding" refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope. An antibody, oligopeptide or other organic molecule that "inhibits the growth of tumor cells expressing a TAT polypeptide" or a "growth inhibitory" antibody, oligopeptide or other organic molecule is one which results in measurable growth inhibition of cancer cells expressing or overexpressing the appropriate TAT 15 polypeptide. The TAT polypeptide may be a transmembrane polypeptide expressed on the surface of a cancer cell or may be a polypeptide that is produced and secreted by a cancer cell. Preferred growth inhibitory anti TAT antibodies, oligopeptides or organic molecules inhibit growth of TAT-expressing tumor cells by greater than 20%, preferably from about 20% to about 50%, and even more preferably, by greater than 50% (e.g., from about 50% to about 100%) as compared to the appropriate control, the control typically being tumor cells 20 not treated with the antibody, oligopeptide or other organic molecule being tested. In one embodiment, growth inhibition can be measured at an antibody concentration of about 0.1 to 30 pg/ml or about 0.5 nM to 200 nM in cell culture, where the growth inhibition is determined 1-10 days after exposure of the tumor cells to the antibody. Growth inhibition of tumor cells in vivo can be determined in various ways such as is described in the Experimental Examples section below. The antibody is growth inhibitory in vivo if administration of the 25 anti-TAT antibody at about 1 pg/kg to about 100 mg/kg body weight results in reduction in tumor size or tumor cell proliferation within about 5 days to 3 months from the first administration of the antibody, preferably within about 5 to 30 days. An antibody, oligopeptide or other organic molecule which "induces apoptosis" is one which induces programmed cell death as determined by binding of annexin V, fragmentation of DNA, cell shrinkage, dilation 30 of endoplasmic reticulum, cell fragmentation, and/or formation of membrane vesicles (called apoptotic bodies). The cell is usually one which overexpresses a TAT polypeptide. Preferably the cell is a tumor cell, e.g., a prostate, breast, ovarian, stomach, endometrial, lung, kidney, colon, bladder cell. Various methods are available for evaluating the cellular events associated with apoptosis. For example, phosphatidyl serine (PS) translocation can be measured by annexin binding; DNA fragmentation can be evaluated through DNA 35 laddering; and nuclear/chromatin condensation along with DNA fragmentation can be evaluated by any increase in hypodiploid cells. Preferably, the antibody, oligopeptide or other organic molecule which induces apoptosis is one which results in about 2 to 50 fold, preferably about 5 to 50 fold, and most preferably about 10 to 50 fold, 66 WO 2004/060270 PCT/US2003/029126 induction of annexin binding relative to untreated cell in an annexin binding assay. Antibody "effector functions" refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of 5 cell surface receptors (e.g., B cell receptor); and B cell activation. "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity in which secreted Ig bound onto Fc receptors (FcRs) present on certain cytotoxic cells (e.g., Natural Killer (NK) cells, neutrophils, and macrophages) enable these cytotoxic effector cells to bind specifically to an antigen-bearing target cell and subsequently kill the target cell with cytotoxins. The antibodies "arm" the cytotoxic cells and 10 are absolutely required for such killing. The primary cells for mediating ADCC, NK cells, express Fe yRIII only, whereas monocytes express Fc yRI, FcyRII and FeyRIII. FeR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991). To assess ADCC activity of a molecule of interest, an in vitro ADCC assay, such as that described in US Patent No. 5,500,362 or 5,821,337 may be performed. Useful effector cells for such assays include peripheral blood 15 mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in a animal model such as that disclosed in Clynes et al. (USA) 95:652-656 (1998). "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. The preferred FcR is a native sequence human FcR. Moreover, a preferred FcR is one which binds an IgG antibody (a gamma 20 receptor) and includes receptors of the FcyRI, FcyRII and FeyRIll subclasses, including allelic variants and alternatively spliced forms of these receptors. FcyRII receptors include FcyRIIA (an "activating receptor") and FeyRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Activating receptor Fc yRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcyRIIB contains an immunoreceptor 25 tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain. (see review M. in Da~ron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FeRs, including those to be identified in the future, are encompassed by the term "FcR" herein. The term also includes the neonatal receptor, FeRn, which is responsible for the transfer of maternal IgGs to 30 the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Inmmunol. 24:249 (1994)). "Human effector cells" are leukocytes which express one or more FcRs and perform effector functions. Preferably, the cells express at least Fe yRIII and perform ADCC effector function. Examples of human leukocytes which mediate ADCC include peripheral blood mononuclear cells (PBMC), natural killer (NK) cells, monocytes, cytotoxic T cells and neutrophils; with PBMCs and NK cells being preferred. The effector cells may 35 be isolated from a native source, e.g., from blood. "Complement dependent cytotoxicity" or "CDC" refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component 67 WO 2004/060270 PCT/US2003/029126 of the complement system (Clq) to antibodies (of the appropriate subclass) which are bound to their cognate antigen. To assess complement activation, a CDC assay, e.g., as described in Gazzano-Santoro et al., 1 Irnmunol. Methods 202:163 (1996), may be performed. The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, 5 carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer 10 of the urinary tract, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, melanoma, multiple myeloma and B-cell lymphoma, brain, as well as head and neck cancer, and associated metastases. The terms "cell proliferative disorder" and "proliferative disorder" refer to disorders that are 15 associated with some degree of abnormal cell proliferation. In one embodiment, the cell proliferative disorder is cancer. "Tumor", as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. 20 An antibody, oligopeptide or other organic molecule which "induces cell death" is one which causes a viable cell to become nonviable. The cell is one which expresses a TAT polypeptide, preferably a cell that overexpresses a TAT polypeptide as compared to a normal cell of the same tissue type. The TAT polypeptide may be a transmembrane polypeptide expressed on the surface of a cancer cell or may be a polypeptide that is produced and secreted by a cancer cell. Preferably, the cell is a cancer cell, e.g., a breast, ovarian, stomach, 25 endometrial, salivary gland, lung, kidney, colon, thyroid, pancreatic or bladder cell. Cell death in vitro may be determined in the absence of complement and immune effector cells to distinguish cell death induced by antibody-dependent cell-mediated cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC). Thus, the assay for cell death may be performed using heat inactivated serum (i.e., in the absence of complement) and in the absence of immune effector cells. To determine whether the antibody, oligopeptide or other organic 30 molecule is able to induce cell death, loss of membrane integrity as evaluated by uptake of propidium iodide (PI), trypan blue (see Moore et al. Cytotechnology 17:1-11 (1995)) or 7AAD can be assessed relative to untreated cells. Preferred cell death-inducing antibodies, oligopeptides or other organic molecules are those which induce PI uptake in the PI uptake assay in BT474 cells. A "TAT-expressing cell" is a cell which expresses an endogenous or transfected TAT polypeptide 35 either on the cell surface or in a secreted form. A "TAT-expressing cancer" is a cancer comprising cells that have a TAT polypeptide present on the cell surface or that produce and secrete a TAT polypeptide. A "TAT expressing cancer" optionally produces sufficient levels of TAT polypeptide on the surface of cells thereof, such 68 WO 2004/060270 PCT/US2003/029126 that an anti-TAT antibody, oligopeptide ot other organic molecule can bind thereto and have a therapeutic effect with respect to the cancer. In another embodiment, a "TAT-expressing cancer" optionally produces and secretes sufficient levels of TAT polypeptide, such that an anti-TAT antibody, oligopeptide ot other organic molecule antagonist can bind thereto and have a therapeutic effect with respect to the cancer. With regard to the latter, the antagonist may be an antisense oligonucleotide which reduces, inhibits or prevents production and 5 secretion of the secreted TAT polypeptide by tumor cells. A cancer which "overexpresses" a TAT polypeptide is one which has significantly higher levels of TAT polypeptide at the cell surface thereof, or produces and secretes, compared to a noncancerous cell of the same tissue type. Such overexpression may be caused by gene amplification or by increased transcription or translation. TAT polypeptide overexpression may be determined in a diagnostic or prognostic assay by evaluating increased levels of the TAT protein present on the surface of 10 a cell, or secreted by the cell (e.g., via an immunohistochemistry assay using anti-TAT antibodies prepared against an isolated TAT polypeptide which may be prepared using recombinant DNA technology from an isolated nucleic acid encoding the TAT polypeptide; FACS analysis, etc.). Alternatively, or additionally, one may measure levels of TAT polypeptide-encoding nucleic acid or mRNA in the cell, e.g., via fluorescent in situ hybridization using a nucleic acid based probe corresponding to a TAT-encoding nucleic acid or the complement 15 thereof; (FISH; see W098/45479 published October, 1998), Southern blotting, Northern blotting, or polymerase chain reaction (PCR) techniques, such as real time quantitative PCR (RT-PCR). One may also study TAT polypeptide overexpression by measuring shed antigen in a biological fluid such as serum, e.g, using antibody based assays (see also, e.g., U.S. Patent No. 4,933,294 issued June 12, 1990; W091/05264 published April 18, 1991; U.S. Patent 5,401,638 issued March 28, 1995; and Sias et al., J. Immunol. Methods 132:73-80 20 (1990)). Aside from the above assays, various in vivo assays are available to the skilled practitioner. For example, one may expose cells within the body of the patient to an antibody which is optionally labeled with a detectable label, e.g., a radioactive isotope, and binding of the antibody to cells in the patient can be evaluated, e.g., by external scanning for radioactivity or by analyzing a biopsy taken from a patient previously exposed to the antibody. 25 As used herein, the term "immunoadhesin" designates antibody-like molecules which combine the binding specificity of a heterologous protein (an "adhesin") with the effector functions of immunoglobulin constant domains. Structurally, the immunoadhesins comprise a fusion of an amino acid sequence with the desired binding specificity which is other than the antigen recognition and binding site of an antibody (i.e., is "heterologous"), and an immunoglobulin constant domain sequence. The adhesin part of an immunoadhesin 30 molecule typically is a contiguous amino acid sequence comprising at least the binding site of a receptor or a ligand. The immunoglobulin constant domain sequence in the immunoadhesin may be obtained from any inimunoglobulin, such as IgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM. The word "label" when used herein refers to a detectable compound or composition which is conjugated 35 directly or indirectly to the antibody, oligopeptide or other organic molecule so as to generate a "labeled" antibody, oligopeptide or other organic molecule. The label may be detectable by itself (e.g. radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate 69 WO 2004/060270 PCT/US2003/029126 compound or composition which is detectable. The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents the function of cells and/or causes destruction of cells. The term is intended to include radioactive isotopes (e.g., X, 113, S12, Y9, Re 186, Re 18, Smiss, Bi , P and radioactive isotopes of Lu), chemotherapeutic agents e.g. methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, 5 mitomycin C, chlorambucil, daunorubicin or other intercalating agents, enzymes and fragments thereof such as nucleolytic enzymes, antibiotics, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof, and the various antitumor or anticancer agents disclosed below. Other cytotoxic agents are described below. A tumoricidal agent causes destruction of tumor cells. 10 A "growth inhibitory agent" when used herein refers to a compound or composition which inhibits growth of a cell, especially a TAT-expressing cancer cell, either in vitro or in vivo. Thus, the growth inhibitory agent may be one which significantly reduces the percentage of TAT-expressing cells in S phase. Examples of growth inhibitory agents include agents that block cell cycle progression (at a place other than S phase), such as agents that induce G1 arrest and M-phase arrest. Classical M-phase blockers include the vincas (vincristine 15 and vinblastine), taxanes, and topoisomerase II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Those agents that arrest GI also spill over into S-phase arrest, for example, DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5 fluorouracil, and ara-C. Further information can be found iifI'he Molecular Basis of Cancer Mendelsohn and Israel, eds., Chapter 1, entitled "Cell cycle regulation, oncogenes, and antineoplastic drugs" by Murakami et 20 al. (WB Saunders: Philadelphia, 1995), especially p. 13. The taxanes (paclitaxel and docetaxel) are anticancer drugs both derived from the yew tree. Docetaxel (TAXOTERE*, Rhone-Poulenc Rorer), derived from the European yew, is a semisynthetic analogue of paclitaxel (TAXOL*, Bristol-Myers Squibb). Paclitaxel and docetaxel promote the assembly of microtubules from tubulin diners and stabilize microtubules by preventing depolymerization, which results in the inhibition of mitosis in cells. 25 "Doxorubicin" is an anthracycline antibiotic. The full chemical name of doxorubicin is (8S-cis)-10-[(3 amino-2,3,6-trideoxya-L-lyxo-hexapyranosyl)oxy]-7,8,9, 10-tetrahydro-6,8, 1 1-trihydroxy-8-(hydroxyacetyl)-l methoxy-5,12-naphthacenedione. The term "cytokine" is a generic term for proteins released by one cell population which act on another cell as intercellular mediators. Examples of such cytokines are lymphokines, monokines, and traditional 30 polypeptide hormones. Included among the cytokines are growth hormone such as human growth hormone, N methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor-a and -p; mullerian-inhibiting substance; mouse 35 gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factors such as NGF-p; platelet-growth factor; transforming growth factors (TGFs) such as TGF-a and TGF-p; insulin-like growth factor-I and -II; erythropoietin (EPO); osteoinductive factors; 70 WO 2004/060270 PCT/US2003/029126 interferon such as interferon -a, -0, and -y; colony stimulating factors (CSFs) such as macrophage-CSF (M CSF); granulocyte-macrophage-CSF (GM-CSF); and granulocyte-CSF (G-CSF); interleukins (ILs) such as IL-I, IL- la, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-11, IL-12; a tumor necrosis factor such as TNF- a or TNF-B; and other polypeptide factors including LIF and kit ligand (KL). As used herein, the term cytokine includes proteins from natural sources or from recombinant cell culture and biologically active equivalents of 5 the native sequence cytokines. The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products. 71 WO 2004/060270 PCT/US2003/029126 Table 1 /* * C-C increased from 12 to 15 * Z is average of EQ 5 * B is average of ND * match with stop is _M; stop-stop = 0; J (joker) match = 0 *1 #define _M -8 /* value of a match with a stop */ 10 int _day[26][263 = { * A B C D E F G H I J K L M N O P Q R S T U V W X Y Z*/ /* A {2, 0,-2, 0, 0,-4, 1,-1,-1,0,-1,-2,-1, 0,_M, 1, 0,-2, 1, 1, 0, 0,-6, 0,-3, 0}, /*B */ (0, 3,-4, 3, 2,-5, 0, 1,-2, 0, 0,-3,-2, 2,_M,-1, 1, 0, 0, 0, 0,-2,-5, Q,-3, 1}, /* C */ {-2,-4,15,-5,-5,-4,-3,-3,-2, 0,-5,-6,-5,-4,_M,-3,-5,-4, 0,-2, 0,-2,-8, 0, 0,-5}, 15 /*D* {0, 3,-5, 4, 3,-6, 1, 1,-2, 0, 0,-4,-3, 2,_M,-1, 2,-1, 0, 0, 0,-2,-7, 0,-4, 2}, /* E */ { 0, 2,-5, 3, 4,-5, 0, 1,-2, 0, 0,-3,-2, 1,_M,-1, 2,-i, 0, 0, 0,-2,-7, 0,-4, 3}, /* F * -4,-5,-4,-6,-5, 9,-5,-2, 1, 0,-5, 2, 0,-4,_M,-5,-5,-4,-3,-3, 0,-1, 0, 0, 7,-5}, /* G */ {1, 0,-3, 1, 0,-5, 5,-2,-3, 0,-2,-4,-3, 0, M,-1,-1,-3, 1, 0, 0,-1,-7, 0,-5, 0), /* H * -1, 1,-3, 1, 1,-2,-2, 6,-2, 0, 02,-2, 2,_M, 0, 3, 2,-1,-1, 0,-2,-3, 0, 0, 2}, 20 /* I */ {-1,-2,-2,-2,-2, 1,-3,-2, 5, 0,-2, 2, 2,-2,_M,-2,-2,-2,-1, 0, 0, 4,-5, 0,-1,-2}, /* J*/ {, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0,0, 0, O,_M, 0, 0, 0,0, 0, 0, 0, 0, 0, 0, 0}, /* K* {-1, 0,-5, 0, 0,-5,-2, 0,-2, 0, 5,-3, 0, 1,_M,-i, 1, 3, 0, 0, 0,-2,-3, 0,-4, 0}, /* L */ {-2,-3,-6,-4,-3, 2,-4,-2, 2, 0,-3, 6, 4,-3,_M,-3,-2,-3,-3,-1, 0, 2,-2, 0,-1,-2}, /* M */ {-1,-2,-5,-3,-2, 0,-3,-2, 2, 0, 0, 4, 6,-2, M,-2,-1, 0,-2,-1, 0, 2,-4, 0,-2,-1}, 25 /* N */ {0, 2,-4, 2, 1,-4, 0, 2,-2, 0, 1,-3,-2, 2, M,-i, 1, 0, 1, 0, 0,-2,-4, 0,-2, 1}, /*0*1 MMMM,M,M,M,,M,M,M,M,M,M0M,MM,M,M,_M,_M, M, M,_M, 4, /* P */ { 1,-1,-3,-1,-1,-5,-1, 0,-2, 0,-1,-3,-2,-1, M, 6, 0, 0, 1, 0, 0,-1,-6, 0,-5, 0}, /*Q*/ { 0, 1,-5, 2, 2,-5,-1, 3,-2, 0, 1,-2,-1, 1,_M, 0, 4, 1,-1,-1,0,-2,-5, 0,-4, 3}, /* R* {-2, 0,-4,-1,-1,-4,-3, 2,-2, 0, 3,-3, 0, 0, M, 0, 1, 6, 0,-1, 0,-2, 2, 0,-4, 0}, 30 /* S */ {1, 0, 0, 0, 0,-3, 1,-1,-1, 0, 0,-3,-2, 1, M, 1,-i, 0, 2, 1, 0,-1,-2, 0,-3, 0}, /* T {1, 0,-2, 0, 0,-3, 0,-1,0 ,-1,-1, 0,M, 0,-1,-1, 1, 3, 0, 0,-5, 0,-3, 0), /* U */ { 00,0, 0, 0 0, 0, 0, 0 ,,M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0}, /* V */ { 0,-2,-2,-2,-2,-1,-1,-2, 4, 0,-2, 2, 2,-2,_M,-1,-2,-2,-1, 0, 0, 4,-6, 0,-2,-2}, /* W */ {-6,-5,-8,-7,-7, 0,-7,-3,-5, 0,-3,-2,-4,-4,_M,-6,-5, 2,-2,-5, 0,-6,17, 0, 0,-6}, 35 /* */ { 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 0, 0, 0,_M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0}, /* Y *1 {-3,-3, 0,-4,-4, 7,-5, 0,-1, 0,-4,-i,-2,-2_M,-5,-4,-4,-3,-3, 0,-2, 0, 0,10,-4}, /* Z */ {0, 1,-5, 2, 3,-5, 0, 2,-2, 0, 0,-2,-1, 1,_M, 0, 3, 0, 0, 0, 0,-2,-6, 0,-4, 4) }; 40 45 50 72 WO 2004/060270 PCT/US2003/029126 Table 1 (cont') /* */ #include <stdio.h> #include <ctype.h> 5 #define MAXJMP 16 I* max jumps in a diag #define MAXGAP 24 1* don't continue to penalize gaps larger than this #define JMPS 1024 / max jmps in an path *I #define MX 4 /* save if there at least MX-l bases since last jmp 10 #defme DMAT 3 1* value of matching bases *1 #derme DMIS 0 /* penalty for mismatched bases #define DINSO 8 I0 penalty for a gap #defme DINSI /* penalty per base 15 #define PINSO 8 1* penalty for a gap 2ee PINS1 4 /* penalty per residue gt strict imp { short n[MAXJMP]; vi size of mp (neg for dely) s t 20 unsigned short x[MAXJMP]; * base no. of jmp in seq x 1; /* limits seq to 2b16e */ struct diag { int score; /* score at last jmp */ 25 long offset; /* offset of prev block *j short ijmp; /* current jmp index */ struct jmp jp; /* list of jmps */ 30 struct path { int spc; /* number of leading spaces short n[JMPS]; I* size of jmp (gap) */ int x[JMPS]; I* bc of imp (last elem before gap) *1 35 char *ofile; /* output file name char *namex[21; /* seq names: getseqs I char *prog; !* prog name for err msgs char *seqx[2]; /* seqs: getseqsO 40 int dmax; /* best diag: nw0 int dmaxO; /* final diag * int dna; /* set if dna: maino int endgaps; /* set if penalizing end gaps int gapx, gapy; I* total gaps in seqs 45 int lenOleni; I* seq lens */ int ngapx, ngapy; /* total size of gaps int smax; max score: nw0 int *xbm; /* bitmap for matching long offset; I* current offset in jmp file 50 struct diag *dx; I* holds diagonals */ struck path pp[2]; /o f holds path for seqs / char *calloc , malloc, indexx, *strcpyf; char *getseq , *g/calloc*; 73 WO 2004/060270 PCT/US2003/029126 Table 1 (c nf' /* Needleman-Wunsch alignment program * * usage: progs file file2 * where file and file2 are two dna or two protein sequences. 5 * The sequences can be in upper- or lower-case an may contain ambiguity * Any lines beginning with ';', '>' or '<' are ignored * Max file length is 65535 (limited by unsigned short x in the jmp struct) * A sequence with 1/3 or more of its elements ACGTU is assumed to be DNA * Output is in the file "align.out" 10 * * The program may create a tmp file in /tmp to hold info about traceback. Original version developed under BSD 4.3 on a vax 8650 */ #include "nw.h" 15 #include "day.h" static _dbval[26] = { 1,14,2,13,0,0,4,11,0,0,12,0,3,15,0,0,0,5,6,8,8,7,9,0,10,0 20 static _pbval[26] { 1, 21(1< <('D'-'A'))I(1< <('N'-'A')), 4, 8, 16, 32, 64, 128, 256, OxFFFFFFF, 1< <10, 1< <11, 1< <12, 1< <13, 1< <14, 1 < < 15, 1 < < 16, 1 < <17, 1 < < 18, 1 < < 19, 1 < < 20, 1 < < 21, 1 < < 22, 25 1<<23, 1<<24, 1<<25|(1<<('E'-'A'))(1 <<('Q'-'A')) }; main(ac, av) main int ac; 30 char *avU; { prog = av[0]; if (ac != 3) { fprintf(stderr, "usage: %s file file2\n", prog); 35 fprintf(stderr, "where file and file2 are two dna or two protein sequences.\n"); fprintf(stderr, "The sequences can be in upper- or lower-case\n"); fprintf(stderr, "Any lines beginning with ';' or '<' are ignored\n"); fprintf(stderr, "Output is in the file \"align.out\"\n"); exit(1); 40 } namex[0] = av[1]; namex[1] = av[2]; seqx[0] = getseq(namex[0], &lenO); seqx[l] = getseq(namex[1], &lenl); 45 xbm = (dna)? _dbval : pbval; endgaps = 0; /* I to penalize endgaps */ ofile = "align.out"; /* output file */ 50 nw(; /* fill in the matrix, get the possible jmps */ readjmps(; /* get the actual jmps */ print; /* print stats, alignment */ cleanup(0); /* unlink any tmp files */} 74 WO 2004/060270 PCT/US2003/029126 Table 1 (cont') /* do the alignment, return best score: main() * dna: values in Fitch and Smith, PNAS, 80, 1382-1386, 1983 * pro: PAM 250 values * When scores are equal, we prefer mismatches to any gap, prefer 5 * a new gap to extending an ongoing gap, and prefer a gap in seqx * to a gap in seq y. *1 nw() 1W { 10 char *px, *py; /* seqs and ptrs */ int *ndely, *dely; /* keep track of delay */ int ndelx, delx; /* keep track of deix */ int *tnp; /* for swapping rowO, rowl */ int mis; /* score for each type */ 15 int insf, ins1; I* insertion penalties */ register id;: /* diagonal index */ register ij; /* jmp index */ register *colo, *coll; /* score for curr, last row */ register xx, yy; /* index into seqs */ 20 dx = (struct diag *)g_ calloc("to get diags", lenO+len1 +1, sizeof(struct diag)); ndely = (int *)g_calloc("to get ndely", len1 + 1, sizeof(int)); dely = (int *)g_calloc("to get dely", len1+ 1, sizeof(int)); colO = (int *)gcalloc("to get colO", len1 + 1, sizeof(int)); 25 colI = (int *)g_calloc("to get col', len1+1, sizeof(int)); insO = (dna)? DINSO : PINSO; ins1 = (dna)? DINS1 PINSI; smax = -10000; if (endgaps) { 30 for (colO[0] = dely[0] = -insO, yy = 1; yy <= lent; yy++) { col0[yy] = dely[yy] = colO[yy-1] - ins1; ndely[yy] = yy; } coIO[0] = 0; /* Waterman Bull Math Biol 84 */ 35 } else for (yy = 1; yy <= len1; yy++) dely[yy] = -insO; /* fill in match matrix 40 */ for (px = seqx[0], xx = 1; xx <= lenO; px++, xx++) { /* initialize first entry in col *1 if (endgaps) { 45 if (xx = = 1) col1[0] = deix = -(insO+ins1); else coll[0] = delx = colO[0] - ins1; ndelx = xx; 50 } else { col1[0] = 0; delx = -insO; ndelx = 0; 55 } 75 WO 2004/060270 PCT/US2003/029126 Table 1 (cont') ... nw for (py =seqx[1], yy = 1; yy <= lenl; py++, yy+ +){ mis = colO[yy-1]; if (dna) 5 mis + = (xbm[*px-'A']&xbm[*py-'A'])? DMAT DMIS; else mis += _day[*px-'A'][*py-'A']; /* update penalty for del in x seq; 10 * favor new del over ongong del * ignore MAXGAP if weighting endgaps */ if (endgaps II ndely[yy] < MAXGAP) { if (colO[yy] - insO > = dely[yy]) { 15 dely[yy] = col0[yy] - (insO+insl); ndely[yy] = 1; } else { dely[yy] -= ins1; ndely[yy]+ +; 20 } } else { if (colO[yy] - (insO+insl) > = dely[yy]) { dely[yy] = colO[yy] - (insO+insl); ndely[yy] = 1; 25 } else ndely[yy] + +; } /* update penalty for del in y seq; 30 * favor new del over ongong del */ if (endgaps | ndelx < MAXGAP) { if (coll[yy-1] - insO > = deix) { deix = coll[yy-1] - (insO+insl); 35 ndelx = 1; } else { delx -= ins1; ndelx+ +; } 40 } else{ if (coll[yy-1] - (insO+insl) > = delx) { delx = coll[yy-l] - (insO+insl); ndelx = 1; }else 45 ndelx+ +; } /* pick the maximum score; we're favoring *.mis over any del and delx over dely 50 */ ... nW id = xx - yy + lenI - 1; if (mis > = delx && mis > = dely[yy]) 55 coll[yy] = mis; 76 WO 2004/060270 PCT/US2003/029126 Table 1 (cont') else if (dex > = dely[yy]) coll[yy] = delx; ij = dx[id].ijmp; if (dx[idl.jp.n[O] && (!dna I (ndelx > = MAXJMP 5 && xx > dx[id].jp.x[ij]+MX) mis > dx[id].score+DINSO)) { dx[id].ijmp++; if (++ij >= MAXJMP){ writejmps(id); ij = dx[id].ijmp 0; 10 dx[id].offset = offset; .offset + = sizeof(struct jmp) + sizeof(offset); } } dx[id].jp.n[ij] = ndelx; 15 dx[id].jp.x[ij] = xx; dx[id].score = delx; } else { coll[yy] = dely[yy]; 20ij = dx[idl.ijmp; if (dx[id].jp.n[0] && (!dna I| (ndely[yy] > = MAXJMP && xx > dx[id].jp.x[ij]+MX) mis > dx[id].score+DINSO)) { dx[id].ijmp++; if (++ij >= MAXJMP){ 25 writejmps(id); ij = dx[id].ijmp = 0; dx[idl.offset = offset; offset += sizeof(struct jmp) + sizeof(offset); } 30} dx[id].jp.n[ij] = -ndely[yy]; dx[id].jp.x[ij] = xx; dx[id].score = dely[yy]; } 35 if (xx lenO && yy < len1){ /* last col */ if (endgaps) coll[yy] -= insO+insl*(enl-yy); 40 if (coIl[yy] > smax) { smax = col1[yy]; dmax = id; } } 45 } if (endgaps && xx < lenO) col1[yy-1] -= ins0+ins1*(1en0-xx); if (col1[yy-1] > smax) { smax = coll[yy-1]; 50 dmax = id; } tmp = colo; colo - coll; coll = tmp; } (void) free((char *)ndely); (void) free((char *)dely); 55 (void) free((char *)colo); (void) free((char *)coll); } 77 WO 2004/060270 PCT/US2003/029126 Table 1 (cont') /* * * print() -- only routine visible outside this module * 5 * static: * getmat() -- trace back best path, count matches: print() * pr align() -- print alignment of described in array p[]: print * dumpblock() - dump a block of lines with numbers, stars: pralign() * nums() -- put out a number line: dumpblock() 10 * putline0 -- put out a line (name, [numi], seq, [num]): dumpblock0 * stars - -put a line of stars: dumpblock( * stripname() -- strip any path and prefix from a seqname */ 15 #include "nw.h" #define SPC 3 #define P LINE 256 1* maximum output line #define P SPC 3 1* space between name or num and seq 20 extern _day[26][26]; it olen; /* set output line length */ FILE *fx; /* output file */ 25 print print { int lx, ly, firstgap, lastgap; /* overlap *1 if ((fx = fopen(ofile, "w")) = = 0) { 30 fprintf(stderr," % s: can't write %s\n", prog, ofile); cleanup(l); } fprintf(fx, "<first sequence: %s (length =%d)\n", namex[0], tenO); fprintf(fx, "<second sequence: %s (length = %d)\n", namex[l1], len1); 35 olen = 60; Ix = lena; ly = len1; firstgap = lastgap = 0; if (dmax < len1 - 1) { /* leading gap in x */ 40 pp[l).spc = firstgap = lent - dmax - 1; ly -= pp[0].spc; } else if (dmax > len1 - 1) { /* leading gap in y */ pp[l].spc = firstgap = dmax - (len1 - 1); 45 1x -= pp[I.spc; } if (dmax0 < lenO - 1) { /* trailing gap in x lastgap = lenO - dmax0 -1; x -= lastgap; 50 } else if (dmax0 > lenO - 1) { /* trailing gap in y */ lastgap = dmax0 - (len0 - 1); ly -= lastgap; } 55 getmat(lx, ly, firstgap, lastgap); praligno; } 78 WO 2004/060270 PCT/US2003/029126 Table 1 (cont') /* * trace back the best path, count matches */ static 5 getmat(Ix, ly, firstgap, lastgap) getmat int 1x, ly; /* "core" (minus endgaps) */ int firstgap, lastgap; /* leading trailing overlap */ { int nn, 10, i1, sizO, sizI; 10 char outx[32]; double pct; register nO, n1; register char *p0, *pl; /* get total matches, score 15 */ 0= i1 = sizO = sizi = 0; p0 seqx[0] + pp[l].spc; pl = seqx[1] + pp[O].spc; nO = pp[ll.spc + 1; 20 n1 = pp[0].spc + 1; nm = 0; while( *pO && *pl ) { if (sizO) { p1 ++; 25 n1++; sizO--; } else if (siz1) { p0++; 30 nO++; sizl--; } else{ if (xbm[*p0-'A']&xbm[*pl-'A']) 35 nm+-+; if (nrO+ + == pp[0].x[i0]) sizO = pp[0].n[iO++]; if (n1++ == pp[l].x[il]) sizi = pp[l].n[i1++]; 40 p0++; p1 ++; } } 45 /* pct homology: * if penalizing endgaps, base is the shorter seq * else, knock off overhangs and take shorter core */ if (endgaps) 50 lx = (1enO < leni)? lenO : len1; else lx = (lx < ly)? lx : ly; pet = 100.*(double)nm/(double)lx; fprintf(fx, "\n"); 55 fprintf(fx, "< %d match%s in an overlap of %d: %.2f percent similarity\n", in, (nm == 1)? e" "es", lx, pct); 79 WO 2004/060270 PCT/US2003/029126 Table 1 (cont') fprintf(fx, "<gaps in first sequence: %d", gapx); ... getmat if (gapx) { (void) sprintf(outx, " (%d %s %s)", ngapx, (dna)? "base":"residue", (ngapx == 1)? "":"s"); 5 fprintf(fx,"%s", outx); fprintf(fx, ", gaps in second sequence: %d", gapy); if (gapy) { (void) sprintf(outx, " (%d %s %s)", ngapy, (dna)? "base":"residue", (ngapy ==1)? "":"s"); 10 fprintf(fx,"%s", outx); } if (dna) fprintf(fx, "\n<score: %d (match = %d, mismatch = %d, gap penalty = %d + %d per base)\n", 15 smax, DMAT, DMIS, DINSO, DINS1); else fprintf(fx, "\n< score: %d (Dayhoff PAM 250 matrix, gap penalty = %d + %d per residue)\n", smax, PINSO, PINSi); 20 if(endgaps) tbrintffx, " <endgaps penalized, left endgap: lid lisls, right eudgap: %d lisls\n", firstgap, (dna)? "base" :"residue", (fzrstgap == 1)? "": "IS", lastgap, (dna)? "base" :"residue", (lastgap = = 0)? "" : 1 25 else fbrintffr, "<endgaps not penalized\n"); } static rim /* matches in core -- for checking static lmax; /* lengths of stripped file names 30 static ij[2]; I* jmp index for a path */ static nc[2]; /* number at start of current line static ni[2]; I* current elem number -- for gaping static siz[2]; static char *ps[2]; I* ptr to current element 35 static char *po[2]; 1* ptr to next output char slot *1 static char out[2][P _LINE]; I* output line */ static char star[PLINE]; /* set by stars *print alignment of described in struct path pp[] 40 * static pf fnalignda pralign it nm ; /* char count - e 45 iut more; register 1; for (i= 0,lImax=0;i< 2; i+±){ nn = stripna le(namex[ia; 50 if (nn > imax) i max n; nc[i] /s r ni[i] m1; siz[i] iji] = 0; 55 ps[i] / rseqx[i]; Po[][_ outLi]; / 80 WO 2004/060270 PCT/US2003/029126 Table 1 (cont') for (na = mm = 0, more = 1; more; ) { ... pralign for (i more = 0; i < 2; i++) { /* 5 * do we have more of this sequence? */ if (!*ps[i]) continue; more+ +; 10 if (pp[i].spc){ /* leading space */ *po[i]++= pp[i].spc--; } else if (siz[i]) { I* in a gap */ 15 *po[i]++ = siz[i]--; I else { /* we're putting a seq element *1 20 *po[i] = *ps[i]; if (islower(*ps[i])) *ps[i] = toupper(*ps[i]); po[i] + +; 25 /* * are we at next gap for this seq? */ if (ni[i] pp[i.x[ijfi]]) { /* 30 * we need to merge all gaps * at this location */ siz[iJ = pp[i].n[ij[i]+ +1; while (ni[i] = = pp[i].x[ij[i]l) 35 siz[i] += pp[i].n[ij[i+ +]; } ni[i] ++; } } 40 if (++nn ==olen I more && nn){ dumpblocko; for (i = 0; i < 2; i++) po[i] = out[i]; nn = 0; 451 /* * dump a block of lines, including numbers, stars: pralign() 50 */ static dumpblock() dumpblock { register i; 55 for (i = 0; i < 2; i++) *po[i]-- = '\0'; 81 WO 2004/060270 PCT/US2003/029126 Table 1 (cont') ... dumpblock (void) putc('\n', fx); for (i = 0; i < 2; i++) { if (*out[i] && (*out[i] != ' I *(po[i]) != ' ')) { 5 if (i ==0) nums(i); if (i == 0 && *out[1]) stars; putline(i); 10 if (i == 0 && *out[1]) fprintf(fx, star); if (i == 1) nums(i); } 15 } } /* * put out a number line: dumpblock() */ 20 static nums(ix) nums int ix; /* index in out[] holding seq line */ { char nline[PLINE]; 25 register i, j; register char *pn, *px, *py; for (pn = nine, i = 0; i < lmax+PSPC; i++, pn++) *pn = ' for (i = nc[ix], py = out[ix]; *py; py++, pn++){ 30 if(*py == ' I I *py == '') *pn= ''; else { if (i%10 == 0 (i == 1 && ne[ix] 1= 1)) { j = (i < 0)? -i: i; 35 for (px = pn; j; j /= 10, px--) *px = j%10 + '0'; if (i < 0) *px = } 40 else *pn = i++; } } 45 *pn ='\0 nc[ix] = i; for (pn = nline; *pn; pn+ +) (void) putc(*pn, fx); (void) putc('\n', fx); 50 } /* * put out a line (name, [num], seq, [num]): dumpblockO */ static 55 putline(ix) putline int ix; { 82 WO 2004/060270 PCT/US2003/029126 Table 1 (cont') ...putline register char *px; 5 for (px = namex[ix], i = 0; *px && *px! :; px++, i++) (void) putc(*px, fx); for (; i < Imax+P_SPC; i++) 10 (void) putc(' ', fx); /* these count from 1: * ni[] is current element (from 1) * nc[I is number at start of current line */ 15 for (px = out[ix]; *px; px++) (void) putc(*px&Ox7F, fx); (void) putc('\n', fx); } 20 /* * put a line of stars (seqs always in out[0], out[1]): dumpblocko */ static 25 stars stars { int i; register char *p0, *p1, ex, *px; 30 if (!*out[0] I (*out[0] ' ' && *(pol0]) = ' ) !