T cell receptors and methods of use thereof

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This PCT application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 880,505, filed July 30, 2019, which is incorporated herein by reference in its entirety.

[0002] Reference to sequence listings submitted electronically via EFS-WEB The contents of the electronically submitted sequence listing (Name: 4285 014PC01 Sequence Listing ST255.txt, Size: 70,689 bytes; and Created: July 28, 2020) are incorporated herein by reference in their entirety.

[0003] Field of the Disclosure The present disclosure provides recombinant T cell receptors ("TCRs") that specifically bind human mucin 5AC (MUC5AC) and uses thereof. [Background technology]

[0004] Immunotherapy has emerged as an important tool in the fight against various diseases, including cancer. T cell therapy is at the forefront of immunotherapeutic development, and adoptive transfer of antitumor T cells has been shown to induce clinical responses in cancer patients. Many T cell therapies target mutated tumor antigens, but the majority of neoantigens are not shared and are unique to each patient.

[0005] The number of potential non-mutated antigens outnumbers the number of mutated antigens by several orders of magnitude. Elucidation of T cell epitopes derived from shared antigens could facilitate the development of effective and safe adoptive T cell therapies that are readily accessible to larger cohorts of cancer patients. However, the sheer number of non-mutated antigens and the high polymorphism of HLA genes may hinder a comprehensive analysis of the specificity of anti-tumor T cell responses to non-mutated antigens. Summary of the Invention [Means for solving the problem]

[0006] Certain aspects of the present disclosure relate to nucleic acid molecules comprising: (i) a first nucleotide sequence encoding a recombinant T cell receptor (TCR) or antigen-binding portion thereof that specifically binds human mucin 5AC (MUCAC) (an "anti-MUC5AC TCR"); and (ii) a second nucleotide sequence, wherein the second nucleotide sequence, or the polypeptide encoded by the second nucleotide sequence, inhibits expression of an endogenous TCR, and the anti-MUC5AC TCR cross-competes with a reference TCR comprising an alpha chain and a beta chain for binding to human MUC5AC, wherein the alpha chain comprises the amino acid sequence set forth in SEQ ID NO:1 and the beta chain comprises the amino acid sequence set forth in SEQ ID NO:2.

[0007] Certain aspects of the present disclosure relate to nucleic acid molecules comprising: (i) a first nucleotide sequence encoding a recombinant T cell receptor (TCR) or antigen-binding portion thereof that specifically binds human MUC5AC (an "anti-MUC5AC TCR"); and (ii) a second nucleotide sequence, wherein the second nucleotide sequence, or the polypeptide encoded by the second nucleotide sequence, inhibits expression of an endogenous TCR, and the anti-MUC5AC TCR binds to the same epitope or an overlapping epitope on human MUC5AC as a reference TCR comprising an alpha chain and a beta chain, wherein the alpha chain comprises the amino acid sequence set forth in SEQ ID NO:1 and the beta chain comprises the amino acid sequence set forth in SEQ ID NO:2.

[0008] In some embodiments, the anti-MUC5AC TCR binds to an epitope of MUC5AC consisting of the amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, this epitope is complexed with an HLA class II molecule. In some embodiments, this HLA class II molecule is an HLA-DP, HLA-DQ, or HLA-DR allele, or any combination thereof. In some embodiments, this HLA class II molecule is an HLA-DP allele. In some embodiments, this HLA class II molecule is an HLA-DP4 allele.

[0009] In some embodiments, 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; and wherein the alpha chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 7. In some embodiments, the beta chain CDR3 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO: 10.

[0010] In some embodiments, the beta chain CDR3 of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO:10.

[0011] In some embodiments, the anti-MUC5AC TCR comprises an alpha chain and a beta chain, wherein the alpha chain comprises a variable region comprising alpha chain CDR1, alpha chain CDR2, and alpha chain CDR3; and wherein the beta chain comprises a variable domain comprising beta chain CDR1, beta chain CDR2, and beta chain CDR3; and wherein the beta chain CDR3 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO:10.

[0012] In some embodiments, the alpha chain CDR3 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO: 7. In some embodiments, the alpha chain CDR1 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO: 5. In some embodiments, the beta chain CDR1 of the anti-MUC5AC TCR comprises amino acids as set forth in SEQ ID NO: 8. In some embodiments, the alpha chain CDR2 of the anti-MUC5AC TCR comprises the amino acid sequence as set forth in SEQ ID NO: 6. In some embodiments, the beta chain CDR2 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO: 9.

[0013] In some embodiments, the alpha chain variable domain of the anti-MUC5AC TCR comprises the amino acid sequence of the variable domain present in the amino acid sequence set forth in SEQ ID NO: 1. In some embodiments, the beta chain variable domain of the anti-MUC5AC TCR comprises the amino acid sequence of the variable domain present in the amino acid sequence set forth in SEQ ID NO: 2.

[0014] In some embodiments, the alpha chain of the anti-MUC5AC TCR further comprises a constant region, which is distinct from the endogenous constant region of the alpha chain.

[0015] In some embodiments, 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 the constant region present in the amino acid sequence set forth in SEQ ID NO:1.

[0016] In some embodiments, the alpha chain constant region comprises an amino acid sequence that contains 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.

[0017] In some embodiments, the beta chain of the anti-MUC5AC TCR further comprises a constant region, which is distinct from the endogenous constant region of the beta chain.

[0018] In some embodiments, 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.

[0019] In some embodiments, the beta chain constant region comprises an amino acid sequence that contains 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.

[0020] In some embodiments, the alpha chain of the anti-MUC5AC TCR comprises the amino acid sequence as set forth in SEQ ID NO: 1. In some embodiments, the beta chain of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO:2.

[0021] In some embodiments, the second nucleotide sequence is one or more siRNAs that reduce expression of an endogenous TCR. In some embodiments, the one or more siRNAs are complementary to a target sequence within the nucleotide sequence encoding the constant region of the endogenous TCR. In some embodiments, the one or more siRNAs comprise one or more nucleotide sequences selected from the group consisting of SEQ ID NOs: 25-28.

[0022] In some embodiments, the anti-MUC5AC TCR comprises an alpha chain constant region, a beta chain constant region, or both; wherein the alpha chain constant region, the beta chain constant region, or both, comprises an amino acid sequence that has at least 1, at least 2, at least 3, at least 4, or at least 5 substitutions in the target sequence relative to the corresponding amino acid sequence of the endogenous TCR.

[0023] In some embodiments, the alpha chain includes a signal peptide, the beta chain includes a signal peptide, or both the alpha and beta chains include a signal peptide. In some embodiments, the single peptide includes an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 20-22, and any combination thereof.

[0024] 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, 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 Sendai virus vector, a baculovirus vector, an Epstein-Barr virus vector, a papovavirus vector, a vaccinia virus vector, a herpes simplex virus vector, a hybrid vector, and an adeno-associated virus (AAV) vector. In some aspects, the vector is a lentivirus.

[0025] Certain aspects of the present disclosure relate to a T cell receptor (TCR) or antigen-binding portion thereof comprising the alpha chain variable domain of an anti-MUC5AC TCR disclosed herein and the beta chain variable domain of an anti-MUC5AC TCR disclosed herein.

[0026] Certain aspects of the present disclosure relate to a recombinant T cell receptor (TCR) or antigen-binding portion thereof (an "anti-MUC5AC TCR") that specifically binds to human MUC5AC; which cross-competes with a reference TCR for binding to human MUC5AC; wherein the reference TCR comprises an alpha chain and a beta chain, the alpha chain comprising the amino acid sequence set forth in SEQ ID NO:1, and the beta chain comprising the amino acid sequence set forth in SEQ ID NO:2; wherein the anti-MUC5AC TCR comprises an alpha chain and a beta chain, the alpha chain comprising a constant region, and the beta chain comprising a constant region; and wherein the alpha chain constant region comprises an amino acid sequence having at least one, at least two, at least three, at least four, or at least five amino acid substitutions relative to the constant region present in the set of amino acid sequences set forth in SEQ ID NO:1, or the beta chain constant region comprises an amino acid sequence having at least one, at least two, at least three, at least four, or at least five amino acid substitutions relative to the constant region present in the amino acid sequence of SEQ ID NO:2.

[0027] Certain aspects of the present disclosure relate to a recombinant T cell receptor (TCR) or antigen-binding portion thereof (an "anti-MUC5AC TCR") that specifically binds to human MUC5AC and binds to the same epitope on human MUC5AC as a reference TCR or an overlapping epitope; wherein the reference TCR comprises an alpha chain and a beta chain, the alpha chain comprising the amino acid sequence set forth in SEQ ID NO:1, and the beta chain comprising the amino acid sequence set forth in SEQ ID NO:2; wherein the anti-MUC5AC TCR comprises an alpha chain and a beta chain, the alpha chain comprising a constant region, and the beta chain comprising a constant region; and wherein the alpha chain constant region comprises an amino acid sequence having at least one, at least two, at least three, at least four, or at least five 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 one, at least two, at least three, at least four, or at least five amino acid substitutions relative to the constant region present in the amino acid sequence set forth in SEQ ID NO:2.

[0028] In some embodiments, the anti-MUC5AC TCR binds to an epitope of MUC5AC consisting of the amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, this epitope is complexed with an HLA class II molecule. In some embodiments, this HLA class II molecule is an HLA-DP, HLA-DQ, or HLA-DR allele, or any combination thereof. In some embodiments, this HLA class II molecule is an HLA-DP allele. In some embodiments, this HLA class II molecule is an HLA-DP4 allele.

[0029] In some embodiments, 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 alpha chain CDR3 of the anti-MUC5AC comprises the amino acid sequence set forth in SEQ ID NO:7.

[0030] In some embodiments, the beta chain CDR3 of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO:10.

[0031] In some embodiments, the alpha chain of the anti-MUC5AC TCR comprises a variable domain comprising alpha chain CDR1, alpha chain CDR2, and alpha chain CDR3; wherein the beta chain of the anti-MUC5AC TCR comprises a variable domain comprising beta chain CDR1, beta chain CDR2, and beta chain CDR3; and wherein the beta chain CDR3 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO:10.

[0032] In some embodiments, the alpha chain CDR3 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO: 7. In some embodiments, the alpha chain CDR1 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO: 5. In some embodiments, the beta chain CDR1 of the anti-MUC5AC TCR comprises amino acids as set forth in SEQ ID NO: 8. In some embodiments, the alpha chain CDR2 of the anti-MUC5AC TCR comprises the amino acid sequence as set forth in SEQ ID NO: 6. In some embodiments, the beta chain CDR2 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO: 9.

[0033] In some embodiments, the alpha chain variable domain of the anti-MUC5AC TCR comprises the amino acid sequence of the variable domain present in the amino acid sequence set forth in SEQ ID NO: 1. In some embodiments, the beta chain variable domain of the anti-MUC5AC TCR comprises the amino acid sequence of the variable domain present in the amino acid sequence set forth in SEQ ID NO: 2.

[0034] In some embodiments, 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 the amino acid sequence of the constant region present in the amino acid sequence set forth in SEQ ID NO:1.

[0035] In some embodiments, 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 amino acid sequence of the constant region present in the amino acid sequence set forth in SEQ ID NO:2.

[0036] In some embodiments, the alpha chain of the anti-MUC5AC TCR comprises the amino acid sequence as set forth in SEQ ID NO: 1. In some embodiments, the beta chain of the anti-MUC5AC TCR comprises the amino acid sequence as set forth in SEQ ID NO:2.

[0037] In some embodiments, the alpha chain comprises a signal peptide, the beta chain comprises a signal peptide, or both the alpha and beta chains comprise a signal peptide, hi some embodiments, the signal peptide comprises an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 20-22, and any combination thereof.

[0038] Certain aspects of the present disclosure relate to bispecific TCRs 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 as disclosed herein.

[0039] In some embodiments, the first antigen-binding domain comprises a single-chain variable fragment ("scFv"). In some embodiments, the second antigen-binding domain specifically binds to a protein expressed on the surface of a T cell. In some embodiments, the second antigen-binding domain specifically binds to CD3. In some embodiments, the second antigen-binding domain comprises an scFv. In some embodiments, the first antigen-binding domain and the second antigen-binding domain are covalently linked or joined. In some embodiments, the first antigen-binding domain and the second antigen-binding domain are linked by a peptide bond.

[0040] Certain embodiments of the present disclosure relate to cells 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 embodiments, the cell further expresses CD3. In some embodiments, 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.

[0041] Certain aspects of the present disclosure relate to methods of treating cancer in a subject in need thereof, comprising administering to the subject a cell as 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, gastric cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, cervical cancer, vaginal carcinoma, 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, and cancer of the penis. The cancer is selected from the group consisting of cancer, chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) (including non-T-cell ALL), chronic lymphocytic leukemia (CLL), childhood solid tumors, lymphocytic lymphoma, bladder cancer, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, other B-cell malignancies, and combinations of the foregoing cancers.

[0042] In some embodiments, the cancer is recurrent or refractory. In some embodiments, the cancer is locally advanced. In some embodiments, the cancer is advanced. In some embodiments, the cancer is metastatic.

[0043] In some embodiments, the cells are obtained from the subject. In some embodiments, the cells are obtained from a donor other than the subject.

[0044] In some embodiments, the subject is preconditioned (pretreated) prior to administration of the cells. In some embodiments, the preconditioning comprises administering to the subject chemotherapy, cytokines, proteins, small molecules, or any combination thereof. In some embodiments, the preconditioning comprises administering an interleukin. In some embodiments, the preconditioning comprises administering IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, or any combination thereof. In some embodiments, the preconditioning comprises administering a preconditioning agent selected from the group consisting of cyclophosphamide, fludarabine, vitamin C, an AKT inhibitor, ATRA, rapamycin, or any combination thereof. In some embodiments, the preconditioning comprises administering cyclophosphamide, fludarabine, or both.

[0045] Certain aspects of the present disclosure relate to methods of engineering antigen-targeted cells, comprising transducing cells collected from a subject in need of T cell therapy with a nucleic acid molecule disclosed herein or a vector disclosed herein. In some aspects, the antigen-targeted cells further express CD4. In some aspects, the cells are T cells or natural killer (NK) cells.

[0046] A particular aspect of the present disclosure relates to an HLA class II molecule complexed with a peptide, the HLA class II molecule comprising an alpha chain and a beta chain; the peptide consisting of the amino acid sequence set forth in SEQ ID NO:13.

[0047] In some embodiments, the HLA class II molecule is an HLA-DP, HLA-DQ, or HLA-DR allele, or any combination thereof. In some embodiments, the HLA class II molecule is an HLA-DP allele. In some embodiments, the HLA class II molecule is an HLA-DQ allele. In some embodiments, the HLA class II molecule is an HLA-DR allele. In some embodiments, the HLA class II molecule is a monomer. In some embodiments, the HLA class II molecule is a dimer. In some embodiments, the HLA class II molecule is a trimer. In some embodiments, the HLA class II molecule is a tetramer. In some embodiments, the HLA class II molecule is a pentamer.

[0048] Certain aspects of the present disclosure relate to antigen-presenting cells (APCs) comprising the HLA class II molecules disclosed herein. In some aspects, the HLA class II molecules are expressed on the surface of the APCs.

[0049] Certain aspects of the present disclosure relate to methods of enriching a target population of 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 after the contacting, the enriched T cell population comprises a greater number of T cells capable of binding to HLA class II molecules relative to the number of T cells capable of binding to HLA class II molecules prior to the contacting.

[0050] Certain aspects of the present disclosure relate to methods of enriching a target population of T cells obtained from a human subject, the method comprising contacting T cells in vitro with a peptide, wherein the peptide consists of the amino acid sequence set forth in SEQ ID NO: 13, and wherein after said contacting, the enriched T cell population comprises a greater number of T cells capable of targeting tumor cells relative to the number of T cells capable of targeting tumor cells prior to said contacting. In some aspects, the T cells obtained from the human subject are tumor-infiltrating lymphocytes (TILs).

[0051] Certain aspects of the present disclosure relate to methods of treating a tumor in a subject in need thereof, comprising administering to the subject one or more enriched T cells disclosed herein.

[0052] Certain aspects of the present disclosure relate to a method of enhancing cytotoxic T cell-mediated targeting of cancer cells in a subject suffering from cancer, comprising administering to the subject a peptide having the amino acid sequence set forth in SEQ ID NO: 13.

[0053] Certain aspects of the present disclosure relate to a cancer vaccine comprising a peptide having the amino acid sequence set forth in SEQ ID NO:13.

