CN117320744A - Therapeutic combinations for the treatment of cancer - Google Patents
Therapeutic combinations for the treatment of cancer Download PDFInfo
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- CN117320744A CN117320744A CN202280025068.8A CN202280025068A CN117320744A CN 117320744 A CN117320744 A CN 117320744A CN 202280025068 A CN202280025068 A CN 202280025068A CN 117320744 A CN117320744 A CN 117320744A
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Landscapes
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to methods and kits for treating a subject (e.g., a patient) suffering from cancer by administering to the subject an anti-cancer vaccine in combination with one or more checkpoint inhibitors.
Description
Technical Field
The present invention relates to methods and kits for treating a subject (e.g., a patient) suffering from cancer by administering to the subject a combination of an anti-cancer vaccine and one or more checkpoint inhibitors.
Background
Although cancer therapy has improved over the past few decades, particularly because early detection and diagnosis has significantly improved survival rates, only about 60% of patients diagnosed with cancer survive 5 years post-diagnosis. In addition to surgical removal of tumors and lesions, current cancer treatments include radiation therapy and cytotoxic chemotherapy, each of which has its well-known advantages and disadvantages.
Recently, immunotherapy has become an alternative to cancer therapy. Therapeutic anti-cancer vaccines represent a class of immunotherapy that acts by stimulating or restoring the ability of the subject's immune system to fight cancer. Therapeutic anti-cancer vaccines are used to treat existing cancers as compared to prophylactic or preventative vaccines. An anti-cancer vaccine may reduce or even eliminate some of the side effects seen in traditional cancer treatments.
One such class of anti-cancer vaccines is those developed by the applicant. They are polypeptides-or polynucleotides encoding such polypeptides, comprising three subunits: targeting units that target Antigen Presenting Cells (APCs), dimerization units, and antigenic units comprising one or more cancer antigens. Due to the dimerization unit, the polypeptide forms a dimeric protein. Such anti-cancer vaccines are disclosed, for example, in WO 2004/076489A1, WO 2011/161244A1, WO 2013/092875A1 and WO 2017/118695 A1.
When administered to a patient as a dimeric protein (or administered to a patient as a polynucleotide and expressed in vivo), the dimeric protein targets APCs, which results in enhanced vaccine efficacy compared to the same non-targeted antigen.
Another type of cancer immunotherapy is a checkpoint inhibitor that targets different immune checkpoints, a key regulator of the immune system, that when stimulated can suppress immune responses to immune stimulation. Some cancers can protect themselves from attack by the human immune system by stimulating immune targets, thereby destroying or even counteracting the therapeutic success of anticancer immunotherapy. Checkpoint inhibitor therapy has been used to block inhibitory checkpoints, thereby restoring immune system function and treating cancer, such as melanoma or non-small cell lung cancer patients. There remains a need for effective cancer treatments.
Disclosure of Invention
The present invention relates to methods and kits for treating a subject (e.g., a patient) suffering from cancer by administering to the subject a combination of an anti-cancer vaccine and one or more checkpoint inhibitors.
Detailed Description
Thus, in a first aspect, the present invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit (e.g., a dimerization unit), and an antigenic unit comprising one or more cancer antigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and
(b) One or more checkpoint inhibitors.
In one embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anti-cancer vaccine comprising:
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, and an antigenic unit comprising one or more cancer antigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein consisting of a plurality of polypeptides defined in (ii); and
(b) One or more checkpoint inhibitors.
In another embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anti-cancer vaccine comprising:
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a dimerization unit, and an antigenic unit comprising one or more cancer antigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A dimeric protein consisting of two polypeptides as defined in (ii); and
(b) One or more checkpoint inhibitors.
As used herein, a "subject" is an animal, such as a mouse, or a human, preferably a human. The terms "subject with cancer" and "patient" are used interchangeably herein.
"cancer" refers to a broad class of diseases characterized by uncontrolled growth of abnormal cells in the body. "cancer" or "cancerous tissue" includes tumors, and as used herein, encompasses solid tumors as well as tumor cells found in bodily fluids such as blood, and includes metastatic cancers. Unregulated cell division and growth results in the formation of malignant tumors that can invade adjacent tissues and can metastasize to distant sites of the body through the lymphatic system or blood flow. After transfer, the distal tumor may be referred to as "derived from" the pre-transferred tumor.
"cancer antigen" includes a neoantigen, a patient-presented consensus cancer antigen (event-present shared cancer antigen), or a consensus cancer antigen (shared cancer antigen), as described herein.
"part" refers to a part/fragment of a cancer antigen, i.e. a part/fragment of the amino acid sequence of a cancer antigen or a nucleotide sequence encoding the same, e.g. an epitope.
The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
Anticancer vaccine
The anti-cancer vaccine used in the methods of the invention may be a personalized anti-cancer vaccine or a non-personalized anti-cancer vaccine, i.e., an "off-the-shelf" anti-cancer vaccine (referred to as a "consensus anti-cancer vaccine"). The antigenic units of these two classes of anti-cancer vaccines differ, as detailed below.
The anti-cancer vaccine used in the methods of the invention may be described as a polypeptide having an N-terminal start and a C-terminal end (as shown in fig. 1). The elements and units of the polypeptide, the Targeting Unit (TU), the multimerizing unit (e.g. the dimerizing unit (DimU) in this figure) and the antigenic unit, may be arranged in the polypeptide such that the antigenic unit is located at the C-terminal end of the polypeptide (fig. 1 a) or at the N-terminal start of the polypeptide (fig. 1 b). Preferably, the antigenic unit is located at the C-terminal end of the polypeptide. The Unit Linker (UL) may link a multimerization unit (e.g., a dimerization unit) to an antigenic unit. FIG. 1 shows an antigenic unit with 4 neo-epitopes (neo 1, neo2, neo3, neo 4) separated by a linker (SUL 1, SUL2, SUL 3). Another way of describing the neo-epitope neo1-neo4 arrangement is that these neo-epitopes are arranged in 3 antigenic subunits, each comprising a neo-epitope and a subunit linker (SUL 1, SUL2, SUL 3), and a terminal neo-epitope (neo 4) that is closest to the C-terminal or N-terminal start of the polypeptide. Subunits are indicated in brackets in the figure. Thus, an antigenic unit comprising n neoepitopes comprises n-1 subunits, each subunit comprising a neoepitope and a subunit linker. As described herein, the 4 neo-epitopes may be the same or different neo-epitopes and the 3 linker/subunit linkers may be the same or different. The order and orientation of the above units and elements are the same in proteins and polynucleotides.
The individual units and elements of the anti-cancer vaccine will be discussed in detail below. These units and elements are present in polynucleotides as nucleic acid sequences encoding these units, while they are present as amino acid sequences in polypeptides or multimeric proteins. For ease of reading, in the following, the explanation of the units of an anti-cancer vaccine is mainly directed to polypeptide/multimeric proteins, i.e. based on the amino acid sequence of such a vaccine.
Antigenic unit
Antigenic units of personalized anti-cancer vaccines
The personalized anti-cancer vaccine for use in the methods of the invention comprises an antigenic unit that is specifically and exclusively designed for the patient to be treated with or to be treated with the vaccine described above. Thus, the antigenic unit of such a vaccine comprises one or more cancer antigens, which are patient-specific antigens or parts thereof, such antigens including neoantigens or consensus cancer antigens present by the patient.
"patient-present consensus cancer antigen" is used herein to describe a consensus cancer antigen or consensus tumor antigen that has been identified as being present in a patient's tumor cells.
"neoantigen or patient-specific cancer antigen" is used herein to describe a cancer antigen or tumor antigen found in a patient's tumor cells that contains one or more mutations compared to normal (i.e., healthy, non-cancerous) cells of the same patient.
"patient-present consensus cancer epitope" is used herein to describe the amino acid sequence contained in or the nucleotide sequence encoding the patient-present consensus cancer antigen, which contains one or more immunogenic mutations, i.e., those mutations are known to be immunogenic or predicted to be immunogenic.
"neoepitope" or patient-specific cancer epitope "is used herein to describe an amino acid sequence contained in a neoantigen or patient-specific cancer antigen or a nucleotide sequence encoding the same, which contains one or more immunogenic mutations, i.e., these mutations are predicted to be immunogenic.
Thus, in one embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, such as a dimerization unit, and an antigenic unit, wherein the antigenic unit comprises one or more patient-specific cancer antigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and
(b) One or more checkpoint inhibitors.
In one embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, and an antigenic unit, wherein the antigenic unit comprises one or more patient-specific cancer antigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein consisting of a plurality of polypeptides defined in (ii); and
(b) One or more checkpoint inhibitors.
In another embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a dimerization unit, and an antigenic unit, wherein the antigenic unit comprises one or more patient-specific cancer antigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A dimeric protein consisting of two polypeptides as defined in (ii); and
(b) One or more checkpoint inhibitors.
In one embodiment, the patient-specific cancer antigen is a consensus cancer antigen present in the patient. Thus, in such embodiments, the antigenic unit comprises one or more patient-present consensus cancer antigen or a portion thereof, e.g., one patient-present consensus cancer antigen or one or more portion of said one patient-present consensus cancer antigen, e.g., one or more epitope, or more patient-present consensus cancer antigen or one or more portion of a plurality of patient-present consensus cancer antigen, e.g., one or more epitope.
In another embodiment, the patient-specific cancer antigen is a neoantigen. Thus, in such embodiments, the antigenic unit comprises one or more neoantigens or parts thereof, e.g. a neoantigen or one or more parts of said one neoantigen, e.g. one or more neoepitopes, or a plurality of neoantigens or one or more parts of a plurality of neoantigens, e.g. one or more neoepitopes.
In another embodiment, the antigenic unit comprises any combination of the preceding embodiments, i.e., any combination of a common cancer antigen or portion thereof present in one or more patients as described above with one or more neoantigens or portions thereof.
Antigenic units of personalized anti-cancer vaccines comprising one or more neoantigens or portions thereof
Cancers develop from normal tissue of a patient by one or more cells that begin abnormal, uncontrolled proliferation due to mutations. Although cancer cells have been mutated, most of the genome in these cells is intact and identical to the rest of the cells in the patient. One approach to attacking tumors is based on the recognition that any tumor in any patient is unique: patient-specific mutations result in the expression of patient-specific muteins, i.e., patient-specific cancer antigens, i.e., neoantigens, which are unique to a particular patient. These novel antigens are not identical to any protein in the normal cells of the patient. Thus, such neoantigens are suitable targets for therapeutic anti-cancer vaccines (i.e. personalized anti-cancer vaccines) that are specifically and solely made for the patient in question.
The mutation may be any mutation resulting in at least one amino acid change. Thus, the mutation may be one of the following:
non-synonymous mutations leading to amino acid changes
Mutation resulting in frame shift, thereby generating a completely different open reading frame in that direction after mutation
Read-through mutations in which the stop codon is modified or deleted, resulting in a longer protein with a tumor-specific epitope
Splice mutations, producing unique tumor specific protein sequences
Chromosomal rearrangements, resulting in chimeric proteins with tumor specific epitopes at the junction of the two proteins. When the mutation is due to chromosomal rearrangement, the tumor-specific epitope may be generated by a change in at least one amino acid or by a combination of two in-frame coding sequences.
In one embodiment, the antigenic unit comprises one or more neoantigens or parts thereof, preferably one or more neoepitopes, and more preferably a plurality of neoepitopes. Such neoepitopes may be selected for inclusion into the antigenic unit according to their predicted therapeutic efficacy, see WO 2017/118695A1, the disclosure of which is incorporated herein by reference.
Thus, in one embodiment, the invention provides a method for treating a subject (e.g., a patient) having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, such as a dimerization unit, and an antigenic unit, wherein the antigenic unit comprises one or more neoantigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and
(b) One or more checkpoint inhibitors.
In one embodiment, the invention provides a method for treating a subject (e.g., a patient) having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, and an antigenic unit, wherein the antigenic unit comprises one or more neoantigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein consisting of a plurality of polypeptides as defined in (ii); and
(b) One or more checkpoint inhibitors.
In another embodiment, the invention provides a method for treating a subject (e.g., a patient) having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a dimerization unit, and an antigenic unit, wherein the antigenic unit comprises one or more neoantigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A dimeric protein consisting of two polypeptides as defined in (ii); and
(b) One or more checkpoint inhibitors.
In one embodiment, the antigenic unit comprises one or more parts of a neoantigen or one or more parts of a neoantigen, preferably one or more neoepitopes. In a preferred embodiment, the neoepitope is separated by a linker in the antigenic unit. Another way of describing the separation of all neo-epitopes by linkers is that all neo-epitopes except the terminal neo-epitope (i.e. the neo-epitope located at the beginning of the N-terminus of the polypeptide or at the end of the C-terminus of the polypeptide) are arranged in antigenic subunits, wherein each subunit comprises a neo-epitope and a subunit linker. Since the neo-epitopes are separated by linkers, each neo-epitope is presented to the immune system in an optimal manner.
Thus, an antigenic unit comprising n neoepitopes comprises n-1 antigenic subunits, wherein each subunit comprises a neoepitope and a subunit linker, and further comprises a terminal neoepitope. In one embodiment, n is an integer from 1 to 50, such as from 3 to 50 or 15 to 40 or 10 to 30 or 10 to 25 or 10 to 20 or 15 to 30 or 15 to 25 or 15 to 20. In a preferred embodiment, the antigenic subunit consists of a neoepitope and subunit linker.
Accordingly, in one embodiment, the present invention provides a method for treating a subject having cancer, the method comprising administering to the subject:
(a) An anti-cancer vaccine comprising:
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerizing unit such as a dimerization unit, and an antigenic unit, wherein the antigenic unit comprises (a) n-1 antigenic subunits, each subunit comprising a neoepitope and a subunit linker, and (B) a terminal neoepitope, and wherein n is the number of neoepitopes in the antigenic unit and n is an integer from 1 to 50; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and
(b) One or more checkpoint inhibitors.
In one embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject:
(a) An anti-cancer vaccine comprising:
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit, a multimerization unit, and an antigenic unit that targets an antigen presenting cell, wherein the antigenic unit comprises (a) n-1 antigenic subunits, each subunit comprising a neoepitope and a subunit linker, and (B) a terminal neoepitope, wherein n is the number of neoepitopes in the antigenic unit and n is an integer from 1 to 50; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein consisting of a plurality of polypeptides defined in (ii); and
(b) One or more checkpoint inhibitors.
In another embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject:
(a) An anti-cancer vaccine comprising:
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit, a dimerization unit, and an antigenic unit that targets an antigen presenting cell, wherein the antigenic unit comprises (a) n-1 antigenic subunits, each subunit comprising a neoepitope and a subunit linker, and (B) a terminal neoepitope, wherein n is the number of neoepitopes in the antigenic unit and n is an integer from 1 to 50; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A dimeric protein consisting of two polypeptides as defined in (ii); and
(b) One or more checkpoint inhibitors.
The neoepitope is preferably of a length suitable for presentation by an HLA (human leukocyte antigen) molecule. Thus, in a preferred embodiment, the neoepitope has a length of 7 to 30 amino acids. More preferably, the neoepitope is 7 to 10 amino acids in length or 13 to 30 amino acids, e.g. 20 to 30 amino acids, e.g. 27 amino acids in length.
HLA is the Major Histocompatibility Complex (MHC) in humans. MHC molecules are mainly of two classes: MHC class I and MHC class II. The terms MHC class I and MHC class II are used interchangeably herein with HLA class I and HLA class II, as are the terms HLA allele and HLA molecule.
Preferably, the antigenic unit comprises a plurality of neoepitopes, i.e. several neoepitopes. In one embodiment, the plurality of neo-epitopes are different neo-epitopes. In another embodiment, the antigenic unit comprises multiple copies of the same neoepitope. In another embodiment, the antigenic unit comprises a plurality of different neoepitopes and a plurality of copies of the same neoepitope.
Thus, it is preferred to include as many neo-epitopes (i.e., different neo-epitopes and/or multiple copies of the same neo-epitope) in the antigenic unit as possible, thereby effectively attacking the cancer without compromising the ability of the vaccine to activate T cells against the neo-epitope due to dilution of the desired T cell effect. Furthermore, to ensure that all neoepitopes are efficiently loaded into the same antigen presenting cell, all neoepitope encoding nucleotide sequences are contained in a continuous polynucleotide chain, resulting in the expressed protein comprising all neoepitopes, rather than expressing each neoepitope as a discrete peptide.
To design the antigenic unit, the patient's tumor exome is analyzed to identify the neoantigen. Preferably, the sequence of the most immunogenic neoepitope from one or more neoantigens is selected for inclusion in the antigenic unit.
The antigenic unit comprises at least 1 neoepitope, preferably at least 3 neoepitopes, more preferably at least 5 neoepitopes, for example 7 neoepitopes. In a more preferred embodiment, the antigenic unit comprises at least 10 neoepitopes. In another more preferred embodiment, the antigenic unit comprises at least 15 neoepitope sequences, e.g. at least 20 or at least 25 or at least 30 or at least 35 or at least 40 or at least 45 neoepitope sequences.
Antigenic singles of personalized anti-cancer vaccines comprising consensus cancer antigen or portion thereof present in one or more patients
Meta
Many tumors express a common tumor antigen, either across patients with the same cancer type, or across patients and across cancer types. One example is HPV16 antigen, a viral antigen, expressed not only in about 50% of head and neck squamous cell carcinoma patients, but also in cervical and vulvar squamous cell carcinoma and other cancer patients. Many of these consensus antigens have previously been characterized as immunogenic and/or known, i.e. their immunogenicity has been confirmed by suitable methods and the results have been disclosed, for example in scientific publications. Other consensus antigens have been predicted to be presented on specific HLA class I or class II alleles, for example by algorithms known in the art, and their predicted immunogenicity has been disclosed, for example in scientific publications, without confirmation of their immunogenicity by appropriate methods.
In one embodiment, the antigenic unit comprises one or more patient-present consensus cancer antigens or portions thereof, e.g., patient-present consensus cancer epitopes, which are known to be immunogenic, have a known expression pattern, and/or are known or have been predicted to bind to specific HLA class I and class II alleles.
T cells specific for the common cancer antigen present in the patient can migrate to the tumor and affect the tumor microenvironment, thereby increasing the likelihood that other tumor-specific T cells will attack the cancer.
Thus, in one embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, such as a dimerization unit, and an antigenic unit, wherein the antigenic unit comprises one or more consensus cancer antigens or portions thereof present in a patient; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and
(b) One or more checkpoint inhibitors.
In one embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, and an antigenic unit, wherein the antigenic unit comprises one or more consensus cancer antigens or portions thereof present in a patient; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein consisting of a plurality of polypeptides defined in (ii); and
(b) One or more checkpoint inhibitors.
In another embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a dimerization unit, and an antigenic unit, wherein the antigenic unit comprises one or more consensus cancer antigens or portions thereof present in a patient; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A dimeric protein consisting of two polypeptides as defined in (ii); and
(b) One or more checkpoint inhibitors.
In one embodiment, the patient is present with a consensus cancer antigen selected from the group consisting of an overexpressed cellular protein, an abnormally expressed cellular protein, a cancer testis antigen, a viral antigen, a differentiation antigen, a mutated oncogene and mutated tumor suppressor gene, a carcinoembryonic antigen, a consensus fusion antigen, a consensus intron retention antigen (shared intron retention antigen), a dark matter antigen (dark matter antigen), and a consensus antigen resulting from a splice mutation or a frameshift mutation.
In one embodiment, the patient is presented with a consensus cancer antigen that is an over-or abnormally expressed human cellular protein, i.e., a cellular protein that is found at elevated levels in tumors as compared to normal, healthy cells and tissues. Examples of such over-or abnormally expressed cellular proteins include tumor protein D52, her-2/neu, hTERT (telomerase), and survivin (survivin).
In another embodiment, the patient presents with a consensus cancer antigen that is a cancer testis antigen that is normally expressed in male germ cells in the testis, but not in adult tissue. In some cases, such antigens are also expressed in ovaries and trophoblasts. In malignant tumors, this gene regulation is disrupted, resulting in antigen expression in a portion of multiple types of tumors. Examples of cancer testis antigens include MAGE-A, MAGE-B, GAGE, PAGE-1, SSX, HOM-MEL-40 (SSX 2), NY-ESO-1, LAGE-1 and SCP-1.
In yet another embodiment, the patient's presence of a common cancer antigen is a differentiation antigen, such as tyrosinase.
In yet another embodiment, the patient's presence of a consensus antigen is a viral antigen. Examples of viral antigens include Human Papilloma Virus (HPV), hepatitis B Virus (HBV), epstein-barr virus (EBV), kaposi sarcoma-associated herpesvirus (KSHV), merck cytoma virus (MCV or MCPyV), human Cytomegalovirus (HCMV), and Human T Lymphocyte Virus (HTLV).
In yet another embodiment, the patient's common cancer antigen is a mutated oncogene. Examples of mutant oncogenes include KRAS, CALR and TRP-2.
In yet another embodiment, the patient's common cancer antigen is a mutated tumor suppressor gene. Examples include mutant p53, mutant pRB, mutant BCL2 and mutant SWI/SNF.
In another embodiment, the patient is presented with a consensus carcinoantigen (oncofetal antigen), such as alpha fetoprotein or carcinoembryonic antigen (carcinoembryonic antigen).
In yet another embodiment, the patient's presence of a consensus antigen is a consensus intron retention antigen or a consensus antigen caused by a frameshift mutation, such as CDX2 or CALR.
In yet another embodiment, the patient's presence of a consensus antigen is a consensus antigen caused by a splice mutation. An example is an antigen caused by a mutation such as SF3B1 mut.
In general, for any cancer antigen, when a patient develops cancer, immune tolerance is likely to occur. An anti-cancer vaccine should specifically trigger an immune response against the antigen incorporated in the vaccine. Peripheral immune tolerance to the selected antigen may be weak or strong. By incorporating such patient-present consensus cancer antigen or one or more portions thereof into an antigenic unit, alone or together with other patient-present consensus cancer antigen or portions thereof and/or neoantigen or neoepitope, the vaccine comprising such antigenic unit elicits an immune response that is sufficiently strong and broad to affect the tumor microenvironment and change the patient's immune response to the tumor from an inhibitory/tolerogenic to a pro-inflammatory type. This may help break tolerance to several other antigens, representing a considerable clinical benefit for the patient. The above concept may be referred to as toppling the cancer immunity set point (tipping the cancer immunity set point).
In one embodiment, the antigenic unit comprises one or more patient-present consensus cancer antigens or parts thereof, which are human cellular proteins, preferably over-expressed or abnormally expressed human cellular proteins or differentiation antigens.
The presence of a common cancer antigen in a patient can be detected in the patient's tissue or body fluid by methods known in the art, including:
sequencing the patient's genome or exome and optionally searching through whole genome/exome sequencing data, e.g., by custom software, to identify mutated oncogenes or mutated tumor suppressor genes, for example;
immunohistochemistry of patient tumor tissue, for example to detect the presence of muteins;
RT-PCR, for example to detect the presence of known mutations in viral antigens or oncogenes;
ELISA using antibodies against, for example, mutant tumor proteins in serum samples;
RNA-seq of tumor tissue and comparison with healthy tissue for detecting e.g. expression/overexpression of consensus cancer antigen;
retrieval in raw RNA sequence data, by, for example, custom software, to identify intron-retained antigens;
retrieval in whole genome sequencing data, by e.g. custom software, to identify transposable elements as elements of dark matter antigens;
detecting short repeat sequences in the raw whole-exome/RNA sequence data to identify, for example, dark matter antigens;
RNA-seq data to identify, for example, consensus viral antigens; and
comparing the patient tumor sample to the patient's own healthy tissue or RNA-seq of a cohort/database (e.g., TCGA) relative to the consensus transcript expression (e.g., GTEX/HPA gene expression data).
In a preferred embodiment, the antigenic unit comprises a consensus cancer antigen or one or more portions of one or more such antigens present in one or more patients, which are known to be immunogenic, e.g. have been described previously as eliciting an immune response in other patients, or have been predicted to bind to HLA class I and/or class II alleles of the patient.
In another preferred embodiment, the antigenic units comprise one or more portions of a common cancer antigen present in one or more patients, for example one or more epitopes known to be immunogenic or predicted to bind to HLA class I and/or class II alleles of a patient.
In one embodiment, the antigenic unit comprises one or more common cancer epitopes present in the patient. In a preferred embodiment, such epitopes have a length suitable for presentation by the patient's HLA allele.
In one embodiment, the antigenic unit comprises one or more patient-presented consensus cancer epitopes of a length suitable for specific presentation on HLA class I or HLA class II. In one embodiment, the epitope has a length of 7 to 11 amino acids for HLA class I presentation. In another embodiment, the epitope has a length of 13 to 30 amino acids for HLA class II presentation.
In one embodiment, the antigenic unit comprises a consensus cancer epitope present in one or more patients, e.g., 7 to 30 amino acids in length, e.g., 7 to 10 amino acids (e.g., 7, 8, 9, or 10 amino acids) or 13 to 30 amino acids (e.g., 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids), e.g., 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids.
The antigenic unit may comprise the full length of the consensus cancer antigen or one or more portions thereof present in one or more patients.
In one embodiment, the antigenic unit comprises a consensus cancer antigen present for a full-length patient. In another embodiment, the antigenic unit comprises a consensus cancer antigen present for a plurality of patients, each of which is full-length.
In yet another embodiment, the antigenic unit comprises one or more portions of a common cancer antigen present in a patient, e.g., one or more common cancer epitopes present in a patient. In yet another embodiment, the antigenic unit comprises one or more portions of a common cancer antigen present in a plurality of patients, e.g., one or more epitopes of a common cancer antigen present in a plurality of patients.
In yet another embodiment, the antigenic unit comprises the full length of the consensus antigen present by one or more patients and one or more portions of the consensus cancer antigen present by one or more patients. Examples include:
an antigenic unit comprising one full length patient-present consensus antigen and one or more epitopes of one patient-present consensus cancer antigen;
an antigenic unit comprising a plurality of patient-present consensus cancer antigens, each of which is full-length, and one or more epitopes of one patient-present consensus cancer antigen;
an antigenic unit comprising one full length patient-present consensus antigen and one or more epitopes of a plurality of patient-present consensus cancer antigens; and
an antigenic unit comprising a plurality of patient-present consensus cancer antigens, each of which is full-length, and one or more epitopes of the plurality of patient-present consensus cancer antigens.
In a preferred embodiment, the aforementioned epitope is known to be immunogenic (e.g. has been described in the literature as immunogenic) or has been predicted to bind to a patient's HLA class I and class II alleles (e.g. as described in the literature), preferably has been predicted to bind to a patient's HLA class I allele. In another preferred embodiment, the immunogenicity of the above-described epitope is predicted, for example, by methods known in the art, such as those disclosed in WO 2021/205027 A1 (the disclosure of which is incorporated herein by reference), or those described in the "methods of designing antigenic units for use in the personalized anti-cancer vaccine of the invention" section contained herein, for example, the prediction of binding of the epitope to one or more patient HLA class I and/or HLA class II molecules.
In one embodiment, the antigenic unit comprises 1 to 10 total length of the patient's consensus antigen present.
In another embodiment, the antigenic unit comprises 1 to 30 portions of a consensus antigen present in one or more patients, wherein the portions comprise one or more epitopes predicted to bind to HLA class I or class II alleles of the patient. In another embodiment, the antigenic unit comprises a consensus cancer epitope present in 1 to 50 patients, optionally an epitope predicted to bind to an HLA class I or class II allele of the patient.
Comprising one or more patient-present consensus cancer antigen or portion thereof and one or more neoantigen or portion thereof
Antigenic units of an individualized anti-cancer vaccine
Such antigenic units are essentially a combination of: a) All of the foregoing embodiments directed to antigenic units (which comprise one or more common cancer antigens or portions thereof present in a patient), and b) all of the foregoing embodiments directed to antigenic units (which comprise one or more neoantigens or portions thereof).
Thus, in one embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, such as a dimerization unit, and an antigenic unit, wherein the antigenic unit comprises one or more consensus cancer antigens or portions thereof present in a patient and one or more neoantigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and
(b) One or more checkpoint inhibitors.
In one embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit, a multimerization unit, and an antigenic unit that targets an antigen presenting cell, wherein the antigenic unit comprises one or more consensus cancer antigens or portions thereof present in a patient and one or more neoantigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein consisting of a plurality of polypeptides defined in (ii); and
(b) One or more checkpoint inhibitors.
In another embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit, a dimerization unit, and an antigenic unit that targets an antigen presenting cell, wherein the antigenic unit comprises one or more consensus cancer antigens or portions thereof present in a patient and one or more neoantigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A dimeric protein consisting of two polypeptides as defined in (ii); and
(b) One or more checkpoint inhibitors.
Method of designing antigenic units for use in the personalized anti-cancer vaccine of the invention
The presence of common cancer antigens and neoantigens in patients identified in a particular patient is preferably further processed to find those antigens that, when incorporated into an antigenic unit, will make the vaccine most effective. The manner and order in which such treatments are performed depends on how the antigen is identified, i.e. on the data forming the basis of such treatments.
In one embodiment, the treatment and selection of one or more antigens incorporating antigenic units is performed as follows:
1) Retrieval is performed in the literature and/or one or more databases to search for information about consensus cancer antigen sequences, and preferably about their expression patterns, immunogenicity or predicted immunogenicity, epitopes and/or HLA presentation. Such a search is also used to determine whether the identified antigen is a consensus cancer antigen or a neoantigen present in the patient.
2) If the identified antigen is determined to be a consensus cancer antigen present in the patient, its sequence is studied to identify epitopes, preferably all epitopes, predicted to bind to the patient's HLA class I/II allele. The prediction may be performed by using prediction tools known in the art, such as prediction software known in the art, such as NetMHCpan and the like.
3) The most promising sequences of consensus cancer antigens present in a patient are selected for inclusion into the antigenic unit, which sequences are the most immunogenic or predicted to be the most immunogenic, i.e. those that show predicted binding to one or more patient HLA class I/II alleles. In one embodiment, the least epitopes are selected, for example if only a few promising epitopes are identified in step 2 or if there are longer fragments of non-immunogenic sequences between the epitopes. In another embodiment, a longer sequence is selected comprising multiple epitopes that bind to a specific HLA allele of the patient. In yet another embodiment, the full length sequence of the antigen is selected for inclusion in the antigenic unit.
4) Based on the predicted immunogenicity of such sequences and binding to the patient's HLA class I/II alleles, the most promising portions of the neoantigen sequence, e.g., neoepitopes, are selected for inclusion into the antigenic unit.
Tumor mutations are found by sequencing tumor and normal tissue and comparing sequences obtained from tumor tissue with sequences of normal tissue. There are a variety of methods available for detecting the presence of a particular mutation or allele in a patient's DNA or RNA. Such methods include dynamic allele-specific hybridization (DASH), microplate Array Diagonal Gel Electrophoresis (MADGE), pyrosequencing, oligonucleotide-specific ligation, taqMan systems, and various DNA "chip" techniques such as Affymetrix SNP chips. Alternatively, mutations can be identified by direct protein sequencing.