*out[l] I} (*outllj == && *(po[l]) == ' return; px = star; for (i = Imax+PSPC; i; i-) 35 *px++ for (pO = out[0], pl out(l]; *p0 && *pl; pO++, p1++) { if (isalpha(*p0) && isalpha(*p1)) { 40 if (xbm[*p0-'A']&xbm[*pl-'A']){ cx = '*'; nm++; } else if (!dna && _day[*p0-'A'][*pl-'A'] > 0) 45 cx-= else cx = else 50 ex *px++ = ex; *px+ + = '\n'; *px = 'O'; 55 } 83 WO 2004/060270 PCT/US2003/029126 Table 1 (cont') /* * strip path or prefix from pn, return len: pr align() */ static 5 stripname(pn) stripname char *pn; /* file name (may be path) */ { register char *px, *py; 10 py=0; for (px = pn; *px; px+ +) if (*px == '') py = px + 1; if (py) 15 (void) strcpy(pn, py); return(strlen(pn)); } 20 84 WO 2004/060270 PCT/US2003/029126 Table 1 (cont') /* * cleanup() - cleanup any tmp file * getseq( -- read in seq, set dna, len, maxlen * gcalloc() - calloco with error checkin 5 * readjmps() - get the good jmps, from tmp file if necessary * writejmps() -- write a filled array of jmps to a tmp file: nwo */ #include "nw.h" #include <sys/file.h> 10 char *jname = "/tmp/homgXXXXXX"; /* tmp file for jmps */ FILE *fj; int cleanup; /* cleanup tmp file */ long Iseeko; 15 * remove any tmp file if we blow */ cleanup(i) cleanup int i; 20 { if(fj) (void) unlink(jname); exit(i); } 25 /* * read, return ptr to seq, set dna, len, maxlen * skip lines starting with ';', ' <', or '>' * seq in upper or lower case */ 30 char * getseq(file, len) getseq char *file; /* file name */ int *len; /* seq len */ { 35 char line[1024], *pseq; register char *px, *py; int natgc, tlen; FILE *fp; if ((fp = fopen(file, "r")) == 0) { 40 fprintf(stderr,"%s: can't read %s\n", prog, file); exit(1); } ten = natgc = 0; while (fgets(line, 1024, fp)) { 45 if (*line == ';' II *fine '<' *ine continue; for (px = line; *px '\n'; px++) if (isupper(*px) I islower(*px)) tlen+ +; 50 } if ((pseq = malloc((unsigned)(tlen+ 6))) == 0) { fprintf(stderr," %s: malloc() failed to get %d bytes for %s\n", prog, tlen+6, file); exit(1); 55 pseq[0] = pseq[1] = pseq[2] = pseq[3] = '\0'; 85 WO 2004/060270 PCT/US2003/029126 Table 1 (cont') ... getseq py = pseq + 4; *len = tien; rewind(fp); 5 while (fgets(line, 1024, fp)) { if (*line == ';' I * = '<' *line = continue; for (px = line; *px ! '\n; px++) { if (isupper(*px)) 10 *py++ = *px; else if (islower(*px)) *py++ = toupper(*px); if (index("ATGCU",*(py-1))) natgc+ +; 15 } } *py++ = '\0'; *py = '\0'; (void) fclose(fp); 20 dna = natgc > (tlen/3); return(pseq+4); } char * g_calloc(msg, nx, sz) gSalloc 25 char *msg; /* program, calling routine */ int nx, sz; /* number and size of elements */ char *px, *calloco; if ((px = calloc((unsigned)nx, (unsigned)sz)) 0) { 30 if (*msg){ fprintf(stderr, "%s: g_calloc() failed %s (n=%d, sz=%d)\n", prog, msg, nx, sz); exit(1); } } 35 return(px); } /* * get final jmps from dx[] or tmp file, set pp[], reset dmax: main() 40 */ readjmps() readjmps { int fd = -1; int siz, io, il; 45 register i, j, xx; if (fj) { (void) fclose(fj); if ((fd = open(jname, 0_RDONLY, 0)) < 0) { fprintf(stderr, "%s: can't open() %s\n", prog, namee; 50 cleanup(l); } for (i = iO = i1 = 0, dmaxO = dmax, xx = lenO; ; i++) { while (1) { 55 for (i = dx[dmax].ijmp; j > = 0 && dx[dmax].jp.x[j] >= xx; j--) 86 WO 2004/060270 PCT/US2003/029126 Table 1 (cont') ... readjmps if (j < 0 && dx[dmax].offset && fj) { (void) 1seek(fd, dx[dmax].offset, 0); (void) read(fd, (char *)&dx[dmax].jp, sizeof(struct jmp)); 5 (void) read(fd, (char *)&dx[dmax].offset, sizeof(dx[dmax].offset)); dx[dmax].ijmp = MAXJMP-1; } else break; } if (i > JMPS) { 10 fprintf(stderr, %s: too many gaps in alignment\n", prog); cleanup(1); } if (j >= 0) { siz = dx[dmax].jp.nj]; 15 xx = dx[dmax].jp.xfj]; dmax += siz; if (siz < 0) { /* gap in second seq */ pp[1].n[il] = -siz; xx + = siz; 20 /* id = xx - yy + len11 */ pp[1].x[il] = xx - dmax + len1 - 1; gapy++; ngapy -= siz; /* ignore MAXGAP when doing endgaps */ 25 siz = (-siz < MAXGAP II endgaps)? -siz: MAXGAP; 11+ +; } else if (siz > 0) { /* gap in first seq */ pp[I.n[iO] = siz; 30 pp[O].x[iO] = xx; gapx++; ngapx + = siz; /* ignore MAXGAP when doing endgaps */ siz = (siz < MAXGAP I endgaps)? siz: MAXGAP; 35 iO++; } } else break; 40 } /* reverse the order of jmps */ for (j = 0, iO--; j < iO; j++, iO--) { i = pp[O].n[j]; pp[0].n[j] = pp[0].n[iO]; pp[O].n[iO] = i; i = pp[0].x[j]; pp[0].xjl = pp[0].x[i0]; pp[0I.x[iO] = i; 45 } for (j = 0, i--; j < i1; j++, i1--) { i = pp[1].nj]; pp[1].nj] = pp[1].n[il]; pp[1].n[il] = i; i = pp[1].x[j]; pp[1].xj] = pp[1].x[il]; pp[l].x[il] = i; 50 if (fd >= 0) (void) close(fd); if (fj) { (void) unlinc(jname); fj = 0; 55 offset = 0; } } 87 WO 2004/060270 PCT/US2003/029126 Table 1 (cont') /* * write a filled jmp strict offset of the prev one (if any): nwo */ 5 writejmps(ix) writejmps int ix; { char *mktemp(; 10 if (!fj){ if (mktemp(jname) < 0) { fprintf(stderr, "%s: can't mktemp() %s\n", prog, jname); cleanup(1); } 15 if ((fj fopen(iname, "w")) 0) { fprintf(stderr, "%s: can't write %sn", prog, jname); exit(1); } } 20 (void) fwrite((char *)&dx[ix].jp, sizeof(struct jmp), 1, fj); (void) fwrite((char *)&dx[ix].offset, sizeof(dx[ix].offset), 1, fj); } 88 WO 2004/060270 PCT/US2003/029126 Table 2 TAT XXXXXXXXXXXXXXX (Length = 15 amino acids) Comparison Protein XXXXXYYYYYYY (Length = 12 amino acids) 5 % amino acid sequence identity = (the number of identically matching amino acid residues between the two polypeptide sequences as determined by ALIGN-2) divided by (the total number of amino acid residues of the TAT polypeptide) = 10 5 divided by 15 = 33.3% Table 3 TAT XXXXXXXXXX (Length = 10 amino acids) 15 Comparison Protein XXXXXYYYYYYZZYZ (Length = 15 amino acids) % amino acid sequence identity = (the number of identically matching amino acid residues between the two polypeptide sequences as determined 20 by ALIGN-2) divided by (the total number of amino acid residues of the TAT polypeptide) = 5 divided by 10 = 50% Table 4 25 TAT-DNA NNNNNNNNNNNNNN (Length = 14 nucleotides) Comparison DNA NNNNNNLLLLLLLLLL (Length = 16 nucleotides) % nucleic acid sequence identity = 30 (the number of identically matching nucleotides between the two nucleic acid sequences as determined by ALIGN-2) divided by (the total number of nucleotides of the TAT-DNA nucleic acid sequence) = 6 divided by 14 = 42.9% 89 WO 2004/060270 PCT/US2003/029126 Table 5 TAT-DNA NNNNNNNNNNNN (Length = 12 nucleotides) Comparison DNA NNNNLLLVV (Length = 9 nucleotides) 5 % nucleic acid sequence identity = (the number of identically matching nucleotides between the two nucleic acid sequences as determined by ALIGN-2) divided by (the total number of nucleotides of the TAT-DNA nucleic acid sequence) = 10 4 divided by 12 = 33.3% II. Compositions and Methods of the Invention A. Anti-TAT Antibodies In one embodiment, the present invention provides anti-TAT antibodies which may find use herein as 15 therapeutic and/or diagnostic agents. Exemplary antibodies include polyclonal, monoclonal, humanized, bispecific, and heteroconjugate antibodies. 1. Polyclonal Antibodies Polyclonal antibodies are preferably raised in animals by multiple subcutaneous (sc) or intraperitoneal (ip) injections of the relevant antigen and an adjuvant. It may be useful to conjugate the relevant antigen 20 (especially when synthetic peptides are used) to a protein that is immunogenic in the species to be immunized. For example, the antigen can be conjugated to keyhole limpet hemocyanin (KLH), serum albumin, bovine thyroglobulin, or soybean trypsin inhibitor, using a bifunctional or derivatizing agent, e.g., maleimidobenzoyl sulfosuccinimide ester (conjugation through cysteine residues), N-hydroxysuccinimide (through lysine residues), glutaraldehyde, succinic anhydride, SOCl 2 , or R'N=C=NR, where R and Ri are different alkyl groups. 25 Animals are immunized against the antigen, immunogenic conjugates, or derivatives by combining, e.g., 100 pg or 5 pg of the protein or conjugate (for rabbits or mice, respectively) with 3 volumes of Freund's complete adjuvant and injecting the solution intradermally at multiple sites. One month later, the animals are boosted with 1/5 to 1/10 the original amount of peptide or conjugate in Freund's complete adjuvant by subcutaneous injection at multiple sites. Seven to 14 days later, the animals are bled and the serum is assayed 30 for antibody titer. Animals are boosted until the titer plateaus. Conjugates also can be made in recombinant cell culture as protein fusions. Also, aggregating agents such as alum are suitably used to enhance the immune response. 2. Monoclonal Antibodies Monoclonal antibodies may be made using the hybridoma method first described by Kohler et al., 35 Nature, 256:495 (1975), or may be made by recombinant DNA methods (U.S. Patent No. 4,816,567). In the hybridoma method, a mouse or other appropriate host animal, such as a hamster, is immunized 90 WO 2004/060270 PCT/US2003/029126 as described above to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the protein used for immunization. Alternatively, lymphocytes may be immunized in vitro. After immunization, lymphocytes are isolated and then fused with a myeloma cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, pp.59-103 (Academic Press, 1986)). 5 The hybridoma cells thus prepared are seeded and grown in a suitable culture medium which medium preferably contains one or more substances that inhibit the growth or survival of the unfused, parental myeloma cells (also referred to as fusion partner). For example, if the parental myeloma cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the selective culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (HAT medium), which substances 10 prevent the growth of HGPRT-deficient cells. Preferred fusion partner myeloma cells are those that fuse efficiently, support stable high-level production of antibody by the selected antibody-producing cells, and are sensitive to a selective medium that selects against the unfused parental cells. Preferred myeloma cell lines are murine myeloma lines, such as those derived from MOPC-21 and MPC-1 1 mouse tumors available from the Salk Institute Cell Distribution Center, 15 San Diego, California USA, and SP-2 and derivatives e.g., X63-Ag8-653 cells available from the American Type Culture Collection, Manassas, Virginia,, USA. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies (Kozbor, J. Immunol., 133:3001 (1984); and Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987)). 20 Culture medium in which hybridoma cells are growing is assayed for production of monoclonal antibodies directed against the antigen. Preferably, the binding specificity of monoclonal antibodies produced by hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard 25 analysis described in Munson et al., Anal. Biochem., 107:220 (1980). Once hybridoma cells that produce antibodies of the desired specificity, affinity, and/or activity are identified, the clones may be subcloned by limiting dilution procedures and grown by standard methods (Goding, Monoclonal Antibodies: Principles and Practice, pp.59-103 (Academic Press, 1986)). Suitable culture media for this purpose include, for example, D-MEM or RPMI-1640 medium. In addition, the hybridoma cells may 30 be grown in vivo as ascites tumors in an animal e.g,, by i.p. injection of the cells into mice. The monoclonal antibodies secreted by the subclones are suitably separated from the culture medium, ascites fluid, or serum by conventional antibody purification procedures such as, for example, affinity chromatography (e.g., using protein A or protein G-Sepharose) or ion-exchange chromatography, hydroxylapatite chromatography, gel electrophoresis, dialysis, etc. 35 DNA encoding the monoclonal antibodies is readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells serve as a preferred source of such DNA. 91 WO 2004/060270 PCT/US2003/029126 Once isolated, the DNA may be placed into expression vectors, which are then transfected into host cells such as E. coli cells, simian COS cells, Chinese Hamster Ovary (CHO) cells, or myeloma cells that do not otherwise produce antibody protein, to obtain the synthesis of monoclonal antibodies inthe recombinant host cells. Review articles on recombinant expression in bacteria of DNA encoding the antibody include Skerra et al., Curr. Opinion in Immunol. 5:256-262 (1993) and Pickthun, Immunol. Revs. 130:151-188 (1992). 5 In a further embodiment, monoclonal antibodies or antibody fragments can be isolated from antibody phage libraries generated using the techniques described in McCafferty et al., Nature, 348:552-554 (1990). Clackson et al., Nature 352:624-628 (1991) and Marks et al., J. Mol. Biol. 222:581-597 (1991) describe the isolation of marine and human antibodies, respectively, using phage libraries. Subsequent publications describe the production of high affinity (nM range) human antibodies by chain shuffling (Marks et al., Bio/Technology, 10 10:779-783 (1992)), as well as combinatorial infection and in vivo recombination as a strategy for constructing very large phage libraries (Waterhouse et al., Nuc. Acids. Res. 21:2265-2266 (1993)). Thus, these techniques are viable alternatives to traditional monoclonal antibody hybridoma techniques for isolation of monoclonal antibodies. The DNA that encodes the antibody may be modified to produce chimeric or fusion antibody 15 polypeptides, for example, by substituting human heavy chain and light chain constant domain (C H and C 1 ) sequences for the homologous marine sequences (U.S. Patent No. 4,816,567; and Morrison, et al., Proc. Natl Acad. Sci. USA, 81:6851 (1984)), or by fusing the immunoglobulin coding sequence with all or part of the coding sequence for a non-immunoglobulin polypeptide (heterologous polypeptide). The non-immunoglobulin polypeptide sequences can substitute for the constant domains of an antibody, or they are substituted for the 20 variable domains of one antigen-combining site of an antibody to create a chimeric bivalent antibody comprising one antigen-combining site having specificity for an antigen and another antigen-combining site having specificity for a different antigen. 3. Human and Humanized Antibodies The anti-TAT antibodies of the invention may further comprise humanized antibodies or human 25 antibodies. Humanized forms of non-human (e.g., marine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab') 2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human 30 species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR 35 regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human iminunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin [Jones 92 WO 2004/060270 PCT/US2003/029126 et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992)]. Methods for humanizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non human amino acid residues are often referred to as "import" residues, which are typically taken from an 5 "import" variable domain. Humanization can be essentially performed following the method of Winter and co workers [Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Verhoeyen et al., Science 239.:1534-1536 (1988)], by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such "humanized" antibodies are chimeric antibodies (U.S. Patent No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the 10 corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies. The choice of human variable domains, both light and heavy, to be used in making the humanized antibodies is very important to reduce antigenicity and HAMA response (human anti-mouse antibody) when the 15 antibody is intended for human therapeutic use. According to the so-called "best-fit" method, the sequence of the variable domain of a rodent antibody is screened against the entire library of known human variable domain sequences. The human V domain sequence which is closest to that of the rodent is identified and the human framework region (FR) within it accepted for the humanized antibody (Sims et al., J. Immunol. 151:2296 (1993); Chothia et al., J. Mol. Biol.. 196:901 (1987)). Another method uses a particular framework region 20 derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains. The same framework may be used for several different humanized antibodies (Carter et al., Proc. Natl. Acad. Sci. USA 89:4285 (1992); Presta et al., J. Immunol. 151:2623 (1993)). It is further important that antibodies be humanized with retention of high binding affinity for the antigen and other favorable biological properties. To achieve this goal, according to a preferred method, 25 humanized antibodies are prepared by a process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the 30 likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen. In this way, FR residues can be selected and combined from the recipient and import sequences so that the desired antibody characteristic, such as increased affinity for the target antigen(s), is achieved. In general, the hypervariable region residues are directly and most substantially involved in influencing antigen binding. 35 Various forms of a humanized anti-TAT antibody are contemplated. For example, the humanized antibody may be an antibody fragment, such as a Fab, which is optionally conjugated with one or more cytotoxic 93 WO 2004/060270 PCT/US2003/029126 agent(s) in order to generate an immunoconjugate. Alternatively, the humanized antibody may be an intact antibody, such as an intact IgG1 antibody. As an alternative to humanization, human antibodies can be generated. For example, it is now possible to produce transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production. For example, it has been 5 described that the homozygous deletion of the antibody heavy-chain joining region (JH) gene in chimeric and germ-line mutant mice results in complete inhibition of endogenous antibody production. Transfer of the human germ-line immunoglobulin gene array into such germ-line mutant mice will result in the production of human antibodies upon antigen challenge. See, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. USA, 90:2551 (1993); Jakobovits et al., Nature 362:255-258 (1993); Bruggemann et al., Year in Immuno. 7:33 (1993); U.S. Patent 10 Nos. 5,545,806, 5,569,825, 5,591,669 (all of GenPharm); 5,545,807; and WO 97/17852. Alternatively, phage display technology (McCafferty et al., Nature 348:552-553 [1990]) can be used to produce human antibodies and antibody fragments in vitro, from immunoglobulin variable (V) domain gene repertoires from unimmunized donors. According to this technique, antibody V domain genes are cloned in frame into either a major or minor coat protein gene of a filamentous bacteriophage, such as M13 or fd, and 15 displayed as functional antibody fragments on the surface of the phage particle. Because the filamentous particle contains a single-stranded DNA copy of the phage genome, selections based on the functional properties of the antibody also result in selection of the gene encoding the antibody exhibiting those properties. Thus, the phage mimics some of the properties of the B-cell. Phage display can be performed in a variety of formats, reviewed in, e.g., Johnson, Kevin S. and Chiswell, David J., Current Opinion in Structural Biology 3:564-571 (1993). 20 Several sources of V-gene segments can be used for phage display. Clackson et al.,Nature 352:624-628 (1991) isolated a diverse array of anti-oxazolone antibodies from a small random combinatorial library of V genes derived from the spleens of immunized mice. A repertoire of V genes from unimmunized human donors can be constructed and antibodies to a diverse array of antigens (including self-antigens) can be isolated essentially following the techniques described by Marks et al., J. Mol. Biol. 222:581-597 (1991), or Griffith et al., EMBO 25 J. 12:725-734 (1993). See, also, U.S. Patent Nos. 5,565,332 and 5,573,905. As discussed above, human antibodies may also be generated by in vitro activated B cells (see U.S. Patents 5,567,610 and 5,229,275). 4. Antibody fragments In certain circumstances there are advantages of using antibody fragments, rather than whole 30 antibodies. The smaller size of the fragments allows for rapid clearance, and may lead to improved access to solid tumors. Various techniques have been developed for the production of antibody fragments. Traditionally, these fragments were derived via proteolytic digestion of intact antibodies (see, e.g., Morimoto et al., Journal of Biochemical and Biophysical Methods 24:107-117 (1992); and Brennan et al., Science 229:81 (1985)). 35 However, these fragments can now be produced directly by recombinant host cells. Fab, Fv and ScFv antibody fragments can all be expressed in and secreted from E. coli, thus allowing the facile production of large amounts of these fragments. Antibody fragments can be isolated from the antibody phage libraries discussed above. 94 WO 2004/060270 PCT/US2003/029126 Alternatively, Fab'-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab')2 fragments (Carter et al., Bio/Technology 10:163-167 (1992)). According to another approach, F(ab') 2 fragments can be isolated directly from recombinant host cell culture. Fab and F(ab'j fragment with increased in vivo half-life comprising a salvage receptor binding epitope residues are described in U.S. Patent No. 5,869,046. Other techniques for the production of antibody fragments will be apparent to the skilled 5 practitioner. In other embodiments, the antibody of choice is a single chain Fv fragment (scFv). See WO 93/16185; U.S. Patent No. 5,571,894; and U.S. Patent No. 5,587,458. Fv and sFv are the only species with intact combining sites that are devoid of constant regions; thus, they are suitable for reduced nonspecific binding during in vivo use. sFv fusion proteins may be constructed to yield fusion of an effector protein at either the amino or the carboxy terminus of an sFv. See Antibody Engineering ed. Borrebaeck, supra. The antibody 10 fragment may also be a "linear antibody", e.g., as described in U.S. Patent 5,641,870 for example. Such linear antibody fragments may be monospecific or bispecific. 5. Bispecific Antibodies Bispecific antibodies are antibodies that have binding specificities for at least two different epitopes. Exemplary bispecific antibodies may bind to two different epitopes of a TAT protein as described herein. Other 15 such antibodies may combine a TAT binding site with a binding site for another protein. Alternatively, an anti TAT arm may be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD3), or Fc receptors for IgG (FcyR), such as FcyRI (CD64), Fc yRII (CD32) and FcyRlII (CD 16), so as to focus and localize cellular defense mechanisms to the TAT-expressing cell. Bispecific antibodies may also be used to localize cytotoxic agents to cells which express TAT. These antibodies possess 20 a TAT-binding arm and an arm which binds the cytotoxic agent (e.g., saporin, anti-interferon-a, vinca alkaloid, ricin A chain, methotrexate or radioactive isotope hapten). Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g., F(ab') 2 bispecific antibodies). WO 96/16673 describes a bispecific anti-ErbB2/anti-FcyRIII antibody and U.S. Patent No. 5,837,234 discloses a bispecific anti-ErbB2/anti-FcyRI antibody. A bispecific anti-ErbB2/Fc a antibody is shown in 25 W098/02463. U.S. Patent No. 5,821,337 teaches a bispecific anti-ErbB2/anti-CD3 antibody. Methods for making bispecific antibodies are known in the art. Traditional production of full length bispecific antibodies is based on the co-expression of two immunoglobulin heavy chain-light chain pairs, where the two chains have different specificities (Millstein et al., Nature 305:537-539 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential 30 mixture of 10 different antibody molecules, of which only one has the correct bispecific structure. Purification of the correct molecule, which is usually done by affinity chromatography steps, is rather cumbersome, and the product yields are low. Similar procedures are disclosed in WO 93/08829, and in Traunecker et al., EMBO J. 10:3655-3659 (1991). According to a different approach, antibody variable domains with the desired binding specificities 35 (antibody-antigen combining sites) are fused to immunoglobulin constant domain sequences. Preferably, the fusion is with an Ig heavy chain constant domain, comprising at least part of the hinge, CH2, and CH 3 regions. It is preferred to have the first heavy-chain constant region (CH1) containing the site necessary for light chain 95 WO 2004/060270 PCT/US2003/029126 bonding, present in at least one of the fusions. DNAs encoding the immunoglobulin heavy chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host cell. This provides for greater flexibility in adjusting the mutual proportions of the three polypeptide fragments in embodiments when unequal ratios of the three polypeptide chains used in the construction provide the optimum yield of the desired bispecific antibody. It is, however, possible to insert the 5 coding sequences for two or all three polypeptide chains into a single expression vector when the expression of at least two polypeptide chains in equal ratios results in high yields or when the ratios have no significant affect on the yield of the desired chain combination. In a preferred embodiment of this approach, the bispecific antibodies are composed of a hybrid immunoglobulin heavy chain with a first binding specificity in one arm, and a hybrid immunoglobulin heavy 10 chain-light chain pair (providing a second binding specificity) in the other arm. It was found that this asymmetric structure facilitates the separation of the desired bispecific compound from unwanted immunoglobulin chain combinations, as the presence of an immunoglobulin light chain in only one half of the bispecific molecule provides for a facile way of separation. This approach is disclosed in WO 94/04690. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology 15 121:210 (1986). According to another approach described in U.S. Patent No. 5,731,168, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH 3 domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with 20 larger side chains (e.g., tyrosine or tryptophan). Compensatory "cavities" of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g., alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers. Bispecific antibodies include cross-linked or "heteroconjugate" antibodies. For example, one of the 25 antibodies in the heteroconjugate can be coupled to avidin, the other to biotin. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Patent No. 4,676,980), and for treatment of HIV infection (WO 91/00360,,WO 92/200373, and EP 03089). Heteroconjugate antibodies may be made using any convenient cross-linking methods. Suitable cross-linking agents are well known in the art, and are disclosed in U.S. Patent No. 4,676,980, along with a number of cross-linking techniques. 30 Techniques for generating bispecific antibodies from antibody fragments have also been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab') 2 fragments. These fragments are reduced in the presence of the dithiol complexing agent, sodium arsenite, to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab' fragments 35 generated are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab'-TNB derivatives is then reconverted to the Fab'-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab'-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used 96 WO 2004/060270 PCT/US2003/029126 as agents for the selective immobilization of enzymes. Recent progress has facilitated the direct recovery of Fab'-SH fragments from E. coli, which can be chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175: 217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab') 2 molecule. Each Fab' fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The 5 bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets. Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al.,J. Immunol. 148(5):1547-1553 (1992). The leucine zipper peptides from the Fos and 10 Jun proteins were linked to the Fab' portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers. The "diabody" technology described by Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments. The fragments comprise a VH connected to 15 a VL by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary V L and VH domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) diners has also been reported. See Gruber et al., J. Immunol., 152:5368 (1994). 20 Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991). 6. ' Heteroconiugate Antibodies Heteroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed 25 to target immune system cells to unwanted cells [U.S. Patent No. 4,676,980], and for treatment of HIV infection [WO 91/00360; WO 92/200373; EP 03089]. It is contemplated that the antibodies may be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins may be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and 30 those disclosed, for example, in U.S. Patent No. 4,676,980. 7. Multivalent Antibodies A multivalent antibody may be internalized (and/or catabolized) faster than a bivalent antibody by a 35 cell expressing an antigen to which the antibodies bind. The antibodies of the present invention can be multivalent antibodies (which are other than of the IgM class) with three or more antigen binding sites (e.g. tetravalent antibodies), which can be readily produced by recombinant expression of nucleic acid encoding the 97 WO 2004/060270 PCT/US2003/029126 polypeptide chains of the antibody. The multivalent antibody can comprise a dimerization domain and three or more antigen binding sites. The preferred dimerization domain comprises (or consists of) an Fe region or a hinge region. In this scenario, the antibody will comprise an Fc region and three or more antigen binding sites amino-terminal to the Fc region. The preferred multivalent antibody herein comprises (or consists of) three to about eight, but preferably four, antigen binding sites. The multivalent antibody comprises at least one 5 polypeptide chain (and preferably two polypeptide chains), wherein the polypeptide chain(s) comprise two or more variable domains. For instance, the polypeptide chain(s) may comprise VD1-(Xl) ,-VD2-(X2)n-Fc, wherein-VD1 is a first variable domain, VD2 is a second variable domain, Fc is one polypeptide chain of an Fe region, X1 and X2 represent an amino acid or polypeptide, and n is 0 or 1. For instance, the polypeptide chain(s) may comprise: VH-CH1-flexible linker-VH-CHl-Fc region chain; or VH-CH1-VH-CH1-Fe region 10 chain. The multivalent antibody herein preferably further comprises at least two (and preferably four) light chain variable domain polypeptides. The multivalent antibody herein may, for instance, comprise from about two to about eight light chain variable domain polypeptides. The light chain variable domain polypeptides contemplated here comprise a light chain variable domain and, optionally, further comprise a CL domain. 8. Effector Function Engineering 15 It may be desirable to modify the antibody of the invention with respect to effector function, e.g., so as to enhance antigen-dependent cell-mediated cyotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC) of the antibody. This may be achieved by introducing one or more amino acid substitutions in an Fc region of the antibody. Alternatively or additionally, cysteine residue(s) may be introduced in the Fe region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated 20 may have improved internalization capability and/or increased complement-mediated cell killing and antibody dependent cellular cytotoxicity (ADCC). See Caron et al.,J. Exp Med. 176:1191-1195 (1992) and Shopes, B. J. Immunol. 148:2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity may also be prepared using heterobifunctional cross-linkers as described in Wolff et al., Cancer Research 53:2560-2565 (1993). Alternatively, an antibody can be engineered which has dual Fe regions and may thereby have enhanced 25 complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Drug Design 3:219-230 (1989). To increase the serum half life of the antibody, one may incorporate a salvage receptor binding epitope into the antibody (especially an antibody fragment) as described in U.S. Patent 5,739,277, for example. As used herein, the term "salvage receptor binding epitope" refers to an epitope of the Fc region of an IgG molecule (e.g., IgG 1 , IgG 2 , IgG 3 , or IgG 4 ) that is responsible for increasing the in vivo serum half-life of the IgG 30 molecule. 9. Immunoconjugates The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, a growth inhibitory agent, a toxin (e.g., an enzymatically active toxin 35 of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope ( i.e., a radioconjugate). 98 WO 2004/060270 PCT/US2003/029126 Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleuritesfordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria 5 officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include 1 2 Bi, "3I, 13In, 90 Y, and 1 86 Re. Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl 10 suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediainine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238: 1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an 15 exemplary chelating agent for conjugation of radionucleotide to the antibody. See W094/11026. Conjugates of an antibody and one or more small molecule toxins, such as a calicheamicin, maytansinoids, a trichothene, and CC1065, and the derivatives of these toxins that have toxin activity, are also contemplated herein. Maytansine and maytansinoids 20 In one preferred embodiment, an anti-TAT antibody (full length or fragments) of the invention is conjugated to one or more maytansinoid molecules. Maytansinoids are mitototic inhibitors which act by inhibiting tubulin polymerization. Maytansine was first isolated from the east African shrub Maytenus serrata (U.S. Patent No. 3,896,111). Subsequently, it was discovered that certain microbes also produce maytansinoids, such as maytansinol and C-3 maytansinol esters 25 (U.S. Patent No. 4,151,042). Synthetic maytansinol and derivatives and analogues thereof are disclosed, for example, in U.S. Patent Nos. 4,137,230; 4,248,870; 4,256,746; 4,260,608; 4,265,814; 4,294,757; 4,307,016; 4,308,268; 4,308,269; 4,309,428; 4,313,946; 4,315,929; 4,317,821; 4,322,348; 4,331,598; 4,361,650; 4,364,866; 4,424,219; 4,450,254; 4,362,663; and 4,371,533, the disclosures of which are hereby expressly incorporated by reference. 