[0054] Certain embodiments of the present disclosure relate to methods of selecting T cells capable of targeting tumor cells, comprising contacting a population of in vitro isolated T cells with a peptide consisting of the amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the T cells are tumor-infiltrating lymphocytes (TILs). In certain embodiments, for example, the following items are provided: (Item 1) (i) a first nucleotide sequence encoding a recombinant T cell receptor (TCR) or antigen-binding portion thereof that specifically binds 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; A nucleic acid molecule wherein the anti-MUC5AC TCR cross-competes for binding to human MUC5AC with a reference TCR comprising an alpha chain and a beta chain, wherein the alpha chain comprises the amino acid sequence set forth in SEQ ID NO:1 and the beta chain comprises the amino acid sequence set forth in SEQ ID NO:2. (Item 2) (i) a first nucleotide sequence encoding a recombinant T cell receptor (TCR) or antigen-binding portion thereof that specifically binds to human MUC5AC (an "anti-MUC5AC TCR"); and (ii) a second nucleotide sequence, wherein the second nucleotide sequence or the polypeptide encoded by the second nucleotide sequence inhibits expression of an endogenous TCR; A nucleic acid molecule wherein the anti-MUC5AC TCR binds to the same epitope on human MUC5AC as or an overlapping epitope with a reference TCR comprising an alpha chain and a beta chain, wherein the alpha chain comprises the amino acid sequence set forth in SEQ ID NO: 1 and the beta chain comprises the amino acid sequence set forth in SEQ ID NO: 2. (Item 3) 3. The nucleic acid molecule of item 1 or 2, wherein the anti-MUC5AC TCR binds to an epitope of MUC5AC consisting of the amino acid sequence set forth in SEQ ID NO: 13. (Item 4) 4. The nucleic acid molecule of item 2 or 3, wherein the epitope is complexed with an HLA class II molecule. (Item 5) 5. The nucleic acid molecule of item 4, wherein the HLA class II molecule is an HLA-DP, HLA-DQ, or HLA-DR allele, or any combination thereof. (Item 6) 5. The nucleic acid molecule of item 4, wherein the HLA class II molecule is an HLA-DP allele. (Item 7) 7. The nucleic acid molecule of any one of items 4 to 6, wherein the HLA class II molecule is an HLA-DP4 allele. (Item 8) the anti-MUC5AC TCR comprises an alpha chain and a beta chain; the alpha chain comprises a variable region comprising alpha chain CDR1, alpha chain CDR2, and alpha chain CDR3; the beta chain comprises a variable domain comprising a beta chain CDR1, a beta chain CDR2, and a beta chain CDR3; 8. The nucleic acid molecule according to any one of items 1 to 7, wherein the alpha chain CDR3 comprises the amino acid sequence shown in SEQ ID NO:7. (Item 9) 9. The nucleic acid molecule of item 8, wherein the beta chain CDR3 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO: 10. (Item 10) the anti-MUC5AC TCR comprises an alpha chain and a beta chain, the alpha chain comprising a variable region comprising alpha chain CDR1, alpha chain CDR2, and alpha chain CDR3; the beta chain comprises a variable domain comprising a beta chain CDR1, a beta chain CDR2, and a beta chain CDR3; 8. The nucleic acid molecule of any one of items 1 to 7, wherein the beta chain CDR3 of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO: 10. (Item 11) 11. The nucleic acid molecule of item 10, wherein the alpha chain CDR3 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO:7. (Item 12) 12. The nucleic acid molecule of any one of items 8 to 11, wherein the alpha chain CDR1 of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO:5. (Item 13) 13. The nucleic acid molecule of any one of items 8 to 12, wherein the beta chain CDR1 of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO:8. (Item 14) 14. The nucleic acid molecule of any one of items 8 to 13, wherein the alpha chain CDR2 of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO:6. (Item 15) 15. The nucleic acid molecule of any one of items 8 to 14, wherein the beta chain CDR2 of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO:9. (Item 16) 16. The nucleic acid molecule of any one of items 8 to 15, wherein the alpha chain variable domain of the anti-MUC5AC TCR comprises the amino acid sequence of the variable domain present in the amino acid sequence shown in SEQ ID NO: 1. (Item 17) 17. The nucleic acid molecule of any one of items 8 to 16, wherein the beta chain variable domain of the anti-MUC5AC TCR comprises the amino acid sequence of a variable domain present in the amino acid sequence shown in SEQ ID NO: 2. (Item 18) 18. The nucleic acid molecule of any one of items 8 to 17, wherein the alpha chain of the anti-MUC5AC TCR further comprises a constant region, wherein the constant region is distinct from the endogenous constant region of the alpha chain. (Item 19) 19. The nucleic acid molecule of any one of items 8 to 18, wherein the alpha chain of the anti-MUC5AC TCR further comprises a constant region, and 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. (Item 20) 20. The nucleic acid molecule of any one of items 18 or 19, wherein the alpha chain constant region comprises an amino acid sequence containing at least one, at least two, at least three, at least four, or at least five amino acid substitutions relative to the constant region present in the alpha chain amino acid sequence set forth in SEQ ID NO:1. (Item 21) 21. The nucleic acid molecule of any one of items 8 to 20, wherein 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. (Item 22) 22. The nucleic acid molecule of any one of items 8 to 21, wherein the beta chain of the anti-MUC5AC TCR further comprises a constant region, and 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 a constant region present in the amino acid sequence set forth in SEQ ID NO:2. (Item 23) 23. The nucleic acid molecule of any one of items 21 or 22, wherein the beta chain constant region comprises an amino acid sequence containing at least one, at least two, at least three, at least four, or at least five amino acid substitutions relative to the constant region present in the amino acid chain sequence set forth in SEQ ID NO:2. (Item 24) 24. The nucleic acid molecule of any one of items 8 to 23, wherein the alpha chain of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO: 1. (Item 25) 25. The nucleic acid molecule of any one of items 8 to 24, wherein the beta chain of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO: 2. (Item 26) 26. The nucleic acid molecule of any one of items 1 to 25, wherein the second nucleotide sequence is one or more siRNAs that reduce expression of an endogenous TCR. (Item 27) 27. The nucleic acid molecule of item 26, wherein the one or more siRNAs are complementary to a target sequence within a nucleotide sequence encoding the constant region of the endogenous TCR. (Item 28) 28. The nucleic acid molecule of any one of items 26 or 27, wherein the one or more siRNAs comprise one or more nucleotide sequences selected from the group consisting of SEQ ID NOs: 25 to 28. (Item 29) 29. The nucleic acid molecule of any one of paragraphs 1 to 28, wherein 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 the target sequence relative to the corresponding amino acid sequence of an endogenous TCR. (Item 30) 30. The nucleic acid molecule of any one of items 1 to 29, wherein 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. (Item 31) 31. The nucleic acid molecule according to Item 30, wherein the signal peptide comprises an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 20 to 22 and any combination thereof. (Item 32) 32. A vector comprising the nucleic acid molecule according to any one of items 1 to 31. (Item 33) 33. The vector of item 32, which is a viral vector, a mammalian vector, or a bacterial vector. (Item 34) 34. The vector according to item 32 or 33, which is a retroviral vector. (Item 35) 34. The vector according to any one of Items 31 to 33, wherein the vector is selected from the group consisting of an adenovirus vector, a lentivirus, a Sendai virus vector, a baculovirus vector, an Epstein-Barr virus vector, a papovavirus vector, a vaccinia virus vector, a herpes simplex virus vector, a hybrid vector, and an adeno-associated virus (AAV) vector. (Item 36) 36. The vector according to any one of items 32 to 35, which is a lentivirus. (Item 37) A T cell receptor (TCR) or an antigen-binding portion thereof, comprising the alpha chain variable domain of the anti-MUC5AC TCR according to any one of items 8 to 31 and the beta chain variable domain of the anti-MUC5AC TCR according to any one of items 8 to 31. (Item 38) a recombinant T cell receptor (TCR) or antigen-binding portion thereof that specifically binds to human MUC5AC (an "anti-MUC5AC TCR") and cross-competes with a reference TCR for binding to human MUC5AC; said reference TCR comprising an alpha chain and a beta chain, said alpha chain comprising the amino acid sequence set forth in SEQ ID NO: 1 and said beta chain comprising the amino acid sequence set forth in SEQ ID NO: 2; said anti-MUC5AC TCR comprising an alpha chain and a beta chain, said alpha chain comprising a constant region and said beta chain comprising a constant region; (i) the alpha chain constant region comprises an amino acid sequence having at least one, at least two, at least three, at least four, or at least five amino acid substitutions relative to the constant region present in the amino acid sequence set forth in SEQ ID NO:1; or (ii) the beta chain constant region comprises an amino acid sequence having at least one, at least two, at least three, at least four, or at least five amino acid substitutions relative to the constant region present in the amino acid sequence of SEQ ID NO:2; The recombinant T cell receptor (TCR) or an antigen-binding portion thereof. (Item 39) a recombinant T cell receptor (TCR) or antigen-binding portion thereof that specifically binds to human MUC5AC (an "anti-MUC5AC TCR"), which binds to the same epitope on human MUC5AC as, or an overlapping epitope with, the reference TCR; said reference TCR comprises an alpha chain and a beta chain, said alpha chain comprising the amino acid sequence set forth in SEQ ID NO:1 and said beta chain comprising the amino acid sequence set forth in SEQ ID NO:2; and said anti-MUC5AC TCR comprises an alpha chain and a beta chain, said alpha chain comprising a constant region and said beta chain comprising a constant region; (i) the alpha chain constant region comprises an amino acid sequence having at least one, at least two, at least three, at least four, or at least five amino acid substitutions relative to the constant region present in the amino acid sequence set forth in SEQ ID NO:1; or (ii) the beta chain constant region comprises an amino acid sequence having at least one, at least two, at least three, at least four, or at least five amino acid substitutions relative to the constant region present in the amino acid sequence set forth in SEQ ID NO:2; The recombinant T cell receptor (TCR) or an antigen-binding portion thereof. (Item 40) 40. The anti-MUC5AC TCR of any one of items 38 or 39, which binds to an epitope of MUC5AC consisting of the amino acid sequence set forth in SEQ ID NO: 13. (Item 41) 41. The anti-MUC5AC TCR of any one of items 39 or 40, wherein the epitope is complexed with an HLA class II molecule. (Item 42) 43. The anti-MUC5AC TCR of item 42, wherein the HLA class II molecule is an HLA-DP, HLA-DQ, or HLA-DR allele, or any combination thereof. (Item 43) 44. The anti-MUC5AC TCR of any one of items 42 or 43, wherein the HLA class II molecule is an HLA-DP allele. (Item 44) 45. The anti-MUC5AC TCR of any one of items 42 to 44, wherein the HLA class II molecule is selected from the HLA-DP4 allele. (Item 45) 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; 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; 45. The anti-MUC5AC TCR of any one of items 38 to 44, wherein the alpha chain CDR3 of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO:7. (Item 46) 46. ​​The anti-MUC5AC TCR of item 45, wherein the beta chain CDR3 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO: 10. (Item 47) 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; 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 45. The anti-MUC5AC TCR of any one of items 38 to 44, wherein the beta chain CDR3 of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO: 10. (Item 48) 48. The anti-MUC5AC TCR of item 47, wherein the alpha chain CDR3 of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO:7. (Item 49) 49. The anti-MUC5AC TCR of item 48, wherein the alpha chain CDR1 of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO:5. (Item 50) 50. The anti-MUC5AC TCR of any one of items 45 to 49, wherein the beta chain CDR1 of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO:8. (Item 51) 51. The anti-MUC5AC TCR of any one of items 45 to 50, wherein the alpha chain CDR2 of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO:6. (Item 52) 52. The anti-MUC5AC TCR of any one of items 45 to 51, wherein the beta chain CDR2 of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO:9. (Item 53) 53. The anti-MUC5AC TCR of any one of Items 45 to 52, wherein the alpha chain variable domain of the anti-MUC5AC TCR comprises the amino acid sequence of the variable domain present in the amino acid sequence shown in SEQ ID NO: 1. (Item 54) 54. The anti-MUC5AC TCR of any one of Items 45 to 53, wherein the beta chain variable domain of the anti-MUC5AC TCR comprises the amino acid sequence of the variable domain present in the amino acid sequence shown in SEQ ID NO:2. (Item 55) 55. The anti-MUC5AC TCR of any one of items 38 to 54, 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 the amino acid sequence of the constant region present in the amino acid sequence shown in SEQ ID NO: 1. (Item 56) 56. The anti-MUC5AC TCR of any one of Items 38 to 55, 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 amino acid sequence of the constant region present in the amino acid sequence set forth in SEQ ID NO:2. (Item 57) 57. The anti-MUC5AC TCR of any one of items 38 to 56, wherein the alpha chain of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO: 1. (Item 58) 58. The anti-MUC5AC TCR of any one of items 38 to 57, wherein the beta chain of the anti-MUC5AC TCR comprises the amino acid sequence shown in SEQ ID NO:2. (Item 59) 59. The anti-MUC5AC TCR of any one of items 38 to 58, wherein 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. (Item 60) 60. The anti-MUC5AC TCR according to Item 59, wherein the signal peptide comprises an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 20 to 22 and any combination thereof. (Item 61) 61. A bispecific TCR comprising a first antigen-binding domain and a second antigen-binding domain, wherein the first antigen-binding domain comprises the TCR or antigen-binding portion thereof according to Aspect 37, or the TCR or antigen-binding portion thereof according to any one of Aspects 38 to 60. (Item 62) 62. The bispecific TCR of claim 61, wherein the first antigen-binding domain comprises a single-chain variable fragment ("scFv"). (Item 63) 63. The bispecific TCR of any one of items 61 or 62, wherein the second antigen-binding domain specifically binds to a protein expressed on the surface of a T cell. (Item 64) 64. The bispecific TCR according to any one of items 61 to 63, wherein the second antigen-binding domain specifically binds to CD3. (Item 65) 65. The bispecific TCR according to any one of items 61 to 64, wherein the second antigen-binding domain comprises an scFv. (Item 66) 66. The bispecific TCR according to any one of items 61 to 65, wherein the first antigen-binding domain and the second antigen-binding domain are linked or bound by a covalent bond. (Item 67) 67. The bispecific TCR according to any one of items 61 to 66, wherein the first antigen-binding domain and the second antigen-binding domain are linked by a peptide bond. (Item 68) A cell comprising the nucleic acid molecule of any one of Items 1 to 31, the vector of any one of Items 32 to 36, the TCR of Item 37, the recombinant TCR of any one of Items 38 to 60, or the bispecific TCR of any one of Items 61 to 67. (Item 69) 69. The cell of item 68, which further expresses CD3. (Item 70) 70. The cell of item 68 or 69, selected from the group consisting of a T cell, a natural killer (NK) cell, a natural killer T (NKT) cell, or an ILC cell. (Item 71) 71. A method for treating cancer in a subject in need thereof, comprising administering to the subject the cells according to any one of items 68 to 70. (Item 72) Item 72. The method according to item 71, wherein 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, gastric cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, cervical cancer, 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, and cancer of the penis. the cancer is selected from the group consisting of cancer, chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) (including non-T-cell ALL), chronic lymphocytic leukemia (CLL), childhood solid tumors, lymphocytic lymphoma, bladder cancer, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, other B-cell malignancies, and combinations of the foregoing cancers. (Item 73) 73. The method of any one of items 71 or 72, wherein the cancer is refractory or recurrent. (Item 74) 74. The method of any one of items 71 to 73, wherein the cancer is locally advanced. (Item 75) 75. The method according to any one of items 71 to 74, wherein the cancer is advanced. (Item 76) 76. The method of any one of items 71 to 75, wherein the cancer is metastatic. (Item 77) 77. The method of any one of items 71 to 76, wherein the cells are obtained from the subject. (Item 78) 78. The method of any one of items 71 to 77, wherein the cells are obtained from a donor other than the subject. (Item 79) 79. The method of any one of items 71 to 78, wherein the subject is preconditioned prior to administration of the cells. (Item 80) 80. The method of claim 79, wherein the preconditioning comprises administering to the subject chemotherapy, cytokines, proteins, small molecules, or any combination thereof. (Item 81) 81. The method of item 79 or 80, wherein the preconditioning comprises administering an interleukin. (Item 82) 82. The method of any one of items 79 to 81, wherein the preconditioning comprises administering IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, or any combination thereof. (Item 83) 83. The method of any one of items 79 to 82, wherein the preconditioning comprises administering a preconditioning agent selected from the group consisting of cyclophosphamide, fludarabine, vitamin C, an AKT inhibitor, ATRA, rapamycin, or any combination thereof. (Item 84) 84. The method of any one of items 79 to 83, wherein the preconditioning comprises administering cyclophosphamide, fludarabine, or both. (Item 85) 37. A method for engineering antigen-targeted cells, comprising transducing cells collected from a subject in need of T cell therapy with the nucleic acid molecule of any one of items 1 to 31 or the vector of any one of items 32 to 36. (Item 86) 86. The method of claim 85, wherein the antigen-targeted cells further express CD4. (Item 87) 87. The method of any one of paragraphs 85 or 86, wherein the cell is a T cell or a natural killer (NK) cell. (Item 88) An HLA class II molecule complexed with a peptide, the HLA class II molecule comprising an alpha chain and a beta chain, and the peptide consisting of the amino acid sequence shown in SEQ ID NO: 13. (Item 89) 89. The HLA class II molecule of item 88, which is an HLA-DP, HLA-DQ, or HLA-DR allele, or any combination thereof. (Item 90) 90. The HLA class II molecule of any one of items 88 or 89, which is an HLA-DP allele. (Item 91) 87. The HLA class II molecule of any one of items 85 or 86, which is an HLA-DQ allele. (Item 92) 87. The HLA class II molecule of any one of items 85 or 86, which is an HLA-DR allele. (Item 93) 93. The HLA class II molecule of any one of items 88 to 92, which is a monomer. (Item 94) 93. The HLA class II molecule of any one of items 88 to 92, which is a dimer. (Item 95) 93. The HLA class II molecule of any one of items 88 to 92, which is a trimer. (Item 96) 93. The HLA class II molecule of any one of items 88 to 92, which is a tetramer. (Item 97) 93. The HLA class II molecule of any one of items 88 to 92, which is a pentamer. (Item 98) An antigen-presenting cell (APC) comprising the HLA class II molecule according to any one of items 88 to 97. (Item 99) 99. The APC of item 98, wherein the HLA class II molecule is expressed on the surface of the APC. (Item 100) 10. A method for enriching a target population of T cells obtained from a human subject, the method comprising contacting the T cells with an HLA class II molecule according to any one of items 88 to 97 or an APC according to item 98 or 99, wherein after said contacting, the enriched T cell population comprises a greater number of T cells capable of binding to HLA class II molecules relative to the number of T cells capable of binding to HLA class II molecules before said contacting. (Item 101) 1. A method for enriching a target population of T cells obtained from a human subject, comprising 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, and wherein following said contacting, the enriched T cell population comprises a greater number of T cells capable of targeting tumor cells relative to the number of T cells capable of targeting tumor cells prior to said contacting. (Item 102) 102. The method of any one of paragraphs 100 or 101, wherein the T cells obtained from the human subject are tumor-infiltrating lymphocytes (TILs). (Item 103) 103. A method of treating a tumor in a subject in need thereof, comprising administering to said subject the enriched T cells according to any one of items 100 to 102. (Item 104) A method for enhancing cytotoxic T cell-mediated targeting of cancer cells in a subject suffering from cancer, comprising administering to the subject a peptide having the amino acid sequence set forth in SEQ ID NO: 13. (Item 105) A cancer vaccine comprising a peptide having the amino acid sequence shown in SEQ ID NO:13. (Item 106) A method for selecting T cells capable of targeting tumor cells, comprising contacting an isolated population of T cells in vitro with a peptide consisting of the amino acid sequence set forth in SEQ ID NO: 13. (Item 107) 107. The method of claim 106, wherein the T cells are tumor-infiltrating lymphocytes (TILs). [Brief explanation of the drawings]

