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WO1997043316A1 - Molecules physiologiquement actives a demi-vies prolongees et methode d'utilisation de ces dernieres - Google Patents

Molecules physiologiquement actives a demi-vies prolongees et methode d'utilisation de ces dernieres Download PDF

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Publication number
WO1997043316A1
WO1997043316A1 PCT/US1997/007707 US9707707W WO9743316A1 WO 1997043316 A1 WO1997043316 A1 WO 1997043316A1 US 9707707 W US9707707 W US 9707707W WO 9743316 A1 WO9743316 A1 WO 9743316A1
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igg
fcrp
molecule
amino acid
physiologically active
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PCT/US1997/007707
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English (en)
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Richard P. Junghans
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Beth Israel Deaconess Medical Center, Inc.
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Publication of WO1997043316A1 publication Critical patent/WO1997043316A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/495—Transforming growth factor [TGF]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/5434—IL-12
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/55—IL-2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70539—MHC-molecules, e.g. HLA-molecules
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2730/00—Reverse transcribing DNA viruses
    • C12N2730/00011—Details
    • C12N2730/10011—Hepadnaviridae
    • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16211—Human Immunodeficiency Virus, HIV concerning HIV gagpol
    • C12N2740/16222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • This invention relates to methods for extending the half-life of physiologically active molecules in subjects to whom the molecules are administered. These methods include modifying physiologically active molecules such that they include regions or domains which can bind to selected receptors, e.g., the FcRp protection receptor, which recycle the molecules to the circulation rather than allowing the molecules to pass to lysosomal catabolism.
  • selected receptors e.g., the FcRp protection receptor
  • Brambell proposed that specific IgG "protection receptors" (FcRp) bind IgG in pinocytotic vacuoles and redirect IgG transport to the circulation.
  • FcRp protection receptors
  • Dr. Brambell also described a second receptor, the neonatal gut transport receptor (FcRn), which is found in neonatal gut and placenta.
  • FcRn neonatal gut transport receptor
  • FcRn has been cloned and characterized (Simister and Mostov (1989) Nature 337:184).
  • FcRn was found to be a heterodimer of a membrane-integral class I-like heavy chain and a ⁇ -2 microglobulin ( ⁇ 2 m) light chain (Simister and Mostov (1989) Nature 337:184), in which both chains make essential contacts with Fc (Burffle et al. (1994) Nature 372:279-383).
  • Fc is mutated in the domains contacting either FcRn heavy or light chain (Burffle et al. (1994) Nature 372:279-383)
  • survival and transport are both adversely affected (Kim et al. (1994) Eur. J. Immunol. 24:2429-2434).
  • mice deleted for light chain ⁇ 2 ⁇ ' FcRn surface expression is lost and neonatal pups are devoid of maternal IgG transport (Israel et al. (1995) J. Immunol. 154:6246-6251).
  • the FcRp and the FcRn receptor systems have several common features. For example, the two receptors mediate transendosomal transport of IgG and can both be saturated with IgG. Brambell (1964) Nature 203:1352- 1355; Humphrey and Fahey (1961) J.
  • the present invention is based, at least in part, on the discovery that the FcRp and the FcRn are the same receptor.
  • This discovery lead to the recognition that the IgG protective capabilities of the FcRp can be imparted on a variety of therapeutics, e.g., human therapeutics, to extend the half-lives of the therapeutics in a subject.
  • the present invention is drawn to physiologically active molecules which have extended half-lives in the circulatory system of a subject, compositions which include these molecules, methods of producing the molecules, and methods of using the molecules to treat subjects.
  • the half-lives of these molecules are extended by modifying their structure such that they are capable of binding to the IgG protection receptor FcRp.
  • the invention takes advantage of the discovery that the FcRp and the FcRn are the same receptor and that modifying physiologically active molecules such that they are capable of binding the IgG protection receptor FcRp allows these molecules to escape lysosomal catabolism and remain in the circulation of a subject for longer periods of time.
  • physiologically active molecules which are modified according to the invention include molecules which can bring about a desired result in a subject.
  • physiologically active molecules can be human therapeutics or human drugs for which an extended half-life is beneficial to a subject, e.g., a human patient.
  • physiologically active molecules include proteins and peptides, e.g., immunoglobulins, immunoglobulin fragments or portions, e.g., all or a portion of IgG3, IgA, IgD, IgE, IgM, and other nonimmunoglobulin molecules including cytokines, e.g., TGF- ⁇ , interleukin-2, interleukin- 10, interleukin- 12, GM-CSF, and vaccine immunogens, e.g., gpl20 for HIV, HBSAg of hepatitis B, hemaglutinin of influenza virus, coat protein of respiratory syncytial virus, tetanus toxoid of C.