30 Mavtansinoid-antibody coniugates In an attempt to improve their therapeutic index, maytansine and maytansinoids have been conjugated to antibodies specifically binding to tumor cell antigens. Immunoconjugates containing maytansinoids and their therapeutic use are disclosed, for example, in U.S. Patent Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1, the disclosures of which are hereby expressly incorporated by reference. Liu et al., Proc. Natl. 35 Acad. Sci. USA 93:8618-8623 (1996) described immunoconjugates comprising a maytansinoid designated DM1 linked to the monoclonal antibody C242 directed against human colorectal cancer. The conjugate was found to be highly cytotoxic towards cultured colon cancer cells, and showed antitumor activity in an in vivo tumor 99 WO 2004/060270 PCT/US2003/029126 growth assay. Chari et al., Cancer Research 52:127-131 (1992) describe immunoconjugates in which a maytansinoid was conjugated via a disulfide linker to the murine antibody A7 binding to an antigen on human colon cancer cell lines, or to another murine monoclonal antibody TA. 1 that binds the HER-2/neu oncogene. The cytotoxicity of the TA. 1-maytansonoid conjugate was tested in vitro on the human breast cancer cell line SK-BR-3, which expresses 3 x 10W HER-2 surface antigens per cell. The drug conjugate achieved a degree of 5 cytotoxicity similar to the free maytansonid drug, which could be increased by increasing the number of maytansinoid molecules per antibody molecule. The A7-maytansinoid conjugate showed low systemic cytotoxicity in mice. Anti-TAT polypeptide antibody-maytansinoid coniugates (imunoconjugates) Anti-TAT antibody-maytansinoid conjugates are prepared by chemically linking an anti-TAT antibody 10 to a maytansinoid molecule without significantly diminishing the biological activity of either the antibody or the maytansinoid molecule. An average of 3-4 maytansinoid molecules conjugated per antibody molecule has shown efficacy in enhancing cytotoxicity of target cells without negatively affecting the function or solubility of the antibody, although even one molecule of toxin/antibody would be expected to enhance cytotoxicity over the use of naked antibody. Maytansinoids are well known in the art and can be synthesized by known techniques 15 or isolated from natural sources. Suitable maytansinoids are disclosed, for example, in U.S. Patent No. 5,208,020 and in the other patents and nonpatent publications referred to hereinabove. Preferred maytansinoids are maytansinol and maytansinol analogues modified in the aromatic ring or at other positions of the maytansinol molecule, such as various maytansinol esters. There are many linking groups known in the art for making antibody-maytansinoid conjugates, 20 including, for example, those disclosed in U.S. Patent No. 5,208,020 or EP Patent 0 425 235 B1, and Chari et al., Cancer Research 52:127-131 (1992). The linking groups include disufide groups, thioether groups, acid labile groups, photolabile groups, peptidase labile groups, or esterase labile groups, as disclosed in the above identified patents, disulfide and thioether groups being preferred. Conjugates of the antibody and maytansinoid may be made using a variety of bifunctional protein 25 coupling agents such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N maleimidomethyl) cyclohexane-1-carboxylate, iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis 30 active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). Particularly preferred coupling agents include N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP) (Carlsson et alfiochem. J. 173:723-737 [1978]) and N-succinimidyl-4-(2-pyridylthio)pentanoate (SPP) to provide for a disulfide linkage. The linker may be attached to the maytansinoid molecule at various positions, depending on the type of the link. For example, an ester linkage may be formed by reaction with a hydroxyl group using conventional 35 coupling techniques. The reaction may occur at the C-3 position having a hydroxyl group, the C-14 position modified with hyrdoxymethyl, the C-15 position modified with a hydroxyl group, and the C-20 position having a hydroxyl group. In a preferred embodiment, the linkage is formed at the C-3 position of maytansinol or a 100 WO 2004/060270 PCT/US2003/029126 maytansinol analogue. Calicheamicin Another immunoconjugate of interest comprises an anti-TAT antibody conjugated to one or more calicheamicin molecules. The calicheamicin family of antibiotics are capable of producing double-stranded DNA breaks at sub-picomolar concentrations. For the preparation of conjugates of the calicheamicin family, 5 see U.S. patents 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, 5,877,296 (all to American Cyanamid Company). Structural analogues of calicheamicin which may be used include, but are not limited to, y , a 2 , as3, N-acetyl-y I, PSAG and 011 (Hinman et al., Cancer Research 53:3336-3342 (1993), Lode et al., Cancer Research 58:2925-2928 (1998) and the aforementioned U.S. patents to American Cyanamid). Another anti-tumor drug that the antibody can be conjugated is QFA which is an antifolate. Both 10 calicheamicin and QFA have intracellular sites of action and do not readily cross the plasma membrane. Therefore, cellular uptake of these agents through antibody mediated internalization greatly enhances their cytotoxic effects. Other cytotoxic agents Other antitumor agents that can be conjugated to the anti-TAT antibodies of the invention include 15 BCNU, streptozoicin, vincristine and 5-fluorouracil, the family of agents known collectively LL-E33288 complex described in U.S. patents 5,053,394, 5,770,710, as well as esperamicins (U.S. patent 5,877,296). Enzymatically active toxins and fragments thereof which can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleuritesfordii proteins, dianthin proteins, Phytolaca 20 americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin and the tricothecenes. See, for example, WO 93/21232 published October 28, 1993. The present invention further contemplates an immunoconjugate formed between an antibody and a compound with nucleolytic activity (e.g., a ribonuclease or a DNA endonuclease such as a deoxyribonuclease; 25 DNase). For selective destruction of the tumor, the antibody may comprise a highly radioactive atom. A variety of radioactive isotopes are available for the production of radioconjugated anti-TAT antibodies. Examples include At 2 , 111, 1125, Y90, Re1 86 , Re 188 , Sm 1 53 , Be 12 p32, Pb 212 and radioactive isotopes of Lu. When the conjugate is used for diagnosis, it may comprise a radioactive atom for scintigraphic studies, for example tc 9 " 30 or I123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri), such as iodine-123 again, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen 17, gadolinium, manganese or iron. The radio- or other labels may be incorporated in the conjugate in known ways. For example, the 35 peptide may be biosynthesized or may be synthesized by chemical amino acid synthesis using suitable amino acid precursors involving, for example, fluorine-19 in place of hydrogen. Labels such as tcm or 123, .Re186 101 WO 2004/060270 PCT/US2003/029126 Re1 88 and In 11 can be attached via a cysteine residue in the peptide. Yttrium- 9 0 can be attached via a lysine residue. The IODOGEN method (Fraker et al (1978) Biochem. Biophys. Res. Commun. 80: 49-57 can be used to incorporate iodine-123. "Monoclonal Antibodies inImmunoscintigraphy" (Chatal,CRC Press 1989) describes other methods in detail. Conjugates of the antibody and cytotoxic agent may be made using a variety of bifunctional protein 5 coupling agents such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N maleimidomethyl) cyclohexane-1-carboxylate, iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis 10 active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl 3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See W094/11026. The linker may be a "cleavable linker" facilitating release of the cytotoxic drug in the cell. For example, an acid-labile linker, peptidase-sensitive linker, photolabile 15 linker, dimethyl linker or disulfide-containing linker (Chari et al., Cancer Research 52:127-131 (1992); U.S. Patent No. 5,208,020) may be used. Alternatively, a fusion protein comprising the anti-TAT antibody and cytotoxic agent may be made, e.g., by recombinant techniques or peptide synthesis. The length of DNA may comprise respective regions encoding the two portions of the conjugate either adjacent one another or separated by a region encoding a linker 20 peptide which does not destroy the desired properties of the conjugate. In yet another embodiment, the antibody may be conjugated to a "receptor" (such streptavidin) for utilization in tumor pre-targeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a "ligand" (e.g., avidin) which is conjugated to a cytotoxic agent (e.g., a radionucleotide). 25 10. Immunoliposomes The anti-TAT antibodies disclosed herein may also be formulated as immunoliposomes. A "liposome" is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug to a mammal. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes. Liposomes containing the antibody are 30 prepared by methods known in the art, such as described in Epstein et al., Proc. Natl. Acad. Sci. USA 82:3688 (1985); Hwang et al.,Proc. Natl Acad. Sci. USA 77:4030 (1980); U.S. Pat. Nos. 4,485,045 and 4,544,545; and W097/38731 published October 23, 1997. Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556. 35 Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG 102 WO 2004/060270 PCT/US2003/029126 PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. Fab' fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al., J. Biol. Chem. 257:286-288 (1982) via a disulfide interchange reaction. A chemotherapeutic agent is optionally contained within the liposome. See Gabizon et al., J. National Cancer Inst. 81(19):1484 (1989). 5 B. TAT Binding Oligopeptides TAT binding oligopeptides of the present invention are oligopeptides that bind, preferably specifically, to a TAT polypeptide as described herein. TAT binding oligopeptides may be chemically synthesized using known oligopeptide synthesis methodology or may be prepared and purified using recombinant technology. TAT binding oligopeptides are usually at least about 5 amino acids in length, alternatively at least about 6, 7, 10 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 amino acids in length or more, wherein such oligopeptides that are capable of binding, preferably specifically, to a TAT polypeptide as described herein. TAT binding oligopeptides may 15 be identified without undue experimentation using well known techniques. In this regard, it is noted that techniques for screening oligopeptide libraries for oligopeptides that are capable of specifically binding to a polypeptide target are well known in the art (see, e.g., U.S. Patent Nos. 5,556,762, 5,750,373, 4,708,871, 4,833,092, 5,223,409, 5,403,484, 5,571,689, 5,663,143; PCT Publication Nos. WO 84/03506 and W084/03564; Geysen et al., Proc. Natl. Acad. Sci. U.S.A., 81:3998-4002 (1984); Geysen et al., Proc. Natl. 20 Acad. Sci. U.S.A., 82:178-182 (1985); Geysen et al., in Synthetic Peptides as Antigens, 130-149 (1986); Geysen et al., J. Immunol. Meth., 102:259-274 (1987); Schoofs et al., J. Immunol., 140:611-616 (1988), Cwirla, S. E. et al. (1990) Proc. Natl. Acad. Sci. USA, 87:6378; Lowman, H.B. et al. (1991) Biochemistry, 30:10832; Clackson, T. et al. (1991) Nature, 352: 624; Marks, J. D. et al. (1991), J. Mol. Biol., 222:581; Kang, A.S. et al. (1991) Proc. Natl. Acad. Sci. USA, 88:8363, and Smith, G. P. (1991) Current Opin. 25 Biotechnol., 2:668). In this regard, bacteriophage (phage) display is one well known technique which allows one to screen large oligopeptide libraries to identify member(s) of those libraries which are capable of specifically binding to a polypeptide target. Phage display is a technique by which variant polypeptides are displayed as fusion proteins to the coat protein on the surface of bacteriophage particles (Scott, J.K. and Smith, G. P. (1990) 30 Science 249: 386). The utility of phage display lies in the fact that large libraries of selectively randomized protein variants (or randomly cloned cDNAs) can be rapidly and efficiently sorted for those sequences that bind to a target molecule with high affinity. Display of peptide (Cwirla, S. E. et al. (1990) Proc. Natl. Acad. Sci. USA, 87:6378) or protein (Lowman, H.B. et al. (1991) Biochemistry, 30:10832; Clackson, T. et al. (1991) Nature, 352: 624; Marks, J. D. et al. (1991), J. Mol. Biol., 222:581; Kang, A.S. et al. (1991) Proc. Natl. 35 Acad. Sci. USA, 88:8363) libraries on phage have been used for screening millions of polypeptides or oligopeptides for ones with specific binding properties (Smith, G. P. (1991) Current Opin. Biotechnol., 2:668). Sorting phage libraries of random mutants requires a strategy for constructing and propagating a large number 103 WO 2004/060270 PCT/US2003/029126 of variants, a procedure for affinity purification using the target receptor, and a means of evaluating the results of binding enrichments. U.S. Patent Nos. 5,223,409, 5,403,484, 5,571,689, and 5,663,143. Although most phage display methods have used filamentous phage, lambdoid phage display systems (WO 95/34683; U.S. 5,627,024), T4 phage display systems (Ren, Z-J. et al. (1998) Gene 215:439; Zhu, Z. (1997) CAN 33:534; Jiang, J. et al. (1997) can 128:44380; Ren, Z-J. et al. (1997) CAN 127:215644; Ren, Z-J. 5 (1996) Protein Sci. 5:1833; Efinov, V. P. et al. (1995) Virus Genes 10:173) and T7 phage display systems (Smith, G. P. and Scott, J.K. (1993) Methods in Enzymology, 217, 228-257; U.S. 5,766,905) are also known. Many other improvements and variations of the basic phage display concept have now been developed. These improvements enhance the ability of display systems to screen peptide libraries for binding to selected target molecules and to display functional proteins with the potential of screening these proteins for desired 10 properties. Combinatorial reaction devices for phage display reactions have been developed (WO 98/14277) and phage display libraries have been used to analyze and control bimolecular interactions (WO 98/20169; WO 98/20159) and properties of constrained helical peptides (WO 98/20036). WO 97/35196 describes a method of isolating an affinity ligand in which a phage display library is contacted with one solution in which the ligand will bind to a target molecule and a second solution in which the affinity ligand will not bind to the target 15 molecule, to selectively isolate binding ligands. WO 97/46251 describes a method of biopanning a random phage display library with an affinity purified antibody and then isolating binding phage, followed by a micropanning process using microplate wells to isolate high affinity binding phage. The use ofStaphlylococcus aureus protein A as an affinity tag has also been reported (Li et al. (1998) Mol Biotech., 9:187). WO 97/47314 'describes the use of substrate subtraction libraries to distinguish enzyme specificities using a combinatorial 20 library which may be a phage display library. A method for selecting enzymes suitable for use in detergents using phage display is described in WO 97/09446. Additional methods of selecting specific binding proteins are described in U.S. Patent Nos. 5,498,538, 5,432,018, and WO 98/15833. Methods of generating peptide libraries and screening these libraries are also disclosed in U.S. Patent Nos. 5,723,286, 5,432,018, 5,580,717, 5,427,908, 5,498,530,'5,770,434, 5,734,018, 5,698,426, 5,763,192, 25 and 5,723,323. C. TAT Binding Organic Molecules TAT binding organic molecules are organic molecules other, than oligopeptides or antibodies as defined herein that bind, preferably specifically, to a TAT polypeptide as described herein. TAT binding organic molecules may be identified and chemically synthesized using known methodology (see, e.g., PCT Publication 30 Nos. WOOO/00823 and WOOO/39585). TAT binding organic molecules are usually less than about 2000 daltons in size, alternatively less than about 1500, 750, 500, 250 or 200 daltons in size, wherein such organic molecules that are capable of binding, preferably specifically, to a TAT polypeptide as described herein may be identified without undue experimentation using well known techniques. In this regard, it is noted that techniques for screening organic molecule libraries for molecules that are capable of binding to a polypeptide target are well 35 known in the art (see, e.g., PCT Publication Nos. WOOO/00823 and WOOO/39585). TAT binding organic molecules may be, for example, aldehydes, ketones, oximes, hydrazones, semicarbazones, carbazides, primary amines, secondary amines, tertiary amines, N-substituted hydrazines, hydrazides, alcohols, ethers, thiols, 104 WO 2004/060270 PCT/US2003/029126 thioethers, disulfides, carboxylic acids, esters, amides, ureas, carbamates, carbonates, ketals, thioketals, acetals, thioacetals, aryl halides, aryl sulfonates, alkyl halides, alkyl sulfonates, aromatic compounds, heterocyclic compounds, anilines, alkenes, alkynes, diols, amino alcohols, oxazolidines, oxazolines, thiazolidines, thiazolines, enamines, sulfonamides, epoxides, aziridines, isocyanates, sulfonyl chlorides, diazo compounds, acid chlorides, or the like. 5 D. Screening for Anti-TAT Antibodies, TAT Binding Oligopeptides and TAT Binding Organic Molecules With the Desired Properties Techniques for generating antibodies, oligopeptides and organic molecules that bind to TAT polypeptides have been described above. One may further select antibodies, oligopeptides or other organic molecules with certain biological characteristics, as desired. 10 The growth inhibitory effects of an anti-TAT antibody, oligopeptide or other organic molecule of the invention may be assessed by methods known in the art, e.g., using cells which express a TAT polypeptide either endogenously or following transfection with the TAT gene. For example, appropriate tumor cell lines and TAT-transfected cells may treated with an anti-TAT monoclonal antibody, oligopeptide or other organic molecule of the invention at various concentrations for a few days (e.g., 2-7) days and stained with crystal violet 15 or MTT or analyzed by some other colorimetric assay. Another method of measuring proliferation would be by comparing 3H-thymidine uptake by the cells treated in the presence or absence an anti-TAT antibody, TAT binding oligopeptide or TAT binding organic molecule of the invention. After treatment, the cells are harvested and the amount of radioactivity incorporated into the DNA quantitated in a scintillation counter. Appropriate positive controls include treatment of a selected cell line with a growth inhibitory antibody known to inhibit 20 growth of that cell line. Growth inhibition of tumor cells in vivo can be determined in various ways known in the art. Preferably, the tumor cell is one that overexpresses a TAT polypeptide. Preferably, the anti-TAT antibody, TAT binding oligopeptide or TAT binding organic molecule will inhibit cell proliferation of a TAT expressing tumor cell in vitro or in vivo by about 25-100% compared to the untreated tumor cell, more preferably, by about 30-100%, and even more preferably by about 50-100% or 70-100%, in one embodiment, 25 at an antibody concentration of about 0.5 to 30 p[g/ml. Growth inhibition can be measured at an antibody concentration of about 0.5 to 30 ptg/ml or about 0.5 nM to 200 nM in cell culture, where the growth inhibition is determined 1-10 days after exposure of the tumor cells to the antibody. The antibody is growth inhibitory in vivo if administration of the anti-TAT antibody at about 1 pg/kg to about 100 mg/kg body weight results in reduction in tumor size or reduction of tumor cell proliferation within about 5 days to 3 months from the first 30 administration of the antibody, preferably within about 5 to 30 days. To select for an anti-TAT antibody, TAT binding oligopeptide or TAT binding organic molecule which induces cell death, loss of membrane integrity as indicated by, e.g., propidium iodide (PI), trypan blue or 7AAD uptake may be assessed relative to control. A PI uptake assay can be performed in the absence of complement and immune effector cells. TAT polypeptide-expressing tumor cells are incubated with medium alone or 35 medium containing the appropriate anti-TAT antibody (e.g, at about 10ig/ml), TAT binding oligopeptide or TAT binding organic molecule. The cells are incubated for a 3 day time period. Following each treatment, cells are washed and aliquoted into 35 mm strainer-capped 12 x 75 tubes (1ml per tube, 3 tubes per treatment 105 WO 2004/060270 PCT/US2003/029126 group) for removal of cell clumps. Tubes then receive PI (10 pg/ml). Samples may be analyzed using a FACSCAN@ flow cytometer and FACSCONVERT* CellQuest software (Becton Dickinson). Those anti-TAT antibodies, TAT binding oligopeptides or TAT binding organic molecules that induce statistically significant levels of cell death as determined by PI uptake may be selected as cell death-inducing anti-TAT antibodies, TAT binding oligopeptides or TAT binding organic molecules. 5 To screen for antibodies, oligopeptides or other organic molecules which bind to an epitope on a TAT polypeptide bound by an antibody of interest, a routine cross-blocking assay such as that described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988), can be performed. This assay can be used to determine if a test antibody, oligopeptide or other organic molecule binds the same site or epitope as a known anti-TAT antibody. Alternatively, or additionally, epitope mapping 10 can be performed by methods known in the art . For example, the antibody sequence can be mutagenized such as by alanine scanning, to identify contact residues. The mutant antibody is initailly tested for binding with polyclonal antibody to ensure proper folding. In a different method, peptides corresponding to different regions of a TAT polypeptide can be used in competition assays with the test antibodies or with a test antibody and an antibody with a characterized or known epitope. 15 E. Antibody Dependent Enzyme Mediated Prodrug Therapy (ADEPT) The antibodies of the present invention may also be used in ADEPT by conjugating the antibody to a prodrug-activating enzyme which converts a prodrug (e.g., a peptidyl chemotherapeutic agent, see W081/01145) to an active anti-cancer drug. See, for example, WO 88/07378 and U.S. Patent No. 4,975,278. The enzyme component of the immunoconjugate useful for ADEPT includes any enzyme capable of 20 acting on a prodrug in such a way so as to covert it into its more active, cytotoxic form. Enzymes that are useful in the method of this invention include, but are not limited to, alkaline phosphatase useful for converting phosphate-containing prodrugs into free drugs; arylsulfatase useful for converting sulfate-containing prodrugs into free drugs; cytosine deaminase useful for converting non-toxic 5 fluorocytosine into the anti-cancer drug, 5-fluorouracil; proteases, such as serratia protease, thermolysin, 25 subtilisin, carboxypeptidases and cathepsins (such as cathepsins B and L), that are useful for converting peptide containing prodrugs into free drugs; D-alanylcarboxypeptidases, useful for converting prodrugs that contain D amino acid substituents; carbohydrate-cleaving enzymes such as p-galactosidase and neuraminidase useful for converting glycosylated prodrugs into free drugs; p-lactamase useful for converting drugs derivatized with p lactams into free drugs; and penicillin amidases, such as penicillin V amidase or penicillin G amidase, useful 30 for converting drugs derivatized at their amine nitrogens with phenoxyacetyl or phenylacetyl groups, respectively, into free drugs. Alternatively, antibodies with enzymatic activity, also known in the art as "abzymes", can be used to convert the prodrugs of the invention into free active drugs (see, e.g., Massey, Nature 328:457-458 (1987)). Antibody-abzyme conjugates can be prepared as described herein for delivery of the abzyme to a tumor cell population. 35 The enzymes of this invention can be covalently bound to the anti-TAT antibodies by techniques well known in the art such as the use of the heterobifunctional crosslinking reagents discussed above. Alternatively, 106 WO 2004/060270 PCT/US2003/029126 fusion proteins comprising at least the antigen binding region of an antibody of the invention linked to at least a functionally active portion of an enzyme of the invention can be constructed using recombinant DNA techniques well known in the art (see, e.g., Neuberger et al., Nature 312:604-608 (1984). F. Full-Length TAT Polypeptides The present invention also provides newly identified and isolated nucleotide sequences encoding 5 polypeptides referred to in the present application as TAT polypeptides. In particular, cDNAs (partial and full length) encoding various TAT polypeptides have been identified and isolated, as disclosed in further detail in the Examples below. As disclosed in the Examples below, various cDNA clones have been deposited with the ATCC. The actual nucleotide sequences of those clones can readily be determined by the skilled artisan by sequencing of 10 the deposited clone using routine methods in the art. The predicted amino acid sequence can be determined from the nucleotide sequence using routine skill. For the TAT polypeptides and encoding nucleic acids described herein, in some cases, Applicants have identified what is believed to be the reading frame best identifiable with the sequence information available at the time. G. Anti-TAT Antibody and TAT Polypeptide Variants 15 In addition to the anti-TAT antibodies and full-length native sequence TAT polypeptides described herein, it is contemplated that anti-TAT antibody and TAT polypeptide variants can be prepared. Anti-TAT antibody and TAT polypeptide variants can be prepared by introducing appropriate nucleotide changes into the encoding DNA, and/or by synthesis of the desired antibody or polypeptide. Those skilled in the art will appreciate that amino acid changes may alter post-translational processes of the anti-TAT antibody or TAT 20 polypeptide, such as changing the number or position of glycosylation sites or altering the membrane anchoring characteristics. Variations in the anti-TAT antibodies and TAT polypeptides described herein, can be made, for example, using any of the techniques and guidelines for conservative and non-conservative mutations set forth, for instance, in U.S. Patent No. 5,364,934. Variations may be a substitution, deletion or insertion of one or 25 more codons encoding the antibody or polypeptide that results in a change in the amino acid sequence as compared with the native sequence antibody or polypeptide. Optionally the variation is by substitution of at least one amino acid with any other amino acid in one or more of the domains of the anti-TAT antibody or TAT polypeptide. Guidance in determining which amino acid residue may be inserted, substituted or deleted without adversely affecting the desired activity may be found by comparing the sequence of the anti-TAT antibody or 30 TAT polypeptide with that of homologous known protein molecules and minimizing the number of amino acid sequence changes made in regions of high homology. Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, such as the replacement of a leucine with a seine, i.e., conservative amino acid replacements. Insertions or deletions may optionally be in the range of about 1 to 5 amino acids. The variation allowed may be determined by 35 systematically making insertions, deletions or substitutions of amino acids in the sequence and testing the resulting variants for activity exhibited by the full-length or mature native sequence. 107 WO 2004/060270 PCT/US2003/029126 Anti-TAT antibody and TAT polypeptide fragments are provided herein. Such fragments may be truncated at the N-terminus or C-terminus, or may lack internal residues, for example, when compared with a full length native antibody or protein. Certain fragments lack amino acid residues that are not essential for a desired biological activity of the anti-TAT antibody or TAT polypeptide. Anti-TAT antibody and TAT polypeptide fragments may be prepared by any of a number of 5 conventional techniques. Desired peptide fragments may be chemically synthesized. An alternative approach involves generating antibody or polypeptide fragments by enzymatic digestion, e.g., by treating the protein with an enzyme known to cleave proteins at sites defined by particular amino acid residues, or by digesting the DNA with suitable restriction enzymes and isolating the desired fragment. Yet another suitable technique involves isolating and amplifying a DNA fragment encoding a desired antibody or polypeptide fragment, by polymerase 10 chain reaction (PCR). Oligonucleotides that define the desired termini of the DNA fragment are employed at the 5' and 3' primers in the PCR. Preferably, anti-TAT antibody and TAT polypeptide fragments share at least one biological and/or immunological activity with the native anti-TAT antibody or TAT polypeptide disclosed herein. In particular embodiments, conservative substitutions of interest are shown in Table 6 under the heading 15 of preferred substitutions. If such substitutions result in a change in biological activity, then more substantial changes, denominated exemplary substitutions in Table 6, or as further described below in reference to amino acid classes, are introduced and the products screened. 108 WO 2004/060270 PCT/US2003/029126 Table 6 Original Exemplary Preferred Residue Substitutions Substitutions Ala (A) val; leu; ile val 5 Arg (R) lys; gin; asn lys Asn (N) gin; his; lys; arg gln Asp (D) glu glu Cys (C) ser ser Gin (Q) asn asn 10 Glu (E) asp asp Gly (G) pro; ala ala His (H) asn; gin; lys; arg arg Ile (I) leu; val; met; ala; phe; norleucine leu 15 Leu (L) norleucine; ile; val; met; ala; phe ile Lys (K) arg; gin; asn arg Met (M) leu; phe; ile leu Phe (F) leu; val; ile; ala; tyr leu 20 Pro(P) ala ala Ser (S) thr thr Thr (T) ser ser Trp (W) tyr; phe tyr Tyr (Y) trp; phe; thr; ser phe 25 Val (V) ile; leu; met; phe; ala; norleucine leu Substantial modifications in function or immunological identity of the anti-TAT antibody or TAT polypeptide are accomplished by selecting substitutions that differ significantly in their effect on maintaining 30 (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. Naturally occurring residues are divided into groups based on common side-chain properties: (1) hydrophobic: norleucine, met, ala, val, leu, ile; (2) neutral hydrophilic: cys, ser, thr; 35 (3) acidic: asp, glu; (4) basic: asn, gin, his, lys, arg; (5) residues that influence chain orientation: gly, pro; and (6) aromatic: trp, tyr, phe. Non-conservative substitutions will entail exchanging a member of one of these classes for another 40 class. Such substituted residues also may be introduced into the conservative substitution sites or, more preferably, into the remaining (non-conserved) sites. The variations can be made using methods known in the art such as oligonucleotide-mediated (site directed) mutagenesis, alanine scanning, and PCR mutagenesis. Site-directed mutagenesis [Carter et al.,Nucl. Acids Res. 13:4331 (1986); Zoller et al., Nucl. Acids Res., 10:6487 (1987)], cassette mutagenesis [Wells et 45 al., Gene, 34:315 (1985)], restriction selection mutagenesis [Wells et al., Philos. Trans. R. Soc. London SerA, 109 WO 2004/060270 PCT/US2003/029126 317:415 (1986)] or other known techniques can be performed on the cloned DNA to produce the anti-TAT antibody or TAT polypeptide variant DNA. Scanning amino acid analysis can also be employed to identify one or more amino acids along a contiguous sequence. Among the preferred scanning amino acids are relatively small, neutral amino acids. Such amino acids include alanine, glycine, serine, and cysteine. Alanine is typically a preferred scanning amino 5 acid among this group because it eliminates the side-chain beyond the beta-carbon and is less likely to alter the main-chain conformation of the variant [Cunningham and Wells, Science 244:1081-1085 (1989)]. Alanine is also typically preferred because it is the most common amino acid. Further, it is frequently found in both buried and exposed positions [Creighton, The Proteins (W.H. Freeman & Co., N.Y.); Chothia, J. Mol. Biol.. 150:1 (1976)]. If alanine substitution does not yield adequate amounts of variant, an isoteric amino acid can be used. 10 Any cysteine residue not involved in maintaining the proper conformation of the anti-TAT antibody or TAT polypeptide also may be substituted, generally with seine, to improve the oxidative stability of the molecule and prevent aberrant crosslinking. Conversely, cysteine bond(s) may be added to the anti-TAT antibody or TAT polypeptide to improve its stability (particularly where the antibody is an antibody fragment such as an Fv fragment). 15 A particularly preferred type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variant(s) selected for further development will have improved biological properties relative to the parent antibody from which they are generated. A convenient way for generating such substitutional variants involves affinity maturation using phage display. Briefly, several hypervariable region sites (e.g., 6-7 sites) are mutated to 20 generate all possible amino substitutions at each site. The antibody variants thus generated are displayed in a monovalent fashion from filamentous phage particles as fusions to the gene III product of M13 packaged within each particle. The phage-displayed variants are then screened for their biological activity (e.g., binding affinity) as herein disclosed. In order to identify candidate hypervariable region sites for modification, alanine scanning mutagenesis can be performed to identify hypervariable region residues contributing significantly to antigen 25 binding. Alternatively, or additionally, it may be beneficial to analyze a crystal structure of the antigen-antibody complex to identify contact points between the antibody and human TAT polypeptide. Such contact residues and neighboring residues are candidates for substitution according to the techniques elaborated herein. Once such variants are generated, the panel of variants is subjected to screening as described herein and antibodies with superior properties in one or more relevant assays may be selected for further development. 30 Nucleic acid molecules encoding amino acid sequence variants of the anti-TAT antibody are prepared by a variety of methods known in the art. These methods include, but are not limited to, isolation from a natural source (in the case of naturally occurring amino acid sequence variants) or preparation by oligonucleotide mediated (or site-directed) mutagenesis, PCR mutagenesis, and cassette mutagenesis of an earlier prepared variant or a non-variant version of the anti-TAT antibody. 35 H. Modifications of Anti-TAT Antibodies and TAT Polypeptides Covalent modifications of anti-TAT antibodies and TAT polypeptides are included within the scope of this invention. One type of covalent modification includes reacting targeted amino acid residues of an anti-TAT 110 WO 2004/060270 PCT/US2003/029126 antibody or TAT polypeptide with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C- terminal residues of the anti-TAT antibody or TAT polypeptide. Derivatization with bifunctional agents is useful, for instance, for crosslinking anti-TAT antibody or TAT polypeptide to a water insoluble support matrix or surface for use in the method for purifying anti-TAT antibodies, and vice-versa. Commonly used crosslinking agents include, e.g., 1,1-bis(diazoacetyl)-2-phenylethane, glutaraldehyde, N 5 hydroxysuccinimide esters, for example, esters with 4-azidosalicylic acid, homobifunctional imidoesters, including disuccinimidyl esters such as 3,3'-dithiobis(succinimidylpropionate), bifunctional maleimides such as bis-N-maleimido-1,8-octane and agents such as methyl-3-[(p-azidophenyl)dithio]propioimidate. Other modifications include deamidation of glutaminyl and asparaginyl residues to the corresponding glutamyl and aspartyl residues, respectively, hydroxylation of proline and lysine, phosphorylation of hydroxyl 10 groups of seryl or threonyl residues, methylation of the a-amino groups of lysine, arginine, and histidine side chains [T.E. Creighton, Proteins: Structure and Molecular Properties, W.H. Freeman & Co., San Francisco, pp. 79-86 (1983)], acetylation of the N-terminal amine, and amidation of any C-terminal carboxyl group. Another type of covalent modification of the anti-TAT antibody or TAT polypeptide included within the scope of this invention comprises altering the native glycosylation pattern of the antibody or polypeptide. 15 "Altering the native glycosylation pattern" is intended for purposes herein to mean deleting one or more carbohydrate moieties found in native sequence anti-TAT antibody or TAT polypeptide (either by removing the underlying glycosylation site or by deleting the glycosylation by chemical and/or enzymatic means), and/or adding one or more glycosylation sites that are not present in the native sequence anti-TAT antibody or TAT polypeptide. In addition, the phrase includes qualitative changes in the glycosylation of the native proteins, 20 involving a change in the nature and proportions of the various carbohydrate moieties present. Glycosylation of antibodies and other polypeptides is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, 25 the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. 0 linked glycosylation refers to the attachment of one of the sugars N-aceylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly seine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. Addition of glycosylation sites to the anti-TAT antibody or TAT polypeptide is conveniently 30 accomplished by altering the amino acid sequence such that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites). The alteration may also be made by the addition of, or substitution by, one or more seine or threonine residues to the sequence of the original anti-TAT antibody or TAT polypeptide (for O-linked glycosylation sites). The anti-TAT antibody or TAT polypeptide amino acid sequence may optionally be altered through changes at the DNA level, particularly by mutating the DNA 35 encoding the anti-TAT antibody or TAT polypeptide at preselected bases such that codons are generated that will translate into the desired amino acids. 