Among the mutations in tumor exons, which may be as many as hundreds or even thousands, the most promising sequences were selected by computer based on predictive HLA binding algorithms. The objective is to identify all relevant epitopes and, after ranking or scoring, to determine the sequences to be included in the antigenic units. Methods known in the art may be suitable for scoring, ranking and selecting neoepitopes, including those disclosed in WO 2020/065023A1 and WO 2020/221/783A 1.
Further, any suitable algorithm for such scoring and ranking may be used, including the following:
free software analysis of peptide-MHC binding (IEDB and NetMHCpan) is available and can be downloaded from the following websites:
www.iedb.org
www.cbs.dtu.dk/services/NetMHC
commercially available high-level software that predicts the best sequence for vaccine design can be found, for example, from the following places:
www.oncoimmunity.com/
omictools.com/t-cell-epitope-category
github.com/griffithlab/pVAC-Seq
crdd.osdd.net/raghava/cancertope/help.php
www.epivax.com/tag/neoantigen/
each mutation is scored for its antigenicity or immunogenicity, and the most antigenic or immunogenic neoepitope is selected and optimally aligned in antigenic units, e.g., as described herein.
Antigenic units of non-personalized anti-cancer vaccines
Non-personalized or "existing" anti-cancer vaccines (also referred to as consensus anti-cancer vaccines) comprise antigenic units comprising one or more consensus cancer antigens or portions thereof.
"consensus cancer antigen" or "consensus tumor antigen" is used herein to describe an antigen that has been described as being expressed by a number of tumors, whether across patients with the same cancer type, or across patients and cancer types.
"consensus cancer epitope" is used herein to describe the amino acid sequence contained in a consensus cancer antigen that is known or predicted to be immunogenic.
In one embodiment, the antigenic units of such non-personalized anti-cancer vaccines comprise one or more consensus cancer antigens or portions thereof, e.g., consensus cancer epitopes, that are known to be immunogenic, have a known expression pattern, and/or are known or predicted to bind to specific HLA class I and class II molecules.
Thus, in one embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, such as a dimerization unit, and an antigenic unit, wherein the antigenic unit comprises one or more consensus cancer antigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and
(b) One or more checkpoint inhibitors.
In one embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, and an antigenic unit, wherein the antigenic unit comprises one or more consensus cancer antigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein consisting of a plurality of polypeptides defined in (ii); and
(b) One or more checkpoint inhibitors.
In another embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a dimerization unit, and an antigenic unit, wherein the antigenic unit comprises one or more consensus cancer antigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A dimeric protein consisting of two polypeptides as defined in (ii); and
(b) One or more checkpoint inhibitors.
Examples of consensus cancer antigens include those disclosed under the heading "antigenic units of a personalized anti-cancer vaccine comprising one or more patient-present consensus cancer antigens or parts thereof" as well as scFv derived from monoclonal igs produced by myeloma or lymphoma, also known as myeloma/lymphoma M component in B-cell lymphoma or multiple myeloma patients, telomerase (e.g., hTERT), HIV derived sequences such as gpl20 or Gag derived sequences, tyrosinase Related Proteins (TRP) -1 or TRP-2, melanoma antigens, prostate specific antigens and idiotypes, HPV antigens such as any antigen selected from E1, E2, E6, E7, L1 and L2 (e.g., E6 and/or E7 of HPV16 and/or HPV 18).
Any sufficient length of consensus cancer antigen sequence including a particular epitope may be used as the antigenic unit. Thus, in one embodiment, an antigenic unit comprises an amino acid sequence of at least 7 amino acids, such as an amino acid sequence of at least 8 amino acids, corresponding to at least about 21 nucleotides, such as at least 24 nucleotides, in a nucleic acid sequence encoding such an antigenic unit.
In yet another embodiment, the antigenic unit comprises one or more portions of a common cancer antigen, e.g., one or more common cancer epitopes. In yet another embodiment, the antigenic unit comprises one or more portions of a plurality of common cancer antigens, e.g., one or more epitopes of a plurality of common cancer antigens. In yet another embodiment, the antigenic unit comprises one or more consensus antigens in full length and one or more portions of one or more consensus cancer antigens. Examples include:
an antigenic unit comprising one or more epitopes of one consensus antigen and one consensus cancer antigen in full length; and
an antigenic unit comprising a plurality of consensus cancer antigens, each antigen being full length, and one or more epitopes of one consensus cancer antigen; and
An antigenic unit comprising one consensus antigen in full length and one or more epitopes of a plurality of consensus cancer antigens; and
an antigenic unit comprising multiple consensus cancer antigens, each antigen being full length, and one or more epitopes of multiple consensus cancer antigens.
Examples of consensus anti-cancer vaccines comprising consensus HPV antigens are disclosed in WO 2013092875A1, which is incorporated herein by reference.
Method for designing antigenic units of a consensus anti-cancer vaccine for use in the method of the invention
For a common anti-cancer vaccine for use in the methods of the invention, the antigenic units are designed to include those sequences that would render the vaccine effective in multiple patients (e.g., multiple patients with a certain type of cancer).
In one embodiment, the antigen to be included in the antigenic unit is selected by searching in the literature and/or one or more databases for information about consensus cancer antigen sequences and preferably about their expression pattern, immunogenicity or predicted immunogenicity, epitopes and/or HLA presentation. Epitopes are then identified which are known or predicted to bind to a plurality of HLA class I/II alleles of a number of patients, or to a specific subset of HLA class I/II alleles which predominate in a certain patient population for a certain cancer indication and/or across different cancer indications. Preferably, the sequence of the most promising, i.e. most immunogenic or predicted to be the most immunogenic, consensus cancer antigen is selected for inclusion in the antigenic unit.
Further embodiments of the antigenic unit
The following applies generally to the antigenic units in the anti-cancer vaccine used in the method of the invention, i.e. the antigenic units comprised in the personalized anti-cancer vaccine and the antigenic units comprised in the consensus anti-cancer vaccine.
The term antigen is used in this section of the application for a neoantigen, a neoepitope, a consensus cancer antigen present in a patient, a portion of a consensus cancer antigen present in a patient (e.g., a consensus cancer epitope present in a patient), a consensus cancer antigen, and a portion of a consensus cancer antigen (e.g., a consensus cancer epitope).
In one embodiment, the antigenic unit comprises only one copy of each antigen, such that when for example 10 different antigens are included in the antigenic unit, a vaccine comprising the antigenic unit can elicit a cell-mediated immune response against all 10 different antigens, thereby effectively attacking the cancer.
However, if only some of the antigen is contained in an antigenic unit, the antigenic unit may contain at least two copies of a particular antigen to enhance the immune response against that antigen.
This may occur in the design of the antigenic units of a personalized anti-cancer vaccine, where only a few neoantigens/neoepitopes predicted to be sufficiently immunogenic/predicted to bind to the patient's HLA allele can be identified in the patient. If in such patients, in addition to the neoantigen/neoepitope, a patient-present consensus cancer antigen is identified, it is preferred that such one or more patient-present consensus cancer antigen sequences or portions thereof be included into the antigenic unit, rather than multiple copies of the same neoantigen/neoepitope.
The length of the antigenic unit is determined by the length of the antigen contained therein and its number. In one embodiment, the antigenic unit comprises from about 21 to about 2000 amino acids, preferably from about 30 amino acids to about 1500 amino acids, more preferably from about 50 to about 1000 amino acids, for example from about 100 to about 500 amino acids, or from about 100 to about 400 amino acids, or from about 100 to about 300 amino acids.
In another embodiment, the antigenic unit comprises up to 3500 amino acids, for example from 60 to 3500 amino acids, for example from about 80 or about 100 or about 150 amino acids to about 3000 amino acids, for example from about 200 to about 2500 amino acids, for example from about 300 to about 2000 amino acids, or from about 400 to about 1500 amino acids, or from about 500 to about 1000 amino acids.
To enhance the immune response, for a personalized anti-cancer vaccine, the antigens may be arranged in antigenic subunits as follows: antigenic units can be described as polypeptides having an N-terminal start and a C-terminal end. The antigenic units are linked to the dimerization unit, preferably by a unit linker. The antigenic unit is located at the COOH-terminus or NH 2-terminus of the polypeptide/dimer protein. Preferably, the antigenic unit is located at the COOH-terminus of the polypeptide/dimer protein. In one embodiment, the antigens, preferably epitopes, are arranged in order of higher antigenicity to lower antigenicity in a direction from the N-terminus of the antigenic unit to the C-terminus of the antigenic unit. Alternatively, it is preferred that one or more of the most hydrophobic antigens are located substantially in the middle of the antigenic unit and that one or more of the most hydrophilic antigens are located at the beginning of the N-terminus and/or the end of the C-terminus, especially if the hydrophilicity/hydrophobicity varies greatly between the antigens.
Since it is only possible to actually locate in the middle of an antigenic unit when the antigenic unit contains an odd number of antigens, the term "substantially" in this context refers to an antigenic unit containing an even number of antigens, wherein the most hydrophobic antigen is located as close to the middle as possible.
For example, an antigenic unit comprises 5 antigenic subunits, each comprising a different epitope, e.g. a different neoepitope, arranged as follows: 1-2-3 x-4-5; wherein 1, 2, 3, 4 and 5 are each different neo-epitopes, -are subunit linkers, ×represent the most hydrophobic neo-epitope, which is located in the middle of the antigenic unit.
In another example, the antigenic unit comprises 6 antigenic subunits, each comprising a different epitope, e.g. a different neoepitope, arranged as follows: 1-2-3 x-4-5-6, or, alternatively, arranged as follows: 1-2-4-3 x-5-6; wherein 1, 2, 3, 4, 5 and 6 are each different neo-epitopes, -are subunit linkers, which represent the most hydrophobic neo-epitope, which is located substantially in the middle of the antigenic unit.
Alternatively, the antigenic subunits may be arranged such that they alternate between hydrophilic and hydrophobic antigens.
Optionally, the GC-rich sequences encoding the antigens (the neo-epitopes or epitope-rich sequences) are arranged in a manner that avoids GC clusters. In one embodiment, the GC-rich sequences encoding the antigen are arranged such that there is at least one non-GC-rich sequence between them.
In one embodiment, the antigenic unit comprises one or more linkers. In another embodiment, the antigenic unit comprises a plurality of antigens, such as a plurality of epitopes, such as neo-epitopes, wherein the antigens are separated by a linker. In another embodiment, the antigenic unit comprises a plurality of antigens, wherein each antigen is separated from the other antigens by a linker. Another way of describing the separation of each antigen from the other antigens by a linker is that all antigens except the terminal antigen, i.e. the antigen located at the N-terminal start of the polypeptide or at the C-terminal end of the polypeptide (i.e. at the end of the antigenic unit not linked to the dimerization unit), are arranged in antigenic subunits, wherein each subunit comprises or consists of an antigen (e.g. a neoepitope) and a subunit linker.
Thus, an antigenic unit comprising n antigens comprises n-1 antigenic subunits, wherein each subunit comprises an antigen and a subunit linker, and further comprises a terminal antigen. In one embodiment, wherein n is an integer from 1 to 50, such as an integer from 3 to 50 or 15 to 40 or 10 to 30 or 10 to 25 or 10 to 20 or 15 to 30 or 15 to 25 or 15 to 20.
Because the linker separates the antigens, each antigen is presented to the immune system in an optimal manner.
Thus, in one embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerizing unit such as a dimerization unit, and an antigenic unit, wherein the antigenic unit comprises (a) n-1 antigenic subunits, each subunit comprising a subunit linker and an antigen selected from the group consisting of a neoantigen, a neoepitope, a patient-present consensus cancer antigen, a patient-present portion of a consensus cancer antigen, and a patient-present consensus cancer epitope, or selected from the group consisting of a consensus cancer antigen, a portion of a consensus cancer antigen, and a consensus cancer epitope, and (B) a terminal antigen, and wherein n is the number of antigens in the antigenic unit, and n is an integer from 1 to 50; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and
(b) One or more checkpoint inhibitors.
In one embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit, a multimerization unit, and an antigenic unit that targets an antigen presenting cell, wherein the antigenic unit comprises (a) n-1 antigenic subunits, each subunit comprising a subunit linker and an antigen selected from a neoantigen, a neoepitope, a consensus cancer antigen present in a patient, a portion of a consensus cancer antigen present in a patient, and a consensus cancer table present in a patient, or selected from a consensus cancer antigen, a portion of a consensus cancer antigen, and a consensus cancer epitope, and (B) a terminal antigen, and wherein n is the number of antigens in the antigenic unit, and n is an integer from 1 to 50; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein consisting of a plurality of polypeptides defined in (ii); and
(b) One or more checkpoint inhibitors.
In another embodiment, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit, a dimerization unit, and an antigenic unit that targets an antigen presenting cell, wherein the antigenic unit comprises (a) n-1 antigenic subunits, each subunit comprising a subunit linker and an antigen selected from the group consisting of a neoantigen, a neoepitope, a consensus cancer antigen present in a patient, a portion of a consensus cancer antigen present in a patient, and a consensus cancer epitope present in a patient, or selected from the group consisting of a consensus cancer antigen, a portion of a consensus cancer antigen, and a consensus cancer epitope, and (B) a terminal antigen, and wherein n is the number of antigens in the antigenic unit, and n is an integer from 1 to 50; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A dimeric protein consisting of two polypeptides as defined in (ii); and
(b) One or more checkpoint inhibitors.
Linkers in antigenic units
The linker in the antigenic unit separates the antigens (e.g., epitopes) contained therein. As described above, all antigens, e.g. neoepitopes, may be separated from each other by linkers and arranged in subunits. Hereinafter, the terms "subunit linker" and "linker" are used interchangeably and both represent linkers in an antigenic unit.
In one embodiment, the subunit linker is designed to be non-immunogenic. It may be a rigid linker, which means that it does not allow the two amino acid sequences to which it is attached to move substantially freely relative to each other. Alternatively, it may be a flexible linker, i.e. a linker allowing the two amino acid sequences to which it is attached to move substantially freely relative to each other.
Both types of joints are available. In one embodiment, the subunit linker is a flexible linker that allows antigen to be presented to T cells in an optimal manner, even if the antigenic unit contains a large amount of antigen.
In one embodiment, the subunit linker is a peptide consisting of 4 to 40 amino acids, e.g., a peptide consisting of 35, 30, 25, or 20 amino acids, e.g., a peptide consisting of 5 to 20 amino acids or 5 to 15 amino acids or 8 to 20 amino acids or 8 to 15 amino acids or 10 to 15 amino acids or 8 to 12 amino acids. In another embodiment, the subunit linker consists of 10 amino acids.
In one embodiment, for example in an antigenic unit comprising a neoepitope, the subunit linker is the same in all antigenic subunits. However, if one or more of the antigens comprises a sequence similar to that of the linker, it may be advantageous to replace adjacent subunit linkers with linkers of a different sequence. Furthermore, if the antigen-subunit linker linkage itself is predicted to constitute an immunogenic epitope, a linker of a different sequence may be used.
In one embodiment, the subunit linker is a flexible linker, preferably a flexible linker comprising a small non-polar (e.g., glycine, alanine, or leucine) or polar (e.g., serine or threonine) amino acid. The small size of these amino acids provides flexibility and allows mobility of the linked amino acid sequences. The incorporation of serine or threonine can reduce adverse interactions between the linker and the antigen by maintaining the stability of the linker in aqueous solution through hydrogen bonding with water molecules. In one embodiment, the flexible linker is a serine (S) and/or glycine (G) rich linker, i.e. a linker comprising several serine and/or several glycine residues. Preferred examples are GGGGS (SEQ ID NO: 24), GGGSS (SEQ ID NO: 25), GGGSG (SEQ ID NO: 26), GGSGG (SEQ ID NO: 27), SGSSGS (SEQ ID NO: 28) or variants thereof, such as GGGGSGGGGS (SEQ ID NO: 29), (GGGGS) m (SEQ ID NO: 30), (GGGSS) m (SEQ ID NO: 31), (GGSGG) m (SEQ ID NO: 32), (GGGSG) m (SEQ ID NO: 33) or (SGSSGS) m (SEQ ID NO: 34), wherein m is an integer from 1 to 5, such as 1, 2, 3, 4 or 5. In a preferred embodiment, m is 2. In another preferred embodiment, the serine and/or glycine rich linker further comprises at least one leucine (L) residue, e.g. at least 1 or at least 2 or at least 3 leucine residues, e.g. 1, 2, 3 or 4 leucine residues.
In one embodiment, the subunit linker comprises or consists of: LGGGS (SEQ ID NO: 35), GLGGS (SEQ ID NO: 36), GGLGS (SEQ ID NO: 37), GGGLS (SEQ ID NO: 38) or GGGGL (SEQ ID NO: 39). In another embodiment, the subunit linker comprises or consists of: LGGSG (SEQ ID NO: 40), GLGSG (SEQ ID NO: 41), GGLSG (SEQ ID NO: 42), GGGLG (SEQ ID NO: 43) or GGGSL (SEQ ID NO: 44). In yet another embodiment, the subunit linker comprises or consists of: LGGSS (SEQ ID NO: 45), GLGSS (SEQ ID NO: 46) or GGLSS (SEQ ID NO: 47).
In another embodiment, the subunit linker comprises or consists of: LGLGS (SEQ ID NO: 48), GLGLS (SEQ ID NO: 49), GLLGS (SEQ ID NO: 50), LGGLS (SEQ ID NO: 51) or GLGGL (SEQ ID NO: 52). In another embodiment, the subunit linker comprises or consists of: LGLSG (SEQ ID NO: 53), GLLSG (SEQ ID NO: 54), GGLSL (SEQ ID NO: 55), GGLLG (SEQ ID NO: 56) or GLGSL (SEQ ID NO: 57). In yet another embodiment, the subunit linker comprises or consists of: LGLSS (SEQ ID NO: 58) or GGLLS (SEQ ID NO: 59).
In another embodiment, the subunit linker is a serine-glycine linker having a length of 10 amino acids and comprising 1 or 2 leucine residues.
In one embodiment, the subunit linker comprises or consists of: LGGGSGGGGS (SEQ ID NO: 60), GLGGSGGGGS (SEQ ID NO: 61), GGLGSGGGGS (SEQ ID NO: 62), GGGLSGGGGS (SEQ ID NO: 63) or GGGGLGGGGS (SEQ ID NO: 64). In another embodiment, the subunit linker comprises or consists of: LGGSGGGGSG (SEQ ID NO: 65), GLGSGGGGSG (SEQ ID NO: 66), GGLSGGGGSG (SEQ ID NO: 67), GGGLGGGGSG (SEQ ID NO: 68) or GGGSLGGGSG (SEQ ID NO: 69). In another embodiment, the subunit linker comprises or consists of: LGGSSGGGSS (SEQ ID NO: 70), GLGSSGGGSS (SEQ ID NO: 71), GGLSSGGGSS (SEQ ID NO: 72), GGGLSGGGSS (SEQ ID NO: 73) or GGGSLGGGSS (SEQ ID NO: 74).
In further embodiments, the subunit linker comprises or consists of: LGGGSLGGGS (SEQ ID NO: 75), GLGGSGLGGS (SEQ ID NO: 76), GGLGSGGLGS (SEQ ID NO: 77), GGGLSGGGLS (SEQ ID NO: 78) or GGGGLGGGGL (SEQ ID NO: 79). In another embodiment, the subunit linker comprises or consists of: LGGSGLGGSG (SEQ ID NO: 80), GLGSGGLGSG (SEQ ID NO: 81), GGLSGGGLSG (SEQ ID NO: 82), GGGLGGGGLG (SEQ ID NO: 83) or GGGSLGGGSL (SEQ ID NO: 84). In yet another embodiment, the subunit linker comprises or consists of: LGGSSLGGSS (SEQ ID NO: 85), GLGSSGLGSS (SEQ ID NO: 86) or GGLSSGGLSS (SEQ ID NO: 87).
In another embodiment, the subunit linker comprises or consists of: GSGGGA (SEQ ID NO: 88), GSGGGAGSGGGA (SEQ ID NO: 89), GSGGGAGSGGGAGSGGGA (SEQ ID NO: 90), GSGGGAGSGGGAGSGGGAGSGGGA SEQ ID NO: 91) or GENLYFQSGG (SEQ ID NO: 92). In another embodiment, the subunit linker comprises or consists of: SGGGSSGGGS (SEQ ID NO: 93), SSGGGSSGGG (SEQ ID NO: 94), GGSGGGGSGG (SEQ ID NO: 95), GSGSGSGSGS (SEQ ID NO: 96), GGGSSGGGSG (amino acids 121-130 of SEQ ID NO: 1), GGGSSS (SEQ ID NO: 97), GGGSSGGGSSGGGSS (SEQ ID NO: 98) or GLGGLAAA (SEQ ID NO: 99).
In another embodiment, the subunit linker is a rigid linker. Such rigid linkers can be used to effectively separate (larger) antigens and prevent them from interfering with each other. In one embodiment, the subunit linker comprises or consists of: KPEPKPAPAPKP (SEQ ID NO: 100), AEAAAKEAAAKA (SEQ ID NO: 101), (EAAAK) m (SEQ ID NO: 102), PSRLEEELRRRLTEP (SEQ ID NO: 103) or SACCCELS (SEQ ID NO: 104).
In yet another embodiment, the subunit linker comprises or consists of TQKSLSLSPGKGLGGL (SEQ ID NO: 105). In yet another embodiment, the subunit linker comprises or consists of SLSLSPGKGLGGL (SEQ ID NO: 106).
In another embodiment, the subunit linker comprises or consists of: GGSAGGSGSGSSGGSSGASGTGTAGGTGSGSGTGSG (SEQ ID NO: 107) or GGSGGGSEGGGSEGGGSEGGGSEGGGSEGGGSGGGS (SEQ ID NO: 108) or ELKTPLGDTTHT (amino acids 94-105 of SEQ ID NO: 1) or EPKSCDTPPPCPRCP (amino acids 106-120 of SEQ ID NO: 1).
In yet another embodiment, the subunit linker is a cleavable linker, e.g., a linker comprising one or more endopeptidase recognition sites, e.g., furin, caspase, cathepsin, and the like. Cleavable linkers can be introduced to release free functional protein domains (e.g., encoded by larger antigens), which can overcome steric hindrance between such domains or other drawbacks due to interference of such domains, e.g., reduced biological activity, altered biological distribution.
Examples of other sequences encoded by subunit linkers are disclosed in paragraphs [0098] - [0099] and cited sequences of WO 2020/176797A1, which are incorporated herein by reference, and in paragraphs [0135] to [0139] of US2019/0022202A1, which are incorporated herein by reference.
Unit joint
The antigenic units are linked to the dimerization unit, preferably by a unit linker. Thus, in one embodiment, the anti-cancer vaccine used in the methods of the invention comprises a nucleotide sequence encoding a unit linker linking the antigenic unit and the dimerization unit.
The unit adaptor may contain restriction sites to facilitate construction of the polynucleotide. In one embodiment, the unit linker is GLGGL (SEQ ID NO: 52) (having the nucleotide sequence of SEQ ID NO: 10) or GLSGL (SEQ ID NO: 109). In another embodiment, the unit linker comprises or consists of: GGGGS (SEQ ID NO: 24), GGGGSGGGGS (SEQ ID NO: 29), (GGGGS) m (SEQ ID NO: 30), EAAAK (SEQ ID NO: 110), (EAAAK) m (SEQ ID NO: 102), (EAAKG) mS (SEQ ID NO: 111), GPSRLEEELRRRLTEPG (SEQ ID NO: 112), AAY or HEYGAEALERAG (SEQ ID NO: 114).
Targeting unit
The anti-cancer vaccine used in the methods of the invention comprises a targeting unit that targets Antigen Presenting Cells (APCs). APCs include Dendritic Cells (DCs) and subpopulations thereof.
The term "targeting unit" as used herein refers to the delivery of a polypeptide/dimer protein (encoded by a polynucleotide as defined above) to an antigen presenting cell for MHC class II restricted presentation to a cd4+ T cell or to produce cross presentation to a cd8+ T cell by MHC class I restriction.
Due to the targeting unit, the anti-cancer vaccine used in the method of the invention attracts DCs, neutrophils and other immune cells. Thus, an anti-cancer vaccine not only targets the antigenic units contained therein to specific cells, but also promotes a response amplifying effect (adjuvant effect) by recruiting specific immune cells to the site of administration of the anti-cancer vaccine. This unique mechanism is important in the clinical setting: the anti-cancer vaccine used in the methods of the invention can be administered to a patient without any adjuvant, as the vaccine itself provides the adjuvant effect.
The targeting unit is designed to target the anti-cancer vaccine used in the method of the invention to surface molecules expressed on APCs, e.g. molecules expressed only on DC subpopulations.
Examples of such surface molecules on APCs are HLA, cluster of differentiation 14 (CD 14), cluster of differentiation 40 (CD 40), CLEC9A, chemokine receptors and Toll-like receptors (TLRs). Chemokine receptors include C-C motif chemokine receptor 1 (CCR 1), C-C motif chemokine receptor 3 (CCR 3), C-C motif chemokine receptor 4 (CCR 4), C-C motif chemokine receptor 5 (CCR 5), C-C motif chemokine receptor 6 (CCR 6), C-C motif chemokine receptor 7 (CCR 7), C-C motif chemokine receptor 8 (CCR 8), and XCR1. Toll-like receptors include TLR-2, TLR-4 and TLR-5. The targeting unit is or comprises a moiety that interacts with these surface molecules.
Thus, in one embodiment, the targeting unit comprises or consists of an antibody binding region, e.g. antibody variable domains (VL and VH) which are specific for HLA, CD14, CD40, CLEC9A or Toll-like receptors. In another embodiment, the targeting unit comprises or consists of a synthetic or natural ligand. Examples include soluble CD40 ligands, natural ligands such as chemokines, e.g. in their human form, e.g. chemokine ligand 5, also known as C-C motif ligand 5 (CCL 5 or RANTES), macrophage inflammatory protein α and isoforms thereof, including mouse CCL3 (or MIP-1α), and human isoforms hCCL3, hCCL3L1, hCCL3L2 and hCCL3L3, chemokine ligand 4 (CCL 4) and isoforms thereof CCL4L, chemokine ligand 19 (CCL 19), chemokine ligand 20 (CCL 20), chemokine ligand 21 (CCL 21), chemokine motif ligand 1 or 2 (XCL 1 or XCL 2), and bacterial antigens, e.g. flagellin.
In one embodiment, the targeting unit has affinity for MHC class II proteins. Thus, in one embodiment, the targeting unit comprises or consists of an antibody binding region, e.g. antibody variable domains (VL and VH), which are specific for MHC class II proteins, e.g. those selected from anti-HLA-DP, anti-HLA-DR and anti-pan HLA class II.
In another embodiment, the targeting unit has affinity for a surface molecule selected from the group consisting of CD14, CD40, TLR-2, TLR-4 and TLR-5. Thus, in one embodiment, the targeting unit comprises or consists of an antibody binding region, e.g., antibody variable domains (VL and VH) that are specific for CD14, CD40, TLR-2, TLR4 or TLR-5, e.g., anti-CD 14, anti-CD 40, anti-TLR-2, anti-TLR-4 or anti-TLR-5. In yet another embodiment, the targeting unit comprises or consists of flagellin, which has affinity for TLR-5. In another embodiment, the targeting unit comprises or consists of an antibody binding region specific for CLEC9A, e.g. anti-CLEC 9A or a variant thereof, e.g. anti-CLEC 9A Fv, or the targeting unit comprises or consists of a CLEC9 ligand, e.g. comprising or consists of a nucleic acid sequence having SEQ ID No. 115 or an amino acid sequence encoded by said nucleic acid sequence.
Preferably, the targeting unit has affinity for a chemokine receptor selected from the group consisting of CCR1, CCR3, CCR5 and CCR7, more preferably for a chemokine receptor selected from the group consisting of CCR1, CCR3 and CCR5. In one embodiment, the targeting unit has affinity for the chemokine receptor CCR 7. In another embodiment, the targeting unit comprises or consists of CCL19, CCL19 being for example CCL19 comprising or consisting of the nucleotide sequence of SEQ ID NO:121 or an amino acid sequence encoded by said nucleotide sequence, or a targeting unit comprises or consists of CCL21, e.g. a human form of CCL19 or CCL 21.
Preferably, the targeting unit comprises or consists of a chemokine, human macrophage inflammatory protein alpha (human MIP-1 alpha (hMIP-1 alpha) variant, also known as LD78 beta or CCL3L 1), which binds to its cognate receptor, including CCR1 and CCR5 expressed on the surface of APC cells. Binding of the targeting unit to its cognate receptor results in internalization of the anti-cancer vaccine into APCs and degradation of the protein into small peptides that are loaded onto MHC molecules and presented to cd4+ and cd8+ T cells to induce a cancer-specific immune response. Once stimulated, with the help of activated cd4+ T cells, cd8+ T cells will target and kill cancer cells expressing the same antigen.
In a preferred embodiment, the targeting unit comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 24-93 of SEQ ID NO. 1, e.g. comprising the amino acid sequence of 26-93 of SEQ ID NO. 1 or comprising the amino acid sequence of 28-93 of SEQ ID NO. 1.
In a further preferred embodiment, the targeting unit comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of 24-93 of SEQ ID NO. 1, e.g. at least 86% or at least 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or at least 99% sequence identity. In another preferred embodiment, the targeting unit comprises the amino acid sequence 24-93 of SEQ ID NO. 1.
In a more preferred embodiment, the targeting unit consists of an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 24-93 of SEQ ID NO. 1, for example consisting of the amino acid sequence of 26-93 of SEQ ID NO. 1 or consisting of the amino acid sequence of 28-93 of SEQ ID NO. 1.
In a further preferred embodiment, the targeting unit consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence of 24-93 of SEQ ID NO. 1, e.g. at least 86% or at least 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or at least 99% sequence identity. In a further preferred embodiment, the targeting unit consists of the amino acid sequence 24-93 of SEQ ID NO. 1.
In a preferred embodiment, the targeting unit comprises the amino acid sequence of 24-93 of SEQ ID NO. 1, except that at most 6 amino acids are substituted, deleted or inserted, e.g. at most 5 amino acids, e.g. at most 4 amino acids, e.g. at most 3 amino acids, e.g. at most 2 amino acids or e.g. at most 1 amino acid. One embodiment of such targeting units is a targeting unit comprising the amino acid sequence of 26-93 of SEQ ID NO. 1 or a targeting unit comprising the amino acid sequence of 28-93 of SEQ ID NO. 1.
In another preferred embodiment, the targeting unit consists of the amino acid sequence of 24-93 of SEQ ID NO. 1, except that at most 6 amino acids are substituted, deleted or inserted, e.g. at most 5 amino acids, e.g. at most 4 amino acids, e.g. at most 3 amino acids, e.g. at most 2 amino acids or e.g. at most 1 amino acid. One embodiment of such targeting units is a targeting unit consisting of the amino acid sequence of 26-93 of SEQ ID NO. 1 or a targeting unit consisting of the amino acid sequence of 28-93 of SEQ ID NO. 1.
In a preferred embodiment, the targeting unit comprises a nucleic acid sequence having at least 80% sequence identity to the nucleic acid sequence having SEQ ID NO. 5.
