T cell receptors and methods of use thereof

Abstract

The present disclosure relates to recombinant T cell receptors capable of binding to a CCND1 epitope and nucleic acid molecules encoding the same. In some aspects, the nucleic acid molecules further comprise a second nucleotide sequence, wherein the second nucleotide sequence or a polypeptide encoded by the second nucleotide sequence inhibits the expression of an endogenous TCR. Other aspects of the present disclosure relate to vectors comprising the nucleic acid molecules and cells comprising the recombinant TCRs, the nucleic acid molecules, or the vectors. Other aspects of the present disclosure relate to methods of using the recombinant TCRs, the nucleic acid molecules, the vectors, and the cells. In some aspects, the methods comprise treating a cancer in a subject in need thereof.

Description

[0001] Cross-reference to related applications

[0002] This PCT application claims priority to U.S. Provisional Application No. 62 / 880,504, filed July 30, 2019, which is incorporated herein by reference in its entirety.

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

[0004] The contents of the sequence list submitted electronically (name: 4285-013PC01_SL_ST25.txt, size: 22,576 bytes; and creation date: July 28, 2020) are incorporated herein by reference in their entirety. Technical Field

[0005] This disclosure provides a recombinant T-cell receptor (“TCR”) that specifically binds to human G1 / S-specific cyclin-D1 (CCND1) and its uses. Background of the Invention

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

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

[0009] Certain aspects of this disclosure relate to a nucleic acid molecule comprising (i) a first nucleotide sequence encoding a recombinant T-cell receptor (TCR) or its antigen-binding moiety that specifically binds to human G1 / S-specific cyclin-D1 (CCND1) (“anti-CCND1 TCR”); and (ii) a second nucleotide sequence wherein the second nucleotide sequence or a polypeptide encoded by the second nucleotide sequence inhibits the expression of an endogenous TCR, wherein the anti-CCND1 TCR cross-competitively binds to human CCND1 with a reference TCR comprising an α chain and a β chain, and wherein the α chain comprises an amino acid sequence as listed in SEQ ID NO:1 and the β chain comprises an amino acid sequence as listed in SEQ ID NO:2.

[0010] Certain aspects of this disclosure relate to a nucleic acid molecule comprising (i) a first nucleotide sequence encoding a recombinant T-cell receptor (TCR) or its antigen-binding portion (“anti-CCND1 TCR”) that specifically binds to human CCND1; and (ii) a second nucleotide sequence, wherein the second nucleotide sequence or a polypeptide encoded by the second nucleotide sequence inhibits the expression of an endogenous TCR, wherein the anti-CCND1 TCR binds to the same or overlapping epitopes of human CCND1 as a reference TCR, the reference TCR comprising an α chain and a β chain, wherein the α chain comprises an amino acid sequence as listed in SEQ ID NO:1 and the β chain comprises an amino acid sequence as listed in SEQ ID NO:2.

[0011] In some aspects, the anti-CCND1 TCR binds to an epitope of CCND1 consisting of the amino acid sequence listed in SEQ ID NO:13. In some aspects, the epitope is complexed with an HLA class II molecule. In some aspects, the HLA class II molecule is an HLA-DP, HLA-DQ, or HLA-DR allele or any combination thereof. In some aspects, the HLA class II molecule is an HLA-DP allele. In some aspects, the HLA class II molecule is an HLA-DP4 allele.

[0012] In some aspects, the anti-CCND1 TCR comprises an α chain and a β chain, wherein the α chain comprises a variable region containing α chain CDR1, α chain CDR2 and α chain CDR3; and wherein the β chain comprises a variable domain containing β chain CDR1, β chain CDR2 and β chain CDR3; wherein the α chain CDR3 comprises an amino acid sequence as listed in SEQ ID NO:7.

[0013] In some aspects, the β-chain CDR3 of the anti-CCND1 TCR comprises an amino acid sequence as listed in SEQ ID NO:10.

[0014] In some aspects, the anti-CCND1 TCR comprises an α chain and a β chain, wherein the α chain comprises a variable region containing α chain CDR1, α chain CDR2 and α chain CDR3; and wherein the β chain comprises a variable domain containing β chain CDR1, β chain CDR2 and β chain CDR3; wherein the β chain CDR3 of the anti-CCND1 TCR comprises an amino acid sequence as listed in SEQ ID NO:10.

[0015] In some aspects, the α-chain CDR3 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:7. In some aspects, the α-chain CDR1 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:5. In some aspects, the β-chain CDR1 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:8. In some aspects, the α-chain CDR2 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:6. In some aspects, the β-chain CDR2 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:9.

[0016] In some aspects, the α-chain variable domain of the anti-CCND1 TCR comprises the amino acid sequence of the variable domain present in the amino acid sequence listed in SEQ ID NO:1. In some aspects, the β-chain variable domain of the anti-CCND1 TCR comprises the amino acid sequence of the variable domain present in the amino acid sequence listed in SEQ ID NO:2.

[0017] In some aspects, the anti-CCND1 TCR α-chain further comprises a constant region, wherein said constant region is different from the endogenous constant region of said α-chain. In some aspects, the anti-CCND1 TCR α-chain further comprises a constant region, wherein said α-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 with the constant region present in the amino acid sequence listed in SEQ ID NO:1. In some aspects, the α-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 constant region present in the amino acid sequence listed in SEQ ID NO:1.

[0018] In some aspects, the anti-CCND1 TCR β-chain further comprises a constant region, wherein said constant region is different from the endogenous constant region of said β-chain. In some aspects, the anti-CCND1 TCR β-chain further comprises a constant region, wherein said β-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 with the constant region present in the amino acid sequence listed in SEQ ID NO:2. In some aspects, the β-chain constant region comprises an amino acid sequence comprising at least two, 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 listed in SEQ ID NO:2.

[0019] In some aspects, the α-chain of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:1. In some aspects, the β-chain of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:2.

[0020] In some aspects, the second nucleotide sequence is one or more siRNAs that reduce the expression of endogenous TCRs. In some aspects, the one or more siRNAs are complementary to a target sequence within a nucleotide sequence encoding a constant region of an endogenous TCR. In some aspects, the one or more siRNAs comprise one or more nucleotide sequences selected from the group consisting of SEQ ID NO:53-56.

[0021] In some aspects, the anti-CCND1 TCR comprises an α-chain constant region, a β-chain constant region, or both; and wherein the α-chain constant region, the β-chain constant region, or both comprise an amino acid sequence having at least one, at least two, at least three, at least four, or at least five substituted amino acid sequences relative to the endogenous TCR within the target sequence.

[0022] In some aspects, the α chain contains a signal peptide, the β chain contains a signal peptide, or both the α chain and the β chain contain a signal peptide. In some aspects, the signal peptide contains an amino acid sequence selected from the amino acid sequences listed in SEQ ID NO:20-22 and any combination thereof.

[0023] Some aspects of this disclosure relate to a vector 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: adenovirus vectors, lentiviruses, Sendaivirus vectors, baculovirus vectors, Epstein-Barr viral vectors, multivaccinia virus vectors, vaccinia virus vectors, herpes simplex virus vectors, hybrid vectors, and adeno-associated virus (AAV) vectors. In some aspects, the vector is a lentivirus.

[0024] Certain aspects of this disclosure relate to a T-cell receptor (TCR) or its antigen-binding portion comprising the α-chain variable domain of the anti-CCND1 TCR disclosed herein and the β-chain variable domain of the anti-CCND1 TCR disclosed herein.

[0025] Certain aspects of this disclosure relate to a recombinant T-cell receptor (TCR) or its antigen-binding portion (“anti-CCND1 TCR”) that specifically binds to human CCND1, cross-competing with a reference TCR to bind to human CCND1; wherein the reference TCR comprises an α-chain and a β-chain, and wherein the α-chain comprises the amino acid sequence as listed in SEQ ID NO:1 and the β-chain comprises the amino acid sequence as listed in SEQ ID NO:2; and wherein the anti-CCND1 TCR comprises an α-chain and a β-chain, wherein the α-chain comprises a constant region, and wherein the β-chain comprises a constant region; wherein the α-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 listed in SEQ ID NO:1, or the β-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.

[0026] Certain aspects of this disclosure relate to a recombinant T-cell receptor (TCR) or its antigen-binding portion (“anti-CCND1 TCR”) that specifically binds to human CCND1, having the same or overlapping epitopes as a reference TCR binding to human CCND1; wherein the reference TCR comprises an α-chain and a β-chain, and wherein the α-chain comprises the amino acid sequence as listed in SEQ ID NO:1 and the β-chain comprises the amino acid sequence as listed in SEQ ID NO:2; and wherein the anti-CCND1 TCR comprises an α-chain and a β-chain, wherein the α-chain comprises a constant region, and wherein the β-chain comprises a constant region; wherein the α-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 listed in SEQ ID NO:1, or the β-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 listed in SEQ ID NO:2.

[0027] In some aspects, the anti-CCND1 TCR binds to an epitope of CCND1 consisting of the amino acid sequence listed in SEQ ID NO:13. In some aspects, the epitope is complexed with an HLA class II molecule. In some aspects, the HLA class II molecule is an HLA-DP, HLA-DQ, or HLA-DR allele or any combination thereof. In some aspects, the HLA class II molecule is an HLA-DP allele. In some aspects, the HLA class II molecule is selected from the HLA-DP4 allele.

[0028] In some aspects, the anti-CCND1 TCR α-chain comprises a variable domain containing α-chain CDR1, α-chain CDR2, and α-chain CDR3; and the anti-CCND1 TCR β-chain comprises a variable domain containing β-chain CDR1, β-chain CDR2, and β-chain CDR3; wherein the anti-CCND1 α-chain CDR3 comprises the amino acid sequence as listed in SEQ ID NO:7. In some aspects, the anti-CCND1 TCR β-chain CDR3 comprises the amino acid sequence as listed in SEQ ID NO:10.

[0029] In some aspects, the α-chain of the anti-CCND1 TCR comprises a variable domain containing α-chain CDR1, α-chain CDR2, and α-chain CDR3; wherein the β-chain of the anti-CCND1 TCR comprises a variable domain containing β-chain CDR1, β-chain CDR2, and β-chain CDR3; and wherein the β-chain CDR3 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:10. In some aspects, the α-chain CDR3 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:7.

[0030] In some aspects, the α-chain CDR1 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:5. In some aspects, the β-chain CDR1 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:8. In some aspects, the α-chain CDR2 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:6. In some aspects, the β-chain CDR2 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:9.

[0031] In some aspects, the α-chain variable domain of the anti-CCND1 TCR comprises the amino acid sequence of the variable domain present in the amino acid sequence listed in SEQ ID NO:1. In some aspects, the β-chain variable domain of the anti-CCND1 TCR comprises the amino acid sequence of the variable domain present in the amino acid sequence listed in SEQ ID NO:2.

[0032] In some aspects, the α-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 with the amino acid sequence present in the constant region listed in SEQ ID NO:1.

[0033] In some aspects, the β-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 with the amino acid sequence present in the constant region listed in SEQ ID NO:2.

[0034] In some aspects, the α-chain of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:1. In some aspects, the β-chain of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:2.

[0035] In some aspects, the α chain contains a signal peptide, the β chain contains a signal peptide, or both the α chain and the β chain contain a signal peptide. In some aspects, the signal peptide contains an amino acid sequence selected from the amino acid sequences listed in SEQ ID NO:20-22 and any combination thereof.

[0036] Some aspects of this disclosure relate to a bispecific TCR comprising a first antigen-binding domain and a second antigen-binding domain, wherein the first antigen-binding domain comprises the TCR disclosed herein or its antigen-binding portion.

[0037] In some aspects, the first antigen-binding domain comprises a single-chain variable fragment (“scFv”). In some aspects, the second antigen-binding domain specifically binds to proteins expressed on the surface of T cells. In some aspects, the second antigen-binding domain specifically binds to CD3. In some aspects, the second antigen-binding domain comprises scFv. In some aspects, the first antigen-binding domain and the second antigen-binding domain are covalently linked or associated. In some aspects, the first antigen-binding domain and the second antigen-binding domain are linked by peptide bonds.

[0038] Certain aspects of this disclosure relate to a cell comprising the nucleic acid molecule disclosed herein, the vector disclosed herein, the TCR disclosed herein, the recombinant TCR disclosed herein, or the bispecific TCR disclosed herein. In some aspects, said cell further expresses CD3.

[0039] In some respects, the cells are selected from the group consisting of: T cells, natural killer (NK) cells, natural killer T (NKT) cells, or ILC cells.

[0040] Some aspects of this disclosure relate to a method of treating a subject with cancer in need, the method comprising administering the cells disclosed herein to the subject. 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, anal region cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, 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), and esophageal cancer. Small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile 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, kidney or ureter cancer, renal pelvis tumor, central nervous system (CNS) sarcoma, 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 thereof.

[0041] In some aspects, the cancer is recurrent or refractory. In some aspects, the cancer is locally advanced. In some aspects, the cancer is advanced. In some aspects, the cancer is metastatic.

[0042] In some aspects, the cells are obtained from a subject. In other aspects, the cells are obtained from a donor other than the subject.

[0043] In some aspects, the subject is pretreated prior to administration of the cells. In some protocols, the pretreatment includes administering chemotherapy, cytokines, proteins, small molecules, or any combination thereof to the subject. In some aspects, the pretreatment includes administering interleukins. In some aspects, the pretreatment includes administering IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, or any combination thereof. In some aspects, the pretreatment includes administering a pretreatment agent selected from the group consisting of cyclophosphamide, fludarabine, vitamin C, AKT inhibitors, ATRA, rapamycin, or any combination thereof. In some aspects, the pretreatment includes administering cyclophosphamide, fludarabine, or both.

[0044] Certain aspects of this disclosure relate to a method for engineering cells that target an antigen, the method comprising transducing cells collected from a subject requiring T-cell therapy using nucleic acid molecules or vectors disclosed herein. In some aspects, the antigen-targeting cells further express CD4. In some aspects, the cells are T cells or natural killer (NK) cells.

[0045] Certain aspects of this disclosure relate to an HLA class II molecule complexed with a peptide, wherein the HLA class II molecule comprises an α chain and a β chain; and wherein the peptide comprises an amino acid sequence as listed in SEQ ID NO:13. In some aspects, the HLA class II molecule is an HLA-DP, HLA-DQ, or HLA-DR allele or any combination thereof. In some aspects, the HLA class II molecule is an HLA-DP allele. In some aspects, the HLA class II molecule is an HLA-DQ allele. In some aspects, the HLA class II molecule is an HLA-DR allele.

[0046] In some aspects, the HLA class II molecule is a monomer. In some aspects, the HLA class II molecule is a dimer. In some aspects, the HLA class II molecule is a trimer. In some aspects, the HLA class II molecule is a tetramer. In some aspects, the HLA class II molecule is a pentamer.

[0047] Some aspects of this disclosure relate to an antigen-presenting cell (APC) that contains HLA class II molecules disclosed herein. In some aspects, the HLA class I molecules are expressed on the surface of the APC.

[0048] Some aspects of this disclosure relate to a method for enriching a population of target T cells obtained from a human subject, the method comprising contacting the T cells with an HLA class II molecule disclosed herein or an APC disclosed herein, wherein after the contact, the enriched population of T cells contains a higher number of T cells capable of binding the HLA class II molecule compared to the number of T cells capable of binding the HLA class II molecule before the contact.

[0049] Some aspects of this disclosure relate to a method for enriching a population of target T cells derived from a human subject, the method comprising contacting the T cells in vitro with a peptide, wherein the peptide comprises an amino acid sequence as listed in SEQ ID NO:13, wherein, after the contact, the enriched population of T cells contains a higher number of tumor-targeting T cells relative to the number of tumor-targeting T cells prior to the contact. In some aspects, the T cells derived from the human subject are tumor-infiltrating lymphocytes (TILs).

[0050] Some aspects of this disclosure relate to a method for treating a tumor in a subject in need, the method comprising administering to the subject enriched T cells disclosed herein.

[0051] Some aspects of this disclosure relate to a method for enhancing cytotoxic T-cell-mediated cancer cell targeting in a subject with cancer, the method comprising administering to the subject a peptide having an amino acid sequence as listed in SEQ ID NO:13.

[0052] Some aspects of this disclosure relate to a cancer vaccine comprising a peptide having an amino acid sequence as listed in SEQ ID NO:13.

[0053] Some aspects of this disclosure relate to a method for selecting T cells capable of targeting tumor cells, the method comprising contacting a population of isolated T cells in vitro with a peptide, wherein the peptide comprises an amino acid sequence as listed in SEQ ID NO:13.

[0054] In some respects, the T cells are tumor-infiltrating lymphocytes (TILs). Attached Figure Description

[0055] Figure 1A-1B Peptide-specific CD4 from melanoma patients + DP4 of T cells L112W / V141M Graphical representation of dimer staining. Primary CD4 + T cells were collected from six DP4 patients. + The melanoma patient purified the sample and stimulated it with DP4-expressing aAPCs, which were then treated with CCND1. 219-238Peptide pulses and homologous DP4 L112W / V141M Dimer staining. This shows DP4. L112W / V141M An example of dimer staining.

[0056] Figure 2A-2D To illustrate from DP4 L112W / V141M Dimer-positive cells were isolated and isolated from human TCR-deficient CD4+ cells. + DP4-restricted recombinant (03-CCND1) in T cells 219-238 Graphical representation of TCR function in DP4-restricted and antigen-specific ways. 03-CCND1 219-238 From DP4 L112W / V141M Dimer-positive cell clones were recombined in TCR-deficient Jurkat 76 / CD4 cells and converted to DP4. L112W / V141M Dimer staining.

[0057] Figure 3 To illustrate the use of CCND1 in the IL-2 ELISPOT assay 219-238 O3-CCND1 stimulated by aAPC of peptide pulses 219-238 Bar graph of IL-2EPISPOT assay results. DP4 / WT1 (clone 9) TCR was used as a negative control. At least two independent experiments were performed. The bar graph and error bars represent the mean ± SD of the results from triplicate experiments.