[0055] [Figure 1] (A-B) Graphical representation of DP4L112W / V141M dimer staining of peptide-specific CD4+ T cells from melanoma patients. Primary CD4+ T cells were purified from six DP4+ melanoma patients, stimulated with DP4-expressing aAPCs individually pulsed with MUC5AC4922-4941 peptide, and stained with the cognate DP4L112W / V141M dimer. Examples of DP4L112W / V141M dimer staining are shown. [Figure 2](A-D) Graphical representation of data showing that the DP4-restricted (05-MUC5AC4922-4941) TCR isolated from DP4L112W / V141M dimer-positive cells and reconstituted in human TCR-deficient CD4+ T cells functioned in a DP4-restricted and antigen-specific manner. 05-MUC5AC4922-4941 was cloned from DP4L112W / V141M dimer-positive cells, reconstituted in TCR-deficient Jurkat 76 / CD4 cells, and stained with the respective DP4L112W / V141M dimer. [Figure 3] 1 is a bar graph showing the results of an IL-2 ELISPOT assay of 05-MUC5AC4922-4941 stimulated by aAPCs pulsed with MUC5AC4922-4941 peptide. DP4 / WT1 (clone 9) TCR was used as a negative control. At least two independent experiments were performed. Bars and error bars represent the mean ± SD of the results of three experiments. [Figure 4-1] (A-E) Graphical representation of data showing that the DP4-restricted MUC5AC4922-4941 TCR isolated from DP4L112W / V141M dimer-positive cells and reconstituted with human primary CD4+ T cells functioned in a DP4-restricted and antigen-specific manner. 05-MUC5AC4922-4941 was retrovirally transduced into human primary CD4+ T cells and stained with the respective DP4L112W / V141M dimer. *P<0.05 by Student's t-test. Bars and error bars represent the mean ± SD of triplicate experiments (Figure 4E). [Figure 4-2] (A-E) Graphical representation of data showing that the DP4-restricted MUC5AC4922-4941 TCR isolated from DP4L112W / V141M dimer-positive cells and reconstituted with human primary CD4+ T cells functioned in a DP4-restricted and antigen-specific manner. 05-MUC5AC4922-4941 was retrovirally transduced into human primary CD4+ T cells and stained with the respective DP4L112W / V141M dimer. *P<0.05 by Student's t-test. Bars and error bars represent the mean ± SD of triplicate experiments (Figure 4E). [Figure 5] 1 is a bar graph showing the results of an IFN-γ ELISPOT assay of human primary T cells retrovirally transduced with 05-MUC5AC4922-4941 and stimulated with peptide-unpulsed HLA-null, or DP4-aAPCs transduced with the MUC5AC4922-4941 minigene (MHYQCQCVCSGW GDPHYITFDGTYYTFLDNCTYVLVQ; SEQ ID NO: 29). *, P<0.05 by Student's t-test. Bars and error bars represent the mean ± SD of the results of three experiments. DETAILED DESCRIPTION OF THE INVENTION

[0056] The present disclosure relates to a TCR or antigen-binding portion thereof that specifically binds to an epitope on MUC5AC, a nucleic acid molecule encoding the same, and a cell comprising the TCR or the nucleic acid molecule. Some aspects of the disclosure relate to a method of treating cancer in a subject in need thereof, comprising administering the cells to the subject. Another aspect of the disclosure relates to an HLA class II molecule complexed with a peptide comprising an epitope of MUC5AC.

[0057] I. Terminology In order that this disclosure may be more readily understood, certain terms are first defined. As used in this application, unless otherwise stated herein, each of the following terms shall have the meaning indicated below. Additional definitions are set forth throughout this application.

[0058] It should be noted that the term "a" or "an" entity refers to one or more of that entity; for example, "a nucleotide sequence" is understood to represent one or more nucleotide sequences. Thus, the terms "a" (or "an"), "one or more," and "at least one" may be used interchangeably herein.

[0059] Furthermore, when used herein, "and / or" shall be construed as a specific disclosure of each of two particular features or components, with or without the other. Thus, the term "and / or" when used in phrases such as "A and / or B" is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, when used in phrases such as "A, B, and / or C," the term "and / or" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0060] The term "about" is used herein to mean approximately, roughly, roughly, or roughly. 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. In general, the term "about" is used herein to modify numerical values ​​above and below the stated value, by a variance of 10%, above or below (greater than or less than).

[0061] Whenever an embodiment is described herein with the word "comprising," it is to be understood that other similar embodiments described with the terms "consisting of" and / or "consisting essentially of" are also provided.

[0062] 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 pertains. 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 those skilled in the art with a general dictionary of many of the terms used in this disclosure.

[0063] Units, prefixes, and symbols are shown in their International System of Units (SI) accepted format. Numerical 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 carboxy orientation. The headings provided herein are not intended to limit the various aspects of the disclosure, which can be had by reference to the specification in its entirety. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0064] "Administering" refers to the physical introduction of a factor into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Exemplary routes of administration of the formulations disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, for example, by injection or infusion. The phrase "parenteral administration," as used herein, refers to a method of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intrathecal, epidural, and intrasternal injection and infusion, and in vivo electroporation. In some embodiments, the formulation is administered via a non-parenteral route, for example, orally. Other non-parenteral routes include topical, epithelial, or mucosal routes of administration, such as intranasally, intravaginally, rectally, sublingually, or topically, and administration can be, for example, single, multiple, and / or over one or more extended periods of time.

[0065] The term "T cell receptor" (TCR) as used herein refers to a heteromeric cell surface receptor that can specifically interact 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 of antigen-presenting cells (APCs). Antigen-presenting cells (APCs) display fragments of foreign proteins (antigens) complexed with major histocompatibility complexes (MHCs; also referred to herein as complexed with HLA molecules, e.g., HLA class II molecules). TCRs recognize and bind peptide:HLA complexes, recruiting CD8 (for MHC class I molecules) or CD4 (for MHC class II molecules) to activate the TCR. Activated TCRs initiate downstream signaling and immune responses, including the destruction of EPCs.

[0066] Generally, a TCR may comprise two chains, an alpha chain and a beta chain (or less commonly, a gamma chain and a delta chain), interconnected by disulfide bonds. Each chain comprises a variable domain (an alpha chain variable domain and a beta chain variable domain) and a constant region (an alpha chain constant region and a beta chain constant region). The variable domains are located distal to the cell membrane, and the variable domains interact with antigen. The constant regions are located proximal to the cell membrane. A TCR may further comprise a transmembrane region and a short cytoplasmic tail. As used herein, the term "constant region" encompasses the transmembrane region and cytoplasmic tail, if present, as well as the conventional "constant region."

[0067] The variable domains can be further subdivided into regions of hypervariability called complementarity-determining regions (CDRs), which are flanked by more conserved regions called framework regions (FRs). Each alpha and beta chain variable domain contains three CDRs and four FRs (FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4). Each variable domain contains a binding domain that interacts with an antigen. All three CDRs in each chain are involved in antigen binding, although CDR3 is considered to be the primary antigen-binding region, while CDR1 and CDR2 are thought to primarily recognize HLA molecules.

[0068] Unless explicitly stated, and unless the context dictates otherwise, the term "TCR" also includes antigen-binding fragments or portions of any TCR disclosed herein, including monovalent and bivalent fragments or portions, and single-chain TCRs. The term "TCR" is not limited to naturally occurring TCRs bound to the surface of T cells. As used herein, the term "TCR" further refers to a TCR 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 described herein that does not include a cell membrane (e.g., an isolated TCR or a soluble TCR).

[0069] "Antigen-binding molecule," "portion of a TCR," or "TCR fragment" refers to any portion of a TCR that is less than the entire TCR. An antigen-binding molecule may include antigenic CDRs.

[0070] "Antigen" refers to any molecule, e.g., a peptide, that can elicit an immune response or be bound by a TCR. As used herein, "epitope" refers to a portion of a polypeptide that can elicit an immune response or be bound by a TCR. The immune response may include antibody production, activation of specific immunologically competent cells, or both. Those skilled in the art will readily understand that virtually any macromolecule, including any protein or peptide, can function as an antigen. Antigens and / or epitopes can be endogenously expressed, i.e., expressed by genomic DNA, or recombinantly expressed. Antigens and / or epitopes can be specific to a particular tissue, such as cancer cells, or they can be broadly expressed. Furthermore, fragments of larger molecules can function as antigens. In one embodiment, the antigen is a tumor antigen. An epitope can be present on a longer polypeptide (e.g., a protein), or it can exist as a fragment of a longer polypeptide. In some embodiments, the epitope is complexed with a major histocompatibility complex (MHC; also referred to herein as complexed with an HLA molecule, e.g., an HLA class 1 molecule).

[0071] As used herein, "MUC5AC" or "mucin 5AC" refers to a human gel-forming glycoprotein in the gastric and respiratory epithelium that protects the mucosa from infection and chemical damage by binding to inhaled microorganisms and particles, which are then removed by the mucosal system.

[0072] As used herein, MUC5AC refers to the full-length canonical sequence as well as variants and fragments thereof. The amino acid sequence of MUC5AC (SEQ ID NO: 16) is shown in Table 1 (UniProtKB-P98088). [Table 1]

[0073] The term "HLA" as used herein refers to human leukocyte antigens. HLA genes encode human major histocompatibility complex (MHC) proteins. MHC proteins are expressed on the surface of cells and are involved in activating immune responses. HLA class II genes encode MHC class II proteins 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 after inflammatory signals are activated. Humans lacking functional MHC class II molecules are highly susceptible to a range of infectious diseases and usually die at a young age.

[0074] 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 an 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, naturally occurring alpha and beta chains each contain a transmembrane domain that anchors the alpha / beta chain to the cell surface and a transmembrane domain that carries antigen and interacts with TCR and / or CD4 expressed on T cells.

[0075] Both MHC class II alpha and beta chains are encoded by the HLA gene complex. The HLA complex is located in the 6p21.3 region of the short arm of human chromosome 6 and contains more than 220 genes of diverse functions. The HLA gene complex is highly diverse, with more than 20,000 HLA alleles and associated alleles, including more than 250 MHC class II alpha chain alleles and more than 5,000 MHC class II beta chain alleles known in the art that encode thousands of MHC class II proteins (see, e.g., hla.alleles.org, last accessed May 20, 2019, incorporated herein by reference). For example, one such HLA-DP allele, DP4, is the most frequently occurring allele in many ethnic groups.

[0076] 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 bind to MHC class II molecules and support their organization and function.

[0077] When MHC class II molecules form a complex with an antigenic peptide, the 10-30 amino acid long antigenic peptide binds to 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 alpha polypeptides, and beta-1 and beta-2 for beta polypeptides). An open-ended peptide-binding groove that holds the presented antigen is found between the alpha-1 and beta-1 domains. Upon interaction with CD4+ T cells, the MHC class II complex interacts with the T cell receptor (TCR) expressed on the surface of the T cell. Furthermore, the beta chain of the MHC class II molecule weakly interacts with CD4 expressed on the surface of the T cell (K). D >2mM). The standard CD4 amino acid sequence (UniProt-P01730) is shown in Table 2 (SEQ ID NO: 17). [Table 2]

[0078] The term "autologous" refers to any material derived from the same individual that is subsequently reintroduced into the individual. For example, autologous T cell therapy involves administering T cells isolated from the same subject to a subject. The term "allogeneic" refers to any material derived from one individual that is then introduced into another individual of the same species. For example, allogeneic T cell transplantation involves administering T cells obtained from a donor other than the subject to a subject.

[0079] "Cancer" refers to a broad group of diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and growth can lead to the formation of malignant tumors that invade adjacent tissues and may metastasize to distant parts of the body through the lymphatic system or bloodstream. "Cancer" or "cancerous tissue" can include tumors. Examples of cancers that can be treated by the methods of the present invention include, but are not limited to, cancers of the immune system, including lymphomas, leukemias, and other white blood cell malignancies. In some embodiments, the methods of the present invention are directed to the treatment of cancers of, for example, bone cancer, kidney cancer, prostate cancer, breast cancer, colon cancer, lung cancer, cutaneous or intraocular malignant melanoma, 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, cancer of the fallopian tubes, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, 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), cancer of the esophagus, 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, cancer of soft tissue It may be used to reduce tumor size in tumors resulting from sarcoma, 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), childhood solid tumors, lymphocytic lymphoma, bladder cancer, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers, including those induced by asbestos, other B-cell malignancies, and combinations of the above cancers. Certain cancers may respond to chemotherapy or radiation therapy, or the cancer may be refractory.

[0080] Refractory cancer refers to cancer that cannot be cured by surgical intervention, the cancer does not respond initially to chemotherapy or radiation therapy, or the cancer becomes unresponsive over time.

[0081] As used herein, "anti-tumor effect" refers to a biological effect that can manifest as 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 survival or progression-free survival, an increase in life expectancy, or an improvement in various physiological symptoms associated with tumors.Anti-tumor effect can also refer to the prevention of tumor development, for example, vaccination.

[0082] The term "progression-free survival," sometimes abbreviated as PFS, as used herein, refers to the time from the date of treatment to the date of disease progression according to the revised IWG Response Criteria for Malignant Lymphoma or death from any cause.

[0083] As used herein, "disease progression" or "progressive disease," which may be abbreviated as PD, refers to the worsening of one or more symptoms associated with a particular disease. For example, disease progression in a subject with cancer may include an increase in the number or size of one or more malignant lesions, tumor metastasis, and death.

[0084] "Duration of response," which may be abbreviated as DOR, as used herein, refers to the time from a subject's first objective response to the date of confirmed disease progression according to the revised IWG Response Criteria for Malignant Lymphoma, or death.

[0085] The term "overall survival," which may be abbreviated as OS, is defined as the time from the date of treatment to the date of death.

[0086] As used herein, a "cytokine" is a non-antibody protein released by one cell in response to contact with a specific antigen, which interacts with a second cell and mediates a response in the second cell. Cytokines may be endogenously expressed by a cell or administered to a subject. Cytokines may be released from immune cells, such as macrophages, B cells, T cells, and mast cells, to propagate an immune response. Cytokines may induce various responses in recipient cells. Cytokines may include homeostatic cytokines, chemokines, proinflammatory cytokines, effector, and acute phase proteins. For example, homeostatic cytokines, such as interleukin (IL) 7 and IL-15, promote immune cell survival and proliferation, and proinflammatory cytokines may 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-1a, IL-1b, 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 placenta 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).

[0087] A "chemokine" is a type of cytokine that mediates chemotaxis, or directional 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 chemoattractant protein 1 (MCP-1 or CCL2), MCP-4, macrophage inflammatory protein 1 alpha (MIP-1α, MIP-1a), MIP-1 beta (MIP-1b), gamma-inducible protein 10 (IP-10), and thymus and activation-regulated chemokine (TARC or CCL17).

[0088] 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 chemoattractant 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), proliferation-inducing ligand (APRIL), CD70, CD153, CD178, glucocorticoid-induced TNFR-related ligand (GITRL), tumor necrosis factor superfamily member 14 (TNFSF14), OX40L, TNF- and ApoL-related leukocyte-expressed ligand 1 (TALL-1), or TNF-related apoptosis-inducing ligand (TRAIL).

[0089] A "therapeutically effective amount," "effective dose," "effective amount," or "therapeutically effective dosage" of a drug or therapeutic agent is any amount of drug that, when used alone or in combination with another therapeutic agent, protects a subject against disease manifestations or promotes disease regression as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of symptom-free periods of the disease, or prevention of impairment or disability due to disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated 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 assaying the activity of the agent in in vitro assays.