In a further preferred embodiment, the targeting unit comprises a nucleic acid sequence having at least 85% sequence identity with the nucleic acid sequence having SEQ ID No. 5, e.g. at least 86% or at least 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or at least 99% sequence identity. In a further preferred embodiment, the targeting unit comprises the nucleic acid sequence of SEQ ID NO. 5.
In a more preferred embodiment, the targeting unit consists of a nucleic acid sequence having at least 80% sequence identity with the nucleic acid sequence having SEQ ID NO. 5.
In a further preferred embodiment, the targeting unit consists of a nucleic acid sequence having at least 85% sequence identity with the nucleic acid sequence of SEQ ID NO. 5, e.g. at least 86% or at least 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or at least 99% sequence identity. In yet another preferred embodiment, the targeting unit has the nucleic acid sequence of SEQ ID NO. 5.
Multimerization unit/dimerization unit
The anti-cancer vaccine used in the methods of the invention comprises multimerization units, such as dimerization units.
As used herein, the term "multimerization unit" refers to a sequence of nucleotides or amino acids between an antigenic unit and a targeting unit. In addition to linking the antigenic unit and the targeting unit, the multimerization unit facilitates multimerization/linking of multiple polypeptides (e.g., two, three, four, or more polypeptides) into multimeric proteins, such as dimeric, trimeric, or tetrameric proteins. Furthermore, the multimerization units also provide flexibility to the multimeric protein to allow optimal binding of the targeting units to surface molecules on APCs even though they are located at different distances. The multimerization unit may be any unit that meets one or more of these requirements.
Multimerization units that promote multimerization/ligation of more than two polypeptides
In one embodiment, the multimerization unit is a trimerization unit, e.g., a collagen-derived trimerization unit, e.g., a human collagen-derived trimerization domain, e.g., a human collagen-derived XVIII trimerization domain (see, e.g., A.Alvarez-Cienfunegos et al, sci Rep 6,28643 (2016)) or a human collagen XV trimerization domain. Thus, in one embodiment, the multimerization unit is a trimerization unit comprising or consisting of the nucleic acid sequence having or encoded by SEQ ID NO. 116. In another embodiment, the trimerization unit is the C-terminal domain of T4 fibrin. Thus, in one embodiment, the multimerization unit is a trimerization unit comprising or consisting of the amino acid sequence having SEQ ID NO. 117.
In another embodiment, the multimerization unit is a tetramerization unit, e.g., a domain derived from p53, optionally further comprising a hinge region as described below. Thus, in one embodiment, the multimerization unit is a tetramerization unit comprising or consisting of the nucleic acid sequence having SEQ ID NO. 113 or an amino acid sequence encoded by the nucleic acid sequence, optionally further comprising a hinge region as described below.
Dimerization unit
The term "dimerization unit" as used herein refers to a nucleotide or amino acid sequence between an antigenic unit and a targeting unit. In addition to linking the antigenic unit and the targeting unit, the dimerization unit also facilitates dimerization/linking of the two monomeric polypeptides into a dimeric protein. Furthermore, the dimerization unit also provides flexibility to the dimeric protein to allow optimal binding of the targeting unit to surface molecules on the APC, even though they are located at different distances. The dimerization unit may be any unit that meets one or more of these requirements.
Thus, in one embodiment, the anti-cancer vaccine used in the methods of the invention comprises a dimerization unit comprising a hinge region. In another embodiment, the dimerization unit comprises a hinge region and another domain that facilitates dimerization. In yet another embodiment, the dimerization unit comprises a hinge region, a dimerization unit linker and another domain that facilitates dimerization, wherein the dimerization unit linker is located between the hinge region and the another domain that facilitates dimerization. In one embodiment, the dimerization unit linker is a glycine-serine rich linker, preferably GGGSSGGGSG (SEQ ID NO: 118), i.e., the dimerization unit comprises a glycine-serine rich dimerization unit linker, and preferably dimerization unit linker GGGSSGGGSG (SEQ ID NO: 118).
The term "hinge region" refers to an amino acid sequence contained in a dimerization unit that facilitates joining two polypeptides, i.e., facilitates the formation of a dimeric protein. In the context of facilitating multimerization of/linking multimerization units of more than two polypeptides, the term "hinge region" refers to an amino acid sequence comprised in a multimerization unit that facilitates linking of more than two polypeptides, e.g., three or four polypeptides and/or serves as a flexible spacer allowing a targeting unit of a multimeric protein to bind simultaneously to multiple surface molecules on an APC even though the surface molecules are located at different distances.
Furthermore, the hinge region acts as a flexible spacer allowing two targeting units of the dimeric protein to bind simultaneously to two surface molecules on APC even though they are located at different distances. The hinge region may be Ig derived, e.g. derived from IgG, e.g. IgG2 or IgG3. In one embodiment, the hinge region is derived from IgM, e.g., comprises or consists of a nucleotide sequence having SEQ ID NO:119 or an amino acid sequence encoded by said nucleic acid sequence. The hinge region may promote dimerization by forming one or more covalent bonds (e.g., one or more disulfide bridges between cysteine residues). Thus, in one embodiment, the hinge region has the ability to form one or more covalent bonds. Preferably, the covalent bond is a disulfide bridge.
In one embodiment, the dimerization unit comprises or consists of hinge exon h1 and hinge exon h4 (human hinge region 1 and human hinge region 4) having an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 94-120 of SEQ ID NO. 1.
In a preferred embodiment, the dimerization unit comprises or consists of hinge exon h1 and hinge exon h4, the amino acid sequence of which has at least 85% sequence identity with the amino acid sequence of 94-120 of SEQ ID No. 1, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98% or such as at least 99% sequence identity.
In a preferred embodiment, the dimerization unit comprises or consists of hinge exon h1 and hinge exon h4, which have the amino acid sequence of 94-120 of SEQ ID NO. 1.
In a preferred embodiment, the dimerization unit comprises or consists of the amino acid sequence 94-120 of SEQ ID NO. 1, except that at most 4 amino acids have been substituted, deleted or inserted, such as at most 3 amino acids, such as at most 2 amino acids or such as at most 1 amino acid.
In a preferred embodiment, the dimerization unit comprises or consists of a nucleic acid sequence having at least 80% sequence identity with the nucleic acid sequence having SEQ ID NO. 8.
In a further preferred embodiment, the dimerization unit comprises or consists of a nucleic acid sequence having at least 85% sequence identity with the nucleic acid sequence having SEQ ID No. 8, e.g. at least 86% or at least 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or at least 99% sequence identity.
In another preferred embodiment, the dimerization unit comprises or consists of the nucleic acid sequence of SEQ ID NO. 8.
In another embodiment, the dimerization unit comprises another domain that promotes dimerization; preferably, the further domain is an immunoglobulin domain, e.g. an immunoglobulin constant domain (C domain), e.g. a CH1 domain, a CH2 domain or a carboxy-terminal C domain (i.e. a CH3 domain), or a sequence substantially identical to such a C domain or a variant thereof. Preferably, the further domain promoting dimerization is a carboxy-terminal C domain derived from IgG. More preferably, the further domain promoting dimerization is a carboxy-terminal C domain derived from IgG 3.
In one embodiment, the dimerization unit comprises or consists of a carboxy-terminal C domain derived from IgG3 having an amino acid sequence having at least 80% sequence identity with the amino acid sequence of 131-237 of SEQ ID NO. 1.
In preferred embodiments, the dimerization unit comprises or consists of a carboxy-terminal C domain derived from IgG3, which has an amino acid sequence having at least 85% sequence identity to the amino acid sequence of 131-237 of SEQ ID NO:1, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98% or such as at least 99% sequence identity.
In a preferred embodiment, the dimerization unit comprises or consists of a carboxy terminal C domain derived from IgG3 having the amino acid sequence of 131-237 of SEQ ID NO. 1.
In a preferred embodiment, the dimerization unit comprises or consists of the amino acid sequence of 131-237 of SEQ ID NO. 1, except that up to 16 amino acids are substituted, deleted or inserted, for example up to 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid.
In a preferred embodiment, the dimerization unit comprises or consists of a nucleic acid sequence having at least 80% sequence identity with the nucleic acid sequence of SEQ ID NO. 10.
In a further preferred embodiment, the dimerization unit comprises or consists of a nucleic acid sequence having at least 85% sequence identity with the nucleic acid sequence having SEQ ID No. 10, e.g. at least 86% or at least 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or at least 99% sequence identity. In a further preferred embodiment, the dimerization unit comprises or consists of the nucleic acid sequence of SEQ ID NO. 10.
Immunoglobulin domains promote dimerization through non-covalent interactions, such as hydrophobic interactions. Thus, in one embodiment, the immunoglobulin domain has the ability to form dimers through non-covalent interactions. Preferably, the non-covalent interactions are hydrophobic interactions.
Preferably, if the dimerization unit comprises a CH3 domain, it does not comprise a CH2 domain and vice versa.
In a preferred embodiment, the dimerization unit comprises hinge exon h1, hinge exon h4, dimerization unit linker and the CH3 domain of human IgG 3. In a further preferred embodiment, the dimerization unit comprises a polypeptide consisting of hinge exon h1, hinge exon h4, a dimerization unit linker and the CH3 domain of human IgG 3.
In another preferred embodiment, the dimerization unit consists of a polypeptide consisting of hinge exon h1, hinge exon h4, dimerization unit linker and the CH3 domain of human IgG 3.
In one embodiment, the dimerization unit comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 94-237 of SEQ ID NO. 1.
In preferred embodiments, the dimerization unit comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of 94-237 of SEQ ID NO. 1, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98% or such as at least 99% sequence identity.
In a more preferred embodiment, the dimerization unit consists of an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 94-237 of SEQ ID NO. 1, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98% or such as at least 99% sequence identity.
In an even more preferred embodiment, the dimerization unit consists of the amino acid sequence of 94-237 of SEQ ID NO. 1.
In a preferred embodiment, the dimerization unit comprises the amino acid sequence of 94-237 of SEQ ID NO. 1 except that up to 22 amino acids are substituted, deleted or inserted, for example up to 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid.
In a preferred embodiment, the dimerization unit consists of the amino acid sequence of 94-237 of SEQ ID NO. 1, except that up to 22 amino acids are substituted, deleted or inserted, for example up to 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid.
In a preferred embodiment, the dimerization unit comprises a nucleic acid sequence having at least 80% sequence identity to the nucleic acid sequence having SEQ ID NO. 12.
In a further preferred embodiment, the dimerization unit comprises a nucleic acid sequence having at least 85% sequence identity to the nucleic acid sequence having SEQ ID No. 12, e.g., at least 86% or at least 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or at least 99% sequence identity. In another preferred embodiment, the dimerization unit comprises the nucleic acid sequence of SEQ ID NO. 12.
In another preferred embodiment, the dimerization unit consists of a nucleic acid sequence having at least 80% sequence identity with the nucleic acid sequence having SEQ ID NO. 12.
In a further preferred embodiment, the dimerization unit consists of a nucleic acid sequence having at least 85% sequence identity with the nucleic acid sequence having SEQ ID NO. 12, e.g., at least 86% or at least 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or at least 99% sequence identity.
In another preferred embodiment, the dimerization unit has the nucleic acid sequence of SEQ ID NO. 12.
In one embodiment, the dimerization unit comprises or consists of a dHLX protein, e.g., a dHLX protein comprising or consisting of a nucleic acid sequence having or encoded by SEQ ID No. 120.
In polypeptides encoded by nucleotide sequences of anti-cancer vaccines for use in the methods of the invention, multimerization units, e.g., dimerization units, may have any orientation relative to the antigenic units and targeting units. In one embodiment, the antigenic unit is attached to the C-terminus of the multimerization/dimerization unit (e.g., via a unit linker) and the targeting unit is attached to the N-terminus of the multimerization/dimerization unit. In another embodiment, the antigenic unit is attached to the N-terminus of the multimerization/dimerization unit (e.g., via a unit linker) and the targeting unit is attached to the C-terminus of the dimerization unit. Preferably, the antigenic unit is attached to the C-terminus of the multimerization/dimerization unit (preferably via a unit linker), and the targeting unit is attached to the N-terminus of the multimerization/dimerization unit.
Signal peptides
In one embodiment, the anti-cancer vaccine used in the methods of the invention is a polynucleotide further comprising a nucleotide sequence encoding a signal peptide. The signal peptide is located at the N-terminus of the targeting unit or at the C-terminus of the targeting unit, depending on the orientation of the targeting unit in the polypeptide. The signal peptide is designed to allow secretion of the polypeptide encoded by the polynucleotide in a cell transfected with the polynucleotide.
Any suitable signal peptide may be used. Examples of suitable peptides are Ig VH signal peptides, such as SEQ ID NO. 2; human TPA signal peptide, e.g., SEQ ID NO:3, and human MIP-1. Alpha. Signal peptide.
In one embodiment, the anti-cancer vaccine used in the methods of the invention is a polynucleotide comprising a nucleotide sequence encoding a signal peptide comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence of 1-23 of SEQ ID No. 1, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98% or such as at least 99% sequence identity.
In another preferred embodiment, the anti-cancer vaccine used in the method of the invention is a polynucleotide comprising a nucleotide sequence encoding a signal peptide comprising the amino acid sequence 1-23 of SEQ ID NO. 1, except that at most 4 amino acids have been substituted, deleted or inserted, such as at most 3 amino acids, such as at most 2 amino acids or such as at most 1 amino acid.
In another preferred embodiment, the anti-cancer vaccine used in the method of the invention is a polynucleotide comprising a nucleotide sequence encoding a signal peptide comprising the amino acid sequence of 1-23 of SEQ ID NO. 1.
In a more preferred embodiment, the anti-cancer vaccine used in the method of the invention is a polynucleotide comprising a nucleotide sequence encoding a signal peptide consisting of an amino acid sequence having at least 80% sequence identity with the amino acid sequence of 1-23 of SEQ ID No. 1, preferably at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98% or such as at least 99% sequence identity.
In another preferred embodiment, the anti-cancer vaccine used in the method of the invention is a polynucleotide comprising a nucleotide sequence encoding a signal peptide consisting of the amino acid sequence 1-23 of SEQ ID NO. 1, except that at most 4 amino acids have been substituted, deleted or inserted, such as at most 3 amino acids, such as at most 2 amino acids or such as at most 1 amino acid.
In another preferred embodiment, the anti-cancer vaccine used in the method of the invention is a polynucleotide comprising a nucleotide sequence encoding a signal peptide having the amino acid sequence of 1-23 of SEQ ID NO. 1.
In a preferred embodiment, the anti-cancer vaccine used in the method of the invention is a polynucleotide comprising a nucleotide sequence encoding a signal peptide, wherein said nucleotide sequence has at least 80% sequence identity to a nucleic acid sequence having SEQ ID NO. 4.
In a further preferred embodiment, the anti-cancer vaccine used in the method of the invention is a polynucleotide comprising a nucleotide sequence encoding a signal peptide, wherein said nucleotide sequence has at least 85% sequence identity, e.g. at least 86% or at least 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or at least 99% sequence identity, to a nucleic acid sequence having SEQ ID No. 4.
In a further preferred embodiment, the anti-cancer vaccine used in the method of the invention is a polynucleotide comprising a nucleotide sequence encoding a signal peptide, wherein said nucleotide sequence is SEQ ID NO. 4.
Sequence identity
Sequence identity can be determined as follows: a high level of sequence identity indicates the likelihood that the second sequence is derived from the first sequence. Amino acid sequence identity requires the same amino acid sequence between two aligned sequences. Thus, a candidate sequence sharing 70% amino acid identity with a reference sequence requires that, after alignment, 70% of the amino acids in the candidate sequence are identical to the corresponding amino acids in the reference sequence. Identity may be determined by means of computer analysis, such as, but not limited to, clustalW computer alignment program (Higgins D., thompson J., gibson T., thompson J.D., higgins D.G., gibson T.J.,1994.CLUSTAL W:improving the sensitivity of progressive multiple sequence alignment through sequence weighting,position-specific gap penalties and weight matrix choice.nucleic Acids Res.22:4673-4680), and default parameters suggested therein. Using this procedure and its default settings, the mature (biologically active) portions of the query and reference polypeptides can be aligned. The number of fully conserved residues is counted and divided by the length of the reference polypeptide. In this process, any tag or fusion protein sequences that form part of the query sequence are ignored in the alignment and subsequent sequence identity determination.
The ClustalW algorithm can be similarly used to align nucleotide sequences. Sequence identity can be calculated in a similar manner as described for the amino acid sequence.
Another preferred mathematical algorithm for comparing sequences is the algorithm of Myers and Miller, CABIOS (1989). Such an algorithm is incorporated into the ALIGN program (version 2.0) which is part of the FASTA sequence alignment software package (Pearson WR, methods Mol Biol,2000, 132:185-219). Align calculates sequence identity based on global alignment. Align0 does not penalty the gap at the end of the sequence. When comparing amino acid sequences using the ALIGN and ALIGN0 programs, the BLOSUM50 substitution matrix with a gap opening/extension penalty of-12/-2 is preferably used.
Amino acid sequence variants may be prepared by introducing appropriate changes into the nucleotide sequence encoding the anti-cancer vaccine or by peptide synthesis. Such modifications include, for example, deletions and/or insertions and/or substitutions of residues within the amino acid sequence. The terms substitution/substitution, deletion/deletion and insertion/insertion as used herein with respect to amino acid sequence and sequence identity are well known and clear to those skilled in the art. Any combination of deletions, insertions, and substitutions may be made to obtain a final construct, provided that the final construct has the desired characteristics. For example, deletions, insertions or substitutions of amino acid residues may produce a silent change and result in a functionally equivalent peptide/polypeptide.
Deliberate amino acid substitutions may be made based on similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues as long as the secondary binding activity of the substance is retained. For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; amino acids having uncharged polar head groups with similar hydrophilicity values include leucine, isoleucine, valine, glycine, alanine, asparagine, glutamine, serine, threonine, phenylalanine, and tyrosine.
Conservative substitutions, i.e., like-for-like substitution, such as basic substitution basic, acidic substitution acidic, polar substitution polar, etc., as well as non-conservative substitutions, i.e., from one type of residue to another, or alternatively involve the inclusion of unnatural amino acids such as ornithine, diaminobutyrate ornithine, norleucine, ornithine, pyridinylalanine, thiophenylalanine, naphthylalanine, and phenylglycine are contemplated herein. Conservative substitutions that may be made are made, for example, in the following groups: basic amino acids (arginine, lysine and histidine), acidic amino acids (glutamic acid and aspartic acid), aliphatic amino acids (alanine, aaline, leucine, isoleucine), polar amino acids (glutamine, asparagine, serine, threonine), aromatic amino acids (phenylalanine, tryptophan, tyrosine), hydroxy amino acids (serine, threonine), large amino acids (phenylalanine, tryptophan) and small amino acids (glycine, alanine).
Substitutions may also be made by unnatural amino acids, and the substitution residues include: α and α -disubstituted amino acids, N-alkylamino acids, lactic acid, halide derivatives of natural amino acids such as trifluorotyrosine, p-Cl-phenylalanine, p-Br-phenylalanine, p-I-phenylalanine, L-allyl-glycine, β -alanine, L-a-aminobutyric acid, L-y-aminobutyric acid, L-a-aminoisobutyric acid, L-e-aminocaproic acid, 7-aminoheptanoic acid, L-methionine sulfone, L-norleucine, L-norvaline, methyl derivatives of p-nitro-L-phenylalanine, L-hydroxyproline, L-thioproline, phenylalanine (Phe) such as 4-methyl-Phe, pentamethyl-Phe, L-Phe (4-amino), L-Tyr (methyl), L-Phe (4-isopropyl) L-3, 3-tetrahydrophe (3, 3-phenylic acid) and 4-benzyl-amino-3-isopropyl-3, 3-d-amino-propionic acid.
In the above paragraph, # denotes the hydrophobicity of the substituted residue, while # denotes the hydrophilicity of the substituted residue, and # denotes the amphipathic nature of the substituted residue. The variant amino acid sequence may include a suitable spacer group that may be inserted between any two amino acid residues of the sequence, including alkyl groups such as methyl, ethyl or propyl in addition to amino acid spacer groups such as glycine or β -alanine residues. Another form of variation involves the presence of one or more amino acid residues in the peptoid (pepoid) form.
Polynucleotide
The anti-cancer vaccine used in the methods of the invention may be in the form of a polynucleotide, such as DNA or RNA, including genomic DNA, cDNA and mRNA, and may be double-stranded or single-stranded. In one embodiment, the anti-cancer vaccine is a DNA vaccine, i.e., the polynucleotide is DNA.
In one embodiment, the polynucleotide is optimized for the species of subject to which it is administered. For administration to humans, in one embodiment, the polynucleotide sequence is human codon optimized.
VB10.NEO
In one embodiment, the anti-cancer vaccine is a personalized DNA anti-cancer vaccine comprising vb10.neo, which is a DNA polynucleotide comprising a nucleotide sequence encoding a signal peptide, a human MIP-1 a targeting unit that targets antigen presenting cells, a human IgG3 dimerization unit, a glycine-rich linker unit, and an antigenic unit comprising one or more neoepitopes. If the antigenic unit comprises more than one neoepitope, the neoepitopes are separated by a linker. A description of neo can be found in international patent application number PCT/EP2017/050206, filed and published as WO 2017/118695A1, for example, on month 1, 5 of 2017.
Vb10.neo consists of a constant part comprising a signal peptide, a targeting unit targeting antigen presenting cells, a dimerization unit and a unit linker, and a variable part comprising an antigenic unit and designed specifically for each patient to whom vb10.neo is administered, comprising one or more neo-epitopes identified in the tumor of the patient to be treated with vb10.neo. Thus, the antigenic unit is specifically designed and is directed only against the patient receiving or to be receiving vaccine treatment and comprises one or more cancer antigens or parts thereof as patient specific antigens, such antigens including neoantigens or common cancer antigens present by the patient. After identifying patient-specific, tumor-specific mutations, an antigenic peptide comprising the neoepitope is selected and the nucleic acid encoding the neoepitope is incorporated into the antigenic unit of vb10. Neo.
The vb10.neo comprises a nucleotide sequence encoding a signal peptide. The signal peptide is a human MIP-1 alpha signal peptide and VB10.NEO comprises a nucleotide sequence encoding the amino acid sequence of 1-23 of SEQ ID NO. 1. VB10.NEO comprises a signal peptide consisting of the nucleic acid sequence of SEQ ID NO. 4.
Vb10.neo comprises a nucleotide sequence encoding a target comprising or consisting of human MIP-1α (ld78β, CCL3L 1), i.e. the amino acid sequence of 24-93 of SEQ ID NO: 1. VB10.NEO comprises a human MIP-1. Alpha. Targeting unit consisting of the nucleic acid sequence of SEQ ID NO: 5.
NEO comprises a nucleotide sequence encoding a dimerization unit comprising hinge exon h1, hinge exon h4, dimerization unit linker and CH3 domain of human IgG 3. VB10.NEO comprises a nucleotide sequence encoding a dimerization unit comprising or consisting of the amino acid sequence of 94-237 of SEQ ID NO. 1. VB10.NEO comprises a dimerization unit having the nucleic acid sequence of SEQ ID NO. 12.
The vb10.neo comprises a nucleotide sequence encoding a unit linker as described herein, for example as described under the heading "unit linker". VB10.NEO comprises a nucleotide sequence encoding a unit linker comprising or consisting of GLGGL (SEQ ID NO: 52) (having the nucleotide sequence of SEQ ID NO: 10) or GLSGL (SEQ ID NO: 109).
VB10.NEO comprises a nucleotide sequence encoding a polypeptide consisting of the amino acid sequence of 1-242 of SEQ ID NO. 1, i.e. the constant part of VB10.NEO consists of a nucleotide sequence encoding a polypeptide consisting of the amino acid sequence of 1-242 of SEQ ID NO. 1. VB10.NEO comprises the nucleic acid sequence of SEQ ID NO. 23, i.e. the constant part of VB10.NEO consists of the nucleic acid sequence of SEQ ID NO. 23.
In one embodiment, vb10.Neo is contained in a vector suitable for expressing a polypeptide or dimeric protein encoded by a polynucleotide (i.e., an expression vector, such as a DNA plasmid). The term "VB10.NEO" can be used for the aforementioned DNA polynucleotides, but can also be used for expression vectors, e.g., DNA plasmids, comprising the aforementioned DNA polynucleotides.
Polypeptides and multimeric/dimeric proteins
The anti-cancer vaccine used in the method of the present invention may be in the form of a polypeptide encoded by a polynucleotide as described above. The polypeptide may be expressed in vitro to produce an anti-cancer vaccine, or the polypeptide may be expressed in vivo as a result of administration of the polynucleotide to a subject, as described above.
Due to the presence of multimerization/dimerization units, multimeric/dimeric proteins are formed when the polypeptide is expressed.
The multimeric/dimeric protein may be a homomultimer or a heteromultimer, e.g., if the protein is a dimeric protein, the dimeric protein may be a homodimer, i.e., a dimeric protein in which the two polypeptide chains are identical and thus comprise the same units and thus comprise the same antigen sequence; alternatively, the dimeric protein may be a heterodimer comprising two polypeptide chains, wherein polypeptide chain 1 comprises a different antigen sequence in its antigenic unit than polypeptide 2. The latter case may be relevant if the number of antigens contained in the antigenic unit exceeds the upper size limit of the antigenic unit. Preferably, the dimeric protein is a homodimeric protein.
Carrier body
The polynucleotide sequence of the anti-cancer vaccine may be a DNA polynucleotide contained in a vector suitable for transfecting a host cell and expressing the polypeptide or multimeric/dimeric protein encoded by the polynucleotide (i.e., an expression vector such as a DNA plasmid). In another embodiment, the vector is suitable for transfecting a host cell and expressing mRNA encoding the polypeptide/multimeric protein.
In one embodiment, the vector allows for easy exchange of the various units described above, particularly antigenic units in the case of personalized anti-cancer vaccines.
In one embodiment, the vector is a pUMVC4a vector or a vector comprising an NTC9385R vector backbone. The antigenic unit may be exchanged with an antigenic unit cassette limited by a SfiI restriction enzyme cassette, wherein the 5 'site is incorporated in the nucleotide sequence encoding the GLGGL (SEQ ID NO: 52)/GLSGL (SEQ ID NO: 109) unit linker and the 3' site is comprised after the stop codon in the vector.
Accordingly, the present invention provides a method for treating a subject (e.g., patient) having cancer, the method comprising administering to the subject
(a) An anti-cancer vaccine comprising a vector comprising a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit such as a dimerization unit, and an antigenic unit comprising one or more cancer antigens; and
(b) One or more checkpoint inhibitors.
In one embodiment, the invention provides a method for treating a subject (e.g., a patient) having cancer, the method comprising administering to the subject
(a) An anti-cancer vaccine comprising a vector comprising a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, and an antigenic unit comprising one or more cancer antigens; and
(b) One or more checkpoint inhibitors.
In another embodiment, the invention provides a method for treating a subject (e.g., a patient) having cancer, the method comprising administering to the subject
(a) An anti-cancer vaccine comprising a vector comprising a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a dimerization unit, and an antigenic unit comprising one or more cancer antigens; and
(b) One or more checkpoint inhibitors.
In a preferred embodiment, the vector is a DNA plasmid and the polynucleotide is DNA.
Vaccine
The anti-cancer vaccine used in the methods of the invention may comprise a pharmaceutically acceptable carrier or diluent, including but not limited to saline, buffered saline such as PBS, dextrose, water, glycerol, ethanol, sterile isotonic aqueous buffer, and combinations thereof.
In one embodiment, the pharmaceutically acceptable carrier or diluent is an aqueous buffer. In another embodiment, the aqueous buffer is a Tyrode buffer, e.g., a Tyrode buffer comprising 140mM sodium chloride, 6mM KCl, 3mM CaCl2, 2mM MgCl2, 10mM 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid (Hepes) pH 7.4, and 10mM glucose.
The anti-cancer vaccine may further comprise an adjuvant. In particular for anti-cancer vaccines comprising polypeptides/proteins, pharmaceutically acceptable adjuvants include, but are not limited to, poly-ICLC, 1018ISS, aluminum salts, amplivax, AS15, BCG, CP-870, 893, cpG7909, cyaA, dSLIM, GM-CSF, IC30, IC31, imiquimod (imiquimod), imufect EV 1P 321, IS Patch, ISS, ISCOMATRIX, juvlmmune, lipoVac, MF59, monophosphoryl lipid a, montanide IMS1312, montanide ISA 206, montanide ISA 50V, montanide ISA-51, OK-432, OM-174, OM-197-MP-EC, ONTAK, PLGA microparticles, resiquimod (resiquimod), SRL172, virions (virosome) and other virus-like particles, YF-17D, VEGF trap, R848, β -glucan, pam3, aquila's 21 spike, vadizan and/or dmaa 404. However, as described above, due to the presence of the targeting unit, the anti-cancer vaccine used in the method of the invention can be administered without additional adjuvant; thus, in some embodiments, the anti-cancer vaccine does not comprise an adjuvant.
In some specific embodiments, an anti-cancer vaccine may comprise a pharmaceutically acceptable amphiphilic block copolymer comprising blocks of poly (ethylene oxide) and poly (propylene oxide).
As used herein, an "amphiphilic block copolymer" is a linear or branched copolymer comprising or consisting of blocks of poly (ethylene oxide) ("PEO") and blocks of poly (propylene oxide) ("PPO"). Typical examples of useful PEO-PPO amphiphilic block copolymers have the general structure PEO-PPO-PEO (poloxamer), PPO PEO PPO, (PEO PPO-) 4ED (poloxamer) and (PPO PEO-) 4ED (antipolloxamine), wherein "ED" is ethylenediamine.
"poloxamer" is a linear amphiphilic block copolymer consisting of one block of poly (ethylene oxide) coupled to one block of poly (propylene oxide) coupled to one block of PEO, i.e., having the structure EOa-POb-EOa, wherein EO is ethylene oxide, PO is propylene oxide, a is an integer from 2 to 130, and b is an integer from 15 to 67. Poloxamers are typically named using a 3-digit identifier, wherein the first 2 digits multiplied by 100 yields an approximate molecular weight of the PPO content, and wherein the last digit multiplied by 10 represents an approximate percentage of the PEO content. For example, "poloxamer 188" refers to a polymer comprising a PPO block of molecular weight about 1800 (corresponding to b of about 31 PPO) and about 80% (w/w) PEO (corresponding to a of about 82). However, these values are known to vary to some extent and commercial products, such as research grades F68 and clinical grade->P188 (poloxamer 188 for both according to the manufacturer's data sheet) shows a large variation in molecular weight (between 7,680 and 9,510) providing a and b values of about 79 and 28, respectively, for these particular products. This reflects the heterogeneity of the block copolymers, meaning that a and bThe values are the average values in the final formulation.
"poloxamine" or "sequential poloxamine (sequential poloxamine)" (under the trade nameCommercially available) is an X-block copolymer having four PEO-PPO arms linked to a central ethylenediamine moiety through a bond between a free OH group in the PEO-PPO-arm and a primary amine group in the ethylenediamine moiety. Trans-poloxamine is also an X-block copolymer with four PPO-PEO arms linked to a central ethylenediamine moiety through a bond between the free OH groups contained in the PPO-PEO arms and the primary amine groups in ethylenediamine.