  • proteins and peptides e.g., immunoglobulins, immunoglobulin fragments or portions, e.g., all or a portion of IgG3, IgA, IgD, IgE, IgM, and other nonimmunoglobul
  • tetani outer membrane proteins of P. pneumoniae, V. cholerae, S. typhae, L. monocytogenes, and M. tuberculosis.
  • physiologically active molecules can be used to treat neoplastic diseases, viral diseases such as AIDS, and other immune diseases and infections.
  • the half-lives of the physiologically active molecules of the invention are increased by modifying the structure of the molecules in a manner which allows them to bind to the IgG protection receptor FcRp.
  • the structure of the physiologically active molecules can be modified to include a specific amino acid sequence which binds to the IgG protection receptor FcRp but which does not bind to an Fc receptor which mediates immune effects or which binds to the IgG protection receptor FcRp but which does not bind to complement.
  • the specific amino acid sequence is substantially homologous, e.g., at least about 60%, 70%, 80%, 90%, 95%, 98%, or 99% or more homologous, to an amino acid sequence of at least a portion of the IgG domain which binds to the IgG protection receptor FcRp.
  • the amino acid sequence is the same as the amino acid sequence of at least a portion of an IgG domain which binds to the IgG protection receptor FcRp.
  • the physiologically active molecules are proteins or peptides and the structure of these molecules is altered by amino acid substitution such that the protein or peptide specifically binds to the IgG protection receptor FcRp.
  • the structure of the physiologically active molecule can be modified to include at least a portion of an antibody which is raised against the IgG protection receptor FcRp and which specifically binds to the IgG protection receptor FcRp.
  • the antibody or portion or fragment thereof binds to the IgG protection receptor at acidic pH, e.g., a pH of about 6.5 or lower, and is released from the IgG protection receptor at neutral pH, e.g., a pH of about 7.0 to about 7.5.
  • the portion or fragment of the antibody can be a Fab fragment, an Fv fragment, a Fab' fragment or a F(ab') 2 fragment.
  • Another aspect of the invention pertains to compositions which include the physiologically active molecules described herein together with a pharmaceutically acceptable carrier.
  • Yet another aspect of the invention pertains to methods for producing a physiologically active molecule which has an extended half-life in the circulatory system of a subject. These methods include modifying the structure of the molecule such that it includes a specific amino acid sequence which binds to the IgG protection receptor FcRp but which does not bind to an Fc receptor which mediates immune effects or which binds to the IgG protection receptor FcRp but which does not bind to complement.
  • the specific amino acid sequence is substantially homologous, e.g., at least about 60%, 70%, 80%, 90%, 95%, 98%, or 99% or more homologous, to an amino acid sequence of at least a portion of the IgG domain which binds to the IgG protection receptor FcRp.
  • the specific amino acid sequence is the same as the amino acid sequence of at least a portion of an IgG domain which binds to the IgG protection receptor FcRp.
  • a still further aspect of the invention pertains to methods for producing a physiologically active protein or peptide having an extended half-life in the circulatory system of a subject. These methods include altering the amino acid sequence of the protein or peptide by amino acid substitution such that the protein or peptide specifically binds to the IgG protection receptor FcRp.
  • the protein or peptide is an immunoglobulin or fragment or portion thereof, e.g., all or a portion IgG3, IgA, IgD, IgE and IgM.
  • the invention also pertains to methods for producing a physiologically active molecule having an extended half-life in the circulatory system of a subject which includes modifying the structure of the molecule such that it includes at least a portion of an antibody, e.g., a Fab, Fv, Fab' or F(ab') 2 fragment, which is raised against the IgG protection receptor FcRp and which binds to the IgG protection receptor FcRp.
  • the antibody or portion or fragment thereof binds to the IgG protection receptor at acidic pH, e.g., a pH of about 6.5 or lower, and is released from the IgG protection receptor at neutral pH, e.g., a pH of about 7.0 to about 7.5.
  • the invention further pertains to methods for treating a subject having a disorder which can be treated with a physiologically active molecule. These methods include administering to the subject the physiologically active molecules or compositions described herein.
  • Figure I is a graph which depicts IgG survival over time in wild-type ( ⁇ ) and in ⁇ 2irr /" (FcRp-) ( ⁇ ) mice. This figure demonstrates that, over time, IgG survival is greater in wild- type mice than in ⁇ 2nW " (FcRp-) mice.
  • Figure 2 is a graph which depicts IgG half-lives with increasing IgG concentrations in wild-type ( ⁇ ) and ⁇ 2 m" / '' (FcRp-)(U) mice. This figure demonstrates that with increasing IgG concentration, IgG survival is suppressed in wild-type mice but not in (FcRp-) mice.