[0090] As used herein, the term "lymphocyte" includes natural killer (NK) cells, T cells, or B cells. NK cells are a type of cytotoxic (cytotoxic) lymphocyte and a major component of the innate immune system. NK cells reject tumor- and virus-infected cells. They function through the process of apoptosis, or programmed cell death. They were called "natural killers" because they do not require activation to kill cells. T cells play a major role in cell-mediated immunity (without the involvement of antibodies). T cell receptors (TCRs) distinguish 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: helper T cells (e.g., CD4+ cells), cytotoxic T cells (TCs, also known as cytotoxic T lymphocytes, CTLs, T killer cells, cytotoxic T cells, CD8+ T cells, or killer T cells), memory T cells ((i) stem memory T cells such as naive cells), and (ii) naive T cells. SCM The cells are CD45RO-, CCR7+, CD45RA+, CD62L+ (L-selectin), CD27+, CD28+, and IL-7Rα+, but they also express large amounts of CD95, IL-2Rβ, CXCR3, and LFA-1, exhibiting many functional attributes characteristic of memory cells; (ii) central memory T CMThe cells express L-selectin and CCR7 and secrete IL-2 but not IFNγ or IL-4, and (iii) effector memory T EM These include T cells (which do not express L-selectin or CCR7 but produce effector cytokines such as IFNγ and IL-4), regulatory T cells (Tregs, suppressor T cells, or CD4+CD25+ regulatory T cells), natural killer T cells (NKT), and gamma delta T cells. B cells, on the other hand, play a major role in humoral immunity (involving antibodies). B cells produce antibodies and antigens, act as antigen-presenting cells (APCs), and transform into memory B cells after activation by antigen interaction. In mammals, immature B cells are formed in the bone marrow, hence their name.

[0091] The term "genetically engineered" or "engineered" refers to methods of modifying the genome of a cell, including, but not limited to, deleting coding or non-coding regions or portions thereof, or inserting coding regions or portions thereof. In some embodiments, the modified cells are lymphocytes, e.g., T cells or modified cells that express CD4, which can be obtained from either a patient or a donor. The cells can be modified to express an exogenous construct, such as a T cell receptor (TCR) disclosed herein, that is integrated into the genome of the cell. In some embodiments, the cells are modified to express CD4.

[0092] "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 antibodies (Abs), cytokines, and complement) produced by any of these cells or the liver that result in the elimination of invading pathogens from the body of a vertebrate and / or the selective targeting, binding, damage, and destruction of pathogen-infected cells or tissues, cancer cells or other abnormal cells, or, in the case of autoimmunity or pathological inflammation, normal human cells or tissues.

[0093] The term "immunotherapy" refers to the treatment of a subject suffering from a disease or at risk of suffering from or recurring with a disease by methods involving inducing, enhancing, suppressing, or otherwise modifying the immune response. Examples of immunotherapy include, but are not limited to, T cell therapy. T cell therapy includes adoptive T cell therapy, tumor infiltrating lymphocyte (TIL) immunotherapy, autologous cell therapy, engineered autologous cell therapy (eACT), and allogeneic T cell transplantation.

[0094] Cells used in the immunotherapies described herein can be derived from sources known in the art. For example, T cells can be differentiated in vitro from a hematopoietic stem cell population, or T cells can be obtained from a subject. T cells can be obtained, for example, from peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from an infection site, ascites, pleural effusion, spleen tissue, and tumors. Furthermore, T cells can be derived from one or more T cell lines available in the art. T cells can also be obtained from a unit of blood collected from a subject using numerous techniques known to those skilled in the art, such as FICOLL™ separation and / or apheresis. Additional methods for isolating T cells for T cell therapy are disclosed in U.S. Patent Publication No. 2013 / 0287748, which is incorporated herein by reference in its entirety. Immunotherapy can also include administering modified cells to a subject, wherein the modified cells express CD4 and TCR as disclosed herein. In some embodiments, the modified cells are not T cells.

[0095] As used herein, a "patient" includes any human suffering from cancer (e.g., lymphoma or leukemia). The terms "subject" and "patient" are used interchangeably herein.

[0096] The terms "peptide," "polypeptide," and "protein" are used interchangeably and refer to compounds composed of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and there is no limit to the maximum number of amino acids that a protein or peptide sequence may contain. A polypeptide includes any peptide or protein containing two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, commonly referred to in the art as peptides, oligopeptides, and oligomers, as well as longer chains, of which there are many varieties, commonly referred to in the art as proteins. "Polypeptides" include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, and fusion proteins, among others. The polypeptide may be a natural peptide, a recombinant peptide, a synthetic peptide, or a combination thereof.

[0097] As used herein, "stimulation" refers to a primary response induced by the binding of a stimulatory molecule to its cognate ligand, which mediates a signal transduction event. A "stimulatory molecule" is a molecule on a T cell, e.g., a T cell receptor (TCR) / CD4 complex, that specifically binds to a cognate stimulatory ligand present on an antigen-presenting cell. A "stimulatory ligand" is a ligand that, when present on an antigen-presenting cell (e.g., an aAPC, a dendritic cell, a B cell, etc.), specifically binds 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, etc. Stimulatory ligands include, but are not limited to, MHC class II molecules loaded with peptides, anti-CD4 antibodies, superagonist anti-CD2 antibodies, superagonist anti-CD28 antibodies, and superagonist anti-CD3 antibodies.

[0098] The terms "conditioning" and "preconditioning" are used interchangeably herein to refer to preparing a patient in need of T cell therapy for the appropriate condition. Conditioning, as used herein, includes, but is not limited to, reducing the number of endogenous lymphocytes, removing cytokine sinks, increasing serum levels of one or more homeostatic cytokines or proinflammatory factors, enhancing effector function of T cells administered after conditioning, enhancing the activation and / or availability of antigen-presenting cells, or any combination thereof prior to T cell therapy. In one embodiment, "conditioning" comprises increasing the serum levels of one or more cytokines, e.g., interleukin 7 (IL-7), interleukin 15 (IL-15), interleukin 10 (IL-10), interleukin 5 (IL-5), gamma-inducible protein 10 (IP-10), interleukin 8 (IL-8), monocyte chemoattractant protein 1 (MCP-1), placenta 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 embodiment, "conditioning" comprises increasing the serum levels of IL-7, IL-15, IP-10, MCP-1, PLGF, CRP, or any combination thereof.

[0099] "Treatment" or "treating" a subject refers to any type of intervention or process performed on a subject, or the administration of an active agent to a subject, for the purpose of reversing, alleviating, ameliorating, inhibiting, slowing, or preventing the onset, progression, development, symptom severity, or recurrence of a symptom, complication, or condition, or biochemical manifestations associated with a disease. In one aspect, "treatment" or "treating" includes partial remission. In another aspect, "treatment" or "treating" includes complete remission.

[0100] The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives. As used herein, the indefinite article "a" or "an" should be understood to refer to "one or more" of the list or any of the listed members.

[0101] The terms "about" or "essentially comprising" refer to a value or composition that is within an acceptable error range of a particular value or composition as determined by one of ordinary skill in the art, which depends in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about" or "essentially comprising" can mean within one standard deviation or more than one standard deviation, per practice in the art. Alternatively, "about" or "essentially comprising" can mean a range of up to 10% (i.e., ±10%). For example, about 3 mg can include any number between 2.7 mg and 3.3 mg (for 10%). Furthermore, particularly with respect to biological systems or processes, the term can mean a value up to an order of magnitude or up to five times greater. When a particular value or composition is provided in this application and claims, unless otherwise specified, the meaning of "about" or "essentially comprising" should be assumed to be within an acceptable error range of that particular value or composition.

[0102] As used herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the recited range, and, where appropriate, fractions thereof (such as 1 / 10 and 1 / 100 of an integer), unless otherwise specified.

[0103] Various aspects of the invention are described in further detail in the following subsections.

[0104] II. Compositions of the Present Disclosure 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 same, and cells comprising the TCRs or nucleic acid molecules. Some aspects of the present disclosure relate to methods of treating cancer in a subject in need thereof, comprising administering to the subject cells comprising a TCR described herein. Other aspects of the present disclosure relate to epitopes of MUC5AC bound by the TCR, and HLA class II molecules complexed with peptides comprising epitopes of MUC5AC.

[0105] T cell receptors, or TCRs, are molecules found on the surface of T cells, or T lymphocytes, that are responsible for recognizing fragments of antigens as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCRs and antigenic peptides is relatively low affinity and degenerate: many TCRs recognize the same antigenic peptide, and many antigenic peptides are recognized by the same TCR.

[0106] The TCR is composed of two different protein chains (i.e., it is a heterodimer). In 95% of human T cells, the TCR is composed of an alpha (α) chain and a beta (β) chain (encoded by TRA and TRB, respectively), whereas in 5% of human T cells, the TCR is composed of a gamma and delta (γ / δ) chain (encoded by TRG and TRD, respectively). This ratio changes during ontogeny and in pathological conditions (e.g., leukemia). It also varies between species. Orthologs of four loci have been mapped in various species. Each locus can generate a variety of polypeptides with constant and variable regions.

[0107] When the TCR engages 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.

[0108] II.A. Nucleic acid molecules Certain embodiments of the present disclosure relate to nucleic acid molecules comprising: (i) a first nucleotide sequence encoding a recombinant TCR or antigen-binding portion thereof ("anti-MUC5AC TCR") that specifically binds to human MUC5AC; and (ii) a second nucleotide sequence, wherein the second nucleotide sequence, or the polypeptide encoded by the second nucleotide sequence, inhibits expression of an endogenous TCR. In some embodiments, the second nucleotide sequence is a non-naturally occurring sequence. In other embodiments, the second nucleotide sequence is synthetic. In still other embodiments, the second nucleotide sequence comprises a sequence that targets a nucleotide sequence encoding an endogenous TCR. In some embodiments, the anti-MUC5AC TCR cross-competes with a reference TCR for binding to human MUC5AC. In some embodiments, the anti-MUC5AC TCR binds to the same epitope on human MUC5AC as the reference TCR, or an overlapping epitope.

[0109] In some aspects, the reference TCR comprises an alpha chain and a beta chain; wherein the alpha chain comprises complementarity determining region 1 (CDR1), CDR2, and CDR3; and wherein the beta chain comprises CDR1, CDR2, and CDR3; and wherein the reference TCR comprises the alpha chain CDR3 set forth in SEQ ID NO:7 and the 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 the amino acid sequence set forth in SEQ ID NO:1 and the beta chain comprises the amino acid sequence set forth in SEQ ID NO:2. [Table 3-1] [Table 3-2] [Table 3-3]

[0110] II.A.1. TCR Encoded by the First Nucleotide Sequence The present disclosure relates to a TCR encoded by a 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 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. In some aspects, the anti-MUC5AC TCR comprises an alpha chain CDR3 comprising the amino acid sequence (CAFMKRAETSGSRLTF) set forth in SEQ ID NO:7. In some aspects, the anti-MUC5AC TCR comprises a beta chain CDR3 comprising the amino acid sequence (CASSYWPTRETQYF) set forth in SEQ ID NO:10. In some embodiments, the non-CDR regions of the alpha and / or beta chains are further modified, e.g., by substitution or mutation of one, two, three, four, five, or six amino acids, such that the alpha and / or beta chain is not naturally occurring. In some embodiments, the substitutions or mutations may improve the TCRs described herein in various ways, e.g., binding affinity, binding specificity, stability, viscosity, or any combination thereof.

[0111] In some embodiments, 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 the amino acid sequence (TSESNYY) set forth in SEQ ID NO: 5. In some embodiments, 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 the amino acid sequence (MNHEY) set forth in SEQ ID NO: 8.

[0112] In some embodiments, 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 the amino acid sequence (QEAYKQQN) set forth in SEQ ID NO: 6. In some embodiments, 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 the amino acid sequence (SVGEGT) set forth in SEQ ID NO: 9.

[0113] In some embodiments, 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 embodiments, 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, and this anti-MUC5AC TCR comprises an alpha chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO:7. In some embodiments, the anti-MUC5AC TCR encoded by the first nucleotide comprises an alpha chain variable domain present in the alpha chain amino acid sequence shown in SEQ ID NO:1.

[0114] In some embodiments, 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 embodiments, 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, and this anti-MUC5AC TCR comprises a beta chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, 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.

[0115] In some embodiments, 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 embodiments, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises an alpha chain constant 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 constant domain of the alpha chain amino acid sequence set forth in SEQ ID NO:1. In some embodiments, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises an alpha chain constant 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 constant region of the alpha chain amino acid sequence set forth in SEQ ID NO: 1, and the anti-MUC5AC TCR comprises an alpha chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7. In some embodiments, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises an alpha chain constant region present in the alpha chain amino acid sequence set forth in SEQ ID NO: 1. In some embodiments, the anti-MUC5AC TCR encoded by the first nucleotide sequence further comprises an alpha constant region that differs from the endogenous (e.g., naturally occurring) constant region of the alpha chain. In some embodiments, the alpha chain constant region comprises an amino acid sequence comprising at least one, at least two, at least three, at least four, or at least five 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.

[0116] In some embodiments, 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 embodiments, 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, and this anti-MUC5AC TCR comprises a beta chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, 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 embodiments, the anti-MUC5AC TCR encoded by the first nucleotide sequence further comprises a beta constant region that differs from the endogenous, e.g., naturally occurring, constant region of the beta chain. In some embodiments, the beta chain constant region comprises an amino acid sequence that comprises at least one, at least two, at least three, at least four, or at least five 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.

[0117] In certain embodiments, 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 embodiments, 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, and this anti-MUC5AC TCR comprises an alpha chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7. In some embodiments, 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.

[0118] In certain embodiments, 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 embodiments, 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 the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises a beta chain comprising the amino acid sequence set forth in SEQ ID NO:2.

[0119] In some embodiments, the anti-MUC5AC TCR encoded by the first nucleotide sequence comprises an alpha chain constant region, a beta chain constant region, or both; wherein the alpha chain constant region, the beta chain constant region, or both comprises an amino acid sequence having at least 1, at least 2, at least 3, at least 4, or at least 5 substitutions in the target sequence relative to the corresponding amino acid sequence of the endogenous TCR.

[0120] In some embodiments, the alpha chain of the anti-MUC5AC TCR encoded by the first nucleotide sequence further comprises a signal peptide. Any signal peptide may be used in the anti-CCDN1 TCR alpha chain disclosed herein. In some embodiments, the signal peptide is a naturally occurring TCR alpha chain signal peptide. In some embodiments, 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 embodiments, the signal peptide is a heterologous signal peptide, e.g., a signal peptide derived from a protein other than the TCR alpha chain. In some embodiments, the signal peptide is a synthetic signal peptide. In some embodiments, 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 embodiments, the alpha chain of the MUC5AC TCR encoded by the first nucleotide sequence does not comprise a signal peptide.

[0121] In some embodiments, the alpha chain signal peptide 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.

[0122] In some embodiments, the beta chain of the anti-MUC5AC TCR encoded by the first nucleotide sequence further comprises a signal peptide. Any signal peptide may be used in the anti-MUC5AC TCR beta chain disclosed herein. In some embodiments, the signal peptide is a naturally occurring TCR beta chain signal peptide. In some embodiments, 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 embodiments, the signal peptide is a heterologous signal peptide, for example, a signal peptide derived from a protein other than the TCR beta chain. In some embodiments, the signal peptide is a synthetic signal peptide. In some embodiments, 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 embodiments, the beta chain of the MUC5AC TCR encoded by the first nucleotide sequence does not comprise a signal peptide.

[0123] In some embodiments, the beta chain signal peptide 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.

[0124] In some aspects, each of the alpha and beta chains 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.

[0125] II.A.2. Epitopes In some embodiments, the anti-MUC5AC TCR encoded by the first nucleotide sequence binds to the same epitope as the reference TCR. In some embodiments, 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 embodiments, the anti-MUC5AC TCR binds to an epitope of MUC5AC consisting of the amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the epitope is amino acid residues 219-238 of MUC5AC (SEQ ID NO: 16), e.g., "MUC5AC 4922-4941 "

[0126] In certain embodiments, an epitope is a portion of a larger polypeptide, such as a peptide comprising the epitope sequence and (i) one or more additional amino acids at the N-terminus of the epitope sequence and / or (ii) one or more additional amino acids at the C-terminus of the epitope sequence. In some embodiments, 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 embodiments, a polypeptide comprising an 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.

[0127] In certain embodiments, a 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, or at least about 15 additional amino acids N-terminal to the epitope. In certain embodiments, a polypeptide comprising the 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, or at least about 15 additional amino acids C-terminal to the epitope.

[0128] In certain embodiments, the epitope is complexed with an HLA class II molecule. The human leukocyte antigen (HLA) system (human major histocompatibility complex [MHC]) is an important part of the immune system and is controlled by genes located on chromosome 6. It encodes cell surface molecules specialized for presenting antigenic peptides to the T cell receptor (TCR) on T cells. (See also Overview of the Immune System.) MHC molecules that present antigens (Ags) are divided into two major classes: class I MHC molecules and class II MHC molecules.

[0129] Class II MHC molecules are present as transmembrane glycoproteins on the surface of professional antigen-presenting cells (APCs). Intact class II molecules consist of an alpha chain and a beta chain. The gene encoding the alpha chain of MHC II class molecules consists of five exons, and the gene encoding the beta chain consists of six exons. Exon 1 encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, and exons 4 and 5 contribute to the transmembrane domains and cytoplasmic tails of the alpha and beta subunits, respectively. Three loci in the HLA complex encode MHC class II proteins: HLA-DR, HLA-DQ, and HLA-DP. T cells expressing CD4 molecules react with class II MHC molecules. These lymphocytes often have cytotoxic functions, activating responses to eliminate self-cells infected with intracellular pathogens or destroy extracellular parasites. Only professional antigen-presenting cells (APCs) express class II MHC molecules, and therefore only these cells present antigens to CD4 T cells (CD4 binds to the non-polymorphic portions of the alpha2 and beta2 domains of the alpha and beta chains of MHC class II molecules, respectively).