The preferred amphiphilic block copolymer is poloxamer or poloxamer. Preferred are poloxamers 407 and 188, in particular poloxamer 188. The preferred poloxamer is the sequential poloxamer of the formula (PEO-PPO) 4-ED. Particularly preferred poloxamine are under the registered trade marks respectively904. 704 and 304. The properties of these poloxamines are as follows: / >904 has a total average molecular weight of 6700, a total average weight of ppo units of 4020, and a peo percentage of about 40%. />704 has a total average molecular weight of 5500, a total average weight of ppo units of 3300, a peo percentage of about 40%; />304 has a total average molecular weight of 1650, a total average weight of ppo units of 990, and a peo percentage of about 40%.
In one embodiment, the anti-cancer vaccine comprises the amphiphilic block copolymer in an amount of 0.2% w/v to 20% w/v, e.g., 0.2% w/v to 18% w/v, 0.2% w/v to 16% w/v, 0.2% w/v to 14% w/v, 0.2% w/v to 12% w/v, 0.2% w/v to 10% w/v, 0.2% w/v to 8% w/v, 0.2% w/v to 6% w/v, 0.2% w/v to 4% w/v, 0.4% w/v to 18% w/v, 0.6% w/v to 18% w/v, 0.8% w/v to 18% w/v, 1% w/v to 18% w/v, 2% w/v to 18% w/v, 1% w/v to 5% w/v, or 2% w/v to 4% w/v. Particularly preferred is an amount in the range of 0.5% w/v to 5% w/v. In another embodiment, the anti-cancer vaccine comprises the amphiphilic block copolymer in an amount of 2% w/v to 5% w/v, for example about 3% w/v.
For anti-cancer vaccines comprising polynucleotides, the vaccine may also comprise molecules that facilitate cell transfection.
The anti-cancer vaccine may be formulated in any manner suitable for administration to a subject, such as a patient, for example, a liquid formulation for injection, such as for intradermal or intramuscular injection.
The anti-cancer vaccine used in the methods of the invention may be administered in any manner suitable for administration of a polypeptide/protein vaccine or polynucleotide vaccine to a subject, e.g., a patient, e.g., by intradermal, intramuscular, intranodal, or subcutaneous injection, or by mucosal or epithelial administration, e.g., intranasal, oral, enteral, or intravesical (to the bladder).
In a preferred embodiment, the anti-cancer vaccine comprises a polynucleotide, preferably a polynucleotide, as described herein and a pharmaceutically acceptable carrier, and is administered by intramuscular or intradermal injection.
The anti-cancer vaccine used in the methods of the invention typically comprises in the range of 0.3mg to 6mg, e.g., about 2mg of the polynucleotide, and 5 μg to 5mg of the polypeptide/protein.
Method for preparing anticancer vaccine for use in the method of the invention
Suitable methods are disclosed in WO 2004/076489A1, WO 2011/161244A1, WO 2013/092875A1, WO 2017/118695A1 and WO 2021/205027 A1, which are incorporated herein by reference, in particular page 15, lines 10-13 and page 17 of WO 2004/076489A1 "construction of vaccine bodies" sections; page 10, lines 10-14 of WO 2011/161244A1 and example 1; page 15 of WO 2013/092875A1 and example 1; the "method of preparing vaccine" section of WO 2017/118695A1 and example 1, and page 26, line 17 to page 27, line 38, page 30, line 23 to page 31, line 27 and example 4 of WO 2021/205027 A1.
Checkpoint inhibitors
The methods of the invention comprise administering one or more checkpoint inhibitors. Checkpoint inhibitors suitable for use in the methods provided herein include antibodies, e.g., monoclonal antibodies, that target PD-1, PD-L1, CTLA-4, or TIGIT.
Exemplary anti-PD 1 inhibitors, such as anti-PD 1 antibodies include, but are not limited to, pembrolizumab (pembrolizumab), nivolumab (nivolumab), and cimetidine Li Shan (cemiplimab). Representative anti-PD-L1 inhibitors, such as anti-PD-L1 antibodies, include, for example, atilizumab (atezolizumab), avilamab (avelumab), and devaluzumab (durvalumab). Exemplary anti-CTLA-4 inhibitors, such as anti-CTLA 4 antibodies, include, for example, ipilimumab (ipilimumab) or tremelimumab (tremelimumab). Representative anti-TIGIT inhibitors, such as anti-TIGIT antibodies, include, for example, tireli Li Youshan anti (tiragolumab), BMS-986207, ociperlimab, COM902, AB154, EOS884448, IBI939, SGNTNT, and Ai Tili mab (etigilimab).
Preferably, the checkpoint inhibitor is selected from the group consisting of an anti-PD-L1 antibody, an anti-TIGIT antibody, an anti-CTLA-4 antibody, and an anti-PD 1 antibody.
In one embodiment, the checkpoint inhibitor is an anti-PD-L1 antibody, e.g., an acter Li Zhushan antibody.
The term "hypervariable region" or "HVR" as used herein refers to each region of an antibody variable domain that is highly variable in sequence and determines antigen binding specificity, e.g., a "complementarity determining region" ("CDR"). Generally, an antibody comprises 6 CDRs: 3 of the heavy chain variable regions (VH) (CDR-H1, CDR-H2, CDR-H3) and 3 of the light chain variable regions (VL) (CDR-L1, CDR-L2, CDR-L3).
In some embodiments, the anti-PD-L1 antibody comprises atilizumab, which comprises:
(a) The heavy chain amino acid sequence of SEQ ID NO. 13, and
(b) The light chain amino acid sequence of SEQ ID NO. 14.
In some embodiments, an anti-PD-L1 antibody comprises:
(a) Sequences of HVR-H1, HVR-H2 and HVR-H3 of GFTFSDSWIH (SEQ ID NO: 15), AWISPYGGSTYYADSVKG (SEQ ID NO: 16) and RHWPGGFDY (SEQ ID NO: 17), respectively, and
(b) HVR-L1, HVR-L2 and HVR-L3 sequences of RASQDVSTAVA (SEQ ID NO: 18), SASFLYS (SEQ ID NO: 19) and QQYLYHPAT (SEQ ID NO: 20), respectively.
The sequences of HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 of the atilizumab are SEQ ID NOS 15-20 respectively.
In some embodiments, an anti-PD-L1 antibody comprises:
(a) A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID No. 21; and
(b) A light chain variable region (VL) comprising the amino acid sequence of SEQ ID No. 22.
The VH of the atilizumab comprises SEQ ID NO. 21; the VL of the atilizumab comprises SEQ ID NO. 22.
Acter Li Zhushan has been approved in many countries as a monotherapy for the treatment of certain cancers. For example, acti Li Zhushan antibodies have been approved in the united states or europe for the following indications: treating an adult patient having locally advanced or metastatic Urothelial Cancer (UC) following prior platinum-containing chemotherapy, or a patient considered unsuitable for cisplatin and having a tumor with 5% or more PD-L1 expression, treating an adult patient having locally advanced or metastatic non-small cell lung cancer (NSCLC) following prior chemotherapy; treating a locally advanced or metastatic UC patient who is not suitable for cisplatin-containing chemotherapy and whose tumor expresses PD-L1 (PD-L1 staining IC covers ≡5% of the tumor area), or who is not suitable for any platinum-containing chemotherapy regardless of the tumor PD-L1 expression level, or who develops disease progression during or after any platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy; and treating metastatic NSCLC patients with disease progression during or after platinum-containing chemotherapy. The atilizumab is also under development as a monotherapy and in combination with other targeted and cytotoxic drugs for the treatment of patients suffering from a variety of solid and hematological tumors, including lung, kidney, colorectal and breast cancers.
All indications currently approved for atilizumab are infused once every 3 weeks (Q3W) with Intravenous (IV) at a dose of 1200mg until disease progression or unacceptable toxicity occurs.
In another embodiment, the checkpoint inhibitor is an anti-TIGIT antibody. In yet another embodiment, the checkpoint inhibitor is an anti-CTLA-4 antibody. In yet another embodiment, the checkpoint inhibitor is an anti-PD 1 antibody.
In one embodiment, the methods of the invention comprise administering two checkpoint inhibitors, e.g., administering an anti-PD-L1 antibody and an anti-TIGIT antibody or administering an anti-PD-L1 antibody and an anti-CTLA-4 antibody or administering an anti-PD-1 antibody and an anti-TIGIT antibody or administering an anti-PD-1 antibody and an anti-CTLA-4 antibody or administering an anti-TIGIT antibody and an anti-CTLA-4 antibody or administering an anti-PD-L1 antibody and an anti-PD-1 antibody.
In another embodiment, the methods of the invention comprise administering three checkpoint inhibitors, e.g., an anti-PD-L1 antibody, an anti-PD-1 antibody, and an anti-CTLA-4 antibody or an anti-TIGIT antibody or an anti-PD-L1 antibody, an anti-CTLA-4 antibody and an anti-TIGIT antibody or an anti-PD-1 antibody, an anti-CTLA-4 antibody and an anti-TIGIT antibody.
In another embodiment, the methods of the invention comprise administering four checkpoint inhibitors, e.g., an anti-PD-L1 antibody, an anti-PD-1 antibody, an anti-CTLA-4 antibody, and an anti-TIGIT antibody.
In a preferred embodiment, the methods of the invention comprise administering an anti-TIGIT antibody or an anti-PD-L1 antibody or an anti-CTLA-4 antibody. In another preferred embodiment, the methods of the invention comprise administering an anti-TIGIT antibody and an anti-PD-L1 antibody or administering an anti-CTLA-4 antibody and an anti-PD-L1 antibody.
In one embodiment, the checkpoint inhibitor, e.g., each checkpoint inhibitor, is contained in a composition suitable for injection. Such a composition may be a liquid composition suitable for injection, e.g. infusion injection, comprising, e.g. sterile water, saline, e.g. isotonic saline, a sugar solution for intravenous administration, e.g. a glucose solution, an electrolyte solution for intravenous administration, e.g. ringer's lactate or ringer's acetate, or an aqueous buffer.
In another embodiment, the plurality of checkpoint inhibitors are comprised in a composition suitable for injection, e.g. a liquid composition suitable for injection, e.g. two, three or four checkpoint inhibitors.
The composition may comprise a total amount of about 0.1mg/kg to about 1mg/kg, for example about 0.2mg/kg to about 0.9mg/kg, about 0.3mg/kg to about 0.8mg/kg, about 0.4mg/kg to about 0.7mg/kg, about 0.5mg/kg to about 0.6mg/kg, or about 1mg/kg to about 1000mg/kg, for example about 2mg/kg to about 900mg/kg, about 3mg/kg to about 800mg/kg, about 4mg/kg to about 700mg/kg, about 5mg/kg to about 600mg/kg, about 6mg/kg to about 550mg/kg, about 7mg/kg to about 500mg/kg, about 8mg/kg to about 450mg/kg, about 9mg/kg to about 400mg/kg, about 5mg/kg to about 200mg/kg, about 2mg/kg to about 150mg/kg, about 5mg/kg to about 100mg/kg, about 10mg to about 60mg/kg of the checkpoint inhibitor, or about 10mg to about 60mg/kg of the checkpoint inhibitor. Further guidance may be provided according to the standard of care for checkpoint inhibitor administration in current cancer treatments.
In one embodiment, the composition comprising the checkpoint inhibitor (e.g., the composition described above) is administered by injection. Injections include subcutaneous, intravenous, intra-arterial, intratumoral, intralymphatic, intraperitoneal, intracardiac, intrathecal and intramuscular injections, as well as infusion injections.
Treatment of
In one embodiment, a subject treated according to the methods of the invention has received one or more anti-cancer treatments prior to being treated according to the methods of the invention. Such anti-cancer treatments include surgery, radiation therapy, chemotherapy, and immunotherapy. In another embodiment, the subject is untreated. In some embodiments, the cancer is non-metastatic. In other embodiments, the cancer is metastatic. In one embodiment, the subject has received a prior treatment to treat the cancer, and the cancer treated by the methods of the invention is recurrent, or refractory to the prior treatment.
Regarding the frequency and schedule of administration of anti-cancer vaccines and checkpoint inhibitors in the methods of the present invention, one of ordinary skill in the art will be able to determine the appropriate frequency and schedule for each of them.
For example, during a treatment cycle, a clinician may decide to administer an anti-cancer vaccine in a single dose or in repeated doses (i.e., in a series of doses, e.g., over a period of days, weeks, or months).
The anticancer vaccine administered each time may be the same, or different anticancer vaccines may be administered, e.g. different anticancer vaccines are administered in different treatment cycles. As an example, a personalized anti-cancer vaccine comprising a polynucleotide encoding 20 neoepitopes (neoepitopes 1-20 with sequences 1-20) or comprising a polypeptide/protein comprising said 20 neoepitopes is administered to a patient in a series of doses, e.g. over a period of days, weeks or months. Neoepitope 1-20 is a subset of a total of 60 different neoepitopes that have been identified in the patient, wherein neoepitope 1-20 is selected for inclusion in a vaccine by the methods described previously in the present application and based on the criteria described previously in the present application. In a subsequent treatment cycle, another personalized anti-cancer vaccine comprising a polynucleotide encoding 20 neoepitopes (neoepitopes 21-40 having sequences 21-40) or comprising a polypeptide/protein comprising said 20 neoepitopes is administered to the same patient, in a series of doses, for example over a period of days, weeks or months. Neoepitope 21-40 is also a subset of a total of 60 different neoepitopes that have been identified in the patient.
In one embodiment, the checkpoint inhibitor is administered simultaneously with the anti-cancer vaccine, e.g. on the same day or at the same time of the same day, as a single dose or in repeated doses, i.e. in a series of doses, e.g. over a period of days, weeks or months. Thus, the first administration of one or more checkpoint inhibitors and the first administration of the anti-cancer vaccine are performed simultaneously, e.g. at the same day or at the same time of the same day.
In another embodiment, the checkpoint inhibitor is administered prior to the anti-cancer vaccine as a single dose or as a repeated dose, i.e. a series of doses, e.g. over a period of days, weeks or months. Thus, the first administration of one or more checkpoint inhibitors is performed prior to the first administration of the anti-cancer vaccine.
In yet another embodiment, the anti-cancer vaccine is administered prior to the one or more checkpoint inhibitors as a single dose or as a repeated dose, i.e. a series of doses, e.g. over a period of days, weeks or months. Thus, the first administration of the anti-cancer vaccine is performed prior to the first administration of the one or more checkpoint inhibitors.
In one embodiment, the method of the invention further comprises one or more of the following steps: identifying neoepitopes in a patient and/or consensus antigens present in the patient, designing antigenic units for the patient and manufacturing a personalized anti-cancer vaccine for the patient, all prior to administration of the personalized anti-cancer vaccine.
In another embodiment, the methods of the invention comprise a vaccination induction period, wherein the anti-cancer vaccine is administered more frequently and/or at a higher dose, and a vaccination maintenance period, wherein the anti-cancer vaccine is administered less frequently and/or at a lower dose.
The actual dosages of each of the anti-cancer vaccine and checkpoint inhibitor administered in the methods of the invention will vary and will depend on the age, weight and general condition of the subject, the severity of the cancer being treated, the judgment of the health care professional, and the particular nature and characteristics of each anti-cancer vaccine and checkpoint inhibitor.
Exemplary lengths of time associated with the methods of treatment of the present invention include about 1-24 weeks, or about 6 to 12 months, or about 1 to 5 years.
The treatment methods of the present invention may be continued as long as the clinician supervising patient care considers the method to be effective and treatment is desired. Non-limiting parameters that indicate the method is effective include any one or more of the following: a decrease in disease progression or disease stabilization, i.e. a progression or non-progression of cancer at a slower rate. This includes tumors growing or not growing and/or spreading slower or not spreading, e.g. spreading to lymph nodes or forming metastases and/or not becoming more invasive. Other non-limiting parameters that suggest that this method is effective include tumor shrinkage (in terms of weight and/or volume); a reduction in the number of individual tumor colonies; tumor elimination; and progression free survival.
The response to the methods of treatment of the invention may be assessed at any suitable point during the course of treatment, e.g., after a single round of treatment, after 2-3 treatment cycles, etc., and may be assessed by any of a variety of suitable methods, including tumor shrinkage (partial response), i.e., assessing tumor size or volume, tumor disappearance, slowing disease progression or disease stabilization, and analyzing one or more tumor test markers, if appropriate.
In another embodiment, the methods of the invention are effective to inhibit the aggregation of regulatory T cells in a subject or to stimulate T cell and/or NK cell activity and/or proliferation of such cells in a subject.
Methods for determining whether a patient has responded to the methods of the present invention are known in the art. The change in tumor size may be determined by any suitable method, such as imaging. Various diagnostic imaging modalities may be employed, such as computed tomography (CT scan), dual energy CDT, positron emission tomography, and MRI. Other secondary indicators of success of treatment include appropriate response (if applicable) to appropriate tumor markers, increased number of NK (natural killer) cells, increased number of T cells, or decreased number of regulatory T cells.
The methods of the invention may be the primary or may be an adjunct method of treating cancer in a patient. For example, the primary treatment may be surgical removal of a tumor, and the methods of the invention are used as adjunctive treatments before and/or after the surgery, alone or in combination with other treatments (e.g., chemotherapy or radiation therapy).
The methods of the invention are useful for treating patients suffering from cancer. For example, the patient may be responsive to an anti-cancer vaccine alone or a checkpoint inhibitor alone, but more responsive to administration of the combination. As a further example, the patient may have only a slight response to the anti-cancer vaccine, or only a slight response to the checkpoint inhibitor, but a response to the combination or a stronger response.
The methods of the invention can be used to treat patients suffering from solid or liquid cancers. Examples of solid cancers include cancers that form solid masses (e.g., tumors). Examples of liquid cancers include cancers present in body fluids, such as lymphomas or blood cancers. Examples of cancers that can be treated with the methods of the invention are breast cancer, ovarian cancer, colon cancer, prostate cancer, bone cancer, colorectal cancer, gastric cancer, lymphoma, malignant melanoma, liver cancer, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, thyroid cancer, renal cancer, cholangiocarcinoma, brain cancer, cervical cancer, bladder cancer, esophageal cancer, hodgkin's disease, and adrenocortical cancer.
Also disclosed herein are:
an anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit (e.g., a dimerization unit), and an antigenic unit comprising one or more cancer antigens; or (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and one or more checkpoint inhibitors for treating a subject having cancer, wherein an anti-cancer vaccine and one or more checkpoint inhibitors are administered to the subject.
Further, disclosed herein is also:
an anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, and an antigenic unit comprising one or more cancer antigens; or (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a multimeric protein consisting of a plurality of polypeptides as defined in (ii); and one or more checkpoint inhibitors for treating a subject having cancer, wherein the anti-cancer vaccine and the one or more checkpoint inhibitors are administered to the subject.
Further, disclosed herein is also:
an anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a dimerization unit, and an antigenic unit comprising one or more cancer antigens; or (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a dimeric protein consisting of two polypeptides as defined in (ii); and one or more checkpoint inhibitors for treating a subject having cancer, wherein the anti-cancer vaccine and the one or more checkpoint inhibitors are administered to the subject.
The anti-cancer vaccine, the one or more checkpoint inhibitors, and their respective administration to a subject are described in detail in the previous section of the present application.
Further, disclosed herein is:
(a) An anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets antigen presenting cells, a multimerization unit such as a dimerization unit, and an antigenic unit comprising one or more cancer antigens; or (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and (b) one or more checkpoint inhibitors, in the manufacture of a medicament for treating a subject having cancer, wherein the medicament is administered to the subject.
Further, disclosed herein is:
(a) An anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets antigen presenting cells, a multimerization unit, and an antigenic unit comprising one or more cancer antigens; or (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a multimeric protein consisting of a plurality of polypeptides as defined in (ii); (b) Use of one or more checkpoint inhibitors in the manufacture of a medicament for treating a subject suffering from cancer, wherein the medicament is administered to the subject.
Further, disclosed herein is:
(a) An anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets antigen presenting cells, a dimerization unit, and an antigenic unit comprising one or more cancer antigens; or (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a dimeric protein consisting of two polypeptides as defined in (ii); and (b) one or more checkpoint inhibitors, in the manufacture of a medicament for treating a subject having cancer, wherein the medicament is administered to the subject.
The anti-cancer vaccine, the one or more checkpoint inhibitors, and their respective administration to a subject are described in detail in the previous section of the present application.
Further, disclosed herein is:
(a) An anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets antigen presenting cells, a multimerization unit such as a dimerization unit, and an antigenic unit comprising one or more cancer antigens; or (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and (b) the use of one or more checkpoint inhibitors for treating a subject suffering from cancer.
Further, disclosed herein is:
(a) An anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets antigen presenting cells, a multimerization unit, and an antigenic unit comprising one or more cancer antigens; or (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a multimeric protein consisting of a plurality of polypeptides as defined in (ii); and (b) the use of one or more checkpoint inhibitors for treating a subject suffering from cancer.
Further, disclosed herein is:
(a) An anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets antigen presenting cells, a dimerization unit, and an antigenic unit comprising one or more cancer antigens; or (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a dimeric protein consisting of two polypeptides as defined in (ii); and (b) the use of one or more checkpoint inhibitors for treating a subject suffering from cancer.
The anti-cancer vaccine, the one or more checkpoint inhibitors and the treatment are described in detail in the previous section of the present application.
Further, disclosed herein is also:
an anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets antigen presenting cells, a multimerizing unit such as a dimerization unit, and an antigenic unit comprising one or more cancer antigens; or (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and one or more checkpoint inhibitors, when used to treat cancer.
Further, disclosed herein is also:
an anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, and an antigenic unit comprising one or more cancer antigens; or (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a multimeric protein consisting of a plurality of polypeptides as defined in (ii); and one or more checkpoint inhibitors, when used to treat cancer.
Further, disclosed herein is also:
an anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a dimerization unit, and an antigenic unit comprising one or more cancer antigens; or (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a dimeric protein consisting of two polypeptides as defined in (ii); and one or more checkpoint inhibitors, when used to treat cancer.
The anti-cancer vaccine, the one or more checkpoint inhibitors and the treatment are described in detail in the previous section of the present application.
Further, disclosed herein is:
(a) An anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets antigen presenting cells, a multimerization unit such as a dimerization unit, and an antigenic unit comprising one or more cancer antigens; or (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a multimeric protein consisting of a plurality of polypeptides as defined in (ii), such as a dimeric protein; and
(b) Use of one or more checkpoint inhibitors for the treatment of cancer.
Further, disclosed herein is:
(a) An anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets antigen presenting cells, a multimerization unit, and an antigenic unit comprising one or more cancer antigens; (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a multimeric protein consisting of a plurality of polypeptides as defined in (ii); and (b) the use of one or more checkpoint inhibitors for the treatment of cancer.
Further, disclosed herein is:
(a) An anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets antigen presenting cells, a dimerization unit, and an antigenic unit comprising one or more cancer antigens; (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a dimeric protein consisting of two polypeptides as defined in (ii); and (b) the use of one or more checkpoint inhibitors for the treatment of cancer.
The anti-cancer vaccine, the one or more checkpoint inhibitors and the treatment are described in detail in the previous section of the present application.
Further, disclosed herein is also:
a medicament for treating cancer in a subject having cancer by administering to the subject (a) an anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets antigen presenting cells, a multimerizing unit such as a dimerization unit, and an antigenic unit comprising one or more cancer antigens; (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and (b) one or more checkpoint inhibitors.
Further, disclosed herein is also:
a medicament for treating cancer in a subject having cancer by administering to the subject (a) an anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets antigen presenting cells, a multimerizing unit, and an antigenic unit comprising one or more cancer antigens; (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a multimeric protein consisting of a plurality of polypeptides as defined in (ii); and (b) one or more checkpoint inhibitors.
Further, disclosed herein is also:
a medicament for treating cancer in a subject having cancer by administering to the subject (a) an anti-cancer vaccine comprising (i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets antigen presenting cells, a dimerization unit, and an antigenic unit comprising one or more cancer antigens; (ii) a polypeptide encoded by a polynucleotide as defined in (i); or (iii) a dimeric protein consisting of two polypeptides as defined in (ii); and (b) one or more checkpoint inhibitors.
The anti-cancer vaccine, the one or more checkpoint inhibitors, their respective administration to a subject, and treatment are described in detail in the previous section of this application.
Kit for detecting a substance in a sample
In another aspect, the invention provides a kit comprising
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit such as a dimerization unit, and an antigenic unit comprising one or more cancer antigens; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and
(b) One or more checkpoint inhibitors.
In one embodiment, the invention provides a kit comprising
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, and an antigenic unit comprising one or more cancer antigens; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein consisting of a plurality of polypeptides defined in (ii); and
(b) One or more checkpoint inhibitors.
In another embodiment, the invention provides a kit comprising
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a dimerization unit, and an antigenic unit comprising one or more cancer antigens; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A dimeric protein consisting of two polypeptides as defined in (ii); and
(b) One or more checkpoint inhibitors.
In another embodiment, the invention provides a kit comprising
(a) An anti-cancer vaccine contained in one or more containers, wherein the anti-cancer vaccine comprises
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, such as a dimerization unit, and an antigenic unit comprising one or more cancer antigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and
(b) One or more checkpoint inhibitors contained in one or more second containers.
The kit may further comprise one or more third containers comprising a pharmaceutically acceptable carrier or diluent, for example a carrier and diluent for reconstitution of the dose of (a) and/or (b).
In another embodiment, the invention provides a kit comprising
(a) An anti-cancer vaccine contained in one or more first containers, wherein the anti-cancer vaccine comprises
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, and an antigenic unit comprising one or more cancer antigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein consisting of a plurality of polypeptides defined in (ii); and
(b) One or more checkpoint inhibitors contained in one or more second containers.
The kit may further comprise one or more third containers comprising a pharmaceutically acceptable carrier or diluent, for example a carrier and diluent for reconstitution of the dose of (a) and/or (b).
In another embodiment, the invention provides a kit comprising
(a) An anti-cancer vaccine contained in one or more first containers, wherein the anti-cancer vaccine comprises
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a dimerization unit, and an antigenic unit comprising one or more cancer antigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A dimeric protein consisting of two polypeptides as defined in (ii); and
(b) One or more checkpoint inhibitors contained in one or more second containers.
The kit may further comprise one or more third containers comprising a pharmaceutically acceptable carrier or diluent, for example a carrier and diluent for reconstitution of the dose of (a) and/or (b).
The kit is for use in a method of treating a subject, such as a patient, having cancer, wherein the method comprises administering to the subject an anti-cancer vaccine and one or more checkpoint inhibitors contained in the kit.
The kit may further comprise instructions for use, including instructions for reconstitution of the dosages of (a) and (b), instructions for administration and/or instructions for determining the appropriate dosages of (a) and (b), and/or instructions for administration of (a) and (b), and/or instructions for the frequency and schedule of administration of (a) and (b).
Anticancer vaccine contained in the kit of the invention
The anti-cancer vaccine contained in the kit is described in detail above in the present application.
In the kit of the first embodiment, the anti-cancer vaccine contained in the kit is provided in a first container comprising the polynucleotide/polypeptide/dimer protein, and a second container contained in the kit comprises a pharmaceutically acceptable carrier or diluent, including, but not limited to, saline, buffered saline such as PBS, dextrose, water, glycerol, ethanol, sterile isotonic aqueous buffer, and combinations thereof. The kit further includes instructions on how to combine the contents of the first and second containers prior to administration to reconstitute the anti-cancer vaccine dose for that administration.
In one embodiment, the kit comprises one such first container and one such second container for reconstitution of a single dose of an anti-cancer vaccine. In another embodiment, the kit comprises a plurality of such first containers and a plurality of such second containers for reconstituting a plurality of doses of the anti-cancer vaccine for repeated administration. In yet another embodiment, the kit comprises a plurality of such first containers and one such second container for reconstituting a plurality of doses of the anti-cancer vaccine for repeated administration, wherein the second container comprises sufficient contents for reconstituting the anti-cancer vaccine contained in the plurality of first containers. The repeated dose may be a series of doses, for example, administered over a period of days, weeks or months.
The container included in the kit of the first embodiment may be any container suitable for containing an anti-cancer vaccine or a pharmaceutically acceptable carrier.
In the kit of the second embodiment, the anti-cancer vaccine contained in the kit is provided in a container, i.e., a single container, comprising a composition comprising the polynucleotide/polypeptide/dimer protein and a pharmaceutically acceptable carrier or diluent, including but not limited to saline, buffered saline such as PBS, dextrose, water, glycerol, ethanol, sterile isotonic aqueous buffer, and combinations thereof. Thus, the anti-cancer vaccine may be in a form ready for administration, or it may require further dilution with a pharmaceutically acceptable carrier or diluent, which may be an additional component in the kit, for example, immediately prior to administration.
The kit of the second embodiment may comprise one or more containers, e.g. one container for a single dose or a plurality of containers for repeated doses, e.g. a series of doses, e.g. for use over a period of days, weeks or months.
The container included in the kit of the second embodiment may be any container suitable for containing an anti-cancer vaccine and a pharmaceutically acceptable carrier.
The pharmaceutically acceptable carrier or diluent of the first embodiment or the anti-cancer vaccine of the second embodiment may further comprise an adjuvant. In particular for anti-cancer vaccines comprising polypeptides/proteins, pharmaceutically acceptable adjuvants include, but are not limited to, poly-ICLC, 1018ISS, aluminum salts, amplivax, AS15, BCG, CP-870, 893, cpG7909, cyaA, dSLIM, GM-CSF, IC30, IC31, imiquimod, imuFact EV 1P 321, IS Patch, ISS, ISCOMATRIX, juvlmmune, lipoVac, MF59, monophosphoryl lipid A, montanide IMS1312, montanide ISA 206, montanide ISA 50V, montanide ISA-51, OK-432, OM-174, OM-197-MP-EC, ONTAK, PLGA microparticles, requimod, SRL172, virions and other virus-like particles, YF-17D, VEGF trap, R848, beta-glucan, pam3Cys, aquila's QS21 spike, vadizman and/or AsA404 (DMXAA).
For an anti-cancer vaccine comprising a polynucleotide, the pharmaceutically acceptable carrier or diluent or anti-cancer vaccine may comprise molecules that are amenable to cell transfection.
The kits of the first and second embodiments preferably comprise instructions for administering an anti-cancer vaccine to a subject (e.g., patient) in need thereof.
In one embodiment, the first container of the kit of the first embodiment or the single container of the kit of the second embodiment comprises an anti-cancer vaccine comprising a polynucleotide, and the second container of the kit of the first embodiment or the single container of the kit of the second embodiment comprises a pharmaceutically acceptable carrier. In a further preferred embodiment, the kit of the first and second embodiments comprises instructions for intramuscular or intradermal injection of the anti-cancer vaccine.
The first container of the kit of the first embodiment or the single container of the kit of the second embodiment typically comprises 0.3mg to 6mg, for example about 2mg (if the anti-cancer vaccine is a polynucleotide); and about 5 μg to 5mg (if the anti-cancer vaccine is a polypeptide/dimer protein).
Checkpoint inhibitors comprised in the kit of the invention
The one or more checkpoint inhibitors contained in the kit are described in detail in the previous section of the present application.