[0058] Figures 4A-4E illustrate the flow from DP4 L112W / V141M Dimer-positive cells were isolated and isolated from human primary CD4 cells. + Recombinant DP4-restricted CCND1 in T cells 219-238 Graphical representation of data on the function of TCR in a DP4-restrictive and antigen-specific manner. 03-CCND1 219-238 Retrovirus transduction to human primary CD4 + T cells, and with the corresponding DP4 L112W / V141M Dimer staining. *Student's t-test, P < 0.05. Bar graph and error bars represent the mean ± SD of the results from three experiments. Figure 4E ).

[0059] Figures 5A-5B Presented DP4-restricted CCND1 cloned from a melanoma patient 219-238 TCR identifies data on peptides that are endogenously processed and presented by K562-based aAPCs. Figure 5A Image showing Western blot analysis of CCND1 endogenously expressed in K562-derived aAPC cells. Figure 5B To illustrate using 03-CCND1 219-238Bar graph of IFN-γ ELISPOT assay results from retroviral transduction and stimulation of human primary T cells with peptide-unpulsed HLA-null or DP4-aAPC. *, P < 0.05 by Student's t-test. Bars and error bars represent the mean ± SD of results from triplicate experiments. Detailed Implementation

[0060] This disclosure relates to a TCR or its antigen-binding portion that specifically binds to an epitope on CCND1, a nucleic acid molecule encoding said TCR, and a cell containing said TCR or said nucleic acid molecule. Some aspects of this disclosure relate to methods of treating cancer in a subject of need. Other aspects of this disclosure relate to HLA class II molecules complexed with a peptide containing an epitope of CCND1.

[0061] I. Terminology

[0062] To make this disclosure more readily understandable, certain terms are first defined. As used in this application, each of the following terms shall have the meaning set forth below unless expressly provided otherwise herein. Other definitions are set forth in this application.

[0063] It should be noted that the term "a / an" refers to one or more of the entities described; for example, "a nucleotide sequence" should be understood to mean one or more nucleotide sequences. Therefore, the terms "a / an," "one or more / species," and "at least one / species" are used interchangeably herein.

[0064] Furthermore, when used herein, "and / or" should be considered as specifically disclosing each of the two specified features or components, in the presence or absence of the other. Therefore, the term "and / or," when used herein in phrases such as "A and / or B," is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, the term "and / or," when used herein in phrases such as "A, B, and / or C," is intended to cover each of the following: 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).

[0065] The term “about” is used herein to mean approximately, roughly, about, or near. When the term “about” is used in conjunction with a numerical range, it modifies the range by expanding the boundaries above and below the stated value. Generally, the term “about” is used herein to modify values ​​that are higher or lower than the stated value by a deviation of 10% upwards or downwards (higher or lower).

[0066] It should be understood that wherever the word “comprising” is used in this document to describe aspects, other similar aspects described in other ways by the terms “composed of” and / or “substantially composed of” are also provided.

[0067] 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. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd edition, 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd edition, 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, revised edition, 2000, Oxford University Press provide those skilled in the art with comprehensive dictionaries of many terms used in this disclosure.

[0068] Units, prefixes, and symbols are represented in their form as accepted by the International System of Units (SI). Numerical ranges include the numbers defining the range. Unless otherwise indicated, nucleotide sequences are written from left to right in a 5' to 3' direction. Amino acid sequences are written from left to right in an amino-to-carboxyl direction. The headings provided herein are not intended to limit the various aspects of this disclosure and may be taken as such by reference to the specification as a whole. Therefore, the terms defined below immediately are defined more fully by reference to this specification in its entirety.

[0069] "Administration" means the physical introduction of an agent into a subject using any of the various methods and delivery systems known to those skilled in the art. Exemplary routes of administration for the formulations disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral administration routes, such as by injection or infusion. As used herein, the phrase "parenteral administration" means a mode of administration other than enteral and local administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrasheathal, intralymphatic, intralesional, intracapsular, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, spinal, epidural, and intrasternal injections and infusions, as well as in vivo electroporation. In some aspects, the formulation is administered via a non-parenteral route (e.g., orally). Other non-parenteral routes include local, transdermal, or transmucosal administration routes, such as intranasal, vaginal, rectal, sublingual, or local administration. It can also be applied, for example, once, multiple times, and / or over one or more extended time periods.

[0070] As used herein, the term “T cell receptor” (TCR) refers to a heterogeneous cell surface receptor capable of specifically interacting with a target antigen. As used herein, “TCR” includes, but is not limited to, naturally occurring and non-naturally occurring TCRs; full-length TCRs and their antigen-binding portions; chimeric TCRs; TCR fusion constructs; and synthetic TCRs. In humans, TCRs are expressed on the surface of T cells and are responsible for T cell recognition and targeting by antigen-presenting cells. Antigen-presenting cells (APCs) display fragments of foreign proteins (antigens) that are complexed with the major histocompatibility complex (MHC; also referred to herein as complexed with HLA molecules, such as HLA class II molecules). TCRs recognize and bind to the peptide:HLA complex and recruit CD8 (for MHC class I molecules) or CD4 (for MHC class II molecules), thereby activating the TCR. Activated TCRs initiate downstream signaling and immune responses, including the disruption of EPCs.

[0071] Generally, a TCR may consist of two chains interconnected by disulfide bonds, an α-chain and a β-chain (or less commonly, a γ-chain and a δ-chain). Each chain contains variable domains (α-chain variable domains and β-chain variable domains) and constant regions (α-chain constant regions and β-chain constant regions). The variable domains are located at the distal end of the cell membrane and interact with the antigen. The constant regions are located at the proximal end of the cell membrane. A TCR may also contain a transmembrane region and a short cytoplasmic tail. As used herein, the term "constant region" encompasses both the transmembrane region and the cytoplasmic tail (when present) as well as the conventional "constant region".

[0072] The variable domains can be further subdivided into highly variable regions, called complementarity-determining regions (CDRs), which are scattered with more conserved regions called framework regions (FRs). Each α-chain and β-chain variable domain contains three CDRs and four FRs: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Each variable domain contains a binding domain that interacts with the antigen. Although all three CDRs on each chain participate in antigen binding, CDR3 is believed to be the primary antigen-binding region, while CDR1 and CDR2 are believed to primarily recognize HLA molecules.

[0073] Unless explicitly stated otherwise, and unless the context otherwise indicates, the term “TCR” also includes antigen-binding fragments or portions of any TCR disclosed herein, and includes 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 TCRs expressed on the surface of cells other than T cells (e.g., cells naturally expressed or modified to express CD4 as described herein), or TCRs without a cell membrane (e.g., isolated or soluble TCRs) as described herein.

[0074] "Antigen-binding molecule," "part of TCR," or "TCR fragment" refers to any portion of the TCR smaller than the whole. Antigen-binding molecules may include antigen CDRs.

[0075] “Antigen” means any molecule, such as a peptide, that elicits an immune response or can be bound by a TCR. As used herein, “epitope” means a portion of a polypeptide that elicits an immune response or can be bound by a TCR. An immune response may involve antibody production or activation of cells with specific immune activity, or both. Those skilled in the art will readily understand that any macromolecule, including virtually all proteins or peptides, can act as an antigen. Antigens and / or epitopes may be expressed endogenously, i.e., expressed from genomic DNA, or may be recombinantly expressed. Antigens and / or epitopes may be specific to a particular tissue (such as cancer cells), or they may be widely expressed. Furthermore, fragments of larger molecules can act as antigens. In one aspect, the antigen is a tumor antigen. Epitopes may be present in longer polypeptides (e.g., proteins), or epitopes may be present as fragments of longer polypeptides. In some aspects, epitopes are complexed with the major histocompatibility complex (MHC; also referred to herein as complexed with HLA molecules, such as HLA class 1 molecules).

[0076] As used herein, “CCND1,” “G1 / S-specific cyclin-D1,” “B-cell lymphoma 1 protein,” “BCL-1,” or “PRAD1” refers to the human regulatory component of the cyclin D1-CDK4 (DC) complex, which phosphorylates and represses members of the retinoblastoma (RB) protein family (including RB1) and regulates the cell cycle during the G1 / S transition. Phosphorylation of RB1 allows the transcription factor E2F to dissociate from the RB / E2F complex, and subsequently transcribes E2F target genes responsible for progression through G1 phase. CCND1 also participates in the hypophosphorylation of RB1 in early G1 phase. The cyclin D-CDK4 complex is a major integrator of various pro-mitotic and anti-mitotic signals. CCND1 is also a substrate of SMAD3, phosphorylating SMAD3 in a cell cycle-dependent manner and repressing its transcriptional activity. CCND1 is also a component of the ternary complex cyclin D1 / CDK4 / CDKN1B, essential for the nuclear translocation and activity of the cyclin D-CDK4 complex. Furthermore, CCND1 exhibits transcriptional co-repressor activity against the NEUROD1 and INS promoters, along with INSM1, in a cell cycle-independent manner. Altered cell cycle processes caused by mutations, amplification, and overexpression of CCND1 are frequently observed in various tumors and can lead to tumorigenesis.

[0077] As used herein, CCND1 refers not only to the full-length canonical sequence but also to its variants and fragments. The amino acid sequence of CCND1 (SEQ ID NO:16) is provided in Table 1 (UniProtKB–P24385).

[0078] Table 1. Amino acid sequence of CCND1

[0079]

[0080] As used herein, the term "HLA" refers to human leukocyte antigens. HLA genes encode major histocompatibility complex (MHC) proteins in humans. MHC proteins are expressed on cell surfaces and are involved in the activation of immune responses. HLA class II genes encode MHC class II proteins expressed on the surface of professional antigen-presenting cells (APCs). Non-restricted examples of professional APCs include monocytes, macrophages, dendritic cells (DCs), and B lymphocytes. Some endothelial and epithelial cells may also express MHC class II molecules after activation by inflammatory signals. Individuals lacking functional MHC class II molecules are highly susceptible to a range of infectious diseases and often die at a young age.

[0081] 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 encoding an MHC class II molecule. Therefore, “HLA class II molecule” and “MHC class II molecule” are used interchangeably herein. A typical MHC class II molecule contains two protein chains: an α chain and a β chain. Generally, naturally occurring α and β chains each contain a transmembrane domain that anchors the α / β chain to the cell surface; and an extracellular domain that carries antigens and interacts with TCR and / or CD4 expressed on T cells.

[0082] Both the α and β chains of MHC class II proteins are encoded by the HLA gene complex. The HLA complex is located in the 6p21.3 region on the short arm of human chromosome 6 and contains more than 220 genes with multiple functions. The HLA gene complex is highly variable, containing more than 20,000 HLA alleles and associated alleles known in the art, including more than 250 MHC class II α chain alleles and 5,000 MHC class II β chain alleles, encoding thousands of MHC class II proteins (see, for example, hla.alleles.org, last accessed May 20, 2019, which is incorporated herein by reference in its entirety). For example, one such HLA-DP allele, DP4, is the most common allele in many ethnic groups.

[0083] 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 are associated with MHC class II molecules and support their configuration and function.

[0084] When MHC class II molecules complex with antigenic peptides, the 10-30 amino acid-long antigenic peptide binds to a peptide-binding groove and is presented extracellularly to CD4+ cells. Both the α and β chains fold into two separate domains; α-1 and α-2 are for the α peptide, and β-1 and β-2 are for the β peptide. An open peptide-binding groove containing the presented antigen is found between the α-1 and β-1 domains. After interaction with CD4+ T cells, the MHC class II complex interacts with the T cell receptor (TCR) expressed on the T cell surface. Furthermore, the β chain of the MHC class II molecule interacts with the CD4 weakly interacting receptor (K-K) expressed on the T cell surface. D >2mM). The typical CD4 amino acid sequence (UniProt-P01730) is provided in 2 (SEQ ID NO:17).

[0085] Table 2. Human CD4 amino acid sequence

[0086]

[0087] The term "autologous" means any material derived from the same individual as the individual into whom the material is subsequently introduced. For example, autologous T-cell therapy involves administering T cells isolated from the same individual to a subject. The term "allogeneic" means any material derived from an individual and subsequently 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.

[0088] "Cancer" refers to a wide range of diseases characterized by the uncontrolled growth of abnormal cells in the body. Disordered cell division and growth lead to the formation of malignant tumors that invade adjacent tissues and can also metastasize to distant parts of the body via the lymphatic system or bloodstream. "Cancer" or "cancer tissue" can include tumors. Examples of cancers treatable by the methods of this invention include, but are not limited to, cancers of the immune system, including lymphoma, leukemia, and other white blood cell malignancies. In some aspects, the method of the present invention can be used to reduce the size of tumors originating from, for example, bone cancer, kidney cancer, prostate cancer, breast cancer, colon cancer, lung cancer, cutaneous or ocular malignant melanoma, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or ocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, 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), esophageal cancer, small bowel cancer, endocrine system cancer, etc. Thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, 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, kidney or ureter cancer, renal pelvis tumor, central nervous system (CNS) spurs, primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem gliomas, pituitary adenomas, 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 thereof. Certain cancers may be responsive to chemotherapy or radiation therapy, or may be refractory to treatment.

[0089] Refractory cancers are those that are not suitable for surgical intervention and that initially do not respond to chemotherapy or radiation therapy or become unresponsive over time.

[0090] As used in this article, "antitumor effect" refers to biological effects that can exist in the following forms: reduction in tumor volume, reduction in the number of tumor cells, reduction in tumor cell proliferation, reduction in the number of metastases, increase in overall survival or progression-free survival, increase in life expectancy, or improvement in various physiological symptoms associated with tumors. Antitumor effect can also refer to the prevention of tumor development, such as through vaccines.

[0091] The term “progression-free survival” may be abbreviated as PFS, which, as used herein, refers to the time from the date of treatment to the date of disease progression or death from any cause according to the revised IWG Response Criteria for Malignant Lymphoma.

[0092] "Disease progression" or "progressive disease" may be abbreviated as PD, which, as used herein, refers to the worsening of one or more symptoms associated with a specific 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.

[0093] "Duration of response" can be abbreviated as DOR, which, as used in this article, refers to the period between the date a subject first objectively responds and the date on which disease progression or death is confirmed according to the revised IWG response guidelines for malignant lymphoma.

[0094] The term "overall survival" can be abbreviated as OS, which is defined as the time from the date of treatment to the date of death.

[0095] As used herein, "cytokine" refers to a non-antibody protein released by a cell in response to contact with a specific antigen, wherein the cytokine interacts with a second cell to mediate a response in the second cell. Cytokines can be expressed endogenously by cells or administered to a subject. Cytokines can be released by immune cells, including macrophages, B cells, T cells, and mast cells, to propagate an immune response. Cytokines can induce various responses in recipient cells. Cytokines can include homeostatic cytokines, chemokines, pro-inflammatory cytokines, effectors, and acute-phase proteins. For example, homeostatic cytokines, including interleukin (IL)7 and IL-15, promote immune cell survival and proliferation, and pro-inflammatory cytokines can promote inflammatory responses. 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)γ. Examples of pro-inflammatory cytokines include, but are not limited to, IL-1a, IL-1b, IL-6, IL-13, IL-17a, tumor necrosis factor (TNF)-α, TNF-β, fibroblast growth factor (FGF)2, granulocyte-macrophage colony-stimulating factor (GM-CSF), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), vascular endothelial growth factor (VEGF), VEGF-C, VEGF-D, and placental growth factor (PLGF). Examples of effectors include, but are not limited to, granzyme A, granzyme B, soluble Fas ligand (sFasL), and perforin. Examples of acute-phase proteins include, but are not limited to, C-reactive protein (CRP) and serum amyloid A (SAA).

[0096] Chemokines are a class of cytokines that mediate cellular chemotaxis or directed movement. Examples of chemokines include, but are not limited to, IL-8, IL-16, eotaxin, eosinophil chemokine-3, macrophage-derived chemokines (MDC or CCL22), monocyte chemoattractant protein 1 (MCP-1 or CCL2), MCP-4, macrophage inflammatory protein 1α (MIP-1α, MIP-1a), MIP-1β (MIP-1b), γ-inducible protein 10 (IP-10), and thymus and activation-regulating chemokines (TARC or CCL17).

[0097] Other examples of analytes and cytokines in this invention include, but are not limited to, chemokine (CC 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), and leukemia inhibitory factor (LIF). Oncogene M (OSM), CD154, lymphotoxin (LT)β, 4-1BB ligand (4-1BBL), proliferation-inducing ligand (APRIL), CD70, CD153, CD178, glucocorticoid-induced TNFR-associated ligand (GITRL), tumor necrosis factor superfamily member 14 (TNFSF14), OX40L, TNF-associated and ApoL-associated leukocyte-expressed ligand 1 (TALL-1) or TNF-associated apoptosis-inducing ligand (TRAIL).

[0098] The “therapeutic effective amount,” “effective dose,” “effective amount,” or “therapeutic effective dose” of a drug or therapeutic agent is any amount by which a drug, when used alone or in combination with another therapeutic agent, prevents the onset of disease in a subject or promotes disease regression proven by a reduction in the severity of disease symptoms, an increase in the frequency and duration of asymptomatic periods of disease, or prevention of injury or disability caused by the suffering caused by the disease. The ability of a therapeutic agent to promote disease regression can be assessed using a variety of methods known to skilled practitioners, such as in human subjects during clinical trials, in animal model systems that predict efficacy in humans, or by assaying activity in vitro using an assay agent.