111 WO 2004/060270 PCT/US2003/029126 Another means of increasing the number of carbohydrate inoieties on the anti-TAT antibody or TAT polypeptide is by chemical or enzymatic coupling of glycosides to the polypeptide. Such methods are described in the art, e.g., in WO 87/05330 published 11 September 1987, and in Aplin and Wriston, CRC Crit. Rev. Biochem. pp. 259-306 (1981). Removal of carbohydrate moieties present on the anti-TAT antibody or TAT polypeptide may be 5 accomplished chemically or enzymatically or by mutational substitution of codons encoding for amino acid residues that serve as targets for glycosylation. Chemical deglycosylation techniques are known in the art and described, for instance, by Hakimuddin, et al., Arch. Biochem. Biophys., 259:52 (1987) and by Edge et al., Anal. Biochem.. 118:131 (1981). Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al., Meth. Enzymol., 10 138:350 (1987). Another type of covalent modification of anti-TAT antibody or TAT polypeptide comprises linking the antibody or polypeptide to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes, in the manner set forth in U.S. Patent Nos. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337. The antibody or polypeptide also may be entrapped in 15 microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (for example, hydroxymethyleellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano particles and nanocapsules), or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th edition, Oslo, A., Ed., (1980). 20 The anti-TAT antibody or TAT polypeptide of the present invention may also be modified in a way to form chimeric molecules comprising an anti-TAT antibody or TAT polypeptide fused to another, heterologous polypeptide or amino acid sequence. In one embodiment, such a chimeric molecule comprises a fusion of the anti-TAT antibody or TAT polypeptide with a tag polypeptide which provides an epitope to which an anti-tag antibody can selectively bind. 25 The epitope tag is generally placed at the amino- or carboxyl- terminus of the anti-TAT antibody or TAT polypeptide. The presence of such epitope-tagged forms of the anti-TAT antibody or TAT polypeptide can be detected using an antibody against the tag polypeptide. Also, provision of the epitope tag enables the anti-TAT antibody or TAT polypeptide to be readily purified by affinity purification using an anti-tag antibody or another type of affinity matrix that binds to the epitope tag. Various tag polypeptides and their respective antibodies 30 are well known in the art. Examples include poly-histidine (poly-his) or poly-histidine-glycine (poly-his-gly) tags; the flu HA tag polypeptide and its antibody 12CA5 [Field et al., Mol. Cell. Biol., 8:2159-2165 (1988)]; the c-myc tag and the 8F9, 3C7, 6E10, G4, B7 and 9E10 antibodies thereto [Evan et al., Molecular and Cellular Biology 5;3610-3616 (1985)]; and the Herpes Simplex virus glycoprotein D (gD) tag and its antibody [Paborsky et al., Protein Engineering, 3(6):547-553 (1990)]. Other tag polypeptides include the Flag-peptide [Hopp et al., 35 BioTechnology, 6:1204-1210 (1988)]; the KT3 epitope peptide [Martin et al., Science 255:192-194 (1992)]; an a-tubulin epitope peptide [Skinner et al., J. Biol. Chem. 266:15163-15166 (1991)]; and the T7 gene 10 protein peptide tag [Lutz-Freyermuth et al., Proc. Natl. Acad. Sci. USA 87:6393-6397 (1990)]. 112 WO 2004/060270 PCT/US2003/029126 In an alternative embodiment, the chimeric molecule may comprise a fusion of the anti-TAT antibody or TAT polypeptide with an immunoglobulin or a particular region of an immunoglobulin. For a bivalent form of the chimeric molecule (also referred to as an "immunoadhesin"), such a fusion could be to the Fc region of an IgG molecule. The Ig fusions preferably include the substitution of a soluble (transmembrane domain deleted or inactivated) form of an anti-TAT antibody or TAT polypeptide in place of at least one variable region within 5 an Ig molecule. In a particularly preferred embodiment, the immunoglobulin fusion includes the hinge, CH 2 and CH 3 , or the hinge, CH 1 , CH 2 and CH 3 regions of an IgG1 molecule. For the production of immunoglobulin fusions see also US Patent No. 5,428,130 issued June 27, 1995. I. Preparation of Anti-TAT Antibodies and TAT Polypeptides The description below relates primarily to production of anti-TAT antibodies and TAT polypeptides 10 by culturing cells transformed or transfected with a vector containing anti-TAT antibody- and TAT polypeptide encoding nucleic acid. It is, of course, contemplated that alternative methods, which are well known in the art, may be employed to prepare anti-TAT antibodies and TAT polypeptides. For instance, the appropriate amino acid sequence, or portions thereof, may be produced by direct peptide synthesis using solid-phase techniques [see, e.g., Stewart et al., Solid-Phase Peptide Synthesis, W.H. Freeman Co., San Francisco, CA (1969); 15 Merrifield, J. Am. Chem. Soc. 85:2149-2154 (1963)]. In vitro protein synthesis may be performed using manual techniques or by automation. Automated synthesis may be accomplished, for instance, using an Applied Biosystems Peptide Synthesizer (Foster City, CA) using manufacturer's instructions. Various portions of the anti-TAT antibody or TAT polypeptide may be chemically synthesized separately and combined using chemical or enzymatic methods to produce the desired anti-TAT antibody or TAT polypeptide. 20 1. Isolation of DNA Encoding Anti-TAT Antibody or TAT Polypeptide DNA encoding anti-TAT antibody or TAT polypeptide may be obtained from a cDNA library prepared from tissue believed to possess the anti-TAT antibody or TAT polypeptide mRNA and to express it at a detectable level. Accordingly, human anti-TAT antibody or TAT polypeptide DNA can be conveniently obtained from a cDNA library prepared from human tissue. The anti-TAT antibody- or TAT polypeptide 25 encoding gene may also be obtained from a genomic library or by known synthetic procedures (e.g., automated nucleic acid synthesis). Libraries can be screened with probes (such as oligonucleotides of at least about 20-80 bases) designed to identify the gene of interest or the protein encoded by it. Screening the cDNA or genomic library with the selected probe may be conducted using standard procedures, such as described in Sambrook et al., Molecular 30 Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989). An alternative means to isolate the gene encoding anti-TAT antibody or TAT polypeptide is to use PCR methodology [Sambrook et al., supra; Dieffenbach et al., PCR Primer: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 1995)]. Techniques for screening a cDNA library are well known in the art. The oligonucleotide sequences 35 selected as probes should be of sufficient length and sufficiently unambiguous that false positives are minimized. The oligonucleotide is preferably labeled such that it can be detected upon hybridization to DNA in the library being screened. Methods of labeling are well known in the art, and include the use of radiolabels like P 113 WO 2004/060270 PCT/US2003/029126 labeled ATP, biotinylation or enzyme labeling. Hybridization conditions, including moderate stringency and high stringency, are provided in Sambrook et al., supra. Sequences identified in such library screening methods can be compared and aligned to other known sequences deposited and available in public databases such as GenBank or other private sequence databases. Sequence identity (at either the amino acid or nucleotide level) within defined regions of the molecule or across 5 the full-length sequence can be determined using methods known in the art and as described herein. Nucleic acid having protein coding sequence may be obtained by screening selected cDNA or genomic libraries using the deduced amino acid sequence disclosed herein for the first time, and, if necessary, using conventional primer extension procedures as described in Sambrook et al., supra. to detect precursors and processing intermediates of mRNA that may not have been reverse-transcribed into cDNA. 10 2. Selection and Transformation of Host Cells Host cells are transfected or transformed with expression or cloning vectors described herein for anti TAT antibody or TAT polypeptide production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences. The culture conditions, such as media, temperature, pH and the like, can be selected by the skilled 15 artisan without undue experimentation. In general, principles, protocols, and practical techniques for maximizing the productivity of cell cultures can be found in Mammalian Cell Biotechnology: a Practical Approach. M. Butler, ed. (IRL Press, 1991) and Sambrook et al., supra. Methods of eukaryotic cell transfection and prokaryotic cell transformation are known to the ordinarily skilled artisan, for example, CaCl 2 , CaPO 4 , liposome-mediated and electroporation. Depending on the host cell 20 used, transformation is performed using standard techniques appropriate to such cells. The calcium treatment employing calcium chloride, as described in Sambrook et al., supra or electroporation is generally used for prokaryotes. Infection with Agrobacterium tumefaciens is used for transformation of certain plant cells, as described by Shaw et al., Gene, 23:315 (1983) and WO 89/05859 published 29 June 1989. For mammalian cells without such cell walls, the calcium phosphate precipitation method of Graham and van der Eb, Virology. 25 52:456-457 (1978) can be employed. General aspects of mammalian cell host system transfections have been described in U.S. Patent No. 4,399,216. Transformations into yeast are typically carried out according to the method of Van Solingen et al., J. Bact. 130:946 (1977) and Hsiao et al., Proc. Natl. Acad. Sci. (USA) 76:3829 (1979). However, other methods for introducing DNA into cells, such as by nuclear microinjection, electroporation, bacterial protoplast fusion with intact cells, or polycations, e.g., polybrene, polyornithine, may 30 also be used. For various techniques for transforming mammalian cells, see Keown et al., Methods in Enzymology 185:527-537 (1990) and Mansour et al., Nature 336:348-352 (1988). Suitable host cells for cloning or expressing the DNA in the vectors herein include prokaryote, yeast, or higher eukaryote cells. Suitable prokaryotes include but are not limited to eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as E. coli. Various E. coli strains are 35 publicly available, such as E. coli K12 strain MM294 (ATCC 31,446); E. coli X1776 (ATCC 31,537); E. coli strain W3110 (ATCC 27,325) and K5 772 (ATCC 53,635). Other suitable prokaryotic host cells include Enterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, 114 WO 2004/060270 PCT/US2003/029126 e.g., Salmonella typhimurium, Serratia, e.g., Serratia marcescans, and Shigella, as well as Bacilli such as B. subtilis and B. licheniformis (e.g., B. lichengformis 41P disclosed in DD 266,710 published 12 April 1989), Pseudomonas such as P. aeruginosa, and Streptonyces. These examples are illustrative rather than limiting. Strain W3110 is one particularly preferred host or parent host because it is a common host strain for recombinant DNA product fermentations. Preferably, the host cell secretes minimal amounts of proteolytic 5 enzymes. For example, strain W3 110 may be modified to effect a genetic mutation in the genes encoding proteins endogenous to the host, with examples of such hosts including E. coli W3110 strain 1A2, which has the complete genotype tonA ; E. coli W3110 strain 9E4, which has the complete genotype tonA ptr3; E. coli W3110 strain 27C7 (ATCC 55,244), which has the complete genotype tonA ptr3phoA E13 (argF-lac)169 degP ompT kan'; E. coli W3110 strain 37D6, which has the complete genotype tonA ptr3 phoA E15 (argF-lac)169 10 degP ompT rbs7 ilvG karf; E. coli W3 110 strain 40B4, which is strain 37D6 with a non-kanamycin resistant degP deletion mutation; and an E. coli strain having mutant periplasmic protease disclosed in U.S. Patent No. 4,946,783 issued 7 August 1990. Alternatively, in vitro methods of cloning, e.g., PCR or other nucleic acid polymerase reactions, are suitable. Full length antibody, antibody fragments, and antibody fusion proteins can be produced in bacteria, 15 in particular when glycosylation and Fc effector function are not needed, such as when the therapeutic antibody is conjugated to a cytotoxic agent (e.g., a toxin) and the immunoconjugate by itself shows effectiveness in tumor cell destruction. Full length antibodies have greater half life in circulation. Production in E. coli is faster and more cost efficient. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. 5,648,237 (Carter et. al.), U.S. 5,789,199 (Joly et al.), and U.S. 5,840,523 (Simmons et al.) which describes 20 translation initiation regio (TIR) and signal sequences for optimizing expressionand secretion, these patents incorporated herein by reference. After expression, the antibody is isolated from the E. coli cell paste in a soluble fraction and can be purified through, e.g., a protein A or G column depending on the isotype. Final purification can be carried out similar to the process for purifying antibody expressed e.g,, in CHO cells. In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning 25 or expression hosts for anti-TAT antibody- or TAT polypeptide-encoding vectors. Saccharomyces cerevisiae is a commonly used lower eukaryotic host microorganism. Others includeSczizosaccharomycespombe (Beach and Nurse, Nature 290: 140 [1981]; EP 139,383 published 2 May 1985); Kluyveronyces hosts (U.S. Patent No. 4,943,529; Fleer et al., Bio/Technolov, 9:968-975 (1991)) such as, e.g., K. lactis (MW98-8C, CBS683, CBS4574; Louvencourt et al., J. Bacteriol., 154(2):737-742 [1983]), K fragilis (ATCC 12,424), K. bulgaricus 30 (ATCC 16,045), K. wickeramii (ATCC 24,178), K. waitii (ATCC 56,500), K. drosophilarum (ATCC 36,906; Van den Berg et al., Bio/Technoloav, 8:135 (1990)), K. thernotolerans, and K marxianus; yarrowia (EP 402,226); Pichiapastoris (EP 183,070; Sreekrishna et al., J. Basic Microbiol., 28:265-278 [1988]); Candida; Trichoderma reesia (EP 244,234); Neurospora crassa (Case et al., Proc. Natl. Acad. Sci. USA. 76:5259-5263 [19791); Schwanniomyces such as Schwanniomyces occidentalis (EP 394,538 published 31 October 1990); and 35 filamentous fungi such as, e.g., Neurospora, Penicillium, Tolypocladium (WO 91/00357 published 10 January 1991), and Aspergillus hosts such as A. nidulans (Ballance et al., Biochem. Biophys. Res. Commun., 112:284 289 [1983]; Tilburn et al., Gene, 26:205-221 [1983]; Yelton et al., Proc. Natl. Acad. Sci. USA. 81: 1470-1474 115 WO 2004/060270 PCT/US2003/029126 [1984]) and A. niger (Kelly and Hynes, EMBO J., 4:475-479 [1985]). Methylotropic yeasts are suitable herein and include, but are not limited to, yeast capable of growth on methanol selected from the genera consisting of Hansenula, Candida, Kloeckera, Pichia, Saccharomyces, Torulopsis, and Rhodotorula. A list of specific species that are exemplary of this class of yeasts may be found in C. Anthony, The Biochemistry of Methylotrophs 269 (1982). 5 Suitable host cells for the expression of glycosylated anti-TAT antibody or TAT polypeptide are derived from multicellular organisms. Examples of invertebrate cells include insect cells such as Drosophila S2 and Spodoptera Sf9, as well as plant cells, such as cell cultures of cotton, corn, potato, soybean, petunia, tomato, and tobacco. Numerous baculoviral strains and variants and corresponding permissive insect host cells from hosts such as Spodoptera frugiperda (caterpillar), Aedes aegypti (mosquito), Aedes albopictus (mosquito), 10 Drosophila melanogaster (fruitfly), and Bombyx mori have been identified. A variety of viral strains for transfection are publicly available, e.g., the L-1 variant of Autographa californica NPV and the Bm-5 strain of Boinbyx mori NPV, and such viruses may be used as the virus herein according to the present invention, particularly for transfection of Spodopterafrugiperda cells. However, interest has been greatest in vertebrate cells, and propagation of vertebrate cells in culture 15 (tissue culture) has become a routine procedure. Examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK, ATCC CCL 10); Chinese hamster ovary cells/-DHFR (CHO, Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); mouse sertoli cells (TM4, Mather, Biol. Reprod. 23:243-251 (1980)); monkey 20 kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat liver cells (BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); human liver cells (Hep G2, HB 8065); mouse mammary tumor (MMT 060562, ATCC CCL51); TRI cells (Mather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982)); MRC 5 cells; FS4 cells; and a human hepatoma line (Hep G2). 25 Host cells are transformed with the above-described expression or cloning vectors for anti-TAT antibody or TAT polypeptide production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences. 3. Selection and Use of a Replicable Vector The nucleic acid (e.g., cDNA or genomic DNA) encoding anti-TAT antibody or TAT polypeptide may 30 be inserted into a replicable vector for cloning (amplification of the DNA) or for expression. Various vectors are publicly available. The vector may, for example, be in the form of a plasmid, cosmid, viral particle, or phage. The appropriate nucleic acid sequence may be inserted into the vector by a variety of procedures. In general, DNA is inserted into an appropriate restriction endonuclease site(s) using techniques known in the art. Vector components generally include, but are not limited to, one or more of a signal sequence, an origin of 35 replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. Construction of suitable vectors containing one or more of these components employs standard ligation techniques which are known to the skilled artisan. 116 WO 2004/060270 PCT/US2003/029126 The TAT may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, which may be a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide. In general, the signal sequence may be a component of the vector, or it may be a part of the anti-TAT antibody- or TAT polypeptide-encoding DNA that is inserted into the vector. The signal sequence may be a prokaryotic signal sequence selected, for example, from the 5 group of the alkaline phosphatase, penicillinase, Ipp, or heat-stable enterotoxin II leaders. For yeast secretion the signal sequence may be, e.g., the yeast invertase leader, alpha factor leader (including Saccharomyces and Kluyveromyces a-factor leaders, the latter described in U.S. Patent No. 5,010,182), or acid phosphatase leader, the C. albicans glucoamylase leader (EP 362,179 published 4 April 1990), or the signal described in WO 90/13646 published 15 November 1990. In mammalian cell expression, mammalian signal sequences may be 10 used to direct secretion of the protein, such as signal sequences from secreted polypeptides of the same or related species, as well as viral secretory leaders. Both expression and cloning vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Such sequences are well known for a variety of bacteria, yeast, and viruses. The origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria, the 2p plasmid 15 origin is suitable for yeast, and various viral origins (SV40, polyoma, adenovirus, VSV or BPV) are useful for cloning vectors in mammalian cells. Expression and cloning vectors will typically contain a selection gene, also termed a selectable marker. Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b) complement auxotrophic deficiencies, or (c) supply critical 20 nutrients not available from complex media, e.g., the gene encoding D-alanine racemase for Bacilli. An example of suitable selectable markers for mammalian cells are those that enable the identification of cells competent to take up the anti-TAT antibody- or TAT polypeptide-encoding nucleic acid, such as DHFR or thymidine kinase. An appropriate host cell when wild-type DHFR is employed is the CHO cell line deficient in DHFR activity, prepared and propagated as described by Urlaub et al., Proc. Natl. Acad. Sci. USA, 77:4216 25 (1980). A suitable selection gene for use in yeast is the trp1 gene present in the yeast plasmid YRp7 [Stinchcomb et al., Nature, 282:39 (1979); Kingsman et al., Gene, 7:141 (1979); Tschemper et al., Gene, 10:157 (1980)]. The trp1 gene provides a selection marker for a mutant strain of yeast lacking the ability to grow in tryptophan, for example, ATCC No. 44076 or PEP4-1 [Jones, Genetics 85:12 (1977)]. Expression and cloning vectors usually contain a promoter operably linked to the anti-TAT antibody 30 or TAT polypeptide-encoding nucleic acid sequence to direct mRNA synthesis. Promoters recognized by a variety of potential host cells are well known. Promoters suitable for use with prokaryotic hosts include thep lactamase and lactose promoter systems [Chang et al., Nature 275:615 (1978); Goeddel et al., Nature 281:544 (1979)], alkaline phosphatase, a tryptophan (trp) promoter system [Goeddel, Nucleic Acids Res. 8:4057 (1980); EP 36,776], and hybrid promoters such as the tac promoter [deBoer et al., Proc. Nat. Acad. Sci. USA. 80:21 35 25 (1983)]. Promoters for use in bacterial systems also will contain a Shine-Dalgarno (S.D.) sequence operably linked to the DNA encoding anti-TAT antibody or TAT polypeptide. Examples of suitable promoting sequences for use with yeast hosts include the promoters for 3 117 WO 2004/060270 PCT/US2003/029126 phosphoglycerate kinase [Hitzeman et al., J. Biol. Chem. 255:2073 (1980)] or other glycolytic enzymes [Hess et al., J. Adv. Enzyme Reg., 7:149 (1968); Holland, Biochemistry 17:4900 (1978)], such As enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose 6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase, and glucokinase. 5 Other yeast promoters, which are inducible promoters having the additional advantage of transcription controlled by growth conditions, are the promoter regions for alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, degradative enzymes associated with nitrogen metabolism, metallothionein, glyceraldehyde-3 phosphate dehydrogenase, and enzymes responsible for maltose and galactose utilization. Suitable vectors and promoters for use in yeast expression are further described in EP 73,657. 10 Anti-TAT antibody or TAT polypeptide transcription from vectors in mammalian host cells is controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowlpox virus (UK 2,211,504 published 5 July 1989), adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus 40 (SV40), from heterologous mammalian promoters, e.g., the actin promoter or an immunoglobulin promoter, and from heat-shock 15 promoters, provided such promoters are compatible with the host cell systems. Transcription of a DNA encoding the anti-TAT antibody or TAT polypeptide by higher eukaryotes may be increased by inserting an enhancer sequence into the vector. Enhancers are cis-acting elements of DNA, usually about from 10 to 300 bp, that act on a promoter to increase its transcription. Many enhancer sequences are now known from mammalian genes (globin, elastase, albumin, a-fetoprotein, and insulin). Typically, 20 however, one will use an enhancer from a eukaryotic cell virus. Examples include the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers. The enhancer may be spliced into the vector at a position 5' or 3' to the anti-TAT antibody or TAT polypeptide coding sequence, but is preferably located at a site 5' from the promoter. 25 Expression vectors used in eukaryotic host cells (yeast, fungi, insect, plant, animal, human, or nucleated cells from other multicellular organisms) will also contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from the 5' and, occasionally 3', untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of-the mRNA encoding anti-TAT 30 antibody or TAT polypeptide. Still other methods, vectors, and host cells suitable for adaptation to the synthesis of anti-TAT antibody or TAT polypeptide in recombinant vertebrate cell culture are described in Gething et al., Nature 293:620-625 (1981); Mantei et al., Nature 281:40-46 (1979); EP 117,060; and EP 117,058. 4. Culturing the Host Cells 35 The host cells used to produce the anti-TAT antibody or TAT polypeptide of this invention may be cultured in a variety of media. Commercially available media such as Ham's FLO (Sigma), Minimal Essential Medium ((MEM), (Sigma), RPMI-1640 (Sigma), and Dulbecco's Modified Eagle's Medium ((DMEM), Sigma) 118 WO 2004/060270 PCT/US2003/029126 are suitable for culturing the host cells. In addition, any of the media described in Ham et alleth. Enz. 58:44 (1979), Barnes et al., Anal. Biochem.102:255 (1980), U.S. Pat. Nos. 4,767,704; 4,657,866; 4,927,762; 4,560,655; or 5,122,469; WO 90/03430; WO 87/00195; or U.S. Patent Re. 30,985 may be used as culture media for the host cells. Any of these media may be supplemented as necessary with hormones and/or other growth factors (such as insulin, transferrin, or epidermal growth factor), salts (such as sodium chloride, 5 calcium, magnesium, and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics (such as GENTAMYCIN
T
" drug), trace elements (defined as inorganic compounds usually present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Any other necessary supplements may also be included at appropriate concentrations that would be known to those skilled in the art. The culture conditions, such as temperature, pH, and the like, are those previously used with the host 10 cell selected for expression, and will be apparent to the ordinarily skilled artisan. 5. Detecting Gene Amplification/Expression Gene amplification and/or expression may be measured in a sample directly, for example, by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA [Thomas, Proc. Natl. Acad. Sci. USA. 77:5201-5205 (1980)], dot blotting (DNA analysis), or in situ hybridization, using an 15 appropriately labeled probe, based on the sequences provided herein. Alternatively, antibodies may be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. The antibodies in turn may be labeled and the assay may be carried out where the duplex is bound to a surface, so that upon the formation of duplex on the surface, the presence of antibody bound to the duplex can be detected. 20 Gene expression, alternatively, may be measured by immunological methods, such as immunohistochemical staining of cells or tissue sections and assay of cell culture or body fluids, to quantitate directly the expression of gene product. Antibodies useful for immunohistochemical staining and/or assay of sample fluids may be either monoclonal or polyclonal, and may be prepared in any mammal. Conveniently, the antibodies may be prepared against a native sequence TAT polypeptide or against a synthetic peptide based 25 on the DNA sequences provided herein or against exogenous sequence fused to TAT DNA and encoding a specific antibody epitope. 6. Purification of Anti-TAT Antibody and TAT Polypeptide Forms of anti-TAT antibody and TAT polypeptide may be recovered from culture medium or from host cell lysates. If membrane-bound, it can be released from the membrane using a suitable detergent solution (e.g. 30 Triton-X 100) or by enzymatic cleavage. Cells employed in expression of anti-TAT antibody and TAT polypeptide can be disrupted by various physical or chemical means, such as freeze-thaw cycling, sonication, mechanical disruption, or cell lysing agents. It may be desired to purify anti-TAT antibody and TAT polypeptide from recombinant cell proteins ,or polypeptides. The following procedures are exemplary of suitable purification procedures: by fractionation 35 on an ion-exchange column; ethanol precipitation; reverse phase HPLC; chromatography on silica or on a cation-exchange resin such as DEAE; chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gel filtration using, for example, Sephadex G-75; protein A Sepharose columns to remove contaminants such as 119 WO 2004/060270 PCT/US2003/029126 IgG; and metal chelating columns to bind epitope-tagged forms of the anti-TAT antibody and TAT polypeptide. Various methods of protein purification may be employed and such methods are known in the art and described for example in Deutscher, Methods in Enzymology. 182 (1990); Scopes, Protein Purification: Principles and Practice, Springer-Verlag, New York (1982). The purification step(s) selected will depend, for example, on the nature of the production process used and the particular anti-TAT antibody or TAT polypeptide produced. 5 When using recombinant techniques, the antibody can be produced intracellularly, in the periplasmic space, or directly secreted into the medium. If the antibody is produced intracellularly, as a first step, the particulate debris, either host cells or lysed fragments, are removed, for example, by centrifugation or ultrafiltration. Carter et al., Bio/Technology 10:163-167 (1992) describe a procedure for isolating antibodies which are secreted to the periplasmic space of E. coli. Briefly, cell paste is thawed in the presence of sodium 10 acetate (pH 3.5), EDTA, and phenylmethylsulfonylfluoride (PMSF) over about 30 min. Cell debris can be removed by centrifugation. Where the antibody is secreted into the medium, supernatants from such expression systems are generally first concentrated using a commercially available protein concentration filter, for example, an Amicon or Millipore Pellicon ultrafiltration unit. A protease inhibitor such as PMSF may be included in any of the foregoing steps to inhibit proteolysis and antibiotics may be included to prevent the growth of adventitious 15 contaminants. The antibody composition prepared from the cells can be purified using, for example, hydroxylapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being the preferred purification technique. The suitability of protein A as an affinity ligand depends on the species and isotype of any inununoglobulin Fc domain that is present in the antibody. Protein A can be used to purify 20 antibodies that are based on human y1, y2 or y4 heavy chains (Lindmark et al., J. Immunol. Meth. 62:1-13 (1983)). Protein G is recommended for all mouse isotypes and for human y3 (Guss et al., EMBO J. 5:15671575 (1986)). The matrix to which the affinity ligand is attached is most often agarose, but other matrices are available. Mechanically stable matrices such as controlled pore glass or poly(styrenedivinyl)benzene allow for faster flow rates and shorter processing times than can be achieved with 25 agarose. Where the antibody comprises a q3 domain, the Bakerbond ABX
T