[0130] In some embodiments, the HLA class II alpha and beta chains are selected from HLA-DR, HLA-DP, and HLA-DQ alleles. In particular embodiments, the HLA class II alpha chain is an HLA-DR alpha chain. In some embodiments, the HLA class II beta chain is an HLA-DR beta chain. In particular embodiments, the HLA class II alpha chain is an HLA-DP alpha chain. In some embodiments, the HLA class II beta chain is an HLA-DP beta chain. In particular embodiments, the HLA class II alpha chain is an HLA-DQ alpha chain. In some embodiments, the HLA class II beta chain is an HLA-DQ beta chain.

[0131] Many HLA-DR, HLA-DP, and HLA-DQ alleles are known in the art, and any of the known alleles may be used in the present disclosure. An up-to-date listing of HLA alleles is available at hla.alleles.org / (last visited June 18, 2019), which is incorporated herein by reference in its entirety.

[0132] II.A.3 Second Nucleotide Sequence The second nucleotide sequence of the nucleic acid molecule disclosed herein may be any sequence or may encode any polypeptide capable of inhibiting expression of an endogenous TCR. In some embodiments, the second nucleotide sequence is one or more siRNAs. In some embodiments, the one or more siRNAs are complementary to a target sequence within the nucleotide sequence encoding the constant region of an endogenous TCR. In certain embodiments, the one or more siRNAs are complementary to a target sequence within the nucleotide sequence encoding the constant region of a wild-type human TCR. In some embodiments, the one or more siRNAs are complementary to a target sequence within the nucleotide sequence encoding the constant region of the alpha chain of a wild-type TCR. In some embodiments, the one or more siRNAs comprise (i) one or more siRNAs complementary to a target sequence within the nucleotide sequence encoding the constant region of the alpha chain of a wild-type TCR, and (ii) one or more siRNAs complementary to a target sequence within the nucleotide sequence encoding the constant region of the beta chain of a wild-type TCR.

[0133] In some embodiments, the one or more siRNAs comprise a nucleotide sequence selected from the group consisting of SEQ ID NOs: 25-28 (Table 4). In some embodiments, the second nucleotide sequence of the nucleic acid molecule encodes one or more siRNAs, wherein the one or more siRNAs are complementary to target sequences within the nucleotide sequence encoding the constant region of the alpha chain of a wild-type TCR, and wherein the one or more siRNAs comprise the nucleic acid sequences set forth in SEQ ID NOs: 25 and 26. [Table 4]

[0134] In some embodiments, the second nucleotide sequence of the nucleic acid molecule encodes one or more siRNAs, wherein the one or more siRNAs are complementary to target sequences within the nucleotide sequence encoding the constant region of the beta chain of the wild-type TCR, wherein the one or more siRNAs comprise the nucleic acid sequences set forth in SEQ ID NOs: 27 and 28. In some embodiments, 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 that are complementary to target sequences within the nucleotide sequence encoding the constant region of the alpha chain of the 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 that are complementary to target sequences within the nucleotide sequence encoding the constant region of the beta chain of the wild-type TCR, wherein the one or more siRNAs comprise the nucleic acid sequences set forth in SEQ ID NOs: 27 and 28.

[0135] In some embodiments, the second nucleotide sequence of the nucleic acid molecule comprises SEQ ID NOs: 25-28. In some embodiments, the second nucleotide sequence comprises SEQ ID NOs: 25-28, wherein one or more of SEQ ID NOs: 25-28 are separated by one or more nucleic acids that do not encode an siRNA. In certain embodiments, the one or more siRNAs are selected from the siRNAs disclosed in U.S. Publication No. 2010 / 0273213 A1, which is incorporated by reference in its entirety.

[0136] In some embodiments, 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 embodiments, the second nucleotide sequence encodes Cas9.

[0137] II.A.3 Vectors 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 viral particle or virus. In some aspects, the vector is a mammalian vector. In some aspects, the vector is a bacterial vector.

[0138] 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 vector, a baculovirus vector, an Epstein-Barr virus vector, a papovavirus vector, a vaccinia virus vector, a herpes simplex virus vector, and an adeno-associated virus (AAV) vector. In certain aspects, the vector is an AAV vector. In some aspects, the vector is a lentivirus. In certain 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 disclosure can be found in Huang and Kamihira, Biotechnol. Adv. 31(2):208-23 (2103), which is incorporated herein by reference in its entirety.

[0139] II.B. Recombinant T Cell Receptors (TCRs) Certain aspects of the present disclosure 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 TCRs are encoded by nucleic acid molecules disclosed herein.

[0140] In some embodiments, the anti-MUC5AC TCR cross-competes with the reference TCR for binding to human MUC5AC. In some embodiments, the anti-MUC5AC TCR binds to the same epitope on human MUC5AC as the reference TCR or an overlapping epitope. In some embodiments, the reference TCR comprises an alpha chain and a beta chain, and the alpha chain is composed of the reference TCR and comprises the amino acid sequence set forth in SEQ ID NO: 1. In some embodiments, the beta chain of the reference TCR comprises the amino acid sequence set forth in SEQ ID NO: 2.

[0141] In some embodiments, the anti-MUC5AC TCR comprises an alpha chain and a beta chain, wherein the alpha chain comprises a constant region and the beta chain comprises a constant region; and wherein the alpha chain constant region comprises an amino acid sequence having at least one, at least two, at least three, at least four, or at least five amino acid substitutions relative to the constant region of the alpha chain comprising the amino acid sequence set forth in SEQ ID NO: 1. In some embodiments, the anti-MUC5AC TCR comprises an alpha chain and a beta chain, wherein the alpha chain comprises a constant region and the beta chain comprises a constant region; and wherein the beta chain constant region comprises an amino acid sequence having at least one, at least two, at least three, at least four, or at least five amino acid substitutions relative to the constant region of the beta chain comprising the amino acid sequence set forth in SEQ ID NO:2.

[0142] In some embodiments, the anti-MUC5AC TCR comprises an alpha chain and a beta chain, wherein the alpha chain comprises a constant region and the beta chain comprises a constant region; wherein (i) the alpha chain constant region comprises an amino acid sequence having at least one, at least two, at least three, at least four, or at least five amino acid substitutions relative to the constant region of the 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 one, at least two, at least three, at least four, or at least five amino acid substitutions relative to the constant region of the beta chain comprising the amino acid sequence set forth in SEQ ID NO:2.

[0143] In some embodiments, 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 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. In some embodiments, the anti-MUC5AC TCR comprises an alpha chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7. In some embodiments, the anti-MUC5AC TCR comprises a beta chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 10.

[0144] In some embodiments, the alpha chain CDR1 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO: 5. In some embodiments, the beta chain CDR1 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO: 8.

[0145] In some embodiments, the alpha chain CDR2 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO: 6. In some embodiments, the beta chain CDR2 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO: 9.

[0146] In some embodiments, 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 embodiments, 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, and the anti-MUC5AC TCR comprises an alpha chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7. In some embodiments, 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.

[0147] In some embodiments, 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 embodiments, 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, and the anti-MUC5AC TCR comprises a beta chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, 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.

[0148] In some embodiments, 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 embodiments, 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 embodiments, 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, and the anti-MUC5AC TCR comprises an alpha chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7. In some embodiments, the anti-MUC5AC TCR comprises an alpha chain constant region present in the alpha chain amino acid sequence set forth in SEQ ID NO: 1. In some embodiments, the anti-MUC5AC TCR encoded by the first nucleotide further comprises an alpha chain constant region that differs from the endogenous, e.g., naturally occurring, constant region of the alpha chain. In some embodiments, the alpha chain constant region comprises an amino acid sequence that comprises at least one, at least two, at least three, at least four, or at least five 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.

[0149] In some embodiments, 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 embodiments, 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, and the anti-MUC5AC TCR comprises a beta chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, 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 embodiments, the anti-MUC5AC TCR encoded by the first nucleotide sequence further comprises a beta constant region that differs from the endogenous, e.g., naturally occurring, constant region of the beta chain. In some embodiments, the beta chain constant region comprises an amino acid sequence that contains at least one, at least two, at least three, at least four, or at least five 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.

[0150] In certain embodiments, 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 embodiments, 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, and the anti-MUC5AC TCR comprises an alpha chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7. In some embodiments, the anti-MUC5AC TCR comprises an alpha chain comprising the amino acid sequence set forth in SEQ ID NO: 1.

[0151] In certain embodiments, 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 embodiments, 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 the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the anti-MUC5AC TCR comprises a beta chain comprising the amino acid sequence set forth in SEQ ID NO: 2.

[0152] In some embodiments, the anti-MUC5AC TCR comprises an alpha chain constant region, a beta chain constant region, or both; wherein the alpha chain constant region, the beta chain constant region, or both, comprises an amino acid sequence that has at least 1, at least 2, at least 3, at least 4, or at least 5 substitutions in the target sequence relative to the corresponding amino acid sequence of the endogenous TCR.

[0153] II.B.2. Epitopes In some embodiments, the anti-MUC5AC TCR binds to the same epitope as a reference TCR. In some embodiments, the anti-MUC5AC TCR binds to an epitope of MUC5AC comprising the amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the anti-MUC5AC TCR binds to an epitope of MUC5AC consisting of the amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the epitope is amino acid residues 4922-4941 of MUC5AC (SEQ ID NO: 16), e.g., "MUC5AC 4922-4941 "

[0154] In certain embodiments, the epitope is complexed with an HLA class II molecule. In some embodiments, the HLA class II molecule comprises an alpha chain and a beta chain. In some embodiments, the alpha chain is selected from an HLA-DR alpha chain, an HLA-DP alpha chain, and an HLA-DQ alpha chain. In some embodiments, the beta chain is selected from an HLA-DR beta chain, an HLA-DP beta chain, and an HLA-DQ beta chain. In certain embodiments, the HLA class II molecule comprises an HLA-DR alpha chain and an HLA-DR beta chain. In certain embodiments, the HLA class II molecule comprises an HLA-DP alpha chain and an HLA-DP beta chain. In certain embodiments, the HLA class II molecule comprises an HLA-DQ alpha chain and an HLA-DQ beta chain.

[0155] Many HLA-DR, HLA-DP, and HLA-DQ alleles are known in the art, and any known alleles may be used in the present disclosure. An up-to-date listing of HLA alleles is available at hla.alleles.org / (last visited February 27, 2019), which is incorporated herein by reference in its entirety.

[0156] II.B.3. Bispecific T cell receptor (TCR) Certain aspects of the present disclosure relate to bispecific TCRs 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").

[0157] 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 not 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 CD3, DC4, CD2, CD5, CD6, CD8, CD11a (LFA-1α), 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.

[0158] In some embodiments, the first and second antigen-binding domains are covalently linked or attached, hi some embodiments, the first and second antigen-binding domains are linked by a peptide bond.

[0159] II.C. TCR-expressing cells Certain aspects of the present disclosure relate to cells 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 may be used in the present disclosure.

[0160] In certain embodiments, the cell expresses CD4. Expression of CD4 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 embodiments, the cell is a T cell, monocyte, macrophage, dendritic cell, or natural killer cell. In certain embodiments, the cell is a T cell selected from a natural killer T (NKT) cell and an innate lymphoid cell (ILC). In some embodiments, the cell is a monocyte. In some embodiments, the cell is a macrophage. In some embodiments, the cell is a dendritic cell.

[0161] In some embodiments, the T cells are isolated from a human subject. In some embodiments, the human subject is the same subject who will ultimately receive the T cell therapy. In other embodiments, the subject is a donor subject, and the donor subject is not the same subject who will receive the T cell therapy.

[0162] In some embodiments, the cell is a cell that does not naturally express CD4, wherein the cell has been modified to express CD4. In some embodiments, the cell comprises a transgene encoding CD4, wherein the transgene is expressed by the cell. In some embodiments, the cell comprises a transgene encoding a protein that activates expression of endogenous CD4 by the cell. In some embodiments, the cell comprises a transgene encoding a protein or siRNA that inhibits an inhibitor of CD4 expression in the cell. In some embodiments, the transgene is integrated into the genome of the cell. In some embodiments, the transgene is not integrated into the genome of the cell.

[0163] In some embodiments, the cells that have been modified to express CD4 are isolated from a human subject. In some embodiments, the human subject is the same subject that will ultimately receive the cell therapy. In other embodiments, the subject is a donor subject, and the donor subject is not the same subject that will receive the cell therapy.

[0164] II.D. HLA class II molecules Certain embodiments of the present disclosure relate to an HLA class II molecule complexed with a peptide, the peptide comprising the amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the peptide consists of the amino acid sequence set forth in SEQ ID NO: 13.

[0165] In some embodiments, the HLA class II molecule is an HLA-DR, HLA-DP, or HLA-DQ allele. In some embodiments, the HLA class II molecule is any HLA allele disclosed at hla.alleles.org / (last visited February 27, 2019).

[0166] In some embodiments, the HLA class II molecule comprises an alpha chain and a beta chain, hi some embodiments, the sequence of the alpha chain is selected from any of the HLA alpha chain protein sequences available at hla.alleles.org (last visited Feb. 27, 2019).

[0167] II.D.1. HLA-DP class II molecules In some embodiments, the alpha chain is an HLA-DP alpha chain. Any HLA-DP alpha chain allele known in the art may be used in the compositions and methods disclosed herein. In some embodiments, the alpha chain is selected from HLA-DPA1*01, HLA-DPA1*02, HLA-DPA1*03, and HLA-DPA1*04 alleles. In certain embodiments, the DP alpha chain comprises an HLA-DPA1*01 allele. In certain embodiments, the DP alpha chain comprises an HLA-DPA1*02 allele. In certain embodiments, the DP alpha chain comprises an HLA-DPA1*03 allele. In certain embodiments, the DP alpha chain comprises an HLA-DPA1*04 allele.

[0168] In certain embodiments, the DP alpha chain is 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, DPA 1*02:02:04, DPA1*02:02:05, DPA1*02:02:06, DPA1*02:03, DPA1*02:04, DPA1*02:05, DPA 1*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, DP A1*02:16, DPA1*03:01:01:01, DPA1*03:01:01:02, DPA1*03:01:01:03, DPA1*03:01:01:0 4, 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.

[0169] In some embodiments, 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 embodiments, the DP beta chain is 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*130, DPB1*131, DPB1*132, DPB1*133, DPB1*134, DPB1*135, DPB1*136, DPB1*137, DPB1*138, DPB1*139, DPB1*140, DPB1*141, DPB1*142, DPB1*143, DPB1*144, DPB1*145, DPB1*146, DPB1*147, DPB1 1*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*13 8, 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, DP B1*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*91 3, DPB1*914, DPB1*915, DPB1*916, DPB1*917, DPB1*918, DPB1*919, DPB1*92, DPB1*920, DPB1*9 21, DPB1*922, DPB1*923, DPB1*924, DPB1*925, DPB1*926, DPB1*927, DPB1*928, DPB1*929, DPB 1*93, DPB1*930, DPB1*931, DPB1*932, DPB1*933, DPB1*934, DPB1*935, DPB1*936, DPB1*937, DP B1*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 embodiments, the DP beta chain comprises an allele selected from 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 alleles, and any combination thereof. In a particular embodiment, the DP beta chain comprises the HLA-DPB1*04 allele. In a particular embodiment, the DP beta chain comprises the HLA-DPB1*04:01 allele.