In one embodiment, the one or more checkpoint inhibitors contained in the kit are provided in one or more containers, e.g., each container contains one checkpoint inhibitor, or one container contains all checkpoint inhibitors. The kit further comprises one or more containers comprising a liquid suitable for injection (including infusion injection), e.g. sterile water, saline such as isotonic saline, a sugar solution for intravenous administration such as a dextrose solution, an electrolyte solution for intravenous administration such as ringer's lactate or ringer's acetate, or an aqueous buffer.
The kit preferably further comprises instructions on how to combine the contents of the one or more containers comprising the one or more checkpoint inhibitors with the contents of the one or more containers comprising a liquid suitable for injection, including infusion injection, to obtain a composition comprising the one or more checkpoint inhibitors ready for administration.
The composition may comprise a total amount of about 0.1mg/kg to about 1mg/kg, for example about 0.2mg/kg to about 0.9mg/kg, about 0.3mg/kg to about 0.8mg/kg, about 0.4mg/kg to about 0.7mg/kg, about 0.5mg/kg to about 0.6mg/kg, or about 1mg/kg to about 1000mg/kg, for example about 2mg/kg to about 900mg/kg, about 3mg/kg to about 800mg/kg, about 4mg/kg to about 700mg/kg, about 5mg/kg to about 600mg/kg, about 6mg/kg to about 550mg/kg, about 7mg/kg to about 500mg/kg, about 8mg/kg to about 450mg/kg, about 9mg/kg to about 400mg/kg, about 5mg/kg to about 200mg/kg, about 2mg/kg to about 150mg/kg, about 5mg/kg to about 100mg/kg, about 10mg to about 60mg/kg of the checkpoint inhibitor or about one or more of the checkpoint inhibitors.
The kit may comprise a plurality of containers suitable for a single dose of one or more checkpoint inhibitors, or a plurality of containers suitable for repeated doses of one or more checkpoint inhibitors, e.g. a series of doses, e.g. for a period of days, weeks or months.
In another embodiment, the kit comprises one or more containers comprising one or more checkpoint inhibitors in a composition suitable for injection (e.g., infusion injection), e.g., each container comprises one checkpoint inhibitor in a composition suitable for injection, or one container comprises all checkpoint inhibitors in a composition suitable for injection. Compositions suitable for injection comprise a suitable pharmaceutically acceptable carrier or diluent, for example sterile water, saline such as isotonic saline, a sugar solution for intravenous administration such as dextrose solution, an electrolyte solution for intravenous administration such as ringer's lactate or ringer's acetate or an aqueous buffer.
The composition may comprise a total amount of about 0.1mg/kg to about 1mg/kg, for example about 0.2mg/kg to about 0.9mg/kg, about 0.3mg/kg to about 0.8mg/kg, about 0.4mg/kg to about 0.7mg/kg, about 0.5mg/kg to about 0.6mg/kg, or about 1mg/kg to about 1000mg/kg, for example about 2mg/kg to about 900mg/kg, about 3mg/kg to about 800mg/kg, about 4mg/kg to about 700mg/kg, about 5mg/kg to about 600mg/kg, about 6mg/kg to about 550mg/kg, about 7mg/kg to about 500mg/kg, about 8mg/kg to about 450mg/kg, about 9mg/kg to about 400mg/kg, about 5mg/kg to about 200mg/kg, about 2mg/kg to about 150mg/kg, about 5mg/kg to about 100mg/kg, about 10mg to about 60mg/kg of the checkpoint inhibitor or about one or more of the checkpoint inhibitors.
The kit may comprise a plurality of containers suitable for a single dose of one or more checkpoint inhibitors, or a plurality of such containers suitable for repeated doses of one or more checkpoint inhibitors, e.g. a series of doses, e.g. for a period of days, weeks or months.
In one embodiment, the kit further comprises instructions for administering one or more checkpoint inhibitors, for example instructions for administering them by injection, for example subcutaneous, intravenous, intra-arterial, intratumoral, intralymphatic, intraperitoneal, intracardiac, intrathecal or intramuscular injection, or infusion injection.
Drawings
Fig. 1: FIGS. 1a and 1b show embodiments of anti-cancer vaccines for use in the methods of the present invention, described as polypeptides having an N-terminal start and a C-terminal end.
Figure 2 shows the results of example 2, i.e. the synergistic effect of administration of a checkpoint inhibitor anti-PD-L1 antibody, an anti-TIGIT antibody or a combination of anti-PD-L1 and anti-TIGIT antibodies and an anti-cancer vaccine VB4085 to mice challenged with CT26 tumor cells. The therapeutic effect of the combination therapy (measured as tumor volume) was compared to the therapeutic effect of the monotherapy (i.e. anti-cancer vaccine VB4085 or anti-PD-L1 antibody or anti-TIGIT antibody or anti-PD-L1 and anti-TIGIT antibody) and to the negative control VB 1026.
Figure 3 shows the results of example 2, i.e. the synergistic effect of administration of the checkpoint inhibitor anti-PD-L1 antibody, anti-TIGIT antibody or a combination of anti-PD-L1 and anti-TIGIT antibody and anti-cancer vaccine VB4085 to mice challenged with CT26 tumor cells. The therapeutic effect of the combination treatment (measured as% of days of survival following tumor challenge) was compared to the therapeutic effect of the monotherapy (i.e. anti-cancer vaccine VB4085 or anti-PD-L1 antibody or anti-TIGIT antibody or anti-PD-L1 and anti-TIGIT antibody) and to negative control VB 1026.
Figure 4 shows the results of example 3, i.e. the synergistic effect of the combined treatment of the checkpoint inhibitor anti-CTLA-4 antibody and the anti-cancer vaccine VB4085 administered to mice challenged with CT26 tumor cells. The therapeutic efficacy of the combination therapy (measured as tumor volume) was compared to the therapeutic effect of the monotherapy (i.e. the anti-cancer vaccine VB4085 or anti-CTLA-4 antibody) and to the negative control VB 1026.
Figure 5 shows the results of example 3, i.e. the synergistic effect of the combined treatment of the checkpoint inhibitor anti-CTLA-4 antibody and the anti-cancer vaccine VB4085 administered to mice challenged with CT26 tumor cells. The therapeutic efficacy of the combination therapy (measured as% of days of survival following tumor challenge) was compared to the therapeutic efficacy of the monotherapy (i.e. the anti-cancer vaccine VB4085 or anti-CTLA-4 antibody) and to the negative control VB 1026.
Examples
The foregoing written description is considered to be sufficient to enable one skilled in the art to practice the invention. The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way. 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 description and fall within the scope of the appended claims.
Example 1: design of anticancer vaccine
Two DNA constructs were designed comprising nucleotide sequences encoding the following units/elements:
anticancer vaccine VB4085:
the previously described exome sequencing and RNA sequencing of the mouse colon cancer cell line CT26 revealed hundreds to thousands of tumor-specific non-synonymous mutations. A computer-based method was used to identify potential immunogenic epitopes, i.e. epitopes containing mutations, and 20 of them (table 1) were selected to be included in the antigenic unit of VB 4085. Each epitope consists of 27 amino acids and is separated from each other by a linker. Thus, all epitopes except the terminal epitope are arranged in subunits, each consisting of one epitope and one flexible glycine-serine linker (GGGGSGGGGS (SEQ ID NO: 29)). VB4085 is the following model: (a) A personalized DNA anti-cancer vaccine comprising a plurality of patient-specific epitopes, e.g., a plurality of neo-epitopes and/or a plurality of patient-present consensus cancer epitopes, wherein the patient-present consensus cancer antigen is a mutated patient-present consensus cancer antigen, and (b) a ready-to-use DNA anti-cancer vaccine comprising a plurality of consensus cancer epitopes, wherein the consensus cancer antigen is a mutated consensus cancer antigen.
VB4085 consists of a DNA sequence encoding a polypeptide having the amino acid sequence SEQ ID NO. 1.
TABLE 1
Negative control VB1026:
the construct is identical to VB4085, but contains neither a unit linker nor an antigenic unit. It was used as a negative control. VB1026 consists of a DNA sequence encoding a polypeptide having the amino acid sequence of 1-237 of SEQ ID NO. 1.
All epitope gene sequences were purchased from Genescript (new jersey, usa) and cloned into the expression vector pucc 4a comprising the nucleotide sequences of the targeting unit and dimerization unit described above.
Example 2: embodiments of methods of treatment with the anti-cancer vaccine and checkpoint inhibitor of the invention against TIGIT and/or against PD-L1 in mice challenged with CT26 tumors compared to treatment with the anti-cancer vaccine or checkpoint inhibitor alone
The treatment protocol of this study is shown in table 2 below.
TABLE 2
x represents the administration of VB1026 and VB4085, respectively; represents administration of checkpoint inhibitors.
anti-PD-L1 antibodies (also referred to as anti-PD-L1 in this example section) were purchased from Bio X Cell, USA. The monoclonal antibody reacts with murine PD-L1 (anti-mouse PD-L1 antibody). anti-TIGIT antibodies (also referred to as anti-TIGIT in this example section) were purchased from Absolute Antibody, USA. The monoclonal antibody reacted with murine TIGIT (anti-mouse TIGIT antibody).
Treatment of Balb/c mice:
each of the a-H groups contained 10 mice, injected 5x10 on day 0 (D) by injection on the left leg 4 Individual tumor cells were inoculated with CT26 tumor cells. On days 0, 7, 13 and 27, mice were vaccinated intramuscularly with a total of 50 μg of construct VB4085 or negative control construct VB1026 (25 μg per tibialis anterior), followed by electroporation. anti-TIG was performed on days 10, 17, 24 and 31 by intraperitoneal injection of 200. Mu.g of each checkpoint inhibitor (i.e., 200. Mu.g of one of the anti-TIGIT or anti-PD-L1 antibodies, or 200. Mu.g of each of the anti-PD-L1 and anti-TIGIT antibodies, for groups E and H)Administration of IT and/or anti-PD-L1 antibodies. Tumor size was measured using calipers. Two-dimensional measurements, i.e. length and width, are made on the tumor and the height is set equal to the width. Tumor volume was calculated by the following formula: tumor volume = length (mm) x width (mm) x height (mm)/2000. The treatment ended on day 43.
Treatment results:
statistical significance was determined by using a two-way ANOVA statistical test and Tukey multiple comparison test.
Tumors in the group treated with VB4085 anti-cancer vaccine alone (group B) showed slower growth compared to the VB1026 negative control group (group a). However, there was no statistical difference in tumor growth difference between the two groups due to intra-group differences.
The difference in treatment efficacy (tumor growth) between the group treated according to the embodiment of the method of the invention (F-H group) and the VB1026 negative control group was statistically significant from day 26 throughout the course of the experiment (fig. 2) (F: p=0.01; g: p=0.005; H: p=0.003; p is the p value).
The difference in therapeutic efficacy (tumor growth) between group F, which received the combination of VB4085 anti-cancer vaccine and anti-TIGIT antibody (embodiment of the method of the invention), and group B, which was monotherapy with VB4085 anti-cancer vaccine, was statistically significant from day 34 onwards (fig. 2) (p=0.0004). .
The difference in therapeutic efficacy (tumor growth) between group G, which received the combination of VB4085 anti-cancer vaccine with anti-PD-L1 antibody (embodiment of the method of the invention), and group B, which was monotherapy with VB4085 anti-cancer vaccine, was statistically significant from day 28 onwards (fig. 2) (p=0.047).
The difference in therapeutic efficacy (tumor growth) between group H, which received the combination of VB4085 anti-cancer vaccine with anti-TIGIT antibody and anti-PD-L1 antibody (embodiment of the method of the invention), and group B, which received VB4085 monotherapy, was statistically significant from day 27 onwards (fig. 2) (p=0.032).
From day 26, the efficacy of treatment (as determined by tumor growth) in the group treated according to embodiments of the methods of the invention (F-H group) was significantly better in each group compared to their respective antibody monotherapy group (C-E group) (fig. 2).
Tumors in group H (embodiments of the methods of the invention) mice never even grew to large sizes, and some tumors were observed only at individual time points.
Furthermore, as shown in table 3 below and fig. 3, the survival (measured as number of deaths per group of mice) of mice treated according to embodiments of the methods of the invention (group F-H) was significantly better than mice that had been treated with an anti-cancer vaccine alone or with a checkpoint inhibitor (group B-E).
TABLE 3 Table 3
Number of deaths | ||
A | VB1026 | 9/10 |
B | VB4085 | 6/10 |
C | Anti TIGIT | 6/10 |
D | anti-PD-L1 | 7/10 |
E | anti-TIGIT + anti-PD-L1 | 7/10 |
F | VB4085+ anti-TIGIT | 1/10 |
G | VB4085+ anti-PD-L1 | 1/10 |
H | VB 4085+anti-TIGIT+anti-PD-L1 | 0/10 |
Conclusion:
tumor growth was on average slower in mice vaccinated with VB4085 anti-cancer vaccine as monotherapy (group B) compared to the negative control group treated with VB1026 (group a). This is consistent with previous studies of CT26 tumor challenge in mice vaccinated with VB4085 and suggests that this DNA anti-cancer vaccine could elicit an immune response against CT26 tumor cells, thereby reducing tumor growth.
Others have shown that CT26 cells express PD-L1 and that the amount of expression increases in response to IFN- γ exposure, suggesting that CT26 cells may evade immune surveillance through the PD-1/PD-L1 axis (Lau et al, nat. Commun 8,2017,1-11). The results of this study demonstrate that blocking PD-L1 by administration of a combination of an anti-PD-L1 antibody with an anti-cancer vaccine VB4085 results in increased anti-tumor efficacy and further reduced tumor growth compared to VB4085 anti-cancer vaccine monotherapy.
Previously, it was shown that treatment of mice vaccinated with CT26 tumor cells with anti-TIGIT antibodies reduced tumor growth (Johnston et al, cancer Cell 26 (6), 2014, 923-937). The results of this study demonstrate that blocking TIGIT signaling pathway by administration of the anti-TIGIT antibody in combination with anti-cancer vaccine VB4085 reduced the extent of tumor growth greater than VB4085 anti-cancer vaccine monotherapy.
In a CT26 tumor mouse model, combined targeting of TIGIT and PD-1/PD-L1 has been shown to be beneficial compared to targeting either checkpoint protein alone (Johnston et al, cancer Cell 26 (6), 2014, 923-937). These findings suggest that the mouse model evades immune surveillance through a variety of pathways. In this study we found that when a combination of anti-TIGIT and anti-PD-L1 antibodies is used, the inclusion of anti-cancer vaccine VB4085 into such treatment can significantly enhance the immune response against tumor cells. Such combination treatments according to embodiments of the methods of the invention exhibit better therapeutic efficacy (as determined by tumor growth and survival) compared to any of the three treatments alone.
Example 3: embodiments of methods of treatment with the anti-cancer vaccine and checkpoint inhibitor anti-CTLA-4 of the invention in mice challenged with CT26 tumors compared to treatment with anti-cancer vaccine or checkpoint inhibitor anti-CTLA-4 alone
Constructs VB4085 and VB1026 described in example 1 were used in this study. The treatment protocol of this study is shown in table 4 below.
TABLE 4 Table 4
x represents the separate administration of VB1026 and VB 4085; represents administration of checkpoint inhibitors.
anti-CTLA-4 (CD 152) antibodies (also referred to as anti-CTLA-4 in this example section) were purchased from Bio X Cell, USA. The monoclonal antibody reacts with murine CTLA-4 (anti-mouse CTLA-4 antibody).
Treatment of Balb/c mice:
each of the A-D groups contained 10 mice, on day 0 (D) by the left hand side5x10 subcutaneous injection in leg 4 Individual tumor cells these mice were vaccinated with CT26 tumor cells. On days 0, 8, 14 and 28 boost, mice were vaccinated intramuscularly with a total of 50 μg (boost of 25 μg) of construct VB4085 or negative control construct VB1026, 25 μg per tibialis anterior (25 μg for boost, right tibialis anterior) and then electroporated. Administration of anti-CTLA-4 antibodies was performed by intraperitoneal injection of 200 μg/mouse on days 11, 18, 26 and 32. Tumor size was measured using calipers. The tumor is measured in two dimensions, namely length and width, and the height is set equal to the width. Tumor volume was calculated by the following formula: tumor volume = length (mm) x width (mm) x height (mm)/2000. The experiment ended on day 39.
Treatment results:
statistical significance was determined by using a two-way ANOVA statistical test and Tukey multiple comparison test.
Differences in therapeutic effects (tumor growth) between VB4085 anti-cancer vaccine monotherapy (group B) and VB1026 negative control (group a) were statistically significant (p=0.0067) from day 26 and after (fig. 4).
The differences in therapeutic effect (tumor growth) between anti-CTLA-4 antibody monotherapy (group C) and VB1026 negative control (group a) were statistically significant (p=0.038) from day 32 and thereafter (fig. 4).
The difference in therapeutic efficacy (tumor growth) between group D, which received the combination of VB4085 anti-cancer vaccine and anti-CTLA-4 antibody (embodiment of the method of the invention), and group VB1026 negative control (group a) was statistically significant (p=0.025) from day 23 and thereafter (fig. 4).
The differences in treatment efficacy (tumor growth) between the group treated according to the embodiment of the method of the invention (group D) and group B monotherapy with the VB4085 anti-cancer vaccine were not statistically significant (p > 0.05) (figure 4).
The differences in therapeutic efficacy (tumor growth) between group D, which received the combination of VB4085 anti-cancer vaccine and anti-CTLA-4 antibody (embodiment of the method of the invention), and group C, which was monotherapy with anti-CTLA 4 antibody, were statistically significant (p=0.032) from day 32 onwards (fig. 4).
Furthermore, as shown in table 5 below and fig. 5, the survival (measured as number of deaths per group of mice) of mice treated according to embodiments of the methods of the invention (group D) was significantly better than mice treated with either the anti-cancer vaccine alone or the checkpoint inhibitor (group B and group C).
TABLE 5
Number of deaths | ||
A | VB1026 | 10/10 |
B | VB4085 | 3/9* |
C | anti-CTLA-4 | 6/10 |
D | VB4085+ anti-CTLA-4 | 0/10 |
* One animal in group VB4085 had to be euthanized on day 32 with spontaneous rectal prolapse. The animals did not develop tumors on day 32.
Conclusion:
tumor growth was significantly slower in mice vaccinated with VB4085 anti-cancer vaccine as monotherapy (group B) compared to the negative control group treated with VB1026 (group a). This is consistent with previous studies of CT26 tumor challenge in mice vaccinated with VB4085 and suggests that this DNA anti-cancer vaccine elicits an immune response against CT26 tumor cells, resulting in reduced tumor growth.
According to previous reports, others have shown anticancer efficacy in CT26 tumor challenged mice treated with anti-CTLA-4 antibody monotherapy (Pedersen et al, cancer Lett 235 (2), 2006,229-238, reviewed in Grosso et al, cancer Immun 13 (1), 2013,5).
The results of this study demonstrate that blocking CTLA-4 signaling pathway by administration of anti-CTLA-4 antibody as monotherapy elicits a partial anti-tumor response, whereas a significant increase in immune response against tumor cells was observed in mice treated with a combination of anti-CTLA-4 antibody and VB4085 anti-cancer vaccine, with 9 out of 10 mice having no tumor at the end of the study (day 39).
Such combination treatments according to embodiments of the methods of the invention exhibit better therapeutic efficacy (as determined by tumor growth and survival) compared to two different monotherapy treatments.
Example 4: embodiments of the therapeutic methods of the invention include administering a combination of a personalized DNA anti-cancer vaccine comprising vb10.neo and atilizumab
Adult patients were treated with a combination of a personalized DNA anti-cancer vaccine comprising vb10.neo with atilizumab. These patients have locally advanced and metastatic tumors that progress after at least 1 available standard of care; or standard treatment has proven ineffective or intolerable to it or is deemed unsuitable for it; or clinical trials of investigational drugs are accepted standards of care therefor.
In one embodiment, the patient has at least one of the following tumors: melanoma, NSCLC, RCC, UC, HNSCC, TNBC, gastric/GEJ cancer, cervical cancer, anal cancer or high MSI tumors
In one embodiment, vb10.neo (3 mg in a pharmaceutically acceptable carrier) is administered by intramuscular injection to induce a course of Q3W (4 doses), followed by maintenance doses Q6W (6 doses) and Q12W (5 doses). The atenolizumab 1200mg was administered by intravenous infusion on day 1 of the 21 day cycle.
In another embodiment, vb10.neo (6 mg in a pharmaceutically acceptable carrier) is administered by intramuscular injection to induce a course of Q3W (4 doses), followed by maintenance doses Q6W (6 doses) and Q12W (5 doses). The atenolizumab 1200mg was administered by intravenous infusion on day 1 of the 21 day cycle.
During and after treatment (from baseline up to 27 months), the main results were determined as follows:
incidence and severity of adverse events
Changes in the measurement of the following vital signs before and after the first vb10.neo injection for each cycle: systolic blood pressure (mmHg); diastolic pressure (mmHg); pulse rate (bpm); respiratory rate (breath/min); body temperature (DEG C).
Changes in clinical laboratory parameters for local analysis before and after the first vb10.neo injection per cycle, including hematology, chemical examination, coagulation, thyroid function test, C-reactive protein, urine analysis, and serology.
During and after treatment, the secondary results were determined as follows:
assessment of antigen-specific immune responses (from baseline to up to 25 months) resulting from vb10.Neo combined administration with atilizumab: the number and intensity of antigen-specific T cell responses before and after initiation of treatment;
Objective response rate (from baseline up to 27 months): determination of complete or partial response;
response duration (from baseline up to 27 months): the time from the first recorded objective response to disease progression or death (based on the first producer) due to any cause;
progression free survival (from baseline up to 27 months): the time from the first treatment to the first occurrence of disease progression or death (based on the first occurrence) due to any cause;
total survival (from baseline up to 27 months): the time from the first treatment to death due to any cause;
determining serum concentration of atilizumab at the indicated time point (starting from baseline up to 25 months);
prevalence of anti-drug antibodies against atilizumab (ADA) at baseline (prevaliance) and incidence of ADA against atilizumab (axidence) (from baseline up to 25 months).
In one embodiment, the method of treatment comprises administering to a patient in need thereof an effective amount of a combination of a personalized DNA anti-cancer vaccine comprising vb10.neo and atilizumab.
In some embodiments, the patient has at least one of the following tumor types: melanoma, NSCLC, RCC, UC, HNSCC, TNBC, gastric/GEJ cancer, cervical cancer, anal cancer or high MSI tumor. In some embodiments, the patient has a localized advanced or metastatic tumor that progresses after at least 1 available standard of care; and/or standard treatment has proven ineffective or intolerable to it or is deemed unsuitable for it; and/or clinical trials of the investigational drug are approved standards of care therefor.
In some embodiments, the effective amount is vb10.Neo (3 mg in a pharmaceutically acceptable carrier) administered by intramuscular injection for an induction course of Q3W (4 doses), followed by maintenance doses Q6W (6 doses) and Q12W (5 doses), and atilizumab 1200mg administered by intravenous infusion on day 1 of the 21 day cycle. In some embodiments, vb10.Neo (6 mg in a pharmaceutically acceptable carrier) is administered by intramuscular injection for an induction course of Q3W (4 doses), followed by maintenance doses Q6W (6 doses) and Q12W (5 doses), and atenolizumab 1200mg is administered by intravenous infusion on day 1 of a 21 day cycle.
In some embodiments, the method of treatment results in improved Overall Response Rate (ORR) and/or improved duration of response (DOR) and/or improved Progression Free Survival (PFS) and/or improved Overall Survival (OS) compared to a reference population. In some embodiments, the reference population is a population treated with a tumor standard of care (SOC).
Sequence(s)
SEQ ID NO:1
VB4085 (amino acids 1-972)/VB 1026 (amino acids 1-237).
M 1 QVSTAALAVLLCTMALCNQVLS 23 A 24 PLAADTPTACCFSYTSRQIPQNFIADYFETSSQCSKPSVIFLTKRGRQVCADPSEEWVQKYVSDLELSA 93 E 94 LKTPLGDTTHT 105 E 106 PKSCDTPPPCPRCP 120 G 121 GGSSGGGSG 1 30 G 131 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGK 237 G 238 LGGL 242 STMLYIRALKNPSLYGFSSGLNKDGIEGGGGSGGGGSGALKKLIYAAKLNTSLKALEGERNQVYGGGGSGGGGSDLVCDFQSFKYYAHATSLAGHLVSCPLGGGGSGGGGSEKLRNPCPNKEKAYQPPFAFRHVLKLTGGGGSGGGGSDTLSAMSNPRAMQVLLQIQQGLQTLATGGGGSGGGGSGDVKIHAHKVVLANISPYFKAMFTGNLGGGGSGGGGSEVIQTSKYYMRDVIAIESAWLLELAPHGGGGSGGGGSFFSFFTHRFGHHVSPQVHIILANLYLLGGGGSGGGGSVILPQAPSGPSYATYLQPAQAQMLTPPGGGGSGGGGSLWVYLRPVPRPATIYLQILRLKPLTGEGGGGSGGGGSFVSPMAHYVPGIMAIESVVARFQFIVPGGGGSGGGGSTLAFLVLSTPAMFNRALKPFLKSCHFQGGGGSGGGGSFLERPMDMPYMIFYPNNPLMTGQLLGSGGGGSGGGGSIPREVGDGTRVDPFPPVQTWMRLPKLVGGGGSGGGGSGSLFGSSRVQYVVNPAVKIVFLNIDPSGGGGSGGGGSNNLQKYIEIYVQKINPSRLPVVIGGLLGGGGSGGGGSAEYGDYQPEVHGVPYFRLEHYLPARVMGGGGSGGGGSTPLRKHTVHAIRKFYLEFKGSSPPPRLGGGGSGGGGSKIYEFDYHLYGQNITMIMTSVSGHLLAGGGGSGGGGSKSWIHCWKYLSVQSQLFRGSSLLFRRV
SEQ ID NO:2
Signal peptides
MNFGLRLIFLVLTLKGVQC
SEQ ID NO:3
Signal peptides
MDAMKRGLCCVLLLCGAVFVSP
SEQ ID NO:4
Nucleotide sequence encoding amino acids 1-23 of SEQ ID NO. 1
ATGCAGGTCTCCACTGCTGCCCTTGCCGTCCTCCTCTGCACCATGGCTCTCTGCAACCAGGTCCTCTCT
SEQ ID NO 5:
Nucleotide sequence encoding amino acids 24-93 of SEQ ID NO. 1
GCACCACTTGCTGCTGACACGCCGACCGCCTGCTGCTTCAGCTACACCTCCCGACAGATTCCACAGAATTTCATAGCTGACTACTTTGAGACGAGCAGCCAGTGCTCCAAGCCCAGTGTCATCTTCCTAACCAAGAGAGGCCGGCAGGTCTGTGCTGACCCCAGTGAGGAGTGGGTCCAGAAATACGTCAGTGACCTGGAGCTGAGTGCC
SEQ ID NO 6:
Nucleotide sequence encoding amino acids 94-105 of SEQ ID NO. 1
GAGCTCAAAACCCCACTTGGTGACACAACTCACACA
SEQ ID NO 7:
Nucleotide sequence encoding amino acids 106-120 of SEQ ID NO. 1
GAGCCCAAATCTTGTGACACACCTCCCCCGTGCCCAAGGTGCCCA
SEQ ID NO:8
Nucleotide sequence encoding amino acids 94-120 of SEQ ID NO. 1
GAGCTCAAAACCCCACTTGGTGACACAACTCACACAGAGCCCAAATCTTGTGACACACCTCCCCCGTGCCCAAGGTGCCCA
SEQ ID NO 9:
Nucleotide sequence encoding amino acids 121-130 of SEQ ID NO. 1
GGCGGTGGAAGCAGCGGAGGTGGAAGTGGA
SEQ ID NO 10:
Nucleotide sequence encoding amino acids 131-237 of SEQ ID NO. 1
GGACAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAGCGGGCAGCCGGAGAACAACTACAACACCACGCCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACATCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCGCTTCACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
SEQ ID NO 11:
Nucleotide sequence encoding amino acids 238-242 of SEQ ID NO. 1
GGCCTCGGTGGCCTG
SEQ ID NO 12:
Nucleotide sequence encoding amino acids 94-237 of SEQ ID NO. 1
GAGCTCAAAACCCCACTTGGTGACACAACTCACACAGAGCCCAAATCTTGTGACACACCTCCCCCGTGCCCAAGGTGCCCAGGCGGTGGAAGCAGCGGAGGTGGAAGTGGAGGACAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAGCGGGCAGCCGGAGAACAACTACAACACCACGCCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACATCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCGCTTCACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
SEQ ID NO 13:
Heavy chain amino acid sequence of atilizumab
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO 14:
Light chain amino acid sequence of atilizumab
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO 15:
HVR-H1 of atilizumab
GFTFSDSWIH
SEQ ID NO 16:
HVR-H21 of Abilizumab
AWISPYGGSTYYADSVKG
SEQ ID NO 17:
HVR-H3 of Abilizumab
RHWPGGFDY
SEQ ID NO 18:
HVR-L1 of atilizumab
RASQDVSTAVA
SEQ ID NO 19:
HVR-L2 of atilizumab
SASFLYS
SEQ ID NO 20:
HVR-L3 of atilizumab
QQYLYHPAT
SEQ ID NO 21:
HV of Abilizumab
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS
SEQ ID NO:22
Africizumab HL
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR
SEQ ID NO:23
Nucleic acid sequence of VB10.NEO
ATGCAGGTCTCCACTGCTGCCCTTGCCGTCCTCCTCTGCACCATGGCTCTCTGCAACCAGGTCCTCTCTGCACCACTTGCTGCTGACACGCCGACCGCCTGCTGCTTCAGCTACACCTCCCGACAGATTCCACAGAATTTCATAGCTGACTACTTTGAGACGAGCAGCCAGTGCTCCAAGCCCAGTGTCATCTTCCTAACCAAGAGAGGCCGGCAGGTCTGTGCTGACCCCAGTGAGGAGTGGGTCCAGAAATACGTCAGTGACCTGGAGCTGAGTGCCGAGCTCAAAACCCCACTTGGTGACACAACTCACACAGAGCCCAAATCTTGTGACACACCTCCCCCGTGCCCAAGGTGCCCAGGCGGTGGAAGCAGCGGAGGTGGAAGTGGAGGACAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAGCGGGCAGCCGGAGAACAACTACAACACCACGCCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACATCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCGCTTCACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAGGCCTCGGTGGCCTG
SEQ ID NO:113
Nucleic acid sequences derived from the tetramerization unit of p53
AAGCCTCTGGACGGAGAGTATTTCACTCTCCAGATCCGGGGCCCCGAAAGGTTCGAAATGTTCCGGGAGCTTAACGAGGCCTTGGAGCTGAAAGACGCACAGGCCGGAAAGGAACCG
SEQ ID NO:114
HEYGAEALERAG
SEQ ID NO:115
Nucleic acid sequences of CLEC9 ligands
TGGCCCAGGTTCCACAGCAGCGTGTTCCACACCCAC
SEQ ID NO:116
Nucleic acid sequences of trimerization domains derived from human collagen
GCTGGGCAGGTGAGGATCTGGGCCACATACCAGACCATGCTGGACAAGATCCGGGAGGTGCCGGAGGGCTGGCTCATCTTTGTGGCCGAGAGGGAAGAGCTCTATGTACGCGTTAGAAATGGCTTCCGGAAGGTGCTGCTGGAGGCCCGGACAGCCCTCCCGAGAGGCACGGGCAATGAG
SEQ ID NO:117
The trimerisation unit is the C-terminal domain of T4 fibrin
GYIPEAPRDGQAYVRKDGEWVLLSTFL
SEQ ID NO:119
Nucleic acid sequences derived from the hinge region of IgM
GCCGAACTCCCGCCCAAGGTGTCCGTGTTCGTCCCTCCCCGCGATGGGTTCTTCGGCAATCCACGAAAATCCAAACTGATTTGTCAGGCCACCGGCTTCTCCCCCCGACAGATCCAGGTGAGTTGGCTACGAGAGGGTAAACAGGTGGGGAGCGGAGTGACCACTGACCAGGTGCAGGCCGAGGCCAAGGAAAGCGGACCCACAACATACAAAGTGACAAGCACTCTGACGATTAAGGAGTCAGACTGGCTCGGCCAATCCATGTTTACATGCCGGGTTGATCACAGAGGGTTGACCTTCCAACAGAACGCATCCAGTATGTGCGTTCCAGAT
SEQ ID NO:120
Nucleic acid sequence of dHLX protein
GGAGAACTGGAGGAATTACTTAAACATCTCAAGGAGTTGCTCAAAGGCCCTAGGAAGGGAGAACTGGAGGAACTCCTCAAACATCTCAAGGAGTTACTAAAGGGA
SEQ ID NO:121
mCCL19
ATGGCCCCCCGTGTGACCCCACTCCTGGCCTTCAGCCTGCTGGTTCTCTGGACCTTCCCAGCCCCAACTCTGGGGGGTGCTAATGATGCGGAAGACTGCTGCCTGTCTGTGACCCAGCGCCCCATCCCTGGGAACATCGTGAAAGCCTTCCGCTACCTTCTTAATGAAGATGGCTGCAGGGTGCCTGCTGTTGTGTTCACCACACTAAGGGGCTATCAGCTCTGTGCACCTCCTGACCAGCCCTGGGTGGATCGCATCATCCGAAGACTGAAGAAGTCTTCTGCCAAGAACAAAGGCAACAGCACCAGAAGGAGCCCTGTGTCT
Description of the embodiments
1. A method for treating a subject having cancer, the method comprising administering to the subject
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, such as a dimerization unit, and an antigenic unit comprising one or more cancer antigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and
(b) One or more checkpoint inhibitors.