"resin (J. T. Baker, Phillipsburg, NJ) is useful for purification. Other techniques for protein purification such as fractionation on an ion-exchange column, ethanol precipitation, Reverse Phase HPLC, chromatography on silica, chromatography on heparin SEPHAROSE"' chromatography on an anion or cation exchange resin (such as a polyaspartic acid column), chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation are also available depending on the antibody 30 to be recovered. Following any preliminary purification step(s), the mixture comprising the antibody of interest and contaminants may be subjected to low pH hydrophobic interaction chromatography using an elution buffer at a pH between about 2.5-4.5, preferably performed at low salt concentrations (e.g., from about 0-0.25M salt). J. Pharmaceutical Formulations 35 Therapeutic formulations of the anti-TAT antibodies, TAT binding oligopeptides, TAT binding organic molecules and/or TAT polypeptides used in accordance with the present invention are prepared for storage by mixing the antibody, polypeptide, oligopeptide or organic molecule having the desired degree of purity with 120 WO 2004/060270 PCT/US2003/029126 optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as acetate, Tris, phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium 5 chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, 10 mannose, or dextrins; chelating agents such as EDTA; tonicifiers such as trehalose and sodium chloride; sugars such as sucrose, mannitol, trehalose or sorbitol; surfactant such as polysorbate; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN*, PLURONICS* or polyethylene glycol (PEG). The antibody preferably comprises the antibody at a concentration of between 5-200 mg/ml, preferably between 10-100 mg/nil. 15 The formulations herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, in addition to an anti-1Tik a-abody, TAT binding oligopeptide, or TAT binding organic molecule, it may be desirable to include in the one formulation, an additional antibody, e.g., a second anti-TAT antibody which binds a different epitope on the TAT polypeptide, or an antibody to some other target 20 such as a growth factor that affects the growth of the particular cancer. Alternatively, or additionally, the composition may further comprise a chemotherapeutic agent, cytotoxic agent, cytokine, growth inhibitory agent, anti-hormonal agent, and/or cardioprotectant. Such molecules are suitably present in combination in amounts that are effective for the purpose intended. The active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation 25 techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences. 16th edition, Osol, A. Ed. (1980). Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations 30 include semi-permeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and y ethyl-L-glutamate, non-degradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT* (injectable 35 microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3 hydroxybutyric acid. The formulations to be used for in vivo administration must be sterile. This is readily accomplished 121 WO 2004/060270 PCT/US2003/029126 by filtration through sterile filtration membranes. K. Diagnosis and Treatment with Anti-TAT Antibodies, TAT Binding Oligopeptides and TAT Binding Organic Molecules To determine TAT expression in the cancer, various diagnostic assays are available. In one embodiment, TAT polypeptide overexpression may be analyzed by immunohistochemistry (IHC). Parrafin 5 embedded tissue sections from a tumor biopsy may be subjected to the IHC assay and accorded a TAT protein staining intensity criteria as follows: Score 0 - no staining is observed or membrane staining is observed in less than 10% of tumor cells. Score 1 + - a faint/barely perceptible membrane staining is detected in more than 10% of the tumor 10 cells. The cells are only stained in part of their membrane. Score 2 + - a weak to moderate complete membrane staining is observed in more than 10% of the tumor cells. Score 3 + - a moderate to strong complete membrane staini'ng is observed in more than 10% of the tumor cells. 15 Those tumors with 0 or 1+ scores for TAT polypeptide expression may be characterized as not overexpressing TAT, whereas those tumors with 2+ or 3+ scores may be characterized as overexpressing TAT. Alternatively, or additionally, FISH assays such as the INFORM® (sold by Ventana, Arizona) or PATHVISION® (Vysis, Illinois) may be carried out on formalin-fixed, paraffin-embedded tumor tissue to 20 determine the extent (if any) of TAT overexpression in the tumor. TAT overexpression or amplification may be evaluated using an in vivo diagnostic assay, e.g., by administering a molecule (such as an antibody, oligopeptide or organic molecule) which binds the molecule to be detected and is tagged with a detectable label (e.g., a radioactive isotope or a fluorescent label) and externally scanning the patient for localization of the label. 25 As described above, the anti-TAT antibodies, oligopeptides and organic molecules of the invention have various non-therapeutic applications. The anti-TAT antibodies, oligopeptides and organic molecules of the present invention can be useful for diagnosis and staging of TAT polypeptide-expressing cancers (e.g., in radioimaging). The antibodies, oligopeptides and organic molecules are also useful for purification or immunoprecipitation of TAT polypeptide from cells, for detection and quantitation of TAT polypeptide in vitro, 30 e.g., in an ELISA or a Western blot, to kill and eliminate TAT-expressing cells from a population of mixed cells as a step in the purification of other cells. Currently, depending on the stage of the cancer, cancer treatment involves one or a combination of the following therapies: surgery to remove the cancerous tissue, radiation therapy, and chemotherapy. Anti-TAT antibody, oligopeptide or organic molecule therapy may be especially desirable in elderly patients who do not 35 tolerate the toxicity and side effects of chemotherapy well and in metastatic disease where radiation therapy has limited usefulness. The tumor targeting anti-TAT antibodies, oligopeptides and organic molecules of the invention are useful to alleviate TAT-expressing cancers upon initial diagnosis of the disease or during relapse. 122 WO 2004/060270 PCT/US2003/029126 For therapeutic applications, the anti-TAT antibody, oligopeptide or organic molecule can be used alone, or in combination therapy with, e.g., hormones, antiangiogens, or radiolabelled compounds, or with surgery, cryotherapy, and/or radiotherapy. Anti-TAT antibody, oligopeptide or organic molecule treatment can be administered in conjunction with other forms of conventional therapy, either consecutively with, pre- or post conventional therapy. Chemotherapeutic drugs such as TAXOTERE@ (docetaxel), TAXOL* (palictaxel), 5 estramustine and mitoxantrone are used in treating cancer, in particular, in good risk patients. In the present method of the invention for treating or alleviating cancer, the cancer patient can be administered anti-TAT antibody, oligopeptide or organic molecule in conduction with treatment with the one or more of the preceding chemotherapeutic agents. In particular, combination therapy with palictaxel and modified derivatives (see, e.g., EP0600517) is contemplated. The anti-TAT antibody, oligopeptide or organic molecule will be administered 10 with a therapeutically effective dose of the chemotherapeutic agent. In another embodiment, the anti-TAT antibody, oligopeptide or organic molecule is administered in conjunction with chemotherapy to enhance the activity and efficacy of the chemotherapeutic agent, e.g., paclitaxel. The Physicians' Desk Reference (PDR) discloses dosages of these agents that have been used in treatment of various cancers. The dosing regimen and dosages of these aforementioned chemotherapeutic drugs that are therapeutically effective will depend on the 15 particular cancer being treated, the extent of the disease and other factors familiar to the physician of skill in the art and can be determined by the physician. In one particular embodiment, a conjugate comprising an anti-TAT antibody, oligopeptide or organic molecule conjugated with a cytotoxic agent is administered to the patient. Preferably, the immunoconjugate bound to the TAT protein is internalized by the cell, resulting in increased therapeutic efficacy of the 20 immunoconjugate in killing the cancer cell to which it binds. In a preferred embodiment, the cytotoxic agent targets or interferes with the nucleic acid in the cancer cell. Examples of such cytotoxic agents are described above and include maytansinoids, calicheamicins, ribonucleases and DNA endonucleases. The anti-TAT antibodies, oligopeptides, organic molecules or toxin conjugates thereof are administered to a human patient, in accord with known methods, such as intravenous administration, e.g.,, as a bolus or by 25 continuous infusion over a period of time,'by intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical, or inhalation routes. Intravenous or subcutaneous administration of the antibody, oligopeptide or organic molecule is preferred. Other therapeutic regimens may be combined with the administration of the anti-TAT antibody, 30 oligopeptide or organic molecule. The combined administration includes co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities. Preferably such combined therapy results in a synergistic therapeutic effect. It may also be desirable to combine administration of the anti-TAT antibody or antibodies, oligopeptides 35 or organic molecules, with administration of an antibody directed against another tumor antigen associated with the particular cancer. In another embodiment, the therapeutic treatment methods of the present invention involves the 123 WO 2004/060270 PCT/US2003/029126 combined administration of an anti-TAT antibody (or antibodies), oligopeptides or organic molecules and one or more chemotherapeutic agents or growth inhibitory agents, including co-administration of cocktails of different chemotherapeutic agents. Chemotherapeutic agents include estramustine phosphate, prednimustine, cisplatin, 5-fluorouracil, melphalan, cyclophosphamide, hydroxyurea and hydroxyureataxanes (such as paclitaxel and doxetaxel) and/or anthracycline antibiotics. Preparation and dosing schedules for such chemotherapeutic 5 agents may be used according to manufacturers' instructions or as determined empirically by the skilled practitioner. Preparation and dosing schedules for such chemotherapy are also described in Chemotherapy Service Ed., M.C. Perry, Williams & Wilkins, Baltimore, MD (1992). The antibody, oligopeptide or organic molecule may be combined with an anti-hormonal compound; e.g., an anti-estrogen compound such as tamoxifen; an anti-progesterone such as onapristone (see, EP 616 812); 10 or an anti-androgen such as flutamide, in dosages known for such molecules. Where the cancer to be treated is androgen independent cancer, the patient may previously have been subjected to anti-androgen therapy and, after the cancer becomes androgen independent, the anti-TAT antibody, oligopeptide or organic molecule (and optionally other agents as described herein) may be administered to the patient. Sometimes, it may be beneficial to also co-administer a cardioprotectant (to prevent or reduce 15 myocardial dysfunction associated with the therapy) or one or more cytokines to the patient. In addition to the above therapeutic regimes, the patient may be subjected to surgical removal of cancer cells and/or radiation therapy, before, simultaneously with, or post antibody, oligopeptide or organic molecule therapy. Suitable dosages for any of the above co-administered agents are those presently used and may be lowered due to the combined action (synergy) of the agent and anti-TAT antibody, oligopeptide or organic molecule. 20 For the prevention or treatment of disease, the dosage and mode of administration will be chosen by the physician according to known criteria. The appropriate dosage of antibody, oligopeptide or organic molecule will depend on the type of disease to be treated, as defined above, the severity and course of the disease, whether the antibody, oligopeptide or organic molecule is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, oligopeptide or organic molecule, 25 and the discretion of the attending physician. The antibody, oligopeptide or organic molecule is suitably administered to the patient at one time or over a series of treatments. Preferably, the antibody, oligopeptide or organic molecule is administered by intravenous infusion or by subcutaneous injections. Depending on the type and severity of the disease, about 1 ptg/kg to about 50 mg/kg body weight (e.g., about 0.1-15mg/kg/dose) of antibody can be an initial candidate dosage for administration to the patient, whether, for example, by one 30 or more separate administrations, or by continuous infusion. A dosing regimen can comprise administering an initial loading dose of about 4 mg/kg, followed by a weekly maintenance dose of about 2 mg/kg of the anti-TAT antibody. However, other dosage regimens may be useful. A typical daily dosage might range from about 1 pg/kg to 100 mg/kg or more, depending on the factors mentioned above. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of 35 disease symptoms occurs. The progress of this therapy can be readily monitored by conventional methods and assays and based on criteria known to the physician or other persons of skill in the art. 124 WO 2004/060270 PCT/US2003/029126 Aside from administration of the antibody protein to the patient, the present application contemplates administration of the antibody by gene therapy. Such administration of nucleic acid encoding the antibody is encompassed by the expression "administering a therapeutically effective amount of an antibody". See, for example, W096/07321 published March 14, 1996 concerning the use of gene therapy to generate intracellular antibodies. 5 There are two major approaches to getting the nucleic acid (optionally contained in a vector) into the patient's cells; in vivo and ex vivo. For in vivo delivery the nucleic acid is injected directly into the patient, usually at the site where the antibody is required. For ex vivo treatment, the patient's cells are removed, the nucleic acid is introduced into these isolated cells and the modified cells are administered to the patient either directly or, for example, encapsulated within porous membranes which are implanted into the patient (see, e.g., 10 U.S. Patent Nos. 4,892,538 and 5,283,187). There are a variety of techniques available for introducing nucleic acids into viable cells. The techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro, or in vivo in the cells of the intended host. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, DEAE dextran, the calcium phosphate precipitation method, etc. A commonly used vector forex vivo delivery of the 15 gene is a retroviral vector. The currently preferred in vivo nucleic acid transfer techniques include transfection with viral vectors (such as adenovirus, Herpes simplex I virus, or adeno-associated virus) and lipid-based systems (useful lipids for lipid-mediated transfer of the gene are DOTMA, DOPE and DC-Chol, for example). For review of the currently known gene marking and gene therapy protocols see Anderson et al., Science 256:808-813 (1992). 20 See also WO 93/25673 and the references cited therein. The anti-TAT antibodies of the invention can be in the different forms encompassed by the definition of "antibody" herein. Thus, the antibodies include full length or intact antibody, antibody fragments, native sequence antibody or amino acid variants, humanized, chimeric or fusion antibodies, immunoconjugates, and functional fragments thereof. In fusion antibodies an antibody sequence is fused to a heterologous polypeptide 25 sequence. The antibodies can be modified in the Fc region to provide desired effector functions. As discussed in more detail in the sections herein, with the appropriate Fc regions, the naked antibody bound on the cell surface can induce cytotoxicity, e.g., via antibody-dependent cellular cytotoxicity (ADCC) or by recruiting complement in complement dependent cytotoxicity, or some other mechanism. Alternatively, where it is desirable to eliminate or reduce effector function, so as to minimize side effects or therapeutic complications, 30 certain other Fc regions may be used. In one embodiment, the antibody competes for binding or bind substantially to, the same epitope as the antibodies of the invention. Antibodies having the biological characteristics of the present anti-TAT antibodies of the invention are also contemplated, specifically including the in vivo tumor targeting and any cell proliferation inhibition or cytotoxic characteristics. 35 Methods of producing the above antibodies are described in detail herein. The present anti-TAT antibodies, oligopeptides and organic molecules are useful for treating a TAT expressing cancer or alleviating one or more symptoms of the cancer in a mammal. Such a cancer includes 125 WO 2004/060270 PCT/US2003/029126 prostate cancer, cancer of the urinary tract, lung cancer, breast cancer, colon cancer and ovarian cancer, more specifically, prostate adenocarcinoma, renal cell carcinomas, colorectal adenocarcinomas, lung adenocarcinomas, lung squamous cell carcinomas, and pleural mesothelioma. The cancers encompass metastatic cancers of any of the preceding. The antibody, oligopeptide or organic molecule is able to bind to at least a portion of the cancer cells that express TAT polypeptide in the mammal. In a preferred embodiment, the 5 antibody, oligopeptide or organic molecule is effective to destroy or kill TAT-expressing tumor cells or inhibit the growth of such tumor cells, in vitro or in vivo, upon binding to TAT polypeptide on the cell. Such an antibody includes a naked anti-TAT antibody (not conjugated to any agent). Naked antibodies that have cytotoxic or cell growth inhibition properties can be further harnessed with a cytotoxic agent to render them even more potent in tumor cell destruction. Cytotoxic properties can be conferred to an anti-TAT antibody by, 10 e.g., conjugating the antibody with a cytotoxic agent, to form an immunoconjugate as described herein. The cytotoxic agent or a growth inhibitory agent is preferably a small molecule. Toxins such as calicheamicin or a maytansinoid and analogs or derivatives thereof, are preferable. The invention provides a composition comprising an anti-TAT antibody, oligopeptide or organic molecule of the invention, and a carrier. For the purposes of treating cancer, compositions can be administered 15 to the patient in need of such treatment, wherein the composition can comprise one or more anti-TAT antibodies present as an immunoconjugate or as the naked antibody. In a further embodiment, the compositions can comprise these antibodies, oligopeptides or organic molecules in combination with other therapeutic agents such as cytotoxic or growth inhibitory agents, including chemotherapeutic agents. The invention also provides formulations comprising an anti-TAT antibody, oligopeptide or organic molecule of the invention, and a carrier. 20 In one embodiment, the formulation is a therapeutic formulation comprising a pharmaceutically acceptable carrier. Another aspect of the invention is isolated nucleic acids encoding the anti-TAT antibodies. Nucleic acids encoding both the H and L chains and especially the hypervariable region residues, chains which encode the native sequence antibody as well as variants, modifications and humanized versions of the antibody, are 25 encompassed. The invention also provides methods useful for treating a TAT polypeptide-expressing cancer or alleviating one or more symptoms of the cancer in a mammal, comprising administering a therapeutically effective amount of an anti-TAT antibody, oligopeptide or organic molecule to the mammal. The antibody, oligopeptide or organic molecule therapeutic compositions can be administered short term (acute) or chronic, 30 or intermittent as directed by physician. Also provided are methods of inhibiting the gronith of, and killing a TAT polypeptide-expressing cell. The invention also provides kits and articles of manufacture comprising at least one anti-TAT antibody, oligopeptide or organic molecule. Kits containing anti-TAT antibodies, oligopeptides or organic molecules find use, e.g., for TAT cell killing assays, for purification or immunoprecipitation of TAT polypeptide from cells. 35 For example, for isolation and purification of TAT, the kit can contain an anti-TAT antibody, oligopeptide or organic molecule coupled to beads (e.g., sepharose beads). Kits can be provided which contain the antibodies, oligopeptides or organic molecules for detection and quantitation of TAT in vitro, e.g., in an ELISA or a 126 WO 2004/060270 PCT/US2003/029126 Western blot. Such antibody, oligopeptide or organic molecule useful for detection may be provided with a label such as a fluorescent or radiolabel. L. Articles of Manufacture and Kits Another embodiment of the invention is an article of manufacture containing materials useful for the treatment of anti-TAT expressing cancer. The article of manufacture comprises a container and a label or 5 package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is effective for treating the cancer condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is an anti-TAT antibody, oligopeptide or organic 10 molecule of the invention. The label or package insert indicates that the composition is used for treating cancer. The label or package insert will further comprise instructions for administering the antibody, oligopeptide or organic molecule composition to the cancer patient. Additionally, the article of manufacture may further comprise a second container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include 15 other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes. Kits are also provided that are useful for various purposes , e.g., for TAT-expressing cell killing assays, for purification or immunoprecipitation of TAT polypeptide from cells. For isolation and purification of TAT polypeptide, the kit can contain an anti-TAT antibody, oligopeptide or organic molecule coupled to 20 beads (e.g., sepharose beads). Kits can be provided which contain the antibodies, oligopeptides or organic molecules for detection and quantitation of TAT polypeptide in vitro, e.g., in an ELISA or a Western blot. As with the article of manufacture, the kit comprises a container and a label or package insert on or associated with the container. The container holds a composition comprising at least one anti-TAT antibody, oligopeptide or organic molecule of the invention. Additional containers may be included that contain, e.g., diluents and 25 buffers, control antibodies. The label or package insert may provide a description of the composition as well as instructions for the intended in vitro or diagnostic use. M. Uses for TAT Polypeptides and TAT-Polypeptide Encoding Nucleic Acids 30 Nucleotide sequences (or their complement) encoding TAT polypeptides have various applications in the art of molecular biology, including uses as hybridization probes, in chromosome and gene mapping and in the generation of anti-sense RNA and DNA probes. TAT-encoding nucleic acid will also be useful for the preparation of TAT polypeptides by the recombinant techniques described herein, wherein those TAT polypeptides may find use, for example, in the preparation of anti-TAT antibodies as described herein. 5 The full-length native sequence TAT gene, or portions thereof, may be used as hybridization probes for a cDNA library to isolate the full-length TAT cDNA or to isolate still other cDNAs (for instance, those encoding naturally-occurring variants of TAT or TAT from other species) which have a desired sequence 127 WO 2004/060270 PCT/US2003/029126 identity to the native TAT sequence disclosed herein. Optionally, the length of the probes will be about 20 to about 50 bases. The hybridization probes may be derived from at least partially novel regions of the full length native nucleotide sequence wherein those regions may be determined without undue experimentation or from genomic sequences including promoters, enhancer elements and introns of native sequence TAT. By way of example, a screeningmethod will comprise isolating the coding region of the TAT gene using the known DNA 5 sequence to synthesize a selected probe of about 40 bases. Hybridization probes may be labeled by a variety of labels, including radionucleotides such as 3P or 5S, or enzymatic labels such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems. Labeled probes having a sequence complementary to that of the TAT gene of the present invention can be used to screen libraries of human cDNA, genomic DNA or mRNA to determine which members of such libraries the probe hybridizes to. Hybridization techniques are described 10 in further detail in the Examples below. Any EST sequences disclosed in the present application may similarly be employed as probes, using the methods disclosed herein. Other useful fragments of the TAT-encoding nucleic acids include antisense or sense oligonucleotides comprising a singe-stranded nucleic acid sequence (either RNA or DNA) capable of binding to target TAT mRNA (sense) or TAT DNA (antisense) sequences. Antisense or sense oligonucleotides, according to the 15 present invention, comprise a fragment of the coding region of TAT DNA. Such a fragment generally comprises at least about 14 nucleotides, preferably from about 14 to 30 nucleotides. The ability to derive an antisense or a sense oligonucleotide, based upon a cDNA sequence encoding a given protein is described in, for example, Stein and Cohen (Cancer Res. 48:2659, 1988) and van der Krol et al. (BioTechniques 6:958, 1988). Binding of antisense or sense oligonucleotides to target nucleic acid sequences results in the formation 20 of duplexes that block transcription or translation of the target sequence by one of several means, including enhanced degradation of the duplexes, premature termination of transcription or translation, or by other means. Such methods are encompassed by the present invention. The antisense oligonucleotides thus may be used to block expression of TAT proteins, wherein those TAT proteins may play a role in the induction of cancer in mammals. Antisense or sense oligonucleotides further comprise oligonucleotides having modified sugar 25 phosphodiester backbones (or other sugar linkages, such as those described in WO 91/06629) and wherein such sugar linkages are resistant to endogenous nucleases. Such oligonucleotides with resistant sugar linkages are stable in vivo (i.e., capable of resisting enzymatic degradation) but retain sequence specificity to be able to bind to target nucleotide sequences. Preferred intragenic sites for antisense binding include the region incorporating the translation 30 initiation/start codon (5'-AUG / 5'-ATG) or termination/stop codon (5'-UAA, 5'-UAG and 5-UGA / 5'-TAA, 5'-TAG and 5'-TGA) of the open reading frame (ORF) of the gene. These regions refer to a portion of the mRNA or gene that encompasses from about 25 to about 50 contiguous nucleotides in either direction (i.e., 5' or 3') from a translation initiation or termination codon. Other preferred regions for antisense binding include: introns; exons; intron-exon junctions; the open reading frame (ORF) or "coding region," which is the region 35 between the translation initiation codon and the translation termination codon; the 5' cap of an mRNA which comprises an N7-methylated guanosine residue joined to the 5'-most residue of the mRNA via a 5-5' triphosphate linkage and includes 5' cap structure itself as well as the first 50 nucleotides adjacent to the cap; 128 WO 2004/060270 PCT/US2003/029126 the 5' untranslated region (5'UTR), the portion of an mRNA in the 5' direction from the translation initiation codon, and thus including nucleotides between the 5' cap site and the translation initiation codon of an mRNA or corresponding nucleotides on the gene; and the 3' untranslated region (3'UTR), the portion of an mRNA in the 3' direction from the translation termination codon, and thus including nucleotides between the translation termination codon and 3' end of an mRNA or corresponding nucleotides on the gene. 5 Specific examples of preferred antisense compounds useful for inhibiting expression of TAT proteins include oligonucleotides containing modified backbones or non-natural internucleoside linkages. Oligonucleotides having modified backbones include those that retain a phosphorus atom in the backbone and those that do not have a phosphorus atom in the backbone. For the purposes of this specification, and as sometimes referenced in the art, modified oligonucleotides that do not have a phosphorus atom in their intemucleoside backbone can 10 also be considered to be oligonucleosides. Preferred modified oligonucleotide backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotri-esters, methyl and other alkyl phosphonates including 3'-alkylene phosphonates, 5'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3'-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, 15 selenophosphates and borano-phosphates having normal 3'-5' linkages, 2'-5' linked analogs of these, and those having inverted polarity wherein one or more internucleotide linkages is a 3' to 3', 5' to 5' or 2' to 2' linkage. Preferred oligonucleotides having inverted polarity comprise a single 3' to 3' linkage at the 3'-most internucleotide linkage i.e. a single inverted nucleoside residue which may be abasic (the nucleobase is missing or has a hydroxyl group in place thereof). Various salts, mixed salts and free acid forms are also included. 20 Representative United States patents that teach the preparation of phosphorus-containing linkages include, but are not limited to, U.S. Pat. Nos.: 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,196; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,306; 5,550,111; 5,563,253; 5,571,799; 5,587,361; 5,194,599; 5,565,555; 5,527,899; 5,721,218; 5,672,697 and 5,625,050, each of which is herein incorporated 25 by reference. Preferred modified oligonucleotide backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic 30 internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; riboacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, 0, S and CH.sub.2 component parts. Representative 35 United States patents that teach the preparation of such oligonucleosides include, but are not limited to,. U.S. Pat. Nos.: 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,264,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 129 WO 2004/060270 PCT/US2003/029126 5,610,289; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437; 5,792,608; 5,646,269 and 5,677,439, each of which is herein incorporated by reference. In other preferred antisense oligonucleotides, both the sugar and the internucleoside linkage, i.e., the backbone, of the nucleotide units are replaced with novel groups. The base units are maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound, an oligonucleotide mimetic 5 that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar-backbone of an oligonucleotide is replaced with an aide containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the aide portion of the backbone. Representative United States patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos.: 5,539,082; 5,714,331; and 10 5,719,262, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found in Nielsen et al., Science, 1991, 254, 1497-1500. Preferred antisense oligonucleotides incorporate phosphorothioate backbones and/or heteroatom backbones, and in particular -CH 2 -NH-0-CH-, -CH 2
-N(CH
3 )-O-CH- [known as a methylene (methylimino) or MMI backbone], -CH 2
-O-N(CH
3 )-CH-, -CH 2
-N(CH
3
)-N(CH
3 )-CH- and -O-N(CH 3 )-CHrCH- [wherein 15 the native phosphodiester backbone is represented as -O-P-O-CH-] described in the above referenced U.S. Pat. No. 5,489,677, and the aide backbones of the above referenced U.S. Pat. No. 5,602,240. Also preferred are antisense oligonucleotides having morpholino backbone structures of the above-referenced U.S. Pat. No. 5,034,506. Modified oligonucleotides may also contain one or more substituted sugar moieties. Preferred 20 oligonucleotides comprise one of the following at the 2' position: OH; F; O-alkyl, S-alkyl, or N-alkyl; 0 alkenyl, S-alkeynyl, or N-alkenyl; O-alkynyl, S-alkynyl or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted C 1 to C , alkyl or C 2 to C 0 alkenyl and alkynyl. Particularly preferred are O[(CH 2 ).O]mCH 3 , O(CH 2
).OCH
3 , O(CH 2 )nNH 2 , O(CH 2
).CH
3 , O(CH 2 )nONH 2 , and
O(CH
2 )a 1
ON[(CH
2
).CH
3
)]
2 , where n and m are from 1 to about 10. Other preferred antisense oligonucleotides 25 comprise one of the following at the 2' position: C 1 to C,, lower alkyl, substituted lower alkyl, alkenyl, alkynyl, alkaryl, aralkyl, 0-alkaryl or O-aralkyl, SH, SCH 3 , OCN, Cl, Br, CN, CF 3 , OCF 3 , SOCH 3 , SO 2 CH,, ONO 2 ,
NO
2 , N,, NH 2 , heterocycloalkyl, heterocycloalkaryl, aminoalkylarnino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide, and 30 other substituents having similar properties. A preferred modification includes 2'-methoxyethoxy (2'-O-CH 2
CH
2
OCH
3 , also known as 2'-O-(2-methoxyethyl) or 2'-MOE) (Martin et al., Helv. Chim. Acta, 1995, 78, 486-504) i.e., an alkoxyalkoxy group. A further preferred modification includes 2'-dimethylaminooxyethoxy, i.e., a O(CH 2
)
2 ON(CH3) 2 group, also known as 2'-DMAOE, as described in examples hereinbelow, and 2'-dimethylaminoethoxyethoxy (also known in the art as 35 2'-0-dimethylaminoethoxyethyl or 2'-DMAEOE), i.e., 2'-O-CH 2
-O-CH
2
-N(CH
2 ). A further prefered modification includes Locked Nucleic Acids (LNAs) in which the 2'-hydroxyl group is linked to the 3' or 4' carbon atom of the sugar ring thereby forming a bicyclic sugar moiety. The linkage is 130 WO 2004/060270 PCT/US2003/029126 preferably a methelyne (-CH-)n group bridging the 2' oxygen atom and the 4' carbon atom wherein n is 1 or 2. LNAs and preparation thereof are described in WO 98/39352 and WO 99/14226. Other preferred modifications include 2-methoxy (2'-O-CHs), 2'-aminopropoxy (2'-OCHCH 2
CH
2
NH
2 ), 2'-allyl (2'-CHr-CH=CH 2 ), 2-O-allyl (2'-O-CH-CH=CH 2 ) and 2-fluoro (2'-F). The 2'-modification may be in the arabino (up) position or ribo (down) position. A preferred 2'-arabino modification is 2'-F. Similar 5 modifications may also be made at other positions on the oligonucleotide, particularly the 3' position of the sugar on the 3' terminal nucleotide or in 2'-5' linked oligonucleotides and the 5' position of 5' terminal nucleotide. Oligonucleotides may also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar. Representative United States patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos.: 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 10 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; 5,792,747; and 5,700,920, each of which is herein incorporated by reference in its entirety. Oligonucleotides may also include nucleobase (often referred to in the art simply as "base") modifications or substitutions. As used herein, "unmodified" or "natural" nucleobases include the purine bases 15 adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified nucleobases include other synthetic and natural nucleobases such as 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl (-C=C-CH 3 or -CH,-C=CH) uracil and cytosine and 20 other alkynyl derivatives of pyrimidine bases, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 2-F-adenine, 2-amino-adenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine. Further modified nucleobases include tricyclic 25 pyrimidines such as phenoxazine cytidine(1H-pyrimido[5,4-b][1,4]benzoxazin-2(3H)-one), phenothiazine cytidine (lH-pyrimido[5,4-b][1,4]benzothiazin-2(3H)-one), G-clamps such as a substituted phenoxazine cytidine (e.g. 9-(2-aminoethoxy)-H-pyrimido[5,4-b][ 1, 4]benzoxazin-2(3H)-one), carbazole cytidine (2H-pyrimido[4,5-b]indol-2-one), pyridoindole cytidine (H-pyrido[3',2':4,5]pyrrolo[2,3-dJpyrimidin-2-one). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other 30 heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobases include those disclosed in U.S. Pat. No. 3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859, Kroschwitz, J. I., ed. John Wiley & Sons, 1990, and those disclosed by Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613. Certain of these nucleobases are particularly useful for increasing the binding affinity of the oligomeric compounds of the 35 invention. These include 5-substituted pyrimidines, 6-azapyriinidines and N-2, N-6 and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5-methyleytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2.degree. C. (Sanghvi et al, Antisense Research 131 WO 2004/060270 PCT/US2003/029126 and Applications, CRC Press, Boca Raton, 1993, pp. 276-278) and are preferred base substitutions, even more particularly when combined with 2'-O-methoxyethyl sugar modifications. Representative United States patents that teach the preparation of modified nucleobases include, but are not limited to: U.S. Pat. No. 3,687,808, as well as U.S. Pat. Nos.: 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121, 5,596,091; 5,614,617; 5 5,645,985; 5,830,653; 5,763,588; 6,005,096; 5,681,941 and 5,750,692, each of which is herein incorporated by reference. Another modification of antisense oligonucleotides chemically linking to the oligonucleotide one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. The compounds of the invention can include conjugate groups covalently bound to functional 10 groups such as primary or secondary hydroxyl groups. Conjugate groups of the invention include intercalators, reporter molecules, polyamines, polyamides, polyethylene glycols, polyethers, groups that enhance the pharmacodynamic properties of oligomers, and groups that enhance the pharmacokinetic properties of oligomers. Typical conjugates groups include cholesterols, lipids, cation lipids, phospholipids, cationic phospholipids, biotin, phenazine, folate, phenanthridine, anthraquinone, acridine, fluoresceins, rhodamines, 15 coumarins, and dyes. Groups that enhance the pharmacodynamic properties, in the context of this invention, include groups that improve oligomer uptake, enhance oligomer resistance to degradation, and/or strengthen sequence-specific hybridization with RNA. Groups that enhance the pharmacokinetic properties, in the context of this invention, include groups that improve oligomer uptake, distribution, metabolism or excretion. Conjugate moieties include but are not limited to lipid moieties such as a cholesterol moiety (Letsinger et al., Proc. Natl. 20 Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Let., 1994, 4, 1053-1060), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem. Let., 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20, 533-538), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al., EMBO J., 1991, 10, 1111-1118; Kabanov et al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., 25 Biochimie, 1993, 75, 49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al., Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969-973), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 30 1264, 229-237), or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety. Oligonucleotides of the invention may also be conjugated to active drug substances, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fenbufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indomethicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic. 35 Oligonucleotide-drug conjugates and their preparation are described in U.S. patent application Ser. No. 09/334, 130 (filed Jun. 15, 1999) and United States patents Nos.: 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; 5,545,730; 5,552,538; 5,578,717, 5,580,731; 5,580,731; 5,591,584; 5,109,124; 5,118,802; 132 WO 2004/060270 PCT/US2003/029126 5,138,045; 5,414,077; 5,486,603; 5,512,439; 5,578,718; 5,608,046; 4,587,044; 4,605,735; 4,667,025; 4,762,779; 4,789,737; 4,824,941; 4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082,830; 5,112,963; 5,214,136; 5,082,830; 5,112,963; 5,214,136; 5,245,022; 5,254,469; 5,258,506; 5,262,536; 5,272,250; 5,292,873; 5,317,098; 5,371,241, 5,391,723; 5,416,203, 5,451,463; 5,510,475; 5,512,667; 5,514,785; 5,565,552; 5,567,810; 5,574,142; 5,585,481; 5,587,371; 5,595,726; 5,597,696; 5,599,923; 5,599,928 and 5 5,688,941, each of which is herein incorporated by reference. It is not necessary for all positions in a given compound to be uniformly modified, and in fact more than one of the aforementioned modifications may be incorporated in a single compound or even at a single nucleoside within an oligonucleotide. The present invention also includes antisense compounds which are chimeric compounds. "Chimeric" antisense compounds or "chimeras," in the context of this invention, are 10 antisense compounds, particularly oligonucleotides, which contain two or more chemically distinct regions, each made up of at least one monomer unit, i.e., a nucleotide in the case of an oligonucleotide compound. These oligonucleotides typically contain at least one region wherein the oligonucleotide is modified so as to confer upon the oligonucleotide increased resistance to nuclease degradation, increased cellular uptake, and/or increased binding affinity for the target nucleic acid. An additional region of the oligonucleotide may serve as a substrate 15 for enzymes capable of cleaving RNA:DNA or RNA:RNA hybrids. By way of example, RNase H is a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of oligonucleotide inhibition of gene expression. Consequently, comparable results can often be obtained with shorter oligonucleotides when chimeric oligonucleotides are used, compared to phosphorothioate deoxyoligonucleotides hybridizing to the same target 20 region. Chimeric antisense compounds of the invention may be formed as composite structures of two or more oligonucleotides, modified oligonucleotides, oligonucleosides and/or oligonucleotide mimetics as described above. Preferred chimeric antisense oligonucleotides incorporate at least one 2' modified sugar (preferably 2'-O-(CH 2
