T cell receptors and methods of use thereof

Abstract

The present disclosure relates to recombinant T cell receptors capable of binding to a MUC5AC epitope and nucleic acid molecules encoding the same. In some aspects, the nucleic acid molecules further comprise a second nucleotide sequence, wherein the second nucleotide sequence or a polypeptide encoded by the second nucleotide sequence inhibits the expression of an endogenous TCR. Other aspects of the present disclosure relate to vectors comprising the nucleic acid molecules and cells comprising the recombinant TCRs, the nucleic acid molecules, or the vectors. Other aspects of the present disclosure relate to methods of using the recombinant TCRs, the nucleic acid molecules, the vectors, and the cells. In some aspects, the methods comprise treating a cancer in a subject in need thereof.

Description

[0001] Cross-references to related applications

[0002] This PCT application claims priority to U.S. Provisional Application No. 62 / 880,505, filed July 30, 2019, which is incorporated herein by reference in its entirety.

[0003] References to sequence lists submitted electronically via EFS-WEB

[0004] The contents of the sequence list submitted electronically (name: 4285_014PC01_Seqlisting_ST25.txt, size: 70,689 bytes; and creation date: July 28, 2020) are incorporated herein by reference in their entirety. Technical Field

[0005] This disclosure provides a recombinant T-cell receptor (“TCR”) that specifically binds to human mucin 5AC (MUC5AC) and its uses. Background of the Invention

[0007] Immunotherapy has emerged as a key tool in the fight against a variety of diseases, including cancer. T-cell therapy is at the forefront of immunotherapy development, and adoptive transfer of anti-tumor T cells has been shown to induce clinical responses in cancer patients. Although many T-cell therapies target mutated tumor antigens, the vast majority of neoantigens are not common to each patient but are unique.

[0008] The number of potential non-mutated antigens exceeds that of mutated antigens by several orders of magnitude. Elucidating T-cell epitopes derived from shared antigens could facilitate the robust development of effective and safe adoptive T-cell therapies readily available to a large population of cancer patients. However, the absolute number of non-mutated antigens and the high polymorphism of HLA genes may have hindered a comprehensive analysis of the specificity of anti-tumor T-cell responses to non-mutated antigens. Summary of the Invention

[0009] Certain aspects of the present disclosure relate to a nucleic acid molecule comprising (i) a first nucleotide sequence encoding a recombinant T cell receptor (TCR) or an antigen binding portion thereof that specifically binds to human mucin 5AC (MUC5AC) ("anti-MUC5AC TCR"); and (ii) a second nucleotide sequence, wherein the second nucleotide sequence or a polypeptide encoded by the second nucleotide sequence inhibits expression of an endogenous TCR, wherein the anti-MUC5AC TCR cross-competes for binding to human MUC5AC with a reference TCR, the reference TCR comprising an alpha chain and a beta chain, and wherein the alpha chain comprises an amino acid sequence as set forth in SEQ ID NO: 1 and the beta chain comprises an amino acid sequence as set forth in SEQ ID NO: 2.

[0010] Certain aspects of the present disclosure relate to a nucleic acid molecule comprising (i) a first nucleotide sequence encoding a recombinant T cell receptor (TCR) or an antigen binding portion thereof that specifically binds to human MUC5AC ("anti-MUC5AC TCR"); and (ii) a second nucleotide sequence, wherein the second nucleotide sequence or a polypeptide encoded by the second nucleotide sequence inhibits expression of an endogenous TCR, wherein the anti-MUC5AC TCR binds to the same epitope or an overlapping epitope of human MUC5AC as a reference TCR, the reference TCR comprising an alpha chain and a beta chain, wherein the alpha chain comprises an amino acid sequence as set forth in SEQ ID NO: 1 and the beta chain comprises an amino acid sequence as set forth in SEQ ID NO: 2.

[0011] In some aspects, the anti-MUC5AC TCR binds to an epitope of MUC5AC consisting of an amino acid sequence as set forth in SEQ ID NO: 13. In some aspects, the epitope is complexed with an HLA class II molecule. In some aspects, the HLA class II molecule is an HLA-DP, HLA-DQ, or HLA-DR allele or any combination thereof. In some aspects, the HLA class II molecule is an HLA-DP allele. In some aspects, the HLA class II molecule is an HLA-DP4 allele.

[0012] In some aspects, the anti-MUC5AC TCR comprises an alpha chain and a beta chain, wherein the alpha chain comprises a variable region comprising an alpha chain CDR1, an alpha chain CDR2, and an alpha chain CDR3; and wherein the beta chain comprises a variable domain comprising a beta chain CDR1, a beta chain CDR2, and a beta chain CDR3; wherein the alpha chain CDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 7.

[0013] In some aspects, the beta chain CDR3 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 10.

[0014] In some aspects, the anti-MUC5AC TCR comprises an alpha chain and a beta chain, wherein the alpha chain comprises a variable region comprising an alpha chain CDR1, an alpha chain CDR2, and an alpha chain CDR3; and wherein the beta chain comprises a variable domain comprising a beta chain CDR1, a beta chain CDR2, and a beta chain CDR3; wherein the beta chain CDR3 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 10.

[0015] In some aspects, the alpha chain CDR3 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 7. In some aspects, the alpha chain CDR1 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 5. In some aspects, the beta chain CDR1 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 8. In some aspects, the alpha chain CDR2 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 6. In some aspects, the beta chain CDR2 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 9.

[0016] In some aspects, the alpha chain variable domain of the anti-MUC5AC TCR comprises an amino acid sequence of a variable domain present in the amino acid sequence set forth in SEQ ID NO: 1. In some aspects, the beta chain variable domain of the anti-MUC5AC TCR comprises an amino acid sequence of a variable domain present in the amino acid sequence set forth in SEQ ID NO: 2.

[0017] In some aspects, the alpha chain of the anti-MUC5AC TCR further comprises a constant region, wherein the constant region is different from the endogenous constant region of the alpha chain.

[0018] In some aspects, the alpha chain of the anti-MUC5AC TCR further comprises a constant region, wherein the alpha chain constant region comprises an amino acid sequence having at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to a constant region present in the amino acid sequence set forth in SEQ ID NO: 1.

[0019] In some aspects, the alpha chain constant region comprises an amino acid sequence comprising at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions relative to the constant region present in the amino acid sequence set forth in SEQ ID NO: 1.

[0020] In some aspects, the beta chain of the anti-MUC5AC TCR further comprises a constant region, wherein the constant region is different from the endogenous constant region of the beta chain.

[0021] In some aspects, the beta chain of the anti-MUC5AC TCR further comprises a constant region, wherein the beta chain constant region comprises an amino acid sequence having at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the constant region present in the amino acid sequence set forth in SEQ ID NO: 2.

[0022] In some aspects, the beta chain constant region comprises an amino acid sequence comprising at least 2, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions relative to the constant region present in the amino acid sequence set forth in SEQ ID NO: 2.

[0023] In some aspects, the alpha chain of the anti-MUC5AC TCR comprises the amino acid sequence as set forth in SEQ ID NO: 1. In some aspects, the beta chain of the anti-MUC5AC TCR comprises the amino acid sequence as set forth in SEQ ID NO: 2.

[0024] In some aspects, the second nucleotide sequence is one or more siRNAs that reduce expression of an endogenous TCR. In some aspects, the one or more siRNAs are complementary to a target sequence within a nucleotide sequence encoding a constant region of an endogenous TCR. In some aspects, the one or more siRNAs comprise one or more nucleotide sequences selected from the group consisting of SEQ ID NOs: 25-28.

[0025] In some aspects, the anti-MUC5AC TCR comprises an alpha chain constant region, a beta chain constant region, or both; and wherein the alpha chain constant region, the beta chain constant region, or both comprise an amino acid sequence having at least 1, at least 2, at least 3, at least 4, or at least 5 substitutions within a target sequence relative to the corresponding amino acid sequence of an endogenous TCR.

[0026] In some aspects, the alpha chain comprises a signal peptide, the beta chain comprises a signal peptide, or both the alpha chain and the beta chain comprise a signal peptide. In some aspects, the signal peptide comprises an amino acid sequence selected from the group consisting of the amino acid sequences set forth in SEQ ID NOs: 20-22, and any combination thereof.

[0027] Certain aspects of the present disclosure relate to a vector comprising a nucleic acid molecule disclosed herein. In some aspects, the vector is a viral vector, a mammalian vector, or a bacterial vector. In some aspects, the vector is a retroviral vector. In some aspects, the vector is selected from the group consisting of an adenoviral vector, a lentivirus, a Sendaivirus vector, a baculovirus vector, an Epstein Barr viral vector, a papovaviral vector, a vaccinia viral vector, a herpes simplex viral vector, a hybrid vector, and an adeno-associated viral (AAV) vector. In some aspects, the vector is a lentivirus.

[0028] Certain aspects of the present disclosure relate to a T cell receptor (TCR) or an antigen binding portion thereof comprising an alpha chain variable domain of an anti-MUC5AC TCR disclosed herein and a beta chain variable domain of an anti-MUC5AC TCR disclosed herein.

[0029] Certain aspects of the present disclosure relate to a recombinant T cell receptor (TCR) or an antigen binding portion thereof that specifically binds to human MUC5AC (“anti-MUC5AC TCR”) that cross-competes for binding to human MUC5AC with a reference TCR; wherein the reference TCR comprises an alpha chain and a beta chain, and wherein the alpha chain comprises an amino acid sequence as set forth in SEQ ID NO: 1 and the beta chain comprises an amino acid sequence as set forth in SEQ ID NO: 2; and wherein the anti-MUC5AC TCR comprises an alpha chain and a beta chain, wherein the alpha chain comprises a constant region, and wherein the beta chain comprises a constant region; wherein the alpha chain constant region comprises an amino acid sequence having at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions relative to the constant region present in the amino acid sequence set forth in SEQ ID NO: 1, or the beta chain constant region comprises an amino acid sequence having at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions relative to the constant region present in the amino acid sequence of SEQ ID NO: 2.

[0030] Certain aspects of the present disclosure relate to a recombinant T cell receptor (TCR) or antigen binding portion thereof that specifically binds to human MUC5AC ("anti-MUC5AC TCR"), which binds to the same epitope or an overlapping epitope of human MUC5AC as a reference TCR; wherein the reference TCR comprises an alpha chain and a beta chain, and wherein the alpha chain comprises an amino acid sequence as set forth in SEQ ID NO: 1 and the beta chain comprises an amino acid sequence as set forth in SEQ ID NO: 2; and wherein the anti-MUC5AC TCR comprises an alpha chain and a beta chain, wherein the alpha chain comprises a constant region, and wherein the beta chain comprises a constant region; wherein the alpha chain constant region comprises an amino acid sequence having at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions relative to the constant region present in the amino acid sequence set forth in SEQ ID NO: 1, or the beta chain constant region comprises an amino acid sequence having at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions relative to the constant region present in the amino acid sequence set forth in SEQ ID NO: 2.

[0031] In some aspects, the anti-MUC5AC TCR binds to an epitope of MUC5AC consisting of an amino acid sequence as set forth in SEQ ID NO: 13. In some aspects, the epitope is complexed with an HLA class II molecule. In some aspects, the HLA class II molecule is an HLA-DP, HLA-DQ, or HLA-DR allele or any combination thereof. In some aspects, the HLA class II molecule is an HLA-DP allele. In some aspects, the HLA class II molecule is selected from an HLA-DP4 allele.

[0032] In some aspects, the alpha chain of the anti-MUC5AC TCR comprises a variable domain comprising an alpha chain CDR1, an alpha chain CDR2, and an alpha chain CDR3; and wherein the beta chain of the anti-MUC5AC TCR comprises a variable domain comprising a beta chain CDR1, a beta chain CDR2, and a beta chain CDR3; wherein the alpha chain CDR3 of the anti-MUC5AC comprises an amino acid sequence as set forth in SEQ ID NO: 7.

[0033] In some aspects, the beta chain CDR3 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 10.

[0034] In some aspects, the alpha chain of the anti-MUC5AC TCR comprises a variable domain comprising an alpha chain CDR1, an alpha chain CDR2, and an alpha chain CDR3; wherein the beta chain of the anti-MUC5AC TCR comprises a variable domain comprising a beta chain CDR1, a beta chain CDR2, and a beta chain CDR3; and wherein the beta chain CDR3 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 10.

[0035] In some aspects, the alpha chain CDR3 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 7. In some aspects, the alpha chain CDR1 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 5. In some aspects, the beta chain CDR1 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 8. In some aspects, the alpha chain CDR2 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 6. In some aspects, the beta chain CDR2 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 9.

[0036] In some aspects, the alpha chain variable domain of the anti-MUC5AC TCR comprises an amino acid sequence of a variable domain present in the amino acid sequence set forth in SEQ ID NO: 1. In some aspects, the beta chain variable domain of the anti-MUC5AC TCR comprises an amino acid sequence of a variable domain present in the amino acid sequence set forth in SEQ ID NO: 2.

[0037] In some aspects, the alpha chain constant region comprises an amino acid sequence having at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of a constant region present in the amino acid sequence set forth in SEQ ID NO: 1.

[0038] In some aspects, the beta chain constant region comprises an amino acid sequence having at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of a constant region present in the amino acid sequence set forth in SEQ ID NO: 2.

[0039] In some aspects, the alpha chain of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 1. In some aspects, the beta chain of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 2.

[0040] In some aspects, the alpha chain comprises a signal peptide, the beta chain comprises a signal peptide, or both the alpha chain and the beta chain comprise a signal peptide. In some aspects, the signal peptide comprises an amino acid sequence selected from the group consisting of the amino acid sequences listed in SEQ ID NOs: 20-22, and any combination thereof.

[0041] Certain aspects of the present disclosure relate to a bispecific TCR comprising a first antigen binding domain and a second antigen binding domain, wherein the first antigen binding domain comprises a TCR or antigen binding portion thereof disclosed herein.

[0042] In some aspects, the first antigen binding domain comprises a single chain variable fragment (“scFv”). In some aspects, the second antigen binding domain specifically binds to a protein expressed on the surface of a T cell. In some aspects, the second antigen binding domain specifically binds to CD3. In some aspects, the second antigen binding domain comprises a scFv. In some aspects, the first antigen binding domain and the second antigen binding domain are linked or associated by a covalent bond. In some aspects, the first antigen binding domain and the second antigen binding domain are linked by a peptide bond.

[0043] Certain aspects of the present disclosure relate to a cell comprising a nucleic acid molecule disclosed herein, a vector disclosed herein, a TCR disclosed herein, a recombinant TCR disclosed herein, or a bispecific TCR disclosed herein. In some aspects, the cell further expresses CD3.

[0044] In some aspects, the cell is selected from the group consisting of a T cell, a natural killer (NK) cell, a natural killer T (NKT) cell, or an ILC cell.

[0045] Certain aspects of the present disclosure relate to a method of treating a cancer in a subject in need thereof, comprising administering to the subject a cell disclosed herein. In some aspects, the cancer is selected from the group consisting of melanoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, NHL, primary mediastinal large B-cell lymphoma (PMBC), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), transformed follicular lymphoma, splenic marginal zone lymphoma (SMZL), esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of the soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) (including non T-cell ALL), chronic lymphocytic leukemia (CLL), solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the CNS, primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, other B-cell malignancies, and combinations of said cancers.

[0046] In some aspects, the cancer is relapsed or refractory. In some aspects, the cancer is locally advanced. In some aspects, the cancer is advanced. In some aspects, the cancer is metastatic.

[0047] In some aspects, the cell is obtained from the subject. In some aspects, the cell is obtained from a donor other than the subject.

[0048] In some aspects, the subject is pre-treated prior to administration of the cells. In some regimens, the pre-treatment comprises administration of chemotherapy, cytokine, protein, small molecule, or any combination thereof to the subject. In some aspects, the pre-treatment comprises administration of interleukin. In some aspects, the pre-treatment comprises administration of IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, or any combination thereof. In some aspects, the pre-treatment comprises administration of a pre-treatment agent selected from the group consisting of cyclophosphamide, fludarabine, Vitamin C, an AKT inhibitor, ATRA, Rapamycin, or any combination thereof. In some aspects, the pre-treatment comprises administration of cyclophosphamide, fludarabine, or both.

[0049] Certain aspects of the present disclosure relate to a method of engineering a cell targeting an antigen, the method comprising transducing a cell collected from a subject in need of a T cell therapy with a nucleic acid molecule disclosed herein or a vector disclosed herein. In some aspects, the cell targeting an antigen further expresses CD4. In some aspects, the cell is a T cell or a natural killer (NK) cell.

[0050] Certain aspects of the present disclosure relate to an HLA class II molecule complexed with a peptide, wherein the HLA class II molecule comprises an alpha chain and a beta chain; and wherein the peptide consists of an amino acid sequence as set forth in SEQ ID NO: 13. In some aspects, the HLA class II molecule is an HLA-DP, HLA-DQ, or HLA-DR allele or any combination thereof. In some aspects, the HLA class II molecule is an HLA-DP allele. In some aspects, the HLA class II molecule is an HLA-DQ allele. In some aspects, the HLA class II molecule is an HLA-DR allele.

[0051] In some aspects, the HLA class II molecule is a monomer. In some aspects, the HLA class II molecule is a dimer. In some aspects, the HLA class II molecule is a trimer. In some aspects, the HLA class II molecule is a tetramer. In some aspects, the HLA class II molecule is a pentamer.

[0052] Certain aspects of the present disclosure relate to an antigen presenting cell (APC) comprising an HLA class II molecule disclosed herein. In some aspects, the HLA class I molecule is expressed on the surface of the APC.

[0053] Certain aspects of the present disclosure relate to a method of enriching a population of target T cells obtained from a human subject, the method comprising contacting the T cells with an HLA class II molecule disclosed herein or an APC disclosed herein, wherein following the contacting, the enriched population of T cells comprises a higher number of T cells capable of binding to the HLA class II molecule relative to the number of T cells capable of binding to the HLA class II molecule prior to the contacting.

[0054] Certain aspects of the present disclosure relate to a method of enriching a population of target T cells obtained from a human subject, the method comprising contacting the T cells in vitro with a peptide, wherein the peptide consists of an amino acid sequence as set forth in SEQ ID NO: 13, wherein following the contacting, the enriched population of T cells comprises a higher number of T cells capable of targeting tumor cells relative to the number of T cells capable of targeting tumor cells prior to the contacting. In some aspects, the T cells obtained from a human subject are tumor infiltrating lymphocytes (TILs).

[0055] Certain aspects of the present disclosure relate to a method of treating a tumor in a subject in need thereof, the method comprising administering to the subject one or more enriched T cells disclosed herein.

[0056] Certain aspects of the present disclosure relate to a method of enhancing cytotoxic T cell-mediated targeting of cancer cells in a subject afflicted with a cancer, the method comprising administering to the subject a peptide having an amino acid sequence as set forth in SEQ ID NO: 13.

[0057] Certain aspects of the present disclosure relate to a cancer vaccine comprising a peptide having an amino acid sequence as set forth in SEQ ID NO: 13.

[0058] Certain aspects of the present disclosure relate to a method of selecting T cells capable of targeting tumor cells, the method comprising contacting a population of isolated T cells in vitro with a peptide, wherein the peptide consists of an amino acid sequence as set forth in SEQ ID NO: 13.

[0059] In some aspects, the T cells are tumor infiltrating lymphocytes (TILs). BRIEF DESCRIPTION OF DRAWINGS

[0060] Figures 1A-1B DP4 T cells from melanoma patients + T cells from melanoma patients L112W / V141M Graphical representation of the dimer staining. Primary CD4 + T cells from six DP4 + Melanoma patients were purified and stimulated with aAPCs expressing DP4, which were loaded with MUC5AC 4922-4941Peptide pulses and homologous DP4 L112W / V141M Dimer staining. This shows DP4. L112W / V141M An example of dimer staining.

[0061] Figures 2A-2D To illustrate from DP4 L112W / V141M Dimer-positive cells were isolated and isolated from human TCR-deficient CD4 cells. + Recombinant DP4-restricted (05-MUC5AC) in T cells 4922-4941 Graphical representation of TCR function in DP4-restricted and antigen-specific ways. 05-MUC5AC 4922-4941 From DP4 L112W / V141M Dimer-positive cell clones were recombined in TCR-deficient Jurkat 76 / CD4 cells and converted to DP4. L112W / V141M Dimer staining.

[0062] Figure 3 To illustrate the use of MUC5AC in the IL-2 ELISPOT assay 4922-4941 O5-MUC5AC stimulated by aAPC of peptide pulses 4922-4941 Bar graph of IL-2EPISPOT assay results. DP4 / WT1 (clone 9) TCR was used as a negative control. At least two independent experiments were performed. The bar graph and error bars represent the mean ± SD of the results from triplicate experiments.

[0063] Figures 4A-4E illustrate the flow from DP4 L112W / V141M Dimer-positive cells were isolated and isolated from human primary CD4 cells. + Recombinant DP4-restricted MUC5AC in T cells 4922-4941 Graphical representation of data on TCR functioning in a DP4-restrictive and antigen-specific manner. 05-MUC5AC 4922-4941 Retrovirus transduction to human primary CD4 + T cells, and with the corresponding DP4 L112W / V141M Dimer staining. *P < 0.05 was determined by Student's t-test. The bar graph and error bars represent the mean ± SD of the results from three experiments. Figure 4E ).

[0064] Figure 5 To demonstrate the use of 05-MUC5AC 4922-4941 Retroviral transduction and HLA-ineffective peptide-inactivated or MUC5AC 4914-4949Bar graph of results from IFN-γ ELISPOT assays of DP4-aAPC stimulated human primary T cells transduced with the mini gene (MHYQCQCVCSGWGDPHYITFDGTYYTFLDNCTYVLVQ; SEQ ID NO: 29). *, P < 0.05 by Student's t-test. Bar graphs and error bars represent the mean ± SD of results in triplicate experiments. DETAILED DESCRIPTION

[0065] The present disclosure relates to TCRs or antigen binding portions thereof that specifically bind to an epitope on MUC5AC, nucleic acid molecules encoding the TCRs, and cells comprising the TCRs or the nucleic acid molecules. Some aspects of the present disclosure relate to methods of treating cancer in a subject in need thereof. Other aspects of the present disclosure relate to HLA class II molecules complexed with a peptide comprising an epitope of MUC5AC.

[0066] I. Terminology

[0067] To make the present disclosure more readily understandable, certain terms are defined first. As used in this application, each of the following terms, unless otherwise indicated, shall have the meaning set forth below. Additional definitions are set forth throughout this application.

[0068] It should be noted that the terms "a" or "an" entity mean one or more than one of the entity; for example, "a nucleotide sequence" should be understood as meaning one or more nucleotide sequences. As such "a" or "an" and "one or more" and "at least one" are used interchangeably herein.

[0069] Also, "and / or" where used herein is to be taken as specific disclosure of each of the two specified features or components and if desired, each of the two specified features or components individually. Likewise, "or" where used herein is to be taken as specific disclosure of each of the two specified features or components and if desired, each of the two specified features or components individually. In other words, "A or / and B" or "A and / or B" shall mean either A or B or both A and B. Likewise, "A, B, and / or C" shall mean A, B, C, A and B, A and C, B and C, A, B and C, or any like combination.

[0070] The term "about" is used herein to refer to approximately, roughly, around, or in the vicinity of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical values by a margin of experimentation. Generally, the term "about" is used herein to modify a numerical value above and below which a number falls that is within a 10% upward or downward deviation from the stated value.

[0071] It should be appreciated that wherever used, the word "comprising" is used herein in the broadest possible sense i.e. to mean including, but not limited to.

[0072] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure.

[0073] Units, prefixes and symbols are denoted in their Systeme International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. Unless otherwise indicated, nucleotide sequences are written left to right in 5' to 3' orientation. Amino acid sequences are written left to right in amino to carboxyl orientation. The headings provided herein are not limitations of the various aspects of the disclosure, which can be had by reference to the specification as a whole. Accordingly, the terms defined immediately below are more fully defined by reference to the specification as a whole.

[0074] "Administration" means the physical introduction of an agent into a subject using any of the various methods and delivery systems known to those skilled in the art. Exemplary routes of administration for the formulations disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral administration routes, such as by injection or infusion. As used herein, the phrase "parenteral administration" means a mode of administration other than enteral and local administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrasheathal, intralymphatic, intralesional, intracapsular, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, spinal, epidural, and intrasternal injections and infusions, as well as in vivo electroporation. In some aspects, the formulation is administered via a non-parenteral route (e.g., orally). Other non-parenteral routes include local, transdermal, or transmucosal administration routes, such as intranasal, vaginal, rectal, sublingual, or local administration. It can also be applied, for example, once, multiple times, and / or over one or more extended time periods.

[0075] As used herein, the term “T cell receptor” (TCR) refers to a heterogeneous cell surface receptor capable of specifically interacting with a target antigen. As used herein, “TCR” includes, but is not limited to, naturally occurring and non-naturally occurring TCRs; full-length TCRs and their antigen-binding portions; chimeric TCRs; TCR fusion constructs; and synthetic TCRs. In humans, TCRs are expressed on the surface of T cells and are responsible for T cell recognition and targeting by antigen-presenting cells. Antigen-presenting cells (APCs) display fragments of foreign proteins (antigens) that are complexed with the major histocompatibility complex (MHC; also referred to herein as complexed with HLA molecules, such as HLA class II molecules). TCRs recognize and bind to the peptide:HLA complex and recruit CD8 (for MHC class I molecules) or CD4 (for MHC class II molecules), thereby activating the TCR. Activated TCRs initiate downstream signaling and immune responses, including the disruption of EPCs.

[0076] Generally, a TCR may consist of two chains interconnected by disulfide bonds, an α-chain and a β-chain (or less commonly, a γ-chain and a δ-chain). Each chain contains variable domains (α-chain variable domains and β-chain variable domains) and constant regions (α-chain constant regions and β-chain constant regions). The variable domains are located at the distal end of the cell membrane and interact with the antigen. The constant regions are located at the proximal end of the cell membrane. A TCR may also contain a transmembrane region and a short cytoplasmic tail. As used herein, the term "constant region" encompasses both the transmembrane region and the cytoplasmic tail (when present) as well as the conventional "constant region".

[0077] The variable domains can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each alpha chain variable domain and beta chain variable domain comprises three CDRs and four FRs: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Each variable domain contains a binding domain that interacts with an antigen. While all three CDRs on each chain are involved in antigen binding, it is believed that CDR3 is the primary antigen binding region, while CDR1 and CDR2 are believed to primarily recognize the HLA molecule.

[0078] The term "TCR" also includes, unless clearly indicated otherwise, and unless otherwise indicated by context, an antigen binding fragment or antigen binding portion of any of the TCRs disclosed herein, and includes monovalent and bivalent fragments or portions, and single chain TCRs. The term "TCR" is not limited to naturally occurring TCRs that bind to the surface of a T cell. As used herein, the term "TCR" further refers to a TCR as described herein expressed on the surface of a cell other than a T cell, e.g., a cell that naturally expresses or is modified to express CD4 as described herein, or a TCR as described herein that is not contained within a cell membrane, e.g., an isolated TCR or a soluble TCR.

[0079] An "antigen binding molecule," "portion of a TCR," or "TCR fragment" refers to any portion of a TCR that is less than the whole. An antigen binding molecule can include an antigen CDR.

[0080] An "antigen" refers to any molecule, e.g., a peptide, that elicits an immune response or is capable of being bound by a TCR. As used herein, an "epitope" refers to the portion of a polypeptide that elicits an immune response or is capable of being bound by a TCR. The immune response can involve antibody production or activation of specific immune-competent cells or both. Those skilled in the art will readily recognize that any large molecule, including virtually all proteins or peptides, can serve as an antigen. An antigen and / or epitope can be expressed endogenously, i.e., from genomic DNA, or can be expressed recombinantly. An antigen and / or epitope can be specific for a certain tissue, such as a cancer cell, or it can be widely expressed. Furthermore, fragments of larger molecules can serve as antigens. In one aspect, the antigen is a tumor antigen. An epitope can exist in a longer polypeptide, e.g., a protein, or an epitope can exist as a fragment of a longer polypeptide. In some aspects, the epitope is complexed with a major histocompatibility complex (MHC; also referred to herein as with an HLA molecule, e.g., an HLA class 1 molecule).

[0081] As used herein, "MUC5AC" or "mucin 5AC" refers to a human gel-forming glycoprotein of the gastric and respiratory epithelium that protects the mucosa from infection and chemical damage by binding to inhaled microorganisms and particles, which are subsequently removed by the mucociliary system.

[0082] As used herein, MUC5AC refers not only to the full-length canonical sequence, but also to variants and fragments thereof. The amino acid sequence of MUC5AC (SEQ ID NO: 16) is provided in Table 1 (UniProtKB - P98088).

[0083] Table 1. MUC5AC amino acid sequence

[0084]

[0085]

[0086]

[0087] As used herein, the term “HLA” refers to human leukocyte antigen. HLA genes encode major histocompatibility complex (MHC) proteins in humans. MHC proteins are expressed on the surface of cells and are involved in the activation of immune responses. HLA class II genes encode MHC class II proteins that are expressed on the surface of professional antigen presenting cells (APCs). Non-limiting examples of professional APCs include monocytes, macrophages, dendritic cells (DCs), and B lymphocytes. Some endothelial and epithelial cells can also express MHC class II molecules upon activation of inflammatory signals. Humans lacking functional MHC class II molecules are highly susceptible to a range of infectious diseases and typically die in early childhood.

[0088] As used herein, “HLA class II molecule” or “MHC class II molecule” refers to the protein product of a wild-type or variant HLA class II gene that encodes a MHC class II molecule. Thus, “HLA class II molecule” and “MHC class II molecule” are used interchangeably herein. A typical MHC class II molecule comprises two protein chains: an alpha chain and a beta chain. Generally, each of the naturally occurring alpha and beta chains comprises a transmembrane domain that anchors the alpha / beta chain to the cell surface and an extracellular domain that carries an antigen and interacts with TCRs and / or CD4 expressed on T cells.

[0089] The MHC class II alpha and beta chains are both encoded by the HLA gene complex. The HLA complex is located within the 6p21.3 region on the short arm of human chromosome 6 and contains over 220 genes with multiple functions. The HLA gene complex is highly variable, with over 20,000 HLA alleles and related alleles known in the art, including over 250 MHC class II alpha chain alleles and 5,000 MHC class II beta chain alleles, which encode thousands of MHC class II proteins (see, e.g., hla.alleles.org, last accessed May 20, 2019, incorporated by reference herein in its entirety). For example, one such HLA-DP allele, DP4, is the most common allele in many ethnic populations.

[0090] Three loci in the HLA complex encode MHC class II proteins: HLA-DP, HLA-DQ, and HLA-DR. HLA-DO and HLA-DM encode proteins that associate with MHC class II molecules and support their configuration and function.

[0091] When MHC class II molecules are complexed with an antigenic peptide, an antigenic peptide 10-30 amino acids long binds the peptide binding groove and is presented extracellularly to CD4+ cells. Both the alpha and beta chains fold into two separate domains; alpha-1 and alpha-2 for the alpha polypeptide, and beta-1 and beta-2 for the beta polypeptide. An open peptide binding groove is found between the alpha-1 domain and the beta-1 domain that accommodates the presented antigen. Upon interaction with CD4+ T cells, the MHC class II complex interacts with a T cell receptor (TCR) expressed on the surface of T cells. In addition, the beta chain of the MHC class II molecule weakly interacts with CD4 expressed on the surface of T cells (K D A typical CD4 amino acid sequence (UniProt - P01730) is provided in Table 2 (SEQ ID NO: 17).

[0092] Table 2. Human CD4 amino acid sequence

[0093]

[0094] The term “autologous” refers to any material derived from the same individual as the individual to which the any material is subsequently reintroduced. For example, an autologous T cell therapy includes administration of T cells isolated from the same subject to the subject. The term “allogeneic” refers to any material derived from one individual and then introduced into another individual of the same species. For example, an allogeneic T cell transplant includes administration of T cells obtained from a donor other than the subject to the subject.

[0095] "Cancer" refers to a large set of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth results in the formation of malignant tumors, which invade neighboring tissues and can also metastasize to distant parts of the body through the lymphatic system or bloodstream. "Cancer" or "cancerous tissue" can include a tumor. Examples of cancers that can be treated by the methods of the present application include, but are not limited to, cancers of the immune system, including lymphomas, leukemias, and other white blood cell malignancies. In some aspects, the methods of the present application can be used to reduce the tumor size of a tumor derived from, for example, bone cancer, kidney cancer, prostate cancer, breast cancer, colon cancer, lung cancer, malignant melanoma of the skin or eye, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma (NHL), primary mediastinal large B cell lymphoma (PMBC), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), transformed follicular lymphoma, splenic marginal zone lymphoma (SMZL), esophageal cancer, small bowel cancer, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) (including non-T cell ALL), chronic lymphocytic leukemia (CLL), solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers (including those induced by asbestos), other B-cell malignancies, and combinations of said cancers. A particular cancer can be responsive to chemotherapy or radiation therapy or the cancer can be refractory.

[0096] Refractory cancer refers to a cancer that is not amenable to surgical intervention and the cancer is initially unresponsive or becomes unresponsive over time to chemotherapy or radiation therapy.

[0097] As used herein, "anti-tumor effect" refers to a biological effect that can exist in the form of a reduction in tumor volume, a reduction in the number of tumor cells, a reduction in tumor cell proliferation, a reduction in the number of metastases, an increase in overall or progression-free survival, an increase in life expectancy, or an improvement in various physiological symptoms associated with the tumor. Anti-tumor effect can also refer to the prevention of tumor occurrence, e.g., a vaccine.

[0098] The term "progression-free survival" can be abbreviated as PFS and, as used herein, refers to the length of time during treatment after which disease progression or death from any cause occurs according to the revised IWG Response Criteria for Malignant Lymphoma.

[0099] "Disease progression" or "progressive disease" can be abbreviated as PD and, as used herein, refers to the worsening of one or more symptoms associated with a particular disease. For example, disease progression in a subject afflicted with cancer can include an increase in the number or size of one or more malignant lesions, tumor metastasis, and death.

[0100] "Duration of response" can be abbreviated as DOR and, as used herein, refers to the length of time between a subject's first objective response and the date of disease progression or death according to the revised IWG Response Criteria for Malignant Lymphoma.

[0101] The term "overall survival" can be abbreviated as OS and is defined as the length of time from the treatment date to the date of death.

[0102] As used herein, “cytokine” refers to a non-antibody protein released by a cell in response to contact with a specific antigen, where the cytokine interacts with a second cell to mediate a response in the second cell. Cytokines can be expressed endogenously by a cell or administered to a subject. Cytokines can be released by immune cells including macrophages, B cells, T cells, and mast cells to propagate an immune response. Cytokines can induce various responses in recipient cells. Cytokines can include homeostatic cytokines, chemokines, proinflammatory cytokines, effectors, and acute phase proteins. For example, homeostatic cytokines including interleukin (IL) 7 and IL-15 promote immune cell survival and proliferation, and proinflammatory cytokines can promote an inflammatory response. Examples of homeostatic cytokines include, but are not limited to, IL-2, IL-4, IL-5, IL-7, IL-10, IL-12p40, IL-12p70, IL-15, and interferon (IFN) gamma. Examples of proinflammatory cytokines include, but are not limited to, IL-la, IL-lb, IL-6, IL-13, IL-17a, tumor necrosis factor (TNF)-alpha, TNF-beta, fibroblast growth factor (FGF) 2, granulocyte macrophage colony-stimulating factor (GM-CSF), soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular adhesion molecule 1 (sVCAM-1), vascular endothelial growth factor (VEGF), VEGF-C, VEGF-D, and placental growth factor (PLGF). Examples of effectors include, but are not limited to, granzyme A, granzyme B, soluble Fas ligand (sFasL), and perforin. Examples of acute phase proteins include, but are not limited to, C-reactive protein (CRP) and serum amyloid A (SAA).

[0103] “Chemokine” is a class of cytokines that mediate chemotaxis or directed movement of cells. Examples of chemokines include, but are not limited to, IL-8, IL-16, eotaxin, eotaxin-3, macrophage-derived chemokine (MDC or CCL22), monocyte chemotactic protein 1 (MCP-1 or CCL2), MCP-4, macrophage inflammatory protein 1 alpha (MIP-1 alpha, MIP-1a), MIP-1 beta (MIP-1b), gamma-inducible protein 10 (IP-10), and thymus and activation-regulated chemokine (TARC or CCL17).