[0170] In some embodiments, the DP beta chain is selected from the group consisting of DPB1*01:01:01:01, 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, D PB1*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, D PB1*02:01:02:21, DPB1*02:01:02:22, DPB1*02:01:02:23, DPB1*02:01:0 2:24, DPB1*02:01:02:25, DPB1*02:01:02:26, ​​DPB1*02:01:02:27, DPB1*0 2:01:02:28, 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*170:01、DPB1*171:01、DPB1*172:01、DPB1*173:01、DPB1*174:01、DPB1*175:01、DPB1*176:01、DPB1*177:01、DPB1*178:01、DPB1*179:01、DPB1*17:01:01:01、DPB1*17:01:01:02、DPB1*17:01:02、DPB1*17:01:03、DPB1*180:01、DPB1*181:01、DPB1*182:01、DPB1*183:01、DPB1*184:01、DPB1*185:01、DPB1*186:01、DPB1*187:01、DPB1*188:01、DPB1*189:01、DPB1*18:01:01:01、DPB1*18:01:01:02、DPB1*18:01:01:03、DPB1*18:01:02、DPB1*18:01:03、DPB1*190:01、DPB1*191:01、DPB1*192:01、DPB1*193:01、DPB1*194:01、DPB1*195:01、DPB1*196:01、DPB1*197:01、DPB1*198:01、DPB1*199:01、DPB1*19:01:01:01、DPB1*19:01:01:02、DPB1*19:01:01:03、 DPB1*200:01、DPB1*201:01、DPB1*202:01、DPB1*203:01:01、DPB1*203:01:02、DPB1*204:01、DPB1*205:01、DPB1*206:01、DPB1*207:01、DPB1*208:01、DPB1*209:01、DPB1*20:01:01:01、DPB1*20:01:01:02、DPB1*20:01:02、DPB1*20:01:03、DPB1*20:01:04、DPB1*210:01、DPB1*211:01、DPB1*212:01、DPB1*213:01:01、DPB1*213:01:02、DPB1*214:01、DPB1*215:01、DPB1*216:01N、DPB1*217:01、DPB1*218:01N、DPB1*219:01、DPB1*21:01、DPB1*220:01、DPB1*221:01、DPB1*222:01、DPB1*223:01、DPB1*224:01、DPB1*225:01、DPB1*226:01、DPB1*227:01:01、DPB1*227:01:02、DPB1*228:01、DPB1*229:01、DPB1*22:01:01:01、DPB1*22:01:01:02、DPB1*230:01、DPB1*231:01、DPB1*232:01、DPB1*233:01、DPB1*234:01、DPB1*235:01、DPB1*236:01:01、DPB1*236:01:02、DPB1*237:01、DPB1*238:01、DPB1*239:01、DPB1*23:01:01:01、DPB1*23:01:01:02、DPB1*23:01:02、DPB1*240:01、DPB1*241:01、DPB1*242:01、DPB1*243:01、DPB1*244:01、DPB1*245:01、DPB1*246:01、DPB1*247:01、DPB1*248:01、DPB1*249:01、DPB1*24:01、DPB1*250:01、DPB1*251:01、DPB1*252:01、DPB1*253:01、DPB1*254:01、DPB1*255:01、DPB1*256:01、DPB1*257:01、DPB1*258:01、DPB1*259:01、DPB1*25:01、DPB1*260:01、DPB1*261:01、DPB1*262:01、DPB1*263:01、DPB1*264:01、DPB1*265:01、DPB1*266:01、DPB1*267:01、DPB1*268:01、DPB1*269:01、DPB1*26:01:01、DPB1*26:01:02、DPB1*26:01:03、DPB1*270:01、DPB1*271:01、DPB1*272:01、DPB1*273:01、DPB1*274:01、DPB1*275:01、DPB1*276:01、DPB1*277:01、DPB1*278:01、DPB1*279:01:01、DPB1*279:01:02、DPB1*27:01、DPB1*280:01、DPB1*281:01、DPB1*282:01、DPB1*283:01、DPB1*284:01、DPB1*285:01、DPB1*286:01、DPB1*287:01、DPB1*288:01、DPB1*289:01、DPB1*28:01、DPB1*290:01、DPB1*291:01、DPB1*292:01、DPB1*293:01、DPB1*294:01、DPB1*295:01、DPB1*296:01、DPB1*297:01、DPB1*298:01、DPB1*299:01、DPB1*29:01、DPB1*300:01、DPB1*301:01、DPB1*302:01、DPB1*303:01、DPB1*304:01、DPB1*305:01、DPB1*306:01、DPB1*307:01、DPB1*308:01、DPB1*309:01、DPB1*30:01:01:01、DPB1*30:01:01:02、DPB1*310:01、DPB1*311:01、DPB1*312:01、DPB1*313:01、DPB1*314:01、DPB1*315:01、DPB1*316:01、DPB1*317:01、DPB1*318:01、DPB1*319:01、DPB1*31:01:01:01、DPB1*31:01:01:02、DPB1*320:01、DPB1*321:01、DPB1*322:01、DPB1*323:01、DPB1*324:01、DPB1*325:01、DPB1*326:01、DPB1*327:01、DPB1*328:01N、DPB1*329:01、DPB1*32:01、DPB1*330:01、DPB1*331:01、DPB1*332:01、DPB1*333:01、DPB1*334:01、DPB1*335:01、DPB1*336:01、DPB1*337:01、DPB1*338:01、DPB1*339:01、DPB1*33:01:01:01、DPB1*33:01:01:02、DPB1*33:01:01:03、DPB1*33:01:01:04、DPB1*33:01:01:05、DPB1*340:01、DPB1*341:01、DPB1*342:01、DPB1*343:01、DPB1*344:01、DPB1*345:01、DPB1*346:01、DPB1*347:01、DPB1*348:01:01、DPB1*348:01:02、DPB1*349:01、DPB1*34:01:01:01、DPB1*34:01:01:02、DPB1*34:01:02、DPB1*350:01、DPB1*351:01、DPB1*352:01:01、DPB1*352:01:02、DPB1*353:01、DPB1*354:01:01、DPB1*354:01:02、DPB1*355:01、DPB1*356:01、DPB1*357:01N、DPB1*358:01、DPB1*359:01、DPB1*35:01:01、DPB1*360:01、DPB1*361:01、DPB1*362:01、DPB1*363:01、DPB1*364:01、DPB1*365:01、DPB1*366:01、DPB1*367:01、DPB1*368:01、DPB1*369:01、DPB1*36:01、DPB1*370:01、DPB1*371:01、DPB1*372:01、DPB1*373:01、DPB1*374:01、DPB1*375:01、DPB1*376:01、DPB1*377:01、DPB1*378:01、DPB1*379:01、DPB1*37:01、DPB1*380:01、DPB1*381:01、DPB1*382:01N、DPB1*383:01、DPB1*384:01、DPB1*385:01、DPB1*386:01、DPB1*387:01、DPB1*388:01、DPB1*389:01、DPB1*38:01、DPB1*390:01、DPB1*391:01、DPB1*392:01、DPB1*393:01、DPB1*394:01、DPB1*395:01、DPB1*396:01、DPB1*397:01、DPB1*398:01、DPB1*399:01、DPB1*39:01:01:01、DPB1*39:01:01:02、DPB1*39:01:01:03、DPB1*39:01:01:04、DPB1*39:01:02、DPB1*39:01:03、DPB1*400:01、DPB1*401:01N、DPB1*402:01、DPB1*403:01N、DPB1*404:01、DPB1*405:01、DPB1*406:01、DPB1*407:01、DPB1*408:01、DPB1*409:01、DPB1*40:01:01:01、DPB1*40:01:01:02、DPB1*40:01:01:03、DPB1*40:01:02、DPB1*410:01、DPB1*411:01、DPB1*412:01、DPB1*413:01、DPB1*414:01:01:01、DPB1*414:01:01:02、DPB1*415:01、DPB1*416:01:01:01、DPB1*416:01:01:02、DPB1*416:01:01:03、DPB1*416:01:02、DPB1*417:01:01、DPB1*417:01:02、DPB1*418:01、DPB1*419:01、DPB1*41:01:01:01、DPB1*41:01:01:02、DPB1*41:01:02、DPB1*420:01、DPB1*421:01、DPB1*422:01、DPB1*423:01:01、DPB1*423:01:02、DPB1*424:01、DPB1*425:01、DPB1*426:01、DPB1*427:01、DPB1*428:01、DPB1*429:01、DPB1*430:01、DPB1*431:01、DPB1*432:01、DPB1*433:01、DPB1*434:01、DPB1*435:01、DPB1*436:01、DPB1*437:01、DPB1*438:01、DPB1*439:01、DPB1*440:01、DPB1*441:01、DPB1*442:01、DPB1*443:01、DPB1*444:01、DPB1*445:01、DPB1*446:01、DPB1*447:01、DPB1*448:01、DPB1*449:01、DPB1*44:01、DPB1*450:01N、DPB1*451:01、DPB1*452:01、DPB1*453:01、DPB1*454:01、DPB1*455:01N、DPB1*456:01、DPB1*457:01、DPB1*458:01、DPB1*459:01、DPB1*45:01、DPB1*460:01、DPB1*461:01、DPB1*462:01、DPB1*463:01:01:01、DPB1*463:01:01:02、DPB1*463:01:01:03、DPB1*464:01、DPB1*465:01、DPB1*466:01、DPB1*467:01、DPB1*468:01、DPB1*469:01、DPB1*46:01:01、DPB1*46:01:02、DPB1*470:01、DPB1*471:01、DPB1*472:01、DPB1*473:01、DPB1*474:01、DPB1*475:01、DPB1*476:01、DPB1*477:01、DPB1*478:01、DPB1*479:01、DPB1*47:01:01:01、DPB1*47:01:01:02、DPB1*47:01:01:03、DPB1*480:01、DPB1*481:01、DPB1*482:01、DPB1*483:01、DPB1*484:01、DPB1*485:01、DPB1*486:01、DPB1*487:01、DPB1*488:01、DPB1*489:01、DPB1*48:01、DPB1*490:01、DPB1*491:01、DPB1*492:01、DPB1*493:01、DPB1*494:01、DPB1*495:01、DPB1*496:01、DPB1*497:01、DPB1*498:01、DPB1*499:01、DPB1*49:01:01:01、DPB1*49:01:01:02、DPB1*49:01:01:03、DPB1*500:01、DPB1*501:01、DPB1*502:01、DPB1*503:01、DPB1*504:01、DPB1*505:01、DPB1*506:01、DPB1*507:01N、DPB1*508:01、DPB1*509:01、DPB1*50:01、DPB1*510:01、DPB1*511:01、DPB1*512:01、DPB1*513:01、DPB1*514:01、DPB1*515:01、DPB1*516:01、DPB1*517:01、DPB1*518:01、DPB1*519:01、DPB1*51:01:01:01、DPB1*51:01:01:02、DPB1*520:01、DPB1*521:01、DP、 B1*522:01、DPB1*523:01:01、DPB1*523:01:02、DPB1*524:01、DPB1*525:01、DPB1*526:01、DPB1*527:01、DPB1*528:01、DPB1*529:01、DPB1*52:01、DPB1*530:01、DPB1*531:01、DPB1*532:01、DPB1*533:01、DPB1*534:01、DPB1*535:01、DPB1*536:01、DPB1*537:01、DPB1*538:01、DPB1*539:01、DPB1*53:01、DPB1*540:01、DPB1*541:01、DPB1*542:01、DPB1*543:01、DPB1*544:01、DPB1*545:01、DPB1*546:01、DPB1*547:01、DPB1*548:01、DPB1*549:01、DPB1*54:01、DPB1*550:01、DPB1*551:01N、DPB1*552:01、DPB1*553:01、DPB1*554:01、DPB1*555:01、DPB1*556:01、DPB1*557:01、DPB1*558:01、DPB1*559:01、DPB1*55:01:01:01、DPB1*55:01:01:02、DPB1*55:01:01:03、DPB1*55:01:01:04、DPB1*55:01:01:05、DPB1*55:01:02、DPB1*560:01、DPB1*561:01、DPB1*562:01、DPB1*563:01、DPB1*564:01、DPB1*565:01、DPB1*566:01、DPB1*567:01、DPB1*568:01、DPB1*569:01、DPB1*56:01、DPB1*570:01N、DPB1*571:01、DPB1*572:01、DPB1*573:01、DPB1*574:01、DPB1*575:01、DPB1*576:01、DPB1*577:01、DPB1*578:01、DPB1*579:01、DPB1*57:01、DPB1*580:01、DPB1*581:01、DPB1*582:01、DPB1*583:01、DPB1*584:01:01:01、DPB1*584:01:01:02、DPB1*584:01:01:03、DPB1*584:01:02:01、DPB1*584:01:02:02、DPB1*585:01:01:01、DPB1*585:01:01:02、DPB1*586:01、DPB1*587:01、DPB1*588:01、DPB1*589:01、DPB1*58:01、DPB1*590:01、DPB1*591:01、DPB1*592:01、DPB1*593:01、DPB1*594:01、DPB1*595:01、DPB1*596:01、DPB1*597:01、DPB1*598:01N、DPB1*599:01、DPB1*59:01、 DPB1*600:01、DPB1*601:01、DPB1*602:01、DPB1*603:01、DPB1*604:01、DPB1*605:01、DPB1*606:01、DPB1*607:01、DPB1*608:01、DPB1*609:01、DPB1*60:01、DPB1*610:01、DPB1*611:01、DPB1*612:01、DPB1*613:01、DPB1*614:01、DPB1*615:01、DPB1*616:01、DPB1*617:01、DPB1*618:01、DPB1*619:01、DPB1*61:01N、DPB1*620:01、DPB1*621:01、DPB1*622:01、DPB1*623:01、DPB1*624:01、DPB1*625:01、DPB1*626:01、DPB1*627:01、DPB1*628:01、DPB1*629:01、DPB1*62:01、DPB1*630:01、DPB1*631:01、DPB1*632:01、DPB1*633:01、DPB1*634:01、DPB1*635:01、DPB1*636:01、DPB1*637:01、DPB1*638:01、DPB1*639:01、DPB1*63:01、DPB1*640:01、DPB1*641:01、DPB1*642:01、DPB1*643:01、DPB1*644:01、DPB1*645:01、DPB1*646:01、DPB1*647:01、DPB1*648:01:01:01、DPB1*648:01:01:02、DPB1*649:01、DPB1*64:01N、DPB1*650:01、DPB1*651:01、DPB1*652:01、DPB1*653:01、DPB1*654:01、DPB1*655:01、DPB1*656:01、DPB1*657:01N、DPB1*658:01、DPB1*659:01、DPB1*65:01:01、DPB1*65:01:02、DPB1*660:01、DPB1*661:01N、DPB1*662:01、DPB1*663:01、DPB1*664:01、DPB1*665:01、DPB1*666:01、DPB1*667:01、DPB1*668:01:01:01、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*96, and any combination thereof.

[0171] II.D.2. HLA-DQ class II molecules In some embodiments, 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 embodiments, 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 embodiments, the alpha chain is 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, *01:04:01:0 3, *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, *02:01:0 1:01, *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, *04:01:01:0 8, *04:01:02:01, *04:01:02:02, *04:01:03, *04:02, *04:03N, *04:04, *04:05, *05:01:01:01, *05:01:01:02, *05:01:01:03, *05 :01:01:04, *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: HLA-DQA1 alleles selected from 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.

[0172] In some embodiments, the beta chain is an HLA-DQ beta chain. Any HLA-DQ beta chain known in the art can be used in the compositions and methods disclosed herein. In some embodiments, the beta chain is selected from the HLA-DQB1*02, HLA-DQB1*03, HLA-DQB1*04, HLA-DQB1*05, and HLA-DQB1*06 alleles.

[0173] In particular, 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、DQB1*02:01:16 2:01:17、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、DQB1*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*02:02:08 B1*02:02:09、DQB1*02:03:01、DQB1*02:03:02、DQB1*02:04、DQB1*02:05、DQB1*02:06、DQB1*02:07:01、DQB1*02:07:02、DQB1*02:08、DQB1*02:09、D QB1*02:10、DQB1*02:100、DQB1*02:101、DQB1*02:102、DQB1*02:103、DQB1*02:104、DQB1*02:105、DQB1*02:106、DQB1*02:107、DQB1*02:108、DQB1*02:109、DQB1*02:11、DQB1*02:110、DQB1*02:111、DQB1*02:112、DQB1*02:113、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、D QB1*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*03:0 1:45、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*03:0 2:08、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* 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,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、DQ B1*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*06:0 2:23、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*06:03:01:0 2、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 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QB1*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, D QB1*06:78, DQB1*06:79:01, DQB1*06:79:02, DQB1*06:80, DQB1*06:81, DQB1*06:82, DQB1*06:83, DQ B1*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.

[0174] II.D.3. HLA-DR class II molecules In some embodiments, the alpha chain is an HLA-DR alpha chain. Any HLA-DR alpha chain allele known in the art can be used in the compositions and methods disclosed herein. In some embodiments, the alpha chain is an HLA-DRA*01 allele. In some embodiments, the alpha chain is an HLA-DRA1 allele selected from *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.

[0175] In some embodiments, the beta chain is an HLA-DR beta chain. Any HLA-DR beta chain known in the art can be used in the compositions and methods disclosed herein. In some embodiments, the beta chain is selected from 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 embodiments, the beta chain is a DRB3 allele. In some embodiments, the beta chain is a DRB4 allele. In some embodiments, the beta chain is a DRB5 allele.