2. The method of embodiment 1, wherein the anti-cancer vaccine is a personalized anti-cancer vaccine.
3. The method of embodiment 2, wherein the antigenic unit comprises one or more neoantigens or parts thereof.
4. The method of embodiment 3, wherein the antigenic units comprise one or more portions of one or more neoantigens.
5. The method of embodiment 4, wherein the moiety is a neoepitope.
6. The method of embodiment 5, wherein the antigenic unit comprises a plurality of neo-epitopes, e.g., a plurality of neo-epitopes separated from each other by a linker.
7. The method of any one of embodiments 5 to 6, wherein the antigenic unit comprises n-1 antigenic subunits and a terminal neoepitope, each subunit comprising a neoepitope and a subunit linker, wherein n is the number of neoepitopes in the antigenic unit and n is an integer from 1 to 50.
8. The method according to any one of embodiments 5 to 7, wherein the neoepitope has a length of 7 to 30 amino acids, e.g. 7 to 10 amino acids (e.g. 7, 8, 9 or 10 amino acids) or 13 to 30 amino acids (e.g. 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 amino acids), e.g. 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids.
9. The method of any one of embodiments 3-8, wherein the antigenic unit further comprises a consensus cancer antigen or portion thereof present in one or more patients.
10. The method of embodiment 9, wherein the antigenic units further comprise one or more portions of a common cancer antigen present in one or more patients.
11. The method of embodiment 10, wherein the moiety is an epitope.
12. The method of embodiment 11, wherein the antigenic unit further comprises a plurality of epitopes.
13. The method of any one of embodiments 9 to 12, wherein the patient has a consensus cancer antigen selected from the group consisting of an overexpressed or aberrantly expressed human cellular protein, a cancer testis antigen, a differentiation antigen, a viral antigen, a mutated oncogene, a mutated tumor suppressor gene, a carcinoembryonic antigen, a consensus intron retention antigen, a consensus antigen resulting from a frameshift mutation, a dark matter antigen, and a consensus antigen resulting from a splice mutation.
14. The method of embodiment 2, wherein the antigenic units comprise a consensus cancer antigen or portion thereof present in one or more patients.
15. The method of embodiment 14, wherein the antigenic units comprise one or more portions of a common cancer antigen present in one or more patients.
16. The method of embodiment 15, wherein the moiety is an epitope.
17. The method of embodiment 16, wherein the antigenic unit comprises a plurality of epitopes.
18. The method of any one of embodiments 14 to 17, wherein the patient has a consensus cancer antigen selected from the group consisting of an overexpressed or aberrantly expressed human cellular protein, a cancer testis antigen, a differentiation antigen, a viral antigen, a mutated oncogene, a mutated tumor suppressor gene, a carcinoembryonic antigen, a consensus intron retention antigen, a consensus antigen resulting from a frameshift mutation, a dark matter antigen, and a consensus antigen resulting from a splice mutation.
19. The method of embodiment 1, wherein the anti-cancer vaccine is a non-personalized anti-cancer vaccine.
20. The method of embodiment 19, wherein the antigenic units comprise one or more consensus cancer antigens or portions thereof.
21. The method of embodiment 20, wherein the antigenic units comprise one or more portions of one or more common cancer antigens.
22. The method of embodiment 21, wherein the moiety is an epitope.
23. The method of embodiment 22, wherein the antigenic unit comprises a plurality of epitopes.
24. The method according to any one of embodiments 20 to 23, wherein the consensus cancer antigen is selected from the group consisting of an overexpressed or aberrantly expressed human cellular protein, a cancer testis antigen, a differentiation antigen, a viral antigen, a mutated oncogene, a mutated tumor suppressor gene, a carcinoembryonic antigen, a consensus intron retention antigen, a consensus antigen resulting from frameshift mutations, a dark matter antigen, and a consensus antigen resulting from spliceosome mutations, a monoclonal Ig-derived scFv derived from myeloma or lymphoma, a telomerase, an HIV antigen, tyrosinase, a tyrosinase-related protein (TRP) -1, TRP-2, a melanoma antigen, a prostate-specific antigen, and an HPV antigen.
25. The method according to any one of embodiments 1 to 24, wherein the antigenic unit comprises up to 3500 amino acids, e.g. about 21 to about 2000 amino acids or about 60 to 3500 amino acids, e.g. about 80 or about 100 or about 150 amino acids to about 3000 amino acids, e.g. about 200 to about 2500 amino acids, e.g. about 300 to about 2000 amino acids or about 400 to about 1500 amino acids or about 500 to about 1000 amino acids.
26. The method of any one of embodiments 1 to 25, wherein the targeting unit is or comprises a moiety that interacts with a surface molecule on an antigen presenting cell.
27. The method of embodiment 26, wherein the surface molecule is selected from the group consisting of HLA, CD14, CD40, CLEC9A, a chemokine receptor such as CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8 or XCR1, and a Toll-like receptor such as TLR-2, TLR-4 or TLR-5.
28. The method of any one of embodiments 26 and 27, wherein the targeting unit comprises or consists of: soluble CD40 ligand, CCL4 and isoforms thereof, CCL5, CCL19, CCL20, CCL21, macrophage inflammatory protein a includes isoforms thereof, such as mouse CCL3, human CCL3L1, human CCL3L2, and human CCL3L3, XCL1, XCL2, flagellin, anti-HLA-DP, anti-HLA-DR, anti-pan HLA class II anti-CD 40, anti-TLR-2, anti-TLR-4, anti-TLR-5, or anti-CLEC 9A.
29. The method of embodiment 28, wherein the targeting unit comprises or consists of human MIP-1α (ld78β, CCL3L 1).
30. The method according to embodiment 29, wherein the targeting unit comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 24-93 of SEQ ID No. 1, such as comprising the amino acid sequence of 26-93 of SEQ ID No. 1 or comprising the amino acid sequence of 28-93 of SEQ ID No. 1.
31. The method according to embodiment 30, wherein the targeting unit consists of an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 24-93 of SEQ ID No. 1, e.g. consisting of the amino acid sequence of 26-93 of SEQ ID No. 1 or consisting of the amino acid sequence of 28-93 of SEQ ID No. 1.
32. The method of embodiment 31, wherein the targeting unit consists of the amino acid sequence of 24-93 of SEQ ID NO. 1.
33. The method according to any one of embodiments 1 to 32, wherein the multimerization unit, e.g. the dimerization unit, comprises a hinge region, e.g. hinge exon h1 and hinge exon h4.
34. The method of embodiment 33, wherein the hinge region has the ability to form one or more covalent bonds.
35. The method of any one of embodiments 33 to 34, wherein the hinge region is Ig-derived.
36. The method of any one of embodiments 33 to 35, wherein the anti-cancer vaccine comprises a dimerization unit and the dimerization unit further comprises another domain that promotes dimerization.
37. The method according to embodiment 36, wherein the further domain is an immunoglobulin domain, preferably an immunoglobulin constant domain.
38. The method according to any one of embodiments 36 to 37, wherein the further domain is a carboxy-terminal C domain derived from IgG, preferably from IgG 3.
39. The method according to any one of embodiments 36 to 38, wherein the dimerization unit further comprises a dimerization unit linker, such as a glycine-serine rich linker, such as GGGSSGGGSG (SEQ ID NO: 118).
40. The method of embodiment 39, wherein the dimerization unit linker connects the hinge region and another domain that promotes dimerization.
41. The method of any one of embodiments 36 to 40, wherein the dimerization unit comprises hinge exon h1 and hinge exon h4, a dimerization unit linker and a CH3 domain of human IgG 3.
42. The method of embodiment 41, wherein the dimerization unit comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 94-237 of SEQ ID NO. 1.
43. The method of embodiment 42, wherein the dimerization unit consists of an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 94-237 of SEQ ID NO. 1.
44. The method of embodiment 43, wherein the dimerization unit consists of the amino acid sequence of 94-237 of SEQ ID NO. 1.
45. The method of any one of embodiments 1 to 44, wherein the anti-cancer vaccine further comprises a unit linker connecting the antigenic units to the multimerization units, e.g., the dimerization units, and wherein the unit linker is a non-immunogenic linker and/or a flexible or rigid linker.
46. The method of any one of embodiments 1 to 45, wherein the anti-cancer vaccine is a polynucleotide, preferably RNA or DNA.
47. The method of embodiment 46, wherein the polynucleotide further comprises a nucleotide sequence encoding a signal peptide.
48. The method of embodiment 47, wherein the signal peptide is selected from the group consisting of an Ig VH signal peptide, a human TPA signal peptide, and a human MIP-1 a signal peptide.
49. The method according to any one of embodiments 47 to 48, wherein the signal peptide comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of 1-23 of SEQ ID NO. 1.
50. The method according to embodiment 49, wherein the signal peptide consists of an amino acid sequence having at least 85% sequence identity to the amino acid sequence of 1-23 of SEQ ID NO. 1.
51. The method of embodiment 50, wherein the signal peptide consists of the amino acid sequence of 1-23 of SEQ ID NO. 1.
52. The method according to any one of embodiments 46 to 51, wherein the polynucleotide is DNA.
53. The method of embodiment 52, wherein the polynucleotide is DNA, which is contained in a vector.
54. The method of any one of embodiments 1 to 53, wherein the anti-cancer vaccine further comprises a pharmaceutically acceptable carrier or diluent.
55. The method of any one of embodiments 1 to 45, wherein the anti-cancer vaccine is a polypeptide or a multimeric protein, such as a dimeric protein.
56. The method of embodiment 55, wherein the anti-cancer vaccine further comprises a pharmaceutically acceptable carrier or diluent.
57. The method of embodiment 56, wherein the anti-cancer vaccine further comprises an adjuvant.
58. The method of any one of embodiments 1-57, wherein the one or more checkpoint inhibitors are selected from the group consisting of an anti-PD-L1 antibody, an anti-TIGIT antibody, an anti-CTLA-4 antibody, and an anti-PD 1 antibody, e.g., wherein the checkpoint inhibitor is an anti-PD-L1 antibody or an anti-TIGIT antibody or an anti-CTLA-4 antibody or an anti-PD-1 antibody or an anti-TIGIT antibody or an anti-PD-4 antibody or an anti-TIGIT antibody or an anti-PD-1 antibody and an anti-CTLA-4 antibody or an anti-TIGIT antibody and an anti-PD-L1 antibody or an anti-PD-1 antibody and an anti-PD-1 antibody, or an anti-PD-1 antibody and an anti-TIGIT antibody, or an anti-PD-1 antibody, or an anti-TIGIT antibody, or an anti-PD-L1 antibody, or an anti-TIGIT antibody, or an anti-PD-1 antibody, or an anti-TIGIT antibody, anti-CTLA-1 antibody and an anti-TIGIT antibody, or an anti-CTLA-4 antibody, or an anti-TIGIT 1 antibody.
59. The method of embodiment 58, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.
60. The method of embodiment 58, wherein the checkpoint inhibitor is an anti-TIGIT antibody.
61. The method of embodiment 58, wherein the checkpoint inhibitor is an anti-PD-L1 antibody and an anti-TIGIT antibody.
62. The method of embodiment 58, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.
63. The method of any one of embodiments 1 to 62, wherein the one or more checkpoint inhibitors are comprised in a composition suitable for injection, such as infusion injection.
64. The method of any one of embodiments 1-63, wherein the one or more checkpoint inhibitors are administered concurrently with an anti-cancer vaccine.
65. The method of any one of embodiments 1 to 62, wherein the one or more checkpoint inhibitors are administered prior to the first administration of the anti-cancer vaccine.
66. The method of any one of embodiments 1-62, wherein the anti-cancer vaccine is administered prior to the first administration of the one or more checkpoint inhibitors.
67. The method of any one of embodiments 1 to 66, wherein each anti-cancer vaccine and one or more checkpoint inhibitors are administered in repeated doses.
68. The method of any one of embodiments 1-67, wherein the cancer is a solid cancer or a liquid cancer.
69. The method of any one of embodiments 1-68, wherein the cancer is selected from breast cancer, ovarian cancer, colon cancer, prostate cancer, bone cancer, colorectal cancer, gastric cancer, lymphoma, malignant melanoma, liver cancer, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, thyroid cancer, renal cancer, bile duct cancer, brain cancer, cervical cancer, bladder cancer, esophageal cancer, hodgkin's disease, and adrenocortical cancer.
70. A kit comprising
(a) An anticancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit such as a dimerization unit, and an antigenic unit comprising one or more cancer antigens; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and
(b) One or more checkpoint inhibitors.
71. The kit of embodiment 70, wherein the anti-cancer vaccine is a personalized anti-cancer vaccine.
72. The kit of embodiment 71, wherein the antigenic unit comprises one or more neoantigens or parts thereof.
73. The kit of embodiment 72, wherein the antigenic units comprise one or more portions of one or more neoantigens.
74. The kit of embodiment 73, wherein the moiety is a neoepitope.
75. The kit of embodiment 74, wherein the antigenic unit comprises a plurality of neo-epitopes, e.g., a plurality of neo-epitopes separated from each other by a linker.
76. The kit of any one of embodiments 74 and 75, wherein the antigenic unit comprises n-1 antigenic subunits and a terminal neoepitope, each subunit comprising a neoepitope and a subunit linker, wherein n is the number of neoepitopes in the antigenic unit and n is an integer from 1 to 50.
77. The kit according to any one of embodiments 74 to 76, wherein the neoepitope has a length of 7 to 30 amino acids, e.g. 7 to 10 amino acids (e.g. 7, 8, 9 or 10 amino acids) or 13 to 30 amino acids (e.g. 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 amino acids), e.g. 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids.
78. The kit of any one of embodiments 72-77, wherein the antigenic unit further comprises a consensus cancer antigen or portion thereof present in one or more patients.
79. The kit of embodiment 78, wherein the antigenic units further comprise one or more portions of a common cancer antigen present in one or more patients.
80. The kit of embodiment 79, wherein the moiety is an epitope.
81. The kit of embodiment 80, wherein the antigenic unit further comprises a plurality of epitopes.
82. The kit of any one of embodiments 78 to 81, wherein the patient has a consensus cancer antigen selected from the group consisting of an overexpressed or aberrantly expressed human cellular protein, a cancer testis antigen, a differentiation antigen, a viral antigen, a mutated oncogene, a mutated tumor suppressor gene, a carcinoembryonic antigen, a consensus intron retention antigen, a consensus antigen resulting from a frameshift mutation, a dark matter antigen, and a consensus antigen resulting from a splice mutation.
83. The kit of embodiment 71, wherein the antigenic units comprise one or more common cancer antigens or parts thereof present in the patient.
84. The kit of embodiment 83, wherein the antigenic units comprise one or more portions of a common cancer antigen present in one or more patients.
85. The kit of embodiment 84, wherein the moiety is an epitope.
86. The kit of embodiment 85, wherein the antigenic unit comprises a plurality of epitopes.
87. The kit of any one of embodiments 83 to 86, wherein the patient has a consensus cancer antigen selected from the group consisting of an overexpressed or aberrantly expressed human cellular protein, a cancer testis antigen, a differentiation antigen, a viral antigen, a mutated oncogene, a mutated tumor suppressor gene, a carcinoembryonic antigen, a consensus intron retention antigen, a consensus antigen resulting from a frameshift mutation, a dark matter antigen, and a consensus antigen resulting from a splice mutation.
88. The kit of embodiment 70, wherein the anti-cancer vaccine is a non-personalized anti-cancer vaccine.
89. The kit of embodiment 88, wherein the antigenic units comprise one or more consensus cancer antigens or portions thereof.
90. The kit of embodiment 89, wherein the antigenic units comprise one or more portions of one or more common cancer antigens.
91. The kit of embodiment 90, wherein the moiety is an epitope.
92. The kit of embodiment 91, wherein the antigenic unit comprises a plurality of epitopes.
93. The kit of any one of embodiments 89 to 92, wherein the consensus cancer antigen is selected from the group consisting of an overexpressed or aberrantly expressed human cellular protein, a cancer testis antigen, a differentiation antigen, a viral antigen, a mutated oncogene, a mutated tumor suppressor gene, a carcinoembryonic antigen, a consensus intron retention antigen, a consensus antigen resulting from a frameshift mutation, a dark matter antigen, and a consensus antigen resulting from a splice mutation, a monoclonal Ig-derived scFv derived from a myeloma or lymphoma, a telomerase, an HIV antigen, a tyrosinase-related protein (TRP) -1, TRP-2, a melanoma antigen, a prostate-specific antigen, and an HPV antigen.
94. The kit according to any one of embodiments 70 to 93, wherein the antigenic unit comprises up to 3500 amino acids, e.g. about 21 to about 2000 amino acids or about 60 to 3500 amino acids, e.g. about 80 or about 100 or about 150 amino acids to about 3000 amino acids, e.g. about 200 to about 2500 amino acids, e.g. about 300 to about 2000 amino acids or about 400 to about 1500 amino acids or about 500 to about 1000 amino acids.
95. The kit of any one of embodiments 70 to 96, wherein the targeting unit is or comprises a moiety that interacts with a surface molecule on an antigen presenting cell.
96. The kit of embodiment 95, wherein the surface molecule is selected from the group consisting of HLA, CD14, CD40, CLEC9A, a chemokine receptor such as CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8 or XCR1, and a Toll-like receptor such as TLR-2, TLR-4 or TLR-5.
97. The kit of any one of embodiments 95 and 96, wherein the targeting unit comprises or consists of: soluble CD40 ligand, CCL4 and isoforms thereof, CCL5, CCL19, CCL20, CCL21, macrophage inflammatory protein a includes isoforms thereof, such as mouse CCL3, human CCL3L1, human CCL3L2, and human CCL3L3, XCL1, XCL2, flagellin, anti-HLA-DP, anti-HLA-DR, anti-pan HLA class II anti-CD 40, anti-TLR-2, anti-TLR-4, anti-TLR-5, or anti-CLEC 9A.
98. The kit of embodiment 97, wherein the targeting unit comprises or consists of human MIP-1α (ld78β, CCL3L 1).
99. The kit of embodiment 98, wherein the targeting unit comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 24-93 of SEQ ID NO. 1.
100. The kit of embodiment 99, wherein the targeting unit consists of an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 24-93 of SEQ ID NO. 1.
101. The kit of embodiment 100, wherein the targeting unit consists of the amino acid sequence of 24-93 of SEQ ID NO. 1.
102. The kit according to any of embodiments 70 to 101, wherein the multimerization unit, e.g. the dimerization unit, comprises a hinge region, e.g. hinge exon h1 and hinge exon h4.
103. The kit of embodiment 102, wherein the hinge region has the ability to form one or more covalent bonds.
104. The kit of any one of embodiments 102-103, wherein the hinge region is Ig-derived.
105. The kit of any one of embodiments 102-104, wherein the anti-cancer vaccine comprises a dimerization unit and the dimerization unit further comprises another domain that promotes dimerization.
106. The kit according to embodiment 105, wherein the further domain is an immunoglobulin domain, preferably an immunoglobulin constant domain.
107. The kit according to any one of embodiments 105 to 106, wherein the further domain is a carboxy-terminal C domain derived from IgG, preferably derived from IgG 3.
108. The kit of any one of embodiments 105 to 107, wherein the dimerization unit further comprises a dimerization unit linker, such as a glycine-serine rich linker, such as GGGSSGGGSG (SEQ ID NO: 118).
109. The kit of embodiment 108, wherein the dimerization unit linker connects the hinge region and another domain that promotes dimerization.
110. The kit of any one of embodiments 105 to 109, wherein the dimerization unit comprises hinge exon h1 and hinge exon h4, a dimerization unit linker and a CH3 domain of human IgG 3.
111. The kit of embodiment 110, wherein the dimerization unit comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 94-237 of SEQ ID NO. 1.
112. The kit of embodiment 111, wherein the dimerization unit consists of an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 94-237 of SEQ ID NO. 1.
113. The kit of embodiment 112, wherein the dimerization unit consists of the amino acid sequence of 94-237 of SEQ ID NO. 1.
114. The kit of any one of embodiments 70 to 113, wherein the anti-cancer vaccine further comprises a unit linker connecting the antigenic unit and the multimerizing unit, such as the dimerization unit, and wherein the unit linker is a non-immunogenic linker and/or a flexible or rigid linker.
115. The kit of any one of embodiments 70 to 114, wherein the anti-cancer vaccine is a polynucleotide, preferably RNA or DNA.
116. The kit of embodiment 115, wherein the polynucleotide further comprises a nucleotide sequence encoding a signal peptide.
117. The kit of embodiment 116, wherein the signal peptide is selected from the group consisting of an Ig VH signal peptide, a human TPA signal peptide, and a human MIP-1 a signal peptide.
118. The kit of any one of embodiments 116 to 117, wherein the signal peptide comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of 1-23 of SEQ ID No. 1.
119. The kit of embodiment 118, wherein the signal peptide consists of an amino acid sequence having at least 85% sequence identity to the amino acid sequence of 1-23 of SEQ ID NO. 1.
120. The kit of embodiment 119, wherein the signal peptide consists of the amino acid sequence of 1-23 of SEQ ID NO. 1.
121. The kit of any one of embodiments 115-120, wherein the polynucleotide is DNA.
122. The kit of embodiment 121, wherein the polynucleotide is DNA, which is contained in a vector.
123. The kit of any one of embodiments 70 to 114, wherein the anti-cancer vaccine is a polypeptide or a multimeric protein, such as a dimeric protein.
124. The kit of any one of embodiments 70-123, wherein the kit further comprises one or more pharmaceutically acceptable carriers or diluents.
125. The kit of embodiment 124, comprising a first container comprising an anti-cancer vaccine and a second container comprising a pharmaceutically acceptable carrier or diluent.
126. The kit of embodiment 125, wherein the anti-cancer vaccine is a polypeptide or multimeric protein, such as a dimeric protein, and the pharmaceutically acceptable carrier or diluent further comprises an adjuvant.
127. The kit of any one of embodiments 125-126, wherein the kit comprises a plurality of such first containers and one or more such second containers.
128. The kit of embodiment 124, comprising a container comprising an anti-cancer vaccine and a pharmaceutically acceptable carrier or diluent.
129. The kit of embodiment 128, comprising a plurality of such containers.
130. The kit of any one of embodiments 70-129, wherein the one or more checkpoint inhibitors are selected from an anti-PD-L1 antibody, an anti-TIGIT antibody, an anti-CTLA-4 antibody, and an anti-PD 1 antibody, e.g., wherein the checkpoint inhibitor is an anti-PD-L1 antibody or an anti-TIGIT antibody or an anti-CTLA-4 antibody or an anti-PD 1 antibody, or wherein the checkpoint inhibitor is an anti-PD-L1 antibody and an anti-TIGIT antibody or an anti-PD-L1 antibody and an anti-CTLA-4 antibody or an anti-TIGIT antibody and an anti-CTLA-4 antibody or an anti-PD-L1 antibody and an anti-PD-1 antibody, or wherein the checkpoint inhibitor is an anti-PD-L1 antibody, an anti-CTLA-4 antibody, or an anti-PD-L1 antibody, an anti-TIGIT antibody, or an anti-PD-L1 antibody, or an anti-TIGIT antibody, or an anti-PD-1 antibody, or an anti-TIGIT antibody, or an anti-CTLA-4 antibody and an anti-CTLA-1 antibody, or an anti-PD-1 antibody, wherein the checkpoint inhibitor is an anti-PD-1 antibody.
131. The kit of embodiment 130, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.
132. The kit of embodiment 130, wherein the checkpoint inhibitor is an anti-TIGIT antibody.
133. The kit of embodiment 130, wherein the checkpoint inhibitor is an anti-PD-L1 antibody and an anti-TIGIT antibody.
134. The kit of embodiment 130, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.
135. The kit of any one of embodiments 70-134, comprising a container comprising a checkpoint inhibitor and a container comprising a liquid suitable for injection into a subject, e.g., infusion injection into a subject.
136. The kit of embodiment 135, comprising a plurality of containers each containing a checkpoint inhibitor, and a container comprising a liquid suitable for injection into a subject, e.g., infusion injection into a subject.
137. The kit of embodiment 135, comprising a plurality of containers each containing a checkpoint inhibitor, and a plurality of containers comprising a liquid suitable for injection into a subject, e.g., infusion injection into a subject.
138. The kit of any one of embodiments 70-134, comprising a container comprising a checkpoint inhibitor and a liquid suitable for injection into a subject, e.g., infusion injection into a subject.
139. The kit of embodiment 138, comprising a plurality of containers.
140. The kit of any one of embodiments 70-139, wherein the kit further comprises instructions for use.
141. The kit of embodiment 140, wherein the instructions for use comprise instructions for reconstitution of (a) and (b) and/or instructions for determining the appropriate dosage of (a) and (b) and/or instructions for administration of (a) and (b) and/or instructions for the frequency and schedule of administration of (a) and (b).
142. The kit of any one of embodiments 70 to 141, for use in a method of treating a subject having cancer, wherein the method comprises administering to the subject an anti-cancer vaccine and one or more checkpoint inhibitors contained in the kit.
143. A kit comprising
(a) An anti-cancer vaccine contained in one or more first containers, wherein the anti-cancer vaccine comprises
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit, such as a dimerization unit, and an antigenic unit comprising one or more cancer antigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and
(b) One or more checkpoint inhibitors contained in one or more second containers.
144. The kit of embodiment 143, wherein the anti-cancer vaccine is a personalized anti-cancer vaccine.
145. The kit of embodiment 144, wherein the antigenic unit comprises one or more neoantigens or parts thereof.
146. The kit of embodiment 145, wherein the antigenic units comprise one or more portions of one or more neoantigens.
147. The kit of embodiment 146, wherein the moiety is a neoepitope.
148. The kit of embodiment 147, wherein the antigenic unit comprises a plurality of neo-epitopes, e.g., a plurality of neo-epitopes separated from each other by a linker.
149. The kit of any one of embodiments 147 and 148, wherein the antigenic unit comprises n-1 antigenic subunits and a terminal neoepitope, each subunit comprising a neoepitope and a subunit linker, and wherein n is the number of neoepitopes in the antigenic unit and n is an integer from 1 to 50.
150. The kit of any one of embodiments 147 to 149, wherein the neoepitope has a length of 7 to 30 amino acids, e.g., a length of 7 to 10 amino acids (e.g., 7, 8, 9, or 10 amino acids) or 13 to 30 amino acids (e.g., 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids), e.g., a length of 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids.
151. The kit of any one of embodiments 145-150, wherein the antigenic unit further comprises a consensus cancer antigen or portion thereof present for one or more patients.
152. The kit of embodiment 151, wherein the antigenic units further comprise one or more portions of a common cancer antigen present in one or more patients.
153. The kit of embodiment 152, wherein the moiety is an epitope.
154. The kit of embodiment 153, wherein the antigenic unit further comprises a plurality of epitopes.
155. The kit of any of embodiments 151-154, wherein the patient has a consensus cancer antigen selected from the group consisting of an overexpressed or aberrantly expressed human cellular protein, a cancer testis antigen, a differentiation antigen, a viral antigen, a mutated oncogene, a mutated tumor suppressor gene, a carcinoembryonic antigen, a consensus intron retention antigen, a consensus antigen resulting from a frameshift mutation, a dark matter antigen, and a consensus antigen resulting from a splice mutation.
156. The kit of embodiment 144, wherein the antigenic units comprise one or more patient-present consensus cancer antigens or portions thereof.
157. The kit of embodiment 156, wherein the antigenic units comprise one or more portions of a common cancer antigen present in one or more patients.
158. The kit of embodiment 157, wherein the moiety is an epitope.
159. The kit of embodiment 158, wherein the antigenic unit comprises a plurality of epitopes.
160. The kit of any of embodiments 156-159, wherein the patient has a consensus cancer antigen selected from the group consisting of an overexpressed or aberrantly expressed human cellular protein, a cancer testis antigen, a differentiation antigen, a viral antigen, a mutated oncogene, a mutated tumor suppressor gene, a carcinoembryonic antigen, a consensus intron retention antigen, a consensus antigen resulting from a frameshift mutation, a dark matter antigen, and a consensus antigen resulting from a splice mutation.
161. The kit of embodiment 143, wherein the anti-cancer vaccine is a non-personalized anti-cancer vaccine.
162. The kit of embodiment 161, wherein the antigenic units comprise one or more consensus cancer antigens or portions thereof.
163. The kit of embodiment 162, wherein the antigenic units comprise one or more portions of one or more common cancer antigens.