[0104] Other examples of analytes and cytokines of the present invention include, but are not limited to, chemokine (C-C motif) ligand (CCL) 1, CCL5, monocyte-specific chemokine 3 (MCP3 or CCL7), Monocyte Chemotactic Protein 2 (MCP-2 or CCL8), CCL13, IL-1, IL-3, IL-9, IL-11, IL-12, IL-14, IL-17, IL-20, IL-21, granulocyte colony-stimulating factor (G-CSF), leukemia inhibitory factor (LIF), oncostatin M (OSM), CD154, lymphotoxin (LT) beta, 4-1BB ligand (4-1BBL), a proliferation-inducing ligand (APRIL), CD70, CD153, CD178, glucocorticoid-induced TNFR-related ligand (GITRL), tumor necrosis factor superfamily member 14 (TNFSF14), OX40L, TNF-related and ApoL-related leukocyte-expressed ligand 1 (TALL-1), or TNF-related apoptosis-inducing ligand (TRAIL).

[0105] A "therapeutically effective amount," "effective dose," "effective amount," or "therapeutically effective dose" of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, prevents the onset of a disease or promotes the regression of a disease as evidenced by a decrease in the severity of symptoms of the disease, an increase in the frequency and duration of symptom-free periods of the disease, or the prevention of impairment or disability due to the disease. The ability of a therapeutic agent to promote the regression of a disease can be assessed using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by determining the activity of the agent in in vitro assays.

[0106] The term "lymphocyte" as used herein includes a natural killer (NK) cell, a T cell, or a B cell. NK cells are a type of cytotoxic / cell toxic lymphocyte that represents a major component of the innate immune system. NK cells reject tumors and cells infected by viruses. They work through a process of apoptosis or programmed cell death. They are called "natural killers" because they do not require activation to kill cells. T cells play a major role in cell-mediated immunity (not involving antibodies). The T cell receptor (TCR) distinguishes T cells from other lymphocyte types. The thymus, a specialized organ of the immune system, is primarily responsible for the maturation of T cells. There are six types of T cells, namely: helper T cells (e.g., CD4+ cells), cytotoxic T cells (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T cell, or killer T cell), memory T cells ((i) stem cell memory T cells (TSCM), (ii) central memory T cells (TCM), (iii) effector memory T cells (TEM), (iv) terminally differentiated effector memory T cells (TEMRA), and (v) peripheral SCMCells (such as naive cells) are CD45RO-, CCR7+, CD45RA+, CD62L+ (L-selectin), CD27+, CD28+, and IL-7Ra+, but they also express large amounts of CD95, IL-2Rβ, CXCR3, and LFA-1, and show many of the functional characteristics unique to memory cells); (ii) central memory T CM Cells express L-selectin and CCR7, secrete IL-2, but not IFNy or IL-4, and (iii) effector memory T EM Cells do not express L-selectin or CCR7, but produce effector cytokines such as IFNy and IL-4), regulatory T cells (Tregs, suppressor T cells, or CD4+CD25+ regulatory T cells), natural killer T cells (NKT), and gd T cells. B cells, on the other hand, play a major role in humoral immunity (involving antibodies). B cells produce antibodies and antigens and function as antigen presenting cells (APCs) and become memory B cells upon activation by antigen interaction. In mammals, immature B cells are formed in the bone marrow from which the B cell designation is derived.

[0107] The term "genetically engineered" or "engineered" refers to a method of modifying the genome of a cell, including but not limited to deletion of a coding or non-coding region or a portion thereof or insertion of a coding region or a portion thereof. In some aspects, the modified cell is a lymphocyte, e.g., a T cell or a modified cell expressing CD4, which can be obtained from a patient or a donor. The cell can be modified to express an exogenous construct, such as a T cell receptor (TCR) as disclosed herein, incorporated into the genome of the cell. In some aspects, the cell is modified to express CD4.

[0108] An "immune response" refers to the actions of cells of the immune system (e.g., T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells, and neutrophils) and soluble macromolecules (including Abs, cytokines, and complement) produced by any of these cells or the liver that result in the selective targeting, binding, damaging, destruction, and / or elimination of an invading pathogen, a pathogen-infected cell or tissue, a cancer cell or other abnormal cell, or a normal human cell or tissue in an autoimmune or pathologic inflammatory situation within a vertebrate animal.

[0109] The term "immunotherapy" refers to the treatment of a subject afflicted with, or at risk for acquiring or experiencing a recurrence of, a disease by a method involving the induction, enhancement, suppression or other modification of an immune response. Examples of immunotherapy include, but are not limited to, T cell therapy. T cell therapy can include adoptive T cell therapy, tumor infiltrating lymphocyte (TIL) immunotherapy, autologous cell therapy, engineered autologous cell therapy (eACT), and allogeneic T cell transplantation.

[0110] The cells used in the immunotherapy described herein can be from any source known in the art. For example, the T cells can be distinguished from a population of hematopoietic stem cells in vitro, or the T cells can be obtained from a subject. The T cells can be obtained from, for example, peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In addition, the T cells can be derived from one or more T cell lines available in the art. The T cells can also be obtained from a subject using methods known to the skilled artisan, such as FICOLL TM Any number of techniques for separation and / or apheresis of a unit of blood collected from a subject. Other methods for isolating T cells for T cell therapy are disclosed in U.S. Patent Publication No. 2013 / 0287748, which is incorporated by reference herein in its entirety. Immunotherapy can also include administering to a subject a modified cell, wherein the modified cell expresses CD4 and a TCR disclosed herein. In some aspects, the modified cell is not a T cell.

[0111] A "patient" as used herein includes any human afflicted with a cancer, such as a lymphoma or leukemia. The terms "subject" and "patient" are used interchangeably herein.

[0112] The terms "peptide," "polypeptide," and "protein" are used interchangeably and refer to a compound comprising amino acid residues linked by peptide bonds. A protein or peptide must contain at least two amino acids, and there is no maximum number of amino acids to which the sequence of a protein or peptide can be limited. A polypeptide includes any peptide or protein comprising two or more amino acids linked to one another by peptide bonds. As used herein, the terms refer to short chains, which are also referred to in the art as, for example, peptides, oligopeptides, and oligomers; as well as to longer chains, which are also referred to in the art as proteins. "Polypeptide" includes, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, polypeptide variants, modified polypeptides, derivatives, analogs, fusion proteins, and the like. A polypeptide includes a natural, recombinant, synthetic, or a combination thereof.

[0113] As used herein, "stimulation" refers to a primary response induced by the binding of a stimulatory molecule to its cognate ligand, wherein the binding mediates a signal transduction event. A "stimulatory molecule" is a molecule on a T cell that specifically binds to a cognate stimulatory ligand present on an antigen presenting cell, such as the T cell receptor (TCR) / CD4 complex. A "stimulatory ligand" is a ligand that, when present on an antigen presenting cell (e.g., aAPC, dendritic cell, B cell, and the like), can specifically bind to a stimulatory molecule on a T cell, thereby mediating a primary response by the T cell, including but not limited to activation, initiation of an immune response, proliferation, and the like. Stimulatory ligands include, but are not limited to, MHC class II molecules loaded with peptide, anti-CD4 antibodies, superagonist anti-CD2 antibodies, superagonist anti-CD28 antibodies, and superagonist anti-CD3 antibodies.

[0114] The terms "treatment" and "pretreatment" are used interchangeably herein and indicate preparing a patient in need of a T cell therapy for suitability. Treatment as used herein includes, but is not limited to, reducing the number of endogenous lymphocytes, removing a cytokine sink, increasing the serum content of one or more homeostatic cytokines or proinflammatory factors, enhancing the effector function of T cells administered post-treatment, enhancing antigen presenting cell activation and / or availability, or any combination thereof prior to a T cell therapy. In one aspect, "treatment" includes increasing the serum content of one or more cytokines, such as interleukin 7 (IL-7), interleukin 15 (IL-15), interleukin 10 (IL-10), interleukin 5 (IL-5), gamma-induced protein 10 (IP-10), interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1), placental growth factor (PLGF), C-reactive protein (CRP), soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular adhesion molecule 1 (sVCAM-1), or any combination thereof. In another aspect, "treatment" includes increasing the serum content of IL-7, IL-15, IP-10, MCP-1, PLGF, CRP, or any combination thereof.

[0115] "Treatment" or "treating" of a subject refers to any type of intervention or process performed on a subject or administration of an active agent to a subject with the objective to reverse, alleviate, ameliorate, inhibit, slow down or prevent the onset, progression, development, severity or recurrence of a symptom, complication or condition associated with a disease or a biochemical marker. In one aspect, "treatment" or "treating" includes partial remission. In another aspect, "treatment" or "treating" includes complete remission.

[0116] The use of the alternative (e.g.,“or”) should be understood to mean either one, but not both, of the alternatives. As used herein, the indefinite article“a” or“an” should be understood to mean“one or more” of any recited or enumerated component.

[0117] The term“about” or“substantially” refers to a value or composition that is within an acceptable error range for the value or composition as determined by one of ordinary skill in the art, which will depend on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example,“about” or“substantially” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively,“about” or“substantially” can mean ranges approximately 10% of the indicated value (i.e., ±10%). For example, about 3 mg can include any number between 2.7 mg and 3.3 mg (for 10%). Also, particularly with respect to biological systems or processes, the terms can mean within one or more orders of magnitude. When a particular value or composition is provided in the application and claims, unless otherwise stated the meaning of“about” or“substantially” should be assumed to be within an acceptable error range of the particular value or composition.

[0118] Unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range described herein is to be understood to include any and all sub-ranges of the same, e.g., every combination of variable endpoints of the ranges listed. For example, a range of“1 to 10” is to be understood to include, individually and / or in combination with one another, the following ranges: 1 to 10; 3 to 7; 5 to 6; 4 to 8; 3 to 9; etc.

[0119] Various aspects of the application are described in more detail in the following subsections.

[0120] II. Compositions of the Disclosure

[0121] The present disclosure relates to T cell receptors (TCRs) or antigen binding portions thereof that specifically bind to an epitope on MUC5AC, nucleic acid molecules encoding the TCRs, and cells comprising the TCRs or the nucleic acid molecules. Some aspects of the present application relate to methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject a cell comprising a TCR described herein. Other aspects of the present disclosure relate to an epitope of MUC5AC bound by a TCR, and an HLA class II molecule complexed with a peptide comprising the epitope of MUC5AC.

[0122] A T cell receptor or TCR is a molecule present on the surface of a T cell or T lymphocyte that is responsible for recognizing a fragment of an antigen as a peptide bound to a major histocompatibility complex (MHC) molecule. The binding between a TCR and an antigen peptide is of relatively low affinity and is degenerate: in other words, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.

[0123] The TCR is composed of two different protein chains (in other words, it is a heterodimer). In 95% of human T cells, the TCR is composed of an alpha (a) chain and a beta (b) chain (encoded by TRA and TRB, respectively), but in 5% of human T cells, the TCR is composed of gamma and delta (g / d) chains (encoded by TRG and TRD, respectively). This ratio changes during ontogeny and in disease states, such as leukemia. It also differs among species. Orthologs of four loci have been mapped in various species. Each locus can produce multiple polypeptides with constant and variable regions.

[0124] When the TCR engages with an antigenic peptide and MHC (peptide / MHC), the T lymphocyte is activated through signal transduction, a series of biochemical events mediated by associated enzymes, co-receptors, specialized adaptor molecules, and activated or released transcription factors.

[0125] II.A. NUCLEIC ACID MOLECULES

[0126] Certain aspects of the present disclosure relate to nucleic acid molecules comprising (i) a first nucleotide sequence encoding a recombinant TCR or antigen binding portion thereof that specifically binds to human MUC5AC ("anti-MUC5AC TCR"); and (ii) a second nucleotide sequence, wherein the second nucleotide sequence or polypeptide encoded by the second nucleotide sequence inhibits expression of an endogenous TCR. In some aspects, the second nucleotide sequence is a non-naturally occurring sequence. In other aspects, the second nucleotide sequence is synthetic. In other aspects, the second nucleotide sequence comprises a sequence that targets a nucleotide sequence encoding an endogenous TCR. In some aspects, the anti-MUC5AC TCR cross-competes for binding to human MUC5AC with a reference TCR. In some aspects, the anti-MUC5AC TCR binds to the same epitope or to an overlapping epitope of human MUC5AC as the reference TCR.

[0127] In some aspects, the reference TCR comprises an alpha chain and a beta chain; wherein the alpha chain comprises a complementarity determining region 1 (CDR1), a CDR2, and a CDR3; wherein the beta chain comprises a CDR1, a CDR2, and a CDR3; and wherein the reference TCR comprises an alpha chain CDR3 set forth in SEQ ID NO: 7 and a beta chain CDR3 set forth in SEQ ID NO: 10. In some aspects, the alpha chain CDR1, CDR2, and CDR3 sequences are present in the amino acid sequence set forth in SEQ ID NO: 1, and the reference TCR comprises the beta chain CDR1, CDR2, and CDR3 sequences present in the amino acid sequence set forth in SEQ ID NO: 2. In some aspects, the reference TCR comprises an alpha chain and a beta chain, wherein the alpha chain comprises an amino acid sequence as set forth in SEQ ID NO: 1 and the beta chain comprises an amino acid sequence as set forth in SEQ ID NO: 2.

[0128] Table 3. Alpha and Beta Chain TCR Sequences

[0129]

[0130]

[0131] II.A.1. TCR Encoded by the First Nucleotide Sequence

[0132] The present disclosure relates to a TCR encoded by the first nucleotide sequence described herein. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises an alpha chain and a beta chain, wherein the alpha chain comprises a variable domain comprising an alpha chain CDR1, an alpha chain CDR2, and an alpha chain CDR3; and wherein the beta chain comprises a variable domain comprising a beta chain CDR1, a beta chain CDR2, and a beta chain CDR3. In some aspects, the anti-MUC5AC TCR comprises an alpha chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 7 (CAFMKRAETSGSRLTF). In some aspects, the anti-MUC5AC TCR comprises a beta chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 10 (CASSYWPTRETQYF). In some aspects, a non-CDR region in the alpha chain and / or the beta chain is further modified, for example, a substitution or mutation of one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, or six amino acids, whereby the alpha chain and / or the beta chain is not naturally occurring. In some aspects, the substitution or mutation can improve the TCR described herein in various ways, for example, binding affinity, binding specificity, stability, viscosity, or any combination thereof.

[0133] In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises an alpha chain CDR1, wherein the alpha chain CDR1 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 5 (TSESNYY). In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises a beta chain CDR1, wherein the beta chain CDR1 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 8 (MNHEY).

[0134] In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises an alpha chain CDR2, wherein the alpha chain CDR2 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 6 (QEAYKQQN). In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises a beta chain CDR2, wherein the beta chain CDR2 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 9 (SVGEGT).

[0135] In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises an alpha chain variable domain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the variable domain of the alpha chain amino acid sequence set forth in SEQ ID NO: 1. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises an alpha chain variable domain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the variable domain of the alpha chain amino acid sequence set forth in SEQ ID NO: 1, wherein the anti-MUC5AC TCR comprises an alpha chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 7. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises an alpha chain variable domain present in the alpha chain amino acid sequence set forth in SEQ ID NO: 1.

[0136] In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises a beta chain variable domain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the variable domain of the beta chain amino acid sequence set forth in SEQ ID NO: 2. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises a beta chain variable domain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the variable domain of the beta chain amino acid sequence set forth in SEQ ID NO: 2, wherein the anti-MUC5AC TCR comprises a beta chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 10. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises a beta chain variable domain present in the amino acid sequence set forth in SEQ ID NO: 2.

[0137] In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence further comprises an alpha chain constant region, a beta chain constant region, or both an alpha chain constant region and a beta chain constant region. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises an alpha chain constant region having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the constant region of the alpha chain amino acid sequence set forth in SEQ ID NO: 1. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises an alpha chain constant region having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the constant region of the alpha chain amino acid sequence set forth in SEQ ID NO: 1, wherein the anti-MUC5AC TCR comprises an alpha chain CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 7. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises the alpha chain constant region present in the alpha chain amino acid sequence set forth in SEQ ID NO: 1. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence further comprises an alpha constant region that is different from the endogenous (e.g., naturally occurring) constant region of the alpha chain. In some aspects, the alpha chain constant region comprises an amino acid sequence comprising at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions relative to the amino acid sequence of the constant region of the alpha chain amino acid sequence set forth in SEQ ID NO: 1.

[0138] In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises a beta chain constant region having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the constant region of the beta chain amino acid sequence set forth in SEQ ID NO:2. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises a beta chain constant region having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the constant region of the beta chain amino acid sequence set forth in SEQ ID NO:2, wherein the anti-MUC5AC TCR comprises a beta chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 10. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises a beta chain constant region present in the amino acid sequence set forth in SEQ ID NO:2. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide further comprises a beta constant region that is different from an endogenous (e.g., naturally occurring) constant region of a beta chain. In some aspects, the beta chain constant region comprises an amino acid sequence comprising at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions relative to the amino acid sequence of the constant region of the beta chain amino acid sequence set forth in SEQ ID NO:2.

[0139] In certain aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises an alpha chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the alpha chain amino acid sequence set forth in SEQ ID NO: 1. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises an alpha chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the alpha chain amino acid sequence set forth in SEQ ID NO: 1, wherein the anti-MUC5AC TCR comprises an alpha chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 7. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises an alpha chain comprising the amino acid sequence set forth in SEQ ID NO: 1.

[0140] In certain aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises a beta chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the beta chain amino acid sequence set forth in SEQ ID NO: 2. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises a beta chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the beta chain amino acid sequence set forth in SEQ ID NO: 2, wherein the anti-MUC5AC TCR comprises a beta chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 10. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises a beta chain comprising an amino acid sequence set forth in SEQ ID NO: 2.

[0141] In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises an alpha chain constant region, a beta chain constant region, or both; and wherein the alpha chain constant region, the beta chain constant region, or both comprise an amino acid sequence having at least 1, at least 2, at least 3, at least 4, or at least 5 substitutions within a target sequence relative to the corresponding amino acid sequence of an endogenous TCR.

[0142] In some aspects, the alpha chain of the anti-MUC5AC TCR encoded by the first nucleotide sequence further comprises a signal peptide. Any signal peptide can be used in the anti-MUC5AC TCR alpha chain disclosed herein. In some aspects, the signal peptide is a naturally occurring TCR alpha chain signal peptide. In some aspects, the signal peptide comprises an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 21. In some aspects, the signal peptide is a heterologous signal peptide, e.g., a signal peptide derived from a protein other than a TCR alpha chain. In some aspects, the signal peptide is a synthetic signal peptide. In some aspects, the signal peptide comprises an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 20 or 22. In some aspects, the alpha chain of the MUC5AC TCR encoded by the first nucleotide sequence does not comprise a signal peptide.

[0143] In some aspects, the signal peptide of the alpha chain is encoded by a nucleic acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the nucleic acid sequence set forth in SEQ ID NO: 23 or 24.

[0144] In some aspects, the beta chain of the anti-MUC5AC TCR encoded by the first nucleotide sequence further comprises a signal peptide. Any signal peptide can be used in the anti-MUC5AC TCR beta chain disclosed herein. In some aspects, the signal peptide is a naturally occurring TCR beta chain signal peptide. In some aspects, the signal peptide comprises an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 22. In some aspects, the signal peptide is a heterologous signal peptide, e.g., a signal peptide derived from a protein other than a TCR beta chain. In some aspects, the signal peptide is a synthetic signal peptide. In some aspects, the signal peptide comprises an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 20 or 21. In some aspects, the beta chain of the MUC5AC TCR encoded by the first nucleotide sequence does not comprise a signal peptide.

[0145] In some aspects, the signal peptide of the beta chain is encoded by a nucleic acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the nucleic acid sequence set forth in SEQ ID NO: 23 or 24.

[0146] In some aspects, each of the alpha chain and the beta chain of the anti-MUC5AC TCR encoded by the first nucleotide sequence further comprises a signal peptide. In some aspects, the signal peptide of the alpha chain is the same as the signal peptide of the beta chain. In some aspects, the signal peptide of the alpha chain is different from the signal peptide of the beta chain.

[0147] II.A.2. Epitope

[0148] In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide sequence binds to the same epitope as a reference TCR. In some aspects, the anti-MUC5AC TCR binds to an epitope of MUC5AC comprising the amino acid sequence set forth in SEQ ID NO: 13 (SGWGDPHYITFDGTYYTFLD). In some aspects, the anti-MUC5AC TCR binds to an epitope of MUC5AC consisting of the amino acid sequence as set forth in SEQ ID NO: 13. In some aspects, the epitope consists of amino acid residues 4922-4941 of MUC5AC (SEQ ID NO: 16), e.g.,“MUC5AC 4922-4941 ”.

[0149] In certain aspects, the epitope is a portion of a larger polypeptide, e.g., a peptide comprising the epitope sequence and (i) one or more additional amino acids N-terminal to the epitope sequence and / or (ii) one or more additional amino acids C-terminal to the epitope sequence. In some aspects, the polypeptide comprising the epitope is at least about 10 amino acids, at least about 11 amino acids, at least about 12 amino acids, at least about 13 amino acids, at least about 14 amino acids, at least about 15 amino acids, at least about 16 amino acids, at least about 17 amino acids, at least about 18 amino acids, at least about 19 amino acids, at least about 20 amino acids, at least about 25 amino acids, at least about 30 amino acids, at least about 35 amino acids, at least about 40 amino acids, at least about 45 amino acids, or at least about 50 amino acids in length. In certain aspects, the polypeptide comprising the epitope is at least about 5 to at least about 10, at least about 5 to at least about 15, at least about 5 to at least about 20, at least about 10 to at least about 15, at least about 10 to at least about 20, at least about 10 to at least about 25, at least about 10 to at least about 30, at least about 10 to at least about 35, at least about 10 to at least about 40, at least about 10 to at least about 45, at least about 10 to at least about 50, at least about 15 to at least about 20, at least about 15 to at least about 25, at least about 15 to at least about 30, at least about 15 to at least about 35, at least about 15 to at least about 40, at least about 15 to at least about 45, or at least about 15 to at least about 50 amino acids in length.

[0150] In certain aspects, the polypeptide comprising an epitope comprises the epitope and at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15 additional amino acids N-terminal to the epitope. In certain aspects, the polypeptide comprising an epitope comprises the epitope and at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15 additional amino acids C-terminal to the epitope.

[0151] In certain aspects, the epitope is complexed with an HLA class II molecule. The human leukocyte antigen (HLA) system (major histocompatibility complex [MHC] in humans) is an important part of the immune system and is controlled by genes located on chromosome 6. It encodes cell surface molecules that are specialized to present antigenic peptides to the T cell receptor (TCR) on T cells. (See also Overview of the Immune System.) MHC molecules that present antigens (Ag) are divided into two major classes: class I MHC molecules and class II MHC molecules.

[0152] Class II MHC molecules exist as transmembrane glycoproteins on the surface of professional antigen-presenting cells (APCs). The complete class II molecule is composed of an alpha chain and a beta chain. The gene encoding the alpha chain of MHC class II molecules consists of five exons, and the gene encoding the beta chain consists of six exons. Exon 1 encodes a leader peptide, exons 2 and 3 encode two extracellular domains, and exons 4 and 5 contribute to the transmembrane domain and cytoplasmic tail of each of the alpha and beta subunits. Three loci in the HLA complex encode MHC class II proteins: HLA-DR, HLA-DQ, and HLA-DP. T cells that express the CD4 molecule react with class II MHC molecules. These lymphocytes generally have cytotoxic function and activate responses to eliminate self cells infected with intracellular pathogens or to destroy extracellular parasites. Because only professional antigen-presenting cells (APCs) express class II MHC molecules, only these cells present antigens to CD4 T cells (CD4 binds to the nonpolymorphic portions of the alpha-2 domain and beta-2 domain of the alpha chain and beta chain, respectively, of MHC class II molecules).

[0153] In some aspects, the HLA class II alpha chain and beta chain are selected from HLA-DR, HLA-DP, and HLA-DQ alleles. In certain aspects, the HLA class II alpha chain is an HLA-DR alpha chain. In some aspects, the HLA class II beta chain is an HLA-DR beta chain. In certain aspects, the HLA class II alpha chain is an HLA-DP alpha chain. In some aspects, the HLA class II beta chain is an HLA-DP beta chain. In certain aspects, the HLA class II alpha chain is an HLA-DQ alpha chain. In some aspects, the HLA class II beta chain is an HLA-DQ beta chain.

[0154] Many HLA-DR, HLA-DP, and HLA-DQ alleles are known in the art, and any of the known alleles can be used in the present disclosure. An updated list of HLA alleles is available at hla.alleles.org / (last accessed June 18, 2019), which is incorporated by reference herein in its entirety.

[0155] II.A.3 Second Nucleotide Sequence

[0156] The second nucleotide sequence of the nucleic acid molecule disclosed herein can be any sequence that is capable of inhibiting the expression of an endogenous TCR or can encode any polypeptide that is capable of inhibiting the expression of an endogenous TCR. In some aspects, the second nucleotide sequence is one or more siRNAs. In some aspects, the one or more siRNAs are complementary to a target sequence within a nucleotide sequence encoding a constant region of an endogenous TCR. In certain aspects, the one or more siRNAs are complementary to a target sequence within a nucleotide sequence encoding a constant region of a wild-type human TCR. In some aspects, the one or more siRNAs are complementary to a target sequence within a nucleotide sequence encoding a constant region of an alpha chain of a wild-type TCR. In some aspects, the one or more siRNAs are complementary to a target sequence within a nucleotide sequence encoding a constant region of a beta chain of a wild-type TCR. In some aspects, the one or more siRNAs comprise (i) one or more siRNAs that are complementary to a target sequence within a nucleotide sequence encoding a constant region of an alpha chain of a wild-type TCR and (ii) one or more siRNAs that are complementary to a target sequence within a nucleotide sequence encoding a constant region of a beta chain of a wild-type TCR.

[0157] In some aspects, the one or more siRNAs comprise a nucleotide sequence selected from the group consisting of SEQ ID NOs: 25-28 (Table 4). In some aspects, the second nucleotide sequence of the nucleic acid molecule encodes one or more siRNAs, wherein the one or more siRNAs are complementary to a target sequence within a nucleotide sequence encoding a constant region of an alpha chain of a wild-type TCR, and wherein the one or more siRNAs comprise the nucleic acid sequences listed in SEQ ID NOs: 25 and 26.

[0158] Table 4. siRNA sequences

[0159]

[0160] In some aspects, the second nucleotide sequence of the nucleic acid molecule encodes one or more siRNAs, wherein the one or more siRNAs are complementary to a target sequence within a nucleotide sequence encoding a constant region of a beta chain of a wild-type TCR, and wherein the one or more siRNAs comprise the nucleic acid sequences set forth in SEQ ID NOs: 27 and 28. In some aspects, the second nucleotide sequence of the nucleic acid molecule encodes one or more siRNAs, wherein the one or more siRNAs comprise (i) one or more siRNAs complementary to a target sequence within a nucleotide sequence encoding a constant region of an alpha chain of a wild-type TCR, wherein the one or more siRNAs comprise the nucleic acid sequences set forth in SEQ ID NOs: 29 and 30; and (ii) one or more siRNAs complementary to a target sequence within a nucleotide sequence encoding a constant region of a beta chain of a wild-type TCR, wherein the one or more siRNAs comprise the nucleic acid sequences set forth in SEQ ID NOs: 27 and 28.

[0161] In some aspects, the second nucleotide sequence of the nucleic acid molecule comprises SEQ ID NOs: 25-28. In some aspects, the second nucleotide sequence comprises SEQ ID NOs: 25-28, wherein one or more of SEQ ID NOs: 25-28 is separated by one or more nucleic acids that do not encode an siRNA. In certain aspects, the one or more siRNAs are selected from the siRNAs disclosed in U.S. Pub. No. 2010 / 0273213 Al, which is incorporated by reference herein in its entirety.

[0162] In some aspects, the second nucleotide sequence of the nucleic acid molecule encodes a protein, wherein the protein is capable of inhibiting expression of an endogenous (e.g., wild-type) TCR. In some aspects, the second nucleotide sequence encodes Cas9.

[0163] II.A.3 Vectors

[0164] Certain aspects of the present disclosure relate to vectors comprising the nucleic acid molecules disclosed herein. In some aspects, the vector is a viral vector. In some aspects, the vector is a virion or virus. In some aspects, the vector is a mammalian vector. In some aspects, the vector is a bacterial vector.

[0165] In certain aspects, the vector is a retroviral vector. In some aspects, the vector is selected from the group consisting of an adenoviral vector, a lentivirus, a Sendai virus, a baculoviral vector, an Epstein Barr virus vector, a papovaviral vector, a vaccinia virus vector, a herpes simplex virus vector, and an adeno-associated virus (AAV) vector. In particular aspects, the vector is an AAV vector. In some aspects, the vector is a lentivirus. In particular aspects, the vector is an AAV vector. In some aspects, the vector is a Sendai virus. In some aspects, the vector is a hybrid vector. Examples of hybrid vectors that can be used in the present application can be found in Huang and Kamihira, Biotechnol. Adv. 31(2):208-23 (2103), which is incorporated by reference herein in its entirety.

[0166] II.B. Recombinant T Cell Receptors (TCRs)

[0167] Certain aspects of the present application relate to recombinant T cell receptors (TCRs) or antigen binding portions thereof that specifically bind to human MUC5AC ("anti-MUC5AC TCRs"). In some aspects, the anti-MUC5AC TCR is encoded by a nucleic acid molecule disclosed herein.

[0168] In some aspects, the anti-MUC5AC TCR cross-competes for binding to human MUC5AC with a reference TCR. In some aspects, the anti-MUC5AC TCR binds to the same epitope or an overlapping epitope of human MUC5AC as the reference TCR. In some aspects, the reference TCR comprises an alpha chain and a beta chain, and the alpha chain of the reference TCR comprises an amino acid sequence as set forth in SEQ ID NO: 1. In some aspects, the beta chain of the reference TCR comprises an amino acid sequence as set forth in SEQ ID NO: 2.

[0169] In some aspects, the anti-MUC5AC TCR comprises an alpha chain and a beta chain, wherein the alpha chain comprises a constant region, and wherein the beta chain comprises a constant region; wherein the alpha chain constant region comprises an amino acid sequence having at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions relative to the constant region of an alpha chain comprising the amino acid sequence set forth in SEQ ID NO: 1. In some aspects, the anti-MUC5AC TCR comprises an alpha chain and a beta chain, wherein the alpha chain comprises a constant region, and wherein the beta chain comprises a constant region; wherein the beta chain constant region comprises an amino acid sequence having at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions relative to the constant region of a beta chain comprising the amino acid sequence set forth in SEQ ID NO: 2.

[0170] In some aspects, an anti-MUC5AC TCR comprises an alpha chain and a beta chain, wherein the alpha chain comprises a constant region, and wherein the beta chain comprises a constant region; wherein (i) the alpha chain constant region comprises an amino acid sequence having at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions relative to the constant region of an alpha chain comprising the amino acid sequence set forth in SEQ ID NO: 1; and (ii) the beta chain constant region comprises an amino acid sequence having at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions relative to the constant region of a beta chain comprising the amino acid sequence set forth in SEQ ID NO: 2.

[0171] In some aspects, an alpha chain of an anti-MUC5AC TCR comprises a variable domain comprising an alpha chain CDR1, an alpha chain CDR2, and an alpha chain CDR3; and a beta chain of an anti-MUC5AC TCR comprises a variable domain comprising a beta chain CDR1, a beta chain CDR2, and a beta chain CDR3. In some aspects, an anti-MUC5AC TCR comprises an alpha chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 7. In some aspects, an anti-MUC5AC TCR comprises a beta chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 10.

[0172] In some aspects, an alpha chain CDR1 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 5. In some aspects, a beta chain CDR1 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 8.

[0173] In some aspects, an alpha chain CDR2 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 6. In some aspects, a beta chain CDR2 of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 9.

[0174] In some aspects, the anti-MUC5AC TCR comprises an alpha chain variable domain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the variable domain of the alpha chain amino acid sequence set forth in SEQ ID NO: 1. In some aspects, the anti-MUC5AC TCR comprises an alpha chain variable domain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the variable domain of the alpha chain amino acid sequence set forth in SEQ ID NO: 1, wherein the anti-MUC5AC TCR comprises an alpha chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 7. In some aspects, the anti-MUC5AC TCR comprises an alpha chain variable domain present in the alpha chain amino acid sequence set forth in SEQ ID NO: 1.

[0175] In some aspects, the anti-MUC5AC TCR comprises a beta chain variable domain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the variable domain of the beta chain amino acid sequence set forth in SEQ ID NO: 2. In some aspects, the anti-MUC5AC TCR comprises a beta chain variable domain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the variable domain of the beta chain amino acid sequence set forth in SEQ ID NO: 2, wherein the anti-MUC5AC TCR comprises a beta chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 10. In some aspects, the anti-MUC5AC TCR comprises a beta chain variable domain present in the beta chain amino acid sequence set forth in SEQ ID NO: 2.

[0176] In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide further comprises an alpha chain constant region, a beta chain constant region, or both an alpha chain constant region and a beta chain constant region. In some aspects, the anti-MUC5AC TCR comprises an alpha chain constant region having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the constant region of the alpha chain amino acid sequence set forth in SEQ ID NO: 1. In some aspects, the anti-MUC5AC TCR comprises an alpha chain constant region having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the constant region of the alpha chain amino acid sequence set forth in SEQ ID NO: 1, wherein the anti-MUC5AC TCR comprises an alpha chain CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 7. In some aspects, the anti-MUC5AC TCR comprises the alpha chain constant region present in the alpha chain amino acid sequence set forth in SEQ ID NO: 1. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide further comprises an alpha constant region that is different from the endogenous (e.g., naturally occurring) constant region of the alpha chain. In some aspects, the alpha chain constant region comprises an amino acid sequence comprising at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions relative to the amino acid sequence of the constant region of the alpha chain amino acid sequence set forth in SEQ ID NO: 1.

[0177] In some aspects, the anti-MUC5AC TCR comprises a beta chain constant region having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the constant region of the beta chain amino acid sequence set forth in SEQ ID NO: 2. In some aspects, the anti-MUC5AC TCR comprises a beta chain constant region having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the constant region of the beta chain amino acid sequence set forth in SEQ ID NO: 2, wherein the anti-MUC5AC TCR comprises a beta chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 10. In some aspects, the anti-MUC5AC TCR comprises a beta chain constant region present in the beta chain amino acid sequence set forth in SEQ ID NO: 2. In some aspects, the anti-MUC5AC TCR encoded by the first nucleotide further comprises a beta constant region that is different from the endogenous (e.g., naturally occurring) constant region of the beta chain. In some aspects, the beta chain constant region comprises an amino acid sequence comprising at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions relative to the amino acid sequence of the constant region of the beta chain amino acid sequence set forth in SEQ ID NO: 2.

[0178] In certain aspects, the anti-MUC5AC TCR comprises an alpha chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the alpha chain amino acid sequence set forth in SEQ ID NO: 1. In some aspects, the anti-MUC5AC TCR comprises an alpha chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the alpha chain amino acid sequence set forth in SEQ ID NO: 1, wherein the anti-MUC5AC TCR comprises an alpha chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 7. In some aspects, the anti-MUC5AC TCR comprises an alpha chain comprising the amino acid sequence set forth in SEQ ID NO: 1.

[0179] In certain aspects, the anti-MUC5AC TCR comprises a beta chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the beta chain amino acid sequence set forth in SEQ ID NO: 2. In some aspects, the anti-MUC5AC TCR comprises a beta chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the beta chain amino acid sequence set forth in SEQ ID NO: 2, wherein the anti-MUC5AC TCR comprises a beta chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 10. In some aspects, the anti-MUC5AC TCR comprises a beta chain comprising an amino acid sequence as set forth in SEQ ID NO: 2.