[0099] As used herein, the term "lymphocyte" includes natural killer (NK) cells, T cells, or B cells. NK cells are a class of cytotoxic / cell-toxic lymphocytes that represent a major component of the innate immune system. NK cells repel tumor cells and cells infected by viruses. They work through the process of apoptosis, or programmed cell death. They are called "natural killers" because they do not require activation to kill cells. T cells play a major role in cell-mediated immunity (without the involvement of antibodies). The T cell receptor (TCR) distinguishes T cells from other lymphocyte types. The thymus, a specialized organ of the immune system, is primarily responsible for the maturation of T cells. There are six types of T cells: helper T cells (e.g., CD4+ cells), cytotoxic T cells (also known as TC, cytotoxic T lymphocytes, CTL, T-killer cells, cytolytic T cells, CD8+ T cells, or killer T cells), memory T cells ((i) stem cell-like memory T cells), and memory T cells ((i) stem cell-like memory T cells). SCMCells (such as naïve 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, and exhibit many of the unique functional characteristics of memory cells; (ii) central memory T cells CM Cells express L-selectin and CCR7, secrete IL-2 but not IFNγ or IL-4, and (iii) however, effector memory T EM B cells 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 (NKTs), and γδ T cells. On the other hand, B cells play a major role in humoral immunity (involving antibodies). B cells produce antibodies and antigens and act as antigen-presenting cells (APCs), and become memory B cells after activation through antigen-antigen interactions. In mammals, immature B cells form in the bone marrow, from which the name B cell originates.

[0100] The terms "genetic engineering" or "engineering" refer to methods of modifying the genome of cells, including but not limited to deleting coding or non-coding regions or portions thereof, or inserting coding regions or portions thereof. In some aspects, the modified cells are lymphocytes, such as T cells, or modified cells expressing CD4, which may be obtained from a patient or donor. Cells may be modified to express exogenous constructs incorporated into the cell's genome, such as the T cell receptor (TCR) disclosed herein. In some aspects, cells are modified to express CD4.

[0101] "Immune response" refers to the action of cells of the immune system (such as T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells, and neutrophils) and soluble macromolecules (including antibodies, cytokines, and complement) produced by any of these cells or the liver, which cause selective targeting, binding, damage, destruction, and / or elimination of invading pathogens, pathogen-infected cells or tissues, cancer cells or other abnormal cells, or normal human cells or tissues in cases of autoimmunity or pathological inflammation in vertebrates.

[0102] The term "immunotherapy" refers to the treatment of a subject who has a disease or is at risk of contracting or relapsing from a disease by means of methods including inducing, enhancing, suppressing, or otherwise altering the immune response. Examples of immunotherapy include, but are not limited to, T-cell therapy. T-cell therapy may include adoptive T-cell therapy, tumor-infiltrating lymphocyte (TIL) immunotherapy, autologous cell therapy, engineered autologous cell therapy (eACT), and allogeneic T-cell transplantation.

[0103] Cells used in the immunotherapy described herein may be derived from any source known in the art. For example, T cells may be distinguishable from hematopoietic stem cell populations in vitro, or T cells may be obtained from the subject. T cells may be obtained from, for example, peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from the site of infection, ascites, pleural effusion, spleen tissue, and tumors. Furthermore, T cells may be derived from one or more T cell lines available in the art. T cells may also be obtained from sources known to those skilled in the art, such as FICOLL. TM Any number of techniques for isolating and / or apheresis of blood components can be used to collect a unit of blood from a subject. Other methods for isolating T cells for T-cell therapy are disclosed in U.S. Patent Publication No. 2013 / 0287748, which is incorporated herein by reference in its entirety. Immunotherapy may also include administering modified cells to a subject, wherein the modified cells express CD4 and the TCR disclosed herein. In some aspects, the modified cells are not T cells.

[0104] As used herein, “patient” includes anyone with cancer (such as lymphoma or leukemia). The terms “subject” and “patient” are used interchangeably in this document.

[0105] The terms “peptide,” “polypeptide,” and “protein” are used interchangeably and refer to compounds containing 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 in a sequence that may contain a protein or peptide. A polypeptide includes any peptide or protein containing two or more amino acids linked together by peptide bonds. As used herein, the term refers to a short chain, which is also commonly referred to in the art, for example, as a peptide, oligopeptide, and oligomer; and to a longer chain, which is commonly referred to in the art, as a protein, which exists in many types. “Polypeptide” includes, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, polypeptide variants, modified polypeptides, derivatives, analogs, fusion proteins, etc. Polypeptides include natural peptides, recombinant peptides, synthetic peptides, or combinations thereof.

[0106] As used herein, “stimulus” refers to a major response induced by the binding of a stimulating molecule to its homologous ligand, wherein the binding mediates a signal transduction event. A “stimulating molecule” is a molecule on a T cell that specifically binds to a homologous stimulating ligand present on an antigen-presenting cell, such as the T cell receptor (TCR) / CD4 complex. A “stimulating ligand” is a ligand that, when present on an antigen-presenting cell (e.g., aAPC, dendritic cells, B cells, and similar cells), can specifically bind to a stimulating molecule on a T cell, thereby mediating a major response induced by the T cell, including but not limited to activation, initiation of an immune response, proliferation, and similar responses. Stimulating ligands include, but are not limited to, peptide-loaded MHC class II molecules, anti-CD4 antibodies, hyperagonist anti-CD2 antibodies, hyperagonist anti-CD28 antibodies, and hyperagonist anti-CD3 antibodies.

[0107] The terms “treatment” and “pretreatment” are used interchangeably herein and refer to preparation for a patient requiring T-cell therapy for an appropriate situation. Treatment as used herein includes, but is not limited to, reducing the number of endogenous lymphocytes prior to T-cell therapy, removing the cytokine sink, increasing serum levels of one or more homeostatic cytokines or pro-inflammatory factors, enhancing the effector function of T cells administered after treatment, enhancing antigen-presenting cell activation and / or availability, or any combination thereof. In one aspect, “treatment” includes increasing serum levels of one or more cytokines, such as interleukin-7 (IL-7), interleukin-15 (IL-15), interleukin-10 (IL-10), interleukin-5 (IL-5), γ-inducible protein 10 (IP-10), interleukin-8 (IL-8), monocyte chemoattractant protein 1 (MCP-1), placental growth factor (PLGF), C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), or any combination thereof. In another aspect, “treatment” includes increasing serum levels of IL-7, IL-15, IP-10, MCP-1, PLGF, CRP, or any combination thereof.

[0108] "Treatment / treating" in a subject refers to any type of intervention or treatment administered to the subject or to an active agent intended to reverse, alleviate, improve, suppress, slow, or prevent the onset, progression, development, severity, or recurrence of symptoms, complications, or lesions or biochemical markers associated with the disease. In one context, "treatment / treating" includes partial remission. In another context, "treatment / treating" includes complete remission.

[0109] The use of substitution (e.g., "or") should be understood to mean one, both, or any combination of the substitutes. As used herein, the indefinite article "a / kind" should be understood to mean "a / kind or more / kinds" of any of the described or enumerated components.

[0110] The terms “about” or “substantially comprise” refer to a specific value or composition that, as determined by a person skilled in the art, is within an acceptable margin of error, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measuring system. For example, “about” or “substantially comprise” may mean within one or more standard deviations according to convention in the art. Alternatively, “about” or “substantially comprise” may mean a range of up to 10% (i.e., ±10%). For example, about 3 mg may include any number between 2.7 mg and 3.3 mg (for 10%). Furthermore, specifically in relation to biological systems or methods, the term may mean up to an order of magnitude or up to five times the value. When specific values ​​or compositions are provided in this application and claims, unless otherwise stated, the meaning of “about” or “substantially comprise” should be assumed to be within an acceptable margin of error for said specific value or composition.

[0111] Unless otherwise stated, as described herein, any concentration range, percentage range, ratio range, or integer range shall be understood to include any integer value within the range and (where appropriate) its fraction (such as tenths and percentes of an integer).

[0112] The various aspects of the invention are described in more detail in the following sections.

[0113] II. Compositions disclosed herein

[0114] This disclosure relates to a T-cell receptor (TCR) or its antigen-binding portion that specifically binds to an epitope on CCND1, a nucleic acid molecule encoding said TCR, and a cell containing said TCR or said nucleic acid molecule. Some aspects of the invention relate to a method of treating cancer in a subject of need, the method comprising administering to the subject cells containing the TCR described herein. Other aspects of this disclosure relate to an epitope of CCND1 that binds to a TCR, and an HLA class II molecule complexed with a peptide containing the epitope of CCND1.

[0115] T-cell receptors, or TCRs, are molecules present on the surface of T cells or T lymphocytes that are responsible for recognizing fragments of antigens as peptides that bind to the major histocompatibility complex (MHC) molecule. The binding between TCRs and antigenic peptides has a relatively low affinity and is degenerate: in other words, many TCRs recognize the same antigenic peptides and many antigenic peptides are recognized by the same TCRs.

[0116] The TCR consists of two distinct protein chains (in other words, it is a heterodimer). In 95% of human T cells, the TCR is composed of an α (α) chain and a β (β) chain (encoded by TRA and TRB, respectively), but in 5% of human T cells, the TCR is composed of a γ and a δ (γ / δ) chain (encoded by TRG and TRD, respectively). This ratio varies during ontogeny and in disease states (such as leukemia). It also differs between species. Orthologs of four loci have been located in various species. Each locus can produce a variety of polypeptides with constant and variable regions.

[0117] When the TCR binds to the antigenic peptide and MHC (peptide / MHC), T lymphocytes are activated through signal transduction, which is a series of biochemical events mediated by related enzymes, co-receptors, specialized adaptor molecules, and activated or released transcription factors.

[0118] II.A. Nucleic acid molecules

[0119] Certain aspects of this disclosure relate to nucleic acid molecules comprising (i) a first nucleotide sequence encoding a recombinant TCR or its antigen-binding portion (“anti-CCND1 TCR”) that specifically binds to human CCND1; and (ii) a second nucleotide sequence, wherein the second nucleotide sequence or a polypeptide encoded by the second nucleotide sequence inhibits the expression of an endogenous TCR. In some aspects, the second nucleotide sequence is a non-naturally occurring sequence. In other aspects, the second nucleotide sequence is synthetic. In other aspects, the second nucleotide sequence comprises a sequence that targets a nucleotide sequence encoding an endogenous TCR. In some aspects, the anti-CCND1 TCR cross-competitively binds to human CCND1 with a reference TCR. In some aspects, the anti-CCND1 TCR binds to the same or overlapping epitopes of human CCND1 as the reference TCR.

[0120] In some aspects, the reference TCR comprises an α chain and a β chain; wherein the α chain comprises complementarity-determining regions 1 (CDR1), CDR2, and CDR3; wherein the β chain comprises CDR1, CDR2, and CDR3; and wherein the reference TCR comprises the α chain CDR3 listed in SEQ ID NO:7 and the β chain CDR3 listed in SEQ ID NO:10. In some aspects, the α chain CDR1, CDR2, and CDR3 sequences are present in the amino acid sequences listed in SEQ ID NO:1, and the reference TCR comprises the β chain CDR1, CDR2, and CDR3 sequences present in the amino acid sequences listed in SEQ ID NO:2. In some aspects, the reference TCR comprises an α chain and a β chain, wherein the α chain comprises the amino acid sequences as listed in SEQ ID NO:1 and the β chain comprises the amino acid sequences as listed in SEQ ID NO:2.

[0121] Table 3. TCR sequences of α-chain and β-chain

[0122]

[0123]

[0124] II.A.1. TCR encoded by the first nucleotide sequence

[0125] This disclosure relates to a TCR encoded by a first nucleotide sequence described herein. In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises an α chain and a β chain, wherein the α chain comprises variable domains containing α chain CDR1, α chain CDR2, and α chain CDR3; and wherein the β chain comprises variable domains containing β chain CDR1, β chain CDR2, and β chain CDR3. In some aspects, the anti-CCND1 TCR comprises an α chain CDR3 containing the amino acid sequence listed in SEQ ID NO:7 (CAVCTLYNFNKFYF). In some aspects, the anti-CCND1 TCR comprises a β chain CDR3 containing the amino acid sequence listed in SEQ ID NO:10 (CASLTDNNEQFF). In some aspects, the non-CDR regions in the α chain and / or β chain are further modified, for example, by substitution or mutation of one, two, three, four, five, or six amino acids, such that the α chain and / or β chain are not naturally occurring. In some respects, substitution or mutation can improve the TCR described herein in various ways, such as binding affinity, binding specificity, stability, viscosity, or any combination thereof.

[0126] In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises an α-chain CDR1, wherein the α-chain CDR1 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:5 (VSNAYN). In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises a β-chain CDR1, wherein the β-chain CDR1 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:8 (MNHEY).

[0127] In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises an α-chain CDR2, wherein the α-chain CDR2 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:6 (GSKP). In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises a β-chain CDR2, wherein the β-chain CDR2 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:9 (SVGAGI).

[0128] In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises an α-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 with the variable domain of the α-chain amino acid sequence listed in SEQ ID NO:1. In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises an α-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 with the variable domain of the α-chain amino acid sequence listed in SEQ ID NO:1, wherein the anti-CCND1 TCR comprises an α-chain CDR3 containing the amino acid sequence as listed in SEQ ID NO:7. In some respects, the anti-CCND1 TCR encoded by the first nucleotide sequence contains the α-chain variable domain present in the α-chain amino acid sequence listed in SEQ ID NO:1.

[0129] In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises a β-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 with the variable domain of the β-chain amino acid sequence listed in SEQ ID NO:2. In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises a β-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 with the variable domain of the β-chain amino acid sequence listed in SEQ ID NO:2, wherein the anti-CCND1 TCR comprises a β-chain CDR3 containing the amino acid sequence as listed in SEQ ID NO:10. In some respects, the anti-CCND1 TCR encoded by the first nucleotide sequence contains a β-chain variable domain present in the amino acid sequence listed in SEQ ID NO:2.

[0130] In some aspects, the anti-CCND1 TCR encoded by the first nucleotide also includes an α-chain constant region, a β-chain constant region, or both an α-chain constant region and a β-chain constant region. In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence includes an α-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 with the constant region of the α-chain amino acid sequence listed in SEQ ID NO:1. In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises an α-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 with the constant region of the α-chain amino acid sequence listed in SEQ ID NO:1, wherein the anti-CCND1 TCR comprises an α-chain CDR3 containing the amino acid sequence as listed in SEQ ID NO:7. In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises an α-chain constant region present in the α-chain amino acid sequence listed in SEQ ID NO:1. In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence further comprises an α-constant region different from an endogenous (e.g., naturally occurring) constant region of the α-chain. In some aspects, the α-chain constant region comprises an amino acid sequence with 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 α-chain listed in SEQ ID NO:1.

[0131] In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises a β-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 with the constant region of the β-chain amino acid sequence listed in SEQ ID NO:2. In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises a β-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 with the constant region of the β-chain amino acid sequence listed in SEQ ID NO:2, wherein the anti-CCND1 TCR comprises a β-chain CDR3 containing the amino acid sequence listed in SEQ ID NO:10. In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence includes a β-chain constant region present in the amino acid sequence listed in SEQ ID NO:2. In some aspects, the anti-CCND1 TCR encoded by the first nucleotide also includes a β-constant region that is an endogenous (e.g., naturally occurring) constant region different from the β-chain. In some aspects, the β-chain constant region includes 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 β-chain amino acid sequence listed in SEQ ID NO:2.

[0132] In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises an α-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 with the α-chain amino acid sequence listed in SEQ ID NO:1. In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises an α-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 with the α-chain amino acid sequence listed in SEQ ID NO:1, wherein the anti-CCND1 TCR comprises an α-chain CDR3 containing the amino acid sequence listed in SEQ ID NO:7. In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises an α-chain containing the amino acid sequence listed in SEQ ID NO:1.

[0133] In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises a β-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 with the β-chain amino acid sequence listed in SEQ ID NO:2. In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises a β-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 with the β-chain amino acid sequence listed in SEQ ID NO:2, wherein the anti-CCND1 TCR comprises a β-chain CDR3 containing the amino acid sequence listed in SEQ ID NO:10. In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises a β-chain containing the amino acid sequence listed in SEQ ID NO:2.

[0134] In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence comprises an α-chain constant region, a β-chain constant region, or both; and wherein the α-chain constant region, the β-chain constant region, or both comprise an amino acid sequence having at least one, at least two, at least three, at least four, or at least five substituted amino acid sequences relative to the endogenous TCR within the target sequence.

[0135] In some aspects, the α-chain of the anti-CCDN1 TCR encoded by the first nucleotide sequence also includes a signal peptide. Any signal peptide may be used in the anti-CCDN1 TCR α-chain disclosed herein. In some aspects, the signal peptide is a naturally occurring TCR α-chain signal peptide. In some aspects, the signal peptide comprises an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity with the amino acid sequence listed in SEQ ID NO:21. In some aspects, the signal peptide is a heterologous signal peptide, such as a signal peptide derived from a protein other than the TCR α-chain. In some aspects, the signal peptide is a synthetic signal peptide. In some aspects, the signal peptide comprises an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity with the amino acid sequence listed in SEQ ID NO: 20 or 22. In some aspects, the α chain of the CCND1 TCR encoded by the first nucleotide sequence does not contain a signal peptide.

[0136] In some aspects, the signal peptide of the α chain is encoded by a nucleic acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity with the nucleic acid sequence listed in SEQ ID NO:23 or 24.

[0137] In some aspects, the β-chain of the anti-CCDN1 TCR encoded by the first nucleotide sequence also includes a signal peptide. Any signal peptide may be used in the anti-CCDN1 TCR β-chain disclosed herein. In some aspects, the signal peptide is a naturally occurring TCR β-chain signal peptide. In some aspects, the signal peptide comprises an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity with the amino acid sequence listed in SEQ ID NO:22. In some aspects, the signal peptide is a heterologous signal peptide, such as a signal peptide derived from a protein other than the TCR β-chain. In some aspects, the signal peptide is a synthetic signal peptide. In some aspects, the signal peptide comprises an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity with the amino acid sequence listed in SEQ ID NO: 20 or 21. In some aspects, the β chain of the CCND1 TCR encoded by the first nucleotide sequence does not contain a signal peptide.

[0138] In some aspects, the signal peptide of the β chain is encoded by a nucleic acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity with the nucleic acid sequence listed in SEQ ID NO:23 or 24.