  • Figures 3A-3B are graphs which depict the survival in wild-type ( Figure 3A) or in ⁇
  • the invention pertains to physiologically active molecules having extended half-lives in the circulatory system of a subject due to modification of the molecules' structures to include a specific amino acid sequence which binds to the IgG protection receptor FcRp but which does not bind to an Fc receptor which mediates immune effects or which binds to the IgG protection receptor FcRp but which does not bind to complement.
  • physiologically active molecule refers to a molecule which has at least one biological activity when administered to a subject.
  • the biological activity of the physiologically active molecule has a beneficial effect, e.g., decreases symptoms of a disorder or prevents infection by an infectious agent, on the subject to whom it is administered.
  • physiologically active molecules include proteins, peptides, lipids, carbohydrates, nucleic acids, inorganic molecules and molecules which are combinations thereof.
  • the physiologically active molecule is a protein or peptide.
  • physiologically active molecules include proteins and peptides, e.g., immunoglobulins, immunoglobulin fragments or portions, e.g., all or a portion of IgG3, IgA, IgD, IgE, and IgM, cytokines such as TGF- ⁇ , interleukin-2, interleukin- 10, interleukin- 12, GM-CSF, and vaccine immunogens such as gpl20 for HIV, HBSAg of hepatitis B, hemaglutinin of influenza virus, coat protein of respiratory syncytial virus, tetanus toxoid of C.
  • tetani outer membrane proteins of P. pneumoniae, V. cholerae, S. typhae, L. monocytogenes, and M. tuberculosis.
  • physiologically active molecules can be used to treat neoplastic diseases, viral diseases such as AIDS, and other immune diseases and infections as described herein.
  • Subjects to whom the physiologically active molecules can be administered include mammals.
  • the subjects are humans.
  • the circulatory or cardiovascular systems of the subject include the heart and blood vessels (arteries, arterioles, capillaries, venules, veins, and sinuses) and the lymphatic system.
  • half-life refers to the time required to eliminate one-half of the quantity of the physiologically active molecule that was present in the circulatory system of a subject at the point when the measurement was begun.
  • extended half-life when used herein to refer to the modified physiologically active molecules of the invention is intended to include physiologically active molecules, modified according to the invention. which have half-lives which are longer than the half-lives of the physiologically active molecules prior to modification according to the invention.
  • the phrase "specific amino acid sequence” refers to an amino acid sequence which includes amino acid residues capable of binding to the FcRp but which do not bind to an Fc receptor which mediates immune effects or which are capable of binding to the FcRp protection receptor but which do not bind to complement.
  • the Fc receptors which mediate immune effects are located on immune cells.
  • the term "immune cell” is intended to include a cell which plays a role in specific immunity (e.g., is involved in an immune response) or plays a role in natural immunity.
  • immune cells include all distinct classes of lymphocytes (T lymphocytes, such as helper T cells and cytotoxic T cells, B lymphocytes, and natural killer cells), monocytes, macrophages, other antigen presenting cells, dendritic cells, and leukocytes (e.g., neutrophils, eosinophils, and basophils).
  • T lymphocytes such as helper T cells and cytotoxic T cells, B lymphocytes, and natural killer cells
  • monocytes e.g., macrophages, other antigen presenting cells, dendritic cells, and leukocytes (e.g., neutrophils, eosinophils, and basophils).
  • Fc receptors on immune cells are surface receptors which specifically bind to the Fc fragment of IgG. See e.g., Unanue, E.R. and Benacerraf, B. Textbook of Immunology, Second Edition (Williams & Wilkins, Baltimore, MD, 1984) 92, 1
  • the Fc receptors (e.g., FcRI, FcRII, and FcRIII) on immune cells are not involved in protection of IgG from catabolism. These Fc receptors do, however, mediate diverse immune effects or effector functions.
  • the term "immune effects” as used herein refers to effects, activities, or functions mediated, directly or indirectly, by an immune cell. These immune effects or effector functions include, but are not limited to regulation of immunoglobulin production, lysosomal enzyme release, tumor necrosis factor ⁇ release, interleukin-1 and interleukin-6 release, interferon ⁇ release, cell-mediated cytotoxicity by immune cells against cells that bind the Fc- containing molecule, van Winkel and Capel (1993) Immunol.
  • the physiologically active molecules described herein are capable of binding to the FcRp to thereby take advantage of its protective effects but do not bind to an Fc receptor which mediates immune effects.
  • the physiologically active molecules of the invention have increased survival in the recipient subject but do not initiate immune effects which can be detrimental to the subject to whom the molecules are administered.
  • the term "complement" is an art recognized term which refers to a system (or a molecule or molecules within the system) of functionally linked proteins, portions, or complexes thereof which interact with one another in a regulated manner to provide many of the effector functions of humoral immunity and inflammation. See Abbas et al.
  • Nonlimiting examples of molecules which are part of the complement system include Cl, Clq, Clr, Cis, C2, C3, C5, C6, C7, C8, C9, Factor B, and Factor D.