[0180] In some aspects, the anti-MUC5AC TCR comprises an alpha chain constant region, a beta chain constant region, or both; and wherein the alpha chain constant region, the beta chain constant region, or both comprise an amino acid sequence having at least 1, at least 2, at least 3, at least 4, or at least 5 substitutions within a target sequence relative to the corresponding amino acid sequence of an endogenous TCR.

[0181] II.B.2. Epitope

[0182] In some aspects, the anti-MUC5AC TCR binds to the same epitope as a reference TCR. In some aspects, the anti-MUC5AC TCR binds to an epitope of MUC5AC comprising the amino acid sequence set forth in SEQ ID NO: 13. In some aspects, the anti-MUC5AC TCR binds to an epitope of MUC5AC consisting of the amino acid sequence as set forth in SEQ ID NO: 13. In some aspects, the epitope consists of amino acid residues 4922-4941 of MUC5AC (SEQ ID NO: 16), e.g.,“MUC5AC 4922-4941 ”.

[0183] In certain aspects, the epitope is complexed with an HLA class II molecule. In some aspects, the HLA class II molecule comprises an alpha chain and a beta chain. In some aspects, the alpha chain is selected from the group consisting of an HLA-DR alpha chain, an HLA-DP alpha chain, and an HLA-DQ alpha chain. In some aspects, the beta chain is selected from the group consisting of an HLA-DR beta chain, an HLA-DP beta chain, and an HLA-DQ beta chain. In certain aspects, the HLA class II molecule comprises an HLA-DR alpha chain and an HLA-DR beta chain. In certain aspects, the HLA class II molecule comprises an HLA-DP alpha chain and an HLA-DP beta chain. In certain aspects, the HLA class II molecule comprises an HLA-DQ alpha chain and an HLA-DQ beta chain.

[0184] Many HLA-DR, HLA-DP, and HLA-DQ alleles are known in the art, and any of the known alleles can be used in the present disclosure. An updated list of HLA alleles is available at hla.alleles.org / (last accessed February 27, 2019), which is incorporated herein by reference in its entirety.

[0185] II.B.3. Bispecific T cell receptors (TCRs)

[0186] Certain aspects of the present disclosure relate to a bispecific TCR comprising a first antigen binding domain and a second antigen binding domain, wherein the first antigen binding domain comprises a TCR or antigen binding portion thereof disclosed herein. In some aspects, the first antigen binding domain comprises a single chain variable fragment (“scFv”).

[0187] In some aspects, the second antigen binding domain specifically binds to a protein expressed on the surface of a T cell. Any protein expressed on the surface of a T cell can be targeted by the bispecific antibodies disclosed herein. In certain aspects, the protein expressed on the surface of a T cell is not expressed by other cells. In some aspects, the protein expressed on the surface of a T cell is expressed on the surface of one or more other human immune cells. In some aspects, the protein expressed on the surface of a T cell is expressed on the surface of one or more other human immune cells, but it is not expressed on the surface of a human non-immune cell. In some aspects, the second antigen binding domain specifically binds to a protein expressed on the surface of a T cell selected from the group consisting of CD3, CD4, CD2, CD5, CD6, CD8, CD11a (LFA-1 alpha), CD43, CD45, and CD53. In certain aspects, the second antigen binding domain specifically binds to CD3. In certain aspects, the second antigen binding domain specifically binds to CD4. In some aspects, the second antigen binding domain comprises an scFv.

[0188] In some aspects, the first antigen binding domain and the second antigen binding domain are linked or associated by a covalent bond. In some aspects, the first antigen binding domain and the second antigen binding domain are linked by a peptide bond.

[0189] II.C. Cells expressing TCRs

[0190] Certain aspects of the present disclosure relate to a cell comprising a nucleic acid molecule disclosed herein, a vector disclosed herein, a recombinant TCR disclosed herein, a bispecific TCR disclosed herein, or any combination thereof. Any cell can be used in the present disclosure.

[0191] In certain aspects, the cell expresses CD4. CD4 expression can be naturally occurring, e.g., CD4 is expressed from a nucleic acid sequence endogenously expressed by the cell. For example, T cells, monocytes, macrophages, dendritic cells, and natural killer (NK) cells naturally express CD4. Thus, in some aspects, the cell is a T cell, a monocyte, a macrophage, a dendritic cell, or a natural killer cell. In certain aspects, the cell is a T cell selected from a natural killer T (NKT) cell and an innate lymphoid cell (ILC). In some aspects, the cell is a monocyte. In some aspects, the cell is a macrophage. In some aspects, the cell is a dendritic cell.

[0192] In some aspects, the T cell is isolated from a human subject. In some aspects, the human subject is the same subject who will ultimately receive the T cell therapy. In other aspects, the subject is a donor subject, where the donor subject is not the same subject who will receive the T cell therapy.

[0193] In some aspects, the cell is a cell that does not naturally express CD4, where the cell has been modified to express CD4. In some aspects, the cell comprises a transgene encoding CD4, where the transgene is expressed by the cell. In some aspects, the cell comprises a transgene encoding a protein that activates endogenous CD4 expression by the cell. In some aspects, the cell comprises a transgene encoding a protein or siRNA that inhibits CD4 expression in the cell. In some aspects, the transgene is incorporated into the genome of the cell. In some aspects, the transgene is not incorporated into the genome of the cell.

[0194] In some aspects, the cell modified to express CD4 is isolated from a human subject. In some aspects, the human subject is the same subject who will ultimately receive the cell therapy. In other aspects, the subject is a donor subject, where the donor subject is not the same subject who will receive the cell therapy.

[0195] II.D. HLA Class II Molecules

[0196] Certain aspects of the present disclosure relate to an HLA Class II molecule complexed with a peptide, where the peptide comprises the amino acid sequence set forth in SEQ ID NO: 13. In some aspects, the peptide consists of the amino acid sequence set forth in SEQ ID NO: 13.

[0197] In some aspects, the HLA Class II molecule is an HLA-DR, HLA-DP, or HLA-DQ allele. In some aspects, the HLA Class II molecule is any HLA allele disclosed at hla.alleles.org / (last accessed February 27, 2019).

[0198] In some aspects, the HLA class II molecule comprises an alpha chain and a beta chain. In some aspects, the sequence of the alpha chain is selected from any of the HLA alpha chain protein sequences available at hla.alleles.org (last accessed February 27, 2019).

[0199] II.D.1. HLA-DP Class II Molecules

[0200] In some aspects, the alpha chain is an HLA-DP alpha chain. Any HLA-DP alpha chain allele known in the art can be used in the compositions and methods disclosed herein. In some aspects, the alpha chain is selected from the HLA-DPA1*01, HLA-DPA1*02, HLA-DPA1*03, and HLA-DPA1*04 alleles. In certain aspects, the DP alpha chain comprises the HLA-DPA1*01 allele. In certain aspects, the DP alpha chain comprises the HLA-DPA1*02 allele. In certain aspects, the DP alpha chain comprises the HLA-DPA1*03 allele. In certain aspects, the DP alpha chain comprises the HLA-DPA1*04 allele.

[0201] In certain aspects, the DP a chain is selected from DPA1*01:03:01:01, DPA1*01:03:01:02, DPA1*01:03:01:03, DPA1*01:03:01:04, DPA1*01:03:01:05, DPA1*01:03:01:06, DPA1*01:03:01:07, DPA1*01:03:01:08, DPA1*01:03:01:09, DPA1*01:03:01:10, DPA1*01:03:01:11, DPA1*01:03:01:12, DPA1*01:03:01:13, DPA1*01:03:01:14, DPA1*01:03:01:15, DPA1*01:03:01:16, DPA1*01:03:01:17, DPA1*01:03:01:18Q, DPA1*01:03:01:19, DPA1*01:03:01:20, DPA1*01:03:01:21, DPA1*01:03:01:22, DPA1*01:03:01:23, DPA1*01:03:02, DPA1*01:03:03, DPA1*01:03:04, DPA1*01:03:05, DPA1*01:03:06, DPA1*01:03:07, DPA1*01:03:08, DPA1*01:03:09, DPA1*01:04, DPA1*01:05, DPA1*01:06:01, DPA1*01:06:02, DPA1*01:07, DPA1*01:08, DPA1*01:09, DPA1*01:10, DPA1*01:11, DPA1*01:12, DPA1*01:13, DPA1*01:14, DPA1*01:15, DPA1*01:16, DPA1*01:17, DPA1*01:18, DPA1*01:19, DPA1*02:01:01:01, DPA1*02:01:01:02, DPA1*02:01:01:03, DPA1*02:01:01:04, DPA1*02:01:01:05, DPA1*02:01:01:06, DPA1*02:01:01:07, DPA1*02:01:01:08, DPA1*02:01:01:09, DPA1*02:01:01:10, DPA1*02:01:01:11, DPA1*02:01:02:01, DPA1*02:01:02:02, DPA1*02:01:03, DPA1*02:01:04, DPA1*02:01:05, DPA1*02:01:06, DPA1*02:01:07,DPA1*02:01:08:01, DPA1*02:01:08:02, DPA1*02:02:02:01, DPA1*02:02:02:02, DPA1*02:02:02:03, DPA1*02:02:02:04, DPA1*02:02:02:05, DPA1*02:02:03, DPA1*02:02:04, DPA1*02:02:05, DPA1*02:02:06, DPA1*02:03, DPA1*02:04, DPA1*02:05, DPA1*02:06, DPA1*02:07:01:01, DPA1*02:07:01:02, DPA1*02:07:01:03, DPA1*02:08, DPA1*02:09, DPA1*02:10, DPA1*02:11, DPA1*02:12, DPA1*02:13N, DPA1*02:14, DPA1*02:15, DPA1*02:16, DPA1*03:01:01:01, DPA1*03:01:01:02, DPA1*03:01:01:03, DPA1*03:01:01:04, DPA1*03:01:01:05, DPA1*03:01:02, DPA1*03:02, DPA1*03:03, DPA1*03:04, DPA1*04:01:01:01, DPA1*04:01:01:02, DPA1*04:01:01:03, DPA1*04:02, or any combination thereof.

[0202] In some aspects, the beta chain is an HLA-DP beta chain. Any HLA-DP beta chain allele known in the art can be used in the compositions and methods disclosed herein. In certain aspects, the DP beta chain comprises an allele selected from the group consisting of DPB1*01, DPB1*02, DPB1*03, DPB1*04, DPB1*05, DPB1*06, DPB1*08, DPB1*09, DPB1*10, DPB1*100, DPB1*101, DPB1*102, DPB1*103, DPB1*104, DPB1*105, DPB1*106, DPB1*107, DPB1*108, DPB1*109, DPB1*11, DPB1*110, DPB1*111, DPB1*112, DPB1*113, DPB1*114, DPB1*115, DPB1*116, DPB1*117, DPB1*118, DPB1*119, DPB1*120, DPB1*121, DPB1*122, DPB1*123, DPB1*124, DPB1*125, DPB1*126, DPB1*127, DPB1*128, DPB1*129, DPB1*13, DPB1*130, DPB1*131, DPB1*132, DPB1*133, DPB1*134, DPB1*135, DPB1*136, DPB1*137, DPB1*138, DPB1*139, DPB1*14, DPB1*140, DPB1*141, DPB1*142, DPB1*143, DPB1*144, DPB1*145, DPB1*146, DPB1*147, DPB1*148, DPB1*149, DPB1*15, DPB1*150, DPB1*151, DPB1*152, DPB1*153, DPB1*154, DPB1*155, DPB1*156, DPB1*157, DPB1*158, DPB1*159, DPB1*16, DPB1*160, DPB1*161, DPB1*162, DPB1*163, DPB1*164, DPB1*165, DPB1*166, DPB1*167, DPB1*168, DPB1*169, DPB1*17, DPB1*170, DPB1*171, DPB1*172, DPB1*173, DPB1*174, DPB1*175, DPB1*176, DPB1*177, DPB1*178, DPB1*179, DPB1*18, DPB1*180, DPB1*181, DPB1*182, DPB1*183, DPB1*184, DPB1*185, DPB1*186, DPB1*187,DPB1*188, DPB1*189, DPB1*19, DPB1*190, DPB1*191, DPB1*192, DPB1*193, DPB1*194, DPB1*195, DPB1*196, DPB1*197, DPB1*198, DPB1*199, DPB1*20, DPB1*200, DPB1*201, DPB1*202, DPB1*203, DPB1*204, DPB1*205, DPB1*206, DPB1*207, DPB1*208, DPB1*209, DPB1*21, DPB1*210, DPB1*211, DPB1*212, DPB1*213, DPB1*214, DPB1*215, DPB1*216, DPB1*217, DPB1*218, DPB1*219, DPB1*22, DPB1*220, DPB1*221, DPB1*222, DPB1*223, DPB1*224, DPB1*225, DPB1*226, DPB1*227, DPB1*228, DPB1*229, DPB1*23, DPB1*230, DPB1*231, DPB1*232, DPB1*233, DPB1*234, DPB1*235, DPB1*236, DPB1*237, DPB1*238, DPB1*239, DPB1*24, DPB1*240, DPB1*241, DPB1*242, DPB1*243, DPB1*244, DPB1*245, DPB1*246, DPB1*247, DPB1*248, DPB1*249, DPB1*25, DPB1*250, DPB1*251, DPB1*252, DPB1*253, DPB1*254, DPB1*255, DPB1*256, DPB1*257, DPB1*258, DPB1*259, DPB1*26, DPB1*260, DPB1*261, DPB1*262, DPB1*263, DPB1*264, DPB1*265, DPB1*266, DPB1*267, DPB1*268, DPB1*269, DPB1*27, DPB1*270, DPB1*271, DPB1*272, DPB1*273, DPB1*274, DPB1*275, DPB1*276, DPB1*277, DPB1*278, DPB1*279, DPB1*28, DPB1*280, DPB1*281, DPB1*282, DPB1*283, DPB1*284, DPB1*285, DPB1*286, DPB1*287, DPB1*288, DPB1*289,DPB1*29, DPB1*290, DPB1*291, DPB1*292, DPB1*293, DPB1*294, DPB1*295, DPB1*296, DPB1*297, DPB1*298, DPB1*299, DPB1*30, DPB1*300, DPB1*301, DPB1*302, DPB1*303, DPB1*304, DPB1*305, DPB1*306, DPB1*307, DPB1*308, DPB1*309, DPB1*31, DPB1*310, DPB1*311, DPB1*312, DPB1*313, DPB1*314, DPB1*315, DPB1*316, DPB1*317, DPB1*318, DPB1*319, DPB1*32, DPB1*320, DPB1*321, DPB1*322, DPB1*323, DPB1*324, DPB1*325, DPB1*326, DPB1*327, DPB1*328, DPB1*329, DPB1*33, DPB1*330, DPB1*331, DPB1*332, DPB1*333, DPB1*334, DPB1*335, DPB1*336, DPB1*337, DPB1*338, DPB1*339, DPB1*34, DPB1*340, DPB1*341, DPB1*342, DPB1*343, DPB1*344, DPB1*345, DPB1*346, DPB1*347, DPB1*348, DPB1*349, DPB1*35, DPB1*350, DPB1*351, DPB1*352, DPB1*353, DPB1*354, DPB1*355, DPB1*356, DPB1*357, DPB1*358, DPB1*359, DPB1*36, DPB1*360, DPB1*361, DPB1*362, DPB1*363, DPB1*364, DPB1*365, DPB1*366, DPB1*367, DPB1*368, DPB1*369, DPB1*37, DPB1*370, DPB1*371, DPB1*372, DPB1*373, DPB1*374, DPB1*375, DPB1*376, DPB1*377, DPB1*378, DPB1*379, DPB1*38, DPB1*380, DPB1*381, DPB1*382, DPB1*383, DPB1*384, DPB1*385, DPB1*386, DPB1*387, DPB1*388, DPB1*389, DPB1*39, DPB1*390,DPB1*391, DPB1*392, DPB1*393, DPB1*394, DPB1*395, DPB1*396, DPB1*397, DPB1*398, DPB1*399, DPB1*40, DPB1*400, DPB1*401, DPB1*402, DPB1*403, DPB1*404, DPB1*405, DPB1*406, DPB1*407, DPB1*408, DPB1*409, DPB1*41, DPB1*410, DPB1*411, DPB1*412, DPB1*413, DPB1*414, DPB1*415, DPB1*416, DPB1*417, DPB1*418, DPB1*419, DPB1*420, DPB1*421, DPB1*422, DPB1*423, DPB1*424, DPB1*425, DPB1*426, DPB1*427, DPB1*428, DPB1*429, DPB1*430, DPB1*431, DPB1*432, DPB1*433, DPB1*434, DPB1*435, DPB1*436, DPB1*437, DPB1*438, DPB1*439, DPB1*44, DPB1*440, DPB1*441, DPB1*442, DPB1*443, DPB1*444, DPB1*445, DPB1*446, DPB1*447, DPB1*448, DPB1*449, DPB1*45, DPB1*450, DPB1*451, DPB1*452, DPB1*453, DPB1*454, DPB1*455, DPB1*456, DPB1*457, DPB1*458, DPB1*459, DPB1*46, DPB1*460, DPB1*461, DPB1*462, DPB1*463, DPB1*464, DPB1*465, DPB1*466, DPB1*467, DPB1*468, DPB1*469, DPB1*47, DPB1*470, DPB1*471, DPB1*472, DPB1*473, DPB1*474, DPB1*475, DPB1*476, DPB1*477, DPB1*478, DPB1*479, DPB1*48, DPB1*480, DPB1*481, DPB1*482, DPB1*483, DPB1*484, DPB1*485, DPB1*486, DPB1*487, DPB1*488, DPB1*489, DPB1*49, DPB1*490, DPB1*491, DPB1*492, DPB1*493, DPB1*494,DPB1*495, DPB1*496, DPB1*497, DPB1*498, DPB1*499, DPB1*50, DPB1*500, DPB1*501, DPB1*502, DPB1*503, DPB1*504, DPB1*505, DPB1*506, DPB1*507, DPB1*508, DPB1*509, DPB1*51, DPB1*510, DPB1*511, DPB1*512, DPB1*513, DPB1*514, DPB1*515, DPB1*516, DPB1*517, DPB1*518, DPB1*519, DPB1*52, DPB1*520, DPB1*521, DPB1*522, DPB1*523, DPB1*524, DPB1*525, DPB1*526, DPB1*527, DPB1*528, DPB1*529, DPB1*53, DPB1*530, DPB1*531, DPB1*532, DPB1*533, DPB1*534, DPB1*535, DPB1*536, DPB1*537, DPB1*538, DPB1*539, DPB1*54, DPB1*540, DPB1*541, DPB1*542, DPB1*543, DPB1*544, DPB1*545, DPB1*546, DPB1*547, DPB1*548, DPB1*549, DPB1*55, DPB1*550, DPB1*551, DPB1*552, DPB1*553, DPB1*554, DPB1*555, DPB1*556, DPB1*557, DPB1*558, DPB1*559, DPB1*56, DPB1*560, DPB1*561, DPB1*562, DPB1*563, DPB1*564, DPB1*565, DPB1*566, DPB1*567, DPB1*568, DPB1*569, DPB1*57, DPB1*570, DPB1*571, DPB1*572, DPB1*573, DPB1*574, DPB1*575, DPB1*576, DPB1*577, DPB1*578, DPB1*579, DPB1*58, DPB1*580, DPB1*581, DPB1*582, DPB1*583, DPB1*584, DPB1*585, DPB1*586, DPB1*587, DPB1*588, DPB1*589, DPB1*59, DPB1*590, DPB1*591, DPB1*592, DPB1*593, DPB1*594, DPB1*595, DPB1*596,DPB1*597, DPB1*598, DPB1*599, DPB1*60, DPB1*600, DPB1*601, DPB1*602, DPB1*603, DPB1*604, DPB1*605, DPB1*606, DPB1*607, DPB1*608, DPB1*609, DPB1*61, DPB1*610, DPB1*611, DPB1*612, DPB1*613, DPB1*614, DPB1*615, DPB1*616, DPB1*617, DPB1*618, DPB1*619, DPB1*62, DPB1*620, DPB1*621, DPB1*622, DPB1*623, DPB1*624, DPB1*625, DPB1*626, DPB1*627, DPB1*628, DPB1*629, DPB1*63, DPB1*630, DPB1*631, DPB1*632, DPB1*633, DPB1*634, DPB1*635, DPB1*636, DPB1*637, DPB1*638, DPB1*639, DPB1*64, DPB1*640, DPB1*641, DPB1*642, DPB1*643, DPB1*644, DPB1*645, DPB1*646, DPB1*647, DPB1*648, DPB1*649, DPB1*65, DPB1*650, DPB1*651, DPB1*652, DPB1*653, DPB1*654, DPB1*655, DPB1*656, DPB1*657, DPB1*658, DPB1*659, DPB1*66, DPB1*660, DPB1*661, DPB1*662, DPB1*663, DPB1*664, DPB1*665, DPB1*666, DPB1*667, DPB1*668, DPB1*669, DPB1*67, DPB1*670, DPB1*671, DPB1*672, DPB1*673, DPB1*674, DPB1*675, DPB1*676, DPB1*677, DPB1*678, DPB1*679, DPB1*68, DPB1*680, DPB1*681, DPB1*682, DPB1*683, DPB1*684, DPB1*685, DPB1*686, DPB1*687, DPB1*688, DPB1*689, DPB1*69, DPB1*690, DPB1*691, DPB1*692, DPB1*693, DPB1*694, DPB1*695, DPB1*696, DPB1*697, DPB1*698,DPB1*699, DPB1*70, DPB1*700, DPB1*701, DPB1*702, DPB1*703, DPB1*704, DPB1*705, DPB1*706, DPB1*707, DPB1*708, DPB1*709, DPB1*71, DPB1*710, DPB1*711, DPB1*712, DPB1*713, DPB1*714, DPB1*715, DPB1*716, DPB1*717, DPB1*718, DPB1*719, DPB1*72, DPB1*720, DPB1*721, DPB1*722, DPB1*723, DPB1*724, DPB1*725, DPB1*726, DPB1*727, DPB1*728, DPB1*729, DPB1*73, DPB1*730, DPB1*731, DPB1*732, DPB1*733, DPB1*734, DPB1*735, DPB1*736, DPB1*737, DPB1*738, DPB1*739, DPB1*74, DPB1*740, DPB1*741, DPB1*742, DPB1*743, DPB1*744, DPB1*745, DPB1*746, DPB1*747, DPB1*748, DPB1*749, DPB1*75, DPB1*750, DPB1*751, DPB1*752, DPB1*753, DPB1*754, DPB1*755, DPB1*756, DPB1*757, DPB1*758, DPB1*759, DPB1*76, DPB1*760, DPB1*761, DPB1*762, DPB1*763, DPB1*764, DPB1*765, DPB1*766, DPB1*767, DPB1*768, DPB1*769, DPB1*77, DPB1*770, DPB1*771, DPB1*772, DPB1*773, DPB1*774, DPB1*775, DPB1*776, DPB1*777, DPB1*778, DPB1*779, DPB1*78, DPB1*780, DPB1*781, DPB1*782, DPB1*783, DPB1*784, DPB1*785, DPB1*786, DPB1*787, DPB1*788, DPB1*789, DPB1*79, DPB1*790, DPB1*791, DPB1*792, DPB1*794, DPB1*795, DPB1*796, DPB1*797, DPB1*798, DPB1*799, DPB1*80, DPB1*800,DPB1*801, DPB1*802, DPB1*803, DPB1*804, DPB1*805, DPB1*806, DPB1*807, DPB1*808, DPB1*809, DPB1*81, DPB1*810, DPB1*811, DPB1*812, DPB1*813, DPB1*814, DPB1*815, DPB1*816, DPB1*817, DPB1*818, DPB1*819, DPB1*82, DPB1*820, DPB1*821, DPB1*822, DPB1*823, DPB1*824, DPB1*825, DPB1*826, DPB1*827, DPB1*828, DPB1*829, DPB1*83, DPB1*830, DPB1*831, DPB1*832, DPB1*833, DPB1*834, DPB1*835, DPB1*836, DPB1*837, DPB1*838, DPB1*839, DPB1*84, DPB1*840, DPB1*841, DPB1*842, DPB1*843, DPB1*844, DPB1*845, DPB1*846, DPB1*847, DPB1*848, DPB1*849, DPB1*85, DPB1*850, DPB1*851, DPB1*852, DPB1*853, DPB1*854, DPB1*855, DPB1*856, DPB1*857, DPB1*858, DPB1*859, DPB1*86, DPB1*860, DPB1*861, DPB1*862, DPB1*863, DPB1*864, DPB1*865, DPB1*866, DPB1*867, DPB1*868, DPB1*869, DPB1*87, DPB1*870, DPB1*871, DPB1*872, DPB1*873, DPB1*874, DPB1*875, DPB1*876, DPB1*877, DPB1*878, DPB1*879, DPB1*88, DPB1*880, DPB1*881, DPB1*882, DPB1*883, DPB1*884, DPB1*885, DPB1*886, DPB1*887, DPB1*888, DPB1*889, DPB1*89, DPB1*890, DPB1*891, DPB1*892, DPB1*893, DPB1*894, DPB1*895, DPB1*896, DPB1*897, DPB1*898, DPB1*899, DPB1*90, DPB1*900, DPB1*901, DPB1*902,DPB1*903, DPB1*904, DPB1*905, DPB1*906, DPB1*907, DPB1*908, DPB1*909, DPB1*91, DPB1*910, DPB1*911, DPB1*912, DPB1*913, DPB1*914, DPB1*915, DPB1*916, DPB1*917, DPB1*918, DPB1*919, DPB1*92, DPB1*920, DPB1*921, DPB1*922, DPB1*923, DPB1*924, DPB1*925, DPB1*926, DPB1*927, DPB1*928, DPB1*929, DPB1*93, DPB1*930, DPB1*931, DPB1*932, DPB1*933, DPB1*934, DPB1*935, DPB1*936, DPB1*937, DPB1*938, DPB1*939, DPB1*94, DPB1*940, DPB1*941, DPB1*942, DPB1*943, DPB1*944, DPB1*945, DPB1*946, DPB1*947, DPB1*948, DPB1*949, DPB1*95, DPB1*950, DPB1*951, DPB1*952, DPB1*953, DPB1*954, DPB1*955, DPB1*956, DPB1*957, DPB1*958, DPB1*959, DPB1*96, DPB1*960, DPB1*961, DPB1*962, DPB1*963, DPB1*964, DPB1*965, DPB1*97, DPB1*98, and DPB1*99. In some aspects, the DP beta chain comprises an HLA-DPB1*01, HLA-DPB1*02, HLA-DPB1*01, HLA-DPB1*03, HLA-DPB1*04, HLA-DPB1*05, HLA-DPB1*06, HLA-DPB1*08, HLA-DPB1*09 allele, and any combination thereof. In certain aspects, the DP beta chain comprises an HLA-DPB1*04 allele. In particular aspects, the DP beta chain comprises an HLA-DPB1*04:01 allele.