164. The kit of embodiment 163, wherein the moiety is an epitope.
165. The kit of embodiment 164, wherein the antigenic unit comprises a plurality of epitopes.
166. The kit of any one of embodiments 162-165, wherein the consensus cancer antigen is selected from the group consisting of an overexpressed or aberrantly expressed human cellular protein, a cancer testis antigen, a differentiation antigen, a viral antigen, a mutated oncogene, a mutated tumor suppressor gene, a carcinoembryonic antigen, a consensus intron retention antigen, a consensus antigen resulting from frameshift mutation, a dark matter antigen, and a consensus antigen resulting from a splice mutation, scFv derived from monoclonal Ig produced by a myeloma or lymphoma, telomerase, HIV antigen, tyrosinase-related protein (TRP) -1, TRP-2, a melanoma antigen, a prostate-specific antigen, and HPV antigen.
167. The kit of any one of embodiments 143 to 166, wherein the antigenic unit comprises up to 3500 amino acids, e.g., about 21 to about 2000 amino acids or about 60 to 3500 amino acids, e.g., about 80 or about 100 or about 150 amino acids to about 3000 amino acids, e.g., about 200 to about 2500 amino acids, e.g., about 300 to about 2000 amino acids or about 400 to about 1500 amino acids or about 500 to about 1000 amino acids.
168. The kit of any one of embodiments 143 to 167, wherein the targeting unit is or comprises a moiety that interacts with a surface molecule on an antigen presenting cell.
169. The kit of embodiment 168, wherein the surface molecule is selected from the group consisting of HLA, CD14, CD40, CLEC9A, a chemokine receptor such as CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8 or XCR1 and a Toll-like receptor such as TLR-2, TLR-4 or TLR-5.
170. The kit of any one of embodiments 168 and 169, wherein the targeting unit comprises or consists of: soluble CD40 ligand, CCL4 and isoforms thereof, CCL5, CCL19, CCL20, CCL21, macrophage inflammatory protein a (including isoforms thereof) such as mouse CCL3, human CCL3L1, human CCL3L2, and human CCL3L3, XCL1, XCL2, flagellin, anti-HLA-DP, anti-HLA-DR, anti-pan HLA class II anti-CD 40, anti-TLR-2, anti-TLR-4, anti-TLR-5, or anti-CLEC 9A.
171. The kit of embodiment 170, wherein the targeting unit comprises or consists of human MIP-1α (ld78β, CCL3L 1).
172. The kit of embodiment 171, wherein the targeting unit comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 24-93 of SEQ ID No. 1.
173. The kit of embodiment 172, wherein the targeting unit consists of an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 24-93 of SEQ ID No. 1.
174. The kit of embodiment 173, wherein the targeting unit consists of the amino acid sequence of 24-93 of SEQ ID NO. 1.
175. The kit of any one of embodiments 143 to 174, wherein the multimerization unit, e.g., dimerization unit, comprises a hinge region, e.g., hinge exon h1 and hinge exon h4.
176. The kit of embodiment 175, wherein the hinge region has the ability to form one or more covalent bonds.
177. The kit of any one of embodiments 175-176, wherein the hinge region is Ig-derived.
178. The kit of any one of embodiments 175-177, wherein the anti-cancer vaccine comprises a dimerization unit and the dimerization unit further comprises another domain that promotes dimerization.
179. The kit of embodiment 178, wherein the another domain is an immunoglobulin domain, preferably an immunoglobulin constant domain.
180. The kit of any one of embodiments 178 to 179, wherein the further domain is a carboxy-terminal C domain derived from IgG, preferably derived from IgG 3.
181. The kit of any one of embodiments 178-180, wherein the dimerization unit further comprises a dimerization unit linker, such as a glycine-serine rich linker, such as GGGSSGGGSG (SEQ ID NO: 118).
182. The kit of embodiment 181, wherein the dimerization unit linker connects the hinge region and another domain that facilitates dimerization.
183. The kit of any one of embodiments 178-182, wherein the dimerization unit comprises hinge exon h1 and hinge exon h4, a dimerization unit linker and a CH3 domain of human IgG 3.
184. The kit of embodiment 183, wherein the dimerization unit comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 94-237 of SEQ ID NO. 1.
185. The kit of embodiment 184, wherein the dimerization unit consists of an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 94-237 of SEQ ID NO. 1.
186. The kit of embodiment 185, wherein the dimerization unit consists of the amino acid sequence of 94-237 of SEQ ID NO. 1.
187. The kit of any one of embodiments 143 to 186, wherein the anti-cancer vaccine further comprises a unit linker connecting the antigenic unit to the multimerization unit, such as the dimerization unit, and wherein the unit linker is a non-immunogenic linker and/or a flexible or rigid linker.
188. The kit of any one of embodiments 143 to 187, wherein the anti-cancer vaccine is a polynucleotide, preferably RNA or DNA.
189. The kit of embodiment 188, wherein the polynucleotide further comprises a nucleotide sequence encoding a signal peptide.
190. The kit of embodiment 189, wherein the signal peptide is selected from the group consisting of an Ig VH signal peptide, a human TPA signal peptide, and a human MIP-1 a signal peptide.
191. The kit of any one of embodiments 189 to 190, wherein the signal peptide comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of 1-23 of SEQ ID No. 1.
192. The kit of embodiment 191, wherein the signal peptide consists of an amino acid sequence having at least 85% sequence identity to the amino acid sequence of 1-23 of SEQ ID NO. 1.
193. The kit of embodiment 192, wherein the signal peptide consists of the amino acid sequence of 1-23 of SEQ ID NO. 1.
194. The kit of any one of embodiments 188-193, wherein the polynucleotide is DNA.
195. The kit of embodiment 194, wherein the polynucleotide is DNA, which is contained in a vector.
196. The kit of any one of embodiments 143 to 195, wherein the anti-cancer vaccine is a polypeptide or a multimeric protein, such as a dimeric protein.
197. The kit of any one of embodiments 143-196, wherein the one or more checkpoint inhibitors are selected from the group consisting of an anti-PD-L1 antibody, an anti-TIGIT antibody, an anti-CTLA-4 antibody, and an anti-PD 1 antibody, e.g., wherein the checkpoint inhibitor is an anti-PD-L1 antibody or an anti-TIGIT antibody or an anti-CTLA-4 antibody or an anti-PD 1 antibody, or wherein the checkpoint inhibitor is an anti-PD-L1 antibody and an anti-TIGIT antibody or an anti-PD-L1 antibody and an anti-CTLA-4 antibody or an anti-TIGIT antibody and an anti-CTLA-4 antibody or an anti-PD-L1 antibody and an anti-PD-1 antibody, or an anti-PD-L1 antibody, an anti-PD-1 antibody and an anti-TIGIT antibody, or an anti-CTLA-4 antibody and an anti-CTLA-1 antibody, or an anti-CTLA-4 antibody and an anti-TIGIT antibody, or an anti-TIGIT-1 antibody, or an anti-TIGIT-PD-1 antibody, or an anti-TIGIT-1 antibody.
198. The kit of embodiment 197, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.
199. The kit of embodiment 197, wherein the checkpoint inhibitor is an anti-TIGIT antibody.
200. The kit of embodiment 197, wherein the checkpoint inhibitor is an anti-PD-L1 antibody and an anti-TIGIT antibody.
201. The kit of embodiment 197, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.
202. The kit of any one of embodiments 143 to 201, wherein the anti-cancer vaccine further comprises a pharmaceutically acceptable carrier or diluent, and wherein the one or more checkpoint inhibitors are comprised in a composition suitable for injection, e.g., infusion injection.
203. The kit of any one of embodiments 143 to 202, wherein the kit further comprises one or more third containers comprising a pharmaceutically acceptable carrier or diluent.
204. The kit of any one of embodiments 143 to 203, wherein the kit further comprises instructions for use, for example instructions for reconstitution of the doses of (a) and (b), and/or instructions for determining the appropriate dose of (a) and (b), and/or instructions for administration of (a) and (b), and/or instructions for the frequency and schedule of administration of (a) and (b).
205. The kit of any one of embodiments 143 to 204 for use in a method of treating a subject having cancer, wherein the method comprises administering to the subject an anti-cancer vaccine and one or more checkpoint inhibitors contained in the kit.
205. A method for treating a subject having cancer, the method comprising administering to the subject
(a) An individualized DNA anti-cancer vaccine comprising
(i) A DNA polynucleotide, such as vb10.Neo, comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a dimerization unit, and an antigenic unit comprising one or more neoepitopes; and
(b) anti-PD-L1 antibodies, such as acter Li Zhushan antibodies.
206. The method of embodiment 205, wherein the targeting unit is or comprises a moiety that interacts with a surface molecule on an antigen presenting cell.
207. The method of embodiment 206, wherein the surface molecule is selected from the group consisting of HLA, CD14, CD40, CLEC9A, a chemokine receptor such as CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8 or XCR1 and a Toll-like receptor such as TLR-2, TLR-4 or TLR-5.
208. The method of any one of embodiments 206 and 207, wherein the targeting unit comprises or consists of: soluble CD40 ligand, CCL4 and isoforms thereof, CCL5, CCL19, CCL20, CCL21, macrophage inflammatory protein a includes isoforms thereof such as mouse CCL3, human CCL3L1, human CCL3L2, and human CCL3L3, XCL1, XCL2, flagellin, anti-HLA-DP, anti-HLA-DR, anti-pan HLA class II anti-CD 40, anti-TLR-2, anti-TLR-4, anti-TLR-5, or anti-CLEC 9A.
209. The method of embodiment 208, wherein the targeting unit comprises or consists of human MIP-1α (ld78β, CCL3L 1).
210. The method according to embodiment 209, wherein the targeting unit comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 24-93 of SEQ ID No. 1, e.g. comprising the amino acid sequence of 26-93 of SEQ ID No. 1 or comprising the amino acid sequence of 28-93 of SEQ ID No. 1.
211. The method according to embodiment 210, wherein the targeting unit consists of an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 24-93 of SEQ ID NO. 1, e.g. consisting of the amino acid sequence of 26-93 of SEQ ID NO. 1 or consisting of the amino acid sequence of 28-93 of SEQ ID NO. 1.
212. The method of embodiment 211, wherein the targeting unit consists of the amino acid sequence of 24-93 of SEQ ID NO. 1.
213. The method of any one of embodiments 205 to 212, wherein the dimerization unit comprises a hinge region, such as hinge exon h1 and hinge exon h4.
214. The method of embodiment 213, wherein the hinge region has the ability to form one or more covalent bonds.
215. The method of any one of embodiments 213 to 214, wherein the hinge region is Ig-derived.
216. The method of any one of embodiments 213 to 215, wherein the dimerization unit further comprises another domain that promotes dimerization.
217. The method of embodiment 216, wherein the another domain is an immunoglobulin domain, preferably an immunoglobulin constant domain.
218. The method according to any one of embodiments 216 to 217, wherein the further domain is a carboxy-terminal C domain derived from IgG, preferably derived from IgG 3.
219. The method of any one of embodiments 216 to 218, wherein the dimerization unit further comprises a dimerization unit linker, such as a glycine-serine rich linker, such as GGGSSGGGSG (SEQ ID NO: 118).
220. The method of embodiment 219, wherein the dimerization unit linker connects the hinge region and the another domain that promotes dimerization.
221. The method of any one of embodiments 216 to 220, wherein the dimerization unit comprises hinge exon h1 and hinge exon h4, a dimerization unit linker and a CH3 domain of human IgG 3.
222. The method of embodiment 221, wherein the dimerization unit comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 94 to 237 of SEQ ID No. 1.
223. The method of embodiment 222, wherein said dimerization unit consists of an amino acid sequence having at least 80% sequence identity with the amino acid sequence of 94-237 of SEQ ID NO. 1.
224. The method of embodiment 223, wherein the dimerization unit consists of the amino acid sequence of 94-237 of SEQ ID NO. 1.
225. The method of any one of embodiments 205 to 224, wherein the anti-cancer vaccine further comprises a unit linker connecting the antigenic unit to the dimerization unit, and wherein the unit linker is a non-immunogenic linker and/or a flexible or rigid linker.
226. The method of embodiments 205-225, wherein the DNA further comprises a nucleotide sequence encoding a signal peptide.
227. The method of embodiment 226, wherein the signal peptide is selected from the group consisting of an Ig VH signal peptide, a human TPA signal peptide, and a human MIP-1 a signal peptide.
228. The method of any one of embodiments 226 to 227, wherein the signal peptide comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of 1-23 of SEQ ID No. 1.
229. The method of embodiment 228, wherein the signal peptide consists of an amino acid sequence having at least 85% sequence identity to the amino acid sequence of 1-23 of SEQ ID NO. 1.
230. The method according to embodiment 229, wherein said signal peptide consists of the amino acid sequence of 1-23 of SEQ ID NO. 1.
231. The method of embodiments 205 to 230, wherein the DNA polynucleotide comprises a nucleotide sequence encoding a polypeptide comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 1-242 of SEQ ID No. 1, e.g., the polypeptide comprises the amino acid sequence of 1-242 of SEQ ID No. 1.
232. The method of embodiment 231, wherein the DNA polynucleotide comprises a nucleotide sequence encoding a polypeptide consisting of an amino acid sequence having at least 80% sequence identity to the amino acid sequence of 1-242 of SEQ ID No. 1, e.g., the polypeptide consists of the amino acid sequence of 1-242 of SEQ ID No. 1.
233. The method of any one of embodiments 205 to 232, wherein the DNA polynucleotide comprises a constant portion and a variable portion, wherein the constant portion consists of a nucleotide sequence encoding a polypeptide consisting of the amino acid sequences of 1-242 of SEQ ID No. 1.
234. The method of any one of embodiments 205 to 233, wherein the DNA polynucleotide is comprised in a vector.
235. The method of any one of embodiments 205 to 234, wherein the anti-cancer vaccine further comprises a pharmaceutically acceptable carrier or diluent.
236. The method of any one of embodiments 205-235, wherein the anti-PD-L1 antibody is contained in an aqueous liquid composition for injection, e.g., infusion injection.
237. The method of any one of embodiments 205-236, wherein the anti-PD-L1 antibody is administered by infusion injection.
238. The method of any one of embodiments 205 to 237, wherein the anti-cancer vaccine is administered intramuscularly.
239. The method of any one of embodiments 205 to 237, wherein the cancer is a solid cancer.
240. A method for treating a subject having a solid cancer, the method comprising administering to the subject
(a) An anti-cancer vaccine by intramuscular administration of a personalized DNA comprising a pharmaceutically acceptable carrier and a DNA polynucleotide, e.g., vb10.Neo, wherein the DNA polynucleotide comprises a constant portion consisting of a nucleotide sequence encoding a polypeptide consisting of the amino acid sequences 1-242 of SEQ ID NO:1 and a variable portion consisting of a nucleotide sequence encoding a polypeptide consisting of one or more neoepitopes separated by a linker; and
(b) anti-PD-L1 antibodies, such as atino Li Zhushan antibodies, are injected by infusion.
241. A method for treating a patient having cancer, the method comprising administering to the patient an effective amount of a combination of a personalized DNA anti-cancer vaccine comprising vb10.Neo and atilizumab, wherein
The patient suffers from at least one of the following tumor types: melanoma, NSCLC, RCC, UC, HNSCC, TNBC, gastric/GEJ cancer, cervical cancer, anal cancer or high MSI tumor; and
wherein the patient has a locally advanced or metastatic tumor that has progressed after at least 1 standard of treatment available; and/or standard treatment has proven ineffective or intolerable to it or is deemed unsuitable for it; and/or clinical trials of the investigational drug are approved standard of care therefor; and
an effective amount is a) vb10.neo (3 mg in a pharmaceutically acceptable carrier) administered by intramuscular injection for an induction course of Q3W (4 doses), followed by maintenance doses Q6W (6 doses) and Q12W (5 doses), and atilizumab 1200mg administered by intravenous infusion on day 1 of the 21 day cycle; or b) vb10.Neo (6 mg in a pharmaceutically acceptable carrier) by intramuscular injection for induction of a course of Q3W (4 doses), followed by maintenance doses Q6W (6 doses) and Q12W (5 doses), and administration of artelizumab 1200mg by intravenous infusion on day 1 of the 21 day cycle; and
The treatment methods result in improved Overall Response Rate (ORR) and/or improved duration of response (DOR) and/or improved Progression Free Survival (PFS) and/or improved Overall Survival (OS) compared to a reference population, and optionally the reference population is a population treated with tumor standard of care (SOC).
Sequence listing
<110> Kande treatment Co., ltd (Nykode Therapeutics AS)
<120> therapeutic combination for treating cancer
<130> P5966PC00
<160> 141
<170> PatentIn version 3.5
<210> 1
<211> 972
<212> PRT
<213> artificial sequence
<220>
<223> VB4085 / VB1026
<220>
<221> site
<222> (1)..(972)
<223> VB4085 (amino acids 1-972)/VB 1026 (amino acids 1-237)
<400> 1
Met Gln Val Ser Thr Ala Ala Leu Ala Val Leu Leu Cys Thr Met Ala
1 5 10 15
Leu Cys Asn Gln Val Leu Ser Ala Pro Leu Ala Ala Asp Thr Pro Thr
20 25 30
Ala Cys Cys Phe Ser Tyr Thr Ser Arg Gln Ile Pro Gln Asn Phe Ile
35 40 45
Ala Asp Tyr Phe Glu Thr Ser Ser Gln Cys Ser Lys Pro Ser Val Ile
50 55 60
Phe Leu Thr Lys Arg Gly Arg Gln Val Cys Ala Asp Pro Ser Glu Glu
65 70 75 80
Trp Val Gln Lys Tyr Val Ser Asp Leu Glu Leu Ser Ala Glu Leu Lys
85 90 95
Thr Pro Leu Gly Asp Thr Thr His Thr Glu Pro Lys Ser Cys Asp Thr
100 105 110
Pro Pro Pro Cys Pro Arg Cys Pro Gly Gly Gly Ser Ser Gly Gly Gly
115 120 125
Ser Gly Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
130 135 140
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
145 150 155 160
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Ser Gly Gln
165 170 175
Pro Glu Asn Asn Tyr Asn Thr Thr Pro Pro Met Leu Asp Ser Asp Gly
180 185 190
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
195 200 205
Gln Gly Asn Ile Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
210 215 220
Arg Phe Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Leu Gly
225 230 235 240
Gly Leu Ser Thr Met Leu Tyr Ile Arg Ala Leu Lys Asn Pro Ser Leu
245 250 255
Tyr Gly Phe Ser Ser Gly Leu Asn Lys Asp Gly Ile Glu Gly Gly Gly
260 265 270
Gly Ser Gly Gly Gly Gly Ser Gly Ala Leu Lys Lys Leu Ile Tyr Ala
275 280 285
Ala Lys Leu Asn Thr Ser Leu Lys Ala Leu Glu Gly Glu Arg Asn Gln
290 295 300
Val Tyr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Leu Val Cys
305 310 315 320
Asp Phe Gln Ser Phe Lys Tyr Tyr Ala His Ala Thr Ser Leu Ala Gly
325 330 335
His Leu Val Ser Cys Pro Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly
340 345 350
Ser Glu Lys Leu Arg Asn Pro Cys Pro Asn Lys Glu Lys Ala Tyr Gln
355 360 365
Pro Pro Phe Ala Phe Arg His Val Leu Lys Leu Thr Gly Gly Gly Gly
370 375 380
Ser Gly Gly Gly Gly Ser Asp Thr Leu Ser Ala Met Ser Asn Pro Arg
385 390 395 400
Ala Met Gln Val Leu Leu Gln Ile Gln Gln Gly Leu Gln Thr Leu Ala
405 410 415
Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Asp Val Lys Ile
420 425 430
His Ala His Lys Val Val Leu Ala Asn Ile Ser Pro Tyr Phe Lys Ala
435 440 445
Met Phe Thr Gly Asn Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Glu Val Ile Gln Thr Ser Lys Tyr Tyr Met Arg Asp Val Ile Ala Ile
465 470 475 480
Glu Ser Ala Trp Leu Leu Glu Leu Ala Pro His Gly Gly Gly Gly Ser
485 490 495
Gly Gly Gly Gly Ser Phe Phe Ser Phe Phe Thr His Arg Phe Gly His
500 505 510
His Val Ser Pro Gln Val His Ile Ile Leu Ala Asn Leu Tyr Leu Leu
515 520 525
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Val Ile Leu Pro Gln Ala
530 535 540
Pro Ser Gly Pro Ser Tyr Ala Thr Tyr Leu Gln Pro Ala Gln Ala Gln
545 550 555 560
Met Leu Thr Pro Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu
565 570 575
Trp Val Tyr Leu Arg Pro Val Pro Arg Pro Ala Thr Ile Tyr Leu Gln
580 585 590
Ile Leu Arg Leu Lys Pro Leu Thr Gly Glu Gly Gly Gly Gly Ser Gly
595 600 605
Gly Gly Gly Ser Phe Val Ser Pro Met Ala His Tyr Val Pro Gly Ile
610 615 620
Met Ala Ile Glu Ser Val Val Ala Arg Phe Gln Phe Ile Val Pro Gly
625 630 635 640
Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Leu Ala Phe Leu Val Leu
645 650 655
Ser Thr Pro Ala Met Phe Asn Arg Ala Leu Lys Pro Phe Leu Lys Ser
660 665 670
Cys His Phe Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Phe Leu
675 680 685
Glu Arg Pro Met Asp Met Pro Tyr Met Ile Phe Tyr Pro Asn Asn Pro
690 695 700
Leu Met Thr Gly Gln Leu Leu Gly Ser Gly Gly Gly Gly Ser Gly Gly
705 710 715 720
Gly Gly Ser Ile Pro Arg Glu Val Gly Asp Gly Thr Arg Val Asp Pro
725 730 735
Phe Pro Pro Val Gln Thr Trp Met Arg Leu Pro Lys Leu Val Gly Gly
740 745 750
Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser Leu Phe Gly Ser Ser Arg
755 760 765
Val Gln Tyr Val Val Asn Pro Ala Val Lys Ile Val Phe Leu Asn Ile
770 775 780
Asp Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asn Asn Leu
785 790 795 800
Gln Lys Tyr Ile Glu Ile Tyr Val Gln Lys Ile Asn Pro Ser Arg Leu
805 810 815
Pro Val Val Ile Gly Gly Leu Leu Gly Gly Gly Gly Ser Gly Gly Gly
820 825 830
Gly Ser Ala Glu Tyr Gly Asp Tyr Gln Pro Glu Val His Gly Val Pro
835 840 845
Tyr Phe Arg Leu Glu His Tyr Leu Pro Ala Arg Val Met Gly Gly Gly
850 855 860
Gly Ser Gly Gly Gly Gly Ser Thr Pro Leu Arg Lys His Thr Val His
865 870 875 880
Ala Ile Arg Lys Phe Tyr Leu Glu Phe Lys Gly Ser Ser Pro Pro Pro
885 890 895
Arg Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Ile Tyr Glu
900 905 910
Phe Asp Tyr His Leu Tyr Gly Gln Asn Ile Thr Met Ile Met Thr Ser
915 920 925
Val Ser Gly His Leu Leu Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly
930 935 940
Ser Lys Ser Trp Ile His Cys Trp Lys Tyr Leu Ser Val Gln Ser Gln
945 950 955 960
Leu Phe Arg Gly Ser Ser Leu Leu Phe Arg Arg Val
965 970
<210> 2
<211> 19
<212> PRT
<213> artificial sequence
<220>
<223> Signal peptide
<220>
<221> site
<222> (1)..(19)
<223> Signal peptide
<400> 2
Met Asn Phe Gly Leu Arg Leu Ile Phe Leu Val Leu Thr Leu Lys Gly
1 5 10 15
Val Gln Cys
<210> 3
<211> 22
<212> PRT
<213> artificial sequence
<220>
<223> Signal peptide
<220>
<221> site
<222> (1)..(22)
<223> Signal peptide
<400> 3
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro
20
<210> 4
<211> 69
<212> DNA
<213> artificial sequence
<220>
<223> nucleotide sequence
<220>
<221> misc_feature
<222> (1)..(69)
<223> nucleotide sequence encoding amino acids 1-23 of SEQ ID NO. 1
<400> 4
atgcaggtct ccactgctgc ccttgccgtc ctcctctgca ccatggctct ctgcaaccag 60
gtcctctct 69
<210> 5
<211> 210
<212> DNA
<213> artificial sequence
<220>
<223> nucleotide sequence
<220>
<221> misc_feature
<222> (1)..(210)
<223> nucleotide sequence encoding amino acids 24-93 of SEQ ID NO. 1
<400> 5
gcaccacttg ctgctgacac gccgaccgcc tgctgcttca gctacacctc ccgacagatt 60
ccacagaatt tcatagctga ctactttgag acgagcagcc agtgctccaa gcccagtgtc 120
atcttcctaa ccaagagagg ccggcaggtc tgtgctgacc ccagtgagga gtgggtccag 180
aaatacgtca gtgacctgga gctgagtgcc 210
<210> 6
<211> 36
<212> DNA
<213> artificial sequence
<220>
<223> nucleotide sequence
<220>
<221> misc_feature
<222> (1)..(36)
<223> nucleotide sequence encoding amino acids 94-105 of SEQ ID NO. 1
<400> 6
gagctcaaaa ccccacttgg tgacacaact cacaca 36
<210> 7
<211> 45
<212> DNA
<213> artificial sequence
<220>
<223> nucleotide sequence
<220>
<221> misc_feature
<222> (1)..(45)
<223> nucleotide sequence encoding amino acids 106 to 120 of SEQ ID NO. 1
<400> 7
gagcccaaat cttgtgacac acctcccccg tgcccaaggt gccca 45
<210> 8
<211> 81
<212> DNA
<213> artificial sequence
<220>
<223> nucleotide sequence
<220>
<221> misc_feature
<222> (1)..(81)
<223> nucleotide sequence encoding amino acids 94-120 of SEQ ID NO. 1
<400> 8
gagctcaaaa ccccacttgg tgacacaact cacacagagc ccaaatcttg tgacacacct 60
cccccgtgcc caaggtgccc a 81
<210> 9
<211> 30
<212> DNA
<213> artificial sequence
<220>
<223> nucleotide sequence
<220>
<221> misc_feature
<222> (1)..(30)
<223> nucleotide sequence encoding amino acids 121-130 of SEQ ID NO. 1
<400> 9
ggcggtggaa gcagcggagg tggaagtgga 30
<210> 10
<211> 321
<212> DNA
<213> artificial sequence
<220>
<223> nucleotide sequence
<220>
<221> misc_feature
<222> (1)..(321)
<223> nucleotide sequence encoding amino acids 131-237 of SEQ ID NO. 1
<400> 10
ggacagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 60
aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 120
tgggagagca gcgggcagcc ggagaacaac tacaacacca cgcctcccat gctggactcc 180
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 240
aacatcttct catgctccgt gatgcatgag gctctgcaca accgcttcac gcagaagagc 300
ctctccctgt ctccgggtaa a 321
<210> 11
<211> 15
<212> DNA
<213> artificial sequence
<220>
<223> nucleotide sequence
<220>
<221> misc_feature
<222> (1)..(15)
<223> nucleotide sequence encoding amino acids 238-242 of SEQ ID NO. 1
<400> 11
ggcctcggtg gcctg 15
<210> 12
<211> 432
<212> DNA
<213> artificial sequence
<220>
<223> nucleotide sequence
<220>
<221> misc_feature
<222> (1)..(432)
<223> nucleotide sequence encoding amino acids 94-237 of SEQ ID NO. 1
<400> 12
gagctcaaaa ccccacttgg tgacacaact cacacagagc ccaaatcttg tgacacacct 60
cccccgtgcc caaggtgccc aggcggtgga agcagcggag gtggaagtgg aggacagccc 120
cgagaaccac aggtgtacac cctgccccca tcccgggagg agatgaccaa gaaccaggtc 180
agcctgacct gcctggtcaa aggcttctac cccagcgaca tcgccgtgga gtgggagagc 240
agcgggcagc cggagaacaa ctacaacacc acgcctccca tgctggactc cgacggctcc 300
ttcttcctct acagcaagct caccgtggac aagagcaggt ggcagcaggg gaacatcttc 360
tcatgctccg tgatgcatga ggctctgcac aaccgcttca cgcagaagag cctctccctg 420
tctccgggta aa 432
<210> 13
<211> 447
<212> PRT
<213> artificial sequence
<220>
<223> heavy chain
<220>
<221> site
<222> (1)..(447)
<223> heavy chain amino acid sequence of Abilizumab
<400> 13
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 14
<211> 214
<212> PRT
<213> artificial sequence
<220>
<223> light chain
<220>
<221> site
<222> (1)..(214)
<223> light chain amino acid sequence of Abilizumab
<400> 14
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 15
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> CDR
<220>
<221> site
<222> (1)..(10)
<223> HVR-H1 of atilizumab
<400> 15
Gly Phe Thr Phe Ser Asp Ser Trp Ile His
1 5 10
<210> 16
<211> 18
<212> PRT
<213> artificial sequence
<220>
<223> CDR
<220>
<221> site
<222> (1)..(18)
<223> HVR-H21 of atilizumab
<400> 16
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
1 5 10 15
Lys Gly
<210> 17
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> CDR
<220>
<221> site
<222> (1)..(9)
<223> HVR-H3 of atilizumab
<400> 17
Arg His Trp Pro Gly Gly Phe Asp Tyr
1 5
<210> 18
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> CDR
<220>
<221> site
<222> (1)..(11)
<223> HVR-L1 of atilizumab
<400> 18
Arg Ala Ser Gln Asp Val Ser Thr Ala Val Ala
1 5 10
<210> 19
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> CDR
<220>
<221> site
<222> (1)..(7)
<223> HVR-L2 of atilizumab
<400> 19
Ser Ala Ser Phe Leu Tyr Ser
1 5
<210> 20
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> CDR
<220>
<221> site
<222> (1)..(9)
<223> HVR-L3 of atilizumab
<400> 20
Gln Gln Tyr Leu Tyr His Pro Ala Thr
1 5
<210> 21
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> HV
<220>
<221> site
<222> (1)..(118)
<223> HV of Abilizumab
<400> 21
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 22
<211> 108
<212> PRT
<213> artificial sequence
<220>
<223> HL
<220>
<221> site
<222> (1)..(108)
<223> HL of Abilizumab
<400> 22
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 23
<211> 726
<212> DNA
<213> artificial sequence
<220>
<223> VB10.NEO
<220>
<221> misc_feature
<222> (1)..(726)
<220>
<221> misc_feature
<222> (1)..(726)
<400> 23
atgcaggtct ccactgctgc ccttgccgtc ctcctctgca ccatggctct ctgcaaccag 60
gtcctctctg caccacttgc tgctgacacg ccgaccgcct gctgcttcag ctacacctcc 120
cgacagattc cacagaattt catagctgac tactttgaga cgagcagcca gtgctccaag 180
cccagtgtca tcttcctaac caagagaggc cggcaggtct gtgctgaccc cagtgaggag 240
tgggtccaga aatacgtcag tgacctggag ctgagtgccg agctcaaaac cccacttggt 300
gacacaactc acacagagcc caaatcttgt gacacacctc ccccgtgccc aaggtgccca 360
ggcggtggaa gcagcggagg tggaagtgga ggacagcccc gagaaccaca ggtgtacacc 420
ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 480
ggcttctacc ccagcgacat cgccgtggag tgggagagca gcgggcagcc ggagaacaac 540
tacaacacca cgcctcccat gctggactcc gacggctcct tcttcctcta cagcaagctc 600
accgtggaca agagcaggtg gcagcagggg aacatcttct catgctccgt gatgcatgag 660
gctctgcaca accgcttcac gcagaagagc ctctccctgt ctccgggtaa aggcctcggt 720
ggcctg 726
<210> 24
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 24
Gly Gly Gly Gly Ser
1 5
<210> 25
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 25
Gly Gly Gly Ser Ser
1 5
<210> 26
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 26
Gly Gly Gly Ser Gly
1 5
<210> 27
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 27
Gly Gly Ser Gly Gly
1 5
<210> 28
<211> 6
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(6)
<223> subunit connector
<400> 28
Ser Gly Ser Ser Gly Ser
1 5
<210> 29
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 29
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 30