  • the specific amino acid sequence described herein can include amino acid sequences found in IgG which are involved in binding to the FcRp protection receptor but which do not bind to Fc receptors which mediate immune effects.
  • FcRI, FcRII, FcRIII, and complement binding activities of IgG are located in the CH2 domain (amino acids 321 to 240) near the hinge and are not involved in FcRp protection receptor binding, these sites are either not included as specific amino acid sequences in the physiologically active molecules or, if they are included as specific amino acid sequences in the physiologically active molecules, they are altered to delete the binding domains for FcRI, FcRII, FcRIII, and complement. If Leu (amino acid 234) and Pro (amino acid 331 ) of the Fc domain of IgG are changed to different amino acid residues, IgG binding to FcRI is abolished. Canfield and Morrison (1991) J. Exp.
  • the FcRp protection receptor is the same receptor as the FcRn receptor which has previously been cloned and characterized. See e.g., Story et al. (1994) J. Exp. Med. 180:2377-2381); Simister and Mostov (1989) Nature 337: 184); Burmeister et al. (1994) Nature 372:279-383; Kim et al. (1994) Eur. J. Immunol. 24:2429-2434; and Israel et al. (1995) J. Immunol. 154:6246-6251.
  • the FcRp protection receptor and the FcRn receptor are the same receptor, it is specifically contemplated by the invention that the FcRp protection receptor can include differences in the nucleic acid encoding the receptor and/or amino acid sequence of the receptor from the nucleic acid encoding the FcRn receptor and/or amino acid sequence of the FcRn receptor wherein the differences do not affect the ability of the physiologically active molecules of the invention to bind to the FcRp protection receptor.
  • both the nucleic acid and amino acid sequences of the FcRp protection receptor are also available to the skilled artisan.
  • regions of the IgG molecule which are involved in binding to the FcRn receptor have also been identified. See Burmeister et al.
  • regions include amino acid residues 248 to 257 (KTLMISRTP) (SEQ ID NOT); amino acid residue 272 (E); amino acid residue 285 (H); amino acid residue 288 (K); amino acid residues 290 to 291 (KP); amino acid residues 308 to 311 (VLHQ) (SEQ ID NO:2); amino acid residue 314 (L); amino acid residues 385 to 387 (GQP); amino acid residue 428 (M); and amino acid residues 433 to 436 (IINHY) (SEQ ID NO:3).
  • These regions form a motif which is referred to herein as the Brambell motif.
  • physiologically active molecules e.g., proteins and peptides
  • the physiologically active molecules can be modified as described herein to include at least a portion of an amino acid sequences which is substantially homologous, e.g., at least about 60%, 70%, 80%, 90%, 95%, 98%, or 99% or more homologous, to an amino acid sequence, e.g., the Brambell motif, of at least a portion of the IgG domain which binds to the IgG protection receptor FcRp.
  • Amino acid sequences which are substantially homologous to an amino acid sequence of at least a portion of the IgG domain which binds to the IgG protection receptor FcRp can include amino acid sequences which are the same as at least a portion of the IgG domain with the exception of at least one conservative amino acid substitution which does not alter or only slightly alters the ability of the amino acid sequence to bind to the FcRp protection receptor.
  • the specific amino acid sequence is the same as the amino acid sequence of at least a portion of an IgG domain which binds to the IgG protection receptor FcRp.
  • the term "homologous”, as used herein, refers to the sequence similarity between two polypeptide molecules or between two nucleic acid molecules.
  • the molecules are homologous at that position.
  • the percent of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared x 100. For example, if 6 of 10, of the positions in two sequences are matched or homologous then the two sequences are 60% homologous.
  • the amino acid sequences Asp-Ala-Glu-Gly-His-Tyr and Val-Ala-Val- Gly-Thr-Tyr share 50% homology.
  • substantially homologous refers to a polypeptide having an amino acid sequence at least about 60%, 70%, 80%, 90%, 95%, 98%, or 99% homologous to at least a portion of an region or domain, e.g., IgG region or domain, e.g., the Brambell motif, which binds to the IgG protection receptor FcRp.
  • the polypeptide includes an amino acid sequence essentially the same as at least a portion of an amino acid sequence of an IgG region or domain which binds to the IgG protection receptor FcRp.
  • the invention pertains to physiologically active proteins or peptides having an extended half-life in the circulatory system of a subject and which have a structure which has been altered by amino acid substitution such that the protein or peptide specifically binds to the IgG protection receptor FcRp.
  • Methods of altering the amino acid sequence of the physiologically active molecules, e.g., proteins and peptides, are known in the art and described herein.
  • IgG nucleic acid sequences encoding amino acid sequences involved in or potentially involved in binding to the IgG protection receptor can be mutagenized and the resulting mutant gene products can be screened using the methods described herein.