[0203] In some respects, the DPβ chain contains alleles selected from the following: DPB1*01:01:01:01, DPB1*01:01:01:02, DPB1*01:01:01:03, DPB1*01:01:01:04, DPB1*01:01:01:05, DPB1*01:01:01:06, DPB1*01:01:01:07, DPB1*01:01:01:08, DPB1*01:01:01:09, DPB1*01:01:01:10, DPB1*01:01:02:01, DPB1*01:01:02:02, DPB1*01:01:03, DPB1*01: 01:04, DPB1*01:01:05, DPB1*01:01:06, DPB1*02:01:02:01, DPB1*02:01: 02:02, DPB1*02:01:02:03, DPB1*02:01:02:04, DPB1*02:01:02:05, DPB1* 02:01:02:06, DPB1*02:01:02:07, DPB1*02:01:02:08, DPB1*02:01:02:09 , DPB1*02:01:02:10, DPB1*02:01:02:11, DPB1*02:01:02:12, DPB1*02:01: 02:13, DPB1*02:01:02:14, DPB1*02:01:02:15, DPB1*02:01:02:16, DPB1* 02:01:02:17, DPB1*02:01:02:18, DPB1*02:01:02:19, DPB1*02:01:02:20 , DPB1*02:01:02:21, DPB1*02:01:02:22, DPB1*02:01:02:23, DPB1*02:01 :02:24, DPB1*02:01:02:25, DPB1*02:01:02:26, ​​DPB1*02:01:02:27, DPB1* 02:01:02:28, DPB1*02:01:02:29, DPB1*02:01:02:30, DPB1*02:01:02:31 , DPB1*02:01:02:32, DPB1*02:01:02:33, DPB1*02:01:02:34, DPB1*02:01: 02:35, DPB1*02:01:02:36, DPB1*02:01:02:37, DPB1*02:01:02:38, DPB1* 02:01:02:39, DPB1*02:01:02:40, DPB1*02:01:02:41, DPB1*02:01:02:42,DPB1*02:01:02:43, DPB1*02:01:03, DPB1*02:01:04, DPB1*02:01:05, DPB1*02:01:06, DPB1*02:01:07, DPB1*02:01:08, DPB1*02:01:09, DPB1*02:01:10, DPB1*02:01:11, DPB1*02:01:12, DPB1*02:01:13, DPB1*02:01:14, DPB1*02:01:15, DPB1*02:01:16, DPB1*02:01:17, DPB1*02:01:18, DPB1*02:01:19, DPB1*02:01:20, DPB1*02:01:21, DPB1*02:01:22, DPB1*02:01:23, DPB1*02:01:24, DPB1*02:01:25, DPB1*02:01:26, DPB1*02:01:27, DPB1*02:01:28, DPB1*02:01:29, DPB1*02:01:30, DPB1*02:01:31, DPB1*02:01:32, DPB1*02:01:33, DPB1*02:01:34, DPB1*02:01:35, DPB1*02:01:36, DPB1*02:01:37, DPB1*02:01:38, DPB1*02:01:39, DPB1*02:01:40, DPB1*02:01:41, DPB1*02:01:42, DPB1*02:01:43, DPB1*02:02:01:01, DPB1*02:02:01:02, DPB1*02:02:01:03, DPB1*02:02:01:04, DPB1*02:02:01:05, DPB1*02:02:01:06, DPB1*02:02:01:07, DPB1*02:02:02, DPB1*02:02:03, DPB1*03:01:01:01, DPB1*03:01:01:02, DPB1*03:01:01:03, DPB1*03:01:01:04, DPB1*03:01:01:05, DPB1*03:01:01:06, DPB1*03:01:01:07, DPB1*03:01:01:08, DPB1*03:01:01:09, DPB1*03:01:01:10, DPB1*03:01:01:11, DPB1*03:01:02, DPB1*03:01:03, DPB1*03:01:04, DPB1*03:01:05, DPB1*03:01:06,DPB1*03:01:07, DPB1*03:01:08, DPB1*03:01:09, DPB1*03:01:10, DPB1*03:01:11, DPB1*03:01:12, DPB1*04:01:01:01, DPB1*04:01:01:02, DPB1*04:01:01:03, DPB1*04:01:01:04, DPB1*04:01:01:05, DPB1*04:01:01:06, DPB1*04:01:01:07, DPB1*04:01:01:08, DPB1*04:01:01:09, DPB1*04:01:01:10, DPB1*04:01:01:11, DPB1*04:01:01:12, DPB1*04:01:01:13, DPB1*04:01:01:14, DPB1*04:01:01:15, DPB1*04:01:01:16, DPB1*04:01:01:17, DPB1*04:01:01:18, DPB1*04:01:01:19, DPB1*04:01:01:20, DPB1*04:01:01:21, DPB1*04:01:01:22, DPB1*04:01:01:23, DPB1*04:01:01:24N, DPB1*04:01:01:25, DPB1*04:01:01:26, DPB1*04:01:01:27, DPB1*04:01:01:28, DPB1*04:01:01:29, DPB1*04:01:01:30, DPB1*04:01:01:31, DPB1*04:01:01:32, DPB1*04:01:01:33, DPB1*04:01:01:34, DPB1*04:01:02, DPB1*04:01:03, DPB1*04:01:04:01, DPB1*04:01:04:02, DPB1*04:01:05, DPB1*04:01:06, DPB1*04:01:07, DPB1*04:01:08, DPB1*04:01:09, DPB1*04:01:10, DPB1*04:01:11, DPB1*04:01:12, DPB1*04:01:13, DPB1*04:01:14, DPB1*04:01:15, DPB1*04:01:16, DPB1*04:01:17, DPB1*04:01:18, DPB1*04:01:19, DPB1*04:01:20, DPB1*04:01:21, DPB1*04:01:22, DPB1*04:01:23,DPB1*04:01:24, DPB1*04:01:25, DPB1*04:01:26, DPB1*04:01:27, DPB1*04:01:28, DPB1*04:01:29, DPB1*04:01:30, DPB1*04:01:31, DPB1*04:01:32, DPB1*04:01:33, DPB1*04:01:34, DPB1*04:01:35, DPB1*04:01:36, DPB1*04:01:37, DPB1*04:01:38, DPB1*04:01:39, DPB1*04:01:40, DPB1*04:02:01:01, DPB1*04:02:01:02, DPB1*04:02:01:03, DPB1*04:02:01:04, DPB1*04:02:01:05, DPB1*04:02:01:06, DPB1*04:02:01:07, DPB1*04:02:01:08, DPB1*04:02:01:09, DPB1*04:02:01:10, DPB1*04:02:01:11, DPB1*04:02:01:12, DPB1*04:02:01:13, DPB1*04:02:01:14, DPB1*04:02:02, DPB1*04:02:03, DPB1*04:02:04, DPB1*04:02:05, DPB1*04:02:06, DPB1*04:02:07, DPB1*04:02:08, DPB1*04:02:09, DPB1*04:02:10, DPB1*04:02:11, DPB1*04:02:12, DPB1*04:02:13, DPB1*04:02:14, DPB1*05:01:01:01, DPB1*05:01:01:02, DPB1*05:01:01:03, DPB1*05:01:01:04, DPB1*05:01:01:05, DPB1*05:01:01:06, DPB1*05:01:01:07, DPB1*05:01:01:08, DPB1*05:01:01:09, DPB1*05:01:01:10, DPB1*05:01:02, DPB1*05:01:03, DPB1*05:01:04, DPB1*05:01:05, DPB1*05:01:06, DPB1*05:01:07, DPB1*05:01:08, DPB1*05:01:09, DPB1*06:01:01:01, DPB1*06:01:01:02, DPB1*06:01:01:03,DPB1*06:01:02, DPB1*06:01:03, DPB1*06:01:04, DPB1*06:01:05, DPB1*08:01, DPB1*09:01:01, DPB1*09:01:02, DPB1*09:01:03, DPB1*09:01:04, DPB1*100:01, DPB1*101:01, DPB1*102:01, DPB1*103:01, DPB1*104:01:01:01, DPB1*104:01:01:02, DPB1*104:01:01:03, DPB1*104:01:01:04, DPB1*104:01:01:05, DPB1*104:01:01:06, DPB1*104:01:02, DPB1*105:01:01:01, DPB1*105:01:01:02, DPB1*105:01:01:03, DPB1*105:01:01:04, DPB1*105:01:01:05, DPB1*105:01:01:06, DPB1*105:01:01:07, DPB1*105:01:01:08, DPB1*105:01:01:09, DPB1*105:01:01:10, DPB1*106:01, DPB1*107:01, DPB1*108:01, DPB1*109:01, DPB1*10:01:01:01, DPB1*10:01:01:02, DPB1*10:01:02, DPB1*10:01:03, DPB1*10:01:04, DPB1*110:01, DPB1*111:01, DPB1*112:01, DPB1*113:01, DPB1*114:01, DPB1*115:01, DPB1*116:01, DPB1*117:01, DPB1*118:01, DPB1*119:01, DPB1*11:01:01:01, DPB1*11:01:01:02, DPB1*11:01:02, DPB1*11:01:03, DPB1*11:01:04, DPB1*120:01N, DPB1*121:01, DPB1*122:01, DPB1*123:01, DPB1*124:01:01:01, DPB1*124:01:01:02, DPB1*124:01:02:01, DPB1*124:01:02:02, DPB1*125:01, DPB1*126:01:01:01, DPB1*126:01:01:02, DPB1*127:01, DPB1*128:01, DPB1*129:01,DPB1*130:01, DPB1*131:01:01:01, DPB1*131:01:01:02, DPB1*131:01:02, DPB1*131:01:03, DPB1*132:01, DPB1*133:01, DPB1*134:01, DPB1*135:01, DPB1*136:01, DPB1*137:01, DPB1*138:01, DPB1*139:01, DPB1*13:01:01:01, DPB1*13:01:01:02, DPB1*13:01:01:03, DPB1*13:01:01:04, DPB1*13:01:01:05, DPB1*13:01:01:06, DPB1*13:01:01:07, DPB1*13:01:01:08, DPB1*13:01:02, DPB1*13:01:03, DPB1*140:01, DPB1*141:01, DPB1*142:01, DPB1*143:01, DPB1*144:01, DPB1*145:01, DPB1*146:01, DPB1*147:01, DPB1*148:01, DPB1*149:01, DPB1*14:01:01:01, DPB1*14:01:01:02, DPB1*14:01:01:03, DPB1*14:01:02, DPB1*14:01:03, DPB1*14:01:04, DPB1*14:01:05, DPB1*14:01:06, DPB1*14:01:07, DPB1*14:01:08, DPB1*14:01:09, DPB1*150:01, DPB1*151:01, DPB1*152:01, DPB1*153:01, DPB1*154:01N, DPB1*155:01:01, DPB1*155:01:02, DPB1*156:01, DPB1*157:01, DPB1*158:01, DPB1*159:01N, DPB1*15:01:01:01, DPB1*15:01:01:02, DPB1*15:01:01:03, DPB1*15:01:01:04, DPB1*15:01:02, DPB1*15:01:03, DPB1*160:01, DPB1*161:01N, DPB1*162:01:01, DPB1*162:01:02, DPB1*163:01, DPB1*164:01, DPB1*165:01, DPB1*166:01, DPB1*167:01, DPB1*168:01, DPB1*169:01,DPB1*16:01:01:01, DPB1*16:01:01:02, DPB1*16:01:02, DPB1*16:01:03, DPB1*17:01, DPB1*17:01:01:01, DPB1*17:01:01:02, DPB1*17:01:02, DPB1*17:01:03, DPB1*18:01, DPB1*18:01:01:01, DPB1*18:01:01:02, DPB1*18:01:01:03, DPB1*18:01:02, DPB1*18:01:03, DPB1*19:01, DPB1*19:01:01:01, DPB1*19:01:01:02, DPB1*19:01:01:03, DPB1*20:01, DPB1*20:01:01:01, DPB1*20:01:01:02, DPB1*20:01:02, DPB1*20:01:03, DPB1*20:01:04, DPB1*21:01, DPB1*22:01, DPB1*23:01, DPB1*24:01, DPB1*25:01, DPB1*26:01, DPB1*27:01, DPB1*28:01, DPB1*29:01, DPB1*2:01:01:01, DPB1*2:01:01:02, DPB1*2:01:02, DPB1*2:01:03, DPB1*2:01:04, DPB1*2:01:05, DPB1*2:01:06, DPB1*2:01:07, DPB1*2:01:08, DPB1*2:01:09, DPB1*2:01:10, DPB1*2:01:11, DPB1*2:01:12, DPB1*2:01:13, DPB1*2:01:14, DPB1*2:01:15, DPB1*2:01:16, DPB1*2:01:17, DPB1*2:01:18, DPB1*2:01:19, DPB1*2:01:20, DPB1*2:01:21, DPB1*2:01:22, DPB1*2:01:23, DPB1*2:01:24, DPB1*2:01:25, DPB1*2:01:26, DPB1*2:01:27, DPB1*2:01:28, DPB1*2:01:29, DPB1*2:01:30, DPB1*2:01:31, DPB1*2:01:32, DPB1*2:01:33, DPB1*2:01:34, DPB1*2:01:35, DPB1*2:01:36, DPB1*2:01:37, DPB1*2:01:38, DPB1*2:01:39, DPB1*2:01:40, DPB1*2:01:41, DPB1*2:01:42, DPB1*2:01:43, DPB1*2:01:44, DPB1*2:01:45, DPB1*2:01:46, DPB1*2:01:47, DPB1*2:01:48, DPB1*2:01:49, DPB1*2:01:50, DPB1*2:01:51, DPB1*2:01:52, DPB1*2:01:53, DPB1*2:01:54, DPB1*2:01:55, DPB1*2:01:56, DPB1*2:01:57, DPB1*2:01:58, DPB1*2:01:59, DPB1*2:01:60, DPB1*2:01:61, DPB1*2:01:62, DPB1*2:01:63, DPB1*2:01:64, DPB1*2:01:65, DPB1*2:01:66, DPB1*2:01:67, DPB1*2:01:68, DPB1*2:01:69, DPB1*2:01:70, DPB1*2:01:71, DPB1*2:01:72, DPB1*2:01:73, DPB1*2:01:74, DPB1*2:01:75, DPB1*2:01:76, DPB1*2:01:77, DPB1*2:01:78, DPB1*2:01:79, DPB1*2:01:80, DPB1*2:01:81, DPB1*2:01:82, DPB1*2:01:83, DPB1*2:01:84, DPB1*2:01:85, DPB1*2:01:86, DPB1*2:01:87, DPB1*2:01:88, DPB1*2:01:89, DPB1*2:01:90, DPB1*2:01:91, DPB1*2:01:92, DPB1*2:01:93, DPB1*2:01:94, DPB1*2:01:95, DPB1*2:01:96, DPB1*2:01:97, DPB1*2:01:98, DPB1*2:01:99, DPB1*2:01:100, DPB1*2:01:101, DPB1*2:01:102, DPB1*2:01:103, DPB1*2:01:104, DPB1*2:01:105, DPB1*2:01:106, DPB1*2:01:107, DPB1*2:01:108, DPB1*2:01:109, DPB1*2:01:110, DPB1*2:01:111, DPB1*2:01:112, DPB1*2:01:113, DPB1*2:01:114, DPB1*2:01:115, DPB1*2:01:116, DPB1*2:01:117, DPB1*2:01:118, DPB1*2:01:119, DPB1*2:01:120, DPB1*2:01:121, DPB1*2:01:122, DPB1*2:01:123, DPB1*2:01:124, DPB1*2:01:125, DPB1*2:01:126, DPB1*2:01:127, DPB1*2:01:128, DPB1*2:01:129, DPB1*2:01:130, DPB1*2:01:131, DPB1*2:01:132, DPB1*2:01:133, DPB1*2:01:134, DPB1*2:01:135, DPB1*2:01:136, DPB1*2:01:137, DPB1*2:01:138, DPB1*2:01:139, 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DPB1*668:01:01:02, DPB1*669:01,DPB1*66:01, DPB1*670:01, DPB1*671:01, DPB1*672:01, DPB1*673:01, DPB1*674:01, DPB1*675:01, DPB1*676:01, DPB1*677:01, DPB1*678:01, DPB1*679:01, DPB1*67:01, DPB1*680:01, DPB1*681:01, DPB1*682:01, DPB1*683:01, DPB1*684:01, DPB1*685:01, DPB1*686:01, DPB1*687:01, DPB1*688:01, DPB1*689:01, DPB1*68:01, DPB1*690:01, DPB1*691:01N, DPB1*692:01, DPB1*693:01N, DPB1*694:01, DPB1*695:01, DPB1*696:01N, DPB1*697:01Q, DPB1*698:01, DPB1*699:01, DPB1*69:01:01:01, DPB1*69:01:01:02, DPB1*700:01N, DPB1*701:01, DPB1*702:01, DPB1*703:01, DPB1*704:01, DPB1*705:01, DPB1*706:01, DPB1*707:01, DPB1*708:01, DPB1*709:01, DPB1*70:01, DPB1*710:01, DPB1*711:01, DPB1*712:01N, DPB1*713:01, DPB1*714:01, DPB1*715:01, DPB1*716:01, DPB1*717:01, DPB1*718:01, DPB1*719:01, DPB1*71:01:01, DPB1*71:01:02, DPB1*720:01, DPB1*721:01, DPB1*722:01, DPB1*723:01, DPB1*724:01N, DPB1*725:01, DPB1*726:01, DPB1*727:01, DPB1*728:01, DPB1*729:01, DPB1*72:01:01:01, DPB1*72:01:01:02, DPB1*72:01:01:03, DPB1*730:01, DPB1*731:01, DPB1*732:01N, DPB1*733:01, DPB1*734:01, DPB1*735:01, DPB1*736:01, DPB1*737:01, DPB1*738:01N,DPB1*739:01, DPB1*73:01, DPB1*740:01, DPB1*741:01, DPB1*742:01, DPB1*743:01N, DPB1*744:01, DPB1*745:01, DPB1*746:01, DPB1*747:01, DPB1*748:01N, DPB1*749:01, DPB1*74:01, DPB1*750:01, DPB1*751:01, DPB1*752:01, DPB1*753:01, DPB1*754:01N, DPB1*755:01, DPB1*756:01N, DPB1*757:01, DPB1*758:01, DPB1*759:01, DPB1*75:01, DPB1*760:01, DPB1*761:01, DPB1*762:01, DPB1*763:01, DPB1*764:01, DPB1*765:01, DPB1*766:01, DPB1*767:01, DPB1*768:01, DPB1*769:01, DPB1*76:01, DPB1*770:01, DPB1*771:01, DPB1*772:01, DPB1*773:01, DPB1*774:01, DPB1*775:01, DPB1*776:01, DPB1*777:01N, DPB1*778:01, DPB1*779:01, DPB1*77:01, DPB1*780:01, DPB1*781:01, DPB1*782:01, DPB1*783:01, DPB1*784:01, DPB1*785:01, DPB1*786:01:01N, DPB1*786:01:02N, DPB1*787:01, DPB1*788:01, DPB1*789:01, DPB1*78:01, DPB1*790:01, DPB1*791:01, DPB1*792:01N, DPB1*794:01N, DPB1*795:01, DPB1*796:01, DPB1*797:01, DPB1*798:01, DPB1*799:01, DPB1*79:01, DPB1*800:01N, DPB1*801:01, DPB1*802:01, DPB1*803:01, DPB1*804:01, DPB1*805:01, DPB1*806:01:01:01, DPB1*806:01:01:02, DPB1*807:01, DPB1*808:01, DPB1*809:01, DPB1*80:01, DPB1*810:01,DPB1*811:01, DPB1*812:01, DPB1*813:01, DPB1*814:01, DPB1*815:01, DPB1*816:01, DPB1*817:01, DPB1*818:01, DPB1*819:01, DPB1*81:01:01:01, DPB1*81:01:01:02, DPB1*81:01:02, DPB1*820:01, DPB1*821:01N, DPB1*822:01, DPB1*823:01, DPB1*824:01, DPB1*825:01, DPB1*826:01, DPB1*827:01, DPB1*828:01, DPB1*829:01, DPB1*82:01, DPB1*830:01, DPB1*831:01N, DPB1*832:01, DPB1*833:01, DPB1*834:01, DPB1*835:01, DPB1*836:01, DPB1*837:01, DPB1*838:01N, DPB1*839:01, DPB1*83:01, DPB1*840:01, DPB1*841:01, DPB1*842:01, DPB1*843:01, DPB1*844:01N, DPB1*845:01, DPB1*846:01, DPB1*847:01, DPB1*848:01, DPB1*849:01, DPB1*84:01, DPB1*850:01, DPB1*851:01, DPB1*852:01, DPB1*853:01, DPB1*854:01, DPB1*855:01, DPB1*856:01, DPB1*857:01, DPB1*858:01, DPB1*859:01, DPB1*85:01:01:01, DPB1*85:01:01:02, DPB1*85:01:02, DPB1*860:01, DPB1*861:01, DPB1*862:01N, DPB1*863:01, DPB1*864:01, DPB1*865:01N, DPB1*866:01N, DPB1*867:01N, DPB1*868:01N, DPB1*869:01N, DPB1*86:01, DPB1*870:01N, DPB1*871:01N, DPB1*872:01N, DPB1*873:01N, DPB1*874:01N, DPB1*875:01N, DPB1*876:01N, DPB1*877:01N, DPB1*878:01N, DPB1*879:01:01:01,DPB1*879:01:01:02, DPB1*879:01:01:03, DPB1*87:01, DPB1*880:01, DPB1*881:01, DPB1*882:01, DPB1*883:01, DPB1*884:01, DPB1*885:01, DPB1*886:01, DPB1*887:01, DPB1*888:01, DPB1*889:01, DPB1*88:01, DPB1*890:01, DPB1*891:01, DPB1*892:01, DPB1*893:01, DPB1*894:01N, DPB1*895:01, DPB1*896:01, DPB1*897:01, DPB1*898:01, DPB1*899:01, DPB1*89:01, DPB1*900:01, DPB1*901:01, DPB1*902:01, DPB1*903:01, DPB1*904:01, DPB1*905:01, DPB1*906:01, DPB1*907:01, DPB1*908:01, DPB1*909:01, DPB1*90:01:01, DPB1*90:01:02, DPB1*910:01, DPB1*911:01N, DPB1*912:01, DPB1*913:01, DPB1*914:01, DPB1*915:01, DPB1*916:01, DPB1*917:01N, DPB1*918:01, DPB1*919:01N, DPB1*91:01:01:01, DPB1*91:01:01:02, DPB1*920:01, DPB1*921:01, DPB1*922:01, DPB1*923:01, DPB1*924:01, DPB1*925:01N, DPB1*926:01, DPB1*927:01, DPB1*928:01, DPB1*929:01, DPB1*92:01, DPB1*930:01, DPB1*931:01, DPB1*932:01, DPB1*933:01, DPB1*934:01Q, DPB1*935:01Q, DPB1*936:01Q, DPB1*937:01, DPB1*938:01, DPB1*939:01N, DPB1*93:01, DPB1*940:01, DPB1*941:01N, DPB1*942:01, DPB1*943:01, DPB1*944:01, DPB1*945:01, DPB1*946:01, DPB1*947:01, DPB1*948:01,DPB1*949:01, DPB1*94:01, DPB1*950:01N, DPB1*951:01, DPB1*952:01, DPB1*953:01, DPB1*954:01, DPB1*955:01, DPB1*956:01, DPB1*957:01, DPB1*958:01, DPB1*959:01N, DPB1*95:01, DPB1*960:01N, DPB1*961:01, DPB1*962:01, DPB1*963:01, DPB1*964:01, DPB1*965:01:01:01, DPB1*965:01:01:02, DPB1*96:01, DPB1*97:01, DPB1*98:01, DPB1*99:01, and any combination thereof.

[0204] II.D.2.HLA-DQ Class II Molecules

[0205] In some aspects, the alpha chain is an HLA-DQ alpha chain. Any HLA-DQ alpha chain allele known in the art can be used in the compositions and methods disclosed herein. In some aspects, the alpha chain is selected from the HLA-DQA1*01, HLA-DQA1*02, HLA-DQA1*03, HLA-DQA1*04, HLA-DQA1*05, and HLA-DQA1*06 alleles. In some aspects, the alpha chain is an HLA-DQA1 allele selected from the group consisting of *01:01:01:01, *01:01:01:02, *01:01:01:03, *01:01:01:05, *01:01:01:06, *01:01:02, *01:01:03, *01:01:04, *01:01:05, *01:02:01:01, *01:02:01:02, *01:02:01:03, *01:02:01:04, *01:02:01:05, *01:02:01:06, *01:02:01:07, *01:02:01:08, *01:02:01:09, *01:02:01:10, *01:02:01:11, *01:02:01:12, *01:02:02:01, *01:02:02:02, *01:02:02:03, *01:02:02:04, *01:02:03, *01:02:04, *01:03:01:01, *01:03:01:02, *01:03:01:03, *01:03:01:04, *01:03:01:05, *01:03:01:06, *01:03:01:07, *01:03:01:08, *01:03:01:09, *01:04:01:01, *01:04:01:02, *01:04:01:03, *01:04:01:04, *01:04:02, *01:05:01, *01:05:02, *01:06, *01:07Q, *01:08, *01:09, *01:10, *01:11, *01:12, *01:13, *01:14, *01:15N, *01:16N, *01:17, *01:18, *01:19, *01:20, *01:21, *01:22, *01:23, *01:24, *01:25, *01:26, *02:01:01:01, *02:01:01:02, *02:01:02, *02:02N, *02:03, *03:01:01, *03:01:03, *03:02:01:01, *03:02:01:02, *03:03:01:01, *03:03:01:02, *03:03:01:03,*03:03:01:04、*03:03:01:05、*03:03:01:06、*03:03:01:07、*03:03:02、*03:04、*03:05、*03:06、*03:07、*04:01:01:01、*04:01:01:02、*04:01:01:03、*04:01:01:04、*04:01:01:05、*04:01:01:06、*04:01:01:07、*04:01:01:08、*04:01:02: 01. 1:04, *05:01:02, *05:01:04, *05:01:05, *05:01:06, *05:02, *05:03:01:01, *05:03:01:02, *05:04, *05:05:01:01, *05: 05:01:02, *05:05:01:03, *05:05:01:04, *05:05:01:05, *05:05:01:06, *05:05:01:07, *05:05:01:08, *05:05:01:09, *05:05:01:10, *05:05:01:11, *05:05:01:12, *05:05:01:13, *05:05:01:14, *05:05:01:15, *05:05:01:16, *05:05:01:17 *05:05:01:18, *05:05:01:19, *05:05:01:20, *05:06:01:01, *05:06:01:02, *05:07, *05:08, *05:09, *05:10, *05:11, *05:12, *05:13, *05:14, *05:15N, *06:01:01:01, *06:01:01:02, *06:01:01:03, *06:01:01:04, *06:01:02, *06:02 and any combination thereof.

[0206] In some aspects, the β chain is the HLA-DQ β chain. Any HLA-DQ β chain allele known in the art may be used in the compositions and methods disclosed herein. In some aspects, the β chain is selected from the HLA-DQB1*02, HLA-DQB1*03, HLA-DQB1*04, HLA-DQB1*05, and HLA-DQB1*06 alleles.

[0207] In some respects, the DQβ chain contains alleles selected from the following: DQB1*02:01:01, DQB1*02:01:02, DQB1*02:01:03, DQB1*02:01:04, DQB1*02:01:05, DQB1*02:01:06, DQB1*02:01:07, DQB1*02:01:08, DQB1*02:01:09, DQB1*02:01:10, DQB1*02:01:11, DQB1*02:01:12, DQB1*02:01:13, DQB1*02:01:14, DQB1*02:01:15, DQB1*02:01:16, DQ B1*02:01:17, DQB1*02:01:18, DQB1*02:01:19, DQB1*02:01:20, DQB1*02: 01:21, DQB1*02:01:22, DQB1*02:01:23, DQB1*02:01:24, DQB1*02:01:25, D QB1*02:01:26, DQB1*02:01:27, DQB1*02:01:28, DQB1*02:01:29, DQB1*02 :01:30, DQB1*02:01:31, DQB1*02:02:01:01, DQB1*02:02:01:02, DQB1*02: 02:01:03, DQB1*02:02:01:04, DQB1*02:02:02, DQB1*02:02:03, DQB1*02: 02:04, DQB1*02:02:05, DQB1*02:02:06, DQB1*02:02:07, DQB1*02:02:08, DQB1*02:02:09, DQB1*02:03:01, DQB1*02:03:02, DQB1*02:04, DQB1*02:0 5. DQB1*02:06, DQB1*02:07:01, DQB1*02:07:02, DQB1*02:08, DQB1*02:09, DQB1*02:10, DQB1*02:100, DQB1*02:101, DQB1*02:102, DQB1*02:103, DQB 1*02:104, DQB1*02:105, DQB1*02:106, DQB1*02:107, DQB1*02:108, DQB1*0 2:109, DQB1*02:11, DQB1*02:110, DQB1*02:111, DQB1*02:112, DQB1*02:1 13. DQB1*02:114, DQB1*02:115, DQB1*02:116, DQB1*02:117, DQB1*02:118,DQB1*02:119, DQB1*02:12, DQB1*02:120, DQB1*02:121, DQB1*02:122, DQB1*02:123, DQB1*02:124, DQB1*02:125, DQB1*02:126, DQB1*02:127, DQB1*02:128, DQB1*02:129N, DQB1*02:13, DQB1*02:130, DQB1*02:131, DQB1*02:132N, DQB1*02:133, DQB1*02:134N, DQB1*02:135, DQB1*02:136, DQB1*02:137, DQB1*02:138, DQB1*02:139, DQB1*02:140, DQB1*02:141, DQB1*02:142, DQB1*02:14:01, DQB1*02:14:02, DQB1*02:15, DQB1*02:16, DQB1*02:17, DQB1*02:18N, DQB1*02:19, DQB1*02:20N, DQB1*02:21, DQB1*02:22, DQB1*02:23, DQB1*02:24, DQB1*02:25, DQB1*02:26, DQB1*02:27, DQB1*02:28, DQB1*02:29, DQB1*02:30, DQB1*02:31, DQB1*02:32, DQB1*02:33, DQB1*02:34, DQB1*02:35, DQB1*02:36, DQB1*02:37, DQB1*02:38, DQB1*02:39, DQB1*02:40, DQB1*02:41, DQB1*02:42, DQB1*02:43, DQB1*02:44, DQB1*02:45, DQB1*02:46, DQB1*02:47, DQB1*02:48, DQB1*02:49, DQB1*02:50, DQB1*02:51, DQB1*02:52, DQB1*02:53Q, DQB1*02:54, DQB1*02:55, DQB1*02:56, DQB1*02:57, DQB1*02:58N, DQB1*02:59, DQB1*02:60, DQB1*02:61, DQB1*02:62, DQB1*02:63, DQB1*02:64, DQB1*02:65, DQB1*02:66, DQB1*02:67NX, DQB1*02:68, DQB1*02:69, DQB1*02:70, DQB1*02:71, DQB1*02:72, DQB1*02:73,DQB1*02:74, DQB1*02:75, DQB1*02:76, DQB1*02:77, DQB1*02:78, DQB1*02:79, DQB1*02:80, DQB1*02:81, DQB1*02:82, DQB1*02:83, DQB1*02:84, DQB1*02:85, DQB1*02:86, DQB1*02:87, DQB1*02:88, DQB1*02:89:01, DQB1*02:89:02, DQB1*02:90, DQB1*02:91, DQB1*02:92, DQB1*02:93, DQB1*02:94, DQB1*02:95, DQB1*02:96N, DQB1*02:97, DQB1*02:98, DQB1*02:99, DQB1*03:01:01:01, DQB1*03:01:01:02, DQB1*03:01:01:03, DQB1*03:01:01:04, DQB1*03:01:01:05, DQB1*03:01:01:06, DQB1*03:01:01:07, DQB1*03:01:01:08, DQB1*03:01:01:09, DQB1*03:01:01:10, DQB1*03:01:01:11, DQB1*03:01:01:12, DQB1*03:01:01:14, DQB1*03:01:01:15, DQB1*03:01:01:16, DQB1*03:01:01:17, DQB1*03:01:01:18, DQB1*03:01:01:19, DQB1*03:01:01:20, DQB1*03:01:02, DQB1*03:01:03, DQB1*03:01:04, DQB1*03:01:05, DQB1*03:01:06, DQB1*03:01:07, DQB1*03:01:08, DQB1*03:01:09, DQB1*03:01:10, DQB1*03:01:11, DQB1*03:01:12, DQB1*03:01:13, DQB1*03:01:14, DQB1*03:01:15, DQB1*03:01:16, DQB1*03:01:17, DQB1*03:01:18, DQB1*03:01:19, DQB1*03:01:20, DQB1*03:01:21, DQB1*03:01:22, DQB1*03:01:23, DQB1*03:01:24, DQB1*03:01:25, DQB1*03:01:26, DQB1*03:01:27,DQB1*03:01:28, DQB1*03:01:29, DQB1*03:01:30, DQB1*03:01:31, DQB1*03:01:32, DQB1*03:01:33, DQB1*03:01:34, DQB1*03:01:35, DQB1*03:01:36, DQB1*03:01:37, DQB1*03:01:38, DQB1*03:01:39, DQB1*03:01:40, DQB1*03:01:41, DQB1*03:01:42, DQB1*03:01:43, DQB1*03:01:44, DQB1*03:01:45, DQB1*03:01:46, DQB1*03:02:01:01, DQB1*03:02:01:02, DQB1*03:02:01:03, DQB1*03:02:01:04, DQB1*03:02:01:05, DQB1*03:02:01:06, DQB1*03:02:01:07, DQB1*03:02:01:08, DQB1*03:02:02, DQB1*03:02:03, DQB1*03:02:04, DQB1*03:02:05, DQB1*03:02:06, DQB1*03:02:07, DQB1*03:02:08, DQB1*03:02:09, DQB1*03:02:10, DQB1*03:02:11, DQB1*03:02:12, DQB1*03:02:13, DQB1*03:02:14, DQB1*03:02:15, DQB1*03:02:16, DQB1*03:02:17, DQB1*03:02:18, DQB1*03:02:19, DQB1*03:02:20, DQB1*03:02:21, DQB1*03:02:22, DQB1*03:02:23, DQB1*03:02:24, DQB1*03:02:25, DQB1*03:02:26, DQB1*03:02:27, DQB1*03:02:28, DQB1*03:02:29, DQB1*03:02:30, DQB1*03:03:02:01, DQB1*03:03:02:02, DQB1*03:03:02:03, DQB1*03:03:02:04, DQB1*03:03:02:05, DQB1*03:03:03, DQB1*03:03:04, DQB1*03:03:05, DQB1*03:03:06, DQB1*03:03:07, DQB1*03:03:08, DQB1*03:03:09,DQB1*03:03:10, DQB1*03:03:11, DQB1*03:03:12, DQB1*03:03:13, DQB1*03:03:14, DQB1*03:03:15, DQB1*03:03:16, DQB1*03:03:17, DQB1*03:03:18, DQB1*03:03:19, DQB1*03:03:20, DQB1*03:03:21, DQB1*03:04:01, DQB1*03:04:02, DQB1*03:04:03, DQB1*03:04:04, DQB1*03:05:01, DQB1*03:05:02, DQB1*03:05:03, DQB1*03:05:04, DQB1*03:06, DQB1*03:07, DQB1*03:08, DQB1*03:09, DQB1*03:100, DQB1*03:101, DQB1*03:102, DQB1*03:103, DQB1*03:104, DQB1*03:105, DQB1*03:106, DQB1*03:107, DQB1*03:108, DQB1*03:109, DQB1*03:10:01, DQB1*03:10:02:01, DQB1*03:10:02:02, DQB1*03:11, DQB1*03:110, DQB1*03:111, DQB1*03:112, DQB1*03:113, DQB1*03:114, DQB1*03:115, DQB1*03:116, DQB1*03:117, DQB1*03:118N, DQB1*03:119, DQB1*03:12, DQB1*03:120, DQB1*03:121, DQB1*03:122, DQB1*03:123, DQB1*03:124, DQB1*03:125, DQB1*03:126, DQB1*03:127, DQB1*03:128, DQB1*03:129, DQB1*03:13, DQB1*03:130, DQB1*03:131, DQB1*03:132, DQB1*03:133, DQB1*03:134, DQB1*03:135, DQB1*03:136, DQB1*03:137, DQB1*03:138, DQB1*03:139, DQB1*03:140, DQB1*03:141, DQB1*03:142, DQB1*03:143, DQB1*03:144, DQB1*03:145, DQB1*03:146, DQB1*03:147, DQB1*03:148,DQB1*03:149, DQB1*03:14:01, DQB1*03:14:02, DQB1*03:15, DQB1*03:150, DQB1*03:151, DQB1*03:152, DQB1*03:153, DQB1*03:154, DQB1*03:155, DQB1*03:156, DQB1*03:157, DQB1*03:158, DQB1*03:159, DQB1*03:16, DQB1*03:160, DQB1*03:161, DQB1*03:162, DQB1*03:163, DQB1*03:164, DQB1*03:165, DQB1*03:166, DQB1*03:167, DQB1*03:168, DQB1*03:169, DQB1*03:170, DQB1*03:171, DQB1*03:172, DQB1*03:173, DQB1*03:174, DQB1*03:175, DQB1*03:176, DQB1*03:177, DQB1*03:178, DQB1*03:179, DQB1*03:17:01, DQB1*03:17:02, DQB1*03:18, DQB1*03:180, DQB1*03:181, DQB1*03:182, DQB1*03:183, DQB1*03:184, DQB1*03:185, DQB1*03:186, DQB1*03:187, DQB1*03:188, DQB1*03:189, DQB1*03:190, DQB1*03:191, DQB1*03:192, DQB1*03:193, DQB1*03:194, DQB1*03:195, DQB1*03:196, DQB1*03:197Q, DQB1*03:198:01, DQB1*03:198:02, DQB1*03:199, DQB1*03:19:01, DQB1*03:19:02, DQB1*03:19:03, DQB1*03:19:04, DQB1*03:20, DQB1*03:200, DQB1*03:201, DQB1*03:202, DQB1*03:203, DQB1*03:204, DQB1*03:205, DQB1*03:206, DQB1*03:207, DQB1*03:208, DQB1*03:209, DQB1*03:21, DQB1*03:210, DQB1*03:211, DQB1*03:212, DQB1*03:213NX, DQB1*03:214, DQB1*03:215,DQB1*03:216, DQB1*03:217, DQB1*03:218, DQB1*03:219, DQB1*03:220, DQB1*03:221, DQB1*03:222, DQB1*03:223, DQB1*03:224, DQB1*03:225, DQB1*03:226, DQB1*03:227, DQB1*03:228, DQB1*03:229, DQB1*03:22:01, DQB1*03:22:02, DQB1*03:230, DQB1*03:231, DQB1*03:232, DQB1*03:233, DQB1*03:234, DQB1*03:235, DQB1*03:236, DQB1*03:237N, DQB1*03:238, DQB1*03:239, DQB1*03:23:01, DQB1*03:23:02, DQB1*03:23:03, DQB1*03:24, DQB1*03:240, DQB1*03:241, DQB1*03:242, DQB1*03:243, DQB1*03:244, DQB1*03:245, DQB1*03:246, DQB1*03:247, DQB1*03:248, DQB1*03:249, DQB1*03:250, DQB1*03:251, DQB1*03:252, 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DQB1*03:320, DQB1*03:321, DQB1*03:322, DQB1*03:323, DQB1*03:324, DQB1*03:326, DQB1*03:327, DQB1*03:328, DQB1*03:329, DQB1*03:33, DQB1*03:330, DQB1*03:331, DQB1*03:332, DQB1*03:333, DQB1*03:334N4bp, DQB1*03:335, DQB1*03:336, DQB1*03:337, DQB1*03:338N, DQB1*03:339N, DQB1*03:34, DQB1*03:340N, DQB1*03:341, DQB1*03:342, DQB1*03:343, DQB1*03:344, DQB1*03:345, DQB1*03:346, DQB1*03:347, DQB1*03:348, DQB1*03:349, DQB1*03:35, DQB1*03:350, DQB1*03:351, DQB1*03:352, DQB1*03:353, DQB1*03:354N, DQB1*03:355, DQB1*03:356NX, DQB1*03:357N, DQB1*03:358N, DQB1*03:36, DQB1*03:37, DQB1*03:38:01, DQB1*03:38:02,DQB1*03:39, DQB1*03:40, DQB1*03:41, DQB1*03:42, DQB1*03:43, DQB1*03:44, DQB1*03:45, DQB1*03:46, DQB1*03:47, DQB1*03:48, DQB1*03:49, DQB1*03:50, DQB1*03:51, DQB1*03:52, DQB1*03:53, DQB1*03:54, DQB1*03:55, DQB1*03:56, DQB1*03:57, DQB1*03:58, DQB1*03:59, DQB1*03:60, DQB1*03:61, DQB1*03:62, DQB1*03:63, DQB1*03:64, DQB1*03:65, DQB1*03:66N, DQB1*03:67, DQB1*03:68, DQB1*03:69, DQB1*03:70, DQB1*03:71, DQB1*03:72, DQB1*03:73, DQB1*03:74, DQB1*03:75, DQB1*03:76, DQB1*03:77, DQB1*03:78, DQB1*03:79, DQB1*03:80, DQB1*03:81, DQB1*03:82, DQB1*03:83, DQB1*03:84N, DQB1*03:85, DQB1*03:86, DQB1*03:87, DQB1*03:88, DQB1*03:89, DQB1*03:90N, DQB1*03:91Q, DQB1*03:92, DQB1*03:93, DQB1*03:94, DQB1*03:95N, DQB1*03:96, DQB1*03:97, DQB1*03:98, DQB1*03:99Q, DQB1*04:01:01:01, DQB1*04:01:01:02, DQB1*04:01:02, DQB1*04:01:03, DQB1*04:01:04, DQB1*04:01:05, DQB1*04:02:01:01, DQB1*04:02:01:04, DQB1*04:02:01:05, DQB1*04:02:01:06, DQB1*04:02:01:07, DQB1*04:02:01:08, DQB1*04:02:01:09, DQB1*04:02:01:10, DQB1*04:02:02, DQB1*04:02:03, DQB1*04:02:04, DQB1*04:02:05, DQB1*04:02:06, DQB1*04:02:07, DQB1*04:02:08,DQB1*04:02:09, DQB1*04:02:10, DQB1*04:02:11, DQB1*04:02:12, DQB1*04:02:13, DQB1*04:02:14, DQB1*04:02:15, DQB1*04:02:16, DQB1*04:02:17, DQB1*04:02:18, DQB1*04:03:01, DQB1*04:03:02, DQB1*04:03:03, DQB1*04:04, DQB1*04:05, DQB1*04:06, DQB1*04:07, DQB1*04:08, DQB1*04:09, DQB1*04:10, DQB1*04:11, DQB1*04:12, DQB1*04:13, DQB1*04:14, DQB1*04:15, DQB1*04:16, DQB1*04:17, DQB1*04:18, DQB1*04:19, DQB1*04:20, DQB1*04:21, DQB1*04:22, DQB1*04:23, DQB1*04:24, DQB1*04:25N, DQB1*04:26, DQB1*04:27, DQB1*04:28, DQB1*04:29, DQB1*04:30, DQB1*04:31, DQB1*04:32, DQB1*04:33, DQB1*04:34, DQB1*04:35, DQB1*04:36N, DQB1*04:37, DQB1*04:38, DQB1*04:39, DQB1*04:40, DQB1*04:41N, DQB1*04:42, DQB1*04:43, DQB1*04:44, DQB1*04:45, DQB1*04:46N, DQB1*04:47, DQB1*04:48, DQB1*04:49, DQB1*04:50, DQB1*04:51, DQB1*04:52, DQB1*04:53, DQB1*04:54, DQB1*04:55, DQB1*04:56, DQB1*04:57, DQB1*04:58, DQB1*04:59N, DQB1*04:60, DQB1*04:61, DQB1*04:62, DQB1*05:01:01:01, DQB1*05:01:01:02, DQB1*05:01:01:03, DQB1*05:01:01:04, DQB1*05:01:01:05, DQB1*05:01:02, DQB1*05:01:03, DQB1*05:01:04, DQB1*05:01:05, DQB1*05:01:06,DQB1*05:01:07, DQB1*05:01:08, DQB1*05:01:09, DQB1*05:01:10, DQB1*05:01:11, DQB1*05:01:12, DQB1*05:01:13, DQB1*05:01:14, DQB1*05:01:15, DQB1*05:01:16, DQB1*05:01:17, DQB1*05:01:18, DQB1*05:01:19, DQB1*05:01:20, DQB1*05:01:21, DQB1*05:01:22, 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DQB1*05:08, DQB1*05:09, DQB1*05:10, DQB1*05:100, DQB1*05:101, DQB1*05:102, DQB1*05:103, DQB1*05:104, DQB1*05:105, DQB1*05:106, DQB1*05:107, DQB1*05:108, DQB1*05:109, DQB1*05:110N, DQB1*05:111, DQB1*05:112, DQB1*05:113, DQB1*05:114, DQB1*05:115, DQB1*05:116, DQB1*05:117, DQB1*05:118, DQB1*05:119, DQB1*05:11:01, DQB1*05:11:02, DQB1*05:12, DQB1*05:120, DQB1*05:121, DQB1*05:122, DQB1*05:123, DQB1*05:124, DQB1*05:125, DQB1*05:126, DQB1*05:127, DQB1*05:128N, DQB1*05:129, DQB1*05:13, DQB1*05:130, DQB1*05:131, DQB1*05:132Q, DQB1*05:133, DQB1*05:134, DQB1*05:135, DQB1*05:136, DQB1*05:137, DQB1*05:138, DQB1*05:139, DQB1*05:14, DQB1*05:140, DQB1*05:141, DQB1*05:142, DQB1*05:143, DQB1*05:144, DQB1*05:145, DQB1*05:146, DQB1*05:147, DQB1*05:148, DQB1*05:149, DQB1*05:15, DQB1*05:150, DQB1*05:151, DQB1*05:152, DQB1*05:153, DQB1*05:154, DQB1*05:155, DQB1*05:156, DQB1*05:157, DQB1*05:158, DQB1*05:159, DQB1*05:16,DQB1*05:160, DQB1*05:161, DQB1*05:162, DQB1*05:163, DQB1*05:164, DQB1*05:165, DQB1*05:166, DQB1*05:167, DQB1*05:168, DQB1*05:169, DQB1*05:17, DQB1*05:170, DQB1*05:171, DQB1*05:172, DQB1*05:173, DQB1*05:174, DQB1*05:175, DQB1*05:176, DQB1*05:177, DQB1*05:178, DQB1*05:179, DQB1*05:18, DQB1*05:180, DQB1*05:181, DQB1*05:182, DQB1*05:183, DQB1*05:184, DQB1*05:185N, DQB1*05:186, DQB1*05:187, DQB1*05:188, DQB1*05:189, DQB1*05:19, DQB1*05:190, DQB1*05:191, DQB1*05:192, DQB1*05:193, DQB1*05:194, DQB1*05:195, DQB1*05:196, DQB1*05:197, DQB1*05:198, DQB1*05:199, DQB1*05:20, DQB1*05:200, DQB1*05:201, DQB1*05:202, DQB1*05:203, DQB1*05:204, DQB1*05:205, DQB1*05:206N, DQB1*05:207, DQB1*05:208N5bp, DQB1*05:209, DQB1*05:21, DQB1*05:210, DQB1*05:211, DQB1*05:212, DQB1*05:213, DQB1*05:214, DQB1*05:215N, DQB1*05:216, DQB1*05:217, DQB1*05:22, DQB1*05:23, DQB1*05:24, DQB1*05:25, DQB1*05:26, DQB1*05:27, DQB1*05:28, DQB1*05:29, DQB1*05:30, DQB1*05:31, DQB1*05:32, DQB1*05:33, DQB1*05:34, DQB1*05:35, DQB1*05:36, DQB1*05:37, DQB1*05:38, DQB1*05:39, DQB1*05:40, DQB1*05:41N, DQB1*05:42,DQB1*05:43:01, DQB1*05:43:02, DQB1*05:44, DQB1*05:45, DQB1*05:46, DQB1*05:47, DQB1*05:48, DQB1*05:49, DQB1*05:50, DQB1*05:51, DQB1*05:52, DQB1*05:53, DQB1*05:54, DQB1*05:55, DQB1*05:56, DQB1*05:57, DQB1*05:58, DQB1*05:59, DQB1*05:60, DQB1*05:61, DQB1*05:62, DQB1*05:63, DQB1*05:64, DQB1*05:65, DQB1*05:66:01, DQB1*05:66:02, DQB1*05:67, DQB1*05:68, DQB1*05:69, DQB1*05:70, DQB1*05:71, DQB1*05:72, DQB1*05:73, DQB1*05:74, DQB1*05:75, DQB1*05:76, DQB1*05:77, DQB1*05:78, DQB1*05:79, DQB1*05:80, DQB1*05:81, DQB1*05:82, DQB1*05:83, DQB1*05:84, DQB1*05:85, DQB1*05:86, DQB1*05:87Q, DQB1*05:88, DQB1*05:89:01, DQB1*05:89:02, DQB1*05:90N, DQB1*05:91, DQB1*05:92, DQB1*05:93, DQB1*05:94, DQB1*05:95, DQB1*05:96, DQB1*05:97, DQB1*05:98, DQB1*05:99, DQB1*06:01:01:01, DQB1*06:01:01:02, DQB1*06:01:02, DQB1*06:01:03, DQB1*06:01:04, DQB1*06:01:05, DQB1*06:01:06, DQB1*06:01:07, DQB1*06:01:08, DQB1*06:01:09, DQB1*06:01:10, DQB1*06:01:11, DQB1*06:01:12, DQB1*06:01:13, DQB1*06:01:14, DQB1*06:01:15, DQB1*06:01:16, DQB1*06:01:17, DQB1*06:01:18, DQB1*06:01:19, DQB1*06:01:20, DQB1*06:01:21,DQB1*06:02:01:01, DQB1*06:02:01:02, DQB1*06:02:01:03, DQB1*06:02:01:04, DQB1*06:02:02, DQB1*06:02:03, DQB1*06:02:04, DQB1*06:02:05, DQB1*06:02:06, DQB1*06:02:07, DQB1*06:02:08, DQB1*06:02:09, DQB1*06:02:10, DQB1*06:02:11, DQB1*06:02:12, DQB1*06:02:13, DQB1*06:02:14, DQB1*06:02:15, DQB1*06:02:16, DQB1*06:02:17, DQB1*06:02:18, DQB1*06:02:19, DQB1*06:02:20, DQB1*06:02:21, DQB1*06:02:22, DQB1*06:02:23, DQB1*06:02:24, DQB1*06:02:25, DQB1*06:02:26, DQB1*06:02:27, DQB1*06:02:28, DQB1*06:02:29, DQB1*06:02:30, DQB1*06:02:31, DQB1*06:02:32, DQB1*06:02:33, DQB1*06:02:34, DQB1*06:02:35, DQB1*06:02:36, DQB1*06:02:37, DQB1*06:02:38, DQB1*06:03:01:01, DQB1*06:03:01:02, DQB1*06:03:01:03, DQB1*06:03:02, DQB1*06:03:03, DQB1*06:03:04, DQB1*06:03:05, DQB1*06:03:06, DQB1*06:03:07, DQB1*06:03:08, DQB1*06:03:09, DQB1*06:03:10, DQB1*06:03:11, DQB1*06:03:12, DQB1*06:03:13, DQB1*06:03:14, DQB1*06:03:15, DQB1*06:03:16, DQB1*06:03:17, DQB1*06:03:18, DQB1*06:03:19, DQB1*06:03:20, DQB1*06:03:21, DQB1*06:03:22, DQB1*06:03:23, DQB1*06:03:24, DQB1*06:03:25, DQB1*06:03:26, DQB1*06:03:27,DQB1*06:03:28, DQB1*06:03:29, DQB1*06:03:30, DQB1*06:03:31, DQB1*06:03:32, DQB1*06:03:33, DQB1*06:03:34, DQB1*06:03:35, DQB1*06:04:01, DQB1*06:04:02, DQB1*06:04:03, DQB1*06:04:04, DQB1*06:04:05, DQB1*06:04:06, DQB1*06:04:07, DQB1*06:04:08, DQB1*06:04:09, DQB1*06:04:10, DQB1*06:04:11, DQB1*06:04:12, DQB1*06:05:01, DQB1*06:05:02, DQB1*06:06, DQB1*06:07:01, DQB1*06:07:02, DQB1*06:08:01, DQB1*06:08:02, DQB1*06:08:03, DQB1*06:09:01:01, DQB1*06:09:01:02, DQB1*06:09:02, DQB1*06:09:03, DQB1*06:09:04, DQB1*06:09:05, DQB1*06:09:06, DQB1*06:09:07, DQB1*06:09:08, DQB1*06:09:09, DQB1*06:09:10, DQB1*06:10, DQB1*06:100, DQB1*06:101, DQB1*06:102N, DQB1*06:103, DQB1*06:104, DQB1*06:105, DQB1*06:106, DQB1*06:107, DQB1*06:108, DQB1*06:109, DQB1*06:110, DQB1*06:111, DQB1*06:112N, DQB1*06:113, DQB1*06:114, DQB1*06:115, DQB1*06:116, DQB1*06:117, DQB1*06:118:01, DQB1*06:118:02, DQB1*06:118:03, DQB1*06:119, DQB1*06:11:01, DQB1*06:11:02, DQB1*06:11:03, DQB1*06:11:04, DQB1*06:12, DQB1*06:120, DQB1*06:121, DQB1*06:122, DQB1*06:123, DQB1*06:124, DQB1*06:125, DQB1*06:126, DQB1*06:127,DQB1*06:128, DQB1*06:129, DQB1*06:130, DQB1*06:131, DQB1*06:132, DQB1*06:133, DQB1*06:134, DQB1*06:135, DQB1*06:136, DQB1*06:137, DQB1*06:138, DQB1*06:139, DQB1*06:13:01, DQB1*06:13:02, DQB1*06:13:03, DQB1*06:140, DQB1*06:141, DQB1*06:142, DQB1*06:143, DQB1*06:144N, DQB1*06:145, DQB1*06:146:01, DQB1*06:146:02, DQB1*06:147, DQB1*06:148, DQB1*06:149, DQB1*06:14:01, DQB1*06:14:02, DQB1*06:14:03, DQB1*06:150, DQB1*06:151, DQB1*06:152, DQB1*06:153:01, DQB1*06:153:02, DQB1*06:154, DQB1*06:155, DQB1*06:156, DQB1*06:157, DQB1*06:158N, DQB1*06:159, DQB1*06:15:01, DQB1*06:15:02, DQB1*06:16, DQB1*06:160, DQB1*06:161, DQB1*06:162, DQB1*06:163, DQB1*06:164, DQB1*06:165, DQB1*06:166, DQB1*06:167, DQB1*06:168, DQB1*06:169, DQB1*06:17, DQB1*06:170, DQB1*06:171, DQB1*06:172, DQB1*06:173, DQB1*06:174, DQB1*06:175, DQB1*06:176, DQB1*06:177, DQB1*06:178, DQB1*06:179N, DQB1*06:180, DQB1*06:181, DQB1*06:182, DQB1*06:183, DQB1*06:184, DQB1*06:185, DQB1*06:186, DQB1*06:187, DQB1*06:188, DQB1*06:189, DQB1*06:18:01, DQB1*06:18:02, DQB1*06:190:01, DQB1*06:190:02, DQB1*06:191, DQB1*06:192,DQB1*06:193N、DQB1*06:194、DQB1*06:195、DQB1*06:196、DQB1*06:197、DQB1*06:198、DQB1*06:199、DQB1*06:19:01、DQB1*06:19:02、DQB1*06:20、DQB1*06:200、DQB1*06:201、DQB1*06:202、DQB1*06:203、DQB1*06:204、DQB1*06:205、DQB1*06:206:01、DQB1*06:206:02、DQB1*06:207、DQB1*06:208 ,DQB1*06:209,DQB1*06:21,DQB1*06:210,DQB1*06:211,DQB1*06:212,DQB1*06:213,DQB1*06:214,DQB1*06:215,DQB1*06:216N,DQB1*06:217,DQB1*06:218,DQB1*06:219,DQB1*06:221,DQB1*06:222,DQB1*06:223,DQB1*06:224,DQB1*06:225,DQB1*06:226,DQB1*06:227,DQB1*06:228,DQB1*06:2 29、DQB1*06:22:01、DQB1*06:22:02、DQB1*06:22:03、DQB1*06:23、DQB1*06:230、DQB1*06:231、DQB1*06:232、DQB1*06:233、DQB1*06:234、DQB1*06:235、DQB1*06:236、DQB1*06:237、DQB1*06:238、DQB1*06:239、DQB1*06:24、DQB1*06:240、DQB1*06:241、DQB1*06:242、DQB1*06:243、DQB1*06:244、DQ B1*06:245、DQB1*06:246、DQB1*06:247、DQB1*06:248、DQB1*06:249、DQB1*06:25、DQB1*06:250、DQB1*06:251、DQB1*06:252N、DQB1*06:253、DQB1*06:254、DQB1*06:255、DQB1*06:256、DQB1*06:257、DQB1*06:258、DQB1*06:259、DQB1*06:260、DQB1*06:261、DQB1*06:262、DQB1*06:263、DQB1*06:264、DQB1*06:265, DQB1*06:266, DQB1*06:267, DQB1*06:268, DQB1*06:269, DQB1*06:26N, DQB1*06:270:01, DQB1*06:270:02, DQB1*06:271, DQB1*06:272, DQB1*06:273, DQB1*06:274, DQB1*06:275, DQB1*06:276, DQB1*06:277, DQB1*06:278, DQB1*06:279, DQB1*06:27:01, DQB1*06:27:02, DQB1*06:28, DQB1*06:280, DQB1*06:281, DQB1*06:282, DQB1*06:283, DQB1*06:284, DQB1*06:285, DQB1*06:286, DQB1*06:287, DQB1*06:288, DQB1*06:289, DQB1*06:29, DQB1*06:290, DQB1*06:291, DQB1*06:292, DQB1*06:293, DQB1*06:294, DQB1*06:295, DQB1*06:296, DQB1*06:297, DQB1*06:298, DQB1*06:299, DQB1*06:30, DQB1*06:300, DQB1*06:301, DQB1*06:302, DQB1*06:303N, DQB1*06:304N, DQB1*06:305, DQB1*06:306N, DQB1*06:307, DQB1*06:308N, DQB1*06:309, DQB1*06:31, DQB1*06:310, DQB1*06:311, DQB1*06:312, DQB1*06:313, DQB1*06:314, DQB1*06:315, DQB1*06:316, DQB1*06:317N, DQB1*06:318, DQB1*06:319, DQB1*06:320, DQB1*06:321, DQB1*06:322, DQB1*06:323, DQB1*06:324, DQB1*06:325, DQB1*06:326, DQB1*06:32:01, DQB1*06:32:02, DQB1*06:33, DQB1*06:34, DQB1*06:35, DQB1*06:36, DQB1*06:37, DQB1*06:38, DQB1*06:39, DQB1*06:40, DQB1*06:41, DQB1*06:42, DQB1*06:43,DQB1*06:44, DQB1*06:45, DQB1*06:46, DQB1*06:47, DQB1*06:48:01, DQB1*06:48:02, DQB1*06:49, DQB1*06:50, DQB1*06:51:01, DQB1*06:51:02, DQB1*06:52, DQB1*06:53:01, DQB1*06:53:02, DQB1*06:54N, DQB1*06:55, DQB1*06:56, DQB1*06:57, DQB1*06:58, DQB1*06:59, DQB1*06:60, DQB1*06:61, DQB1*06:62, DQB1*06:63, DQB1*06:64, DQB1*06:65, DQB1*06:66, DQB1*06:67, DQB1*06:68, DQB1*06:69:01, DQB1*06:69:02, DQB1*06:70, DQB1*06:71, DQB1*06:72, DQB1*06:73, DQB1*06:74, DQB1*06:75NX, DQB1*06:76, DQB1*06:77N, DQB1*06:78, DQB1*06:79:01, DQB1*06:79:02, DQB1*06:80, DQB1*06:81, DQB1*06:82, DQB1*06:83, DQB1*06:84, DQB1*06:85, DQB1*06:86, DQB1*06:87, DQB1*06:88, DQB1*06:89, DQB1*06:90, DQB1*06:91, DQB1*06:92:01, DQB1*06:92:02, DQB1*06:93, DQB1*06:94, DQB1*06:95, DQB1*06:96:01, DQB1*06:96:02, DQB1*06:97, DQB1*06:98, DQB1*06:99:01, DQB1*06:99:02, and any combination thereof.