)
2
-O-CH
3 ) at the 3' terminal to confer nuclease resistance and a region with at least 4 contiguous 2'-H sugars to confer RNase H activity. Such compounds have also been referred to in the art as hybrids or gapmers. 25 Preferred gapmers have a region of 2' modified sugars (preferably 2'-O-(CH 2 )-O-CH) at the 3'-terminal and at the 5' terminal separated by at least one region having at least 4 contiguous 2'-H sugars and preferably incorporate phosphorothioate backbone linkages. Representative United States patents that teach the preparation of such hybrid structures include, but are not limited to, U.S. Pat. Nos. 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711; 5,491,133; 5,565,350; 5,623,065; 5,652,355; 5,652,356; and 5,700,922, 30 each of which is herein incorporated by reference in its entirety. The antisense compounds used in accordance with this invention may be conveniently and routinely made through the well-known technique of solid phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, Calif.). Any other means for such synthesis known in the art may additionally or alternatively be employed. It is well known to use similar 35 techniques to prepare oligonucleotides such as the phosphorothioates and alkylated derivatives. The compounds of the invention may also be admixed, encapsulated, conjugated or otherwise associated with other molecules, molecule structures or mixtures of compounds, as for example, liposomes, receptor targeted molecules, oral, 133 WO 2004/060270 PCT/US2003/029126 rectal, topical or other formulations, for assisting in uptake, distribution and/or absorption. Representative United States patents that teach the preparation of such uptake, distribution and/or absorption assisting formulations include, but are not limited to, U.S. Pat. Nos. 5,108,921; 5,354,844; 5,416,016; 5,459,127; 5,521,291; 5,543,158; 5,547,932; 5,583,020; 5,591,721; 4,426,330; 4,534,899; 5,013,556; 5,108,921; 5,213,804; 5,227,170; 5,264,221; 5,356,633; 5,395,619; 5,416,016; 5,417,978; 5,462,854; 5,469,854; 5 5,512,295; 5,527,528; 5,534,259; 5,543,152; 5,556,948; 5,580,575; and 5,595,756, each of which is herein incorporated by reference. Other examples of sense or antisense oligonucleotides include those oligonucleotides which are covalently linked to organic moieties, such as those described in WO 90/10048, and other moieties that increases affinity of the oligonucleotide for a target nucleic acid sequence, such as poly-(L-lysine). Further still, 10 intercalating agents, such as ellipticine, and alkylating agents or metal complexes may be attached to sense or antisense oligonucleotides to modify binding specificities of the antisense or sense oligonucleotide for the target nucleotide sequence. Antisense or sense oligonucleotides may be introduced into a cell containing the target nucleic acid sequence by any gene transfer method, including, for example, CaPO,-mediated DNA transfection, 15 electroporation, or by using gene transfer vectors such as Epstein-Barr virus. In a preferred procedure, an antisense or sense oligonucleotide is inserted into a suitable retroviral vector. A cell containing the target nucleic acid sequence is contacted with the recombinant retroviral vector, either in vivo or ex vivo. Suitable retroviral vectors include, but are not limited to, those derived from the murine retrovirus M-MuLV, N2 (a retrovirus derived from M-MuLV), or the double copy vectors designated DCT5A, DCT5B and DCT5C (see 20 WO 90/13641). Sense or antisense oligonucleotides also may be introduced into a cell containing the target nucleotide sequence by formation of a conjugate with a ligand binding molecule, as described in WO 91/04753. Suitable ligand binding molecules include, but are not limited to, cell surface receptors, growth factors, other cytokines, or other ligands that bind to cell surface receptors. Preferably, conjugation of the ligand binding molecule does 25 not substantially interfere with the ability of the ligand binding molecule to bind to its corresponding molecule or receptor, or block entry of the sense or antisense oligonucleotide or its conjugated version into the cell. Alternatively, a sense or an antisense oligonucleotide may be introduced into a cell containing the target nucleic acid sequence by formation of an oligonucleotide-lipid complex, as described in WO 90/10448. The 30 sense or antisense oligonucleotide-lipid complex is preferably dissociated within the cell by an endogenous lipase. Antisense or sense RNA or DNA molecules are generally at least about 5 nucleotides in length, alternatively at least about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 35 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 134 WO 2004/060270 PCT/US2003/029126 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 nucleotides in length, wherein in this context the term "about" means the referenced nucleotide sequence length plus or minus 10% of that referenced length. The probes may also be employed in PCR techniques to generate a pool of sequences for identification of closely related TAT coding sequences. 5 Nucleotide sequences encoding a TAT can also be used to construct hybridization probes for mapping the gene which encodes that TAT and for the genetic analysis of individuals with genetic disorders. The nucleotide sequences provided herein may be mapped to a chromosome and specific regions of a chromosome using known techniques, such as in situ hybridization, linkage analysis against known chromosomal markers, and hybridization screening with libraries. 10 When the coding sequences for TAT encode a protein which binds to another protein (example, where the TAT is a receptor), the TAT can be used in assays to identify the other proteins or molecules involved in the binding interaction. By such methods, inhibitors of the receptor/ligand binding interaction can be identified. Proteins involved in such binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction. Also, the receptor TAT can be used to isolate correlative ligand(s). 15 Screening assays can be designed to find lead compounds that mimic the biological activity of a native TAT or a receptor for TAT. Such screening assays will include assays amenable to high-throughput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates. Small molecules contemplated include synthetic organic or inorganic compounds. The assays can be performed in a variety of formats, including protein-protein binding assays, biochemical screening assays, immunoassays and 20 cell based assays, which are well characterized in the art. Nucleic acids which encode TAT or its modified forms can also be used to generate either transgenic animals or "knock out" animals which, in turn, are useful in the development and screening of therapeutically useful reagents. A transgenic animal (e.g., a mouse or rat) is an animal having cells that contain a transgene, which transgene was introduced into the animal or an ancestor of the animal at a prenatal, e.g., an embryonic 25 stage. A transgene is a DNA which is integrated into the genome of a cell from which a transgenic animal develops. In one embodiment, cDNA encoding TAT can be used to clone genomic DNA encoding TAT in accordance with established techniques and the genomic sequences used to generate transgenic animals that contain cells which express DNA encoding TAT. Methods for generating transgenic animals, particularly animals such as mice or rats, have become conventional in the art and are described, for example, in U.S. 30 Patent Nos. 4,736,866 and 4,870,009. Typically, particular cells would be targeted for TAT transgene incorporation with tissue-specific enhancers. Transgenic animals that include a copy of a transgene encoding TAT introduced into the germ line of the animal at an embryonic stage can be used to examine the effect of increased expression of DNA encoding TAT. Such animals can be used as tester animals for reagents thought to confer protection from, for example, pathological conditions associated with its overexpression. In 35 accordance with this facet of the invention, an animal is treated with the reagent and a reduced incidence of the pathological condition, compared to untreated animals bearing the transgene, would indicate a potential therapeutic intervention for the pathological condition. 135 WO 2004/060270 PCT/US2003/029126 Alternatively, non-human homologues of TAT can be used to construct a TAT "knock out" animal which has a defective or altered gene encoding TAT as a result of homologous recombination between the endogenous gene encoding TAT and altered genomic DNA encoding TAT introduced into an embryonic stem cell of the animal. For example, cDNA encoding TAT can be used to clone genomic DNA encoding TAT in accordance with established techniques. A portion of the genomic DNA encoding TAT can be deleted or 5 replaced with another gene, such as a gene encoding a selectable marker which can be used to monitor integration. Typically, several kilobases of unaltered flanking DNA (both at the 5' and 3' ends) are included in the vector [see e.g., Thomas and Capecchi, Cell, 51:503 (1987) for a description of homologous recombination vectors]. The vector is introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced DNA has homologously recombined with the endogenous DNA are selected 10 [see e.g., Li et al., Cell, 69:915 (1992)]. The selected cells are then injected into a blastocyst of an animal (e.g., a mouse or rat) to form aggregation chimeras [see e.g., Bradley, in Teratocarcinomas and Embryonic Stem Cells: A Practical Approach, E. J. Robertson, ed. (IRL, Oxford, 1987), pp. 113-152]. A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term to create a "knock out" animal. Progeny harboring the homologously recombined DNA in their germ cells can 15 be identified by standard techniques and used to breed animals in which all cells of the animal contain the homologously recombined DNA. Knockout animals can be characterized for instance, for their ability to defend against certain pathological conditions and for their development of pathological conditions due to absence of the TAT polypeptide. Nucleic acid encoding the TAT polypeptides may also be used in gene therapy. In gene therapy 20 applications, genes are introduced into cells in order to achieve in vivo synthesis of a therapeutically effective genetic product, for example for replacement of a defective gene. "Gene therapy" includes both conventional gene therapy where a lasting effect is achieved by a single treatment, and the administration of gene therapeutic agents, which involves the one time or repeated administration of a therapeutically effective DNA or mRNA. Antisense RNAs and DNAs can be used as therapeutic agents for blocking the expression of certain genes in 25 vivo. It has already been shown that short antisense oligonucleotides can be imported into cells where they act as inhibitors, despite their low intracellular concentrations caused by their restricted uptake by the cell membrane. (Zamecnik et al., Proc. Natl. Acad. Sci. USA 83:4143-4146 [1986]). The oligonucleotides can be modified to enhance their uptake, e.g. by substituting their negatively charged phosphodiester groups by uncharged groups. 30 There are a variety of techniques available for introducing nucleic acids into viable cells. The techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro, or in vivo in the cells of the intended host. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, DEAE-dextran, the calcium phosphate precipitation method, etc. The currently preferred in vivo gene transfer techniques include 35 transfection with viral (typically retroviral) vectors and viral coat protein-liposome mediated transfection (Dzau et al., Trends in Biotechnology 11, 205-210 [1993]). In some situations it is desirable to provide the nucleic acid source with an agent that targets the target cells, such as an antibody specific for a cell surface membrane 136 WO 2004/060270 PCT/US2003/029126 protein or the target cell, a ligand for a receptor on the target cell, etc. Where liposomes are employed, proteins which bind to a cell surface membrane protein associated with endocytosis may be used for targeting and/or to facilitate uptake, e.g. capsid proteins or fragments thereof tropic for a particular cell type, antibodies for proteins which undergo internalization in cycling, proteins that target intracellular localization and enhance intracellular half-life. The technique of receptor-mediated endocytosis is described, for example, by Wu et al., 5 J. Biol. Chem. 262, 4429-4432 (1987); and Wagner et al., Proc. Natl. Acad. Sci. USA 87, 3410-3414 (1990). For review of gene marking and gene therapy protocols see Anderson et al., Science 256, 808-813 (1992). The nucleic acid molecules encoding the TAT polypeptides or fragments thereof described herein are useful for chromosome identification. In this regard, there exists an ongoing need to identify new chromosome markers, since relatively few chromosome marking reagents, based upon actual sequence data are presently 10 available. Each TAT nucleic acid molecule of the present invention can be used as a chromosome marker. The TAT polypeptides and nucleic acid molecules of the present invention may also be used diagnostically for tissue typing, wherein the TAT polypeptides of the present invention may be differentially expressed in one tissue as compared to another, preferably in a diseased tissue as compared to a normal tissue of the same tissue type. TAT nucleic acid molecules will find use for generating probes for PCR, Northern 15 analysis, Southern analysis and Western analysis. This invention encompasses methods of screening compounds to identify those that mimic the TAT polypeptide (agonists) or prevent the effect of the TAT polypeptide (antagonists). Screening assays for antagonist drug candidates are designed to identify compounds that bind or complex with the TAT polypeptides encoded by the genes identified herein, or otherwise interfere with the interaction of the encoded polypeptides 20 with other cellular proteins, including e.g., inhibiting the expression of TAT polypeptide from cells. Such screening assays will include assays amenable to high-throughput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates. The assays can be performed in a variety of formats, including protein-protein binding assays, biochemical screening assays, immunoassays, and cell-based assays, which are well characterized in the art. 25 All assays for antagonists are common in that they call for contacting the drug candidate with a TAT polypeptide encoded by a nucleic acid identified herein under conditions and for a time sufficient to allow these two components to interact. In binding assays, the interaction is binding and the complex formed can be isolated or detected in the 30 reaction mixture. In a particular embodiment, the TAT polypeptide encoded by the gene identified herein or the drug candidate is immobilized on a solid phase, e.g., on a microtiter plate, by covalent or non-covalent attachments. Non-covalent attachment generally is accomplished by coating the solid surface with a solution of the TAT polypeptide and drying. Alternatively, an immobilized antibody, e.g., a monoclonal antibody, specific for the TAT polypeptide to be immobilized can be used to anchor it to a solid surface. The assay is 35 performed by adding the non-immobilized component, which may be labeled by a detectable label, to the immobilized component, e.g., the coated surface containing the anchored component. When the reaction is complete, the non-reacted components are removed, e.g., by washing, and complexes anchored on the solid 137 WO 2004/060270 PCT/US2003/029126 surface are detected. When the originally non-immobilized component carries a detectable label, the detection of label immobilized on the surface indicates that complexing occurred. Where the originally non-immobilized component does not carry a label, complexing can be detected, for example, by using a labeled antibody specifically binding the immobilized complex. If the candidate compound interacts with but does not bind to a particular TAT polypeptide encoded 5 by a gene identified herein, its interaction with that polypeptide can be assayed by methods well known for detecting protein-protein interactions. Such assays include traditional approaches, such as, e.g., cross-linking, co-immunoprecipitation, and co-purification through gradients or chromatographic columns. In addition, protein-protein interactions can be monitored by using a yeast-based genetic system described by Fields and co workers (Fields and Song, Nature (London). 340:245-246 (1989); Chien et al., Proc. Nat. Acad. Sci. USA. 10 88:9578-9582 (1991)) as disclosed by Chevray and Nathans, Proc. Natl. Acad. Sci. USA 89: 5789-5793 (1991). Many transcriptional activators, such as yeast GAL4, consist of two physically discrete modular domains, one acting as the DNA-binding domain, the other one functioning as the transcription-activation domain. The yeast expression system described in the foregoing publications (generally referred to as the "two hybrid system") takes advantage of this property, and employs two hybrid proteins, one in which the target 15 protein is fused to the DNA-binding domain of GAL4, and another, in which candidate activating proteins are fused to the activation domain. The expression of a GALl- lacZ reporter gene under control of a GAL4 activated promoter depends on reconstitution of GAL4 activity via protein-protein interaction. Colonies containing interacting polypeptides are detected with a chromogenic substrate for p-galactosidase. A complete kit (MATCHMAKER Tm ) for identifying protein-protein interactions between two specific proteins using the two 20 hybrid technique is commercially available from Clontech. This system can also be extended to map protein domains involved in specific protein interactions as well as to pinpoint amino acid residues that are crucial for these interactions. Compounds that interfere with the interaction of a gene encoding a TAT polypeptide identified herein and other intra- or extracellular components can be tested as follows: usually a reaction mixture is prepared 25 containing the product of the gene and the intra- or extracellular component under conditions and for a time allowing for the interaction and binding of the two products. To test the ability of a candidate compound to inhibit binding, the reaction is run in the absence and in the presence of the test compound. In addition, a placebo may be added to a third reaction mixture, to serve as positive control. The binding (complex formation) between the test compound and the intra- or extracellular component present in the mixture is monitored as 30 described hereinabove. The formation of a complex in the control reaction(s) but not in the reaction mixture containing the test compound indicates that the test compound interferes with the interaction of the test compound and its reaction partner. To assay for antagonists, the TAT polypeptide may be added to a cell along with the compound to be screened for a particular activity and the ability of the compound to inhibit the activity of interest in the presence 35 of the TAT polypeptide indicates that the compound is an antagonist to the TAT polypeptide. Alternatively, antagonists may be detected by combining the TAT polypeptide and a potential antagonist with membrane-bound TAT polypeptide receptors or recombinant receptors under appropriate conditions for a competitive inhibition 138 WO 2004/060270 PCT/US2003/029126 assay. The TAT polypeptide can be labeled, such as by radioactivity, such that the number of TAT polypeptide molecules bound to the receptor can be used to determine the effectiveness of the potential antagonist. The gene encoding the receptor can be identified by numerous methods known to those of skill in the art, for example, ligand panning and FACS sorting. Coligan et al., Current Protocols in Immun. 1(2): Chapter 5 (1991). Preferably, expression cloning is employed wherein polyadenylated RNA is prepared from a cell responsive to 5 the TAT polypeptide and a cDNA library created from this RNA is divided into pools and used to transfect COS cells or other cells that are not responsive to the TAT polypeptide. Transfected cells that are grown on glass slides are exposed to labeled TAT polypeptide. The TAT polypeptide can be labeled by a variety of means including iodination or inclusion of a recognition site for a site-specific protein kinase. Following fixation and incubation, the slides are subjected to autoradiographic analysis. Positive pools are identified and sub-pools are 10 prepared and re-transfected using an interactive sub-pooling and re-screening process, eventually yielding a single clone that encodes the putative receptor. As an alternative approach for receptor identification, labeled TAT polypeptide can be photoaffinity linked with cell membrane or extract preparations that express the receptor molecule. Cross-linked material is resolved by PAGE and exposed to X-ray film. The labeled complex containing the receptor can be excised, 15 resolved into peptide fragments, and subjected to protein micro-sequencing. The amino acid sequence obtained from micro- sequencing would be used to design a set of degenerate oligonucleotide probes to screen a cDNA library to identify the gene encoding the putative receptor. In another assay for antagonists, mammalian cells or a membrane preparation expressing the receptor would be incubated with labeled TAT polypeptide in the presence of the candidate compound. The ability of 20 the compound to enhance or block this interaction could then be measured. More specific examples of potential antagonists include an oligonucleotide that binds to the fusions of immunoglobulin with TAT polypeptide, and, in particular, antibodies including, without limitation, poly- and monoclonal antibodies and antibody fragments, single-chain antibodies, anti-idiotypic antibodies, and chimeric or humanized versions of such antibodies or fragments, as well as human antibodies and antibody fragments. 25 Alternatively, a potential antagonist may be a closely related protein, for example, a mutated form of the TAT polypeptide that recognizes the receptor but imparts no effect, thereby competitively inhibiting the action of the TAT polypeptide. Another potential TAT polypeptide antagonist is an antisense RNA or DNA construct prepared using antisense technology, where, e.g., an antisense RNA or DNA molecule acts to block directly the translation of 30 mRNA by hybridizing to targeted mRNA and preventing protein translation. Antisense technology can be used to control gene expression through triple-helix formation or antisense DNA or RNA, both of which methods are based on binding of a polynucleotide to DNA or RNA. For example, the 5' coding portion of the polynucleotide sequence, which encodes the mature TAT polypeptides herein, is used to design an antisense RNA oligonucleotide of from about 10 to 40 base pairs in length. A DNA oligonucleotide is designed to be 35 complementary to a region of the gene involved in transcription (triple helix - see Lee et al., Nucl. Acids Res., 6:3073 (1979); Cooney et al., Science 241: 456 (1988); Dervan et al., Science 251:1360 (1991)), thereby preventing transcription and the production of the TAT polypeptide. The antisense RNA oligonucleotide 139 WO 2004/060270 PCT/US2003/029126 hybridizes to the mRNA in vivo and blocks translation of the mRNA molecule into the TAT polypeptide (antisense - Okano, Neurochem. 56:560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression (CRC Press: Boca Raton, FL, 1988). The oligonucleotides described above can also be delivered to cells such that the antisense RNA or DNA may be expressed in vivo to inhibit production of the TAT polypeptide. When antisense DNA is used, oligodeoxyribonucleotides derived from the translation-initiation 5 site, e.g., between about -10 and +10 positions of the target gene nucleotide sequence, are preferred. Potential antagonists include small molecules that bind to the active site, the receptor binding site, or growth factor or other relevant binding site of the TAT polypeptide, thereby blocking the normal biological activity of the TAT polypeptide. Examples of small molecules include, but are not limited to, small peptides or peptide-like molecules, preferably soluble peptides, and synthetic non-peptidyl organic or inorganic 10 compounds. Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. Ribozymes act by sequence-specific hybridization to the complementary target RNA, followed by endonucleolytic cleavage. Specific ribozyme cleavage sites within a potential RNA target can be identified by knowntechniques. For further details see, e.g., RossCurrent Biology, 4:469-471 (1994), and PCT publication 15 No. WO 97/33551 (published September 18, 1997). Nucleic acid molecules in triple-helix formation used to inhibit transcription should be single-stranded and composed of deoxynucleotides. The base composition of these oligonucleotides is designed such that it promotes triple-helix formation via Hoogsteen base-pairing rules, which generally require sizeable stretches of purines or pyrimidines on one strand of a duplex. For further details see, e.g., PCT publication No. WO 20 97/33551, supra. These small molecules can be identified by any one or more of the screening assays discussed hereinabove and/or by any other screening techniques well known for those skilled in the art. Isolated TAT polypeptide-encoding nucleic acid can be used herein for recombinantly producing TAT polypeptide using techniques well known in the art and as described herein. In turn, the produced TAT 25 polypeptides can be employed for generating anti-TAT antibodies using techniques well known in the art and as described herein. Antibodies specifically binding a TAT polypeptide identified herein, as well as other molecules identified by the screening assays disclosed hereinbefore, can be administered for the treatment of various disorders, including cancer, in the form of pharmaceutical compositions. 30 If the TAT polypeptide is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred. However, lipofections or liposomes can also be used to deliver the antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred. For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the 35 target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. See, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA. 90: 7889-7893 (1993). The formulation herein may also contain more than one active compound as necessary for the particular 140 WO 2004/060270 PCT/US2003/029126 indication being treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the composition may comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended. The following examples are offered for illustrative purposes only, and are not intended to limit the 5 scope of the present invention in any way. All patent and literature references cited in the present specification are hereby incorporated by reference in their entirety. EXAMPLES 10 Commercially available reagents referred to in the examples were used according to manufacturer's instructions unless otherwise indicated. The source of those cells identified in the following examples, and throughout the specification, by ATCC accession numbers is the American Type Culture Collection, Manassas, VA. 15 EXAMPLE 1: Identification of Tumor-Specific Amplified Chromosomal Regions From the GenBank and NCBI databases, we retrieved over 4-million EST sequences representing a variety of normal and diseased tissues. Excluding ESTs from normalized or subtracted libraries, there are approximately 1.2 million EST sequences from normal and 1.7 million EST sequences from tumor tissues. In order to quantify the expression level for each known or novel gene for a tissue of interest, we computed the 20 normalized EST abundance and expressed this as the digital expression level (DEL = EST abundance per million ESTs). In our previous studies, we have found a linear correlation between DEL and normalized mRNA level measured by real-time PCR analysis. The DEL values for each gene can then be plotted along each chromosome according to its genomic coordinates, producing transcriptome maps for both normal and tumor tissues in each tissue. In some specific 25 regions, genes located close to one another appeared to be co-upregulated in the tumor tissue when compared with normal. One such example is a 1.8 MB region corresponding to chromosome 17ql 1 where 33 genes are expressed at a higher level in the breast tumor samples than in normal breast tissue (data not shown). This region, which includes the ERBB2 gene, is known to be amplified in 30% of breast cancer patients and roughly corresponds to known breast tumor amplicons in size. We were able to visually identify a number of other 30 tumor-related regions like this one, which we herein call RITEs (regions of increased tumor expression). To determine whether RITEs merely represent isolated cases or common features on chromosome, we took a computational approach to identify all RITEs in ten different tumor types. For each gene, a two-proportion Z-test was performed using the EST distribution data in normal and tumor samples, and the resulting Z-score was used to measure the extent of upregulation in the tumor. In order to systematically 35 identify RITEs and to reduce noises caused by individual genes, we scanned the human genome in a 500-KB window with a 100-KB offset and calculated the trimmed mean of Z-scores (TMZ) for the genes in each window. We then empirically devised a sensing index that captures consecutive windows with TMZ above 141 WO 2004/060270 PCT/US2003/029126 genomic average. Scanning the genomic regions with the breast data revealed a number of genomic regions with an exceptionally high sensing index (data not shown). When the cutoff of sensing index was empirically set to 3, we found 67 RITEs for breast tumor as compared to normal breast tissue. Since EST clones come from multiple individual tissue libraries, these RITEs are representations of the entire patient population with breast cancer rather than individual patients. We then refined the boundaries of each RITE by trimming off 5 genes on each side whose Z-scores were less than 4 times the genomic mean. Visual inspection of these putative RITEs confirmed clusters of genes with higher expression in a tumor type. To address the concern that the RITEs identified are simply coincidental clustering of individual tumor-specific genes, we performed a series of permutation analyses where the chromosomal coordinates of each gene were randomly shuffled with other available coordinates. We analyzed 10,000 permuted breast data 10 sets to record the number of RITEs. Under permuted condition, the average number of RITEs was 5.4 with a standard deviation of 1.2, which is significantly below that detected under the native condition. We also performed similar analyses on nine other tissues: brain, colon, kidney, liver, lung, pancreas, prostate, stomach, and testis, respectively. In all tissues, the observed number of RITEs under native conditions was at least 25 standard deviations higher than the average number in the permutations. This demonstrates that the clustering 15 of tumor-upregulated genes is not the result of random variation in the distribution of these genes over the genome. The presence of these RITEs could be attributed to either genomic alteration or transcriptional control. To examine the relationship between RITEs and known amplicons, we retrieved the cytogenetic marker for each RITE to compare with known data. Identification of amplicons in tumor usually requires laborious approaches 20 such as fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH). In brain, breast, and lung tissues where CGH data are most abundant, about 50% of RITEs correspond to amplicons identified by CGH analysis, suggesting that these RITEs are the results of genomic DNA amplification in tumor. The alternative mechanism for the presence of RITEs requires coordinated gene expression at the transcription level. Even though eukaryotic genes are known to be controlled on an individual basis, there is accumulating 25 evidence for large domains of similarly expressed genes in eukaryotic genomes. A preliminary analysis of the upstream DNA sequences failed to identify promoter elements common to all genes in the RITE regions (data not shown); however, it is still possible that these regions are organized in some forms of chromosomal scaffold that enable coordinated expression in tumor. In summary, by using a computational approach and available public data sources, we were able to 30 rapidly identify non-random clusters of genes with increased expression in tumors. It is likely most of the herein identified RITEs are the consequence of allelic imbalance in tumor cells. DNA microarray-based CGH have recently been adapted for high-throughput detection of chromosomal imbalance; however, the result is often limited by the requirement for large number of microarray experiments using samples from various cancer patients, and the resolution is restricted by the density of the genomic DNA array. While microarray-based 35 CGH analysis is effective in finding tumor-specific amplicons, the EST-based transcriptome analysis has the advantage of identifying potential amplicons present in large number of cancer types and patients. The availability of these RITE regions would enable us to study the mechanism of aberrant DNA amplification in 142 WO 2004/060270 PCT/US2003/029126 tumors and to identify novel target genes for therapeutic intervention. The results from these analyses are shown in the accompanying Appendices B through J. In each of Appendix B through J, the first page of the appendix shows the tissue type for the results shown. Then, throughout each appendix, the location of each tumor-specific amplified chromosomal region (RITE) for that tumor tissue type is given in bold font showing first the chromosome name or number (e.g., "chr1") followed 5 by the numerical coordinates of the starting position and ending position, respectively, of the amplified region on that specific chromosome. The numerical coordinates relate to those that appear in the Build 29 release of human genome sequence data from the NCBI (May 2002). For example, the RITE designated by the phrase "chr1.147531064.149694137" is an amplified region on chromosome 1 with a starting point at position 147531064 and an ending point at position 149694137 as appearing in the Build 29 release of human genome 10 sequence data from the NCBI (May 2002). Under the location of each individual RITE are a listing of figures showing the cDNA sequences which are expressed from genes located within that specific amplified chromosomal region. The following appendices are shown: Appendix B - 14 RITEs identified in brain tumor tissue (overexpressed cDNA sequences shown in Figures 1-682 (SEQ ID NOS: 1-682); 15 Appendix C - 22 RITEs identified in breast tumor tissue (overexpressed cDNA sequences shown in Figures 683 1007 (SEQ ID NOS:683-1007); Appendix D - 4 RITEs identified in kidney tumor tissue (overexpressed cDNA sequences shown in Figures 1008-1162 (SEQ ID NOS:1008-1162); Appendix E - 50 RITEs identified in liver tumor tissue (overexpressed cDNA sequences shown in Figures 1163 20 1880 (SEQ ID NOS:1163-1880); Appendix F - 41 RITEs identified in lung tumor tissue (overexpressed cDNA sequences shown in Figures 1881 3158 (SEQ ID NOS:1881-3158); Appendix G - 40 RITEs identified in pancreatic tumor tissue (overexpressed cDNA sequences shown in Figures 25 3159-4326 (SEQ ID NOS:3159-4326); Appendix H - 12 RITEs identified in prostate tumor tissue (overexpressed cDNA sequences shown in Figures 4327-4457 (SEQ ID NOS:4327-4457); Appendix I - 3 RITEs identified in stomach tumor tissue (overexpressed cDNA sequences shown in Figures 4458-4516 (SEQ ID NOS:4458-4516); and 30 Appendix J - 20 RITEs identified in testis tumor tissue (overexpressed cDNA sequences shown in Figures 4517 4622 (SEQ ID NOS:4517-4622). 