[0176] In some embodiments, this is a case of 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*01:07. 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*0 1:01:26、DRB1*01:01:27、DRB1*01:01:28、DRB1*01:01:29、DRB1*01:01:3 0、DRB1*01:01:31、DRB1*01:01:32、DRB1*01:01:33、DRB1*01:02:01:01、DR B1*01:02:01:02、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*01:02:0 9、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*01:04、 DRB1*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. 13、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、DRB 1*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、DRB 1*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*01:93 1:94、DRB1*01:95、DRB1*01:96、DRB1*01:97、DRB1*01:98、DRB1*01:99、DR B1*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、DRB 1*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*03:06、DRB1*03:06、 RB1*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*03:10、DRB1*03:10、DRB1*03:100:01 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6、DRB1*08:57、DRB1*08:58、DRB1*08:59、DRB1*08:60N、DRB1*08:61、DRB1*08:62、DRB1*08:63、DRB1*08:64、DRB1*08:65、DRB1*08:66、DRB1*08:67、D RB1*08:68:01、DRB1*08:68:02、DRB1*08:69、DRB1*08:70、DRB1*08:71、DRB1*08:72、DRB1*08:73、DRB1*08:74、DRB1*08:75、DRB1*08:76、DRB1*08:77、DRB1*08:78N、DRB1*08:79、DRB1*08:80、DRB1*08:81、DRB1*08:82、DRB1*08:83、DRB1*08:84、DRB1*08:85、DRB1*08:86、DRB1*08:87、DRB1*08:88、DRB1*08:88 1*08:89N、DRB1*08:90、DRB1*09:01:02:01、DRB1*09:01:02:02、DRB1*09: 01:03、DRB1*09:01:04、DRB1*09:01:05、DRB1*09:01:06、DRB1*09:01:07、D RB1*09:01:08、DRB1*09:01:09、DRB1*09:01:10、DRB1*09:01:11、DRB1*09:02:01、DRB1*09:02:02、DRB1*09:03、DRB1*09:04、DRB1*09:05、DRB1*09:0 6、DRB1*09:07、DRB1*09:08、DRB1*09:09、DRB1*09:10、DRB1*09:11、DRB1*09:12、DRB1*09:13、DRB1*09:14、DRB1*09:15、DRB1*09:16、DRB1*09:17、DRB1*09:17 B1*09:18, DRB1*09:19, DRB1*09:20, DRB1*09:21, DRB1*09:22, DRB1*09:23, DRB1*09:24, DRB1*09:25, DRB1*09:26, DRB1*09:27, DRB1*09:28, DRB1*09:29, DRB1*09:30, DRB1*09:31, DRB1*09:32, DRB1*09:33, DRB1*09:34, DRB1*09:35, DRB1*09:36, DRB1*09:37N, DRB1*09:38, DRB1*09:39, DRB1*09:4 0、DRB1*10:01:01:01、DRB1*10:01:01:02、DRB1*10:01:01:03、DRB1*10:01:02、DRB1*10:01:03、DRB1*10:01:04、DRB1*10:01:05、DRB1*10:01:06、DRB1*10:01:07、DRB1*10:01:08、DRB1*10:01:09、DRB1*10:01:10、DRB1*10:01:11、DRB1*10:01:12、DRB1*10:02、DRB1*10:03、DRB1*10:04、DRB1*10:05、DRB1*10:06、DRB1*10:07、DRB1*10:08、DRB1*10:09、DRB1*10:10、DRB1*10:11、DRB1*10:12、DRB1*10:13、DRB1*10:14、DRB1*10:15、DRB1*10:16、DRB1*10:17、DRB1*10:18、DRB1*10:19、DRB1*10:20、DRB1*10:21、DRB1*10:22、DRB1*10:23、DRB1*10:24、DRB1*10:25、DRB1*10:26、DRB1*10:27、DRB1*1 0:28, DRB1*10:29, DRB1*10:30, DRB1*10:31, DRB1*10:32, DRB1*10:33, DRB1*11:01:01, DRB1*11:01:01:02, DRB1*11:01:01:03, DRB1*11:01:01:04, DRB1*11:01:02, DRB1*11:01:03, DRB1*11:01:04, DRB1*11:01:05, DRB1*11:01:06, DRB1*11:01:07, DRB1*11:01:08, DRB1*11:01:09, DRB1*11: 01:10, DRB1*11:01:11, DRB1*11:01:12, DRB1*11:01:13, DRB1*11:01:14, DRB1*11:01:15, DRB1*11:01:16, DRB1*11:01:17, DRB1*11:01:18, DRB1*11:01:19, DRB1*11:01:20, DRB1*11:01:21, DRB1*11:01:22, DRB1*11:01:23, DRB1*11:01:24, DRB1*11:01:25, DRB1*11:01:26, DRB1*11:01:27, DRB1 *11:01:28、DRB1*11:01:29、DRB1*11:01:30、DRB1*11:01:31、DRB1*11:01:32、DRB1*11:01:33、DRB1*11:02:01、DRB1*11:02:02、DRB1*11:02:03、DRB1*11:02:04、DRB1*11:02:05、DRB1*11:03:01、DRB1*11:03:02、DRB1*11:03:03、DRB1*11:03:04、DRB1*11:04:01、DRB1*11:04:02、DRB1*11:04:03、DRB1*11:04:04、DRB1*11:04:05、DRB1*11:04:06、DRB1*11:04:07、DRB1*11:04:08、DRB1*11:04:09、DRB1*11:04:10、DRB1*11:04:11、DRB1*11:04:12 、DRB1*11:04:13、DRB1*11:04:14、DRB1*11:04:15、DRB1*11:04:16、DRB1* 11:04:17、DRB1*11:04:18、DRB1*11:05、DRB1*11:06:01、DRB1*11:06:02、D RB1*11:06:03、DRB1*11:07:01、DRB1*11:07:02、DRB1*11:08:01、DRB1*11:08:02、DRB1*11:03、DRB1*11:09、DRB1*11:100、DRB1*11:101:01、DRB1*11:101:02、DRB1*11:102:01、DRB1*11:102:02、DRB1*11:103:01、DRB1*11:103:02、DRB1*11:104、DRB1*11:105、DRB1*11:106、DRB1*11:107、DRB1*1 1:108、DRB1*11:109、DRB1*11:10:01、DRB1*11:10:02、DRB1*11:110、DRB1*11:111、DRB1*11:112、DRB1*11:113、DRB1*11:114、DRB1*11:115、DRB1*11:11 :116、DRB1*11:117:01、DRB1*11:117:02、DRB1*11:118、DRB1*11:119、DRB1*11:11:01、DRB1*11:11:03、DRB1*11:120、DRB1*11:121、DRB1*11:122、DRB1*11:11:122 B1*11:123、DRB1*11:124:01、DRB1*11:124:02、DRB1*11:125、DRB1*11:126、DRB1*11:127、DRB1*11:128、DRB1*11:129、DRB1*11:12:01、DRB1*11:12:02、DRB1*11:12:03、DRB1*11:130、DRB1*11:131、DRB1*11:132、DRB1*11:133、DRB1*11:134、DRB1*11:135、DRB1*11:136、DRB1*11:137、DRB1*11:138、DRB1*11:139、DRB1*11:13:01、DRB1*11:13:02、DRB1*11:140、DRB1*11:141、DRB1*11:142、DRB1*11:143、DRB1*11:144、DRB1*11:145、DRB1*11:146、DRB1*11:147:01、DRB1*11:147:02、DRB1*11:148、DRB1*11:149、DRB1*11:14:01、DRB1*11:14:02、DRB1*11:15、DRB1*11:150、DRB1*11:151、DRB1*11:1 52、DRB1*11:153、DRB1*11:154、DRB1*11:155、DRB1*11:156、DRB1*11:157、DRB1*11:158、DRB1*11:159、DRB1*11:16、DRB1*11:160、DRB1*11:161、DRB1*11:161 1*11:162、DRB1*11:163、DRB1*11:164、DRB1*11:165:01、DRB1*11:165:02、DRB1*11:166、DRB1*11:167、DRB1*11:168、DRB1*11:169、DRB1*11:17、DRB1*11:169 B1*11:170、DRB1*11:171、DRB1*11:172、DRB1*11:173、DRB1*11:174、DRB1*11:175、DRB1*11:176、DRB1*11:177、DRB1*11:178、DRB1*11:179、DRB1*11 :18、DRB1*11:180、DRB1*11:181、DRB1*11:182、DRB1*11:183、DRB1*11:184、DRB1*11:185、DRB1*11:186、DRB1*11:187、DRB1*11:188、DRB1*11:189、D RB1*11:190、DRB1*11:191、DRB1*11:192、DRB1*11:193:01、DRB1*11:193:02、DRB1*11:194、DRB1*11:195、DRB1*11:196、DRB1*11:197、DRB1*11:198、DRB1*11:199、DRB1*11:19:01、DRB1*11:19:02、DRB1*11:19:03、DRB1*11:20、DRB1*11:200、DRB1*11:201、DRB1*11:202、DRB1*11:203、DRB1*11:204、DRB1*11:205、DRB1*11:206、DRB1*11:207、DRB1*11:208、DRB1*11:209、DRB1*11:21、DRB1*11:210、DRB1*11:211、DRB1*11:212、DRB1*11:213、DRB1*11:、 214、DRB1*11:215、DRB1*11:216、DRB1*11:217N、DRB1*11:218、DRB1*11:219、DRB1*11:22、DRB1*11: 220、DRB1*11:221、DRB1*11:222、DRB1*11:223、DRB1*11:224、DRB1*11:225、DRB1*11:226、DRB1*11: 227、DRB1*11:228、DRB1*11:229、DRB1*11:230、DRB1*11:231、DRB1*11:232、DRB1*11:233、DRB1*11:234、DRB1*11:235、DRB1*11:236、DRB1*11:237、DRB1*11:238、DRB1*11:239、DRB1*11:23:01、DRB1*11 :23:02、DRB1*11:240、DRB1*11:241、DRB1*11:242、DRB1*11:243、DRB1*11:244、DRB1*11:245、DRB1* 11:246N、DRB1*11:247、DRB1*11:248Q、DRB1*11:249、DRB1*11:24:01、DRB1*11:24:02、DRB1*11:25、D RB1*11:250N、DRB1*11:251、DRB1*11:252、DRB1*11:253、DRB1*11:254、DRB1*11:26、DRB1*11:27:01 、DRB1*11:27:02、DRB1*11:27:03、DRB1*11:28:01、DRB1*11:28:02、DRB1*11:29:01、DRB1*11:29:02、 DRB1*11:30、DRB1*11:31、DRB1*11:32、DRB1*11:33、DRB1*11:34、DRB1*11:35、DRB1*11:36、DRB1*11:37:01、DRB1*11:37:02、DRB1*11:38、DRB1*11:39、DRB1*11:40、DRB1*11:41、DRB1*11:42:01、DRB1*11:42:02、DRB1*11:43、DRB1*11:44、DRB1*11:45、DRB1*11:46:01、DRB1*11:46:02、DRB1*11:47 、DRB1*11:48、DRB1*11:49:01、DRB1*11:49:02、DRB1*11:50、DRB1*11:51、DRB1*11:52、DRB1*11:53、DRB1*11:54:01、DRB1*11:54:02、DRB1*11:55、DRB1*11:55 RB1*11:56、DRB1*11:57、DRB1*11:58:01、DRB1*11:58:02、DRB1*11:59、DRB1*11:60、DRB1*11:61、DRB1*11:62:01、DRB1*11:63:01、DRB1*11:63:01 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RB1*12:02:01:04、DRB1*12:02:02、DRB1*12:02:03、DRB1*12:02:04、DRB1*12:02:05、DRB1*12:02:06、DRB1*12:02:07、DRB1*12:02:08、DRB1*12:02:09、DRB1*12:03:02、DRB1*12:03:03、DRB1*12:04、DRB1*12:05、DRB1*12:06、DRB1*12:07、DRB1*12:08、DRB1*12:09、DRB1*12:10、DRB1*12:11、DRB1*1 2:12、DRB1*12:13、DRB1*12:14、DRB1*12:15、DRB1*12:16:01、DRB1*12:16:02、DRB1*12:16:03、DRB1*12:17、DRB1*12:18、DRB1*12:19、DRB1*12:20、DRB1*12:20 RB1*12:21、DRB1*12:22、DRB1*12:23、DRB1*12:24N、DRB1*12:25、DRB1*12:26、DRB1*12:27、DRB1*12:28、DRB1*12:29、DRB1*12:30、DRB1*12:31、DRB1*12:31 1*12:32、DRB1*12:33、DRB1*12:34、DRB1*12:35、DRB1*12:36、DRB1*12:37、DRB1*12:38、DRB1*12:39、DRB1*12:40、DRB1*12:41、DRB1*12:42、DRB1*12:43、DRB1*12:44、DRB1*12:45、DRB1*12:46、DRB1*12:47、DRB1*12:48、DRB1*12:49、DRB1*12:50、DRB1*12:51、DRB1*12:52、DRB1*12:53、DRB1*12:54、DRB1*12:55、DRB1*12:56、DRB1*12:57、DRB1*12:58、DRB1*12:59、DRB1*12:60N、DRB1*12:61、DRB1*12:62、DRB1*12:63、DRB1*12:64、DRB1*12:65、D RB1*12:66、DRB1*12:67、DRB1*12:68、DRB1*12:69、DRB1*12:70、DRB1*12:71、DRB1*12:72N、DRB1*12:73、DRB1*12:74N、DRB1*12:75、DRB1*13:01 :01、DRB1*13:01:01:02、DRB1*13:01:02、DRB1*13:01:03、DRB1*13:01:04、DRB1*13:01:05、DRB1*13:01:06、DRB1*13:01:07、DRB1*13:01:08、DRB1* 13:01:09、DRB1*13:01:10、DRB1*13:01:11、DRB1*13:01:12、DRB1*13:01:13、DRB1*13:01:14、DRB1*13:01:15、DRB1*13:01:16、DRB1*13:01:17、DRB1*13:01:17 1*13:01:18、DRB1*13:01:19、DRB1*13:01:20、DRB1*13:01:21、DRB1*13:01:22、DRB1*13:01:23、DRB1*13:01:24、DRB1*13:01:25、DRB1*13:01:26、DRB1*13:02:01:01、DRB1*13:02:01:02、DRB1*13:02:01:03、DRB1*13:02:02、DRB1*13:02:03、DRB1*13:02:04、DRB1*13:02:05、DRB1*13:02:06、DRB1 *13:02:07, DRB1*13:02:08, DRB1*13:02:09, DRB1*13:02:10, DRB1*13:02:11, DRB1*13:02:12, DRB1*13:02:13, DRB1*13:02:14, DRB1*13:02:15, DRB1*13:02:16, DRB1*13:02:17, DRB1*13:03:01, DRB1*13:03:02, DRB1*13:03:03, DRB1*13:03:04, DRB1*13:03:05, DRB1*13:03:06, DRB1*13:03:07,DRB1*13:03:08、DRB1*13:03:09、DRB1*13:04、DRB1*13:05:01、DRB1*13:05:02、DRB1*13:05:03、DRB1*13:06、DRB1*13:07:01、DRB1*13:07:02、DRB1* 13:08、DRB1*13:09、DRB1*13:10、DRB1*13:100、DRB1*13:101、DRB1*13:102、DRB1*13:103、DRB1*13:104、DRB1*13:105、DRB1*13:106、DRB1*13:107、DRB1*13:107 RB1*13:108、DRB1*13:109、DRB1*13:110、DRB1*13:111、DRB1*13:112、DRB1*13:113N、DRB1*13:114、DRB1*13:115、DRB1*13:116、DRB1*13:117、DRB1*13:118、DRB1*13:119、DRB1*13:11:01、DRB1*13:11:02、DRB1*13:120、DRB1*13:121、DRB1*13:122、DRB1*13:123、DRB1*13:124、DRB1*13:125、DRB1*1 3:126、DRB1*13:127、DRB1*13:128、DRB1*13:129、DRB1*13:12:01、DRB1*13:12:02、DRB1*13:12:03、DRB1*13:12:04、DRB1*13:13、DRB1*13:130、DRB1*13:131、DRB1*13:132、DRB1*13:133、DRB1*13:134、DRB1*13:135、DRB1*13:136、DRB1*13:137N、DRB1*13:138、DRB1*13:139、DRB1*13:140、DRB1*13: 141、DRB1*13:142N、DRB1*13:143、DRB1*13:144、DRB1*13:145、DRB1*13:146、DRB1*13:147、DRB1*13:148、DRB1*13:149、DRB1*13:14:01、DRB1*13:14:02、DRB1*13:14:03、DRB1*13:15、DRB1*13:150、DRB1*13:151、DRB1*13:152、DRB1*13:153、DRB1*13:154、DRB1*13:155、DRB1*13:156、DRB1*13:157、DRB1*13:158、DRB1*13:159、DRB1*13:16、DRB1*13:160、DRB1*13:161、DRB1*13:162、DRB1*13:163、DRB1*13:164、DRB1*13:165、DRB1*13:166、DRB1*13:167、DRB1*13:168、DRB1*13:169、DRB1*13:17、DRB1*13:170、DRB1*13:171:01、DRB1*13:171:02、DRB1*13:172、DRB1*13:173、DRB1*13:174、DRB1 *13:175、DRB1*13:176、DRB1*13:177、DRB1*13:178、DRB1*13:179、DRB1*13:18、DRB1*13:180、DRB1*13:181、DRB1*13:182、DRB1*13:183、DRB1*13:1 84、DRB1*13:185N、DRB1*13:186、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*13:193 B1*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*13:202 3:203、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*13:2 49N、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、DRB 1*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*13:28:01、DRB1*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*13:47、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*1 3:66:02, 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、DRB1*14:04:03、DRB1*14:04:04、DRB1*14:04:05、DRB1*14:04:06、DRB1*14:05:01、DRB1*14:05:01 1*14:05:01:02、DRB1*14:05:02、DRB1*14:05:03、DRB1*14:05:04、DRB1*14:06:01、DRB1*14:06:02、DRB1*14:06:03、DRB1*14:06:04、DRB1*14:07:01、DRB1*14:07:02、DRB1*14:08、DRB1*14:09、DRB1*14:10、DRB1*14:100、DRB1*14:101、DRB1*14:102、DRB1*14:103、DRB1*14:104、DRB1*14:105、DRB1* 14:106、DRB1*14:107、DRB1*14:108、DRB1*14:109、DRB1*14:11、DRB1*14:110、DRB1*14:111、DRB1*14:112、DRB1*14:113、DRB1*14:114、DRB1*14:115、DRB1*14:116、DRB1*14:117、DRB1*14:118、DRB1*14:119、DRB1*14:120、DRB1*14:121、DRB1*14:122、DRB1*14:123、DRB1*14:124、DRB1*14:125、DRB1 *14:126:01, DRB1*14:126:02, DRB1*14:127:01, DRB1*14:127:02, DRB1*14:128, DRB1*14:129, DRB1*14:12:01, DRB1*14:12:02, DRB1*14:13, DRB1*14:130, DRB1*14:131, DRB1*14:132, DRB1*14:133, DRB1*14:134, DRB1*14:135, DRB1*14:136, DRB1*14:137N, DRB1*14:138, DRB1*14:139, DRB1*14:14,DRB1*14:140, DRB1*14:141, DRB1*14:142, DRB1*14:143, DRB1*14:144, DRB1*14:145, DRB1*14:146, DRB1*14:147, 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*14:15 9、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*14:1 78、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、DRB 1*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*14:5 4:01:03, 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*14:6 8:01, 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、DRB1*15:02:06、DRB1*15:02:07、DRB1*15:02:08、DRB1*15:02:09、DRB1*15:02:10、DRB1*15:02:11、DRB1*15:02:12、DRB1*15:02:13、DRB1*15:02:14、DRB1*15:02:15、DRB1*15:02:16、DRB1*15:02:17、DRB1*15:02:18、DRB1*15:02:19、DRB1*15:03:01:01、DRB1*15:03:01:02、DRB1*15:03:01:03、DRB1*15:03:02、DRB1*15:03:03、DRB1*15:03:04、DRB1*15:04、DRB1*15:05、DRB1*15:06:01、DRB1*15:06:02、DRB1*15:06:03、DRB1*15:06:04、DRB1*15:07:01、DRB1*15:07:02、DRB1*15:07:03、DRB1*15:08、DRB1*15:09、DRB1*15:10、DRB1*15:100、DRB1*15:101、DRB1*15:102、DRB1*15:103、DRB1*1 5:104:01、DRB1*15:104:02、DRB1*15:104:03、DRB1*15:105:01、DRB1*15:105:02、DRB1*15:106、DRB1*15:107、DRB1*15:108、DRB1*15:109、DRB1*15:110、DRB1*15:111、DRB1*15:112、DRB1*15:113N、DRB1*15:114、DRB1*15:115N、DRB1*15:116、DRB1*15:117、DRB1*15:118、DRB1*15:119、DRB1*15:11: 01、DRB1*15:11:02、DRB1*15:12、DRB1*15:120、DRB1*15:121、DRB1*15:122、DRB1*15:123、DRB1*15:124、DRB1*15:125、DRB1*15:126、DRB1*15:127、DRB1*15:128、DRB1*15:129N、DRB1*15:13、DRB1*15:130、DRB1*15:131、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*15:16 2、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、D RB1*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*1 5:38、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*15:45 9、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*15:80、DRB1*15:81、DRB1*15:80DRB1*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*16:02:02 2:03、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*1 6:13N, 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*01:40:01N、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、DRB 3*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*02:1 5、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、DRB 3*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、DRB 3*03:20、DRB3*03:21、DRB3*03:22、DRB3*03:23、DRB3*03:24、DRB3*03:2 5、DRB4*01:01:01:01、DRB4*01:01:02、DRB4*01:01:03、DRB4*01:01:04、D RB4*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.