[0208] II.D.3.HLA-DR Class II molecules

[0209] In some aspects, the a chain is an HLA-DR a chain. Any HLA-DR a chain allele known in the art can be used in the compositions and methods disclosed herein. In some aspects, the a chain is an HLA-DRA*01 allele. In some aspects, the a chain is an HLA-DRA1 allele selected from the group consisting of *01:01:01:01, *01:01:01:02, *01:01:01:03, *01:01:02, *01:02:01, *01:02:02, *01:02:03, and any combination thereof.

[0210] In some aspects, the β chain is an HLA-DR β chain. Any HLA-DR β chain allele known in the art can be used in the compositions and methods disclosed herein. In some aspects, the β chain is selected from the group consisting of HLA-DRB1*01, HLA-DRB1*03, HLA-DRB1*04, HLA-DRB1*07, HLA-DRB1*08, HLA-DRB1*09, HLA-DRB1*10, HLA-DRB1*11, HLA-DRB1*12, HLA-DRB1*13, HLA-DRB1*14, HLA-DRB1*15, and HLA-DRB1*16 alleles. In some aspects, the β chain is a DRB3 allele. In some aspects, the β chain is a DRB4 allele. In some aspects, the β chain is a DRB5 allele.

[0211] In some aspects, the β-chain is selected from DRB1*01:01:01, DRB1*01:01:02, DRB1*01:01:03, DRB1*01:01:04, DRB1*01:01:05, DRB1*01:01:06, DRB1*01:01:07, DRB1*01:01:08, DRB1*01:01:09, DRB1*01:01:10, DRB1*01:01:11, DRB1*01:01:12, DRB1*01:01:13, DRB1*01:01:14, DRB1*01:01:15, DRB1*01:01:16, DRB1*01:01:17 、DRB1*01:01:18、DRB1*01:01:19、DRB1*01:01:20、DRB1*01:01:21、DRB1*01:01:22、DRB1*01:01:23、DRB1*01:01:24、DRB1*01:01:25、DRB1*01:01:25 26、DRB1*01:01:27、DRB1*01:01:28、DRB1*01:01:29、DRB1*01:01:30、DRB1*01:01:31、DRB1*01:01:32、DRB1*01:01:33、DRB1*01:01:01、DRB1*01:01:01 1:02:01:02、DRB1*01:02:02、DRB1*01:02:03、DRB1*01:02:04、DRB1*01:02:05、DRB1*01:02:06、DRB1*01:02:07、DRB1*01:02:08、DRB1*01:02:09、DRB1*01:02:10、DRB1*01:02:11、DRB1*01:02:12、DRB1*01:02:13、DRB1*01:03:01、DRB1*01:03:02、DRB1*01:03:03、DRB1*01:03:04、DRB1*01 B1*01:05、DRB1*01:06、DRB1*01:07、DRB1*01:08、DRB1*01:09、DRB1*01:10、DRB1*01:100、DRB1*01:11:01、DRB1*01:11:02、DRB1*01:12、DRB1*01:10 3、DRB1*01:14、DRB1*01:15、DRB1*01:16、DRB1*01:17、DRB1*01:18:01、DRB1*01:18:02、DRB1*01:19、DRB1*01:20:01、DRB1*01:20:02、DRB1*01:21、DRB1*01:22, DRB1*01:23, DRB1*01:24:01, DRB1*01:24:02, DRB1*01:25, DRB1*01:26, DRB1*01:27, DRB1*01:28, DRB1*01:29:01, DRB1*01:29:02, DRB1*01:30, DRB1*01:31, DRB1*01:32, DRB1*01:33N, DRB1*01:34, DRB1*01:35, DRB1*01:36, DRB1*01:37, DRB1*01:38, DRB1*01:39N, DRB1*01:40N, DRB1*01:41, DRB1*01:42, DRB1*01:43, DRB1*01:44:01, DRB1*01:44:02, DRB1*01:45, DRB1*01:46, DRB1*01:47, DRB1*01:48, DRB1*01:49, DRB1*01:50, DRB1*01:51, DRB1*01:52N, DRB1*01:53, DRB1*01:54, DRB1*01:55, DRB1*01:56, DRB1*01:57, DRB1*01:58, DRB1*01:59, DRB1*01:60, DRB1*01:61, DRB1*01:62N, DRB1*01:63, DRB1*01:64, DRB1*01:65:01, DRB1*01:65:02, DRB1*01:66, DRB1*01:67, DRB1*01:68N, DRB1*01:69, DRB1*01:70, DRB1*01:71, DRB1*01:72, DRB1*01:73, DRB1*01:74, DRB1*01:75, DRB1*01:76, DRB1*01:77, DRB1*01:78, DRB1*01:79, DRB1*01:80, DRB1*01:81, DRB1*01:82, DRB1*01:83, DRB1*01:84, DRB1*01:85, DRB1*01:86, DRB1*01:87, DRB1*01:88, DRB1*01:89, DRB1*01:90, DRB1*01:91Q, DRB1*01:92, DRB1*01:93, DRB1*01:94, DRB1*01:95, DRB1*01:96, DRB1*01:97, DRB1*01:98, DRB1*01:99, DRB1*03:01:01:01, DRB1*03:01:01:02, DRB1*03:01:01:03, DRB1*03:01:02,DRB1*03:01:03, DRB1*03:01:04, DRB1*03:01:05, DRB1*03:01:06, DRB1*03:01:07, DRB1*03:01:08, DRB1*03:01:09, DRB1*03:01:10, DRB1*03:01:11, DRB1*03:01:12, DRB1*03:01:13, DRB1*03:01:14, DRB1*03:01:15, DRB1*03:01:16, DRB1*03:01:17, DRB1*03:01:18, DRB1*03:01:19, DRB1*03:01:20, DRB1*03:01:21, DRB1*03:01:22, DRB1*03:01:23, DRB1*03:01:24, DRB1*03:01:25, DRB1*03:01:26, DRB1*03:01:27, DRB1*03:01:28, DRB1*03:02:01, DRB1*03:02:02, DRB1*03:02:03, DRB1*03:03, DRB1*03:04:01, DRB1*03:04:02, DRB1*03:05:01, DRB1*03:05:02, DRB1*03:05:03, DRB1*03:06, DRB1*03:07:01, DRB1*03:07:02, DRB1*03:08, DRB1*03:09, DRB1*03:10, DRB1*03:100:01, DRB1*03:100:02, DRB1*03:101, DRB1*03:102, DRB1*03:103, DRB1*03:104, DRB1*03:105, DRB1*03:106, DRB1*03:107, DRB1*03:108, DRB1*03:109, DRB1*03:110, DRB1*03:111, DRB1*03:112, DRB1*03:113, DRB1*03:114, DRB1*03:115, DRB1*03:116, DRB1*03:117, DRB1*03:118, DRB1*03:119, DRB1*03:11:01, DRB1*03:12, DRB1*03:120, DRB1*03:121, DRB1*03:122, DRB1*03:123, DRB1*03:124, DRB1*03:125, DRB1*03:126, DRB1*03:127, DRB1*03:128, DRB1*03:129, DRB1*03:130, DRB1*03:131, DRB1*03:132,DRB1*03:133, DRB1*03:134, DRB1*03:135, DRB1*03:136, DRB1*03:137, DRB1*03:138, DRB1*03:139, DRB1*03:13:01, DRB1*03:13:02, DRB1*03:14, DRB1*03:140, DRB1*03:141, DRB1*03:142, DRB1*03:143, DRB1*03:144, DRB1*03:145, DRB1*03:146, DRB1*03:147, DRB1*03:148, DRB1*03:149, DRB1*03:150, DRB1*03:151, DRB1*03:152, DRB1*03:153, DRB1*03:154, DRB1*03:155, DRB1*03:156N, DRB1*03:157, DRB1*03:158, DRB1*03:15:01, DRB1*03:15:02, DRB1*03:16, DRB1*03:17, DRB1*03:18, DRB1*03:19, DRB1*03:20, DRB1*03:21, DRB1*03:22, DRB1*03:23, DRB1*03:24, DRB1*03:25:01, DRB1*03:25:02, DRB1*03:26, DRB1*03:27, DRB1*03:28, DRB1*03:29, DRB1*03:30, DRB1*03:31, DRB1*03:32, DRB1*03:33, DRB1*03:34, DRB1*03:35, DRB1*03:36, DRB1*03:37, DRB1*03:38, DRB1*03:39, DRB1*03:40, DRB1*03:41:01, DRB1*03:41:02, DRB1*03:42, DRB1*03:43, DRB1*03:44, DRB1*03:45, DRB1*03:46, DRB1*03:47, DRB1*03:48, DRB1*03:49, DRB1*03:50, DRB1*03:51, DRB1*03:52, DRB1*03:53, DRB1*03:54, DRB1*03:55, DRB1*03:56, DRB1*03:57, DRB1*03:58, DRB1*03:59, DRB1*03:60, DRB1*03:61, DRB1*03:62, DRB1*03:63, DRB1*03:64, DRB1*03:65, DRB1*03:66, DRB1*03:67N, DRB1*03:68N,DRB1*03:69、DRB1*03:70、DRB1*03:71:01、DRB1*03:71:02、DRB1*03:72、DRB1*03:73、DRB1*03:74、DRB1*03:75、DRB1*03:76、DRB1*03:77、DRB1*03:78、DRB1*03:79、DRB1*03:80、DRB1*03:81、DRB1*03:82、DRB1*03:83、DRB1*03:84、DRB1*03:85、DRB1*03:86、DRB1*03:87、DRB1*03:88、DRB1*03:89 、DRB1*03:90、DRB1*03:91、DRB1*03:92、DRB1*03:93、DRB1*03:94、DRB1*03:95、DRB1*03:96、DRB1*03:97、DRB1*03:98、DRB1*03:99、DRB1*04:01:0 1:01、DRB1*04:01:01:02、DRB1*04:01:01:03、DRB1*04:01:02、DRB1*04:0 1:03、DRB1*04:01:04、DRB1*04:01:05、DRB1*04:01:06、DRB1*04:01:07、D RB1*04:01:08、DRB1*04:01:09、DRB1*04:01:10、DRB1*04:01:11、DRB1*04:01:12、DRB1*04:01:13、DRB1*04:01:14、DRB1*04:01:15、DRB1*04:01:16、DRB1*04:01:17、DRB1*04:01:18、DRB1*04:01:19、DRB1*04:01:20、DRB1*04:01:21、DRB1*04:02:01、DRB1*04:02:02、DRB1*04:02:03、DRB1*04:02 :04、DRB1*04:02:05、DRB1*04:02:06、DRB1*04:03:01:01、DRB1*04:03:01:02、DRB1*04:03:02、DRB1*04:03:03、DRB1*04:03:04、DRB1*04:03:05、DRB1*04:03:06、DRB1*04:03:07、DRB1*04:03:08、DRB1*04:03:09、DRB1*04:03:10、DRB1*04:03:11、DRB1*04:03:12、DRB1*04:03:13、DRB1*04:03:14、DRB1*04:03:15, DRB1*04:04:01, DRB1*04:04:02, DRB1*04:04:03, DRB1*04:04:04, DRB1*04:04:05, DRB1*04:04:06, DRB1*04:04:07, DRB1*04:04:08, DRB1*04:04:09, DRB1*04:04:10, DRB1*04:04:11, DRB1*04:04:12, DRB1*04:04:13, DRB1*04:04:14, DRB1*04:04:15, DRB1*04:05:01:01, DRB1*04:05:01:02, DRB1*04:05:01:03, DRB1*04:05:02, DRB1*04:05:03, DRB1*04:05:04, DRB1*04:05:05, DRB1*04:05:06, DRB1*04:05:07, DRB1*04:05:08, DRB1*04:05:09, DRB1*04:05:10, DRB1*04:05:11, DRB1*04:05:13, DRB1*04:05:14, DRB1*04:05:15, DRB1*04:05:16, DRB1*04:05:17, DRB1*04:05:18, DRB1*04:05:19, DRB1*04:05:20, DRB1*04:06:01, DRB1*04:06:02, DRB1*04:06:03, DRB1*04:06:04, DRB1*04:06:05, DRB1*04:06:06, DRB1*04:06:07, DRB1*04:07:01:01, DRB1*04:07:01:02, DRB1*04:07:02, DRB1*04:07:03, DRB1*04:07:04, DRB1*04:07:05, DRB1*04:07:06, DRB1*04:08:01, DRB1*04:08:02, DRB1*04:08:03, DRB1*04:08:04, DRB1*04:09, DRB1*04:100, DRB1*04:101, DRB1*04:102, DRB1*04:103, DRB1*04:104, DRB1*04:105:01, DRB1*04:105:02, DRB1*04:106, DRB1*04:107, DRB1*04:108, DRB1*04:109, DRB1*04:10:01, DRB1*04:10:02, DRB1*04:10:03, DRB1*04:110, DRB1*04:111,DRB1*04:112, DRB1*04:113, DRB1*04:114, DRB1*04:115, DRB1*04:116, DRB1*04:117, DRB1*04:118, DRB1*04:119N, DRB1*04:11:01, DRB1*04:11:02, DRB1*04:11:03, DRB1*04:11:04, DRB1*04:11:05, DRB1*04:12, DRB1*04:120N, DRB1*04:121, DRB1*04:122, DRB1*04:123, DRB1*04:124, DRB1*04:125, DRB1*04:126, DRB1*04:127, DRB1*04:128, DRB1*04:129, DRB1*04:13, DRB1*04:130, DRB1*04:131:01, DRB1*04:131:02, DRB1*04:132, DRB1*04:133, DRB1*04:134, DRB1*04:135, DRB1*04:136, DRB1*04:137, DRB1*04:138, DRB1*04:139, DRB1*04:14, DRB1*04:140, DRB1*04:141, DRB1*04:142N, DRB1*04:143, DRB1*04:144, DRB1*04:145, DRB1*04:146, DRB1*04:147, DRB1*04:148, DRB1*04:149, DRB1*04:15, DRB1*04:150, DRB1*04:151, DRB1*04:152, DRB1*04:153, DRB1*04:154, DRB1*04:155, DRB1*04:156, DRB1*04:157N, DRB1*04:158N, DRB1*04:159, DRB1*04:16, DRB1*04:160, DRB1*04:161, DRB1*04:162, DRB1*04:163, DRB1*04:164, DRB1*04:165, DRB1*04:166, DRB1*04:167, DRB1*04:168, DRB1*04:169, DRB1*04:170, DRB1*04:171, DRB1*04:172, DRB1*04:173, DRB1*04:174, DRB1*04:175, DRB1*04:176, DRB1*04:177, DRB1*04:178N, DRB1*04:179, DRB1*04:17:01, DRB1*04:17:02,DRB1*04:18, DRB1*04:180, DRB1*04:181, DRB1*04:182, DRB1*04:183, DRB1*04:184, DRB1*04:185, DRB1*04:186N, DRB1*04:187, DRB1*04:188, DRB1*04:189, DRB1*04:19, DRB1*04:190, DRB1*04:191, DRB1*04:192, DRB1*04:193, DRB1*04:194, DRB1*04:195, DRB1*04:196, DRB1*04:197, DRB1*04:198, DRB1*04:199, DRB1*04:20, DRB1*04:200, DRB1*04:201, DRB1*04:202, DRB1*04:203, DRB1*04:204, DRB1*04:205, DRB1*04:206, DRB1*04:207, DRB1*04:208, DRB1*04:209, DRB1*04:21, DRB1*04:210, DRB1*04:211, DRB1*04:212N, DRB1*04:213, DRB1*04:214N, DRB1*04:215, DRB1*04:216, DRB1*04:217, DRB1*04:218, DRB1*04:219, DRB1*04:22, DRB1*04:220, DRB1*04:221, DRB1*04:222, DRB1*04:223, DRB1*04:224, DRB1*04:225, DRB1*04:226:01, DRB1*04:226:02, DRB1*04:227, DRB1*04:228, DRB1*04:229, DRB1*04:23, DRB1*04:230, DRB1*04:231, DRB1*04:232, DRB1*04:233, DRB1*04:234, DRB1*04:235, DRB1*04:236, DRB1*04:237, DRB1*04:238, DRB1*04:239, DRB1*04:24, DRB1*04:240, DRB1*04:241, DRB1*04:242, DRB1*04:243, DRB1*04:244, DRB1*04:245, DRB1*04:246, DRB1*04:247N, DRB1*04:248, DRB1*04:249, DRB1*04:25, DRB1*04:250, DRB1*04:251, DRB1*04:252, DRB1*04:253,DRB1*04:254, DRB1*04:255, DRB1*04:256, DRB1*04:257, DRB1*04:258, DRB1*04:259, DRB1*04:26, DRB1*04:260, DRB1*04:261, DRB1*04:262, DRB1*04:263, DRB1*04:264N, DRB1*04:265, DRB1*04:266N, DRB1*04:267N, DRB1*04:268, DRB1*04:269, DRB1*04:27, DRB1*04:270, DRB1*04:271, DRB1*04:272, DRB1*04:28, DRB1*04:29, DRB1*04:30, DRB1*04:31, DRB1*04:32, DRB1*04:33, DRB1*04:34, DRB1*04:35, DRB1*04:36, DRB1*04:37, DRB1*04:38, DRB1*04:39, DRB1*04:40, DRB1*04:41, DRB1*04:42, DRB1*04:43, DRB1*04:44:01, DRB1*04:44:02, DRB1*04:45, DRB1*04:46, DRB1*04:47, DRB1*04:48, DRB1*04:49, DRB1*04:50, DRB1*04:51, DRB1*04:52, DRB1*04:53:01, DRB1*04:53:02, DRB1*04:54, DRB1*04:55, DRB1*04:56:01, DRB1*04:56:02, DRB1*04:57, DRB1*04:58, DRB1*04:59, DRB1*04:60, DRB1*04:61, DRB1*04:62, DRB1*04:63, DRB1*04:64, DRB1*04:65, DRB1*04:66, DRB1*04:67, DRB1*04:68, DRB1*04:69, DRB1*04:70, DRB1*04:71, DRB1*04:72:01, DRB1*04:72:02, DRB1*04:73:01, DRB1*04:73:02, DRB1*04:74, DRB1*04:75, DRB1*04:76, DRB1*04:77, DRB1*04:78, DRB1*04:79, DRB1*04:80, DRB1*04:81N, DRB1*04:82, DRB1*04:83, DRB1*04:84, DRB1*04:85, DRB1*04:86, DRB1*04:87,DRB1*04:88, DRB1*04:89, DRB1*04:90, DRB1*04:91, DRB1*04:92, DRB1*04:93, DRB1*04:94:01N, DRB1*04:95:01, DRB1*04:95:02, DRB1*04:96, DRB1*04:97, DRB1*04:98:01, DRB1*04:98:02, 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DRB1*13:187, DRB1*13:188, DRB1*13:189, DRB1*13:19, DRB1*13:190, DRB1*13:191, DRB1*13:192, DRB1*13:193, DRB1*13:194, DRB1*13:195, DRB1*13:196, DRB1*13:197, DRB1*13:198, DRB1*13:199, DRB1*13:20, DRB1*13:200N, DRB1*13:201, DRB1*13:202, DRB1*13:203, DRB1*13:204, DRB1*13:205, DRB1*13:206, DRB1*13:207, DRB1*13:208, DRB1*13:209, DRB1*13:210, DRB1*13:211, DRB1*13:212, DRB1*13:213, DRB1*13:214, DRB1*13:215, DRB1*13:216, DRB1*13:217, DRB1*13:218, DRB1*13:219, DRB1*13:21:01, DRB1*13:21:02, DRB1*13:220, DRB1*13:221, DRB1*13:222, DRB1*13:223, DRB1*13:224, DRB1*13:225, DRB1*13:226, DRB1*13:227, DRB1*13:228, DRB1*13:229, DRB1*13:22:01, DRB1*13:22:02, DRB1*13:230, DRB1*13:231, DRB1*13:232, DRB1*13:233, DRB1*13:234, DRB1*13:235, DRB1*13:236, DRB1*13:237, DRB1*13:238, DRB1*13:239, DRB1*13:23:01, DRB1*13:23:02, DRB1*13:24, DRB1*13:240, DRB1*13:241, DRB1*13:242:01, DRB1*13:242:02, DRB1*13:243, DRB1*13:244,DRB1*13:245、DRB1*13:246、DRB1*13:247、DRB1*13:248、DRB1*13:249N、DRB1*13:25、DRB1*13:250、DRB1*13:251、DRB1*13:252N、DRB1*13:253、DRB1*13:254、DRB1*13:255N、DRB1*13:256、DRB1*13:257、DRB1*13:258、DRB1*13:259、DRB1*13:260、DRB1*13:261、DRB1*13:262、DRB1*13:263、DRB1* 13:264、DRB1*13:265、DRB1*13:266、DRB1*13:267、DRB1*13:268N、DRB1*13:269、DRB1*13:26:01、DRB1*13:26:02、DRB1*13:27、DRB1*13:270、DRB1 *13:271、DRB1*13:272、DRB1*13:273、DRB1*13:274、DRB1*13:275、DRB1*13:276、DRB1*13:277、DRB1*13:278Q、DRB1*13:279、DRB1*13:280、DRB1*13:278 13:28:02, DRB1*13:29, DRB1*13:30, DRB1*13:31, DRB1*13:32, DRB1*13:33:01, DRB1*13:33:02, DRB1*13:33:03, DRB1*13:34, DRB1*13:35, DRB1*13:36, DRB1*13:37, DRB1*13:38, DRB1*13:39, DRB1*13:40, DRB1*13:41, DRB1*13:42, DRB1*13:43, DRB1*13:44, DRB1*13:45, DRB1*13:46, DRB1*13:4 7、DRB1*13:48、DRB1*13:49、DRB1*13:50:01、DRB1*13:50:02、DRB1*13:50:03、DRB1*13:51、DRB1*13:52、DRB1*13:53、DRB1*13:54、DRB1*13:55、DRB1*13:56、DRB1*13:57、DRB1*13:58、DRB1*13:59、DRB1*13:60、DRB1*13:61:01、DRB1*13:61:02、DRB1*13:62、DRB1*13:63、DRB1*13:64、DRB1*13:65、DRB1*13:66:01, DRB1*13:66:02, DRB1*13:67, DRB1*13:68, DRB1*13:69, DRB1*13:70, DRB1*13:71, DRB1*13:72, DRB1*13:73, DRB1*13:74, DRB1*13:75, DRB1*13:76, DRB1*13:77, DRB1*13:78, DRB1*13:79, DRB1*13:80, DRB1*13:81, DRB1*13:82, DRB1*13:83, DRB1*13:84, DRB1*13:85, DRB1*13:86, DRB1*13:87, DRB1*13:88, DRB1*13:89:01, DRB1*13:89:02, DRB1*13:90, DRB1*13:91, DRB1*13:92, DRB1*13:93, DRB1*13:94:01, DRB1*13:94:02, DRB1*13:95, DRB1*13:96:01, DRB1*13:96:02, DRB1*13:97:01, DRB1*13:97:02, DRB1*13:98, DRB1*13:99, DRB1*14:01:01, DRB1*14:01:02, DRB1*14:01:03, DRB1*14:01:04, DRB1*14:02:01:01, DRB1*14:02:01:02, DRB1*14:02:02, DRB1*14:02:03, DRB1*14:02:04, DRB1*14:02:05, DRB1*14:02:06, DRB1*14:02:07, DRB1*14:03:01, DRB1*14:03:02, DRB1*14:04:01, DRB1*14:04:02, 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DRB1*14:148, DRB1*14:149, DRB1*14:15, DRB1*14:150, DRB1*14:151, DRB1*14:152N, DRB1*14:153, DRB1*14:154, DRB1*14:155, DRB1*14:156, DRB1*14:157, DRB1*14:158, DRB1*14:159, DRB1*14:16, DRB1*14:160, DRB1*14:161, DRB1*14:162, DRB1*14:163, DRB1*14:164, DRB1*14:165, DRB1*14:166N, DRB1*14:167, DRB1*14:168, DRB1*14:169, DRB1*14:17, DRB1*14:170, DRB1*14:171, DRB1*14:172, DRB1*14:173, DRB1*14:174, DRB1*14:175, DRB1*14:176,DRB1*14:177, DRB1*14:178, DRB1*14:179, DRB1*14:18, DRB1*14:180, DRB1*14:181, DRB1*14:182, DRB1*14:183, DRB1*14:184, DRB1*14:185, DRB1*14:186, DRB1*14:187, DRB1*14:188N, DRB1*14:189, DRB1*14:19, DRB1*14:190, DRB1*14:191, DRB1*14:192, DRB1*14:193, DRB1*14:194, DRB1*14:195N, DRB1*14:196, DRB1*14:197N, DRB1*14:198, DRB1*14:199, DRB1*14:20, DRB1*14:200, DRB1*14:201, DRB1*14:202, DRB1*14:203, DRB1*14:204, DRB1*14:205, DRB1*14:206, DRB1*14:207, DRB1*14:208, DRB1*14:209, DRB1*14:21, DRB1*14:210Q, DRB1*14:211, DRB1*14:22, DRB1*14:23:01, DRB1*14:23:02, DRB1*14:23:03, DRB1*14:23:04, DRB1*14:24, DRB1*14:25:01, DRB1*14:25:02, DRB1*14:26, DRB1*14:27:01, DRB1*14:27:02, DRB1*14:28, DRB1*14:29, DRB1*14:30, DRB1*14:31, DRB1*14:32:01, DRB1*14:32:02, DRB1*14:32:03, DRB1*14:33, DRB1*14:34, DRB1*14:35, DRB1*14:36, DRB1*14:37, DRB1*14:38:01, DRB1*14:38:02, DRB1*14:39, DRB1*14:40, DRB1*14:41, DRB1*14:42, DRB1*14:43, DRB1*14:44:01, DRB1*14:44:02, DRB1*14:44:03, DRB1*14:45, DRB1*14:46, DRB1*14:47, DRB1*14:48, DRB1*14:49, DRB1*14:50, DRB1*14:51, DRB1*14:52, DRB1*14:53, DRB1*14:54:01:01,DRB1*14:54:01:02, DRB1*14:54:01:03, DRB1*14:54:01:04, DRB1*14:54:02, DRB1*14:54:03, DRB1*14:54:04, DRB1*14:54:05, DRB1*14:54:06, DRB1*14:54:07, DRB1*14:55, DRB1*14:56, DRB1*14:57, DRB1*14:58, DRB1*14:59, DRB1*14:60, DRB1*14:61, DRB1*14:62, DRB1*14:63, DRB1*14:64, DRB1*14:65, DRB1*14:67, DRB1*14:68:01, DRB1*14:68:02, DRB1*14:69, DRB1*14:70, DRB1*14:71, DRB1*14:72, DRB1*14:73, DRB1*14:74, DRB1*14:75, DRB1*14:76, DRB1*14:77, DRB1*14:78, DRB1*14:79, DRB1*14:80, DRB1*14:81, DRB1*14:82, DRB1*14:83, DRB1*14:84, DRB1*14:85, DRB1*14:86, DRB1*14:87, DRB1*14:88, DRB1*14:89, DRB1*14:90, DRB1*14:91, DRB1*14:92N, DRB1*14:93, DRB1*14:94, DRB1*14:95, DRB1*14:96, DRB1*14:97, DRB1*14:98, DRB1*14:99, DRB1*15:01:01:01, DRB1*15:01:01:02, DRB1*15:01:01:03, DRB1*15:01:01:04, DRB1*15:01:01:05, DRB1*15:01:02, DRB1*15:01:03, DRB1*15:01:04, DRB1*15:01:05, DRB1*15:01:06, DRB1*15:01:07, DRB1*15:01:08, DRB1*15:01:09, DRB1*15:01:10, DRB1*15:01:11, DRB1*15:01:12, DRB1*15:01:13, DRB1*15:01:14, DRB1*15:01:15, DRB1*15:01:16, DRB1*15:01:17, DRB1*15:01:18, DRB1*15:01:19, DRB1*15:01:20,DRB1*15:01:21, DRB1*15:01:22, DRB1*15:01:23, DRB1*15:01:24, DRB1*15:01:25, DRB1*15:01:26, DRB1*15:01:27, DRB1*15:01:28, DRB1*15:01:29, DRB1*15:01:30, DRB1*15:01:31, DRB1*15:01:32, DRB1*15:01:33, DRB1*15:01:34, DRB1*15:01:35, DRB1*15:01:36, DRB1*15:01:37, DRB1*15:01:38, DRB1*15:01:39, DRB1*15:01:40, DRB1*15:01:41, DRB1*15:02:01:01, DRB1*15:02:01:02, DRB1*15:02:01:03, DRB1*15:02:02, DRB1*15:02:03, DRB1*15:02:04, DRB1*15:02:05, 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DRB1*15:132, DRB1*15:133, DRB1*15:134N, DRB1*15:135, DRB1*15:136, DRB1*15:137N, DRB1*15:138N, DRB1*15:139, DRB1*15:14, DRB1*15:140, DRB1*15:141, DRB1*15:142, DRB1*15:143, DRB1*15:144, DRB1*15:145, DRB1*15:146, DRB1*15:147, DRB1*15:148N, DRB1*15:149, DRB1*15:150, DRB1*15:151, DRB1*15:152, DRB1*15:153, DRB1*15:154N, DRB1*15:155, DRB1*15:156, DRB1*15:157, DRB1*15:158, DRB1*15:159N, DRB1*15:15:01, DRB1*15:15:02, DRB1*15:15:03, DRB1*15:16, DRB1*15:160, DRB1*15:161, DRB1*15:162, DRB1*15:163N, DRB1*15:164Q, DRB1*15:165, DRB1*15:166, DRB1*15:167, DRB1*15:168, DRB1*15:169, DRB1*15:170, DRB1*15:17N, DRB1*15:18, DRB1*15:19, DRB1*15:20, DRB1*15:21, DRB1*15:22, DRB1*15:23, DRB1*15:24, DRB1*15:25, DRB1*15:26,DRB1*15:27, DRB1*15:28, DRB1*15:29, DRB1*15:30, DRB1*15:31:01, DRB1*15:31:02, DRB1*15:32, DRB1*15:33, DRB1*15:34, DRB1*15:35, DRB1*15:36, DRB1*15:37:01, DRB1*15:37:02, DRB1*15:38, DRB1*15:39, DRB1*15:40, DRB1*15:41, DRB1*15:42, DRB1*15:43, DRB1*15:44, DRB1*15:45, DRB1*15:46, DRB1*15:47, DRB1*15:48, DRB1*15:49, DRB1*15:50N, DRB1*15:51, DRB1*15:52, DRB1*15:53, DRB1*15:54, DRB1*15:55, DRB1*15:56, DRB1*15:57, DRB1*15:58, DRB1*15:59, DRB1*15:60, DRB1*15:61, DRB1*15:62, DRB1*15:63, DRB1*15:64, DRB1*15:65, DRB1*15:66:01, DRB1*15:66:02, DRB1*15:67, DRB1*15:68, DRB1*15:69, DRB1*15:70, DRB1*15:71, DRB1*15:72, DRB1*15:73, DRB1*15:74, DRB1*15:75, DRB1*15:76, DRB1*15:77, DRB1*15:78, DRB1*15:79, DRB1*15:80N, DRB1*15:81, DRB1*15:82, DRB1*15:83, DRB1*15:84, DRB1*15:85, DRB1*15:86, DRB1*15:87, DRB1*15:88, DRB1*15:89, DRB1*15:90, DRB1*15:91, DRB1*15:92, DRB1*15:93, DRB1*15:94, DRB1*15:95, DRB1*15:96, DRB1*15:97, DRB1*15:98, DRB1*15:99, DRB1*16:01:01, DRB1*16:01:02, DRB1*16:01:03, DRB1*16:01:04, DRB1*16:01:05, DRB1*16:01:06, DRB1*16:01:07, DRB1*16:01:08, DRB1*16:01:09, DRB1*16:01:10,DRB1*16:01:11, DRB1*16:01:12, DRB1*16:01:13, DRB1*16:01:14, DRB1*16:01:15, DRB1*16:01:16, DRB1*16:02:01:01, DRB1*16:02:01:02, DRB1*16:02:01:03, DRB1*16:02:02, DRB1*16:02:03, DRB1*16:02:04, DRB1*16:02:05, DRB1*16:02:06, DRB1*16:02:07, DRB1*16:02:08, DRB1*16:03, DRB1*16:04:01, DRB1*16:04:02, DRB1*16:05:01, DRB1*16:05:02, DRB1*16:07, DRB1*16:08, DRB1*16:09:01, DRB1*16:09:02, DRB1*16:10:01, DRB1*16:10:02, DRB1*16:11, DRB1*16:12, DRB1*16:13N, DRB1*16:14, DRB1*16:15, DRB1*16:16, DRB1*16:17, DRB1*16:18, DRB1*16:19, DRB1*16:20, DRB1*16:21N, DRB1*16:22, DRB1*16:23, DRB1*16:24, DRB1*16:25, DRB1*16:26, DRB1*16:27, DRB1*16:28, DRB1*16:29, DRB1*16:30, DRB1*16:31, DRB1*16:32, DRB1*16:33, DRB1*16:34, DRB1*16:35, DRB1*16:36, DRB1*16:37, DRB1*16:38:01, DRB1*16:38:02, DRB1*16:39, DRB1*16:40, DRB1*16:41N, DRB1*16:42, DRB1*16:43, DRB1*16:44, DRB1*16:45, DRB1*16:46, DRB1*16:47, DRB1*16:48, DRB1*16:49, DRB1*16:50, DRB1*16:51, DRB1*16:52, DRB1*16:53, DRB1*16:54, DRB1*16:55N, DRB1*16:56, DRB3*01:01:02:01, DRB3*01:01:02:02, DRB3*01:01:02:03, DRB3*01:01:03, DRB3*01:01:04, DRB3*01:01:05,DRB3*01 :01 :06, DRB3*01 :01 :07, DRB3*01 :01 :08, DRB3*01 :01 :09, DRB3*01 :01 :10, DRB3*01 :02, DRB3*01 :03, DRB3*01 :04, DRB3*01 :05, DRB3*01 :06, DRB3*01 :07, DRB3*01 :08, DRB3*01 :09, DRB3*01 :10, DRB3*01 :11, DRB3*01 :12, DRB3*01 :13, DRB3*01 :14, DRB3*01 :15, DRB3*01 :16, DRB3*01 :17, DRB3*01 :18, DRB3*01 :19, DRB3*01 :20, DRB3*01 :21, DRB3*01 :22, DRB3*01 :23, DRB3*01 :24, DRB3*01 :25, DRB3*01 :26N, DRB3*01 :27, DRB3*01 :28, DRB3*01 :29, DRB3*01 :30, DRB3*01 :31, DRB3*01 :32, DRB3*01 :33, DRB3*01 :34, DRB3*01 :35, DRB3*01 :36, DRB3*01 :37, DRB3*01 :38, DRB3*01 :39, DRB3*01 :40:01 N, DRB3*01 :40:02N, DRB3*01 :41, DRB3*01 :42, DRB3*01 :43, DRB3*01 :44, DRB3*01 :45, DRB3*01 :46, DRB3*01 :47, DRB3*01 :48, DRB3*01 :49, DRB3*01 :50, DRB3*01 :51, DRB3*01 :52, DRB3*01 :53, DRB3*01 :54, DRB3*01 :55, DRB3*01 :56, DRB3*01 :57, DRB3*01 :58, DRB3*01 :59, DRB3*01 :60, DRB3*01 :61, DRB3*01 :62, DRB3*02:01, DRB3*02:02:01 :01, DRB3*02:02:01 :02, DRB3*02:02:01 :03, DRB3*02:02:01 :04, DRB3*02:02:02, DRB3*02:02:03, DRB3*02:02:04, DRB3*02:02:05, DRB3*02:02:06, DRB3*02:02:07, DRB3*02:02:08, DRB3*02:02:09, DRB3*02:02:10, DRB3*02:02:11, DRB3*02:02:12,DRB3*02:02:13, DRB3*02:02:14, DRB3*02:02:15, DRB3*02:02:16, DRB3*02:02:17, DRB3*02:02:18, DRB3*02:02:19, DRB3*02:02:20, DRB3*02:02:21, DRB3*02:03, DRB3*02:04, DRB3*02:05, DRB3*02:06, DRB3*02:07, DRB3*02:08, DRB3*02:09, DRB3*02:10, DRB3*02:11, DRB3*02:12, DRB3*02:13, DRB3*02:14, DRB3*02:15, DRB3*02:16, DRB3*02:17, DRB3*02:18, DRB3*02:19, DRB3*02:20, DRB3*02:21, DRB3*02:22:01, DRB3*02:22:02, DRB3*02:23, DRB3*02:24, DRB3*02:25, DRB3*02:26, DRB3*02:27, DRB3*02:28, DRB3*02:29N, DRB3*02:30, DRB3*02:31:01, DRB3*02:31:02, DRB3*02:32, DRB3*02:33, DRB3*02:34, DRB3*02:35, DRB3*02:36, DRB3*02:37, DRB3*02:38, DRB3*02:39, DRB3*02:40, DRB3*02:41, DRB3*02:42, DRB3*02:43, DRB3*02:44, DRB3*02:45, DRB3*02:46, DRB3*02:47, DRB3*02:48, DRB3*02:49, DRB3*02:50, DRB3*02:51, DRB3*02:52, DRB3*02:53, DRB3*02:54, DRB3*02:55N, DRB3*02:56, DRB3*02:57, DRB3*02:58, DRB3*02:59, DRB3*02:60, DRB3*02:61Q, DRB3*02:62, DRB3*02:63, DRB3*02:64, DRB3*02:65, DRB3*02:66, DRB3*02:67N, DRB3*02:68, DRB3*02:69, DRB3*02:70, DRB3*02:71, DRB3*02:72, DRB3*02:73, DRB3*02:74, DRB3*02:75, DRB3*02:76, DRB3*02:77, DRB3*02:78,DRB3*02:79, DRB3*02:80N, DRB3*02:81, DRB3*02:82, DRB3*02:83, DRB3*02:84, DRB3*02:85, DRB3*02:86, DRB3*02:87, DRB3*02:88, DRB3*02:89, DRB3*02:90, DRB3*02:91, DRB3*02:92, DRB3*02:93, DRB3*02:94, DRB3*02:95N, DRB3*03:01:01:01, DRB3*03:01:01:02, DRB3*03:01:02, DRB3*03:01:03, DRB3*03:01:04, DRB3*03:01:05, DRB3*03:01:06, DRB3*03:01:07, DRB3*03:02, DRB3*03:03, DRB3*03:04, DRB3*03:05, DRB3*03:06, DRB3*03:07, DRB3*03:08, DRB3*03:09, DRB3*03:10, DRB3*03:11, DRB3*03:12, DRB3*03:13, DRB3*03:14, DRB3*03:15, DRB3*03:16, DRB3*03:17, DRB3*03:18, DRB3*03:19, DRB3*03:20, DRB3*03:21, DRB3*03:22, DRB3*03:23, DRB3*03:24, DRB3*03:25, DRB4*01:01:01:01, DRB4*01:01:02, DRB4*01:01:03, DRB4*01:01:04, DRB4*01:01:05, DRB4*01:01:06, DRB4*01:02, DRB4*01:03:01:01, DRB4*01:03:01:02N, DRB4*01:03:01:03, DRB4*01:03:01:04, DRB4*01:03:01:05, DRB4*01:03:01:06, DRB4*01:03:01:07, DRB4*01:03:01:08, DRB4*01:03:01:09, DRB4*01:03:01:10, DRB4*01:03:01:11, DRB4*01:03:02, DRB4*01:03:03, DRB4*01:03:04, DRB4*01:03:05, DRB4*01:03:06, DRB4*01:03:07, DRB4*01:03:08, DRB4*01:03:09, DRB4*01:03:10, DRB4*01:03:11,DRB4*01:04, DRB4*01:05, DRB4*01:06, DRB4*01:07:01, DRB4*01:07:02, DRB4*01:08, DRB4*01:09, DRB4*01:10, DRB4*01:11, DRB4*01:12, DRB4*01:13, DRB4*01:14, DRB4*01:15, DRB4*01:16N, DRB4*01:17, DRB4*01:18, DRB4*01:19, DRB4*01:20, DRB4*01:21, DRB4*01:22, DRB4*01:23, DRB4*01:24, DRB4*01:25, DRB4*01:26, DRB4*01:27, DRB4*01:28, DRB4*01:29, DRB4*01:30, DRB4*01:31, DRB4*01:32, DRB4*01:33, DRB4*01:34, DRB4*01:35, DRB4*01:36, DRB4*01:37, DRB4*01:38N, DRB4*01:39, DRB4*01:40, DRB4*01:41, DRB4*01:42, DRB4*01:43, DRB4*01:44, DRB4*01:45, DRB4*01:46, DRB4*01:47, DRB4*01:48, DRB4*01:49, DRB4*01:50, DRB4*01:51, DRB4*01:52, DRB4*01:53, DRB4*01:54N, DRB4*01:55, DRB4*01:56N, DRB4*01:57N, DRB4*01:58, DRB4*01:59, DRB4*01:60, DRB4*01:61N, DRB4*01:62, DRB4*01:63, DRB4*01:64, DRB4*01:65N, DRB4*01:66, DRB4*01:67, DRB4*01:68, DRB4*01:69, DRB4*01:70, DRB4*01:71N, DRB4*01:72, DRB4*01:73, DRB4*01:74, DRB4*01:75, DRB4*01:76, DRB4*01:77, DRB4*01:78, DRB4*01:79, DRB4*01:80N, DRB4*01:81, DRB4*01:82, DRB4*01:83, DRB4*01:84N, DRB4*01:85, DRB4*01:86, DRB4*01:87, DRB4*01:88, DRB4*01:89, DRB4*01:90, DRB4*01:91,DRB4*01:92, DRB4*01:93, DRB4*02:01N, DRB5*01:01:01:01, DRB5*01:01:01:02, DRB5*01:01:02, DRB5*01:01:03, DRB5*01:01:04, DRB5*01:02, DRB5*01:03, DRB5*01:04, DRB5*01:05, DRB5*01:06, DRB5*01:07, DRB5*01:08N, DRB5*01:09, DRB5*01:10N, DRB5*01:11, DRB5*01:12, DRB5*01:13, DRB5*01:14, DRB5*01:15, DRB5*01:16, DRB5*01:17, DRB5*01:18, DRB5*01:19, DRB5*01:20, DRB5*01:21, DRB5*01:22:01, DRB5*01:22:02, DRB5*01:23, DRB5*01:24, DRB5*01:25, DRB5*01:26, DRB5*01:27N, DRB5*01:28, DRB5*01:29, DRB5*01:30, DRB5*01:31, DRB5*01:32, DRB5*01:33, DRB5*01:34, DRB5*01:35, DRB5*01:36, DRB5*01:37, DRB5*01:38, DRB5*01:39, DRB5*01:40, DRB5*01:41, DRB5*01:42, DRB5*01:43, DRB5*01:44, DRB5*01:45, DRB5*01:46, DRB5*01:47, DRB5*01:48N, DRB5*01:49N, DRB5*01:50, DRB5*01:51, DRB5*01:52N, DRB5*01:53N, DRB5*01:54, DRB5*01:55, DRB5*02:02:01, DRB5*02:02:02, DRB5*02:02:03, DRB5*02:03, DRB5*02:04, DRB5*02:05, DRB5*02:06, DRB5*02:07, DRB5*02:08, DRB5*02:09, DRB5*02:10, DRB5*02:11, DRB5*02:12, DRB5*02:13, DRB5*02:14, DRB5*02:15, DRB5*02:16, DRB5*02:17, DRB5*02:18, DRB5*02:19N, DRB5*02:20, DRB5*02:21, DRB5*02:22,DRB5*02:23, DRB5*02:24, and any combination thereof.

[0212] In some aspects, the HLA Class II molecule is monomeric. In some aspects, the HLA Class II molecule is dimeric. In some aspects, the HLA Class II molecule is multimeric. In some aspects, the HLA Class II molecule is trimeric. In some aspects, the HLA Class II molecule is tetrameric. In some aspects, the HLA Class II molecule is pentameric.

[0213] Certain aspects of the present disclosure relate to an antigen presenting cell (APC) comprising any of the HLA Class II molecules disclosed herein. In certain aspects, the APC expresses an HLA Class II molecule on the surface of the APC. In certain aspects, the APC comprises more than one HLA Class II molecule disclosed herein.

[0214] II.E. Vaccines

[0215] Certain aspects of the present disclosure relate to a cancer vaccine comprising a peptide comprising an amino acid sequence as set forth in SEQ ID NO: 13. In some aspects, the cancer vaccine comprises a peptide consisting of the amino acid sequence set forth in SEQ ID NO: 13. In some aspects, the vaccine further comprises one or more excipients. In some aspects, the vaccine further comprises one or more other peptides. In some aspects, the one or more other peptides comprise one or more other epitopes.

[0216] III. Methods of the Disclosure

[0217] Certain aspects of the present disclosure relate to methods of treating a cancer in a subject in need thereof. Other aspects of the present disclosure relate to methods of engineering a cell to target an antigen. Other aspects of the present disclosure relate to methods of enriching a population of target T cells obtained from a human subject.

[0218] III.A. Methods of Treating Cancer

[0219] Certain aspects of the present disclosure relate to methods of treating a cancer in a subject in need thereof, comprising administering to the subject a nucleic acid molecule disclosed herein, a recombinant TCR disclosed herein, a bispecific TCR disclosed herein, an epitope disclosed herein, or an HLA Class II molecule disclosed herein, or a vector or cell comprising any of the foregoing.

[0220] In some aspects, the cancer is selected from melanoma, bone cancer, kidney cancer, prostate cancer, breast cancer, colon cancer, lung cancer, cutaneous or intraocular malignant melanoma, pancreatic cancer, skin cancer, cancer of the head or neck, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma (NHL), primary mediastinal large B cell lymphoma (PMBC), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), transformed follicular lymphoma, splenic marginal zone lymphoma (SMZL), esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) (including non T-cell ALL), chronic lymphocytic leukemia (CLL), solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, other B-cell malignancies, and combinations of said cancers. In some aspects, the cancer is melanoma.

[0221] In some aspects, the cancer is recurrent. In some aspects, the cancer is refractory. In some aspects, the cancer is advanced. In some aspects, the cancer is metastatic.

[0222] In some aspects, the methods disclosed herein treat a cancer in a subject. In some aspects, the methods disclosed herein reduce the severity of one or more symptoms of a cancer. In some aspects, the methods disclosed herein reduce the size or number of tumors derived from a cancer. In some aspects, the methods disclosed herein increase overall survival of a subject relative to a subject not provided the methods disclosed herein. In some aspects, the methods disclosed herein increase progression-free survival of a subject relative to a subject not provided the methods disclosed herein. In some aspects, the methods disclosed herein induce a partial response in a subject. In some aspects, the methods disclosed herein induce a complete response in a subject.

[0223] In some aspects, the methods disclosed herein comprise treating a cancer in a subject in need thereof, comprising administering to the subject a cell described herein, wherein the cell comprises a nucleic acid molecule disclosed herein, a vector disclosed herein, a recombinant TCR disclosed herein, and / or a bispecific antibody disclosed herein. In some aspects, the cell is a T cell. In some aspects, the cell is a cell modified to express CD4.

[0224] In some aspects, the cell (e.g., T cell) is obtained from a subject. In some aspects, the cell (e.g., T cell) is obtained from a donor other than the subject.

[0225] In some aspects, the subject is pre-treated prior to administration of the cell. The pre-treatment can comprise any substance that aids in T cell function and / or survival. In some aspects, the pre-treatment comprises administration of chemotherapy, a cytokine, a protein, a small molecule, or any combination thereof to the subject. In some aspects, the pre-treatment comprises administration of an interleukin. In some aspects, the pre-treatment comprises administration of IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, or any combination thereof. In some aspects, the pre-treatment comprises administration of cyclophosphamide, fludarabine, or both. In some aspects, the pre-treatment comprises administration of vitamin C, an AKT inhibitor, ATRA (vesanoid, retinoic acid), rapamycin, or any combination thereof.

[0226] III.B. Methods of engineering cells to target an antigen

[0227] Certain aspects of the disclosure relate to methods of engineering cells to target an antigen. In some aspects, the antigen is a MUC5AC antigen. In some aspects, the method comprises transducing a cell with a nucleic acid molecule disclosed herein or a vector disclosed herein. The cell can be any cell described herein. In some aspects, the cell is a T cell described herein. In some aspects, the cell is a cell modified to express CD4 as described herein. In some aspects, the cell (e.g., T cell) is obtained from a subject in need of a T cell therapy. In some aspects, the cell is obtained from a donor other than a subject in need of a T cell therapy. In some aspects, the cell is a T cell or a natural killer cell.

[0228] III.C. Methods of enriching a target T cell population

[0229] Certain aspects of the present disclosure relate to methods of enriching a population of target T cells obtained from a human subject. In some aspects, the method comprises contacting the T cells with an HLA class II molecule disclosed herein. In some aspects, the method comprises contacting the T cells with an APC disclosed herein. In some aspects, following the contacting, the enriched population of T cells comprises a higher number of T cells capable of binding to the HLA class II molecule relative to the number of T cells capable of binding to the HLA class II molecule prior to the contacting.

[0230] In some aspects, the method comprises contacting the T cells in vitro with a peptide, wherein the peptide comprises the amino acid sequence set forth in SEQ ID NO: 13. In some aspects, the method comprises contacting the T cells in vitro with a peptide, wherein the peptide consists of the amino acid sequence set forth in SEQ ID NO: 13. In some aspects, following the contacting, the enriched population of T cells comprises a higher number of T cells capable of binding to the HLA class II molecule relative to the number of T cells capable of binding to the HLA class II molecule prior to the contacting.

[0231] Some aspects of the present disclosure relate to a method of selecting a T cell capable of targeting a tumor cell. In some aspects, the method comprises contacting a population of isolated T cells in vitro with a peptide, wherein the peptide consists of the amino acid sequence set forth in SEQ ID NO: 13. In some aspects, the T cells are obtained from a human subject.

[0232] The T cells obtained from a human subject can be any T cell disclosed herein. In some aspects, the T cells obtained from a human subject are tumor infiltrating lymphocytes (TILs).

[0233] In some aspects, the method further comprises administering the enriched T cells to a human subject. In some aspects, the subject is pretreated prior to receiving the T cells as described herein.

[0234] The various aspects, aspects, and options described herein can all be combined in any and all variations.

[0235] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the extent allowable under the patent laws. The incorporation should not be understood as an express or implied admission that any of the foregoing is inconsistent or

[0236] Having generally described this application, a further understanding can be obtained by reference to the examples provided herein. These examples are for purposes of illustration only and are not intended to be limiting.

[0237] Examples

[0238] Example 1 - Method

[0239] Cells

[0240] Peripheral mononuclear cells were obtained via density gradient centrifugation (Ficoll-Paque PLUS, GE Healthcare Life Sciences, Marlborough, MA). The K562 cell line is an erythroleukemia cell line with defective HLA class I / II expression. K562-based artificial APCs (aAPCs) that express various HLA class I genes individually as single HLA alleles in combination with CD80 and CD83 have been previously reported (Butler et al., PloS One 7, e30229 (2012). The Jurkat 76 cell line is a T cell leukemia cell line that lacks endogenous TCR, CD4, and CD8 expression. Jurkat 76 / CD4 cells were generated by retroviral transduction of the human CD4 gene. HEK293T cells and melanoma cell lines were grown in DMEM supplemented with 10% FBS and 50 pg / ml gentamicin (Thermo Fisher Scientific, Waltham, MA). K562 and Jurkat 76 cell lines were cultured in RPMI 1640 supplemented with 10% FBS and 50 pg / ml gentamicin.

[0241] Peptides

[0242] MUC5AC 4922-4941 Synthetic peptides were purchased from Genscript (Piscataway, NJ) and dissolved in DMSO at 50 pg / ml.

[0243] Genes

[0244] New TCR genes were cloned by 5'-rapid amplification of cDNA ends (RACE) PCR using the SMARTer RACE 5' / 3' kit (Takara Bio, Shiga, Japan) and sequenced as previously described. All genes were cloned into the pMX retroviral vector and transduced into cell lines using a retroviral system based on 293GPG and PG13 cells.

[0245] Antibodies

[0246] The following antibodies were used for flow cytometry analysis: APC-Cy7-conjugated anti-CD4 (RPA-T4, Biolegend, San Diego, CA) 44anti-His tag conjugated to PE (AD1.1.10, Abeam, Cambridge, MA). Dead cells were distinguished using the Live / Dead Fixable Near-IR Dead Cell Staining Kit 465 (Thermo Fisher Scientific, Waltham, MA). Stained cells were analyzed with a Canto II or LSRFortessa X-20 (BD Biosciences, Franklin Lakes, NJ). Cell sorting was performed using a FACS Aria II (BD Biosciences, Franklin Lakes, NJ). Data analysis was performed using FlowJo software (Tree Star, Ashland, OR).

[0247] TCR transduction into primary T cells

[0248] CD3 + and CD4 + T cells were purified using the Pan T Cell Isolation Kit (Miltenyi Biotec, Bergisch Gladbach, Germany) and CD4 + T Cell Isolation Kit (Miltenyi Biotec, Bergisch Gladbach, Germany). Purified T cells were stimulated with 200 Gy irradiated aAPC / mOKT3 at an E:T ratio of 20:1. Activated T cells were retrovirally transduced with cloned TCR genes or using Retronectin-coated plates (Takara Bio, Shiga, Japan) via centrifugation at 32 °C at 1,000 x g for 1 hour for 3 consecutive days starting on the second day. On the second day, 100 IU / ml IL-2 and 10 ng / ml IL-15 were added to the TCR transduced T cells. Media was replenished every 2-3 days.

[0249] Generation of HLA class II monomers and dimers

[0250] The extracellular domain of the wild-type class II alpha gene was fused via a GGGS (SEQ ID NO: 30) linker to an acidic leucine zipper, followed by a GS linker to a 6xHis tag (see SEQ ID NO: 15; Table 5). The extracellular domain of the class II beta gene carrying the mutation (see SEQ ID NO: 14) was similarly linked via a GGGS (SEQ ID NO: 30) linker (see SEQ ID NO: 14) to a basic leucine zipper. HEK293T cells and A375 cells were transfected with the alpha and beta genes using a 293GPG cell-based retroviral system and cultured in DMEM supplemented with 10% FBS and 50 pg / ml gentamicin. For DP4 dimer staining, HEK293T cells stably secreting soluble DP4 L112W / V141M Protein were grown until confluence and the medium was exchanged for serum-free 293SFM II medium (Thermo Fisher Scientific, Waltham, MA). After 48 hours, the conditioned medium was harvested and concentrated using Amicon Ultra filters (10 kDa molecular weight cut-off (MWCO)) (MilliporeSigma, Burlington, MA). The supernatant containing soluble HLA class II was then mixed with 100 pg / ml of the peptide of interest for 20-24 hours at 37°C to perform in vitro peptide exchange. Monomers that did not undergo peptide exchange were used as a control. The concentration of monomers was measured by specific ELISA using nickel-coated plates (XPressBio, Frederick, MD) and anti-His tag biotinylated mAb (AD1.1.10, R&D Systems, Minneapolis, MN). Soluble HLA class II monomers were dimerized at a 2:1 molar ratio using PE-conjugated anti-His mAb (AD1.1.10, Abeam, Cambridge, MA) for 1.5 hours at 4°C to perform staining.

[0251] Table 5: HLA-DP class II molecules

[0252]

[0253] DP4-restricted antigen-specific CD4 + Stimulation of CD4

[0254] CD4 + T cells using CD4 +T cell isolation kits (Miltenyi Biotec, Bergisch Gladbach, Germany) were used for purification. Purified T cells were stimulated with DP4-expressing aAPCs pulsed with DP4 restricting peptides at 10 pg / ml and irradiated at 200 Gy at an E:T ratio of 20:1. Forty-eight hours later, 10 IU / ml IL-2 and 10 ng / ml IL-15 were added to the CD4 + T. Media supplemented with IL-2 (10 IU / ml) and IL-15 (10 ng / ml) were replenished every 2-3 days. After 2 weeks of stimulation, T cells were stained for DP4 L112W / V141M dimer.

[0255] HLA class II dimer staining

[0256] Primary T cells and Jurkat 76 / CD4 T cells transduced with endogenous TCR genes were pre-treated with 50 nM dasatinib (LC Laboratories, Woburn, MA) for 30 min at 37 °C 46 and stained with 5-15 pg / ml class II dimers for 4-5 h at room temperature. After washing, cell surface molecules were restained with APC-Cy7-conjugated anti-CD4 mAb.

[0257] ELISPOT assay

[0258] Cytokine ELISPOT assays were performed as previously reported (see, e.g., Yamashita et al., Nat. Commun. 8: 15244 (2017); and Anczurowski et al., Sci. Rep. 8: 4804 (2018)).

[0259] Statistical analysis

[0260] Statistical analysis was performed using GraphPad Prism 6.0 software (GraphPad Software, San Diego, CA). Unpaired two-tailed Student’s t test was used for two sample comparisons. Statistical methods were not used to predetermine sample size. The investigator was not allocated non-blind during the experiment or outcome evaluation. The experiment was not randomized.