143 WO 2004/060270 PCT/US2003/029126 Methods: Human EST and mRNA Collection The human EST collection consists of all sequences in the EST division of GenBank, plus human SAGE sequences from NCBI. Quality information contained in the GenBank flat file was used to trim poor sequence. Tissue and histology labels were added using library information from NCI/CGAP 5 (http://cgap.nci.nih.gov/Tissues/). The human mRNA collection (46515 transcripts) consists of mRNA sequences mapped onto the assembled human genome from NCBI (release 29, May 2002), as specified in the GenBank style flat file for each chromosome. The location of each mRNA in its chromosome was determined by using contig order information plus position information from the flatfile. Pseudogenes, mRNAs labeled "similar to ALU SUBFAMILY", and mRNAs with anomalies in the location specification were eliminated. 10 Among 24491 genes that have EST coverage, 24388 non-overlapping genes were selected for expression profiling analysis. EST-based expression level calculation The sequence alignment program BLAST 19 was used to identify all EST sequences which matches at least 60 base pairs with >98% identity to a gene of interest. Matched ESTs were grouped by their source 15 libraries, which were further consolidated by library tissue types. For each tissue category, a DEL (digital expression level) value was calculated as the total number of matching EST clones divided by the sum of library sizes and multiplied by 1,000,000. Even though a typical EST library contains only a few thousand-clone sequences, multiple libraries from the same tissue type can be aggregated to form a composite data source that is more information-rich and better represents rare genes. These normalized EST abundances were calculated 20 for both normal and tumor groups for each tissue. Comparison of two proportions with Z-test The Z-test is applied to test whether the proportions from twg independent populations are identical. For a given gene, the common relative abundance (p) was computed in all libraries by taking the sum of clone counts for the gene over all libraries and dividing by the total number of clones over all libraries. The relative 25 abundance for tumor (p1) and normal (p2) libraries were also calculated, respectively. The test statistic Z-score is calculated as follows: z = (p1 minus p2) divided by the square root of X, where X is: p(1-p)[(l/Nt)+(l/Nn)] where Nt is the total number of EST clones derived from a given tumor tissue and Nn is the total number of 30 EST clones derived from a given normal tissue. 144 WO 2004/060270 PCT/US2003/029126 Calculation of trimmed mean of Z-score (TMZ) and sensing index TMZ is calculated using a 500 kbp window moving along the chromosome with 100 kbp interval and defined a-s: 5 I zi -max-min TMZ = n-2 10 where z; is the Z-score of the gene in a 500 kbp window. max is the, maximum Z-score in the window. min is the minimum Z-score in the window. 15 n is the number of genes in the window. The sensing index (S) is calculated as follows: s = (m - g) x V where 20 m is the TMZ mean of consecutive windows whose TMZ is greater than genomic mean (g). g is the mean of TMZ for all windows n is the number of consecutive windows whose TMZ is greater than genomic mean (g). 25 If the trimmed mean of the window is less than the genomic mean, S= m - g. For regions with consecutive windows whose trimmed means are greater than the genomic mean, S (n - g)* [H. Each window within the region has the same S value. 30 35 145 WO 2004/060270 PCT/US2003/029126 EXAMPLE 2: Use of TAT as a hybridization probe The following method describes use of a nucleotide sequence encoding TAT as a hybridization probe for, i.e., diagnosis of the presence of a tumor in a mammal. DNA comprising the coding sequence of full-length or mature TAT as disclosed herein can also be employed as a probe to screen for homologous DNAs (such as those encoding naturally-occurring variants of 5 TAT) in human tissue eDNA libraries or human tissue genomic libraries. Hybridization and washing of filters containing either library DNAs is performed under the following high stringency conditions. Hybridization of radiolabeled TAT-derived probe to the filters is performed in a solution of 50% formamide, 5x SSC, 0.1% SDS, 0.1% sodium pyrophosphate, 50 mM sodium phosphate, pH 6.8, 2x Denhardt's solution, and 10% dextran sulfate at 42 0 C for 20 hours. Washing of the filters is performed 10 in an aqueous solution of 0. lx SSC and 0.1% SDS at 42 0 C. DNAs having a desired sequence identity with the DNA encoding full-length native sequence TAT can then be identified using standard techniques known in the art. EXAMPLE 3: Expression of TAT in E. coli 15 This example illustrates preparation of an unglycosylated form of TAT by recombinant expression in E. coli. The DNA sequence encoding TAT is initially amplified using selected PCR primers. The primers should contain restriction enzyme sites which correspond to the restriction enzyme sites on the selected expression vector. A variety of expression vectors may be employed. An example of a suitable vector is 20 pBR322 (derived from E. coli; see Bolivar et al., Gene, 295 (1977)) which contains genes for ampicillin and tetracycline resistance. The vector is digested with restriction enzyme and dephosphorylated. The PCR amplified sequences are then ligated into the vector. The vector will preferably include sequences which encode for an antibiotic resistance gene, a trp promoter, a polyhis leader (including the first six STII codons, polyhis sequence, and enterokinase cleavage site), the TAT coding region, lambda transcriptional terminator, and an 25 argU gene. The ligation mixture is then used to transform a selected E. coli strain using the methods described in Sambrook et al., supra. Transformants are identified by their ability to grow on LB plates and antibiotic resistant colonies are then selected. Plasmid DNA can be isolated and confirmed by restriction analysis and DNA sequencing. 30 Selected clones can be grown overnight in liquid culture medium such as LB broth supplemented with antibiotics. The overnight culture may subsequently be used to inoculate a larger scale culture. The cells are then grown to a desired optical density, during which the expression promoter is turned on. After culturing the cells for several more hours, the cells can be harvested by centrifugation. The cell pellet obtained by the centrifugation can be solubilized using various agents known in the art, and the solubilized 35 TAT protein can then be purified using a metal chelating column under conditions that allow tight binding of the protein. 146 WO 2004/060270 PCT/US2003/029126 TAT may be expressed in E. coli in a poly-His tagged form, using the following procedure. The DNA encoding TAT is initially amplified using selected PCR primers. The primers will contain restriction enzyme sites which correspond to the restriction enzyme sites on the selected expression vector, and other useful sequences providing for efficient and reliable translation initiation, rapid purification on a metal chelation column, and proteolytic removal with enterokinase. The PCR-amplified, poly-His tagged sequences are then 5 ligated into an expression vector, which is used to transform an E. coli host based on strain 52 (W3 110 fuhA(tonA) lon galE rpoHts(htpRts) clpP(laclq). Transformants are first grown in LB containing 50 mg/ml carbenicillin at 30*C with shaking until an O.D.600 of 3-5 is reached. Cultures are then diluted 50-100 fold into CRAP media (prepared by mixing 3.57 g (NH 4
)
2
SO
4 , 0.71 g sodium citratee2H20, 1.07 g KCl, 5.36 g Difco yeast extract, 5.36 g Sheffield hycase SF in 500 mL water, as well as 110 mM MPOS, pH 7.3, 0.55% 10 (w/v) glucose and 7 mM MgSO 4 ) and grown for approximately 20-30 hours at 30'C with shaking. Samples are removed to verify expression by SDS-PAGE analysis, and the bulk culture is centrifuged to pellet the cells. Cell pellets are frozen until purification and refolding. E. coli paste from 0.5 to 1 L fermentations (6-10 g pellets) is resuspended in 10 volumes (w/v) in 7 M guanidine, 20 mM Tris, pH 8 buffer. Solid sodium sulfite and sodium tetrathionate is added to make final 15 concentrations of 0.1M and 0.02 M, respectively, and the solution is stirred overnight at 4*C. This step results in a denatured protein with all cysteine residues blocked by sulfitolization. The solution is centrifuged at 40,000 rpm in a Beckman Ultracentifuge for 30 min. The supernatant is diluted with 3-5 volumes of metal chelate column buffer (6 M guanidine, 20 mM Tris, pH 7.4) and filtered through 0.22 micron filters to clarify. The clarified extract is loaded onto a 5 ml Qiagen Ni-NTA metal chelate column equilibrated in the metal chelate 20 column buffer. The column is washed with additional buffer containing 50 mM imidazole (Calbiochem, Utrol grade), pH 7.4. The protein is eluted with buffer containing 250 mM imidazole. Fractions containing the desired protein are pooled and stored at 4*C. Protein concentration is estimated by its absorbance at 280 nm using the calculated extinction coefficient based on its amino acid sequence. The proteins are refolded by diluting the sample slowly into freshly prepared refolding buffer consisting 25 of: 20 mM Tris, pH 8.6, 0.3 M NaCl, 2.5 M urea, 5 mM cysteine, 20 mM glycine and 1 mM EDTA. Refolding volumes are chosen so that the final protein concentration is between 50 to 100 micrograms/ml. The refolding solution is stirred gently at 4*C for 12-36 hours. The refolding reaction is quenched by the addition of TFA to a final concentration of 0.4% (pH of approximately 3). Before further purification of the protein, the solution is filtered through a 0.22 micron filter and acetonitrile is added to 2-10% final concentration. The 30 refolded protein is chromatographed on a Poros RI/H reversed phase column using a mobile buffer of 0.1% TFA with elution with a gradient of acetonitrile from 10 to 80%. Aliquots of fractions with A280 absorbance are analyzed on SDS polyacrylamide gels and fractions containing homogeneous refolded protein are pooled. Generally, the properly refolded species of most proteins are eluted at the lowest concentrations of acetonitrile since those species are the most compact with their hydrophobic interiors shielded from interaction with the 35 reversed phase resin. Aggregated species are usually eluted at higher acetonitrile concentrations. In addition to resolving misfolded forms of proteins from the desired form, the reversed phase step also removes endotoxin from the samples. 147 WO 2004/060270 PCT/US2003/029126 Fractions containing the desired folded TAT polypeptide are pooled and the acetonitrile removed using a gentle stream of nitrogen directed at the solution. Proteins are formulated into 20 mM Hepes, pH 6.8 with 0.14 M sodium chloride and 4% mannitol by dialysis or by gel filtration using G25 Superfine (Pharmacia) resins equilibrated in the formulation buffer and sterile filtered. Certain of the TAT polypeptides disclosed herein have been successfully expressed and purified using 5 this technique(s). EXAMPLE 4: Expression of TAT in mammalian cells This example illustrates preparation of a potentially glycosylated form of TAT by recombinant expression in mammalian cells. 10 The vector, pRK5 (see EP 307,247, published March 15, 1989), is employed as the expression vector. Optionally, the TAT DNA is ligated into pRK5 with selected restriction enzymes to allow insertion of the TAT DNA using ligation methods such as described in Sambrook et al., supra. The resulting vector is called pRK5 TAT. In one embodiment, the selected host cells may be 293 cells. Human 293 cells (ATCC CCL 1573) are 15 grown to confluence in tissue culture plates in medium such as DMEM supplemented with fetal calf serum and optionally, nutrient components and/or antibiotics. About 10 ptg pRK5-TAT DNA is mixed with about 1 ig DNA encoding the VA RNA gene [Thimmappaya et al., Cell 3_:543 (1982)] and dissolved in 500 pl of 1 mM Tris-HCI, 0.1 mM EDTA, 0.227 M CaCl 2 . To this mixture is added, dropwise, 50Ql of 50 mM HEPES (pH 7.35), 280 mM NaCl, 1.5 mM NaPO 4 , and a precipitate is allowed to form for 10 minutes at 25 *C. The 20 precipitate is suspended and added to the 293 cells and allowed to settle for about four hours at 37 "C. The culture medium is aspirated off and 2 ml of 20% glycerol in PBS is added for 30 seconds. The 293 cells are then washed with serum free medium, fresh medium is added and the cells are incubated for about 5 days. Approximately 24 hours after the transfections, the culture medium is removed and replaced with culture medium (alone) or culture medium containing 200 pCi/ml "S-cysteine and 200 pCi/ml "S-methionine. 25 After a 12 hour incubation, the conditioned medium is collected, concentrated on a spin filter, and loaded onto a 15% SDS gel. The processed gel may be dried and exposed to film for a selected period of time to reveal the presence of TAT polypeptide. The cultures containing transfected cells may undergo further incubation (in serum free medium) and the medium is tested in selected bioassays. In an alternative technique, TAT may be introduced into 293 cells transiently using the dextran sulfate 30 method described by Somparyrac et al., Proc. Natl. Acad. Sci.. 12:7575 (1981). 293 cells are grown to maximal density in a spinner flask and 700 pg pRK5-TAT DNA is added. The cells are first concentrated from the spinner flask by centrifugation and washed with PBS. The DNA-dextran precipitate is incubated on the cell pellet for four hours. The cells are treated with 20% glycerol for 90 seconds, washed with tissue culture medium, and re-introduced into the spinner flask containing tissue culture medium, 5 pg/ml bovine insulin and 35 0.1 pg/ml bovine transferrin. After about four days, the conditioned media is centrifuged and filtered to remove cells and debris. The sample containing expressed TAT can then be concentrated and purified by any selected method, such as dialysis and/or column chromatography. 148 WO 2004/060270 PCT/US2003/029126 In another embodiment, TAT can be expressed in CHO cells. The pRK5-TAT can be transfected into CHO cells using known reagents such as CaPO 4 or DEAE-dextran. As described above, the cell cultures can be incubated, and the medium replaced with culture medium (alone) or medium containing a radiolabel such as "S-methionine. After determining the presence of TAT polypeptide, the culture medium may be replaced with serum free medium. Preferably, the cultures are incubated for about 6 days, and then the conditioned 5 medium is harvested. The medium containing the expressed TAT can then be concentrated and purified by any selected method. Epitope-tagged TAT may also be expressed in host CHO cells. The TAT may be subcloned out of the pRK5 vector. The subclone insert can undergo PCR to fuse in frame with a selected epitope tag such as a poly his tag into a Baculovirus expression vector. The poly-his tagged TAT insert can then be subcloned into a SV40 10 driven vector containing a selection marker such as DHFR for selection of stable clones. Finally, the CHO cells can be transfected (as described above) with the SV40 driven vector. Labeling may be performed, as described above, to verify expression. The culture medium containing the expressed poly-His tagged TAT can then be concentrated and purified by any selected method, such as by Ni-"chelate affinity chromatography. TAT may also be expressed in CHO and/or COS cells by a transient expression procedure or in CHO 15 cells by another stable expression procedure. Stable expression in CHO cells is performed using the following procedure. The proteins are expressed as an IgG construct (immunoadhesin), in which the coding sequences for the soluble forms (e.g. extracellular domains) of the respective proteins are fused to an IgGI constant region sequence containing the hinge, CH2 and CH2 domains and/or is a poly-His tagged form. 20 Following PCR amplification, the respective DNAs are subcloned in a CHO expression vector using standard techniques as described in Ausubel et al., Current Protocols of Molecular Bioloav Unit 3.16, John Wiley and Sons (1997). CHO expression vectors are constructed to have compatible restriction sites 5' and 3' of the DNA of interest to allow the convenient shuttling of cDNA's. The vector used expression in CHO cells is as described in Lucas et al., Nucl. Acids Res. 24:9 (1774-1779 (1996), and uses the SV40 early 25 promoter/enhancer to drive expression of the cDNA of interest and dihydrofolate reductase (DHFR). DHFR expression permits selection for stable maintenance of the plasmid following transfection. Twelve micrograms of the desired plasmid DNA is introduced into approximately 10 million CHO cells using commercially available transfection reagents Superfect' (Quiagen), Dosper" or Fugene" (Boehringer Mannheim). The cells are grown as described in Lucas set al., supra. Approximately 3 x 107 cells are frozen 30 in an ampule for further growth and production as described below. The ampules containing the plasmid DNA are thawed by placement into water bath and mixed by vortexing. The contents are pipetted into a centrifuge tube containing 10 mLs of media and centrifuged at 1000 rpm for 5 minutes. The supernatant is aspirated and the cells are resuspended in 10 mL of selective media (0.2 pm filtered PS20 with 5% 0.2 ym diafiltered fetal bovine serum). The cells are then aliquoted into a 100 mL 35 spinner containing 90 mL of selective media. After 1-2 days, the cells are transferred into a 250 mL spinner filled with 150 mL selective growth medium and incubated at 37*C. After another 2-3 days, 250 mL, 500 mL and 2000 mL spinners are seeded with 3 x 10W cells/mL. The cell media is exchanged with fresh media by 149 WO 2004/060270 PCT/US2003/029126 centrifugation and resuspension in production medium. Although any suitable CHO media may be employed, a production medium described in U.S. Patent No. 5,122,469, issued June 16, 1992 may actually be used. A 3L production spinner is seeded at 1.2 x 106 cells/mL. On day 0, the cell number pH ie determined. On day 1, the spinner is sampled and sparging with filtered air is commenced. On day 2, the spinner is sampled, the temperature shifted to 33"C, and 30 mL of 500 g/L glucose and 0.6 mL of 10% antifoam (e.g., 35% 5 polydimethylsiloxane emulsion, Dow Corning 365 Medical Grade Emulsion) taken. Throughout the production, the pH is adjusted as necessary to keep it at around 7.2. After 10 days, or until the viability dropped below 70%, the cell culture is harvested by centrifugation and filtering through a 0.22 pm filter. The filtrate was either stored at 4:C or immediately loaded onto columns for purification. For the poly-His tagged constructs, the proteins are purified using a Ni-NTA column (Qiagen). Before 10 purification, imidazole is added to the conditioned media to a concentration of 5 mM. The conditioned media is pumped onto a 6 ml Ni-NTA column equilibrated in 20 mM Hepes, pH 7.4, buffer containing 0.3 M NaCl and 5 mM imidazole at a flow rate of 4-5 ml/min. at 4"C. After loading, the column is washed with additional equilibration buffer and the protein eluted with equilibration buffer containing 0.25 M imidazole. The highly purified protein is subsequently desalted into a storage buffer containing 10 mM Hepes, 0.14 M NaCl and 4% 15 mannitol, pH 6.8, with a 25 ml G25 Superfine (Pharmacia) column and stored at -80*C. Immunoadhesin (Fc-containing) constructs are purified from the conditioned media as follows. The conditioned medium is pumped onto a 5 ml Protein A column (Pharmacia) which had been equilibrated in 20 mM Na phosphate buffer, pH 6.8. After loading, the column is washed extensively with equilibration buffer before elution with 100 mM citric acid, pH 3.5. The eluted protein is immediately neutralized by collecting 20 1 ml fractions into tubes containing 275 yL of 1 M Tris buffer, pH 9. The highly purified protein is subsequently desalted into storage buffer as described above for the poly-His tagged proteins. The homogeneity is assessed by SDS polyacrylamide gels and by N-terminal amino acid sequencing by Edman degradation. Certain of the TAT polypeptides disclosed herein have been successfully expressed and purified using this technique(s). 25 EXAMPLE 5: Expression of TAT in Yeast The following method describes recombinant expression of TAT in yeast. First, yeast expression vectors are constructed for intracellular production or secretion of TAT from the ADH2/GAPDH promoter. DNA encoding TAT and the promoter is inserted into suitable restriction enzyme 30 sites in the selected plasmid to direct intracellular expression of TAT. For secretion, DNA encoding TAT can be cloned into the selected plasmid, together with DNA encoding the ADH2/GAPDH promoter, a native TAT signal peptide or other mammalian signal peptide, or, for example, a yeast alpha-factor or invertase secretory signal/leader sequence, and linker sequences (if needed) for expression of TAT. Yeast cells, such as yeast strain AB 110, can then be transformed with the expression plasmids described 35 above and cultured in selected fermentation media. The transformed yeast supernatants can be analyzed by precipitation with 10% trichloroacetic acid and separation by SDS-PAGE, followed by staining of the gels with Coomassie Blue stain. 150 WO 2004/060270 PCT/US2003/029126 Recombinant TAT can subsequently be isolated and purified by removing the yeast cells from the fermentation medium by centrifugation and then concentrating the medium using selected cartridge filters. The concentrate containing TAT may further be purified using selected column chromatography resins. Certain of the TAT polypeptides disclosed herein have been successfully expressed and purified using this technique(s). 5 EXAMPLE 6: Expression of TAT in Baculovirus-Infected Insect Cells The following method describes recombinant expression of TAT in Baculovirus-infected insect cells. The sequence coding for TAT is fused upstream of an epitope tag contained within a baculovirus expression vector. Such epitope tags include poly-his tags and immunoglobulin tags (like Fc regions of IgG). 10 A variety of plasmids may be employed, including plasmids derived from commercially available plasmids such as pVL1393 (Novagen). Briefly, the sequence encoding TAT or the desired portion of the coding sequence of TAT such as the sequence encoding an extracellular domain of a transmembrane protein or the sequence encoding the mature protein if the protein is extracellular is amplified by PCR with primers complementary to the 5' and 3' regions. The 5' primer may incorporate flanking (selected) restriction enzyme sites. The product 15 is then digested with those selected restriction enzymes and subcloned into the expression vector. Recombinant baculovirus is generated by co-transfecting the above plasmid and BaculoGold TM virus DNA (Pharmingen) into Spodopterafrugiperda ("Sf9") cells (ATCC CRL 1711) using lipofectin (commercially available from GIBCO-BRL). After 4 - 5 days of incubation at 28 "C, the released viruses are harvested and used for further amplifications. Viral infection and protein expression are performed as described by O'Reilley 20 et al., Baculovirus expression vectors: A Laboratory Manual Oxford: Oxford University Press (1994). Expressed poly-his tagged TAT can then be purified, for example, by Niz+-chelate affinity chromatography as follows. Extracts are prepared from recombinant virus-infected Sf9 cells as described by Rupert et al., Nature 362:175-179 (1993). Briefly, Sf9 cells are washed, resuspended in sonication buffer (25 mL Hepes, pH 7.9; 12.5 mM MgCl 2 ; 0.1 mM EDTA; 10% glycerol; 0.1% NP-40; 0.4 M KCl), and sonicated 25 twice for 20 seconds on ice. The sonicates are cleared by centrifugation, and the supernatant is diluted 50-fold in loading buffer (50 mM phosphate, 300 mM NaCl, 10% glycerol, pH 7.8) and filtered through a 0.45 pm filter. A Ni 2 +-NTA agarose column (commercially available from Qiagen) is prepared with a bed volume of 5 mL, washed with 25 mL of water and equilibrated with 25 mL of loading buffer. The filtered cell extract is loaded onto the column at 0.5 mL per minute. The column is washed to baseline A 28 0 with loading buffer, at 30 which point fraction collection is started. Next, the column is washed with a secondary wash buffer (50 mM phosphate; 300 mM NaCl, 10% glycerol, pH 6.0), which elutes nonspecifically bound protein. After reaching A,,, baseline again, the column is developed with a 0 to 500 mM Imidazole gradient in the secondary wash buffer. One mL fractions are collected and analyzed by SDS-PAGE and silver staining or Western blot with Niz+-NTA-conjugated to alkaline phosphatase (Qiagen). Fractions containing the eluted Hilo-tagged TAT are 35 pooled and dialyzed against loading buffer. Alternatively, purification of the IgG tagged (or Fc tagged) TAT can be performed using known chromatography techniques, including for instance, Protein A or protein G column chromatography. 151 WO 2004/060270 PCT/US2003/029126 Certain of the TAT polypeptides disclosed herein have been successfully expressed and purified using this technique(s). EXAMPLE 7: Preparation of Antibodies that Bind TAT This example illustrates preparation of monoclonal antibodies which can specifically bind TAT. 5 Techniques for producing the monoclonal antibodies are known in the art and are described, for instance, in Goding, supra. Immunogens that may be employed include purified TAT, fusion proteins containing TAT, and cells expressing recombinant TAT on the cell surface. Selection of the immunogen can be made by the skilled artisan without undue experimentation. Mice, such as Balb/c, are immunized with the TAT immunogen emulsified in complete Freund's 10 adjuvant and injected subcutaneously or intraperitoneally in an amount from 1-100 micrograms. Alternatively, the immunogen is emulsified in MPL-TDM adjuvant (Ribi Immunochemical Research, Hamilton, MT) and injected into the animal's hind foot pads. The immunized mice are then boosted 10 to 12 days later with additional immunogen emulsified in the selected adjuvant. Thereafter, for several weeks, the mice may also be boosted with additional immunization injections. Serum samples may be periodically obtained from the mice 15 by retro-orbital bleeding for testing in ELISA assays to detect anti-TAT antibodies. After a suitable antibody titer has been detected, the animals "positive " for antibodies can be injected with a final intravenous injection of TAT. Three to four days later, the mice are sacrificed and the spleen cells are harvested. The spleen cells are then fused (using 35% polyethylene glycol) to a selected murine myeloma cell line such as P3X63AgU. 1, available from ATCC, No. CRL 1597. The fusions generate hybridoma cells 20 which can then be plated in 96 well tissue culture plates containing HAT (hypoxanthine, aminopterin, and thymidine) medium to inhibit proliferation of non-fused cells, myeloma hybrids, and spleen cell hybrids. The hybridoma cells will be screened in an ELISA for reactivity against TAT. Determination of "positive" hybridoma cells secreting the desired monoclonal antibodies against TAT is within the skill in the art. The positive hybridoma cells can be injected intraperitoneally into syngeneic Balb/c mice to produce 25 ascites containing the anti-TAT monoclonal antibodies. Alternatively, the hybridoma cells can be grown in tissue culture flasks or roller bottles. Purification of the monoclonal antibodies produced in the ascites can be accomplished using ammonium sulfate precipitation, followed by gel exclusion chromatography. Alternatively, affinity chromatography based upon binding of antibody to protein A or protein G can be employed. 30 EXAMPLE 8: Purification of TAT Polypeptides Using Specific Antibodies Native or recombinant TAT polypeptides may be purified by a variety of standard techniques in the art of protein purification. For example, pro-TAT polypeptide, mature TAT polypeptide, or pre-TAT polypeptide is purified by immunoaffmity chromatography using antibodies specific for the TAT polypeptide of interest. In general, an immunoaffinity column is constructed by covalently coupling the anti-TAT 35 polypeptide antibody to an activated chromatographic resin. Polyclonal immunoglobulins are prepared from immune sera either'by precipitation with ammonium sulfate or by purification on immobilized Protein A (Pharmacia LKB Biotechnology, Piscataway, N.J.). 152 WO 2004/060270 PCT/US2003/029126 Likewise, monoclonal antibodies are prepared from mouse ascites fluid by ammonium sulfate precipitation or chromatography on immobilized Protein A. Partially purified immunoglobulin is covalently attached to a chromatographic resin such as CnBr-activated SEPHAROSETm (Pharmacia LKB Biotechnology). The antibody is coupled to the resin, the resin is blocked, and the derivative resin is washed according to the manufacturer's instructions. 5 Such an immunoaffinity column is utilized in the purification of TAT polypeptide by preparing a fraction from cells containing TAT polypeptide in a soluble form. This preparation is derived by solubilization of the whole cell or of a subcellular fraction obtained via differential centrifugation by the addition of detergent or by other methods well known in the art. Alternatively, soluble TAT polypeptide containing a signal sequence may be secreted in useful quantity into the medium in which the cells are grown. 10 A soluble TAT polypeptide-containing preparation is passed over the immunoaffinity column, and the column is washed under conditions that allow the preferential absorbance of TAT polypeptide (e.g., high ionic strength buffers in the presence of detergent). Then, the column is eluted under conditions that disrupt antibody/TAT polypeptide binding (e.g., a low pH buffer such as approximately pH 2-3, or a high concentration of a chaotrope such as urea or thiocyanate ion), and TAT polypeptide is collected. 15 EXAMPLE 9: In Vitro Tumor Cell Killing Assay Mammalian cells expressing the TAT polypeptide of interest may be obtained using standard expression vector and cloning techniques. Alternatively, many tumor cell lines expressing TAT polypeptides of interest are publicly available, for example, through the ATCC and can be routinely identified using standard ELISA 20 or FACS analysis. Anti-TAT polypeptide monoclonal antibodies (and toxin conjugated derivatives thereof) may then be employed in assays to determine the ability of the antibody to kill TAT polypeptide expressing cells in vitro. For example, cells expressing the TAT polypeptide of interest are obtained as described above and plated into 96 well dishes. In one analysis, the antibody/toxin conjugate (or naked antibody) is included 25 throughout the cell incubation for a period of 4 days. In a second independent analysis, the cells are incubated for 1 hour with the antibody/toxin conjugate (or naked antibody) and then washed and incubated in the absence of antibody/toxin conjugate for a period of 4 days. Cell viability is then measured using the Cel1Titer-Glo Luminescent Cell Viability Assay from Promega (Cat# G7571). Untreated cells serve as a negative control. 30 EXAMPLE 10: In Vivo Tumor Cell Killing Assay To test the efficacy of conjugated or unconjugated anti-TAT polypeptide monoclonal antibodies, anti TAT antibody is injected intraperitoneally into nude mice 24 hours prior to receiving tumor promoting cells subcutaneously in the flank. Antibody injections continue twice per week for the remainder of the study. Tumor volume is then measured twice per week. 35 The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the invention. The present invention is not to be limited in scope by the construct deposited, since the deposited embodiment is intended as a single illustration of certain aspects of the invention and any constructs 153 WO 2004/060270 PCT/US2003/029126 that are functionally equivalent are within the scope of this invention. The deposit of material herein does not constitute an admission that the written description herein contained is inadequate to enable the practice of any aspect of the invention, including the best mode thereof, nor is it to be construed as limiting the scope of the claims to the specific illustrations that it represents. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing 5 description and fall within the scope of the appended claims. 154

Claims (185)

1. Isolated nucleic acid having a nucleotide sequence that has at least 80% nucleic acid sequence identity to: (a) the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622); (b) the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ 5 ID NOS:1-4622); or (c) the complement of (a) or (b).