[0139] In some aspects, each of the α-chain and β-chain of the anti-CCND1 TCR encoded by the first nucleotide sequence also contains a signal peptide. In some aspects, the signal peptide of the α-chain is the same as the signal peptide of the β-chain. In some aspects, the signal peptide of the α-chain is different from the signal peptide of the β-chain.

[0140] II.A.2. Epitope

[0141] In some aspects, the anti-CCND1 TCR encoded by the first nucleotide sequence binds to the same epitope as the reference TCR. In some aspects, the anti-CCND1 TCR binds to an epitope of CCND1 comprising the amino acid sequence listed in SEQ ID NO:13 (SPNNFLSYYRLTRFLSRVIK). In some aspects, the anti-CCND1 TCR binds to an epitope of CCND1 consisting of the amino acid sequence as listed in SEQ ID NO:13. In some aspects, the epitope consists of amino acid residues 219-238 of CCND1 (SEQ ID NO:16), for example, “CCND1”. 219-238 ".

[0142] In some aspects, the epitope is part of a larger polypeptide, for example, a peptide comprising an epitope sequence and (i) one or more additional amino acids located at the N-terminus of the epitope sequence and / or (ii) one or more additional amino acids located at the C-terminus of the epitope sequence. In some aspects, the length of 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 some aspects, the length of the polypeptide containing the epitope is at least about 5 to at least about 10, at least about 5 to at least about 15, at least about 5 to at least about 20, at least about 10 to at least about 15, at least about 10 to at least about 20, at least about 10 to at least about 25, at least about 10 to at least about 30, at least about 10 to at least about 35, at least about 10 to at least about 40, at least about 10 to at least about 45, at least about 10 to at least about 50, at least about 15 to at least about 20, at least about 15 to at least about 25, at least about 15 to at least about 30, at least about 15 to at least about 35, at least about 15 to at least about 40, at least about 15 to at least about 45, or at least about 15 to at least about 50 amino acids.

[0143] In some aspects, the polypeptide containing an epitope comprises an epitope and at least about 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 additional amino acids located at the N-terminus of the epitope. In some aspects, the polypeptide containing an epitope comprises an epitope and at least about 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 additional amino acids located at the C-terminus of the epitope.

[0144] In some respects, epitopes are associated with HLA class II molecules. The human leukocyte antigen (HLA) system (the major histocompatibility complex [MHC] in humans) is an important part of the immune system and is controlled by genes located on chromosome 6. It encodes cell surface molecules that are specialized to present antigenic peptides to T cell receptors (TCRs) on T cells. (See also Overview of the Immune System.) Antigen-presenting MHC molecules are divided into two main classes: class I MHC molecules and class II MHC molecules.

[0145] Class II MHC molecules exist as transmembrane glycoproteins on the surface of professional antigen-presenting cells (APCs). A complete class II molecule consists of an α-chain and a β-chain. The gene encoding the α-chain of a class II MHC molecule consists of five exons, and the gene encoding the β-chain consists of six exons. Exon 1 encodes a leader peptide, exons 2 and 3 encode two extracellular domains, and exons 4 and 5 contribute to the transmembrane domains and cytoplasmic tails of each of the α and β subunits. Three loci in the HLA complex encode class II MHC proteins: HLA-DR, HLA-DQ, and HLA-DP. T cells expressing CD4 molecules respond to class II MHC molecules. These lymphocytes typically possess cytotoxic functions and activate responses to eliminate self-infected intracellular pathogens or destroy extracellular parasites. Because only professional antigen-presenting cells (APCs) express class II MHC molecules, only these cells present the antigens of CD4 T cells (CD4 binds to the non-polymorphic portions of the α-2 and β-2 domains of the α and β chains of the class II MHC molecules, respectively).

[0146] In some respects, the HLA class II α and β chains are selected from the HLA-DR, HLA-DP, and HLA-DQ alleles. In some respects, the HLA class II α chain is the HLA-DR α chain. In some respects, the HLA class II β chain is the HLA-DR β chain. In some respects, the HLA class II α chain is the HLA-DP α chain. In some respects, the HLA class II β chain is the HLA-DP β chain. In some respects, the HLA class II α chain is the HLA-DQ α chain. In some respects, the HLA class II β chain is the HLA-DQ β chain.

[0147] Many HLA-DR, HLA-DP, and HLA-DQ alleles are known in the art, and any of the known alleles may be used in this disclosure. An updated list of HLA alleles is available at hla.alleles.org / (last accessed June 18, 2019), which is incorporated herein by reference in its entirety.

[0148] II.A.3 Second nucleotide sequence

[0149] The second nucleotide sequence of the nucleic acid molecule disclosed herein may be any sequence capable of inhibiting the expression of endogenous TCR or any polypeptide capable of inhibiting the expression of endogenous TCR. In some aspects, the second nucleotide sequence is one or more siRNAs. In some aspects, one or more siRNAs are complementary to a target sequence within the nucleotide sequence encoding a constant region of the endogenous TCR. In some aspects, one or more siRNAs are complementary to a target sequence within the nucleotide sequence encoding a constant region of the wild-type human TCR. In some aspects, one or more siRNAs are complementary to a target sequence within the nucleotide sequence encoding a constant region of the α chain of the wild-type TCR. In some aspects, one or more siRNAs are complementary to a target sequence within the nucleotide sequence encoding a constant region of the β chain of the wild-type TCR. In some aspects, one or more siRNAs comprise (i) one or more siRNAs complementary to a target sequence within the nucleotide sequence encoding a constant region of the α chain of the wild-type TCR and (ii) one or more siRNAs complementary to a target sequence within the nucleotide sequence encoding a constant region of the β chain of the wild-type TCR.

[0150] In some aspects, one or more siRNAs comprise nucleotide sequences selected from the group consisting of SEQ ID NO:25-28 (Table 4). In some aspects, a second nucleotide sequence of a nucleic acid molecule encodes one or more siRNAs, wherein said one or more siRNAs are complementary to a target sequence within a nucleotide sequence encoding a constant region of the α chain of a wild-type TCR, and wherein said one or more siRNAs comprise nucleic acid sequences listed in SEQ ID NO:25 and 26.

[0151] Table 4. siRNA sequences

[0152]

[0153] In some aspects, the second nucleotide sequence of a nucleic acid molecule encodes one or more siRNAs, wherein the one or more siRNAs are complementary to a target sequence within a nucleotide sequence encoding a constant region of the β chain of a wild-type TCR, and wherein the one or more siRNAs comprise the nucleic acid sequences listed in SEQ ID NO:27 and 28. In some aspects, the second nucleotide sequence of a nucleic acid molecule encodes one or more siRNAs, wherein the one or more siRNAs comprise (i) one or more siRNAs complementary to a target sequence within a nucleotide sequence encoding a constant region of the α chain of a wild-type TCR, wherein the one or more siRNAs comprise the nucleic acid sequences listed in SEQ ID NO:25 and 26; and (ii) one or more siRNAs complementary to a target sequence within a nucleotide sequence encoding a constant region of the β chain of a wild-type TCR, wherein the one or more siRNAs comprise the nucleic acid sequences listed in SEQ ID NO:27 and 28.

[0154] In some aspects, the second nucleotide sequence of the nucleic acid molecule comprises SEQ ID NO:25-28. In some aspects, the second nucleotide sequence comprises SEQ ID NO:25-28, wherein one or more of SEQ ID NO:25-28 are separated by one or more nucleic acids that do not encode siRNA. In some aspects, the one or more siRNAs are selected from the siRNAs disclosed in U.S. Publication No. 2010 / 0273213A1, which is incorporated herein by reference in its entirety.

[0155] In some respects, the second nucleotide sequence of a nucleic acid molecule encodes a protein that can suppress the expression of an endogenous (e.g., wild-type) TCR. In some respects, the second nucleotide sequence encodes Cas9.

[0156] II.A.3 carrier

[0157] Some aspects of this invention relate to vectors comprising 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.

[0158] In some aspects, the vector is a retroviral vector. In some aspects, the vector is selected from the group consisting of: adenovirus vectors, lentiviruses, Sendai virus, baculovirus vectors, Epstein-Barr virus vectors, lactoviral vectors, vaccinia virus vectors, herpes simplex virus vectors, and adeno-associated virus (AAV) vectors. 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 Sendai virus. In some aspects, the vector is a hybrid vector. Examples of hybrid vectors that can be used in this invention can be found in Huang and Kamihira, Biotechnol. Adv. 31(2):208-23(2103), which is incorporated herein by reference in its entirety.

[0159] II.B. Recombinant T-cell receptor (TCR)

[0160] Some aspects of the present invention relate to the specific binding of the recombinant T-cell receptor (TCR) of human CCND1 or its antigen-binding moiety (“anti-CCND1 TCR”). In some aspects, the anti-CCND1 TCR is encoded by a nucleic acid molecule disclosed herein.

[0161] In some aspects, the anti-CCND1 TCR cross-competitively binds to human CCND1 with a reference TCR. In some aspects, the anti-CCND1 TCR binds to the same or overlapping epitopes of human CCND1 with the reference TCR. In some aspects, the reference TCR comprises an α chain and a β chain, and the α chain of the reference TCR comprises the amino acid sequence as listed in SEQ ID NO:1. In some aspects, the β chain of the reference TCR comprises the amino acid sequence as listed in SEQ ID NO:2.

[0162] In some aspects, the anti-CCND1 TCR comprises an α chain and a β chain, wherein the α chain comprises a constant region, and wherein the β chain comprises a constant region; wherein the constant region of the α chain 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 α chain comprising the amino acid sequence listed in SEQ ID NO:1. In some aspects, the anti-CCND1 TCR comprises an α chain and a β chain, wherein the α chain comprises a constant region, and wherein the β chain comprises a constant region; wherein the constant region of the β chain 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 β chain comprising the amino acid sequence listed in SEQ ID NO:2.

[0163] In some aspects, the anti-CCND1 TCR comprises an α chain and a β chain, wherein the α chain comprises a constant region, and wherein the β chain comprises a constant region; wherein (i) the α chain constant region comprises an amino acid sequence having at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions relative to the constant region of the α chain comprising the amino acid sequence listed in SEQ ID NO:1; and (ii) the β chain constant region comprises an amino acid sequence having at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions relative to the constant region of the β chain comprising the amino acid sequence listed in SEQ ID NO:2.

[0164] In some aspects, the α-chain of the anti-CCND1 TCR includes variable domains containing α-chain CDR1, α-chain CDR2, and α-chain CDR3; and the β-chain of the anti-CCND1 TCR includes variable domains containing β-chain CDR1, β-chain CDR2, and β-chain CDR3. In some aspects, the anti-CCND1 TCR includes an α-chain CDR3 containing the amino acid sequence listed in SEQ ID NO:7. In some aspects, the anti-CCND1 TCR includes a β-chain CDR3 containing the amino acid sequence listed in SEQ ID NO:10.

[0165] In some aspects, the α-chain CDR1 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:5. In some aspects, the β-chain CDR1 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:8.

[0166] In some aspects, the α-chain CDR2 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:6. In some aspects, the β-chain CDR2 of the anti-CCND1 TCR comprises the amino acid sequence as listed in SEQ ID NO:9.

[0167] In some aspects, the anti-CCND1 TCR comprises an α-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 with the variable domain of the α-chain amino acid sequence listed in SEQ ID NO:1. In some aspects, the anti-CCND1 TCR comprises an α-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 with the variable domain of the α-chain amino acid sequence listed in SEQ ID NO:1, wherein the anti-CCND1 TCR comprises an α-chain CDR3 containing the amino acid sequence as listed in SEQ ID NO:7. In some aspects, the anti-CCND1 TCR comprises an α-chain variable domain present in the α-chain amino acid sequence listed in SEQ ID NO:1.

[0168] In some aspects, the anti-CCND1 TCR comprises a β-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 with the variable domain of the β-chain amino acid sequence listed in SEQ ID NO:2. In some aspects, the anti-CCND1 TCR comprises a β-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 with the variable domain of the β-chain amino acid sequence listed in SEQ ID NO:2, wherein the anti-CCND1 TCR comprises a β-chain CDR3 containing the amino acid sequence as listed in SEQ ID NO:10. In some aspects, the anti-CCND1 TCR comprises a β-chain variable domain present in the β-chain amino acid sequence listed in SEQ ID NO:2.

[0169] In some aspects, the anti-CCND1 TCR encoded by the first nucleotide further comprises an α-chain constant region, a β-chain constant region, or both an α-chain constant region and a β-chain constant region. In some aspects, the anti-CCND1 TCR comprises an α-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 with the constant region of the α-chain amino acid sequence listed in SEQ ID NO:1. In some aspects, the anti-CCND1 TCR comprises an α-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 with the constant region of the α-chain amino acid sequence listed in SEQ ID NO:1, wherein the anti-CCND1 TCR comprises an α-chain CDR3 containing the amino acid sequence as listed in SEQ ID NO:7. In some aspects, the anti-CCND1 TCR includes an α-chain constant region present in the α-chain amino acid sequence listed in SEQ ID NO:1. In some aspects, the anti-CCND1 TCR encoded by the first nucleotide also includes an α-constant region that is an endogenous (e.g., naturally occurring) constant region different from the α-chain. In some aspects, the α-chain constant region includes 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 α-chain amino acid sequence listed in SEQ ID NO:1.

[0170] In some aspects, the anti-CCND1 TCR comprises a β-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 with the constant region of the β-chain amino acid sequence listed in SEQ ID NO:2. In some aspects, the anti-CCND1 TCR comprises a β-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 with the constant region of the β-chain amino acid sequence listed in SEQ ID NO:2, wherein the anti-CCND1 TCR comprises a β-chain CDR3 containing the amino acid sequence as listed in SEQ ID NO:10. In some aspects, the anti-CCND1 TCR comprises a β-chain constant region present in the β-chain amino acid sequence listed in SEQ ID NO:2. In some aspects, the anti-CCND1 TCR encoded by the first nucleotide also includes a β constant region, which is an endogenous (e.g., naturally occurring) constant region different from the β chain. In some aspects, the β chain constant region includes an amino acid sequence relative to the β chain amino acid sequence listed in SEQ ID NO:2, comprising an amino acid sequence with at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions.

[0171] In some aspects, the anti-CCND1 TCR comprises an α-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 with the α-chain amino acid sequence listed in SEQ ID NO:1. In some aspects, the anti-CCND1 TCR comprises an α-chain CDR3 containing the amino acid sequence listed in SEQ ID NO:7. In some aspects, the anti-CCND1 TCR comprises an α-chain containing the amino acid sequence listed in SEQ ID NO:1.

[0172] In some aspects, the anti-CCND1 TCR comprises a β-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 with the β-chain amino acid sequence listed in SEQ ID NO:2. In some aspects, the anti-CCND1 TCR comprises a β-chain CDR3 containing the amino acid sequence listed in SEQ ID NO:10. In some aspects, the anti-CCND1 TCR comprises a β-chain containing the amino acid sequence listed in SEQ ID NO:2.

[0173] In some aspects, the anti-CCND1 TCR comprises an α-chain constant region, a β-chain constant region, or both; and wherein the α-chain constant region, the β-chain constant region, or both comprise an amino acid sequence having at least one, at least two, at least three, at least four, or at least five substituted amino acid sequences relative to the endogenous TCR within the target sequence.

[0174] II.B.2. Epitope

[0175] In some aspects, the anti-CCND1 TCR binds to the same epitope as the reference TCR. In some aspects, the anti-CCND1 TCR binds to an epitope of CCND1 comprising the amino acid sequence listed in SEQ ID NO:13. In some aspects, the anti-CCND1 TCR binds to an epitope of CCND1 consisting of an amino acid sequence as listed in SEQ ID NO:13. In some aspects, the epitope consists of amino acid residues 219-238 of CCND1 (SEQ ID NO:16), for example, “CCND1”. 219-238 ".

[0176] In some respects, the epitope is complexed with HLA class II molecules. In some respects, HLA class II molecules contain both α and β chains. In some respects, the α chain is selected from HLA-DRα, HLA-DPα, and HLA-DQα chains. In some respects, the β chain is selected from HLA-DRβ, HLA-DPβ, and HLA-DQβ chains. In some respects, HLA class II molecules contain both HLA-DRα and HLA-DRβ chains. In some respects, HLA class II molecules contain both HLA-DPα and HLA-DPβ chains. In some respects, HLA class II molecules contain both HLA-DQα and HLA-DQβ chains.

[0177] Many HLA-DR, HLA-DP, and HLA-DQ alleles are known in the art, and any of these known alleles may be used in this disclosure. An updated list of HLA alleles is available at hla.alleles.org / (last accessed February 27, 2019), which is incorporated herein by reference in its entirety.

[0178] II.B.3. Bispecific T-cell receptor (TCR)

[0179] Certain aspects of this disclosure relate to a bispecific TCR comprising a first antigen-binding domain and a second antigen-binding domain, wherein the first antigen-binding domain comprises a TCR disclosed herein or an antigen-binding portion thereof. In some aspects, the first antigen-binding domain comprises a single-stranded variable fragment (“scFv”).

[0180] In some aspects, the second antigen-binding domain specifically binds to proteins expressed on the surface of T cells. Any protein expressed on the surface of T cells can be targeted by the bispecific antibody disclosed herein. In some aspects, the protein expressed on the surface of T cells is not expressed by other cells. In some aspects, the protein expressed on the surface of T cells is expressed on the surface of one or more other human immune cells. In some aspects, the protein expressed on the surface of T cells is expressed on the surface of one or more other human immune cells, but not on the surface of human non-immune cells. In some aspects, the second antigen-binding domain specifically binds to proteins selected from the following expressed on the surface of T cells: CD3, CD4, CD2, CD5, CD6, CD8, CD11a (LFA-1α), CD43, CD45, and CD53. In some aspects, the second antigen-binding domain specifically binds to CD3. In some aspects, the second antigen-binding domain specifically binds to CD4. In some aspects, the second antigen-binding domain includes scFv.