[0261] Example 2 - MUC5AC 4922-4941 Characterization of TCRs

[0262] DP4 + Primary CD4 +T cells were stimulated only once with DP4-aAPC pulsed with a peptide fragment of MUC5AC (4922-4941) and loaded with the cognate DP4 tetramer L112W / V141M Dimer staining. To avoid potential in vitro priming, weak stimulation conditions were used. By dimer staining it was found that MUC5AC 4922-4941 were immunogenic (data not shown).

[0263] To validate the dimer staining results, DP4 restricted TCR genes specific for MUC5AC 4922-4941 were cloned from dimer positive T cells (Table 5). Figures 1A-1B and Table 5) when introduced into human CD4 + TCR deficient T cells, MUC5AC 4922-4941 TCR were successfully stained by the cognate DP4 L112W / V141M tetramer (Figures 2A-8D) and functioned in a DP4 restricted and antigen specific manner Figure 3 ).

[0264] TCR 03-MUC5AC 4922-4941 were able to recognize the cognate peptide endogenously processed and presented by DP4 (Figures 4A-4E and 5).

[0265] Table 5: DP4 restricted TCR

[0266] SEQUENCE LISTING <110> University Health Network <120> T cell receptors and methods of use thereof <130> 4285.014PC01 / C-K / BMD <150> US 62 / 880,505 <151> 2019-07-30 <160> 30 <170> PatentIn version 3.5 <210> 1 <211> 257 <212> PRT <213> artificial sequence <220> <223> alpha chain <400> 1 Gln Thr Val Thr Gln Ser Gln Pro Glu Met Ser Val Gln Glu Ala Glu 1 5 10 15 Thr Val Thr Leu Ser Cys Thr Tyr Asp Thr Ser Glu Ser Asn Tyr Tyr 20 25 30 Leu Phe Trp Tyr Lys Gln Pro Pro Ser Arg Gln Met Ile Leu Val Ile 35 40 45 Arg Gln Glu Ala Tyr Lys Gln Gln Asn Ala Thr Glu Asn Arg Phe Ser 50 55 60 Val Asn Phe Gln Lys Ala Ala Lys Ser Phe Ser Leu Lys Ile Ser Asp 65 70 75 80 Ser Gln Leu Gly Asp Thr Ala Met Tyr Phe Cys Ala Phe Met Lys Arg 85 90 95 Ala Glu Thr Ser Gly Ser Arg Leu Thr Phe Gly Glu Gly Thr Gln Leu 100 105 110 Thr Val Asn Pro Asp Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu 115 120 125 Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe 130 135 140 Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile 145 150 155 160 Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn 165 170 175 Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala 180 185 190 Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu 195 200 205 Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr 210 215 220 Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu 225 230 235 240 Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser 245 250 255 Ser <210> 2 <211> 292 <212> PRT <213> Artificial sequence <220> <223> Beta chain <400> 2 Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Arg Val Leu Lys Thr Gly 1 5 10 15 Gln Ser Met Thr Leu Leu Cys Ala Gln Asp Met Asn His Glu Tyr Met 20 25 30 Tyr Trp Tyr Arg Gin Asp Pro Gly Met Gly Leu Arg Leu lie His Tyr 35 40 45 Ser Val Gly Glu Gly Thr Thr Ala Lys Gly Glu Val Pro Asp Gly Tyr 50 55 60 Asn Val Ser Arg Leu Lys Lys Gin Asn Phe Leu Leu Gly Leu Glu Ser 65 70 75 80 Ala Ala Pro Ser Gin Thr Ser Val Tyr Phe Cys Ala Ser Ser Tyr Trp 85 90 95 Pro Thr Arg Glu Thr Gin Tyr Phe Gly Pro Gly Thr Arg Leu Leu Val 100 105 110 Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu 115 120 125 Pro Ser Glu Ala Glu lie Ser His Thr Gin Lys Ala Thr Leu Val Cys 130 135 140 Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val 145 150 155 160 Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gin Pro Leu 165 170 175 Lys Glu Gin Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg 180 185 190 Leu Arg Val Ser Ala Thr Phe Trp Gin Asn Pro Arg Asn His Phe Arg 195 200 205 Cys Gin Val Gin Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gin 210 215 220 Asp Arg Ala Lys Pro Val Thr Gin He Val Ser Ala Glu Ala Trp Gly 225 230 235 240 Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gin Gin Gly Val Leu 245 250 255 Ser Ala Thr He Leu Tyr Glu He Leu Leu Gly Lys Ala Thr Leu Tyr 260 265 270 Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys Arg Lys 275 280 285 Asp Ser Arg Gly 290 <210> 3 <400> 3 000 <210> 4 <400> 4 000 <210> 5 <211> 7 <212> PRT <213> artificial sequence <220> <223> alpha chain <400> 5 Thr Ser Glu Ser Asn Tyr Tyr 1 5 <210> 6 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Anti-MUC5AC TCR <400> 6 Gln Glu Ala Tyr Lys Gln Gln Asn 1 5 <210> 7 <211> 16 <212> PRT <213> Artificial sequence <220> <223> TCR-alpha CDR 3 <400> 7 Cys Ala Phe Met Lys Arg Ala Glu Thr Ser Gly Ser Arg Leu Thr Phe 1 5 10 15 <210> 8 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Anti-MUC5AC TCR <400> 8 Met Asn His Glu Tyr 1 5 <210> 9 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Anti-MUC5AC TCR <400> 9 Ser Val Gly Glu Gly Thr 1 5 <210> 10 <211> 14 <212> PRT <213> artificial sequence <220> <223> TCR-beta CDR 3 <400> 10 Cys Ala Ser Ser Tyr Trp Pro Thr Arg Glu Thr Gin Tyr Phe 1 5 10 <210> 11 <400> 11 000 <210> 12 <400> 12 000 <210> 13 <211> 20 <212> PRT <213> artificial sequence <220> <223> Epitope of MUC5AC <400> 13 Ser Gly Trp Gly Asp Pro His Tyr He Thr Phe Asp Gly Thr Tyr Tyr 1 5 10 15 Thr Phe Leu Asp 20 <210> 14 <211> 265 <212> PRT <213> artificial sequence <220> <223> Signal peptide <400> 14 Met Met Arg Pro He Val Leu Val Leu Leu Phe Ala Thr Ser Ala Leu 1 5 10 15 Ala Arg Ala Thr Pro Glu Asn Tyr Leu Phe Gin Gly Arg Gin Glu Cys 20 25 30 Tyr Ala Phe Asn Gly Thr Gin Arg Phe Leu Glu Arg Tyr He Tyr Asn 35 40 45 Arg Glu Glu Phe Ala Arg Phe Asp Ser Asp Val Gly Glu Phe Arg Ala 50 55 60 Val Thr Glu Leu Gly Arg Pro Ala Ala Glu Tyr Trp Asn Ser Gin Lys 65 70 75 80 Asp He Leu Glu Glu Lys Arg Ala Val Pro Asp Arg Met Cys Arg His 85 90 95 Asn Tyr Glu Leu Gly Gly Pro Met Thr Leu Gin Arg Arg Val Gin Pro 100 105 110 Arg Val Asn Val Ser Pro Ser Lys Lys Gly Pro Leu Gin His His Asn 115 120 125 Trp Leu Val Cys His Val Thr Asp Phe Tyr Pro Gly Ser He Gin Val 130 135 140 Arg Trp Phe Leu Asn Gly Gin Glu Glu Thr Ala Gly Val Met Ser Thr 145 150 155 160 Asn Leu He Arg Asn Gly Asp Trp Thr Phe Gin He Leu Val Met Leu 165 170 175 Glu Met Thr Pro Gin Gin Gly Asp Val Tyr Thr Cys Gin Val Glu His 180 185 190 Thr Ser Leu Asp Ser Pro Val Thr Val Glu Trp Lys Ala Gln Ser Asp 195 200 205 Ser Ala Arg Ser Lys Gly Gly Gly Gly Ser Leu Glu Ile Glu Ala Ala 210 215 220 Phe Leu Glu Arg Glu Asn Thr Ala Leu Glu Thr Arg Val Ala Glu Leu 225 230 235 240 Arg Gln Arg Val Gln Arg Leu Arg Asn Arg Val Ser Gln Tyr Arg Thr 245 250 255 Arg Tyr Gly Pro Leu Gly Gly Gly Lys 260 265 <210> 15 <211> 269 <212> PRT <213> artificial sequence <220> <223> signal peptide <400> 15 Met Met Arg Pro Ile Val Leu Val Leu Leu Phe Ala Thr Ser Ala Leu 1 5 10 15 Ala Ile Lys Ala Asp His Val Ser Thr Tyr Ala Ala Phe Val Gln Thr 20 25 30 His Arg Pro Thr Gly Glu Phe Met Phe Glu Phe Asp Glu Asp Glu Met 35 40 45 Phe Tyr Val Asp Leu Asp Lys Lys Glu Thr Val Trp His Leu Glu Glu 50 55 60 Phe Gly Gln Ala Phe Ser Phe Glu Ala Gln Gly Gly Leu Ala Asn Ile 65 70 75 80 Ala Ile Leu Asn Asn Asn Leu Asn Thr Leu Ile Gln Arg Ser Asn His 85 90 95 Thr Gln Ala Thr Asn Asp Pro Pro Glu Val Thr Val Phe Pro Lys Glu 100 105 110 Pro Val Glu Leu Gly Gln Pro Asn Thr Leu Ile Cys His Ile Asp Lys 115 120 125 Phe Phe Pro Pro Val Leu Asn Val Thr Trp Leu Cys Asn Gly Glu Leu 130 135 140 Val Thr Glu Gly Val Ala Glu Ser Leu Phe Leu Pro Arg Thr Asp Tyr 145 150 155 160 Ser Phe His Lys Phe His Tyr Leu Thr Phe Val Pro Ser Ala Glu Asp 165 170 175 Phe Tyr Asp Cys Arg Val Glu His Trp Gly Leu Asp Gln Pro Leu Leu 180 185 190 Lys His Trp Glu Ala Gln Glu Pro Ile Gln Met Pro Glu Thr Thr Glu 195 200 205 Thr Gly Gly Gly Gly Ser Leu Glu Ile Arg Ala Ala Phe Leu Arg Gln 210 215 220 Arg Asn Thr Ala Leu Arg Thr Glu Val Ala Glu Leu Glu Gin Glu Val 225 230 235 240 Gln Arg Leu Glu Asn Glu Val Ser Gin Tyr Glu Thr Arg Tyr Gly Pro 245 250 255 Leu Gly Gly Gly Lys Gly Ser His His His His His His 260 265 <210> 16 <211> 5654 <212> PRT <213> artificial sequence <220> <223> MUC5AC <400> 16 Met Ser Val Gly Arg Arg Lys Leu Ala Leu Leu Trp Ala Leu Ala Leu 1 5 10 15 Ala Leu Ala Cys Thr Arg His Thr Gly His Ala Gin Asp Gly Ser Ser 20 25 30 Glu Ser Ser Tyr Lys His His Pro Ala Leu Ser Pro Ile Ala Arg Gly 35 40 45 Pro Ser Gly Val Pro Leu Arg Gly Ala Thr Val Phe Pro Ser Leu Arg 50 55 60 Thr Ile Pro Val Val Arg Ala Ser Asn Pro Ala His Asn Gly Arg Val 65 70 75 80 Cys Ser Thr Trp Gly Ser Phe His Tyr Lys Thr Phe Asp Gly Asp Val 85 90 95 Phe Arg Phe Pro Gly Leu Cys Asn Tyr Val Phe Ser Glu His Cys Gly 100 105 110 Ala Ala Tyr Glu Asp Phe Asn Ile Gln Leu Arg Arg Ser Gln Glu Ser 115 120 125 Ala Ala Pro Thr Leu Ser Arg Val Leu Met Lys Val Asp Gly Val Val 130 135 140 Ile Gln Leu Thr Lys Gly Ser Val Leu Val Asn Gly His Pro Val Leu 145 150 155 160 Leu Pro Phe Ser Gln Ser Gly Val Leu Ile Gln Gln Ser Ser Ser Tyr 165 170 175 Thr Lys Val Glu Ala Arg Leu Gly Leu Val Leu Met Trp Asn His Asp 180 185 190 Asp Ser Leu Leu Leu Glu Leu Asp Thr Lys Tyr Ala Asn Lys Thr Cys 195 200 205 Gly Leu Cys Gly Asp Phe Asn Gly Met Pro Val Val Ser Glu Leu Leu 210 215 220 Ser His Asn Thr Lys Leu Thr Pro Met Glu Phe Gly Asn Leu Gln Lys 225 230 235 240 Met Asp Asp Pro Thr Asp Gin Cys Gin Asp Pro Val Pro Glu Pro Pro 245 250 255 Arg Asn Cys Ser Thr Gly Phe Gly Ile Cys Glu Glu Leu Leu His Gly 260 265 270 Gln Leu Phe Ser Gly Cys Val Ala Leu Val Asp Val Gly Ser Tyr Leu 275 280 285 Glu Ala Cys Arg Gin Asp Leu Cys Phe Cys Glu Asp Thr Asp Leu Leu 290 295 300 Ser Cys Val Cys His Thr Leu Ala Glu Tyr Ser Arg Gin Cys Thr His 305 310 315 320 Ala Gly Gly Leu Pro Gin Asp Trp Arg Gly Pro Asp Phe Cys Pro Gin 325 330 335 Lys Cys Pro Asn Asn Met Gin Tyr His Glu Cys Arg Ser Pro Cys Ala 340 345 350 Asp Thr Cys Ser Asn Gin Glu His Ser Arg Ala Cys Glu Asp His Cys 355 360 365 Val Ala Gly Cys Phe Cys Pro Glu Gly Thr Val Leu Asp Asp Ile Gly 370 375 380 Gln Thr Gly Cys Val Pro Val Ser Lys Cys Ala Cys Val Tyr Asn Gly 385 390 395 400 Ala Ala Tyr Ala Pro Gly Ala Thr Tyr Ser Thr Asp Cys Thr Asn Cys 405 410 415 Thr Cys Ser Gly Gly Arg Trp Ser Cys Gln Glu Val Pro Cys Pro Gly 420 425 430 Thr Cys Ser Val Leu Gly Gly Ala His Phe Ser Thr Phe Asp Gly Lys 435 440 445 Gln Tyr Thr Val His Gly Asp Cys Ser Tyr Val Leu Thr Lys Pro Cys 450 455 460 Asp Ser Ser Ala Phe Thr Val Leu Ala Glu Leu Arg Arg Cys Gly Leu 465 470 475 480 Thr Asp Ser Glu Thr Cys Leu Lys Ser Val Thr Leu Ser Leu Asp Gly 485 490 495 Ala Gln Thr Val Val Val Ile Lys Ala Ser Gly Glu Val Phe Leu Asn 500 505 510 Gln Ile Tyr Thr Gln Leu Pro Ile Ser Ala Ala Asn Val Thr Ile Phe 515 520 525 Arg Pro Ser Thr Phe Phe Ile Ile Ala Gln Thr Ser Leu Gly Leu Gln 530 535 540 Leu Asn Leu Gln Leu Val Pro Thr Met Gln Leu Phe Met Gln Leu Ala 545 550 555 560 Pro Lys Leu Arg Gly Gin Thr Cys Gly Leu Cys Gly Asn Phe Asn Ser 565 570 575 Ile Gin Ala Asp Asp Phe Arg Thr Leu Ser Gly Val Val Glu Ala Thr 580 585 590 Ala Ala Ala Phe Phe Asn Thr Phe Lys Thr Gin Ala Ala Cys Pro Asn 595 600 605 Ile Arg Asn Ser Phe Glu Asp Pro Cys Ser Leu Ser Val Glu Asn Glu 610 615 620 Lys Tyr Ala Gin His Trp Cys Ser Gin Leu Thr Asp Ala Asp Gly Pro 625 630 635 640 Phe Gly Arg Cys His Ala Ala Val Lys Pro Gly Thr Tyr Tyr Ser Asn 645 650 655 Cys Met Phe Asp Thr Cys Asn Cys Glu Arg Ser Glu Asp Cys Leu Cys 660 665 670 Ala Ala Leu Ser Ser Tyr Val His Ala Cys Ala Ala Lys Gly Val Gin 675 680 685 Leu Gly Gly Trp Arg Asp Gly Val Cys Thr Lys Pro Met Thr Thr Cys 690 695 700 Pro Lys Ser Met Thr Tyr His Tyr His Val Ser Thr Cys Gln Pro Thr 705 710 715 720 Cys Arg Ser Leu Ser Glu Gly Asp Ile Thr Cys Ser Val Gly Phe Ile 725 730 735 Pro Val Asp Gly Cys Ile Cys Pro Lys Gly Thr Phe Leu Asp Asp Thr 740 745 750 Gly Lys Cys Val Gln Ala Ser Asn Cys Pro Cys Tyr His Arg Gly Ser 755 760 765 Met Ile Pro Asn Gly Glu Ser Val His Asp Ser Gly Ala Ile Cys Thr 770 775 780 Cys Thr His Gly Lys Leu Ser Cys Ile Gly Gly Gln Ala Pro Ala Pro 785 790 795 800 Val Cys Ala Ala Pro Met Val Phe Phe Asp Cys Arg Asn Ala Thr Pro 805 810 815 Gly Asp Thr Gly Ala Gly Cys Gln Lys Ser Cys His Thr Leu Asp Met 820 825 830 Thr Cys Tyr Ser Pro Gln Cys Val Pro Gly Cys Val Cys Pro Asp Gly 835 840 845 Leu Val Ala Asp Gly Glu Gly Gly Cys Ile Thr Ala Glu Asp Cys Pro 850 855 860 Cys Val His Asn Glu Ala Ser Tyr Arg Ala Gly Gin Thr He Arg Val 865 870 875 880 Gly Cys Asn Thr Cys Thr Cys Asp Ser Arg Met Trp Arg Cys Thr Asp 885 890 895 Asp Pro Cys Leu Ala Thr Cys Ala Val Tyr Gly Asp Gly His Tyr Leu 900 905 910 Thr Phe Asp Gly Gin Ser Tyr Ser Phe Asn Gly Asp Cys Glu Tyr Thr 915 920 925 Leu Val Gin Asn His Cys Gly Gly Lys Asp Ser Thr Gin Asp Ser Phe 930 935 940 Arg Val Val Thr Glu Asn Val Pro Cys Gly Thr Thr Gly Thr Thr Cys 945 950 955 960 Ser Lys Ala He Lys He Phe Leu Gly Gly Phe Glu Leu Lys Leu Ser 965 970 975 His Gly Lys Val Glu Val He Gly Thr Asp Glu Ser Gin Glu Val Pro 980 985 990 Tyr Thr He Arg Gin Met Gly He Tyr Leu Val Val Asp Thr Asp He 995 1000 1005 Gly Leu Val Leu Leu Trp Asp Lys Lys Thr Ser He Phe He Asn 1010 1015 1020 Leu Ser Pro Glu Phe Lys Gly Arg Val Cys Gly Leu Cys Gly Asn 1025 1030 1035 Phe Asp Asp Ile Ala Val Asn Asp Phe Ala Thr Arg Ser Arg Ser 1040 1045 1050 Val Val Gly Asp Val Leu Glu Phe Gly Asn Ser Trp Lys Leu Ser 1055 1060 1065 Pro Ser Cys Pro Asp Ala Leu Ala Pro Lys Asp Pro Cys Thr Ala 1070 1075 1080 Asn Pro Phe Arg Lys Ser Trp Ala Gln Lys Gln Cys Ser Ile Leu 1085 1090 1095 His Gly Pro Thr Phe Ala Ala Cys His Ala His Val Glu Pro Ala 1100 1105 1110 Arg Tyr Tyr Glu Ala Cys Val Asn Asp Ala Cys Ala Cys Asp Ser 1115 1120 1125 Gly Gly Asp Cys Glu Cys Phe Cys Thr Ala Val Ala Ala Tyr Ala 1130 1135 1140 Gln Ala Cys His Glu Val Gly Leu Cys Val Ser Trp Arg Thr Pro 1145 1150 1155 Ser Ile Cys Pro Leu Phe Cys Asp Tyr Tyr Asn Pro Glu Gly Gln 1160 1165 1170 Cys Glu Trp His Tyr Gin Pro Cys Gly Val Pro Cys Leu Arg Thr 1175 1180 1185 Cys Arg Asn Pro Arg Gly Asp Cys Leu Arg Asp Val Arg Gly Leu 1190 1195 1200 Glu Gly Cys Tyr Pro Lys Cys Pro Pro Glu Ala Pro Ile Phe Asp 1205 1210 1215 Glu Asp Lys Met Gin Cys Val Ala Thr Cys Pro Thr Pro Pro Leu 1220 1225 1230 Pro Pro Arg Cys His Val His Gly Lys Ser Tyr Arg Pro Gly Ala 1235 1240 1245 Val Val Pro Ser Asp Lys Asn Cys Gin Ser Cys Leu Cys Thr Glu 1250 1255 1260 Arg Gly Val Glu Cys Thr Tyr Lys Ala Glu Ala Cys Val Cys Thr 1265 1270 1275 Tyr Asn Gly Gin Arg Phe His Pro Gly Asp Val Ile Tyr His Thr 1280 1285 1290 Thr Asp Gly Thr Gly Gly Cys Ile Ser Ala Arg Cys Gly Ala Asn 1295 1300 1305 Gly Thr Ile Glu Arg Arg Val Tyr Pro Cys Ser Pro Thr Thr Pro 1310 1315 1320 Val Pro Pro Thr Thr Phe Ser Phe Ser Thr Pro Pro Leu Val Val 1325 1330 1335 Ser Ser Thr His Thr Pro Ser Asn Gly Pro Ser Ser Ala His Thr 1340 1345 1350 Gly Pro Pro Ser Ser Ala Trp Pro Thr Thr Ala Gly Thr Ser Pro 1355 1360 1365 Arg Thr Arg Leu Pro Thr Ala Ser Ala Ser Leu Pro Pro Val Cys 1370 1375 1380 Gly Glu Lys Cys Leu Trp Ser Pro Trp Met Asp Val Ser Arg Pro 1385 1390 1395 Gly Arg Gly Thr Asp Ser Gly Asp Phe Asp Thr Leu Glu Asn Leu 1400 1405 1410 Arg Ala His Gly Tyr Arg Val Cys Glu Ser Pro Arg Ser Val Glu 1415 1420 1425 Cys Arg Ala Glu Asp Ala Pro Gly Val Pro Leu Arg Ala Leu Gly 1430 1435 1440 Gln Arg Val Gln Cys Ser Pro Asp Val Gly Leu Thr Cys Arg Asn 1445 1450 1455 Arg Glu Gln Ala Ser Gly Leu Cys Tyr Asn Tyr Gln Ile Arg Val 1460 1465 1470 Gln Cys Cys Thr Pro Leu Pro Cys Ser Thr Ser Ser Ser Pro Ala 1475 1480 1485 Gln Thr Thr Pro Pro Thr Thr Ser Lys Thr Thr Glu Thr Arg Ala 1490 1495 1500 Ser Gly Ser Ser Ala Pro Ser Ser Thr Pro Gly Thr Val Ser Leu 1505 1510 1515 Ser Thr Ala Arg Thr Thr Pro Ala Pro Gly Thr Ala Thr Ser Val 1520 1525 1530 Lys Lys Thr Phe Ser Thr Pro Ser Pro Pro Pro Val Pro Ala Thr 1535 1540 1545 Ser Thr Ser Ser Met Ser Thr Thr Ala Pro Gly Thr Ser Val Val 1550 1555 1560 Ser Ser Lys Pro Thr Pro Thr Glu Pro Ser Thr Ser Ser Cys Leu 1565 1570 1575 Gln Glu Leu Cys Thr Trp Thr Glu Trp Ile Asp Gly Ser Tyr Pro 1580 1585 1590 Ala Pro Gly Ile Asn Gly Gly Asp Phe Asp Thr Phe Gln Asn Leu 1595 1600 1605 Arg Asp Glu Gly Tyr Thr Phe Cys Glu Ser Pro Arg Ser Val Gln 1610 1615 1620 Cys Arg Ala Glu Ser Phe Pro Asn Thr Pro Leu Ala Asp Leu Gly 1625 1630 1635 Gln Asp Val Ile Cys Ser His Thr Glu Gly Leu Ile Cys Leu Asn 1640 1645 1650 Lys Asn Gln Leu Pro Pro Ile Cys Tyr Asn Tyr Glu Ile Arg Ile 1655 1660 1665 Gln Cys Cys Glu Thr Val Asn Val Cys Arg Asp Ile Thr Arg Leu 1670 1675 1680 Pro Lys Thr Val Ala Thr Thr Arg Pro Thr Pro His Pro Thr Gly 1685 1690 1695 Ala Gln Thr Gln Thr Thr Phe Thr Thr His Met Pro Ser Ala Ser 1700 1705 1710 Thr Glu Gln Pro Thr Ala Thr Ser Arg Gly Gly Pro Thr Ala Thr 1715 1720 1725 Ser Val Thr Gln Gly Thr His Thr Thr Leu Val Thr Arg Asn Cys 1730 1735 1740 His Pro Arg Cys Thr Trp Thr Lys Trp Phe Asp Val Asp Phe Pro 1745 1750 1755 Ser Pro Gly Pro His Gly Gly Asp Lys Glu Thr Tyr Asn Asn Ile 1760 1765 1770 Ile Arg Ser Gly Glu Lys Ile Cys Arg Arg Pro Glu Glu Ile Thr 1775 1780 1785 Arg Leu Gin Cys Arg Ala Lys Ser His Pro Glu Val Ser Ile Glu 1790 1795 1800 His Leu Gly Gin Val Val Gin Cys Ser Arg Glu Glu Gly Leu Val 1805 1810 1815 Cys Arg Asn Gin Asp Gin Gin Gly Pro Phe Lys Met Cys Leu Asn 1820 1825 1830 Tyr Glu Val Arg Val Leu Cys Cys Glu Thr Pro Arg Gly Cys His 1835 1840 1845 Met Thr Ser Thr Pro Gly Ser Thr Ser Ser Ser Pro Ala Gin Thr 1850 1855 1860 Thr Pro Ser Thr Thr Ser Lys Thr Thr Glu Thr Gin Ala Ser Gly 1865 1870 1875 Ser Ser Ala Pro Ser Ser Thr Pro Gly Thr Val Ser Leu Ser Thr 1880 1885 1890 Ala Arg Thr Thr Pro Ala Pro Gly Thr Ala Thr Ser Val Lys Lys 1895 1900 1905 Thr Phe Ser Thr Pro Ser Pro Pro Pro Val Pro Ala Thr Ser Thr 1910 1915 1920 Ser Ser Met Ser Thr Thr Ala Pro Gly Thr Ser Val Val Ser Ser 1925 1930 1935 Lys Pro Thr Pro Thr Glu Pro Ser Thr Ser Ser Cys Leu Gln Glu 1940 1945 1950 Leu Cys Thr Trp Thr Glu Trp Ile Asp Gly Ser Tyr Pro Ala Pro 1955 1960 1965 Gly Ile Asn Gly Gly Asp Phe Asp Thr Phe Gln Asn Leu Arg Asp 1970 1975 1980 Glu Gly Tyr Thr Phe Cys Glu Ser Pro Arg Ser Val Gln Cys Arg 1985 1990 1995 Ala Glu Ser Phe Pro Asn Thr Pro Leu Ala Asp Leu Gly Gln Asp 2000 2005 2010 Val Ile Cys Ser His Thr Glu Gly Leu Ile Cys Leu Asn Lys Asn 2015 2020 2025 Gln Leu Pro Pro Ile Cys Tyr Asn Tyr Glu Ile Arg Ile Gln Cys 2030 2035 2040 Cys Glu Thr Val Asn Val Cys Arg Asp Ile Thr Arg Pro Pro Lys 2045 2050 2055 Thr Val Ala Thr Thr Arg Pro Thr Pro His Pro Thr Gly Ala Gln 2060 2065 2070 Thr Gln Thr Thr Phe Thr Thr His Met Pro Ser Ala Ser Thr Glu 2075 2080 2085 Gln Pro Thr Ala Thr Ser Arg Gly Gly Pro Thr Ala Thr Ser Val 2090 2095 2100 Thr Gln Gly Thr His Thr Thr Pro Val Thr Arg Asn Cys His Pro 2105 2110 2115 Arg Cys Thr Trp Thr Thr Trp Phe Asp Val Asp Phe Pro Ser Pro 2120 2125 2130 Gly Pro His Gly Gly Asp Lys Glu Thr Tyr Asn Asn Ile Ile Arg 2135 2140 2145 Ser Gly Glu Lys Ile Cys Arg Arg Pro Glu Glu Ile Thr Arg Leu 2150 2155 2160 Gln Cys Arg Ala Lys Ser His Pro Glu Val Ser Ile Glu His Leu 2165 2170 2175 Gly Gln Val Val Gln Cys Ser Arg Glu Glu Gly Leu Val Cys Arg 2180 2185 2190 Asn Gln Asp Gln Gln Gly Pro Phe Lys Met Cys Leu Asn Tyr Glu 2195 2200 2205 Val Arg Val Leu Cys Cys Glu Thr Pro Lys Gly Cys Pro Val Thr 2210 2215 2220 Ser Thr Pro Val Thr Ala Pro Ser Thr Pro Ser Gly Arg Ala Thr 2225 2230 2235 Ser Pro Thr Gln Ser Thr Ser Ser Trp Gln Lys Ser Arg Thr Thr 2240 2245 2250 Thr Leu Val Thr Thr Ser Thr Thr Ser Thr Pro Gln Thr Ser Thr 2255 2260 2265 Thr Tyr Ala His Thr Thr Ser Thr Thr Ser Ala Pro Thr Ala Arg 2270 2275 2280 Thr Thr Ser Ala Pro Thr Thr Arg Thr Thr Ser Ala Ser Pro Ala 2285 2290 2295 Ser Thr Thr Ser Gly Pro Gly Asn Thr Pro Ser Pro Val Pro Thr 2300 2305 2310 Thr Ser Thr Ile Ser Ala Pro Thr Thr Ser Ile Thr Ser Ala Pro 2315 2320 2325 Thr Thr Ser Thr Thr Ser Ala Pro Thr Ser Ser Thr Thr Ser Gly 2330 2335 2340 Pro Gly Thr Thr Pro Ser Pro Val Pro Thr Thr Ser Ile Thr Ser 2345 2350 2355 Ala Pro Thr Thr Ser Thr Thr Ser Ala Pro Thr Thr Ser Thr Thr 2360 2365 2370 Ser Ala Arg Thr Ser Ser Thr Thr Ser Ala Thr Thr Thr Ser Arg 2375 2380 2385 Ile Ser Gly Pro Glu Thr Thr Pro Ser Pro Val Pro Thr Thr Ser 2390 2395 2400 Thr Thr Ser Ala Thr Thr Thr Ser Thr Thr Ser Ala Pro Thr Thr 2405 2410 2415 Ser Thr Thr Ser Ala Pro Thr Ser Ser Thr Thr Ser Ser Pro Gln 2420 2425 2430 Thr Ser Thr Thr Ser Ala Pro Thr Thr Ser Thr Thr Ser Gly Pro 2435 2440 2445 Gly Thr Thr Pro Ser Pro Val Pro Thr Thr Ser Thr Thr Ser Ala 2450 2455 2460 Pro Thr Thr Arg Thr Thr Ser Ala Pro Lys Ser Ser Thr Thr Ser 2465 2470 2475 Ala Ala Thr Thr Ser Thr Thr Ser Gly Pro Glu Thr Thr Pro Arg 2480 2485 2490 Pro Val Pro Thr Thr Ser Thr Thr Ser Ser Pro Thr Thr Ser Thr 2495 2500 2505 Thr Ser Ala Pro Thr Thr Ser Thr Thr Ser Ala Ser Thr Thr Ser 2510 2515 2520 Thr Thr Ser Gly Ala Gly Thr Thr Pro Ser Pro Val Pro Thr Thr 2525 2530 2535 Ser Thr Thr Ser Ala Pro Thr Thr Ser Thr Thr Ser Ala Pro Ile 2540 2545 2550 Ser Ser Thr Thr Ser Ala Thr Thr Thr Ser Thr Thr Ser Gly Pro 2555 2560 2565 Gly Thr Thr Pro Ser Pro Val Pro Thr Thr Ser Thr Thr Ser Ala 2570 2575 2580 Pro Thr Thr Ser Thr Thr Ser Gly Pro Gly Thr Thr Pro Ser Ala 2585 2590 2595 Val Pro Thr Thr Ser Ile Thr Ser Ala Pro Thr Thr Ser Thr Asn 2600 2605 2610 Ser Ala Pro Ile Ser Ser Thr Thr Ser Ala Thr Thr Thr Ser Arg 2615 2620 2625 Ile Ser Gly Pro Glu Thr Thr Pro Ser Pro Val Pro Thr Ala Ser 2630 2635 2640 Thr Thr Ser Ala Ser Thr Thr Ser Thr Thr Ser Gly Pro Gly Thr 2645 2650 2655 Thr Pro Ser Pro Val Pro Thr Thr Ser Thr Ile Ser Val Pro Thr 2660 2665 2670 Thr Ser Thr Thr Ser Ala Ser