  • amino acid sequence variants of a molecule can be prepared by random mutagenesis or non-random (directed mutagenesis) of DNA which encodes the molecule or a particular domain or region of a polypeptide.
  • random mutagenesis methods include PCR mutagenesis (see e.g., Leung et al. (1989) Technique 1 :1 1-15) and saturation mutagenesis (see e.g., Mayers et al. (1985) Science 229:242).
  • a library of random amino acid sequence variants can also be generated by the synthesis of a set of degenerate oligonucieotide sequences.
  • Non-random mutagenesis can be used to create variants which include, e.g., deletions, insertions, or substitutions, of residues of the known amino acid sequence of a protein or peptide.
  • the sites for mutation can be modified individually or in series, e.g., by (1) substituting first with conserved amino acids and then with more radical choices depending upon results achieved, (2) deleting the target residue, or (3) inserting residues of the same or a different class adjacent to the located site, or combinations of options 1-3.
  • non-random mutagenesis examples include alanine scanning mutagenesis (see, e.g., Cunningham and Wells (1989) Science 244:1081 - 1085), oligonucleotide-mediated mutagenesis (see, e.g., Adelman et al. (1983) DNA 2: 183; Crea et al. (1978) Proc. Natl. Acad. Sci. USA 75: 5765), cassette mutagenesis (see, e.g., Wells et al. (1985) Gene, 34:315), and combinatorial mutagenesis (see, e.g., Ladner et al., WO 88/06630)
  • Techniques for screening large gene libraries often include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the genes under conditions in which detection of a desired activity, e.g., binding to the IgG protection receptor FcRp but no binding to an Fc receptor which mediates immune effects or binding to the IgG protection receptor FcRp but no binding to complement, facilitates relatively easy isolation of the vector encoding the gene whose product was detected.
  • Several techniques are amenable to high through-put analysis for screening large numbers of sequences created, e.g., by random mutagenesis techniques.
  • the invention pertains to physiologically active molecules having an extended half-life in the circulatory system of a subject and which have a structure which is modified to include at least a portion of an antibody which is raised against the IgG protection receptor FcRp and which specifically binds to the IgG protection receptor FcRp.
  • An antibody, or fragment, portion, or derivative thereof, which can be included in the structure of the physiologically active molecules of the invention can be derived from polyclonal antisera containing antibodies reactive with a number of epitopes on the antigen, e.g., the IgG protection receptor FcRp. More preferably, however, monoclonal antibodies are raised against the IgG protection receptor (or FcRn receptor) using the IgG protection receptor FcRp (or FcRn receptor) or a cell having the receptor on its surface as the immunogen.
  • Polyclonal and monoclonal antibodies for use in the invention can be prepared by standard techniques known in the art.
  • a mammal e.g., a mouse, hamster, or rabbit
  • an antigen e.g., IgG protection receptor FcRp or a portion thereof
  • a cell which expresses the antigen (e.g., on the cell surface) to elicit an antibody response against the antigen in the mammal.
  • tissue or a whole organ which expresses the antigen can be used to elicit antibodies.
  • the progress of immunization can be monitored by detection of antibody titers in plasma or serum. Standard ELISA or other immunoassay can be used with the antigen to assess the levels of antibodies.
  • antibody producing cells can be harvested from an immunized animal and fused with myeloma cells by standard somatic cell fusion procedures thus immortalizing these cells and yielding hybridoma cells.
  • myeloma cells can be harvested from an immunized animal and fused with myeloma cells by standard somatic cell fusion procedures thus immortalizing these cells and yielding hybridoma cells.
  • Hybridoma cells can be screened immunochemically for production of antibodies specifically reactive with the antigen and monoclonal antibodies isolated.
  • Another method of generating specific antibodies, or antibody fragments, reactive against epitopes on an antigen is to screen expression libraries encoding immunoglobulin genes, or portions thereof, expressed in bacteria with the antigen (or a portion thereof)- For example, complete Fab fragments, Vf ⁇ regions, Fv regions and single chain antibodies can be expressed in bacteria using phage expression libraries. See, e.g., Ward et al. (1989) Nature 341 ;544-546; Huse et al. (1989) Science 246:1275-1281 ; and McCafferty et al. (1990) Nature 348:552-554.
  • the Xenomouse can be used to produce antibodies, or fragments thereof (available from Cell Genesys).
  • Antibodies of the appropriate binding specificity which are made by these techniques can be used to alter an antigen on a donor cell.
  • a preferred antibody portion or fragment for altering an epitope is a F(ab')2 fragment.
  • Antibodies can be fragmented using conventional techniques. For example, the Fc portion of an antibody can be removed by treating an intact antibody with pepsin, thereby generating a F(ab')2 fragment. In a standard procedure for generating F(ab')2 fragments, intact antibodies are incubated with immobilized pepsin and the digested antibody mixture is applied to an immobilized protein A column. The free Fc portion binds to the column while the F(ab')2 fragments passes through the column.