[0181] In some aspects, the first antigen-binding domain and the second antigen-binding domain are linked or associated by covalent bonds. In some aspects, the first antigen-binding domain and the second antigen-binding domain are linked by peptide bonds.

[0182] II.C. Cells expressing TCR

[0183] Certain aspects of this disclosure relate to cells comprising the nucleic acid molecules disclosed herein, the vectors disclosed herein, the recombinant TCRs disclosed herein, the bispecific TCRs disclosed herein, or any combination thereof. Any cell may be used in this disclosure.

[0184] In some respects, the cell expresses CD4. CD4 expression can be natural, for example, CD4 can be expressed from a nucleic acid sequence that is expressed endogenously within the cell. For example, T cells, monocytes, macrophages, dendritic cells, and natural killer (NK) cells naturally express CD4. Therefore, in some respects, the cell is a T cell, monocyte, macrophage, dendritic cell, or natural killer cell. In some respects, the cell is a T cell selected from natural killer T (NKT) cells and innate lymphoid cells (ILC). In some respects, the cell is a monocyte. In some respects, the cell is a macrophage. In some respects, the cell is a dendritic cell.

[0185] In some respects, the T cells are isolated from a human subject. In some respects, the human subject is the same subject who will ultimately receive T-cell therapy. In other respects, the subject is a donor subject, wherein the donor subject is not the same subject who will receive T-cell therapy.

[0186] In some aspects, the cell is a cell that does not naturally express CD4, wherein the cell has been modified to express CD4. In some aspects, the cell contains a transgene encoding CD4, wherein the transgene is expressed by the cell. In some aspects, the cell contains a transgene encoding a protein encoding endogenous CD4 expression in activated cells. In some aspects, the cell contains a transgene encoding a protein or siRNA encoding a CD4 expression inhibitor in the cell. In some aspects, the transgene is incorporated into the cell's genome. In some aspects, the transgene is not incorporated into the cell's genome.

[0187] In some respects, cells modified to express CD4 are isolated from human subjects. In some respects, the human subject is the same subject who will ultimately receive the cell therapy. In other respects, the subject is a donor subject, wherein the donor subject is not the same subject who will receive the cell therapy.

[0188] II.D.HLA class II molecules

[0189] Some aspects of this disclosure relate to an HLA class II molecule complexed with a peptide, wherein the peptide comprises the amino acid sequence listed in SEQ ID NO:13. In some aspects, the peptide consists of the amino acid sequence listed in SEQ ID NO:13.

[0190] In some aspects, the HLA class II molecule is an HLA-DR, HLA-DP, or HLA-DQ allele. In some aspects, the HLA class II molecule is any HLA allele disclosed at hla.alleles.org / (last accessed February 27, 2019).

[0191] In some respects, HLA class II molecules contain both an α chain and a β chain. In some respects, the α chain sequence is selected from any of the HLA α chain protein sequences available at hla.alleles.org (last accessed February 27, 2019).

[0192] II.D.1. HLA-DP class II molecules

[0193] In some aspects, the α chain is the HLA-DPα chain. Any HLA-DPα chain allele known in the art may be used in the compositions and methods disclosed herein. In some aspects, the α chain is selected from the HLA-DPA1*01, HLA-DPA1*02, HLA-DPA1*03, and HLA-DPA1*04 alleles. In some aspects, the DPα chain comprises the HLA-DPA1*01 allele. In some aspects, the DPα chain comprises the HLA-DPA1*02 allele. In some aspects, the DPα chain comprises the HLA-DPA1*03 allele. In some aspects, the DPα chain comprises the HLA-DPA1*04 allele.

[0194] In some aspects, the DPα chain is selected from DPA1*01:03:01:01, DPA1*01:03:01:02, DPA1*01:03:01:03, DPA1*01:03:01:04, DPA1*01:03:01:05, DPA1*01:03:01:06, DPA1*01:03:01:07, DPA1*01:03:01:08, DPA1*01:03:01:09, DPA1*01:03:01:10, DPA1*01:03:01:11, DPA1*01:03:01:12, DPA1*01:03:01:13, DPA1*01:03:01:14, DPA1*01:03:01:15, DPA1*01:03:01:16, DPA1*01:03:01:17, DPA1*01:03:01:18Q, DPA1*01:03:01:19, DPA1*01:03:01:20, DPA1*01:03:01:21, DPA1*01:03:01:22, DPA1*01:03:01:23, DPA1*01:03:02, DPA1*01:03:03, DPA1*01:03:04, DPA1*01:03:05, DPA1*01:03:06, DPA1*01:03:07, DPA1*01:03:08, DPA1*01:03:09, DPA1*01:04, DPA1*01:05, DPA1*01:06:01, DPA1*01:06:02, DPA1*01:07, DPA1*01:08, DPA1*01:09, DPA1*01:10, DPA1*01:11, DPA1*01:12, DPA1*01:13, DPA1*01:14, DPA1*01:15, DPA1*01:16, DPA1*01:17, DPA1*01:18, DPA1*01:19, DPA1*02:01:01:01, DPA1*02:0DPA1*02:01:08:01, DPA1*02:01:08:02, DPA1*02:02:02:01, DPA1*02:02:02:02, DPA1*02:02:02:03, DPA1*02:02:02:04, DPA1*02:02:02:05, DPA1*02:02:03, DPA1*02:02:04, DPA1*02:02:05, DPA1*02:02:06, DPA1*02:03, DPA1*02:04, DPA1*02:05, DPA1*02:06, DPA1*02:07:01:01, DPA1*02:07:01:02, DPA1*02:07:01:03, DPA1*02:08, DPA1*02:09, DPA1*02:10, DPA1*02:11, DPA1*02:12, DPA1*02:13N, DPA1*02:14, DPA1*02:15, DPA1*02:16, DPA1*03:01:01:01, DPA1*03:01:01:02, DPA1*03:01:01:03, DPA1*03:01:01:04, DPA1*03:01:01:05, DPA1*03:01:02, DPA1*03:02, DPA1*03:03, DPA1*03:04, DPA1*04:01:01:01, DPA1*04:01:01:02, DPA1*04:01:01:03, or any combination thereof.

[0195] In some aspects, the β chain is an HLA-DPβ chain. Any HLA-DPβ chain allele known in the art can be used in the compositions and methods disclosed herein. In some aspects, the DPβ chain comprises alleles selected from the following: 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*1 14. 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*12 7. DPB1*128, DPB1*129, DPB1*13, DPB1*130, DPB1*131, DPB1*132, DPB1*133, DPB1*134, DPB1*135, DPB1*136, DPB1*137, DPB1*138, DPB1*139, DPB1*14, DPB1*140, DPB1*141, DPB1*142, DPB1*143, DPB1*144, DPB1*145, DPB1*146, DPB1*147, DPB1*148, DPB1*149, DPB1*15, DPB1*150, DPB 1*151, DPB1*152, DPB1*153, DPB1*154, DPB1*155, DPB1*156, DPB1*157, DPB1*158, DPB1*159, DPB1*16, DPB1*160, DPB1*161, DPB1*162, DPB1* 163, DPB1*164, DPB1*165, DPB1*166, DPB1*167, DPB1*168, DPB1*169, DPB1*17, DPB1*170, DPB1*171, DPB1*172, DPB1*173, DPB1*174, DPB1*17 5. DPB1*176, DPB1*177, DPB1*178, DPB1*179, DPB1*18, DPB1*180, DPB1*181, DPB1*182, DPB1*183, DPB1*184, DPB1*185, DPB1*186, DPB1*187,DPB1*188、DPB1*189、DPB1*19、DPB1*190、DPB1*191、DPB1*192、DPB1*193、DPB1*194、DPB1*195、DPB1*196、DPB1*197、DPB1*198、DPB1*199、DPB1*20、DPB1*200、DPB1*201、DPB1*202、DPB1*203、DPB1*204、DPB1*205、DPB1*206、DPB1*207、DPB1*208、DPB1*209、DPB1*21、DPB1*210、DPB1*211、DPB1*212、DPB1*213、DPB1*214、DPB1*215、DPB1*216、DPB1*217、DPB1*218、DPB1*219、DPB1*22、DPB1*220、DPB1*221、DPB1*222、DPB1*223、DPB1*224、DPB1*225、DPB1*226、DPB1*227、DPB1*228、DPB1*229、DPB1*23、DPB1*230、DPB1*231、DPB1*232、DPB1*233、DPB1*234、DPB1*235、DPB1*236、DPB1*237、DPB1*238、DPB1*239、DPB1*24、DPB1*240、DPB1*241、DPB1*242、DPB1*243、DPB1*244、DPB1*245、DPB1*246、DPB1*247、DPB1*248、DPB1*249、DPB1*25、DPB1*250、DPB1*251、DPB1*252、DPB1*253、DPB1*254、DPB1*255、DPB1*256、DPB1*257、DPB1*258、DPB1*259、DPB1*26、DPB1*260、DPB1*261、DPB1*262、DPB1*263、DPB1*264、DPB1*265、DPB1*266、DPB1*267、DPB1*268、DPB1*269、DPB1*27、DPB1*270、DPB1*271、DPB1*272、DPB1*273、DPB1*274、DPB1*275、DPB1*276、DPB1*277、DPB1*278、DPB1*279、DPB1*28、DPB1*280、DPB1*281、DPB1*282、DPB1*283、DPB1*284、DPB1*285、DPB1*286、DPB1*287、DPB1*288、DPB1*289、DPB1*29、DPB1*290、DPB1*291、DPB1*292、DPB1*293、DPB1*294、DPB1*295、DPB1*296、DPB1*297、DPB1*298、DPB1*299、DPB1*30、DPB1*300、DPB1*301、DPB1*302、DPB1*303、DPB1*304、DPB1*305、DPB1*306、DPB1*307、DPB1*308、DPB1*309、DPB1*31、DPB1*310、DPB1*311、DPB1*312、DPB1*313、DPB1*314、DPB1*315、DPB1*316、DPB1*317、DPB1*318、DPB1*319、DPB1*32、DPB1*320、DPB1*321、DPB1*322、DPB1*323、DPB1*324、DPB1*325、DPB1*326、DPB1*327、DPB1*328、DPB1*329、DPB1*33、DPB1*330、DPB1*331、DPB1*332、DPB1*333、DPB1*334、DPB1*335、DPB1*336、DPB1*337、DPB1*338、DPB1*339、DPB1*34、DPB1*340、DPB1*341、DPB1*342、DPB1*343、DPB1*344、DPB1*345、DPB1*346、DPB1*347、DPB1*348、DPB1*349、DPB1*35、DPB1*350、DPB1*351、DPB1*352、DPB1*353、DPB1*354、DPB1*355、DPB1*356、DPB1*357、DPB1*358、DPB1*359、DPB1*36、DPB1*360、DPB1*361、DPB1*362、DPB1*363、DPB1*364、DPB1*365、DPB1*366、DPB1*367、DPB1*368、DPB1*369、DPB1*37、DPB1*370、DPB1*371、DPB1*372、DPB1*373、DPB1*374、DPB1*375、DPB1*376、DPB1*377、DPB1*378、DPB1*379、DPB1*38、DPB1*380、DPB1*381、DPB1*382、DPB1*383、DPB1*384、DPB1*385、DPB1*386、DPB1*387、DPB1*388、DPB1*389、DPB1*39、DPB1*390、DPB1*391、DPB1*392、DPB1*393、DPB1*394、DPB1*395、DPB1*396、DPB1*397、DPB1*398、DPB1*399、DPB1*40、DPB1*400、DPB1*401、DPB1*402、DPB1*403、DPB1*404、DPB1*405、DPB1*406、DPB1*407、DPB1*408、DPB1*409、DPB1*41、DPB1*410、DPB1*411、DPB1*412、DPB1*413、DPB1*414、DPB1*415、DPB1*416、DPB1*417、DPB1*418、DPB1*419、DPB1*420、DPB1*421、DPB1*422、DPB1*423、DPB1*424、DPB1*425、DPB1*426、DPB1*427、DPB1*428、DPB1*429、DPB1*430、DPB1*431、DPB1*432、DPB1*433、DPB1*434、DPB1*435、DPB1*436、DPB1*437、DPB1*438、DPB1*439、DPB1*44、DPB1*440、DPB1*441、DPB1*442、DPB1*443、DPB1*444、DPB1*445、DPB1*446、DPB1*447、DPB1*448、DPB1*449、DPB1*45、DPB1*450、DPB1*451、DPB1*452、DPB1*453、DPB1*454、DPB1*455、DPB1*456、DPB1*457、DPB1*458、DPB1*459、DPB1*46、DPB1*460、DPB1*461、DPB1*462、DPB1*463、DPB1*464、DPB1*465、DPB1*466、DPB1*467、DPB1*468、DPB1*469、DPB1*47、DPB1*470、DPB1*471、DPB1*472、DPB1*473、DPB1*474、DPB1*475、DPB1*476、DPB1*477、DPB1*478、DPB1*479、DPB1*48、DPB1*480、DPB1*481、DPB1*482、DPB1*483、DPB1*484、DPB1*485、DPB1*486、DPB1*487、DPB1*488、DPB1*489、DPB1*49、DPB1*490、DPB1*491、DPB1*492、DPB1*493、DPB1*494、DPB1*495、DPB1*496、DPB1*497、DPB1*498、DPB1*499、DPB1*50、DPB1*500、DPB1*501、DPB1*502、DPB1*503、DPB1*504、DPB1*505、DPB1*506、DPB1*507、DPB1*508、DPB1*509、DPB1*51、DPB1*510、DPB1*511、DPB1*512、DPB1*513、DPB1*514、DPB1*515、DPB1*516、DPB1*517、DPB1*518、DPB1*519、DPB1*52、DPB1*520、DPB1*521、DPB1*522、DPB1*523、DPB1*524、DPB1*525、DPB1*526、DPB1*527、DPB1*528、DPB1*529、DPB1*53、DPB1*530、DPB1*531、DPB1*532、DPB1*533、DPB1*534、DPB1*535、DPB1*536、DPB1*537、DPB1*538、DPB1*539、DPB1*54、DPB1*540、DPB1*541、DPB1*542、DPB1*543、DPB1*544、DPB1*545、DPB1*546、DPB1*547、DPB1*548、DPB1*549、DPB1*55、DPB1*550、DPB1*551、DPB1*552、DPB1*553、DPB1*554、DPB1*555、DPB1*556、DPB1*557、DPB1*558、DPB1*559、DPB1*56、DPB1*560、DPB1*561、DPB1*562、DPB1*563、DPB1*564、DPB1*565、DPB1*566、DPB1*567、DPB1*568、DPB1*569、DPB1*57、DPB1*570、DPB1*571、DPB1*572、DPB1*573、DPB1*574、DPB1*575、DPB1*576、DPB1*577、DPB1*578、DPB1*579、DPB1*58、DPB1*580、DPB1*581、DPB1*582、DPB1*583、DPB1*584、DPB1*585、DPB1*586、DPB1*587、DPB1*588、DPB1*589、DPB1*59、DPB1*590、DPB1*591、DPB1*592、DPB1*593、DPB1*594、DPB1*595、DPB1*596、DPB1*597、DPB1*598、DPB1*599、DPB1*60、DPB1*600、DPB1*601、DPB1*602、DPB1*603、DPB1*604、DPB1*605、DPB1*606、DPB1*607、DPB1*608、DPB1*609、DPB1*61、DPB1*610、DPB1*611、DPB1*612、DPB1*613、DPB1*614、DPB1*615、DPB1*616、DPB1*617、DPB1*618、DPB1*619、DPB1*62、DPB1*620、DPB1*621、DPB1*622、DPB1*623、DPB1*624、DPB1*625、DPB1*626、DPB1*627、DPB1*628、DPB1*629、DPB1*63、DPB1*630、DPB1*631、DPB1*632、DPB1*633、DPB1*634、DPB1*635、DPB1*636、DPB1*637、DPB1*638、DPB1*639、DPB1*64、DPB1*640、DPB1*641、DPB1*642、DPB1*643、DPB1*644、DPB1*645、DPB1*646、DPB1*647、DPB1*648、DPB1*649、DPB1*65、DPB1*650、DPB1*651、DPB1*652、DPB1*653、DPB1*654、DPB1*655、DPB1*656、DPB1*657、DPB1*658、DPB1*659、DPB1*66、DPB1*660、DPB1*661、DPB1*662、DPB1*663、DPB1*664、DPB1*665、DPB1*666、DPB1*667、DPB1*668、DPB1*669、DPB1*67、DPB1*670、DPB1*671、DPB1*672、DPB1*673、DPB1*674、DPB1*675、DPB1*676、DPB1*677、DPB1*678、DPB1*679、DPB1*68、DPB1*680、DPB1*681、DPB1*682、DPB1*683、DPB1*684、DPB1*685、DPB1*686、DPB1*687、DPB1*688、DPB1*689、DPB1*69、DPB1*690、DPB1*691、DPB1*692、DPB1*693、DPB1*694、DPB1*695、DPB1*696、DPB1*697、DPB1*698、DPB1*699、DPB1*70、DPB1*700、DPB1*701、DPB1*702、DPB1*703、DPB1*704、DPB1*705、DPB1*706、DPB1*707、DPB1*708、DPB1*709、DPB1*71、DPB1*710、DPB1*711、DPB1*712、DPB1*713、DPB1*714、DPB1*715、DPB1*716、DPB1*717、DPB1*718、DPB1*719、DPB1*72、DPB1*720、DPB1*721、DPB1*722、DPB1*723、DPB1*724、DPB1*725、DPB1*726、DPB1*727、DPB1*728、DPB1*729、DPB1*73、DPB1*730、DPB1*731、DPB1*732、DPB1*733、DPB1*734、DPB1*735、DPB1*736、DPB1*737、DPB1*738、DPB1*739、DPB1*74、DPB1*740、DPB1*741、DPB1*742、DPB1*743、DPB1*744、DPB1*745、DPB1*746、DPB1*747、DPB1*748、DPB1*749、DPB1*75、DPB1*750、DPB1*751、DPB1*752、DPB1*753、DPB1*754、DPB1*755、DPB1*756、DPB1*757、DPB1*758、DPB1*759、DPB1*76、DPB1*760、DPB1*761、DPB1*762、DPB1*763、DPB1*764、DPB1*765、DPB1*766、DPB1*767、DPB1*768、DPB1*769、DPB1*77、DPB1*770、DPB1*771、DPB1*772、DPB1*773、DPB1*774、DPB1*775、DPB1*776、DPB1*777、DPB1*778、DPB1*779、DPB1*78、DPB1*780、DPB1*781、DPB1*782、DPB1*783、DPB1*784、DPB1*785、DPB1*786、DPB1*787、DPB1*788、DPB1*789、DPB1*79、DPB1*790、DPB1*791、DPB1*792、DPB1*794、DPB1*795、DPB1*796、DPB1*797、DPB1*798、DPB1*799、DPB1*80、DPB1*800、DPB1*801、DPB1*802、DPB1*803、DPB1*804、DPB1*805、DPB1*806、DPB1*807、DPB1*808、DPB1*809、DPB1*81、DPB1*810、DPB1*811、DPB1*812、DPB1*813、DPB1*814、DPB1*815、DPB1*816、DPB1*817、DPB1*818、DPB1*819、DPB1*82、DPB1*820、DPB1*821、DPB1*822、DPB1*823、DPB1*824、DPB1*825、DPB1*826、DPB1*827、DPB1*828、DPB1*829、DPB1*83、DPB1*830、DPB1*831、DPB1*832、DPB1*833、DPB1*834、DPB1*835、DPB1*836、DPB1*837、DPB1*838、DPB1*839、DPB1*84、DPB1*840、DPB1*841、DPB1*842、DPB1*843、DPB1*844、DPB1*845、DPB1*846、DPB1*847、DPB1*848、DPB1*849、DPB1*85、DPB1*850、DPB1*851、DPB1*852、DPB1*853、DPB1*854、DPB1*855、DPB1*856、DPB1*857、DPB1*858、DPB1*859、DPB1*86、DPB1*860、DPB1*861、DPB1*862、DPB1*863、DPB1*864、DPB1*865、DPB1*866、DPB1*867、DPB1*868、DPB1*869、DPB1*87、DPB1*870、DPB1*871、DPB1*872、DPB1*873、DPB1*874、DPB1*875、DPB1*876、DPB1*877、DPB1*878、DPB1*879、DPB1*88、DPB1*880、DPB1*881、DPB1*882、DPB1*883、DPB1*884、DPB1*885、DPB1*886、DPB1*887、DPB1*888、DPB1*889、DPB1*89、DPB1*890、DPB1*891、DPB1*892、DPB1*893、DPB1*894、DPB1*895、DPB1*896、DPB1*897、DPB1*898、DPB1*899、DPB1*90、DPB1*900、DPB1*901、DPB1*902、DPB1*903, DPB1*904, DPB1*905, DPB1*906, DPB1*907, DPB1*908, DPB1*909, DPB1*91, DPB1*910 , DPB1*911, DPB1*912, DPB1*913, DPB1*914, DPB1*915, DPB1*916, DPB1*917, DPB1*918, DPB1*91 9. DPB1*92, DPB1*920, DPB1*921, DPB1*922, DPB1*923, DPB1*924, DPB1*925, DPB1*926, DPB1*92 7. DPB1*928, DPB1*929, DPB1*93, DPB1*930, DPB1*931, DPB1*932, DPB1*933, DPB1*934, DPB1*93 5. DPB1*936, DPB1*937, DPB1*938, DPB1*939, DPB1*94, DPB1*940, DPB1*941, DPB1*942, DPB1*94 3. DPB1*944, DPB1*945, DPB1*946, DPB1*947, DPB1*948, DPB1*949, DPB1*95, DPB1*950, DPB1*95 1. DPB1*952, DPB1*953, DPB1*954, DPB1*955, DPB1*956, DPB1*957, DPB1*958, DPB1*959, DPB1*9 6. DPB1*960, DPB1*961, DPB1*962, DPB1*963, DPB1*964, DPB1*965, DPB1*97, DPB1*98 and DPB1*99. In some respects, the DPβ chain contains the HLA-DPB1*01, HLA-DPB1*02, HLA-DPB1*01, HLA-DPB1*03, HLA-DPB1*04, HLA-DPB1*05, HLA-DPB1*06, HLA-DPB1*08, and HLA-DPB1*09 alleles, and any combinations thereof. In some respects, the DPβ chain contains the HLA-DPB1*04 allele. In certain respects, the DPβ chain contains the HLA-DPB1*04:01 allele.