Thr Thr Ser Thr Thr Ser Ala Ser 2675 2680 2685 Thr Thr Ser Thr Thr Ser Gly Pro Gly Thr Thr Pro Ser Pro Val 2690 2695 2700 Pro Thr Thr Ser Thr Thr Ser Ala Pro Thr Thr Ser Thr Thr Ser 2705 2710 2715 Ala Pro Thr Thr Ser Thr Ile Ser Ala Pro Thr Thr Ser Thr Thr 2720 2725 2730 Ser Ala Thr Thr Thr Ser Thr Thr Ser Ala Pro Thr Pro Arg Arg 2735 2740 2745 Thr Ser Ala Pro Thr Thr Ser Thr Ile Ser Ala Ser Thr Thr Ser 2750 2755 2760 Thr Thr Ser Ala Thr Thr Thr Ser Thr Thr Ser Ala Thr Thr Thr 2765 2770 2775 Ser Thr Ile Ser Ala Pro Thr Thr Ser Thr Thr Leu Ser Pro Thr 2780 2785 2790 Thr Ser Thr Thr Ser Thr Thr Ile Thr Ser Thr Thr Ser Ala Pro 2795 2800 2805 Ile Ser Ser Thr Thr Ser Thr Pro Gln Thr Ser Thr Thr Ser Ala 2810 2815 2820 Pro Thr Thr Ser Thr Thr Ser Gly Pro Gly Thr Thr Ser Ser Pro 2825 2830 2835 Val Pro Thr Thr Ser Thr Thr Ser Ala Pro Thr Thr Ser Thr Thr 2840 2845 2850 Ser Ala Pro Thr Thr Arg Thr Thr Ser Val Pro Thr Ser Ser Thr 2855 2860 2865 Thr Ser Thr Ala Thr Thr Ser Thr Thr Ser Gly Pro Gly Thr Thr 2870 2875 2880 Pro Ser Pro Val Pro Thr Thr Ser Thr Thr Ser Ala Pro Thr Thr 2885 2890 2895 Arg Thr Thr Ser Ala Pro Thr Thr Ser Thr Thr Ser Ala Pro Thr 2900 2905 2910 Thr Ser Thr Thr Ser Ala Pro Thr Ser Ser Thr Thr Ser Ala Thr 2915 2920 2925 Thr Thr Ser Thr Ile Ser Val Pro Thr Thr Ser Thr Thr Ser Val 2930 2935 2940 Pro Gly Thr Thr Pro Ser Pro Val Pro Thr Thr Ser Thr Ile Ser 2945 2950 2955 Val Pro Thr Thr Ser Thr Thr Ser Ala Ser Thr Thr Ser Thr Thr 2960 2965 2970 Ser Gly Pro Gly Thr Thr Pro Ser Pro Val Pro Thr Thr Ser Thr 2975 2980 2985 Thr Ser Ala Pro Thr Thr Ser Thr Thr Ser Ala Pro Thr Thr Ser 2990 2995 3000 Thr Ile Ser Ala Pro Thr Thr Ser Thr Pro Ser Ala Pro Thr Thr 3005 3010 3015 Ser Thr Thr Leu Ala Pro Thr Thr Ser Thr Thr Ser Ala Pro Thr 3020 3025 3030 Thr Ser Thr Thr Ser Thr Pro Thr Ser Ser Thr Thr Ser Ser Pro 3035 3040 3045 Gln Thr Ser Thr Thr Ser Ala Ser Thr Thr Ser Ile Thr Ser Gly 3050 3055 3060 Pro Gly Thr Thr Pro Ser Pro Val Pro Thr Thr Ser Thr Thr Ser 3065 3070 3075 Ala Pro Thr Thr Ser Thr Thr Ser Ala Ala Thr Thr Ser Thr Ile 3080 3085 3090 Ser Ala Pro Thr Thr Ser Thr Thr Ser Ala Pro Thr Thr Ser Thr 3095 3100 3105 Thr Ser Ala Ser Thr Ala Ser Lys Thr Ser Gly Leu Gly Thr Thr 3110 3115 3120 Pro Ser Pro Ile Pro Thr Thr Ser Thr Thr Ser Pro Pro Thr Thr 3125 3130 3135 Ser Thr Thr Ser Ala Ser Thr Ala Ser Lys Thr Ser Gly Pro Gly 3140 3145 3150 Thr Thr Pro Ser Pro Val Pro Thr Thr Ser Thr Ile Phe Ala Pro 3155 3160 3165 Arg Thr Ser Thr Thr Ser Ala Ser Thr Thr Ser Thr Thr Pro Gly 3170 3175 3180 Pro Gly Thr Thr Pro Ser Pro Val Pro Thr Thr Ser Thr Ala Ser 3185 3190 3195 Val Ser Lys Thr Ser Thr Ser His Val Ser Ile Ser Lys Thr Thr 3200 3205 3210 His Ser Gln Pro Val Thr Arg Asp Cys His Leu Arg Cys Thr Trp 3215 3220 3225 Thr Lys Trp Phe Asp Ile Asp Phe Pro Ser Pro Gly Pro His Gly 3230 3235 3240 Gly Asp Lys Glu Thr Tyr Asn Asn Ile Ile Arg Ser Gly Glu Lys 3245 3250 3255 Ile Cys Arg Arg Pro Glu Glu Ile Thr Arg Leu Gln Cys Arg Ala 3260 3265 3270 Glu Ser His Pro Glu Val Ser lie Glu His Leu Gly Gin Val Val 3275 3280 3285 Gln Cys Ser Arg Glu Glu Gly Leu Val Cys Arg Asn Gin Asp Gin 3290 3295 3300 Gln Gly Pro Phe Lys Met Cys Leu Asn Tyr Glu Val Arg Val Leu 3305 3310 3315 Cys Cys Glu Thr Pro Lys Gly Cys Pro Val Thr Ser Thr Pro Val 3320 3325 3330 Thr Ala Pro Ser Thr Pro Ser Gly Arg Ala Thr Ser Pro Thr Gin 3335 3340 3345 Ser Thr Ser Ser Trp Gin Lys Ser Arg Thr Thr Thr Leu Val Thr 3350 3355 3360 Thr Ser Thr Thr Ser Thr Pro Gin Thr Ser Thr Thr Ser Ala Pro 3365 3370 3375 Thr Thr Ser Thr Thr Ser Ala Pro Thr Thr Ser Thr Thr Ser Ala 3380 3385 3390 Pro Thr Thr Ser Thr Thr Ser Thr Pro Gin Thr Ser lie Ser Ser 3395 3400 3405 Ala Pro Thr Ser Ser Thr Thr Ser Ala Pro Thr Ser Ser Thr lie 3410 3415 3420 Ser Ala Arg Thr Thr Ser Ile Ile Ser Ala Pro Thr Thr Ser Thr 3425 3430 3435 Thr Ser Ser Pro Thr Thr Ser Thr Thr Ser Ala Thr Thr Thr Ser 3440 3445 3450 Thr Thr Ser Ala Pro Thr Ser Ser Thr Thr Ser Thr Pro Gln Thr 3455 3460 3465 Ser Lys Thr Ser Ala Ala Thr Ser Ser Thr Thr Ser Gly Ser Gly 3470 3475 3480 Thr Thr Pro Ser Pro Val Thr Thr Thr Ser Thr Ala Ser Val Ser 3485 3490 3495 Lys Thr Ser Thr Ser His Val Ser Val Ser Lys Thr Thr His Ser 3500 3505 3510 Gln Pro Val Thr Arg Asp Cys His Pro Arg Cys Thr Trp Thr Lys 3515 3520 3525 Trp Phe Asp Val Asp Phe Pro Ser Pro Gly Pro His Gly Gly Asp 3530 3535 3540 Lys Glu Thr Tyr Asn Asn Ile Ile Arg Ser Gly Glu Lys Ile Cys 3545 3550 3555 Arg Arg Pro Glu Glu Ile Thr Arg Leu Gln Cys Arg Ala Lys Ser 3560 3565 3570 His Pro Glu Val Ser Ile Glu His Leu Gly Gln Val Val Gln Cys 3575 3580 3585 Ser Arg Glu Glu Gly Leu Val Cys Arg Asn Gln Asp Gln Gln Gly 3590 3595 3600 Pro Phe Lys Met Cys Leu Asn Tyr Glu Val Arg Val Leu Cys Cys 3605 3610 3615 Glu Thr Pro Lys Gly Cys Pro Val Thr Ser Thr Ser Val Thr Ala 3620 3625 3630 Pro Ser Thr Pro Ser Gly Arg Ala Thr Ser Pro Thr Gln Ser Thr 3635 3640 3645 Ser Ser Trp Gln Lys Ser Arg Thr Thr Thr Leu Val Thr Ser Ser 3650 3655 3660 Ile Thr Ser Thr Thr Gln Thr Ser Thr Thr Ser Ala Pro Thr Thr 3665 3670 3675 Ser Thr Thr Pro Ala Ser Ile Pro Ser Thr Thr Ser Ala Pro Thr 3680 3685 3690 Thr Ser Thr Thr Ser Ala Pro Thr Thr Ser Thr Thr Ser Ala Pro 3695 3700 3705 Thr Thr Ser Thr Thr Ser Thr Pro Gln Thr Thr Thr Ser Ser Ala 3710 3715 3720 Pro Thr Ser Ser Thr Thr Ser Ala Pro Thr Thr Ser Thr Ile Ser 3725 3730 3735 Ala Pro Thr Thr Ser Thr Ile Ser Ala Pro Thr Thr Ser Thr Thr 3740 3745 3750 Ser Ala Pro Thr Ala Ser Thr Thr Ser Ala Pro Thr Ser Thr Ser 3755 3760 3765 Ser Ala Pro Thr Thr Asn Thr Thr Ser Ala Pro Thr Thr Ser Thr 3770 3775 3780 Thr Ser Ala Pro Ile Thr Ser Thr Ile Ser Ala Pro Thr Thr Ser 3785 3790 3795 Thr Thr Ser Thr Pro Gln Thr Ser Thr Ile Ser Ser Pro Thr Thr 3800 3805 3810 Ser Thr Thr Ser Thr Pro Gln Thr Ser Thr Thr Ser Ser Pro Thr 3815 3820 3825 Thr Ser Thr Thr Ser Ala Pro Thr Thr Ser Thr Thr Ser Ala Pro 3830 3835 3840 Thr Thr Ser Thr Thr Ser Thr Pro Gln Thr Ser Ile Ser Ser Ala 3845 3850 3855 Pro Thr Ser Ser Thr Thr Ser Ala Pro Thr Ala Ser Thr Ile Ser 3860 3865 3870 Ala Pro Thr Thr Ser Thr Thr Ser Phe His Thr Thr Ser Thr Thr 3875 3880 3885 Ser Pro Pro Thr Ser Ser Thr Ser Ser Thr Pro Gln Thr Ser Lys 3890 3895 3900 Thr Ser Ala Ala Thr Ser Ser Thr Thr Ser Gly Ser Gly Thr Thr 3905 3910 3915 Pro Ser Pro Val Pro Thr Thr Ser Thr Ala Ser Val Ser Lys Thr 3920 3925 3930 Ser Thr Ser His Val Ser Val Ser Lys Thr Thr His Ser Gln Pro 3935 3940 3945 Val Thr Arg Asp Cys His Pro Arg Cys Thr Trp Thr Lys Trp Phe 3950 3955 3960 Asp Val Asp Phe Pro Ser Pro Gly Pro His Gly Gly Asp Lys Glu 3965 3970 3975 Thr Tyr Asn Asn Ile Ile Arg Ser Gly Glu Lys Ile Cys Arg Arg 3980 3985 3990 Pro Glu Glu Ile Thr Arg Leu Gln Cys Arg Ala Glu Ser His Pro 3995 4000 4005 Glu Val Ser Ile Glu His Leu Gly Gln Val Val Gln Cys Ser Arg 4010 4015 4020 Glu Glu Gly Leu Val Cys Arg Asn Gin Asp Gin Gin Gly Pro Phe 4025 4030 4035 Lys Met Cys Leu Asn Tyr Glu Val Arg Val Leu Cys Cys Glu Thr 4040 4045 4050 Pro Lys Gly Cys Pro Val Thr Ser Thr Pro Val Thr Ala Pro Ser 4055 4060 4065 Thr Pro Ser Gly Arg Ala Thr Ser Pro Thr Gin Ser Thr Ser Ser 4070 4075 4080 Trp Gin Lys Ser Arg Thr Thr Thr Leu Val Thr Thr Ser Thr Thr 4085 4090 4095 Ser Thr Pro Gin Thr Ser Thr Thr Ser Ala Pro Thr Thr Ser Thr 4100 4105 4110 Ile Pro Ala Ser Thr Pro Ser Thr Thr Ser Ala Pro Thr Thr Ser 4115 4120 4125 Thr Thr Ser Ala Pro Thr Thr Ser Thr Thr Ser Ala Pro Thr His 4130 4135 4140 Arg Thr Thr Ser Gly Pro Thr Thr Ser Thr Thr Leu Ala Pro Thr 4145 4150 4155 Thr Ser Thr Thr Ser Ala Pro Thr Thr Ser Thr Asn Ser Ala Pro 4160 4165 4170 Thr Thr Ser Thr Ile Ser Ala Ser Thr Thr Ser Thr Ile Ser Ala 4175 4180 4185 Pro Thr Thr Ser Thr Ile Ser Ser Pro Thr Ser Ser Thr Thr Ser 4190 4195 4200 Thr Pro Gln Thr Ser Lys Thr Ser Ala Ala Thr Ser Ser Thr Thr 4205 4210 4215 Ser Gly Ser Gly Thr Thr Pro Ser Pro Val Pro Thr Thr Ser Thr 4220 4225 4230 Thr Ser Ala Ser Thr Thr Ser Thr Thr Ser Ala Pro Thr Thr Ser 4235 4240 4245 Thr Thr Ser Gly Pro Gly Thr Thr Pro Ser Pro Val Pro Ser Thr 4250 4255 4260 Ser Thr Thr Ser Ala Ala Thr Thr Ser Thr Thr Ser Ala Pro Thr 4265 4270 4275 Thr Arg Thr Thr Ser Ala Pro Thr Ser Ser Met Thr Ser Gly Pro 4280 4285 4290 Gly Thr Thr Pro Ser Pro Val Pro Thr Thr Ser Thr Thr Ser Ala 4295 4300 4305 Pro Thr Thr Ser Thr Thr Ser Gly Pro Gly Thr Thr Pro Ser Pro 4310 4315 4320 Val Pro Thr Thr Ser Thr Thr Ser Ala Pro Ile Thr Ser Thr Thr 4325 4330 4335 Ser Gly Pro Gly Ser Thr Pro Ser Pro Val Pro Thr Thr Ser Thr 4340 4345 4350 Thr Ser Ala Pro Thr Thr Ser Thr Thr Ser Ala Ser Thr Ala Ser 4355 4360 4365 Thr Thr Ser Gly Pro Gly Thr Thr Pro Ser Pro Val Pro Thr Thr 4370 4375 4380 Ser Thr Thr Ser Ala Pro Thr Thr Arg Thr Thr Ser Ala Ser Thr 4385 4390 4395 Ala Ser Thr Thr Ser Gly Pro Gly Ser Thr Pro Ser Pro Val Pro 4400 4405 4410 Thr Thr Ser Thr Thr Ser Ala Pro Thr Thr Arg Thr Thr Pro Ala 4415 4420 4425 Ser Thr Ala Ser Thr Thr Ser Gly Pro Gly Thr Thr Pro Ser Pro 4430 4435 4440 Val Pro Thr Thr Ser Thr Thr Ser Ala Ser Thr Thr Ser Thr Ile 4445 4450 4455 Ser Leu Pro Thr Thr Ser Thr Thr Ser Ala Pro Ile Thr Ser Met 4460 4465 4470 Thr Ser Gly Pro Gly Thr Thr Pro Ser Pro Val Pro Thr Thr Ser 4475 4480 4485 Thr Thr Ser Ala Pro Thr Thr Ser Thr Thr Ser Ala Ser Thr Ala 4490 4495 4500 Ser Thr Thr Ser Gly Pro Gly Thr Thr Pro Ser Pro Val Pro Thr 4505 4510 4515 Thr Ser Thr Thr Ser Ala Pro Thr Thr Ser Thr Thr Ser Ala Ser 4520 4525 4530 Thr Ala Ser Thr Thr Ser Gly Pro Gly Thr Ser Leu Ser Pro Val 4535 4540 4545 Pro Thr Thr Ser Thr Thr Ser Ala Pro Thr Thr Ser Thr Thr Ser 4550 4555 4560 Gly Pro Gly Thr Thr Pro Ser Pro Val Pro Thr Thr Ser Thr Thr 4565 4570 4575 Ser Ala Pro Thr Thr Ser Thr Thr Ser Gly Pro Gly Thr Thr Pro 4580 4585 4590 Ser Pro Val Pro Thr Thr Ser Thr Thr Pro Val Ser Lys Thr Ser 4595 4600 4605 Thr Ser His Leu Ser Val Ser Lys Thr Thr His Ser Gln Pro Val 4610 4615 4620 Thr Ser Asp Cys His Pro Leu Cys Ala Trp Thr Lys Trp Phe Asp 4625 4630 4635 Val Asp Phe Pro Ser Pro Gly Pro His Gly Gly Asp Lys Glu Thr 4640 4645 4650 Tyr Asn Asn Ile Ile Arg Ser Gly Glu Lys Ile Cys Arg Arg Pro 4655 4660 4665 Glu Glu Ile Thr Arg Leu Gln Cys Arg Ala Glu Ser His Pro Glu 4670 4675 4680 Val Asn Ile Glu His Leu Gly Gln Val Val Gln Cys Ser Arg Glu 4685 4690 4695 Glu Gly Leu Val Cys Arg Asn Gln Asp Gln Gln Gly Pro Phe Lys 4700 4705 4710 Met Cys Leu Asn Tyr Glu Val Arg Val Leu Cys Cys Glu Thr Pro 4715 4720 4725 Arg Gly Cys Pro Val Thr Ser Val Thr Pro Tyr Gly Thr Ser Pro 4730 4735 4740 Thr Asn Ala Leu Tyr Pro Ser Leu Ser Thr Ser Met Val Ser Ala 4745 4750 4755 Ser Val Ala Ser Thr Ser Val Ala Ser Ser Ser Val Ala Ser Ser 4760 4765 4770 Ser Val Ala Tyr Ser Thr Gin Thr Cys Phe Cys Asn Val Ala Asp 4775 4780 4785 Arg Leu Tyr Pro Ala Gly Ser Thr Ile Tyr Arg His Arg Asp Leu 4790 4795 4800 Ala Gly His Cys Tyr Tyr Ala Leu Cys Ser Gin Asp Cys Gin Val 4805 4810 4815 Val Arg Gly Val Asp Ser Asp Cys Pro Ser Thr Thr Leu Pro Pro 4820 4825 4830 Ala Pro Ala Thr Ser Pro Ser Ile Ser Thr Ser Glu Pro Val Thr 4835 4840 4845 Glu Leu Gly Cys Pro Asn Ala Val Pro Pro Arg Lys Lys Gly Glu 4850 4855 4860 Thr Trp Ala Thr Pro Asn Cys Ser Glu Ala Thr Cys Glu Gly Asn 4865 4870 4875 Asn Val Ile Ser Leu Arg Pro Arg Thr Cys Pro Arg Val Glu Lys 4880 4885 4890 Pro Thr Cys Ala Asn Gly Tyr Pro Ala Val Lys Val Ala Asp Gin 4895 4900 4905 Asp Gly Cys Cys His His Tyr Gin Cys Gin Cys Val Cys Ser Gly 4910 4915 4920 Trp Gly Asp Pro His Tyr lie Thr Phe Asp Gly Thr Tyr Tyr Thr 4925 4930 4935 Phe Leu Asp Asn Cys Thr Tyr Val Leu Val Gin Gin lie Val Pro 4940 4945 4950 Val Tyr Gly His Phe Arg Val Leu Val Asp Asn Tyr Phe Cys Gly 4955 4960 4965 Ala Glu Asp Gly Leu Ser Cys Pro Arg Ser lie lie Leu Glu Tyr 4970 4975 4980 His Gin Asp Arg Val Val Leu Thr Arg Lys Pro Val His Gly Val 4985 4990 4995 Met Thr Asn Glu lie lie Phe Asn Asn Lys Val Val Ser Pro Gly 5000 5005 5010 Phe Arg Lys Asn Gly lie Val Val Ser Arg lie Gly Val Lys Met 5015 5020 5025 Tyr Ala Thr lie Pro Glu Leu Gly Val Gin Val Met Phe Ser Gly 5030 5035 5040 Leu lie Phe Ser Val Glu Val Pro Phe Ser Lys Phe Ala Asn Asn 5045 5050 5055 Thr Glu Gly Gin Cys Gly Thr Cys Thr Asn Asp Arg Lys Asp Glu 5060 5065 5070 Cys Arg Thr Pro Arg Gly Thr Val Val Ala Ser Cys Ser Glu Met 5075 5080 5085 Ser Gly Leu Trp Asn Val Ser Ile Pro Asp Gln Pro Ala Cys His 5090 5095 5100 Arg Pro His Pro Thr Pro Thr Thr Val Gly Pro Thr Thr Val Gly 5105 5110 5115 Ser Thr Thr Val Gly Pro Thr Thr Val Gly Ser Thr Thr Val Gly 5120 5125 5130 Pro Thr Thr Pro Pro Ala Pro Cys Leu Pro Ser Pro Ile Cys Gln 5135 5140 5145 Leu Ile Leu Ser Lys Val Phe Glu Pro Cys His Thr Val Ile Pro 5150 5155 5160 Pro Leu Leu Phe Tyr Glu Gly Cys Val Phe Asp Arg Cys His Met 5165 5170 5175 Thr Asp Leu Asp Val Val Cys Ser Ser Leu Glu Leu Tyr Ala Ala 5180 5185 5190 Leu Cys Ala Ser His Asp Ile Cys Ile Asp Trp Arg Gly Arg Thr 5195 5200 5205 Gly His Met Cys Pro Phe Thr Cys Pro Ala Asp Lys Val Tyr Gln 5210 5215 5220 Pro Cys Gly Pro Ser Asn Pro Ser Tyr Cys Tyr Gly Asn Asp Ser 5225 5230 5235 Ala Ser Leu Gly Ala Leu Pro Glu Ala Gly Pro Ile Thr Glu Gly 5240 5245 5250 Cys Phe Cys Pro Glu Gly Met Thr Leu Phe Ser Thr Ser Ala Gln 5255 5260 5265 Val Cys Val Pro Thr Gly Cys Pro Arg Cys Leu Gly Pro His Gly 5270 5275 5280 Glu Pro Val Lys Val Gly His Thr Val Gly Met Asp Cys Gln Glu 5285 5290 5295 Cys Thr Cys Glu Ala Ala Thr Trp Thr Leu Thr Cys Arg Pro Lys 5300 5305 5310 Leu Cys Pro Leu Pro Pro Ala Cys Pro Leu Pro Gly Phe Val Pro 5315 5320 5325 Val Pro Ala Ala Pro Gln Ala Gly Gln Cys Cys Pro Gln Tyr Ser 5330 5335 5340 Cys Ala Cys Asn Thr Ser Arg Cys Pro Ala Pro Val Gly Cys Pro 5345 5350 5355 Glu Gly Ala Arg Ala Ile Pro Thr Tyr Gln Glu Gly Ala Cys Cys 5360 5365 5370 Pro Val Gin Asn Cys Ser Trp Thr Val Cys Ser lie Asn Gly Thr 5375 5380 5385 Leu Tyr Gin Pro Gly Ala Val Val Ser Ser Ser Leu Cys Glu Thr 5390 5395 5400 Cys Arg Cys Glu Leu Pro Gly Gly Pro Pro Ser Asp Ala Phe Val 5405 5410 5415 Val Ser Cys Glu Thr Gin lie Cys Asn Thr His Cys Pro Val Gly 5420 5425 5430 Phe Glu Tyr Gin Glu Gin Ser Gly Gin Cys Cys Gly Thr Cys Val 5435 5440 5445 Gln Val Ala Cys Val Thr Asn Thr Ser Lys Ser Pro Ala His Leu 5450 5455 5460 Phe Tyr Pro Gly Glu Thr Trp Ser Asp Ala Gly Asn His Cys Val 5465 5470 5475 Thr His Gin Cys Glu Lys His Gin Asp Gly Leu Val Val Val Thr 5480 5485 5490 Thr Lys Lys Ala Cys Pro Pro Leu Ser Cys Ser Leu Asp Glu Ala 5495 5500 5505 Arg Met Ser Lys Asp Gly Cys Cys Arg Phe Cys Pro Pro Pro Pro 5510 5515 5520 Pro Pro Tyr Gin Asn Gin Ser Thr Cys Ala Val Tyr His Arg Ser 5525 5530 5535 Leu lie lie Gin Gin Gin Gly Cys Ser Ser Ser Glu Pro Val Arg 5540 5545 5550 Leu Ala Tyr Cys Arg Gly Asn Cys Gly Asp Ser Ser Ser Met Tyr 5555 5560 5565 Ser Leu Glu Gly Asn Thr Val Glu His Arg Cys Gin Cys Cys Gin 5570 5575 5580 Glu Leu Arg Thr Ser Leu Arg Asn Val Thr Leu His Cys Thr Asp 5585 5590 5595 Gly Ser Ser Arg Ala Phe Ser Tyr Thr Glu Val Glu Glu Cys Gly 5600 5605 5610 Cys Met Gly Arg Arg Cys Pro Ala Pro Gly Asp Thr Gin His Ser 5615 5620 5625 Glu Glu Ala Glu Pro Glu Pro Ser Gin Glu Ala Glu Ser Gly Ser 5630 5635 5640 Trp Glu Arg Gly Val Pro Val Ser Pro Met His 5645 5650 <210> 17 <211> 458 <212> PRT <213> artificial sequence <220> <223> Human CD4 amino acid sequence <400> 17 Met Asn Arg Gly Val Pro Phe Arg His Leu Leu Leu Val Leu Gln Leu 1 5 10 15 Ala Leu Leu Pro Ala Ala Thr Gln Gly Lys Lys Val Val Leu Gly Lys 20 25 30 Lys Gly Asp Thr Val Glu Leu Thr Cys Thr Ala Ser Gln Lys Lys Ser 35 40 45 Ile Gln Phe His Trp Lys Asn Ser Asn Gln Ile Lys Ile Leu Gly Asn 50 55 60 Gln Gly Ser Phe Leu Thr Lys Gly Pro Ser Lys Leu Asn Asp Arg Ala 65 70 75 80 Asp Ser Arg Arg Ser Leu Trp Asp Gln Gly Asn Phe Pro Leu Ile Ile 85 90 95 Lys Asn Leu Lys Ile Glu Asp Ser Asp Thr Tyr Ile Cys Glu Val Glu 100 105 110 Asp Gln Lys Glu Glu Val Gln Leu Leu Val Phe Gly Leu Thr Ala Asn 115 120 125 Ser Asp Thr His Leu Leu Gln Gly Gln Ser Leu Thr Leu Thr Leu Glu 130 135 140 Ser Pro Pro Gly Ser Ser Pro Ser Val Gin Cys Arg Ser Pro Arg Gly 145 150 155 160 Lys Asn Ile Gin Gly Gly Lys Thr Leu Ser Val Ser Gin Leu Glu Leu 165 170 175 Gln Asp Ser Gly Thr Trp Thr Cys Thr Val Leu Gin Asn Gin Lys Lys 180 185 190 Val Glu Phe Lys Ile Asp Ile Val Val Leu Ala Phe Gin Lys Ala Ser 195 200 205 Ser Ile Val Tyr Lys Lys Glu Gly Glu Gin Val Glu Phe Ser Phe Pro 210 215 220 Leu Ala Phe Thr Val Glu Lys Leu Thr Gly Ser Gly Glu Leu Trp Trp 225 230 235 240 Gln Ala Glu Arg Ala Ser Ser Ser Lys Ser Trp Ile Thr Phe Asp Leu 245 250 255 Lys Asn Lys Glu Val Ser Val Lys Arg Val Thr Gin Asp Pro Lys Leu 260 265 270 Gln Met Gly Lys Lys Leu Pro Leu His Leu Thr Leu Pro Gin Ala Leu 275 280 285 Pro Gin Tyr Ala Gly Ser Gly Asn Leu Thr Leu Ala Leu Glu Ala Lys 290 295 300 Thr Gly Lys Leu His Gin Glu Val Asn Leu Val Val Met Arg Ala Thr 305 310 315 320 Gln Leu Gin Lys Asn Leu Thr Cys Glu Val Trp Gly Pro Thr Ser Pro 325 330 335 Lys Leu Met Leu Ser Leu Lys Leu Glu Asn Lys Glu Ala Lys Val Ser 340 345 350 Lys Arg Glu Lys Ala Val Trp Val Leu Asn Pro Glu Ala Gly Met Trp 355 360 365 Gln Cys Leu Leu Ser Asp Ser Gly Gin Val Leu Leu Glu Ser Asn Ile 370 375 380 Lys Val Leu Pro Thr Trp Ser Thr Pro Val Gin Pro Met Ala Leu Ile 385 390 395 400 Val Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile 405 410 415 Phe Phe Cys Val Arg Cys Arg His Arg Arg Arg Gin Ala Glu Arg Met 420 425 430 Ser Gin Ile Lys Arg Leu Leu Ser Glu Lys Lys Thr Cys Gin Cys Pro 435 440 445 His Arg Phe Gin Lys Thr Cys Ser Pro Ile 450 455 <210> 18 <211> 771 <212> DNA <213> artificial sequence <220> <223> alpha chain <400> 18 cagacagtca ctcagtctca accagagatg tctgtgcagg aggcagagac tgtgaccctg 60 agttgcacat atgacaccag tgagagtaat tattatttgt tctggtacaa acagcctccc 120 agcaggcaga tgattctcgt tattcgccaa gaagcttata agcaacagaa tgcaacggag 180 aatcgtttct ctgtgaactt ccagaaagca gccaaatcct tcagtctcaa gatctcagac 240 tcacagctgg gggacactgc gatgtatttc tgtgctttca tgaagcgggc cgaaaccagt 300 ggctctaggt tgacctttgg ggaaggaaca cagctcacag tgaatcctga tatccagaac 360 cctgaccctg ccgtgtacca gctgagagac tctaaatcca gtgacaagtc tgtctgccta 420 ttcaccgatt ttgattctca aacaaatgtg tcacaaagta aggattctga tgtgtatatc 480 acagacaaaa ctgtgctaga catgaggtct atggacttca agagcaacag tgctgtggcc 540 tggagcaaca aatctgactt tgcatgtgca aacgccttca acaacagcat tattccagaa 600 gacaccttct tccccagccc agaaagttcc tgtgatgtca agctggtcga gaaaagcttt 660 gaaacagata cgaacctaaa ctttcaaaac ctgtcagtga ttgggttccg aatcctcctc 720 ctgaaagtgg ccgggtttaa tctgctcatg acgctgcggc tgtggtccag c 771 <210> 19 <211> 876 <212> DNA <213> artificial sequence <220> <223> beta chain <400> 19 aatgctggtg tcactcagac cccaaaattc cgggtcctga agacaggaca gagcatgaca 60 ctgctgtgtg ctcaggatat gaaccatgaa tacatgtact ggtatcgaca agacccaggc 120 atggggctga ggctgattca ttactcagtt ggtgagggta caactgccaa aggagaggtc 180 cctgatggct acaatgtctc cagattaaaa aaacagaatt tcctgctggg gttggagtcg 240 gctgctccct cccaaacatc tgtgtacttc tgtgccagca gttactggcc gacgcgggag 300 acccagtact tcgggccagg cacgcggctc ctggtgctcg aggacctgaa aaacgtgttc 360 ccacccgagg tcgctgtgtt tgagccatca gaagcagaga tctcccacac ccaaaaggcc 420 GAGCAGACTGTGGCTTCACCTCCGAGTCTTACCAGCAAGGGGTCCTGTC TGCCACCATC 60 AATGGGAAGGAGGTGCACAGTGGGGTCAGCACAGACCCGCAGCCCCTCAAGGAGC AGCCC 540 GCCCTCAATGACTCCAGATACTGCCTGAGCAGCCGCCTGAGG GTCTCGGCACCTTCTGG 600 CAGAACCCCCGCAACCAC TCCGCTGTCAAGTCCAGTTCTACGGGCTCTCGGAGAATGAC 660 GAGTGGACCCAGGATAGGGCCA AACCTGTCACCCAGATCGTCAGCGCCGAGGCCTGGG GT 720 AGAGCAGACTGTGGCTTCACCTCCGAGTCTTACCAGCAAGGGGTCCTGTC TGCCACCATC 780 CTCTATGAGATCTTGCTAGGGAAGGCCACCTTGTATGCCGTGCTG GTCAGTGCCCTCGTG 840 CTGATGGCCATGgtcaagagaaaggatagcagaggc 876 <210> 20 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Signal peptide (derived from silk protein-L) <400> 20 Met Met Arg Pro Ile Val Leu Val Leu Leu Phe Ala Thr Ser Ala Leu 1 5 10 15 Ala <210> 21 <211> 21 <212> PRT <213> artificial sequence <220> <223> alpha chain signal peptide <400> 21 Met Thr Arg Val Ser Leu Leu Trp Ala Val Val Val Ser Thr Cys Leu 1 5 10 15 Glu Ser Gly Met Ala 20 <210> 22 <211> 15 <212> PRT <213> artificial sequence <220> <223> beta chain signal peptide <400> 22 Met Gly Ala Val Ala Ser Ala Leu Ser Phe Ser Ala Gly Pro Val 1 5 10 15 <210> 23 <211> 63 <212> DNA <213> artificial sequence <220> <223> alpha chain signal peptide <400> 23 atgacacgtg ttagcttgct gtgggcagtc gtggtctcca cctgtcttga atccggcatg 60 gcc 63 <210> 24 <211> 45 <212> DNA <213> artificial sequence <220> <223> beta chain signal peptide <400> 24 atgggggctg tagcatcagc tttgtccttc tctgcaggtc cagtg 45 <210> 25 <211> 21 <212> DNA <213> artificial sequence <220> <223> siRNA-TCRa-1 <400> 25 guaaggauuc ugauguguat t 21 <210> 26 <211> 21 <212> DNA <213> artificial sequence <220> <223> siRNA-TCRa-2 <400> 26 uacacaucag aauccuuact t 21 <210> 27 <211> 21 <212> DNA <213> artificial sequence <220> <223> siRNA-TCRb-1 <400> 27 ccaccauccu cuaugagaut t 21 <210> 28 <211> 21 <212> DNA <213> artificial sequence <220> <223> siRNA-TCRb-2 <400> 28 aucucauaga ggaugguggt t 21 <210> 29 <211> 37 <212> PRT <213> artificial sequence <220> <223> MUC5AC minigene <400> 29 Met His Tyr Gin Cys Gin Cys Val Cys Ser Gly Trp Gly Asp Pro His 1 5 10 15 Tyr He Thr Phe Asp Gly Thr Tyr Tyr Thr Phe Leu Asp Asn Cys Thr 20 25 30 Tyr Val Leu Val Gin 35 <210> 30 <211> 4 <212> PRT <213> artificial sequence <220> <223> Gly Serine bridge <400> 30 Gly Gly Gly Ser 1