  • the F(ab')2 fragments can be further purified by HPLC or FPLC. F(ab')2 fragments can be treated to reduce disulfide bridges to produce Fab' fragments.
  • the antibody or portion thereof binds to the IgG protection receptor at acidic pH, e.g. a pH of about 6.5 or lower, and is released from (or does not bind to) the IgG protection receptor at neutral pH, e.g., a pH of about 7.0 to about 7.5.
  • physiologically active molecules modified to include the antibody or portion thereof can escape lysosomal catabolism by remaining bound to the IgG protection receptor at low pH and remain in the circulation of a subject for longer periods of time by being released from the IgG protection receptor at neutral pH.
  • compositions which include the physiologically active molecules described herein together with a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and abso ⁇ tion delaying agents, and the like, compatible with pharmaceutical administration.
  • the use of such media and agents for physiologically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the physiologically active molecule, use thereof in the compositions is contemplated.
  • the invention pertains to methods for producing physiologically active molecules which have an extended half-life in the circulatory system of a subject.
  • physiologically active molecules can be modified by a variety of methods including, for example, altering the amino acid sequence of the physiologically active molecule as described herein to include amino acid sequences which bind to the appropriate receptor; surface reshaping; coupling of two nucleic acid molecules one of which encodes the physiologically active molecule and another which encodes an amino acid sequence capable of binding to the FcRp to generate a fusion protein (see e.g., Capon et al. (1989) Nature 337:525-531 ; U.S. Patent No.
  • disorders which can be treated according to the method of the invention include disorders the detrimental effects of which can be alleviated, minimized, decreased, e.g., temporarily or permanently, or abolished by administration of a physiologically active molecule.
  • disorders include autoimmune disorders such as systemic lupus erythematosis, arthritis, and autoimmune thyroiditis (TGF ⁇ and IL-10); immunodeficiencies such as Wiskott-Aldrich syndrome and AIDS (IgM); neoplastic disorders such as melanomas and carcinomas (IL-2), e.g., renal cell carcinoma; disorders resulting from the presence of infectious agents such as viruses (e.g., HIV, hepatitis B virus, influenza virus, respiratory syncytial virus) and bacteria (e.g., P.
  • infectious agents such as viruses (e.g., HIV, hepatitis B virus, influenza virus, respiratory syncytial virus) and bacteria (e.g., P.
  • mice wild-type and genetic knockout mice (FcRp-) were obtained from The Jackson Labs, Bar Harbor, Maine, with either a mixed C57BL/6 x 129/Ola background or an inbred C57BL/6J background. The mice were raised under low pathogen conditions (Sell and Fahey (1964) J. Immunol. 93:81-87; Sell (1964) J. Exp. Med. 120:967-986) to yield low endogenous IgG levels.
  • mice Animals (mixed background ⁇ 2m"' / "or wildtype; Jackson Labs) raised under low pathogen conditions as described above were injected with mixtures of 131 I murine anti-Tac antibody ( ⁇ , wildtype; ⁇ , mutant) and 125 I murine albumin (Inter-Cell).
  • Anti-Tac is an IgG2a, ⁇ antibody against human IL2R ⁇ and is not reactive with any mouse proteins or tissues. Five mice were used per group. Blood was sampled at indicated times and processed for protein-bound counts by trichloroacetic acid precipitation as previously described (Junghans and Waldmann (1996) J. Exp. Med. 183:1587-1602).
  • Plasma immunoglobulin levels were assayed, in which IgG was approximately 10-fold lower in mutant than in wild-type mice, as noted previously (Israel et al. (1995) Immunol. 154:6246-6251), whereas IgA and IgM were the same between groups. This direct relation of increased catabolic rates and decreased blood levels of IgG is compatible with pharmacokinetic predictions.
  • Example II Suppression of Antibody Survival by Increased IgG Concentration in Wild-type but not in ⁇ 2m"/" Mice.
  • the disruption of the FcRp is predicted to disrupt the classical pattern of decreased IgG survival with higher IgG concentration (Brambell et al. (1964) Nature 203: 1352-1355; Humphrey and Fahey (1961 ) J.
  • Figure 3 A confirm the observation of differential catabolism in the wild-type mice described herein, with longer survival of antibody than antigen associated with antibody.
  • Med 183:1587-1602 approximates the value of 0.45 ⁇ 0.07 day for IgG and albumin in the ⁇ 2m " ' ⁇ mice ( Figure 1 ), and is also comparable to the non-renal component of L chain and Fab catabolism (Wochner et al. (1967) J. Exp. Med. 126:207) and to total catabolism for IgM (Junghans and Waldmann ( 1996) J. Exp. Med. 183 : 1587-
  • the unifying feature of the FcRn and the protection receptor is high affinity binding at low pH, present both in bowel and in endosome, and low affinity at normal plasma pH.