[0196] In some respects, the DPβ chain contains alleles selected from the following: DPB1*01:01:01:01, DPB1*01:01:01:02, DPB1*01:01:01:03, DPB1*01:01:01:04, DPB1*01:01:01:05, DPB1*01:01:01:06, DPB1*01:01:01:07, DPB1*01:01:01:08. DPB1*01:01:01:09, DPB1*01:01:01:10, DPB1*01:01:02:01, DPB1*01:01:02:02, DPB1*01:01:0 3. DPB1*01:01:04, DPB1*01:01:05, DPB1*01:01:06, DPB1*02:01:02:01, DPB1*02:01:02:02, DP D D PB1*02:01:02:13, DPB1*02:01:02:14, DPB1*02:01:02:15, DPB1*02:01:02:16, D PB1*02:01:02:18, DPB1*02:01:02:19, DPB1*02:01:02:20, DPB1*02:01:02:21, D PB1*02:01:02:23, DPB1*02:01:02:24, DPB1*02:01:02:25, DPB1*02:01:02:26, ​​DPB1*02:01:02:27, DPB1*02:01:02:28, DPB1*02:01:02:29, DPB1*02:01:02:30, DPB1*02:01:02:31, DPB1*02:01:02:32, DPB1*02:01:02:33, DPB1*02:01:02:34, DPB1*02:01:02:35, DPB1*02:01:02:36, DPB1*02:01:02:37, DPB1*02:01:02:38, DPB1*02:01:02:39, DPB1*02:01:02:40, DPB1*02:01:02:41, DPB1*02:01:02:42,DPB1*02:01:02:43、DPB1*02:01:03、DPB1*02:01:04、DPB1*02:01:05、DPB1*02:01:06、DPB1*02:01:07、DPB1*02:01:08、DPB1*02:01:09、DPB1*02:01:10、DPB1*02:01:11、DPB1*02:01:12、DPB1*02:01:13、DPB1*02:01:14、DPB1*02:01:15、DPB1*02:01:16、DPB1*02:01:17、DPB1*02:01:18、DPB1*02:01:19、DPB1*02:01:20、DPB1*02:01:21、DPB1*02:01:22、DPB1*02:01:23、DPB1*02:01:24、DPB1*02:01:25、DPB1*02:01:26、DPB1*02:01:27、DPB1*02:01:28、DPB1*02:01:29、DPB1*02:01:30、DPB1*02:01:31、DPB1*02:01:32、DPB1*02:01:33、DPB1*02:01:34、DPB1*02:01:35、DPB1*02:01:36、DPB1*02:01:37、DPB1*02:01:38、DPB1*02:01:39、DPB1*02:01:40、DPB1*02:01:41、DPB1*02:01:42、DPB1*02:01:43、DPB1*02:02:01:01、DPB1*02:02:01:02、DPB1*02:02:01:03、DPB1*02:02:01:04、DPB1*02:02:01:05、DPB1*02:02:01:06、DPB1*02:02:01:07、DPB1*02:02:02、DPB1*02:02:03、DPB1*03:01:01:01、DPB1*03:01:01:02、DPB1*03:01:01:03、DPB1*03:01:01:04、DPB1*03:01:01:05、DPB1*03:01:01:06、DPB1*03:01:01:07、DPB1*03:01:01:08、DPB1*03:01:01:09、DPB1*03:01:01:10、DPB1*03:01:01:11、DPB1*03:01:02、DPB1*03:01:03、DPB1*03:01:04、DPB1*03:01:05、DPB1*03:01:06、DPB1*03:01:07、DPB1*03:01:08、DPB1*03:01:09、DPB1*03:01:10、DPB1*03:01:11、DPB1*03:01:12、DPB1*04:01:01:01、DPB1*04:01:01:02、DPB1*04:01:01:03、DPB1*04:01:01:04、DPB1*04:01:01:05、DPB1*04:01:01:06、DPB1*04:01:01:07、DPB1*04:01:01:08、DPB1*04:01:01:09、DPB1*04:01:01:10、DPB1*04:01:01:11、DPB1*04:01:01:12、DPB1*04:01:01:13、DPB1*04:01:01:14、DPB1*04:01:01:15、DPB1*04:01:01:16、DPB1*04:01:01:17、DPB1*04:01:01:18、DPB1*04:01:01:19、DPB1*04:01:01:20、DPB1*04:01:01:21、DPB1*04:01:01:22、DPB1*04:01:01:23、DPB1*04:01:01:24N、DPB1*04:01:01:25、DPB1*04:01:01:26、DPB1*04:01:01:27、DPB1*04:01:01:28、DPB1*04:01:01:29、DPB1*04:01:01:30、DPB1*04:01:01:31、DPB1*04:01:01:32、DPB1*04:01:01:33、DPB1*04:01:01:34、DPB1*04:01:02、DPB1*04:01:03、DPB1*04:01:04:01、DPB1*04:01:04:02、DPB1*04:01:05、DPB1*04:01:06、DPB1*04:01:07、DPB1*04:01:08、DPB1*04:01:09、DPB1*04:01:10、DPB1*04:01:11、DPB1*04:01:12、DPB1*04:01:13、DPB1*04:01:14、DPB1*04:01:15、DPB1*04:01:16、DPB1*04:01:17、DPB1*04:01:18、DPB1*04:01:19、DPB1*04:01:20、DPB1*04:01:21、DPB1*04:01:22、DPB1*04:01:23、DPB1*04:01:24、DPB1*04:01:25、DPB1*04:01:26、DPB1*04:01:27、DPB1*04:01:28、DPB1*04:01:29、DPB1*04:01:30、DPB1*04:01:31、DPB1*04:01:32、DPB1*04:01:33、DPB1*04:01:34、DPB1*04:01:35、DPB1*04:01:36、DPB1*04:01:37、DPB1*04:01:38、DPB1*04:01:39、DPB1*04:01:40、DPB1*04:02:01:01、DPB1*04:02:01:02、DPB1*04:02:01:03、DPB1*04:02:01:04、DPB1*04:02:01:05、DPB1*04:02:01:06、DPB1*04:02:01:07、DPB1*04:02:01:08、DPB1*04:02:01:09、DPB1*04:02:01:10、DPB1*04:02:01:11、DPB1*04:02:01:12、DPB1*04:02:01:13、DPB1*04:02:01:14、DPB1*04:02:02、DPB1*04:02:03、DPB1*04:02:04、DPB1*04:02:05、DPB1*04:02:06、DPB1*04:02:07、DPB1*04:02:08、DPB1*04:02:09、DPB1*04:02:10、DPB1*04:02:11、DPB1*04:02:12、DPB1*04:02:13、DPB1*04:02:14、DPB1*05:01:01:01、DPB1*05:01:01:02、DPB1*05:01:01:03、DPB1*05:01:01:04、DPB1*05:01:01:05、DPB1*05:01:01:06、DPB1*05:01:01:07、DPB1*05:01:01:08、DPB1*05:01:01:09、DPB1*05:01:01:10、DPB1*05:01:02、DPB1*05:01:03、DPB1*05:01:04、DPB1*05:01:05、DPB1*05:01:06、DPB1*05:01:07、DPB1*05:01:08、DPB1*05:01:09、DPB1*06:01:01:01、DPB1*06:01:01:02、DPB1*06:01:01:03、DPB1*06:01:02、DPB1*06:01:03、DPB1*06:01:04、DPB1*06:01:05、DPB1*08:01、DPB1*09:01:01、DPB1*09:01:02、DPB1*09:01:03、DPB1*09:01:04、DPB1*100:01、DPB1*101:01、DPB1*102:01、DPB1*103:01、DPB1*104:01:01:01、DPB1*104:01:01:02、DPB1*104:01:01:03、DPB1*104:01:01:04、DPB1*104:01:01:05、DPB1*104:01:01:06、DPB1*104:01:02、DPB1*105:01:01:01、DPB1*105:01:01:02、DPB1*105:01:01:03、DPB1*105:01:01:04、DPB1*105:01:01:05、DPB1*105:01:01:06、DPB1*105:01:01:07、DPB1*105:01:01:08、DPB1*105:01:01:09、DPB1*105:01:01:10、DPB1*106:01、DPB1*107:01、DPB1*108:01、DPB1*109:01、DPB1*10:01:01:01、DPB1*10:01:01:02、DPB1*10:01:02、DPB1*10:01:03、DPB1*10:01:04、DPB1*110:01、DPB1*111:01、DPB1*112:01、DPB1*113:01、DPB1*114:01、DPB1*115:01、DPB1*116:01、DPB1*117:01、DPB1*118:01、DPB1*119:01、DPB1*11:01:01:01、DPB1*11:01:01:02、DPB1*11:01:02、DPB1*11:01:03、DPB1*11:01:04、DPB1*120:01N、DPB1*121:01、DPB1*122:01、DPB1*123:01、DPB1*124:01:01:01、DPB1*124:01:01:02、DPB1*124:01:02:01、DPB1*124:01:02:02、DPB1*125:01、DPB1*126:01:01:01、DPB1*126:01:01:02、DPB1*127:01、DPB1*128:01、DPB1*129:01、DPB1*130:01、DPB1*131:01:01:01、DPB1*131:01:01:02、DPB1*131:01:02、DPB1*131:01:03、DPB1*132:01、DPB1*133:01、DPB1*134:01、DPB1*135:01、DPB1*136:01、DPB1*137:01、DPB1*138:01、DPB1*139:01、DPB1*13:01:01:01、DPB1*13:01:01:02、DPB1*13:01:01:03、DPB1*13:01:01:04、DPB1*13:01:01:05、DPB1*13:01:01:06、DPB1*13:01:01:07、DPB1*13:01:01:08、DPB1*13:01:02、DPB1*13:01:03、DPB1*140:01、DPB1*141:01、DPB1*142:01、DPB1*143:01、DPB1*144:01、DPB1*145:01、DPB1*146:01、DPB1*147:01、DPB1*148:01、DPB1*149:01、DPB1*14:01:01:01、DPB1*14:01:01:02、DPB1*14:01:01:03、DPB1*14:01:02、DPB1*14:01:03、DPB1*14:01:04、DPB1*14:01:05、DPB1*14:01:06、DPB1*14:01:07、DPB1*14:01:08、DPB1*14:01:09、DPB1*150:01、DPB1*151:01、DPB1*152:01、DPB1*153:01、DPB1*154:01N、DPB1*155:01:01、DPB1*155:01:02、DPB1*156:01、DPB1*157:01、DPB1*158:01、DPB1*159:01N、DPB1*15:01:01:01、DPB1*15:01:01:02、DPB1*15:01:01:03、DPB1*15:01:01:04、DPB1*15:01:02、DPB1*15:01:03、DPB1*160:01、DPB1*161:01N、DPB1*162:01:01、DPB1*162:01:02、DPB1*163:01、DPB1*164:01、DPB1*165:01、DPB1*166:01、DPB1*167:01、DPB1*168:01、DPB1*169:01、DPB1*16:01:01:01、DPB1*16:01:01:02、DPB1*16:01:02、DPB1*16:01:03、DPB1*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、DPB1*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, DPB 1*954:01, DPB1*955:01, DPB1*956:01, DPB1*957:01, DPB1*958:01, DPB1*959:01N, DPB1*9 5:01, DPB1*960:01N, DPB1*961:01, DPB1*962:01, DPB1*963:01, DPB1*964:01, DPB1*965:01:01:01, DPB1*965:01:01:02, DPB1*96:01, DPB1*97:01, DPB1*98:01, DPB1*99:01, and any combination thereof.

[0197] II.D.2.HLA-DQ Class II Molecules

[0198] In some aspects, the α chain is the HLA-DQα chain. Any HLA-DQα chain allele known in the art may be used in the compositions and methods disclosed herein. In some aspects, the α 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 respects, the α chain is selected from the following HLA-DQA1 alleles: *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, 4. *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, *0 1:16N、*01:17、*01:18、*01:19、*01:20、*01:21、*01:22、*01:23、*01:24、*01:25、*01:26、*02:01:01:01、*02:01:01:02、*02: 01:02, *02:02N, *02:03, *03:01:01, *03:01:03, *03:02:01:01, *03:02:01:02, *03:03:01:01, *03:03:01:02, *03:03:01:03,*03:03:01:04、*03:03:01:05、*03:03:01:06、*03:03:01:07、*03:03:02、*03:04、*03:05、*03:06、*03:07、*04:01:01:01、*04:01:01:02、*04:01:01:03、*04:01:01:04、*04:01:01:05、*04:01:01:06、*04:01:01:07、*04:01:01:08、*04:01:02: 01. 1:04, *05:01:02, *05:01:04, *05:01:05, *05:01:06, *05:02, *05:03:01:01, *05:03:01:02, *05:04, *05:05:01:01, *05: 05:01:02, *05:05:01:03, *05:05:01:04, *05:05:01:05, *05:05:01:06, *05:05:01:07, *05:05:01:08, *05:05:01:09, *05:05:01:10, *05:05:01:11, *05:05:01:12, *05:05:01:13, *05:05:01:14, *05:05:01:15, *05:05:01:16, *05:05:01:17 *05:05:01:18, *05:05:01:19, *05:05:01:20, *05:06:01:01, *05:06:01:02, *05:07, *05:08, *05:09, *05:10, *05:11, *05:12, *05:13, *05:14, *05:15N, *06:01:01:01, *06:01:01:02, *06:01:01:03, *06:01:01:04, *06:01:02, *06:02 and any combination thereof.