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<220>
<221> site
<222> (1)..(5)
<223> the sequence may be repeated m times, where m is an integer from 1 to 5, such as 1, 2, 3, 4 or 5
<400> 30
Gly Gly Gly Gly Ser
1 5
<210> 31
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<220>
<221> site
<222> (1)..(5)
<223> the sequence may be repeated m times, where m is an integer from 1 to 5, such as 1, 2, 3, 4 or 5
<400> 31
Gly Gly Gly Ser Ser
1 5
<210> 32
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<220>
<221> site
<222> (1)..(5)
<223> the sequence may be repeated m times, where m is an integer from 1 to 5, such as 1, 2, 3, 4 or 5
<400> 32
Gly Gly Ser Gly Gly
1 5
<210> 33
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<220>
<221> site
<222> (1)..(5)
<223> the sequence may be repeated m times, where m is an integer from 1 to 5, such as 1, 2, 3, 4 or 5
<400> 33
Gly Gly Gly Ser Gly
1 5
<210> 34
<211> 6
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(6)
<223> subunit connector
<220>
<221> site
<222> (1)..(6)
<223> the sequence may be repeated m times, where m is an integer from 1 to 5, such as 1, 2, 3, 4 or 5
<400> 34
Ser Gly Ser Ser Gly Ser
1 5
<210> 35
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 35
Leu Gly Gly Gly Ser
1 5
<210> 36
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 36
Gly Leu Gly Gly Ser
1 5
<210> 37
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 37
Gly Gly Leu Gly Ser
1 5
<210> 38
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 38
Gly Gly Gly Leu Ser
1 5
<210> 39
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 39
Gly Gly Gly Gly Leu
1 5
<210> 40
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 40
Leu Gly Gly Ser Gly
1 5
<210> 41
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 41
Gly Leu Gly Ser Gly
1 5
<210> 42
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 42
Gly Gly Leu Ser Gly
1 5
<210> 43
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 43
Gly Gly Gly Leu Gly
1 5
<210> 44
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 44
Gly Gly Gly Ser Leu
1 5
<210> 45
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 45
Leu Gly Gly Ser Ser
1 5
<210> 46
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 46
Gly Leu Gly Ser Ser
1 5
<210> 47
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 47
Gly Gly Leu Ser Ser
1 5
<210> 48
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 48
Leu Gly Leu Gly Ser
1 5
<210> 49
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 49
Gly Leu Gly Leu Ser
1 5
<210> 50
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 50
Gly Leu Leu Gly Ser
1 5
<210> 51
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 51
Leu Gly Gly Leu Ser
1 5
<210> 52
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 52
Gly Leu Gly Gly Leu
1 5
<210> 53
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 53
Leu Gly Leu Ser Gly
1 5
<210> 54
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 54
Gly Leu Leu Ser Gly
1 5
<210> 55
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 55
Gly Gly Leu Ser Leu
1 5
<210> 56
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 56
Gly Gly Leu Leu Gly
1 5
<210> 57
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 57
Gly Leu Gly Ser Leu
1 5
<210> 58
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 58
Leu Gly Leu Ser Ser
1 5
<210> 59
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 59
Gly Gly Leu Leu Ser
1 5
<210> 60
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 60
Leu Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 61
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 61
Gly Leu Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 62
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 62
Gly Gly Leu Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 63
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 63
Gly Gly Gly Leu Ser Gly Gly Gly Gly Ser
1 5 10
<210> 64
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 64
Gly Gly Gly Gly Leu Gly Gly Gly Gly Ser
1 5 10
<210> 65
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 65
Leu Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10
<210> 66
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 66
Gly Leu Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10
<210> 67
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 67
Gly Gly Leu Ser Gly Gly Gly Gly Ser Gly
1 5 10
<210> 68
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 68
Gly Gly Gly Leu Gly Gly Gly Gly Ser Gly
1 5 10
<210> 69
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 69
Gly Gly Gly Ser Leu Gly Gly Gly Ser Gly
1 5 10
<210> 70
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 70
Leu Gly Gly Ser Ser Gly Gly Gly Ser Ser
1 5 10
<210> 71
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 71
Gly Leu Gly Ser Ser Gly Gly Gly Ser Ser
1 5 10
<210> 72
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 72
Gly Gly Leu Ser Ser Gly Gly Gly Ser Ser
1 5 10
<210> 73
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 73
Gly Gly Gly Leu Ser Gly Gly Gly Ser Ser
1 5 10
<210> 74
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 74
Gly Gly Gly Ser Leu Gly Gly Gly Ser Ser
1 5 10
<210> 75
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> subunit connector
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 75
Leu Gly Gly Gly Ser Leu Gly Gly Gly Ser
1 5 10
<210> 76
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 76
Gly Leu Gly Gly Ser Gly Leu Gly Gly Ser
1 5 10
<210> 77
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 77
Gly Gly Leu Gly Ser Gly Gly Leu Gly Ser
1 5 10
<210> 78
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 78
Gly Gly Gly Leu Ser Gly Gly Gly Leu Ser
1 5 10
<210> 79
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 79
Gly Gly Gly Gly Leu Gly Gly Gly Gly Leu
1 5 10
<210> 80
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 80
Leu Gly Gly Ser Gly Leu Gly Gly Ser Gly
1 5 10
<210> 81
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 81
Gly Leu Gly Ser Gly Gly Leu Gly Ser Gly
1 5 10
<210> 82
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 82
Gly Gly Leu Ser Gly Gly Gly Leu Ser Gly
1 5 10
<210> 83
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 83
Gly Gly Gly Leu Gly Gly Gly Gly Leu Gly
1 5 10
<210> 84
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 84
Gly Gly Gly Ser Leu Gly Gly Gly Ser Leu
1 5 10
<210> 85
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 85
Leu Gly Gly Ser Ser Leu Gly Gly Ser Ser
1 5 10
<210> 86
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 86
Gly Leu Gly Ser Ser Gly Leu Gly Ser Ser
1 5 10
<210> 87
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 87
Gly Gly Leu Ser Ser Gly Gly Leu Ser Ser
1 5 10
<210> 88
<211> 6
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(6)
<223> subunit connector
<400> 88
Gly Ser Gly Gly Gly Ala
1 5
<210> 89
<211> 12
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(12)
<223> subunit connector
<400> 89
Gly Ser Gly Gly Gly Ala Gly Ser Gly Gly Gly Ala
1 5 10
<210> 90
<211> 18
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(18)
<223> subunit connector
<400> 90
Gly Ser Gly Gly Gly Ala Gly Ser Gly Gly Gly Ala Gly Ser Gly Gly
1 5 10 15
Gly Ala
<210> 91
<211> 24
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(24)
<223> subunit connector
<400> 91
Gly Ser Gly Gly Gly Ala Gly Ser Gly Gly Gly Ala Gly Ser Gly Gly
1 5 10 15
Gly Ala Gly Ser Gly Gly Gly Ala
20
<210> 92
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 92
Gly Glu Asn Leu Tyr Phe Gln Ser Gly Gly
1 5 10
<210> 93
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 93
Ser Gly Gly Gly Ser Ser Gly Gly Gly Ser
1 5 10
<210> 94
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 94
Ser Ser Gly Gly Gly Ser Ser Gly Gly Gly
1 5 10
<210> 95
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 95
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
1 5 10
<210> 96
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(10)
<223> subunit connector
<400> 96
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
1 5 10
<210> 97
<211> 6
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(6)
<223> subunit connector
<400> 97
Gly Gly Gly Ser Ser Ser
1 5
<210> 98
<211> 15
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(15)
<223> subunit connector
<400> 98
Gly Gly Gly Ser Ser Gly Gly Gly Ser Ser Gly Gly Gly Ser Ser
1 5 10 15
<210> 99
<211> 8
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(8)
<223> subunit connector
<400> 99
Gly Leu Gly Gly Leu Ala Ala Ala
1 5
<210> 100
<211> 12
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(12)
<223> subunit connector
<400> 100
Lys Pro Glu Pro Lys Pro Ala Pro Ala Pro Lys Pro
1 5 10
<210> 101
<211> 12
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(12)
<223> subunit connector
<400> 101
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala
1 5 10
<210> 102
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<220>
<221> site
<222> (1)..(5)
<223> the sequence may be repeated m times, m being an integer from 1 to 5, e.g. 1, 2, 3, 4 or 5
<400> 102
Glu Ala Ala Ala Lys
1 5
<210> 103
<211> 15
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(15)
<223> subunit connector
<400> 103
Pro Ser Arg Leu Glu Glu Glu Leu Arg Arg Arg Leu Thr Glu Pro
1 5 10 15
<210> 104
<211> 8
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(8)
<223> subunit connector
<400> 104
Ser Ala Cys Tyr Cys Glu Leu Ser
1 5
<210> 105
<211> 16
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(16)
<223> subunit connector
<400> 105
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Leu Gly Gly Leu
1 5 10 15
<210> 106
<211> 13
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(13)
<223> subunit connector
<400> 106
Ser Leu Ser Leu Ser Pro Gly Lys Gly Leu Gly Gly Leu
1 5 10
<210> 107
<211> 36
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(36)
<223> subunit connector
<400> 107
Gly Gly Ser Ala Gly Gly Ser Gly Ser Gly Ser Ser Gly Gly Ser Ser
1 5 10 15
Gly Ala Ser Gly Thr Gly Thr Ala Gly Gly Thr Gly Ser Gly Ser Gly
20 25 30
Thr Gly Ser Gly
35
<210> 108
<211> 36
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(36)
<223> subunit connector
<400> 108
Gly Gly Ser Gly Gly Gly Ser Glu Gly Gly Gly Ser Glu Gly Gly Gly
1 5 10 15
Ser Glu Gly Gly Gly Ser Glu Gly Gly Gly Ser Glu Gly Gly Gly Ser
20 25 30
Gly Gly Gly Ser
35
<210> 109
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 109
Gly Leu Ser Gly Leu
1 5
<210> 110
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(5)
<223> subunit connector
<400> 110
Glu Ala Ala Ala Lys
1 5
<210> 111
<211> 6
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(6)
<223> subunit connector
<220>
<221> site
<222> (1)..(5)
<223> the sequence may be repeated m times, m being an integer from 1 to 5, e.g. 1, 2, 3, 4 or 5
<400> 111
Glu Ala Ala Lys Gly Ser
1 5
<210> 112
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(17)
<223> subunit connector
<400> 112
Gly Pro Ser Arg Leu Glu Glu Glu Leu Arg Arg Arg Leu Thr Glu Pro
1 5 10 15
Gly
<210> 113
<211> 117
<212> DNA
<213> artificial sequence
<220>
<223> multimerization units derived from p53
<400> 113
aagcctctgg acggagagta tttcactctc cagatccggg gccccgaaag gttcgaaatg 60
ttccgggagc ttaacgaggc cttggagctg aaagacgcac aggccggaaa ggaaccg 117
<210> 114
<211> 12
<212> PRT
<213> artificial sequence
<220>
<223> joint
<220>
<221> site
<222> (1)..(12)
<223> subunit connector
<400> 114
His Glu Tyr Gly Ala Glu Ala Leu Glu Arg Ala Gly
1 5 10
<210> 115
<211> 36
<212> DNA
<213> artificial sequence
<220>
<223> ligand
<220>
<221> misc_feature
<222> (1)..(36)
<223> CLEC9 ligand
<400> 115
tggcccaggt tccacagcag cgtgttccac acccac 36
<210> 116
<211> 180
<212> DNA
<213> artificial sequence
<220>
<223> trimerization unit
<220>
<221> misc_feature
<222> (1)..(180)
<223> human collagen XV trimerization Domain
<400> 116
gctgggcagg tgaggatctg ggccacatac cagaccatgc tggacaagat ccgggaggtg 60
ccggagggct ggctcatctt tgtggccgag agggaagagc tctatgtacg cgttagaaat 120
ggcttccgga aggtgctgct ggaggcccgg acagccctcc cgagaggcac gggcaatgag 180
<210> 117
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> subunit connector
<220>
<221> site
<222> (1)..(27)
<223> human collagen XV trimerization Domain
<400> 117
Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys
1 5 10 15
Asp Gly Glu Trp Val Leu Leu Ser Thr Phe Leu
20 25
<210> 118
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> dimerization unit linker
<220>
<221> site
<222> (1)..(10)
<223> dimerization unit linker
<400> 118
Gly Gly Gly Ser Ser Gly Gly Gly Ser Gly
1 5 10
<210> 119
<211> 333
<212> DNA
<213> artificial sequence
<220>
<223> hinge region
<220>
<221> misc_feature
<222> (1)..(333)
<223> IgM-derived hinge region
<400> 119
gccgaactcc cgcccaaggt gtccgtgttc gtccctcccc gcgatgggtt cttcggcaat 60
ccacgaaaat ccaaactgat ttgtcaggcc accggcttct ccccccgaca gatccaggtg 120
agttggctac gagagggtaa acaggtgggg agcggagtga ccactgacca ggtgcaggcc 180
gaggccaagg aaagcggacc cacaacatac aaagtgacaa gcactctgac gattaaggag 240
tcagactggc tcggccaatc catgtttaca tgccgggttg atcacagagg gttgaccttc 300
caacagaacg catccagtat gtgcgttcca gat 333
<210> 120
<211> 105
<212> DNA
<213> artificial sequence
<220>
<223> dHLX protein
<220>
<221> misc_feature
<222> (1)..(105)
<223> dHLX protein
<400> 120
ggagaactgg aggaattact taaacatctc aaggagttgc tcaaaggccc taggaaggga 60
gaactggagg aactcctcaa acatctcaag gagttactaa aggga 105
<210> 121
<211> 324
<212> DNA
<213> mice (Mus musculus)
<400> 121
atggcccccc gtgtgacccc actcctggcc ttcagcctgc tggttctctg gaccttccca 60
gccccaactc tggggggtgc taatgatgcg gaagactgct gcctgtctgt gacccagcgc 120
cccatccctg ggaacatcgt gaaagccttc cgctaccttc ttaatgaaga tggctgcagg 180
gtgcctgctg ttgtgttcac cacactaagg ggctatcagc tctgtgcacc tcctgaccag 240
ccctgggtgg atcgcatcat ccgaagactg aagaagtctt ctgccaagaa caaaggcaac 300
agcaccagaa ggagccctgt gtct 324
<210> 122
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 122
Ser Thr Met Leu Tyr Ile Arg Ala Leu Lys Asn Pro Ser Leu Tyr Gly
1 5 10 15
Phe Ser Ser Gly Leu Asn Lys Asp Gly Ile Glu
20 25
<210> 123
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 123
Gly Ala Leu Lys Lys Leu Ile Tyr Ala Ala Lys Leu Asn Thr Ser Leu
1 5 10 15
Lys Ala Leu Glu Gly Glu Arg Asn Gln Val Tyr
20 25
<210> 124
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 124
Asp Leu Val Cys Asp Phe Gln Ser Phe Lys Tyr Tyr Ala His Ala Thr
1 5 10 15
Ser Leu Ala Gly His Leu Val Ser Cys Pro Leu
20 25
<210> 125
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 125
Glu Lys Leu Arg Asn Pro Cys Pro Asn Lys Glu Lys Ala Tyr Gln Pro
1 5 10 15
Pro Phe Ala Phe Arg His Val Leu Lys Leu Thr
20 25
<210> 126
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 126
Asp Thr Leu Ser Ala Met Ser Asn Pro Arg Ala Met Gln Val Leu Leu
1 5 10 15
Gln Ile Gln Gln Gly Leu Gln Thr Leu Ala Thr
20 25
<210> 127
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 127
Gly Asp Val Lys Ile His Ala His Lys Val Val Leu Ala Asn Ile Ser
1 5 10 15
Pro Tyr Phe Lys Ala Met Phe Thr Gly Asn Leu
20 25
<210> 128
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<400> 128
Glu Val Ile Gln Thr Ser Lys Tyr Tyr Met Arg Asp Val Ile Ala Ile
1 5 10 15
Glu Ser Ala Trp Leu Leu Glu Leu Ala Pro His
20 25
<210> 129
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 129
Phe Phe Ser Phe Phe Thr His Arg Phe Gly His His Val Ser Pro Gln
1 5 10 15
Val His Ile Ile Leu Ala Asn Leu Tyr Leu Leu
20 25
<210> 130
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 130
Val Ile Leu Pro Gln Ala Pro Ser Gly Pro Ser Tyr Ala Thr Tyr Leu
1 5 10 15
Gln Pro Ala Gln Ala Gln Met Leu Thr Pro Pro
20 25
<210> 131
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 131
Leu Trp Val Tyr Leu Arg Pro Val Pro Arg Pro Ala Thr Ile Tyr Leu
1 5 10 15
Gln Ile Leu Arg Leu Lys Pro Leu Thr Gly Glu
20 25
<210> 132
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 132
Phe Val Ser Pro Met Ala His Tyr Val Pro Gly Ile Met Ala Ile Glu
1 5 10 15
Ser Val Val Ala Arg Phe Gln Phe Ile Val Pro
20 25
<210> 133
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 133
Thr Leu Ala Phe Leu Val Leu Ser Thr Pro Ala Met Phe Asn Arg Ala
1 5 10 15
Leu Lys Pro Phe Leu Lys Ser Cys His Phe Gln
20 25
<210> 134
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 134
Phe Leu Glu Arg Pro Met Asp Met Pro Tyr Met Ile Phe Tyr Pro Asn
1 5 10 15
Asn Pro Leu Met Thr Gly Gln Leu Leu Gly Ser
20 25
<210> 135
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 135
Ile Pro Arg Glu Val Gly Asp Gly Thr Arg Val Asp Pro Phe Pro Pro
1 5 10 15
Val Gln Thr Trp Met Arg Leu Pro Lys Leu Val
20 25
<210> 136
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 136
Gly Ser Leu Phe Gly Ser Ser Arg Val Gln Tyr Val Val Asn Pro Ala
1 5 10 15
Val Lys Ile Val Phe Leu Asn Ile Asp Pro Ser
20 25
<210> 137
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 137
Asn Asn Leu Gln Lys Tyr Ile Glu Ile Tyr Val Gln Lys Ile Asn Pro
1 5 10 15
Ser Arg Leu Pro Val Val Ile Gly Gly Leu Leu
20 25
<210> 138
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 138
Ala Glu Tyr Gly Asp Tyr Gln Pro Glu Val His Gly Val Pro Tyr Phe
1 5 10 15
Arg Leu Glu His Tyr Leu Pro Ala Arg Val Met
20 25
<210> 139
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 139
Thr Pro Leu Arg Lys His Thr Val His Ala Ile Arg Lys Phe Tyr Leu
1 5 10 15
Glu Phe Lys Gly Ser Ser Pro Pro Pro Arg Leu
20 25
<210> 140
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 140
Lys Ile Tyr Glu Phe Asp Tyr His Leu Tyr Gly Gln Asn Ile Thr Met
1 5 10 15
Ile Met Thr Ser Val Ser Gly His Leu Leu Ala
20 25
<210> 141
<211> 27
<212> PRT
<213> artificial sequence
<220>
<223> New antigen Table 1
<220>
<221> site
<222> (1)..(27)
<223> New antigen
<400> 141
Lys Ser Trp Ile His Cys Trp Lys Tyr Leu Ser Val Gln Ser Gln Leu
1 5 10 15
Phe Arg Gly Ser Ser Leu Leu Phe Arg Arg Val
20 25
Claims (47)
1. A method for treating a subject having cancer, the method comprising administering to the subject
(a) An anti-cancer vaccine comprising
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit such as a dimerization unit, and an antigenic unit comprising one or more cancer antigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and
(b) One or more checkpoint inhibitors.
2. The method of claim 1, wherein the anti-cancer vaccine is a personalized anti-cancer vaccine.
3. The method of claim 2, wherein the antigenic units comprise one or more neoantigens or parts thereof, such as one or more neoepitopes.
4. The method of claim 3, wherein the antigenic unit comprises a plurality of neoepitopes separated from each other by linkers.
5. The method of any one of claims 3 to 4, wherein the antigenic units further comprise one or more patient-present consensus cancer antigen or portion thereof, such as an epitope, such as a plurality of epitopes.
6. The method of claim 2, wherein the antigenic units comprise one or more patient-present consensus cancer antigen or portion thereof, such as an epitope, such as a plurality of epitopes.
7. The method of claim 1, wherein the anti-cancer vaccine is a non-personalized anti-cancer vaccine.
8. The method of claim 7, wherein the antigenic units comprise one or more consensus cancer antigens or parts thereof, such as epitopes, e.g. multiple epitopes.
9. The method of any one of claims 1 to 8, wherein the one or more checkpoint inhibitors are selected from the group consisting of anti-PD-L1 antibodies, anti-TIGIT antibodies, and anti-CTLA-4 antibodies.
10. The method of claim 9, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.
11. The method of claim 9, wherein the checkpoint inhibitor is an anti-PD-L1 antibody and an anti-TIGIT antibody.
12. The method according to any one of claims 1 to 11, wherein the targeting unit is or comprises a moiety that interacts with a surface molecule on the antigen presenting cell, such as a surface molecule selected from HLA, CD14, CD40, CLEC9A, a chemokine receptor such as CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8 or XCR1, and a Toll-like receptor such as TLR-2, TLR-4 or TLR-5.
13. The method of claim 12, wherein the targeting unit comprises or consists of: soluble CD40 ligand, CCL4 and isoforms thereof, CCL5, CCL19, CCL20, CCL21, macrophage inflammatory protein a includes isoforms thereof, such as mouse CCL3, human CCL3L1, human CCL3L2, and human CCL3L3, XCL1, XCL2, flagellin, anti-HLA-DP, anti-HLA-DR, anti-pan HLA class II anti-CD 40, anti-TLR-2, anti-TLR-4, anti-TLR-5, or anti-CLEC 9A.
14. The method according to any one of claims 1 to 13, wherein the multimerization unit is a trimerization unit, such as the C-terminal domain of T4 fibrin, or such as a collagen-derived trimerization unit, such as the human collagen-derived XVIII trimerization domain or the human collagen XV trimerization domain, or a tetramerization unit, such as a domain derived from p 53.
15. The method according to any one of claims 1 to 13, wherein the multimerization unit is a dimerization unit, such as a dimerization unit comprising a hinge region and an immunoglobulin domain, such as an immunoglobulin constant domain, or a dimerization unit comprising a dHLX protein.
16. The method of any one of claims 1 to 15, wherein the anti-cancer vaccine further comprises a unit linker connecting the antigenic unit to the multimerization unit, e.g. dimerization unit, and wherein the unit linker is a non-immunogenic linker and/or a flexible or rigid linker.
17. The method according to any one of claims 1 to 16, wherein the anti-cancer vaccine is a polynucleotide, such as RNA or DNA comprised in a vector.
18. The method of claim 17, wherein the polynucleotide further comprises a nucleotide sequence encoding a signal peptide.
19. The method of claim 18, wherein the anti-cancer vaccine comprises a DNA polynucleotide encoding: a human MIP-1 alpha signal peptide, a human MIP-1 alpha targeting unit comprising a hinge exon h1, a hinge exon h4, a dimerization unit linker and a dimerization unit of the CH3 domain of human IgG3, a unit linker and an antigenic unit comprising one or more neoepitopes.
20. The method of claim 19, wherein the checkpoint inhibitor is an anti-PD-L1 antibody or an anti-TIGIT antibody or an anti-CTLA 4 antibody, or wherein the checkpoint inhibitor is an anti-PD-L1 antibody and an anti-TIGIT antibody.
21. The method of any one of claims 1 to 20, wherein the anti-cancer vaccine further comprises a pharmaceutically acceptable carrier or diluent, and wherein the one or more checkpoint inhibitors are comprised in a composition suitable for injection, such as infusion injection.
22. The method of any one of claims 1 to 21, wherein the one or more checkpoint inhibitors are administered simultaneously with the anti-cancer vaccine or prior to the first administration of the anti-cancer vaccine, or wherein the anti-cancer vaccine is administered prior to the administration of the one or more checkpoint inhibitors.
23. The method according to any one of claims 1 to 22, wherein the cancer is a solid or liquid cancer, such as a cancer selected from breast cancer, ovarian cancer, colon cancer, prostate cancer, bone cancer, colorectal cancer, gastric cancer, lymphoma, malignant melanoma, liver cancer, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, thyroid cancer, renal cancer, cholangiocarcinoma, brain cancer, cervical cancer, bladder cancer, esophageal cancer, hodgkin's disease and adrenocortical cancer.
24. A kit comprising
(a) An anti-cancer vaccine contained in one or more first containers, wherein the anti-cancer vaccine comprises
(i) A polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets an antigen presenting cell, a multimerization unit such as a dimerization unit, and an antigenic unit comprising one or more cancer antigens or portions thereof; or (b)
(ii) A polypeptide encoded by a polynucleotide as defined in (i); or (b)
(iii) A multimeric protein, e.g. a dimeric protein, consisting of a plurality of polypeptides as defined in (ii), e.g. consisting of two polypeptides; and
(b) One or more checkpoint inhibitors contained in one or more second containers.
25. The kit of claim 24, wherein the anti-cancer vaccine is a personalized anti-cancer vaccine.
26. The kit of claim 25, wherein the antigenic units comprise one or more neoantigens or parts thereof, such as one or more neoepitopes.
27. The kit of claim 26, wherein the antigenic units comprise a plurality of neoepitopes separated from each other by linkers.
28. The kit of any one of claims 26 to 27, wherein the antigenic units further comprise one or more patient-present consensus cancer antigen or portion thereof, such as an epitope, such as a plurality of epitopes.
29. The kit of claim 28, wherein the antigenic units comprise one or more patient-present consensus cancer antigen or portion thereof, such as an epitope, such as a plurality of epitopes.
30. The kit of claim 24, wherein the anti-cancer vaccine is a non-personalized anti-cancer vaccine.
31. The kit of claim 30, wherein the antigenic units comprise one or more consensus cancer antigens or parts thereof, such as epitopes, e.g. multiple epitopes.
32. The kit of any one of claims 24 to 31, wherein the one or more checkpoint inhibitors are selected from the group consisting of anti-PD-L1 antibodies, anti-TIGIT antibodies, and anti-CTLA-4 antibodies.
33. The kit of claim 32, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.
34. The kit of claim 32, wherein the checkpoint inhibitor is an anti-PD-L1 and anti-TIGIT antibody.
35. The kit according to any one of claims 24 to 34, wherein the targeting unit is or comprises a moiety that interacts with a surface molecule on the antigen presenting cell, such as a surface molecule selected from HLA, CD14, CD40, CLEC9A, a chemokine receptor such as CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8 or XCR1, and a Toll-like receptor such as TLR-2, TLR-4 or TLR-5.
36. The kit of claim 35, wherein the targeting unit comprises or consists of: soluble CD40 ligand, CCL4 and isoforms thereof, CCL5, CCL19, CCL20, CCL21, macrophage inflammatory protein a includes isoforms thereof, such as mouse CCL3, human CCL3L1, human CCL3L2, and human CCL3L3, XCL1, XCL2, flagellin, anti-HLA-DP, anti-HLA-DR, anti-pan HLA class II anti-CD 40, anti-TLR-2, anti-TLR-4, anti-TLR-5, or anti-CLEC 9A.
37. Kit according to any one of claims 24 to 36, wherein the multimerization unit is a trimerization unit, such as the C-terminal domain of T4 fibrin, or such as a collagen-derived trimerization unit, such as the human collagen-derived XVIII trimerization domain or the human collagen XV trimerization domain, or a tetramerization unit, such as a domain derived from p 53.
38. Kit according to any one of claims 24 to 36, wherein the multimerization unit is a dimerization unit, such as a dimerization unit comprising a hinge region and an immunoglobulin domain, such as an immunoglobulin constant domain, or a dimerization unit comprising a dHLX protein.
39. The kit of any one of claims 24 to 38, wherein the anti-cancer vaccine further comprises a unit linker connecting the antigenic unit to the multimerization unit, such as a dimerization unit, and wherein the unit linker is a non-immunogenic linker and/or a flexible or rigid linker.
40. The kit of any one of claims 24 to 39, wherein the anti-cancer vaccine is a polynucleotide, such as RNA or DNA contained in a vector.
41. The kit of claim 40, wherein the polynucleotide further comprises a nucleotide sequence encoding a signal peptide.
42. The kit of claim 41, wherein the anti-cancer vaccine comprises a DNA polynucleotide encoding: a human MIP-1 alpha signal peptide, a human MIP-1 alpha targeting unit comprising a hinge exon h1, a hinge exon h4, a dimerization unit linker and a dimerization unit of the CH3 domain of human IgG3, a unit linker and an antigenic unit comprising one or more neoepitopes.
43. The kit of claim 42, wherein the checkpoint inhibitor is an anti-PD-L1 antibody or an anti-TIGIT antibody or an anti-CTLA 4 antibody, or wherein the checkpoint inhibitor is an anti-PD-L1 antibody and an anti-TIGIT antibody.
44. The kit of any one of claims 24 to 43, wherein the anti-cancer vaccine further comprises a pharmaceutically acceptable carrier or diluent, and wherein the one or more checkpoint inhibitors are comprised in a composition suitable for injection, such as infusion injection.
45. The kit of any one of claims 24 to 44, wherein the kit further comprises one or more third containers comprising a pharmaceutically acceptable carrier or diluent.
46. Kit according to any one of claims 24 to 45, wherein the kit further comprises instructions for use, for example instructions for reconstitution of the doses of (a) and (b), and/or instructions for determining the appropriate dose of (a) and (b), and/or instructions for administration of (a) and (b), and/or instructions for the frequency and schedule of administration of (a) and (b).
47. The kit of any one of claims 24 to 46, for use in a method of treating a subject having cancer, wherein the method comprises administering the anti-cancer vaccine and the one or more checkpoint inhibitors contained in the kit to the subject.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DKPA202100317 | 2021-03-26 | ||
DKPA202170182 | 2021-04-21 | ||
DKPA202170182 | 2021-04-21 | ||
PCT/EP2022/057955 WO2022200590A1 (en) | 2021-03-26 | 2022-03-25 | Therapeutic combination for treating cancer |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117320744A true CN117320744A (en) | 2023-12-29 |
Family
ID=89250372
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN202280025068.8A Pending CN117320744A (en) | 2021-03-26 | 2022-03-25 | Therapeutic combinations for the treatment of cancer |
Country Status (1)
Country | Link |
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CN (1) | CN117320744A (en) |
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2022
- 2022-03-25 CN CN202280025068.8A patent/CN117320744A/en active Pending
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