  • IgG is not bound to FcRp on the cell surface at all, but only after IgG is passively internalized by ongoing pinocytosis into endosomes where it is returned to circulation with reversal of binding at neutral physiologic pH.
  • the present studies show that normal IgG catabolism is regulated principally through the Brambell receptor (FcRp) because deletion of a subunit of the receptor renders its catabolism indistinguishable from that of albumin in the same mice.
  • Example IV Modification of IgM to Extend Half-Life in Circulatory System of a Subject
  • Physiologically active molecules e.g., physiologically active proteins or peptides
  • Physiologically active molecules can be generated by modifying their structure to include the sequences, e.g., amino acid sequences, which are involved in IgG binding to the FcRp protection receptor in positions according to computerized or manual spatial analysis to approximate the orientation of the domains of IgG. These amino acid sequences are described herein.
  • the amino acid sequence of an IgM protein against a microorganism or a cancer is altered to include the amino acid sequences set forth in Table I below. These alterations allow IgM to bind to the IgG protection receptor FcRp but not to an Fc receptor which mediates immune effects. In addition, these alterations do not interfere with the ability of IgM to bind complement. Subsets of these alterations or analogous alterations can also be used to alter the amino acid sequence of IgM to impart thereon the ability to bind to the IgG protection receptor FcRp but not to an Fc receptor which mediated immune effects. TABLE I
  • amino acid GQP (IgG amino acids 385-387) is preserved in IgM (amino acids 492-494) and does not require modification.
  • IgM is advantageous for use in treatment of gram negative bacterial sepsis (Ziegler et al. (1991) N. Engl. J. Med. 324:429-436) and of infection hypersusceptibility of Wiskott- Aldrich syndrome. As the normal survival of IgM in humans is about five days (Waldmann and Strober (1969) Progr. Allergy 13:1-1 10), treatment using IgM requires redosing on a frequent basis. When IgM is modified by altering its amino acid sequence as shown in Table I, its half-life in a human is increased to about 23 days which is equivalent to the half-life of IgG in a human. This increase in half-life results in a reduced redosing schedule and an approximately 80% savings in IgM.
  • Example V Modification of IgA to Extend Half-Life in Circulatory System of a Subject
  • the amino acid sequence of an IgA protein against a microorganism or a cancer is altered to include the amino acid sequences set forth in Table II below. These alterations allow IgA to bind to the IgG protection receptor FcRp but not to an Fc receptor which mediates immune effects. Subsets of these alterations or analogous alterations can also be used to alter the amino acid sequence of IgM to impart thereon the ability to bind to the IgG protection receptor FcRp but not to an Fc receptor which mediates immune effects. TABLE II
  • IgA is advantageous for use in treatment of viral infections.
  • IgA is modified by altering its amino acid sequence as shown in Table II, its half-life in a human is increased to about 23 days which is equivalent to the half-life of IgG in a human. This increase in half-life results in a reduced redosing schedule and an approximately 80% savings in IgA.
  • Example VI Modification of Hepatitis B Surface Antigen to Extend Half-Life in Circulatory System of a Subject
  • Hepatitis B surface antigen (HBSAg) is used to vaccinate subjects against hepatitis B viral infection. Subjects are vaccinated against hepatitis B viral infection through the administration of repeated doses of HBSAg.
  • HBSAg has a half-life of about three hours in the circulatory system of a subject.
  • nucleic acid encoding HBSAg is coupled to a nucleic acid molecule encoding an amino acid sequence which includes the Brambell motif as described herein.
  • HBSAg is a protein of 400 amino acids with several domains of secondary structure and few glycosylation sites (Neurath et al. (1987) Microbiol. Sciences 4:45-51). Seven T and B cell epitopes in HBSAg have been defined. These epitopes are not disrupted when HBSAg is modified according to the invention.
  • the Brambell motif is inserted into the region encompassed by amino acid residues 60 to 80, which is flanked by ⁇ sheets, amino acid residues 220-245, the ⁇ turn domain, or amino acid residues 160 to 180, the ⁇ helix domain of HBSAg.
  • HBSAg modified according to this method has a half-life of about 23 days in a human.
  • Example VII Modification of HIV Envelope Protein gpl20 to Extend Half-Life in Circulatory System of a Subject
  • the HIV envelope protein gpl20 is a major target for immune responses in HIV infection and can be used as a vaccine immunogen.
  • the half-life of gpl20 is about 4 days in the circulatory system of the subject.
  • selected domains are preserved while others are modified.
  • gpl20 is 510 amino acids in length with a structure which includes disulfides, glycosylations, and five neutralization domains. The disulfide structure and the neutralization domains are preserved.