Claims

1. A nucleic acid molecule comprising (i) a first nucleotide sequence encoding a recombinant anti-MUC5AC T cell receptor TCR or antigen binding portion thereof that specifically binds to human mucin 5AC (MUC5AC); wherein, The anti-MUC5AC TCR comprises an alpha chain and a beta chain, wherein the alpha chain comprises a variable domain comprising an alpha chain CDR1, an alpha chain CDR2, and an alpha chain CDR3; and wherein the beta chain comprises a variable domain comprising a beta chain CDR1, a beta chain CDR2, and a beta chain CDR3; and wherein: (a) the amino acid sequence of the beta chain CDR3 of the anti-MUC5AC TCR is set forth in SEQ ID NO: 10; (b) the amino acid sequence of the beta chain CDR2 of the anti-MUC5AC TCR is set forth in SEQ ID NO: 9; (c) the amino acid sequence of the beta chain CDR1 of the anti-MUC5AC TCR is set forth in SEQ ID NO: 8; (d) the amino acid sequence of the alpha chain CDR3 of the anti-MUC5AC TCR is set forth in SEQ ID NO: 7; (e) the amino acid sequence of the alpha chain CDR2 of the anti-MUC5AC TCR is set forth in SEQ ID NO: 6; and (f) the amino acid sequence of the alpha chain CDR1 of the anti-MUC5AC TCR is set forth in SEQ ID NO: 5; and (ii) a second nucleotide sequence, wherein the second nucleotide sequence or a polypeptide encoded by the second nucleotide sequence inhibits expression of an endogenous TCR.

2. The nucleic acid molecule of claim 1, wherein (i) the alpha chain of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 1; (ii) the beta chain of the anti-MUC5AC TCR comprises an amino acid sequence as set forth in SEQ ID NO: 2; or (iii) both (i) and (ii).

3. The nucleic acid molecule of claim 1, wherein the second nucleotide sequence is one or more siRNAs that reduce expression of an endogenous TCR, wherein the one or more siRNAs are complementary to a target sequence within a nucleotide sequence encoding a constant region of the endogenous TCR.

4. The nucleic acid molecule of claim 3, wherein the one or more siRNAs comprise one or more nucleotide sequences selected from SEQ ID NOs: 25-28.

5. A vector comprising the nucleic acid molecule of any one of claims 1 to 4.

6. The vector of claim 5, which is a viral vector, a mammalian vector, or a bacterial vector.

7. The vector of claim 5, which is a retroviral vector.

8. The vector of claim 5, which is an adenoviral vector, a lentiviral vector, a Sendai viral vector, a baculoviral vector, an Epstein Barr viral vector, a papovaviral vector, a vaccinia viral vector, a herpes simplex viral vector, a hybrid vector, and an adeno-associated viral (AAV) vector.

9. The vector of claim 5, which is a lentiviral vector.

10. A cell comprising the nucleic acid molecule of any one of claims 1 to 4 or the vector of any one of claims 5 to 9.

11. The cell of claim 10, further expressing CD3.

12. The cell of claim 10 or 11, which is a T cell.

13. The cell of claim 10 or 11, which is a natural killer cell.

14. The cell of claim 10 or 11, which is a natural killer T cell.

15. The cell of claim 10 or 11, which is an ILC cell.

16. Use of the cell of any one of claims 10 to 15 in the manufacture of a medicament for treating melanoma in a subject in need thereof.

17. The use of claim 16, wherein the melanoma is relapsed or refractory.

18. The use of claim 16, wherein the melanoma is locally advanced.

19. The use of claim 16, wherein the melanoma is advanced.

20. The use of claim 16, wherein the melanoma is metastatic.

21. The use of claim 16, wherein the cell is obtained from the subject.

22. The use of claim 16, wherein the cell is obtained from a donor other than the subject.

23. A method of engineering a cell targeting an antigen, the method comprising transducing a cell collected from a subject in need of a T cell therapy with the nucleic acid molecule of any one of claims 1 to 4 or the vector of any one of claims 5 to 9.

24. The method of claim 23, wherein the cell targeting an antigen further expresses CD4.

25. The method of claim 23, wherein the cell is a T cell.

26. The method of claim 23, wherein the cell is a natural killer cell.

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