[0199] In some aspects, the β chain is the HLA-DQ β chain. Any HLA-DQ β chain allele known in the art may be used in the compositions and methods disclosed herein. In some aspects, the β chain is selected from the HLA-DQB1*02, HLA-DQB1*03, HLA-DQB1*04, HLA-DQB1*05, and HLA-DQB1*06 alleles.

[0200] In some respects, the DQβ chain contains alleles selected from the following: DQB1*02:01:01, DQB1*02:01:02, DQB1*02:01:03, DQB1*02:01:04, DQB1*02:01:05, DQB1*02:01:06, DQB1*02:01:07, DQB1*02:01:08, DQB1*02:01:09, DQB1*02:01:10, DQB1*02:01:11, DQB1*02:01:12, DQB1*02:01:13, DQB1*02:01:14, DQB1*02:01:15, DQB1*02:01:16, DQ B1*02:01:17, DQB1*02:01:18, DQB1*02:01:19, DQB1*02:01:20, DQB1*02: 01:21, DQB1*02:01:22, DQB1*02:01:23, DQB1*02:01:24, DQB1*02:01:25, D QB1*02:01:26, DQB1*02:01:27, DQB1*02:01:28, DQB1*02:01:29, DQB1*02 :01:30, DQB1*02:01:31, DQB1*02:02:01:01, DQB1*02:02:01:02, DQB1*02: 02:01:03, DQB1*02:02:01:04, DQB1*02:02:02, DQB1*02:02:03, DQB1*02: 02:04, DQB1*02:02:05, DQB1*02:02:06, DQB1*02:02:07, DQB1*02:02:08, DQB1*02:02:09, DQB1*02:03:01, DQB1*02:03:02, DQB1*02:04, DQB1*02:0 5. DQB1*02:06, DQB1*02:07:01, DQB1*02:07:02, DQB1*02:08, DQB1*02:09, DQB1*02:10, DQB1*02:100, DQB1*02:101, DQB1*02:102, DQB1*02:103, DQB 1*02:104, DQB1*02:105, DQB1*02:106, DQB1*02:107, DQB1*02:108, DQB1*0 2:109, DQB1*02:11, DQB1*02:110, DQB1*02:111, DQB1*02:112, DQB1*02:1 13. DQB1*02:114, DQB1*02:115, DQB1*02:116, DQB1*02:117, DQB1*02:118,DQB1*02:119、DQB1*02:12、DQB1*02:120、DQB1*02:121、DQB1*02:122、DQB1*02:123、DQB1*02:124、DQB1*02:125、DQB1*02:126、DQB1*02:127、DQB1*02:128、DQB1*02:129N、DQB1*02:13、DQB1*02:130、DQB1*02:131、DQB1*02:132N、DQB1*02:133、DQB1*02:134N、DQB1*02:135、DQB1*02:136、DQB1*02: 137、DQB1*02:138、DQB1*02:139、DQB1*02:140、DQB1*02:141、DQB1*02:142、DQB1*02:14:01、DQB1*02:14:02、DQB1*02:15、DQB1*02:16、DQB1*02:17、DQB1*02:18N、DQB1*02:19、DQB1*02:20N、DQB1*02:21、DQB1*02:22、DQB1*02:23、DQB1*02:24、DQB1*02:25、DQB1*02:26、DQB1*02:27、DQB1*02:28、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: 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: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、D QB1*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*0 6:56、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*06:64 B1*06:65、DQB1*06:66、DQB1*06:67、DQB1*06:68、DQB1*06:69:01、DQB1*06:69:02、DQB1*06:70、DQB1*06:71、DQB1 *06:72、DQB1*06:73、DQB1*06:74、DQB1*06:75NX、DQB1*06:76、DQB1*06:77N、DQB1*06:78、DQB1*06:79:01、DQB1* 06:79:02、DQB1*06:80、DQB1*06:81、DQB1*06:82、DQB1*06:83、DQB1*06:84、DQB1*06:85、DQB1*06:86、DQB1*06:87 、DQB1*06:88、DQB1*06:89、DQB1*06:90、DQB1*06:91、DQB1*06:92:01、DQB1*06:92:02、DQB1*06:93、DQB1*06:94、 DQB1*06:95、DQB1*06:96:01、DQB1*06:96:02、DQB1*06:97、DQB1*06:98、DQB1*06:99:01、DQB1*06:99:02 and also any combination.、

[0201] II.D.3.HLA-DR II

[0202] In some aspects, the α chain is the HLA-DRα chain. Any HLA-DRα chain allele known in the art may be used in the compositions and methods disclosed herein. In some aspects, the α chain is the HLA-DRA*01 allele. In some aspects, the α chain is selected from the HLA-DRA1 alleles 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.

[0203] In some aspects, the β chain is the HLA-DRβ chain. Any HLA-DRβ chain allele known in the art may be used in the compositions and methods disclosed herein. In some aspects, the β chain is selected from the HLA-DRB1*01, HLA-DRB1*03, HLA-DRB1*04, HLA-DRB1*07, HLA-DRB1*08, HLA-DRB1*09, HLA-DRB1*10, HLA-DRB1*11, HLA-DRB1*12, HLA-DRB1*13, HLA-DRB1*14, HLA-DRB1*15, and HLA-DRB1*16 alleles. In some aspects, the β chain is the DRB3 allele. In some aspects, the β chain is the DRB4 allele. In some aspects, the β chain is the DRB5 allele.