[0177] In some embodiments, the HLA class II molecule is a monomer. In some embodiments, the HLA class II molecule is a dimer. In some embodiments, the HLA class II molecule is a multimer. In some embodiments, the HLA class II molecule is a trimer. In some embodiments, the HLA class II molecule is a tetramer. In some embodiments, the HLA class II molecule is a pentamer.

[0178] Certain embodiments of the present disclosure relate to antigen-presenting cells (APCs) comprising any of the HLA class II molecules disclosed herein. In certain embodiments, the APCs express HLA class II molecules on their surface. In certain embodiments, the APCs comprise two or more HLA class II molecules disclosed herein.

[0179] II.E. Vaccines Certain embodiments of the present disclosure disclose a cancer vaccine comprising a peptide comprising the amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the cancer vaccine comprises a peptide consisting of the amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the vaccine further comprises one or more excipients. In some embodiments, the vaccine further comprises one or more additional peptides. In some embodiments, the one or more additional peptides comprise one or more additional epitopes.

[0180] III. Methods of the Disclosure Certain 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 methods of engineering antigen-targeted cells. Other aspects of the present disclosure relate to methods of enriching a target population of T cells obtained from a human subject.

[0181] III.A. Cancer Treatment Methods Certain aspects of the present disclosure relate to methods of treating 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 above.

[0182] In some embodiments, the cancer is melanoma, bone cancer, kidney cancer, prostate cancer, breast cancer, colon cancer, lung cancer, cutaneous or intraocular malignant melanoma, 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, cancer of the fallopian tubes, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, 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), cancer of the esophagus, 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, soft tissue In some embodiments, the cancer is selected from sarcoma of the bladder, 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), childhood solid tumors, lymphocytic lymphoma, bladder cancer, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, other B-cell malignancies, and combinations of these cancers. In some embodiments, the cancer is melanoma.

[0183] In some embodiments, the cancer is recurrent. In some embodiments, the cancer is refractory. In some embodiments, the cancer is progressive. In some embodiments, the cancer is metastatic.

[0184] In some embodiments, the methods disclosed herein treat cancer in a subject. In some embodiments, the methods disclosed herein reduce the severity of one or more symptoms of cancer. In some embodiments, the methods disclosed herein reduce the size or number of tumors resulting from cancer. In some embodiments, the methods disclosed herein extend the overall survival of a subject relative to a subject not provided with a method disclosed herein. In some embodiments, the methods disclosed herein increase the progression-free survival of a subject relative to a subject not provided with a method disclosed herein. In some embodiments, the methods disclosed herein result in a partial response in a subject. In some embodiments, the methods disclosed herein result in a complete remission in a subject.

[0185] In some embodiments, the methods disclosed herein include treating 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 embodiments, the cell is a T cell. In some embodiments, the cell is a cell that has been modified to express CD4.

[0186] In some embodiments, the cells, e.g., T cells, are obtained from the subject. In some embodiments, the cells, e.g., T cells, are obtained from a donor other than the subject.

[0187] In some embodiments, the subject is pretreated (preconditioned) prior to administering the cells. Preconditioning can include any substance that promotes T cell function and / or survival. In some embodiments, preconditioning includes administering to the subject chemotherapy, cytokines, proteins, small molecules, or any combination thereof. In some embodiments, preconditioning includes administering an interleukin. In some embodiments, preconditioning includes administering IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, or any combination thereof. In some embodiments, preconditioning includes administering cyclophosphamide, fludarabine, or both. In some embodiments, preconditioning includes administering vitamin C, an AKT inhibitor, ATRA (vesanoid, tretinoin), rapamycin, or any combination thereof.

[0188] III.B. Methods for Engineering Antigen-Targeted Cells Certain embodiments of the present disclosure relate to methods for engineering antigen-targeted cells. In some embodiments, the antigen is a MUC5AC antigen. In some embodiments, the method includes 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 embodiments, the cell is a T cell described herein. In some embodiments, the cell is a cell that has been modified to express CD4 as described herein. In some embodiments, the cell, e.g., a T cell, is obtained from a subject in need of T cell therapy. In some embodiments, the cell is obtained from a donor other than the subject in need of T cell therapy. In some embodiments, the cell is a T cell or a natural killer cell.

[0189] III. Methods for Enriching Target Populations of CT Cells Certain embodiments of the present disclosure relate to methods for enriching a target population of T cells obtained from a human subject. In some embodiments, the method comprises contacting T cells with an HLA class II molecule as disclosed herein. In some embodiments, the method comprises contacting T cells with an APC as disclosed herein. In some embodiments, after contacting, the enriched population of T cells comprises a greater number of T cells capable of binding to HLA class II molecules relative to the number of T cells capable of binding to HLA class II molecules before contacting.

[0190] In some embodiments, the method comprises contacting T cells in vitro with a peptide comprising the amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the method comprises contacting T cells in vitro with a peptide consisting of the amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, after contacting, the enriched population of T cells comprises a greater number of T cells capable of binding to HLA class II molecules relative to the number of T cells capable of binding to HLA class II molecules before contacting.

[0191] Some embodiments of the present disclosure relate to methods for selecting T cells capable of targeting tumor cells. In some embodiments, the methods comprise contacting a population of in vitro isolated T cells with a peptide consisting of the amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the T cells are obtained from a human subject.

[0192] The T cells obtained from the human subject can be any T cells disclosed herein. In some embodiments, the T cells obtained from the human subject are tumor-infiltrating lymphocytes (TILs).

[0193] In some embodiments, the method further comprises administering the enriched T cells to a human subject, hi some embodiments, the subject is preconditioned as described herein prior to receiving the T cells.

[0194] All of the various aspects, features, and options described herein may be combined in any and all variations.

[0195] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0196] Having generally described the present disclosure, a further understanding can be obtained by reference to the examples provided herein, which are for illustrative purposes only and are not intended to be limiting. [Example]

[0197] Example 1 - Method

[0198] cell Peripheral blood mononuclear cells were obtained by density gradient centrifugation (Ficoll-Paque PLUS, GE Healthcare Life Sciences, Marlborough, MA). The K562 cell line is an erythroleukemia cell line that is deficient in HLA class I / II expression. K562-based artificial APCs (aAPCs) expressing various HLA class II 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 Jurkat76 cell line is a T-cell leukemia cell line lacking expression of endogenous TCR, CD4, and CD8. Jurkat76 / 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 μg / ml gentamicin (Thermo Fisher Scientific, Waltham, MA). K562 and Jurkat76 cell lines were cultured in RPMI 1640 supplemented with 10% FBS and 50 μg / ml gentamicin.

[0199] peptide

[0200] MUC5AC 4922-4941 Synthetic peptides were purchased from Gencript (Piscataway, NJ) and dissolved in DMSO at 50 μg / ml.

[0201] gene

[0202] Novel TCR genes were cloned via 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 pMX retroviral vectors and transduced into cell lines using the 293GPG and PG13 cell-based retroviral systems.

[0203] antibody

[0204] The following antibodies were used for flow cytometry analysis: APC-Cy7-conjugated anti-CD4 (RPA-T4, Biolegend, San Diego, CA); 44 , and PE-conjugated anti-His tag (AD1.1.10, Abcam, Cambridge, MA). Dead cells were identified using the LIVE / DEAD Fixable Near-IR Dead Cell Stain Kit 465 (Thermo Fisher Scientific, Waltham, MA). Stained cells were analyzed on a Canto II or LSR Fortessa 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).

[0205] TCR transduction of primary T cells

[0206] CD3 + and CD4 +T cells were isolated using a Pan T Cell Isolation Kit (Miltenyi Biotec, Bergish Gladbach, Germany) and CD4 + T cells were purified using a T Cell Isolation Kit (Miltenyi Biotec, Bergish Gladbach, Germany). Purified T cells were stimulated with 200 Gy-irradiated aAPC / mOKT3 at an E:T ratio of 20:1. Starting the next day, activated T cells were retrovirally transduced with cloned TCR genes by continuous centrifugation at 1,000 × g at 32°C for 3 days or by using Retronectin-coated plates (Takara Bio, Shiga, Japan). The following day, 100 IU / ml IL-2 and 10 ng / ml IL-15 were added to the TCR-transduced T cells. The culture medium was replenished every 2–3 days.

[0207] Formation of HLA class II monomers and dimers

[0208] The extracellular domain of the wild-type class II α gene was fused to an acidic leucine zipper via a GGGS (SEQ ID NO: 30) linker, followed by a 6xHis tag via a GS linker (SEQ ID NO: 15; see Table 5). The extracellular domain of the mutated class II β gene (SEQ ID NO: 14) was similarly linked to a basic leucine zipper via a GGGS (SEQ ID NO: 30) linker (SEQ ID NO: 14). HEK293T cells and A375 cells were transfected with the α and β genes using the 293GPG cell-based retroviral system and cultured in DMEM supplemented with 10% FBS and 50 μg / ml gentamicin. DP4 dimer staining revealed soluble DP4. L112W / V141MHEK293T cells stably secreting proteins were grown to confluence and their medium was changed to serum-free 293 SFM II medium (Thermo Fisher Scientific, Waltham, MA). After 48 h, the conditioned medium was collected and concentrated using an Amicon Ultra filter (molecular weight cutoff (MWCO) 10 kDa) (MilliporeSigma, Burlington, MA). The supernatant containing soluble HLA class II was then mixed with 100 μg / ml of the peptide of interest for 20–24 h at 37°C for in vitro peptide exchange. Monomers that did not undergo peptide exchange served as controls. Monomer concentrations were measured by specific ELISA using nickel-coated plates (XPressBio, Frederick, MD) and an anti-His tag biotinylated mAb (AD1.1.10, R&D Systems, Minneapolis, MN). Soluble HLA class II monomers were dimerized with PE-conjugated anti-His mAb (AD1.1.10, Abcam, Cambridge, MA) at a molar ratio of 2:1 for 1.5 h at 4°C for staining. [Table 5-1] [Table 5-2]

[0209] DP4-restricted antigen-specific CD4 + T cell stimulation

[0210] CD4 + T cells are CD4 + T cells were purified using a T cell isolation kit (Miltenyi Biotec, Bergisch Glandbach). Purified T cells were stimulated with DP4-expressing aAPCs pulsed with 10 μg / ml of DP4-restricted peptide and irradiated with 200 Gy at an E:T ratio of 20:1. 48 hours later, 10 IU / ml of IL-2 and 10 ng / ml of IL-15 were administered to CD4 +The T cells were cultured in a culture medium supplemented with IL-2 (10 IU / ml) and IL-15 (10 ng / ml) every 2–3 days. After 2 weeks of stimulation, the T cells were cultured in a culture medium supplemented with DP4 L112W / V141M The cells were subjected to dimer staining.

[0211] HLA class II dimer staining

[0212] Primary T cells transduced with exogenous TCR genes and Jurkat 76 / CD4 T cells were pretreated with 50 nM dasatinib (LC Laboratories, Woburn, MA) for 30 minutes at 37°C. 46 The cells were stained with 5-15 μg / ml class II dimer for 4-5 hours at room temperature. After washing, cell surface molecules were counterstained with APC-Cy7-conjugated anti-CD4 mAb.

[0213] ELISPOT assay

[0214] 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)).

[0215] statistical analysis Statistical analysis was performed using GraphPad Prism 6.0 software (GraphPad Software, San Diego, CA). An unpaired two-tailed Student's t-test was used to compare two samples. No statistical methods were used to predetermine sample size. Researchers were blinded to the allocation during the experiment or outcome evaluation. The experiment was not randomized.

[0216] Example 2 - MUC5AC 4922-4941 TCR characterization 6 DP4s + Primary CD4 isolated from melanoma patients +T cells were stimulated once with DP4-aAPCs individually pulsed with peptide fragments of MUC5AC (4922–4941) to induce the cognate DP4 L112W / V141M We used weak stimulation conditions to avoid potential in vitro priming. 4922-4941 was found to be immunogenic by dimer staining (data not shown).

[0217] To verify the results of dimer staining, we isolated MUC5AC from dimer-positive T cells. 4922-4941 (Figures 1A-1B and Table 5) We cloned a DP4-restricted TCR gene specific for human CD4 + When clonotype-specifically rearranged in TCR-deficient T cells, MUC5AC 4922-4941 TCR is a homologous DP4 L112W / V141M The dimer was successfully stained (Figures 2A-8D) and was functional in a DP4-restricted, antigen-specific manner (Figure 3).

[0218] TCR 03-MUC5AC 4922-4941 were able to recognize the cognate peptide endogenously processed and presented by DP4 (Figures 4A-4E and 5). [Table 6]

Claims

1. (i) a first nucleotide sequence encoding a recombinant T cell receptor (TCR) or antigen binding portion thereof ("anti-MUC5AC TCR") that specifically binds to a complex comprising an epitope of human mucin 5AC (MUC5AC) consisting of the amino acid sequence set forth in SEQ ID NO: 13 and an HLA class II molecule HLA-DP allele, wherein the anti-MUC5AC TCR comprises an alpha chain and a beta chain, wherein the alpha chain comprises an alpha chain variable domain and an alpha chain constant domain, wherein the alpha chain variable domain comprises an alpha chain CDR1, an alpha chain CDR2, and an alpha chain CDR3, wherein the beta chain comprises a beta chain variable domain and a beta chain constant domain, wherein the beta chain variable domain comprises beta chain CDR1, beta chain CDR2, and beta chain CDR3, wherein: (a) the beta chain CDR3 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO:10; (b) the beta chain CDR2 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO:9; (c) the beta chain CDR1 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO:8; (d) the alpha chain CDR3 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO:7; (e) the alpha chain CDR2 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO:6; and (f) the alpha chain CDR1 of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO:5; a first nucleotide sequence; (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; and A nucleic acid molecule comprising:

2. The nucleic acid molecule of claim 1, wherein the HLA class II molecule HLA-DP allele is an HLA-DP4 allele.

3. (i) the alpha chain variable domain of the anti-MUC5AC TCR comprises the amino acid sequence of the alpha chain variable domain present in the amino acid sequence set forth in SEQ ID NO:1; (ii) the beta chain variable domain of the anti-MUC5AC TCR comprises the amino acid sequence of the beta chain variable domain present in the amino acid sequence set forth in SEQ ID NO:2; or (iii) both (i) and (ii); A nucleic acid molecule according to claim 1 or 2.

4. The alpha chain constant domain comprises an amino acid sequence having at least 90% sequence identity to a constant domain present in the amino acid sequence set forth in SEQ ID NO:

1. A nucleic acid molecule according to any one of claims 1 to 3.

5. The beta chain constant domain comprises an amino acid sequence having at least 90% sequence identity to a constant domain present in the amino acid sequence set forth in SEQ ID NO:

2. A nucleic acid molecule according to any one of claims 1 to 4.

6. (i) the alpha chain of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO:1; (ii) the beta chain of the anti-MUC5AC TCR comprises the amino acid sequence set forth in SEQ ID NO:2; or (iii) both (i) and (ii); A nucleic acid molecule according to any one of claims 1 to 5.

7. The nucleic acid molecule of any one of claims 1 to 6, wherein the second nucleotide sequence is one or more siRNAs that reduce expression of an endogenous TCR, and the one or more siRNAs are complementary to a target sequence within a nucleotide sequence encoding a constant domain of the endogenous TCR.

8. A vector comprising the nucleic acid molecule according to any one of claims 1 to 7.

9. 8. A T cell receptor (TCR) or an antigen-binding portion thereof comprising the alpha chain variable domain of the anti-MUC5AC TCR of any one of claims 1 to 7 and the beta chain variable domain of the anti-MUC5AC TCR of any one of claims 1 to 7.

10. A cell selected from the group consisting of T cells, natural killer (NK) cells, natural killer T (NKT) cells, and ILC cells, comprising a nucleic acid molecule described in any one of claims 1 to 7, or a vector described in claim 8, or a TCR or its antigen-binding portion described in claim 9.

11. A composition comprising the cells of claim 10 for treating cancer in a subject in need thereof.

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