2. Isolated nucleic acid having: (a) the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622); 10 (b) the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS:1-4622); or (c) the complement of (a) or (b).
3. Isolated nucleic acid that hybridizes to: 15 (a) the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622); (b) the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS:1-4622); or (c) the complement of (a) or (b). 20
4. The nucleic acid of Claim 3, wherein the hybridization occurs under stringent conditions.
5. The nucleic acid of Claim 3 which is at least about 5 nucleotides in length.
6. An expression vector comprising the nucleic acid of Claim 1, 2 or 3. 25
7. The expression vector of Claim 6, wherein said nucleic acid is operably linked to control sequences recognized by a host cell transformed with the vector.
8. A host cell comprising the expression vector of Claim 7. 30
9. The host cell of Claim 8 which is a CHO cell, an E. coli cell or a yeast cell.
10. A process for producing a polypeptide comprising culturing the host cell of Claim 8 under conditions suitable for expression of said polypeptide and recovering said polypeptide from the cell culture. 35
11. An isolated polypeptide having at least 80% amino acid sequence identity to: (a) a polypeptide encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID 155 WO 2004/060270 PCT/US2003/029126 NOS: 1-4622); or (b) a polypeptide encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622).
12. An isolated polypeptide having: 5 (a) an amino acid sequence encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622); or (b) an amino acid sequence encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622). 10
13. A chimeric polypeptide comprising the polypeptide of Claim 11 or 12 fused to a heterologous polypeptide.
14. The chimeric polypeptide of Claim 13, wherein said heterologous polypeptide is an epitope tag sequence or an Fc region of an immunoglobulin. 15
15. An isolated antibody that binds to a polypeptide having at least 80% amino acid sequence identity to: (a) a polypeptide encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS:1-4622); or 20 (b) a polypeptide encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622).
16. An isolated antibody that binds to a polypeptide having: (a) an amino acid sequence encoded by the nucleotide sequence shown in any one of Figures 1-4622 25 (SEQ ID NOS:1-4622); or (b) an amino acid sequence encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622).
17. The antibody of Claim 15 or 16 which is a monoclonal antibody. 30
18. The antibody of Claim 15 or 16 which is an antibody fragment.
19. The antibody of Claim 15 or 16 which is a chimeric or a humanized antibody. 35
20. The antibody of Claim 15 or 16 which is conjugated to a growth inhibitory agent.
21. The antibody of Claim 15 or 16 which is conjugated to a cytotoxic agent. 156 WO 2004/060270 PCT/US2003/029126
22. The antibody of Claim 21, wherein the cytotoxic agent is selected from the group consisting of toxins, antibiotics, radioactive isotopes and nucleolytic enzymes.
23. The antibody of Claim 21, wherein the cytotoxic agent is a toxin. 5
24. The antibody of Claim 23, wherein the toxin is selected from the group consisting of maytansinoid and calicheamicin.
25. The antibody of Claim 23, wherein the toxin is a maytansinoid. 10
26. The antibody of Claim 15 or 16 which is produced in bacteria.
27. The antibody of Claim 15 or 16 which is produced in CHO cells.
28. The antibody of Claim 15 or 16 which induces death of a cell to which it binds. 15
29. The antibody of Claim 15 or 16 which is detectably labeled.
30. An isolated nucleic acid having a nucleotide sequence that encodes the antibody of Claim 15 or 16. 20
31. An expression vector comprising the nucleic acid of Claim 30 operably linked to control sequences recognized by a host cell transformed with the vector.
32. A host cell comprising the expression vector of Claim 31. 25
33. The host cell of Claim 32 which is a CHO cell, an E. coli cell or a yeast cell.
34. A process for producing an antibody comprising culturing the host cell of Claim 32 under conditions suitable for expression of said antibody and recovering said antibody from the cell culture. 30
35. An isolated oligopeptide that binds to a polypeptide having at least 80% amino acid sequence identity to: (a) a polypeptide encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS:1-4622); or 35 (b) a polypeptide encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622). 157 WO 2004/060270 PCT/US2003/029126
36. An isolated oligopeptide that binds to a polypeptide having: (a) an amino acid sequence encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS:1-4622); or (b) an amino acid sequence encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622). 5
37. The oligopeptide of Claim 35 or 36 which is conjugated to a growth inhibitory agent.
38. The oligopeptide of Claim 35 or 36 which is conjugated to a cytotoxic agent. 10
39. The oligopeptide of Claim 38, wherein the cytotoxic agent is selected from the group consisting of toxins, antibiotics, radioactive isotopes and nucleolytic enzymes.
40. The oligopeptide of Claim 38, wherein the cytotoxic agent is a toxin. 15
41. The oligopeptide of Claim 40, wherein the toxin is selected from the group consisting of maytansinoid and calicheamicin.
42. The oligopeptide of Claim 40, wherein the toxin is a maytansinoid. 20
43. The oligopeptide of Claim 35 or 36 which induces death of a cell to which it binds.
44. The oligopeptide of Claim 35 or 36 which is detectably labeled.
45. A TAT binding organic molecule that binds to a polypeptide having at least 80% amino acid 25 sequence identity to: (a) a polypeptide encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS:1-4622); or (b) apolypeptide encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622). 30
46. The organic molecule of Claim 45 that binds to a polypeptide having: (a) an amino acid sequence encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622); or (b) an amino acid sequence encoded by the full-length coding region of the nucleotide sequence shown 35 in any one of Figures 1-4622 (SEQ ID NOS: 1-4622).
47. The organic molecule of Claim 45 or 46 which is conjugated to a growth inhibitory agent. 158 WO 2004/060270 PCT/US2003/029126
48. The organic molecule of Claim 45 or 46 which is conjugated to a cytotoxic agent.
49. The organic molecule of Claim 48, wherein the cytotoxic agent is selected from the group consisting of toxins, antibiotics, radioactive isotopes and nucleolytic enzymes. 5
50. The organic molecule of Claim 48, wherein the cytotoxic agent is a toxin.
51. The organic molecule of Claim 50, wherein the toxin is selected from the group consisting of maytansinoid and calicheamicin. 10
52. The organic molecule of Claim 50, wherein the toxin is a maytansinoid.
53. The organic molecule of Claim 45 or 46 which induces death of a cell to which it binds.
54. The organic molecule of Claim 45 or 46 which is detectably labeled. 15
55. A composition of matter comprising: (a) the polypeptide of Claim 11; (b) the polypeptide of Claim 12; (c) the chimeric polypeptide of Claim 13; 20 (d) the antibody of Claim 15; (e) the antibody of Claim 16; (f) the oligopeptide of Claim 35; (g) the oligopeptide of Claim 36; (h) the TAT binding organic molecule of Claim 45; or 25 (i) the TAT binding organic molecule of Claim 46; in combination with a carrier.
56. The composition of matter of Claim 55, wherein said carrier is a pharmaceutically acceptable carrier. 30
57. An article of manufacture comprising: (a) a container; and (b) the composition of matter of Claim 55 contained within said container.
58. The article of manufacture of Claim 57 further comprising a label affixed to said container, 35 or a package insert included with said container, referring to the use of said composition of matter for the therapeutic treatment of or the diagnostic detection of a cancer. 159 WO 2004/060270 PCT/US2003/029126
59. A method of inhibiting the growth of a cell that expresses a protein having at least 80% amino acid sequence identity to: (a) a polypeptide encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622); or (b) a polypeptide encoded by the full-length coding region of the nucleotide sequence shown in any one 5 of Figures 1-4622 (SEQ ID NOS: 1-4622), said method comprising contacting said cell with an antibody, oligopeptide or organic molecule that binds to said protein, the binding of said antibody, oligopeptide or organic molecule to said protein thereby causing an inhibition of growth of said cell.
60. The method of Claim 59, wherein said antibody is a monoclonal antibody. 10
61. The method of Claim 59, wherein said antibody is an antibody fragment.
62. The method of Claim 59, wherein said antibody is a chimeric or a humanized antibody. 15
63. The method of Claim 59, wherein said antibody, oligopeptide or organic molecule is conjugated to a growth inhibitory agent.
64. The method of Claim 59, wherein said antibody, oligopeptide or organic molecule is conjugated to a cytotoxic agent. 20
65. The method of Claim 64, wherein said cytotoxic agent is selected from the group consisting of toxins, antibiotics, radioactive isotopes and nucleolytic enzymes. 25
66. The method of Claim 64, wherein the cytotoxic agent is a toxin.
67. The method of Claim 66, wherein the toxin is selected from the group consisting of maytansinoid and calicheamicin. 30
68. The method of Claim 66, wherein the toxin is a maytansinoid.
69. The method of Claim 59, wherein said antibody is produced in bacteria.
70. The method of Claim 59, wherein said antibody is produced in CHO cells. 35
71. The method of Claim 59, wherein said cell is a cancer cell. 160 WO 2004/060270 PCT/US2003/029126
72. The method of Claim 71, wherein said cancer cell is further exposed to radiation treatment or a chemotherapeutic agent.
73. The method of Claim 71, wherein said cancer cell is selected from the group consisting of a breast cancer cell, a colorectal cancer cell, a lung cancer cell, an ovarian cancer cell, a central nervous system 5 cancer cell, a liver cancer cell, a bladder cancer cell, a pancreatic cancer cell, a cervical cancer cell, a melanoma cell and a leukemia cell.
74. The method of Claim 71, wherein said protein is more abundantly expressed by said cancer cell as compared to a normal cell of the same tissue origin. 10
75. The method of Claim 59 which causes the death of said cell.
76. The method of Claim 59, wherein said protein has: (a) an amino acid sequence encoded by the nucleotide sequence shown in any one of Figures 1-4622 15 (SEQ ID NOS:1-4622); or (b) an amino acid sequence encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS:1-4622).
77. A method of therapeutically treating a mammal having a cancerous tumor comprising cells 20 that express a protein having at least 80% amino acid sequence identity to: (a) a polypeptide encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS:1-4622); or (b) a polypeptide encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622), said method comprising administering to said mammal a 25 therapeutically effective amount of an antibody, oligopeptide or organic molecule that binds to said protein, thereby effectively treating said mammal.
78. The method of Claim 77, wherein said antibody is a monoclonal antibody. 30
79. The method of Claim 77, wherein said antibody is an antibody fragment.
80. The method of Claim 77, wherein said antibody is a chimeric or a humanized antibody.
81. The method of Claim 77, wherein said antibody, oligopeptide or organic molecule is 35 conjugated to a growth inhibitory agent. 161 WO 2004/060270 PCT/US2003/029126
82. The method of Claim 77, wherein said antibody, oligopeptide or organic molecule is conjugated to a cytotoxic agent.
83. The method of Claim 82, wherein said cytotoxic agent is selected from the group consisting of toxins, antibiotics, radioactive isotopes and nucleolytic enzymes. 5
84. The method of Claim 82, wherein the cytotoxic agent is a toxin.
85. The method of Claim 84, wherein the toxin is selected from the group consisting of maytansinoid and calicheamicin. 10
86. The method of Claim 84, wherein tie toxin is a maytansinoid.
87. The method of Claim 77, wherein said antibody is produced in bacteria. 15
88. The method of Claim 77, wherein said antibody is produced in CHO cells.
89. The method of Claim 77, wherein said tumor is further exposed to radiation treatment or a chemotherapeutic agent. 20
90. The method of Claim 77, wherein said tumor is a breast tumor, a colorectal tumor, a lung tumor, an ovarian tumor, a central nervous system tumor, a liver tumor, a bladder tumor, a pancreatic tumor, or a cervical tumor.
91. The method of Claim 77, wherein said protein is more abundantly expressed by the cancerous 25 cells of said tumor as compared to a normal cell of the same tissue origin.
92. The method of Claim 77, wherein said protein has: (a) an amino acid sequence encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS:1-4622); or 30 (b) an amino acid sequence encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622).
93. A method of determining the presence of a protein in a sample suspected of containing said protein, wherein said protein has at least 80% amino acid sequence identity to: 35 (a) a polypeptide encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS:1-4622); or 162 WO 2004/060270 PCT/US2003/029126 (b) a polypeptide encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS:1-4622), said method comprising exposing said sample to an antibody, oligopeptide or organic molecule that binds to said protein and determining binding of said antibody, oligopeptide or organic molecule to said protein in said sample, wherein binding of the antibody, oligopeptide or organic molecule to said protein is indicative of the presence of said protein in said sample. 5
94. The method of Claim 93, wherein said sample comprises a cell suspected of expressing said protein.
95. The method of Claim 94, wherein said cell is a cancer cell. 10
96. The method of Claim 93, wherein said antibody, oligopeptide or organic molecule is detectably labeled.
97. The method of Claim 93, wherein said protein has: 15 (a) an amino acid sequence encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622); or (b) an amino acid sequence encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622). 20
98. A method of diagnosing the presence of a tumor in a mammal, said method comprising determining the level of expression of a gene encoding a protein having at least 80% amino acid sequence identity to: (a) a polypeptide encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS:1-4622); or 25 (b) a polypeptide encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622), in a test sample of tissue cells obtained from said mammal and in a control sample of known normal cells of the same tissue origin, wherein a higher level of expression of said protein in the test sample, as compared to the control sample, is indicative of the presence of tumor in the mammal from which the test sample was obtained. 30
99. The method of Claim 98, wherein the step of determining the level of expression of a gene encoding said protein comprises employing an oligonucleotide in an in situ hybridization or RT-PCR analysis.
100. The method of Claim 98, wherein the step determining the level of expression of a gene 35 encoding said protein comprises employing an antibody in an immunohistochemistry or Western blot analysis. 163 WO 2004/060270 PCT/US2003/029126
101. The method of Claim 98, wherein said protein has: (a) an amino acid sequence encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS:1-4622); or (b) an amino acid sequence encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622). 5
102. A method of diagnosing the presence of a tumor in a mammal, said method comprising contacting a test sample of tissue cells obtained from said mammal with an antibody, oligopeptide or organic molecule that binds to a protein having at least 80% amino acid sequence identity to: (a) a polypeptide encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID 10 NOS:1-4622); or (b) a polypeptide encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622), and detecting the formation of a complex between said antibody, oligopeptide or organic molecule and said protein in the test sample, wherein the formation of a complex is indicative of the presence of a tumor in said mammal. 15
103. The method of Claim 102, wherein said antibody, oligopeptide or organic molecule is detectably labeled.
104. The method of Claim 102, wherein said test sample of tissue cells is obtained from an 20 individual suspected of having a cancerous tumor.
105. The method of Claim 102, wherein said protein has: (a) an amino acid sequence encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS:1-4622); or 25 (b) an amino acid sequence encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622).
106. A method for treating or preventing a cell proliferative disorder associated with increased expression or activity of a protein having at least 80% amino acid sequence identity to: 30 (a) a polypeptide encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622); or (b) a polypeptide encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622), said method comprising administering to a subject in need of such treatment an effective amount of an antagonist of said protein, thereby effectively treating or preventing said 35 cell proliferative disorder.
107. The method of Claim 106, wherein said cell proliferative disorder is cancer. 164 WO 2004/060270 PCT/US2003/029126
108. The method of Claim 106, wherein said antagonist is an anti-TAT polypeptide antibody, TAT binding oligopeptide, TAT binding organic molecule or antisense oligonucleotide.
109. A method of binding an antibody, oligopeptide or organic molecule to a cell that expresses a protein having at least 80% amino acid sequence identity to: 5 (a) a polypeptide encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622); or (b) a polypeptide encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622), said method comprising contacting said cell with an antibody, oligopeptide or organic molecule that binds to said protein and allowing the binding of the antibody, oligopeptide 10 or organic molecule to said protein to occur, thereby binding said antibody, oligopeptide or organic molecule to said cell.
110. The method of Claim 109, wherein said antibody is a monoclonal antibody. 15
111. The method of Claim 109, wherein said antibody is an antibody fragment.
112. The method of Claim 109, wherein said antibody is a chimeric or a humanized antibody.
113. The method of Claim 109, wherein said antibody, oligopeptide or organic molecule is 20 conjugated to a growth inhibitory agent.
114. The method of Claim 109, wherein said antibody, oligopeptide or organic molecule is conjugated to a cytotoxic agent. 25
115. The method of Claim 114, wherein said cytotoxic agent is selected from the group consisting of toxins, antibiotics, radioactive isotopes and nucleolytic enzymes.
116. The method of Claim 114, wherein the cytotoxic agent is a toxin. 30
117. The method of Claim 116, wherein the toxin is selected from the group consisting of maytansinoid and calicheamicin.
118. The method of Claim 116, wherein the toxin is a maytansinoid. 35
119. The method of Claim 109, wherein said antibody is produced in bacteria.
120. The method of Claim 109, wherein said antibody is produced in CHO cells. 165 WO 2004/060270 PCT/US2003/029126
121. The method of Claim 109, wherein said cell is a cancer cell.
122. The method of Claim 121, wherein said cancer cell is further exposed to radiation treatment or a chemotherapeutic agent. 5
123. The method of Claim 121, wherein said cancer cell is selected from the group consisting of a breast cancer cell, a colorectal cancer cell, a lung cancer cell, an ovarian cancer cell, a central nervous system cancer cell, a liver cancer cell, a bladder cancer cell, a pancreatic cancer cell, a cervical cancer cell, a melanoma cell and a leukemia cell. 10
124. The method of Claim 123, wherein said protein is more abundantly expressed by said cancer cell as compared to a normal cell of the same tissue origin.
125. The method of Claim 109 which causes the death of said cell. 15
126. Use of a nucleic acid as claimed in any of Claims 1 to 5 or 30 in the preparation of a medicament for the therapeutic treatment or diagnostic detection of a cancer.
127. Use of a nucleic acid as claimed in any of Claims 1 to 5 or 30 in the preparation of a medicament for treating a tumor. 20
128. Use of a nucleic acid as claimed in any of Claims 1 to 5 or 30 in the preparation of a medicament for treatment or prevention of a cell proliferative disorder.
129. Use of an expression vector as claimed in any of Claims 6, 7 or 31 in the preparation of a 25 medicament for the therapeutic treatment or diagnostic detection of a cancer.
130. Use of an expression vector as claimed in any of Claims 6, 7 or 31 in the preparation of medicament for treating a tumor. 30
131. Use of an expression vector as claimed in any of Claims 6, 7 or 31 in the preparation of a medicament for treatment or prevention of a cell proliferative disorder.
132. Use of a host cell as claimed in any of Claims 8, 9, 32, or 33 in the preparation of a medicament for the therapeutic treatment or diagnostic detection of a cancer. 35
133. Use of a host cell as claimed in any of Claims 8, 9, 32 or 33 in the preparation of a medicament for treating a tumor. 166 WO 2004/060270 PCT/US2003/029126
134. Use of a host cell as claimed in any of Claims 8, 9, 32 or 33 in the preparation of a medicament for treatment or prevention of a cell proliferative disorder.
135. Use of a polypeptide as claimed in any of Claims 11 to 14 in the preparation of a medicament for the therapeutic treatment or diagnostic detection of a cancer. 5
136. Use of a polypeptide as claimed in any of Claims 11 to 14 in the preparation of a medicament for treating a tumor.
137. Use of a polypeptide as claimed in any of Claims 11 to 14 in the preparation of a medicament 10 for treatment or prevention of a cell proliferative disorder.
138. Use of an antibody as claimed in any of Claims 15 to 29 in the preparation of a medicament for the therapeutic treatment or diagnostic detection of a cancer. 15
139. Use of an antibody as claimed in any of Claims 15 to 29 in the preparation of a medicament for treating a tumor.
140. Use of an antibody as claimed in any of Claims 15 to 29 in the preparation of a medicament for treatment or prevention of a cell proliferative disorder. 20
141. Use of an oligopeptide as claimed in any of Claims 35 to 44 in the preparation of a medicament for the therapeutic treatment or diagnostic detection of a cancer.
142. Use of an oligopeptide as claimed in any of Claims 35 to 44 in the preparation of a 25 medicament for treating a tumor.
143. Use of an oligopeptide as claimed in any of Claims 35 to 44 in the preparation of a medicament for treatment or prevention of a cell proliferative disorder. 30
144. Use of a TAT binding organic molecule as claimed in any of Claims 45 to 54 in the preparation of a medicament for the therapeutic treatment or diagnostic detection of a cancer.
145. Use of a TAT binding organic molecule as claimed in any of Claims 45 to 54 in the preparation of a medicament for treating a tumor. 35
146. Use of a TAT binding organic molecule as claimed in any of Claims 45 to 54 in the preparation of a medicament for treatment or prevention of a cell proliferative disorder. 167 WO 2004/060270 PCT/US2003/029126
147. Use of a composition of matter as claimed in any of Claims 55 or 56 in the preparation of a medicament for the therapeutic treatment or diagnostic detection of a cancer.
148. Use of a composition of matter as claimed in any of Claims 55 or 56 in the preparation of a medicament for treating a tumor. 5
149. Use of a composition of matter as claimed in any of Claims 55 or 56 in the preparation of a medicament for treatment or prevention of a cell proliferative disorder.
150. Use of an article of manufacture as claimed in any of Claims 57 or 58 in the preparation of 10 a medicament for the therapeutic treatment or diagnostic detection of a cancer.
151. Use of an article of manufacture as claimed in any of Claims 57 or 58 in the preparation of a medicament for treating a tumor. 15
152. Use of an article of manufacture as claimed in any of Claims 57 or 58 in the preparation of a medicament for treatment or prevention of a cell proliferative disorder.
153. A method for inhibiting the growth of a cell, wherein the growth of said cell is at least in part dependent upon a growth potentiating effect of a protein having at least 80% amino acid sequence identity to: 20 (a) a polypeptide encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622); or (b) a polypeptide encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622), said method comprising contacting said protein with an antibody, oligopeptide or organic molecule that binds to said protein, there by inhibiting the growth of said cell. 25
154. The method of Claim 153, wherein said cell is a cancer cell.
155. The method of Claim 153, wherein said protein is expressed by said cell. 30
156. The method of Claim 153, wherein the binding of said antibody, oligopeptide or organic molecule to said protein antagonizes a cell growth-potentiating activity of said protein.
157. The method of Claim 153, wherein the binding of said antibody, oligopeptide or organic molecule to said protein induces the death of said cell. 35
158. The method of Claim 153, wherein said antibody is a monoclonal antibody. 168 WO 2004/060270 PCT/US2003/029126
159. The method of Claim 153, wherein said antibody is an antibody fragment.
160. The method of Claim 153, wherein said antibody is a chimeric or a humanized antibody.
161. The method of Claim 153, wherein said antibody, oligopeptide or organic molecule is 5 conjugated to a growth inhibitory agent.
162. The method of Claim 153, wherein said antibody, oligopeptide or organic molecule is conjugated to a cytotoxic agent. 10
163. The method of Claim 162, wherein said cytotoxic agent is selected from the group consisting of toxins, antibiotics, radioactive isotopes and nucleolytic enzymes.
164. The method of Claim 162, wherein the cytotoxic agent is a toxin. 15
165. The method of Claim 164, wherein the toxin is selected from the group consisting of maytansinoid and calicheamicin.
166. The method of Claim 164, wherein the toxin is a maytansinoid. 20
167. The method of Claim 153, wherein said antibody is produced in bacteria.
168. The method of Claim 153, wherein said antibody is produced in CHO cells.
169. The method of Claim 153, wherein said protein has: 25 (a) an amino acid sequence encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS:1-4622); or (b) an amino acid sequence encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622). 30
170. A method of therapeutically treating a tumor in a mammal, wherein the growth of said tumor is at least in part dependent upon a growth potentiating effect of a protein having at least 80% amino acid sequence identity to: (a) a polypeptide encoded by the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS:1-4622); or 35 (b) a polypeptide encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622), said method comprising contacting said protein with an antibody, 169 WO 2004/060270 PCT/US2003/029126 oligopeptide or organic molecule that binds to said protein, thereby effectively treating said tumor.
171. The method of Claim 170, wherein said protein is expressed by cells of said tumor.
172. The method of Claim 170, wherein the binding of said antibody, oligopeptide or organic 5 molecule to said protein antagonizes a cell growth-potentiating activity of said protein.
173. The method of Claim 170, wherein said antibody is a monoclonal antibody.
174. The method of Claim 170, wherein said antibody is an antibody fragment. 10
175. The method of Claim 170, wherein said antibody is a chimeric or a humanized antibody.
176. The method of Claim 170, wherein said antibody, oligopeptide or organic molecule is conjugated to a growth inhibitory agent. 15
177. The method of Claim 170, wherein said antibody, oligopeptide or organic molecule is conjugated to a cytotoxic agent.
178. The method of Claim 177, wherein said cytotoxic agent is selected from the group consisting 20 of toxins, antibiotics, radioactive isotopes and nucleolytic enzymes.
179. The method of Claim 177, wherein the cytotoxic agent is a toxin.
180. The method of Claim 179, wherein the toxin is selected from the group consisting of 25 maytansinoid and calicheamicin.
181. The method of Claim 179, wherein the toxin is a maytansinoid.
182. The method of Claim 170, wherein said antibody is produced in bacteria. 30
183. The method of Claim 170, wherein said antibody is produced in CHO cells.
184. The method of Claim 170, wherein said protein has: (a) an amino acid sequence encoded by the nucleotide sequence shown in any one of Figures 1-4622 35 (SEQ ID NOS:1-4622); or (b) an amino acid sequence encoded by the full-length coding region of the nucleotide sequence shown in any one of Figures 1-4622 (SEQ ID NOS: 1-4622). 170 WO 2004/060270 PCT/US2003/029126
185. A method of diagnosing the presence of tumor in a mammal, said method comprising determining the presence or absence of amplification of one of the amplified chromosomal regions shown in any one of Appendices B through J in a tissue sample obtained from said mammal, wherein the presence of amplification of said chromosomal region is indicative of the presence of tumor in said mammal. 171
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Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003225535A1 (en) * 2002-01-31 2003-09-02 Millennium Pharmaceuticals, Inc. Methods and compositions for treating cancer
EP1562969A4 (en) * 2002-03-28 2006-07-05 Bristol Myers Squibb Co Novel human cell surface protein with immunoglobulin folds, bgs-19
WO2003091402A2 (en) * 2002-04-23 2003-11-06 University Of Georgia Research Foundation, Inc. N-ACETYLGLUCOSAMINYLTRANSFERASE Vb CODING SEQUENCE, RECOMBINANT CELLS AND METHODS
US20050186577A1 (en) 2004-02-20 2005-08-25 Yixin Wang Breast cancer prognostics
EP1584684A1 (en) * 2004-02-20 2005-10-12 Samsung Electronics Co., Ltd. Breast cancer related protein, gene encoding the same, and method of diagnosing breast cancer using the protein and gene
DK2319925T3 (en) 2004-08-16 2018-11-05 Quark Pharmaceuticals Inc Therapeutic applications of RTP801 inhibitors
GB0422211D0 (en) * 2004-10-06 2004-11-03 Randox Lab Ltd Method
EP1812794A4 (en) * 2004-10-13 2008-09-10 A & G Pharmaceutical Inc Autocrine growth factor receptors and methods
JP2007008844A (en) * 2005-06-29 2007-01-18 Nippon Flour Mills Co Ltd Monoclonal antibody to specifically react with septin-2 protein, hybridoma to produce the same, and method and kit for detecting cancer
UY30097A1 (en) 2006-01-20 2007-08-31 Atugen Ag THERAPEUTIC USES OF RTP801 INHIBITORS
US20070237713A1 (en) 2006-04-04 2007-10-11 Fan Rong A PCan065 Antibody Compositions and Methods of Use
GB2450840B (en) 2006-05-11 2010-12-29 Quark Pharmaceuticals Inc Screening Systems Utilizing RTP801
EP3399450A1 (en) * 2006-05-18 2018-11-07 Caris MPI, Inc. System and method for determining individualized medical intervention for a disease state
EP2026843A4 (en) 2006-06-09 2011-06-22 Quark Pharmaceuticals Inc Therapeutic uses of inhibitors of rtp801l
EP2137205A2 (en) 2007-02-26 2009-12-30 Quark Pharmaceuticals, Inc. Inhibitors of rtp801 and their use in disease treatment
US20100196898A1 (en) * 2007-05-24 2010-08-05 The Brigham & Women's Hospital, Inc. Disease-associated genetic variations and methods for obtaining and using same
US8614311B2 (en) 2007-12-12 2013-12-24 Quark Pharmaceuticals, Inc. RTP801L siRNA compounds and methods of use thereof
JP2012501167A (en) * 2008-08-27 2012-01-19 オンコセラピー・サイエンス株式会社 Pancreatic cancer-related gene TTLL4
MX2011008430A (en) 2009-02-20 2011-09-29 Ganymed Pharmaceuticals Ag Methods and compositions for diagnosis and treatment of cancer.
EP3305813B1 (en) 2009-11-11 2020-01-15 Ganymed Pharmaceuticals GmbH Antibodies specific for claudin 6 (cldn6)
WO2011150400A1 (en) * 2010-05-28 2011-12-01 New York Blood Center, Inc. Nuclear scaffold protein stip/tfip11 target for cancer therapy
EP2404936A1 (en) 2010-07-06 2012-01-11 Ganymed Pharmaceuticals AG Cancer therapy using CLDN6 target-directed antibodies in vivo
EP3421496B1 (en) 2011-05-13 2024-08-07 Astellas Pharma Inc. Antibodies for treatment of cancer expressing claudin 6
SG11201503567SA (en) 2012-12-05 2015-06-29 Novartis Ag Compositions and methods for antibodies targeting epo
ES2670529T3 (en) * 2013-03-15 2018-05-30 Translate Bio, Inc. Synergistic improvement of nucleic acid delivery through mixed formulations
WO2015014376A1 (en) 2013-07-31 2015-02-05 Biontech Ag Diagnosis and therapy of cancer involving cancer stem cells
US20180230540A1 (en) 2015-08-12 2018-08-16 Novartis Ag Methods of treating ophthalmic disorders
US11180535B1 (en) 2016-12-07 2021-11-23 David Gordon Bermudes Saccharide binding, tumor penetration, and cytotoxic antitumor chimeric peptides from therapeutic bacteria
EP4119133A1 (en) 2017-05-24 2023-01-18 Thoeris GmbH Glutamine synthetase protein conjugate
JP2022186461A (en) * 2021-06-04 2022-12-15 地方独立行政法人東京都健康長寿医療センター Pharmaceutical composition for prostate cancer treatment

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MXPA03001645A (en) * 2000-08-24 2004-05-14 Genentech Inc Compositions and methods for the diagnosis and treatment of tumor.
EP1311662A2 (en) * 2000-08-24 2003-05-21 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
MXPA03001643A (en) * 2000-08-24 2004-05-14 Genentech Inc Compositions and methods for the diagnosis and treatment of tumor.

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