  • the IgG domains which interact with the FcRp protection receptor are mainly in two broad bands of about 50 to 70 amino acids each that are exposed with intervening buried ⁇ sheets. Disulfide delimited loops accomplish a similar sequence externalization and exposure as that of the IgG domains which interact with FcRp. Loops SS2 and SS3 are, therefore, modified to include the Brambell motif. gp!20 modified according to this method has a half-life of about 23 days in a human.
  • Example VIII to Example X several different small molecules are modified by linking the molecules to a carrier molecule which (1) binds to the FcRp protection receptor but which does not bind to an Fc receptor which mediates immune effects; or (2) binds to the FcRp protection receptor but which does not bind to complement.
  • the carrier molecule is an amino acid sequence which includes amino acid residues which bind to the FcRp protection receptor but which do not bind to an Fc receptor which mediates immune effects; and/or (2) which bind to the FcRp protection receptor but which do not bind to complement.
  • a carrier molecule which includes these amino acid residues can be produced by selectively modifying the Fc region of IgG, for example, IgGl .
  • the Fc region of IgG includes the amino acid residues which are involved in binding to the FcRp protection receptor but which also include amino acid residues which are involved in binding to Fc receptors which mediate immune effects and/or amino acid residues which arc involved in binding to complement.
  • the Fc region of IgG is then modified to preserve the amino acid residues which are involved in binding to the FcRp protection receptor but to delete, e.g., by substitution, the amino acid residues which are involved in binding to Fc receptors which mediate immune effects or amino acid residues which are involved in binding to complement.
  • the modified Fc region of IgG which has been converted to a carrier molecule is then linked to the physiologically active molecule to increase the half-life of the molecule.
  • Glycophorin A is the target for P. falciparum malarial parasite for red blood cell invasion. Blocking GpA with antibody blocks access of parasite to the red blood cell invasion pathway, but treatment with antibody cannot be used in vivo because of danger to the red blood cells from the antibody exposure.
  • the reverse strategy is to block the parasite with a soluble GpA.
  • the half-life of GpA is about one hour.
  • GpA is modified as described above. Specifically, the extracellular domain of GpA, which includes only about 85 amino acids, is expressed as a fusion protein which includes the extracellular domain linked to a carrier molecule as described above.
  • Example IX Modification of IL-10 and TGF ⁇ to Extend Half-Life in
  • IL-10 and TGF ⁇ can abort active autoimmune responses in subjects with autoimmune diseases (Sporn and Roberts (1990) Cell. Regul. 1 :875-882; Moore et al. (1993) Ann. Rev. Immunol. 1 1 : 165-190). Both IL-10 and TGF ⁇ have short half-lives, about one hour each. To increase the half-lives of these molecules to about 23 days, the molecules are modified by linking thereto a carrier molecule as described above. Specifically, IL-10 (18kD) and TGF ⁇ (25kD) are expressed as fusion proteins which include these small molecules linked to a carrier molecule as described above.
  • Example X Modification of IL-2 to Extend Half-Life in Circulatory System of a Subject
  • IL-2 has been approved for the treatment of renal cell carcinoma and is additionally effective for the treatment of melanoma and other cancers (Rosenberg et al. (1989) Ann. Surg. 210(4):474-485).
  • the short half-life (about one hour) of IL-2 necessitates continuous infusion or repeated intravenous or subcutaneous dosing.
  • IL-2 is modified by linking thereto a carrier molecule as described above.
  • IL-2 is expressed as a fusion protein which includes IL-2 linked to a carrier molecule as described above.
  • MOLECULE TYPE peptide
  • FRAGMENT TYPE internal
  • MOLECULE TYPE peptide
  • FRAGMENT TYPE internal
  • MOLECULE TYPE peptide
  • FRAGMENT TYPE internal
  • MOLECULE TYPE peptide
  • FRAGMENT TYPE internal

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Abstract

Molécules physiologiquement actives présentant une demi-vie prolongée dans le système circulatoire d'un sujet, compositions comprenant ces molécules, méthodes de production de ces molécules et méthodes d'utilisation de ces molécules à des fins thérapeutiques. Les demi-vies de ces molécules physiologiquement actives sont prolongées par une modification de leur structure qui les rend capables de se fixer aux récepteurs FcRp protecteurs de l'IgG. En modifiant de cette manière les molécules physiologiquement actives, on met à profit la découverte du fait que le FcRp et le FcRn sont le même récepteur et que la modification de ces molécules pour leur permettre de se fixer au récepteur de protection FcRp permet à ces molécules d'échapper au catabolisme lysosomal et de rester dans le système circulatoire d'un sujet pendant une plus longue durée.
PCT/US1997/007707 1996-05-10 1997-05-06 Molecules physiologiquement actives a demi-vies prolongees et methode d'utilisation de ces dernieres WO1997043316A1 (fr)

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