[0204] In some aspects, the β-chain is selected from DRB1*01:01:01, DRB1*01:01:02, DRB1*01:01:03, DRB1*01:01:04, DRB1*01:01:05, DRB1*01:01:06, DRB1*01:01:07, DRB1*01:01:08, DRB1*01:01:09, DRB1*01:01:10, DRB1*01:01:11, DRB1*01:01:12, DRB1*01:01:13, DRB1*01:01:14, DRB1*01:01:15, DRB1*01:01:16, DRB1*01:01:17 、DRB1*01:01:18、DRB1*01:01:19、DRB1*01:01:20、DRB1*01:01:21、DRB1*01:01:22、DRB1*01:01:23、DRB1*01:01:24、DRB1*01:01:25、DRB1*01:01:25 26、DRB1*01:01:27、DRB1*01:01:28、DRB1*01:01:29、DRB1*01:01:30、DRB1*01:01:31、DRB1*01:01:32、DRB1*01:01:33、DRB1*01:01:01、DRB1*01:01:01 1:02:01:02、DRB1*01:02:02、DRB1*01:02:03、DRB1*01:02:04、DRB1*01:02:05、DRB1*01:02:06、DRB1*01:02:07、DRB1*01:02:08、DRB1*01:02:09、DRB1*01:02:10、DRB1*01:02:11、DRB1*01:02:12、DRB1*01:02:13、DRB1*01:03:01、DRB1*01:03:02、DRB1*01:03:03、DRB1*01:03:04、DRB1*01 B1*01:05、DRB1*01:06、DRB1*01:07、DRB1*01:08、DRB1*01:09、DRB1*01:10、DRB1*01:100、DRB1*01:11:01、DRB1*01:11:02、DRB1*01:12、DRB1*01:10 3、DRB1*01:14、DRB1*01:15、DRB1*01:16、DRB1*01:17、DRB1*01:18:01、DRB1*01:18:02、DRB1*01:19、DRB1*01:20:01、DRB1*01:20:02、DRB1*01:21、DRB1*01:22、DRB1*01:23、DRB1*01:24:01、DRB1*01:24:02、DRB1*01:25、DRB1*01:26、DRB1*01:27、DRB1*01:28、DRB1*01:29:01、DRB1*01:29:02、DRB1*01:30、DRB1*01:31、DRB1*01:32、DRB1*01:33N、DRB1*01:34、DRB1*01:35、DRB1*01:36、DRB1*01:37、DRB1*01:38、DRB1*01:39N、DRB1*01:40N、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*01:90 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 3、DRB1*03:104、DRB1*03:105、DRB1*03:106、DRB1*03:107、DRB1*03:108、DRB1*03:109、DRB1*03:110、DRB1*03:111、DRB1*03:112、DRB1*03:113、DRB1*03:113 1*03:114、DRB1*03:115、DRB1*03:116、DRB1*03:117、DRB1*03:118、DRB1*03:119、DRB1*03:11:01、DRB1*03:12、DRB1*03:120、DRB1*03:121、DRB1*03:122、DRB1*03:123、DRB1*03:124、DRB1*03:125、DRB1*03:126、DRB1*03:127、DRB1*03:128、DRB1*03:129、DRB1*03:130、DRB1*03:131、DRB1*03:132、DRB1*03:133、DRB1*03:134、DRB1*03:135、DRB1*03:136、DRB1*03:137、DRB1*03:138、DRB1*03:139、DRB1*03:13:01、DRB1*03:13:02、DRB1*03:14、DRB1*03:140、DRB1*03:141、DRB1*03:142、DRB1*03:143、DRB1*03:144、DRB1*03:145、DRB1*03:146、DRB1*03:147、DRB1*03:148、DRB1*03:149、DRB1*0 3:150, DRB1*03:151, DRB1*03:152, DRB1*03:153, DRB1*03:154, DRB1*03:155, DRB1*03:156N, DRB1*03:157, DRB1*03:158, DRB1*03:15:01, DRB1*03:15:02, DRB1*03:16, DRB1*03:17, DRB1*03:18, DRB1*03:19, DRB1*03:20, DRB1*03:21, DRB1*03:22, DRB1*03:23, DRB1*03:24, DRB1*03:25:01, DRB1*0 3:25:02, DRB1*03:26, DRB1*03:27, DRB1*03:28, DRB1*03:29, DRB1*03:30, DRB1*03:31, DRB1*03:32, DRB1*03:33, DRB1*03:34, DRB1*03:35, DRB1*03:36, DRB1*03:37, DRB1*03:38, DRB1*03:39, DRB1*03:40, DRB1*03:41:01, DRB1*03:41:02, DRB1*03:42, DRB1*03:43, DRB1*03:44, DRB1*03:45, DRB1* 03:46, DRB1*03:47, DRB1*03:48, DRB1*03:49, DRB1*03:50, DRB1*03:51, DRB1*03:52, DRB1*03:53, DRB1*03:54, DRB1*03:55, DRB1*03:56, DRB1*03:57, DRB1*03:58, DRB1*03:59, DRB1*03:60, DRB1*03:61, DRB1*03:62, DRB1*03:63, DRB1*03:64, DRB1*03:65, DRB1*03:66, DRB1*03:67N, DRB1*03:68N,DRB1*03:69、DRB1*03:70、DRB1*03:71:01、DRB1*03:71:02、DRB1*03:72、DRB1*03:73、DRB1*03:74、DRB1*03:75、DRB1*03:76、DRB1*03:77、DRB1*03:78、DRB1*03:79、DRB1*03:80、DRB1*03:81、DRB1*03:82、DRB1*03:83、DRB1*03:84、DRB1*03:85、DRB1*03:86、DRB1*03:87、DRB1*03:88、DRB1*03:89 、DRB1*03:90、DRB1*03:91、DRB1*03:92、DRB1*03:93、DRB1*03:94、DRB1*03:95、DRB1*03:96、DRB1*03:97、DRB1*03:98、DRB1*03:99、DRB1*04:01:0 1:01、DRB1*04:01:01:02、DRB1*04:01:01:03、DRB1*04:01:02、DRB1*04:0 1:03、DRB1*04:01:04、DRB1*04:01:05、DRB1*04:01:06、DRB1*04:01:07、D RB1*04:01:08、DRB1*04:01:09、DRB1*04:01:10、DRB1*04:01:11、DRB1*04:01:12、DRB1*04:01:13、DRB1*04:01:14、DRB1*04:01:15、DRB1*04:01:16、DRB1*04:01:17、DRB1*04:01:18、DRB1*04:01:19、DRB1*04:01:20、DRB1*04:01:21、DRB1*04:02:01、DRB1*04:02:02、DRB1*04:02:03、DRB1*04:02 :04、DRB1*04:02:05、DRB1*04:02:06、DRB1*04:03:01:01、DRB1*04:03:01:02、DRB1*04:03:02、DRB1*04:03:03、DRB1*04:03:04、DRB1*04:03:05、DRB1*04:03:06、DRB1*04:03:07、DRB1*04:03:08、DRB1*04:03:09、DRB1*04:03:10、DRB1*04:03:11、DRB1*04:03:12、DRB1*04:03:13、DRB1*04:03:14、DRB1*04:03:15、DRB1*04:04:01、DRB1*04:04:02、DRB1*04:04:03、DRB1*04:04:04、DRB1*04:04:05、DRB1*04:04:06、DRB1*04:04:07、DRB1*04:04:08、DRB1*04:04:09、DRB1*04:04:10、DRB1*04:04:11、DRB1*04:04:12、DRB1*04:04:13、DRB1*04:04:14、DRB1*04:04:15、DRB1*04:05:01:01、DRB1*04:0 5:01:02、DRB1*04:05:01:03、DRB1*04:05:02、DRB1*04:05:03、DRB1*04:0 5:04、DRB1*04:05:05、DRB1*04:05:06、DRB1*04:05:07、DRB1*04:05:08、DR B1*04:05:09、DRB1*04:05:10、DRB1*04:05:11、DRB1*04:05:13、DRB1*04: 05:14、DRB1*04:05:15、DRB1*04:05:16、DRB1*04:05:17、DRB1*04:05:18、D RB1*04:05:19、DRB1*04:05:20、DRB1*04:06:01、DRB1*04:06:02、DRB1*04:06:03、DRB1*04:06:04、DRB1*04:06:05、DRB1*04:06:06、DRB1*04:06:07、DRB1*04:07:01:01、DRB1*04:07:01:02、DRB1*04:07:02、DRB1*04:07:03、DRB1*04:07:04、DRB1*04:07:05、DRB1*04:07:06、DRB1*04:08:01、DRB1*04 :08:02、DRB1*04:08:03、DRB1*04:08:04、DRB1*04:09、DRB1*04:100、DRB1*04:101、DRB1*04:102、DRB1*04:103、DRB1*04:104、DRB1*04:105:01、DRB1*04:105:02、DRB1*04:106、DRB1*04:107、DRB1*04:108、DRB1*04:109、DRB1*04:10:01、DRB1*04:10:02、DRB1*04:10:03、DRB1*04:110、DRB1*04:111、DRB1*04:112、DRB1*04:113、DRB1*04:114、DRB1*04:115、DRB1*04:116、DRB1*04:117、DRB1*04:118、DRB1*04:119N、DRB1*04:11:01、DRB1*04:11:02、DRB1*04:11:03、DRB1*04:11:04、DRB1*04:11:05、DRB1*04:12、DRB1*04:120N、DRB1*04:121、DRB1*04:122、DRB1*04:123、DRB1*04:124、DRB1*04:1 25、DRB1*04:126、DRB1*04:127、DRB1*04:128、DRB1*04:129、DRB1*04:13、DRB1*04:130、DRB1*04:131:01、DRB1*04:131:02、DRB1*04:132、DRB1*04:133、DRB1*04:134、DRB1*04:135、DRB1*04:136、DRB1*04:137、DRB1*04:138、DRB1*04:139、DRB1*04:14、DRB1*04:140、DRB1*04:141、DRB1*04:142N、 DRB1*04:143、DRB1*04:144、DRB1*04:145、DRB1*04:146、DRB1*04:147、DRB1*04:148、DRB1*04:149、DRB1*04:15、DRB1*04:150、DRB1*04:151、DRB1*04:152、DRB1*04:153、DRB1*04:154、DRB1*04:155、DRB1*04:156、DRB1*04:157N、DRB1*04:158N、DRB1*04:159、DRB1*04:16、DRB1*04:160、DRB1*04: 161、DRB1*04:162、DRB1*04:163、DRB1*04:164、DRB1*04:165、DRB1*04:166、DRB1*04:167、DRB1*04:168、DRB1*04:169、DRB1*04:170、DRB1*04:171、DRB1*04:172、DRB1*04:173、DRB1*04:174、DRB1*04:175、DRB1*04:176、DRB1*04:177、DRB1*04:178N、DRB1*04:179、DRB1*04:17:01、DRB1*04:17:02、DRB1*04:18、DRB1*04:180、DRB1*04:181、DRB1*04:182、DRB1*04:183、DRB1*04:184、DRB1*04:185、DRB1*04:186N、DRB1*04:187、DRB1*04:188、DRB1 *04:189、DRB1*04:19、DRB1*04:190、DRB1*04:191、DRB1*04:192、DRB1*04:193、DRB1*04:194、DRB1*04:195、DRB1*04:196、DRB1*04:197、DRB1*04:19 8、DRB1*04:199、DRB1*04:20、DRB1*04:200、DRB1*04:201、DRB1*04:202、DRB1*04:203、DRB1*04:204、DRB1*04:205、DRB1*04:206、DRB1*04:207、DRB1*04:208、DRB1*04:209、DRB1*04:21、DRB1*04:210、DRB1*04:211、DRB1*04:212N、DRB1*04:213、DRB1*04:214N、DRB1*04:215、DRB1*04:216、DRB1*04: 217、DRB1*04:218、DRB1*04:219、DRB1*04:22、DRB1*04:220、DRB1*04:221、DRB1*04:222、DRB1*04:223、DRB1*04:224、DRB1*04:225、DRB1*04:226 1、DRB1*04:226:02、DRB1*04:227、DRB1*04:228、DRB1*04:229、DRB1*04:23、DRB1*04:230、DRB1*04:231、DRB1*04:232、DRB1*04:233、DRB1*04:234、D RB1*04:235、DRB1*04:236、DRB1*04:237、DRB1*04:238、DRB1*04:239、DRB1*04:24、DRB1*04:240、DRB1*04:241、DRB1*04:242、DRB1*04:243、DRB1*04:244、DRB1*04:245、DRB1*04:246、DRB1*04:247N、DRB1*04:248、DRB1*04:249、DRB1*04:25、DRB1*04:250、DRB1*04:251、DRB1*04:252、DRB1*04:253、DRB1*04:254、DRB1*04:255、DRB1*04:256、DRB1*04:257、DRB1*04:258、DRB1*04:259、DRB1*04:26、DRB1*04:260、DRB1*04:261、DRB1*04:262、DRB1*04:262 04:263、DRB1*04:264N、DRB1*04:265、DRB1*04:266N、DRB1*04:267N、DRB1*04:268、DRB1*04:269、DRB1*04:27、DRB1*04:270、DRB1*04:271、DRB1*04:269 272、DRB1*04:28、DRB1*04:29、DRB1*04:30、DRB1*04:31、DRB1*04:32、DRB1*04:33、DRB1*04:34、DRB1*04:35、DRB1*04:36、DRB1*04:37、DRB1*04:38、DRB1*04:39、DRB1*04:40、DRB1*04:41、DRB1*04:42、DRB1*04:43、DRB1*04:44:01、DRB1*04:44:02、DRB1*04:45、DRB1*04:46、DRB1*04:47、DRB1*04:4 8、DRB1*04:49、DRB1*04:50、DRB1*04:51、DRB1*04:52、DRB1*04:53:01、DRB1*04:53:02、DRB1*04:54、DRB1*04:55、DRB1*04:56:01、DRB1*04:56:02、DRB1*04:57、DRB1*04:58、DRB1*04:59、DRB1*04:60、DRB1*04:61、DRB1*04:62、DRB1*04:63、DRB1*04:64、DRB1*04:65、DRB1*04:66、DRB1*04:67、DRB1* 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DRB1*07:18, DRB1*07:19, DRB1 *07:20, DRB1*07:21, DRB1*07:22, DRB1*07:23, DRB1*07:24, DRB1*07:25, DRB1*07:26N, DRB1*07:27, DRB1*07:28, DRB1*07:29, DRB1*07:30, DRB1*07:31, DRB1*07:32, DRB1*07:33, DRB1*07:34, DRB1*07:35, DRB1*07:36, DRB1*07:37, DRB1*07:38, DRB1*07:39, DRB1*07:40, DRB1*07:41, DRB1*07:42,DRB1*07:43、DRB1*07:44、DRB1*07:45、DRB1*07:46、DRB1*07:47、DRB1*07:48、DRB1*07:49、DRB1*07:50、DRB1*07:51、DRB1*07:52、DRB1*07:53、DRB1*07:53 1*07:54、DRB1*07:55、DRB1*07:56、DRB1*07:57、DRB1*07:58N、DRB1*07:59、DRB1*07:60、DRB1*07:61、DRB1*07:62、DRB1*07:63、DRB1*07:64、DRB1*07:64 07:65、DRB1*07:66、DRB1*07:67、DRB1*07:68N、DRB1*07:69、DRB1*07:70、DRB1*07:71、DRB1*07:72、DRB1*07:73、DRB1*07:74、DRB1*07:75、DRB1*07:75 :76、DRB1*07:77、DRB1*07:78、DRB1*07:79、DRB1*07:80、DRB1*07:81、DRB1*07:82、DRB1*07:83、DRB1*07:84、DRB1*07:85、DRB1*07:86、DRB1*07:87 N、DRB1*07:88、DRB1*07:89、DRB1*07:90、DRB1*07:91、DRB1*07:92、DRB1*07:93、DRB1*07:94、DRB1*07:95、DRB1*07:96、DRB1*07:97、DRB1*07:98、D 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1*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*11:224 228、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、DRB1*11:250N、DRB1*11:251、DRB1*11:252、DRB1*11:25 3、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、D 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,DRB1*12:01:01:02,DRB1*12:01:01:03,DRB1*12:01:01:04,DRB1*12:01:01:05,DRB1*12:01:01:06,DRB1*12:01:02,DRB1*12:01:03,DRB1*12:01:04,DRB1*12:01:05,DRB1*12:01:06,DRB1*12:01:07,DRB1*12:01:08,DRB1*12:01:09,DRB1*12:02:01:01,DRB1*12:02:01:02,DRB1*12:02:01:03,DRB1*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*12:08 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*12:11 RB1*12:12、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*12:21、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*1 2:31N, DRB1*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*12:5 3、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、DRB1*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*13:01:01:01、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*13:01:18、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*1 3:02:06、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*13:03:06 B1*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*13:108、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*13:116 1*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*13:124 1*13:125、DRB1*13:126、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*1 3:183、DRB1*13:184、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*13:194、DRB1*13:195、DRB1*13:196、DRB1*13:197、DRB1*13:198、DRB1*13:199、DRB1*13:20、DRB1*13:200、DRB1*13:201、DRB1*13:201 *13:202、DRB1*13:203、DRB1*13:204、DRB1*13:205、DRB1*13:206、DRB1*13:207、DRB1*13:208、DRB1*13:209、DRB1*13:210、DRB1*13:211、DRB1*13:2 12、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、DRB1*13:22 0. RB1*13:22:02, DRB1*13:230, DRB1*13:231, DRB1*13:232, DRB1*13:233, DRB1*13:234, DRB1*13:235, DRB1*13:236, DRB1*13:237, DRB1*13:238, DRB1*13:239, DRB1*13:23:01, DRB1*13:23:02, DRB1*13:24, DRB1*13:240, DRB1*13:241, DRB1*13:242:01, DRB1*13:242:02, DRB1*13:243, DRB1*13:244,DRB1*13:245、DRB1*13:246、DRB1*13:247、DRB1*13:248、DRB1*13:249N、DRB1*13:25、DRB1*13:250、DRB1*13:251、DRB1*13:252N、DRB1*13:253、DRB1*13:254、DRB1*13:255N、DRB1*13:256、DRB1*13:257、DRB1*13:258、DRB1*13:259、DRB1*13:260、DRB1*13:261、DRB1*13:262、DRB1*13:263、DRB1* 13:264、DRB1*13:265、DRB1*13:266、DRB1*13:267、DRB1*13:268N、DRB1*13:269、DRB1*13:26:01、DRB1*13:26:02、DRB1*13:27、DRB1*13:270、DRB1 *13:271、DRB1*13:272、DRB1*13:273、DRB1*13:274、DRB1*13:275、DRB1*13:276、DRB1*13:277、DRB1*13:278Q、DRB1*13:279、DRB1*13:280、DRB1*13:278 13:28:02, DRB1*13:29, DRB1*13:30, DRB1*13:31, DRB1*13:32, DRB1*13:33:01, DRB1*13:33:02, DRB1*13:33:03, DRB1*13:34, DRB1*13:35, DRB1*13:36, DRB1*13:37, DRB1*13:38, DRB1*13:39, DRB1*13:40, DRB1*13:41, DRB1*13:42, DRB1*13:43, DRB1*13:44, DRB1*13:45, DRB1*13:46, DRB1*13:4 7、DRB1*13:48、DRB1*13:49、DRB1*13:50:01、DRB1*13:50:02、DRB1*13:50:03、DRB1*13:51、DRB1*13:52、DRB1*13:53、DRB1*13:54、DRB1*13:55、DRB1*13:56、DRB1*13:57、DRB1*13:58、DRB1*13:59、DRB1*13:60、DRB1*13:61:01、DRB1*13:61:02、DRB1*13:62、DRB1*13:63、DRB1*13:64、DRB1*13:65、DRB1*13:66:01、DRB1*13:66:02、DRB1*13:67、DRB1*13:68、DRB1*13:69、DRB1*13:70、DRB1*13:71、DRB1*13:72、DRB1*13:73、DRB1*13:74、DRB1*13:71 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、D RB1*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*14:01:0 3、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*14:04:06 1*14:05:01:01, DRB1*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*14:12 4、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 2、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*14:137、DRB1*14:138、DRB1*14:138 1*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*14:144 148、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、D RB1*14:158、DRB1*14:159、DRB1*14:16、DRB1*14:160、DRB1*14:161、DRB1*14:162、DRB1*14:163、DRB1*14:164、DRB1*14:165、DRB1*14:166N、DRB1*14:167、DRB1*14:168、DRB1*14:169、DRB1*14:17、DRB1*14:170、DRB1*14:171、DRB1*14:172、DRB1*14:173、DRB1*14:174、DRB1*14:175、DRB1*14:176、DRB1*14:177、DRB1*14:178、DRB1*14:179、DRB1*14:18、DRB1*14:180、DRB1*14:181、DRB1*14:182、DRB1*14:183、DRB1*14:184、DRB1*14:185、DRB1*14:186、DRB1*14:187、DRB1*14:188N、DRB1*14:189、DRB1*14:19、DRB1*14:190、DRB1*14:191、DRB1*14:192、DRB1*14:193、DRB1*14:194、DRB1*14:1 95N、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*14:26 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*14:36 1*14:37, DRB1*14:38:01, DRB1*14:38:02, DRB1*14:39, DRB1*14:40, DRB1*14:41, DRB1*14:42, DRB1*14:43, DRB1*14:44:01, DRB1*14:44:02, DRB1*14:44:03, DRB1*14:45, DRB1*14:46, DRB1*14:47, DRB1*14:48, DRB1*14:49, DRB1*14:50, DRB1*14:51, DRB1*14:52, DRB1*14:53, DRB1*14:54:01:01,DRB1*14:54:01:02、DRB1*14:54:01:03、DRB1*14:54:01:04、DRB1*14:54:02、DRB1*14:54:03、DRB1*14:54:04、DRB1*14:54:05、DRB1*14:54:06、DRB1*14:54:06 B1*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*14:64 B1*14:65、DRB1*14:67、DRB1*14:68:01、DRB1*14:68:02、DRB1*14:69、DRB1*14:70、DRB1*14:71、DRB1*14:72、DRB1*14:73、DRB1*14:74、DRB1*14:7 5、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、D RB1*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*15:0 1:38、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、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*15:06:02 B1*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*15:104:01、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*15:117 B1*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、DRB 1*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*15:1 43、DRB1*15:144、DRB1*15:145、DRB1*15:146、DRB1*15:147、DRB1*15:148N、DRB1*15:149、DRB1*15:150、DRB1*15:151、DRB1*15:152、DRB1*15:153、DRB1*15:154N、DRB1*15:155、DRB1*15:156、DRB1*15:157、DRB1*15:158、DRB1*15:159N、DRB1*15:15:01、DRB1*15:15:02、DRB1*15:15:03、DRB1*15: 16、DRB1*15:160、DRB1*15:161、DRB1*15:162、DRB1*15:163N、DRB1*15:164Q、DRB1*15:165、DRB1*15:166、DRB1*15:167、DRB1*15:168、DRB1*15:169、DRB1*15:170、DRB1*15:17N、DRB1*15:18、DRB1*15:19、DRB1*15:20、DRB1*15:21、DRB1*15:22、DRB1*15:23、DRB1*15:24、DRB1*15:25、DRB1*15:26、DRB1*15:27、DRB1*15:28、DRB1*15:29、DRB1*15:30、DRB1*15:31:01、DRB1*15:31:02、DRB1*15:32、DRB1*15:33、DRB1*15:34、DRB1*15:35、DRB1*15:36、DRB1*15:37:01、DRB1*15:37:02、DRB1*15:38、DRB1*15:39、DRB1*15:40、DRB1*15:41、DRB1*15:42、DRB1*15:43、DRB1*15:44、DRB1*15:45、DRB1*1 5:46、DRB1*15:47、DRB1*15:48、DRB1*15:49、DRB1*15:50N、DRB1*15:51、DRB1*15:52、DRB1*15:53、DRB1*15:54、DRB1*15:55、DRB1*15:56、DRB1*15:52 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、DRB1*15:02、DRB1*15:02 5:67、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*15:7 8、DRB1*15:79、DRB1*15:80N、DRB1*15:81、DRB1*15:82、DRB1*15:83、DRB1*15:84、DRB1*15:85、DRB1*15:86、DRB1*15:87、DRB1*15:88、DRB1*15:89、D RB1*15:90、DRB1*15:91、DRB1*15:92、DRB1*15:93、DRB1*15:94、DRB1*15:95、DRB1*15:96、DRB1*15:97、DRB1*15:98、DRB1*15:99、DRB1*16:01:01、DRB1*16:01:02、DRB1*16:01:03、DRB1*16:01:04、DRB1*16:01:05、DRB1*16:01:06、DRB1*16:01:07、DRB1*16:01:08、DRB1*16:01:09、DRB1*16:01:10、DRB1*16:01:11、DRB1*16:01:12、DRB1*16:01:13、DRB1*16:01:14、DRB1*16:01:15、DRB1*16:01:16、DRB1*16:02:01:01、DRB1*16:02:01:02、DRB1*16:02:01:03、DRB1*16:02:02、DRB1*16:02:03、DRB1*16:02:04、DRB1*16:02:05、DRB1*16:02:06、DRB1*16:02:07、DRB1*16:02:08、DRB1*16:03、DRB1* 16:04:01, DRB1*16:04:02, DRB1*16:05:01, DRB1*16:05:02, DRB1*16:07, DRB1*16:08, DRB1*16:09:01, DRB1*16:09:02, DRB1*16:10:01, DRB1*16:10:02, DRB1*16:11, DRB1*16:12, DRB1*16:13N, DRB1*16:14, DRB1*16:15, DRB1*16:16, DRB1*16:17, DRB1*16:18, DRB1*16:19, DRB1*16:20, DRB1*16:21 N、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、D RB1*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*16:41、DRB1*16:41 2、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*16:53 B1*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、DR B3*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、DRB 3*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*0 1:61, 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, D RB3*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*02:02:12DRB3*02:02:13, DRB3*02:02:14, DRB3*02:02:15, DRB3*02:02:16, DRB3*02:02:17, DRB3*02:02:18, DRB3*02:02:19, DRB3*02:02:20, DRB3*02:02:21 、DRB3*02:03、DRB3*02:04、DRB3*02:05、DRB3*02:06、DRB3*02:07、DRB3*02:08、DRB3*02:09、DRB3*02:10、DRB3*02:11、DRB3*02:12、DRB3*02:13、DRB 3*02:14、DRB3*02:15、DRB3*02:16、DRB3*02:17、DRB3*02:18、DRB3*02:19、DRB3*02:20、DRB3*02:21、DRB3*02:22:01、DRB3*02:22:02、DRB3*02:23、D RB3*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*02:3 3, 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, DR B3*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*02:78DRB3*02:79、DRB3*02:80N、DRB3*02:81、DRB3*02:82、DRB3*02:83、DRB3*02:84、DRB3*02:85、DRB3*02:86、DRB3*02:87、DRB3*02:88、DRB3*02:89、DRB3*02:90、DRB3*02:91、DRB3*02:92、DRB3*02:93、DRB3*02:94、DRB3*02:95N、DRB3*03:01:01:01、DRB3*03:01:01:02、DRB3*03:01:02、DRB3*03:01:03、DRB3*03:01:04、DRB3*03:01:05、DRB3*03:01:06、DRB3*03:01:07、DRB3*03:02、DRB3*03:03、DRB3*03:04、DRB3*03:05、DRB3*03:06、DRB3*03:07、DRB3*03:08、DRB3*03:09、DRB3*03:10、DRB3*03:11、DRB3*03:12、DRB3*03:13、DRB3*03:14、DRB3*03:15、DRB3*03:16、DRB3*03:17、DRB3*03:18、DRB3*03:19、DRB3*03:20、DRB3*03:21、DRB3*03:22、DRB3*03:23、DRB3*03:24、DRB3*03:25、DRB4*01:01:01:01、DRB4*01:01:02、DRB4*01:01:03、DRB4*01:01:04、DRB4*01:01:05、DRB4*01:01:06、DRB4*01:02、DRB4*01:03:01:01、DRB4*01:03:01:02N、DRB4*01:03:01:03、DRB4*01:03:01:04、DRB4*01:03:01:05、DRB4*01:03:01:06、DRB4*01:03:01:07、DRB4*01:03:01:08、DRB4*01:03:01:09、DRB4*01:03:01:10、DRB4*01:03:01:11、DRB4*01:03:02、DRB4*01:03:03、DRB4*01:03:04、DRB4*01:03:05、DRB4*01:03:06、DRB4*01:03:07、DRB4*01:03:08、DRB4*01:03:09、DRB4*01:03:10、DRB4*01:03:11、DRB4*01:04、DRB4*01:05、DRB4*01:06、DRB4*01:07:01、DRB4*01:07:02、DRB4*01:08、DRB4*01:09、DRB4*01:10、DRB4*01:11、DRB4*01:12、DRB4*01:13、DRB4*01:14、DRB4*01:15、DRB4*01:16N、DRB4*01:17、DRB4*01:18、DRB4*01:19、DRB4*01:20、DRB4*01:21、DRB4*01:22、DRB4*01:23、DRB4*01:24、DRB4*01:25、DRB4*01:26、DRB4*01:27、DRB4*01:28、DRB4*01:29、DRB4*01:30、DRB4*01:31、DRB4*01:32、DRB4*01:33、DRB4*01:34、DRB4*01:35、DRB4*01:36、DRB4*01:37、DRB4*01:38N、DRB4*01:39、DRB4*01:40、DRB4*01:41、DRB4*01:42、DRB4*01:43、DRB4*01:44、DRB4*01:45、DRB4*01:46、DRB4*01:47、DRB4*01:48、DRB4*01:49、DRB4*01:50、DRB4*01:51、DRB4*01:52、DRB4*01:53、DRB4*01:54N、DRB4*01:55、DRB4*01:56N、DRB4*01:57N、DRB4*01:58、DRB4*01:59、DRB4*01:60、DRB4*01:61N、DRB4*01:62、DRB4*01:63、DRB4*01:64、DRB4*01:65N、DRB4*01:66、DRB4*01:67、DRB4*01:68、DRB4*01:69、DRB4*01:70、DRB4*01:71N、DRB4*01:72、DRB4*01:73、DRB4*01:74、DRB4*01:75、DRB4*01:76、DRB4*01:77、DRB4*01:78、DRB4*01:79、DRB4*01:80N、DRB4*01:81、DRB4*01:82、DRB4*01:83、DRB4*01:84N、DRB4*01:85、DRB4*01:86、DRB4*01:87、DRB4*01:88、DRB4*01:89、DRB4*01:90、DRB4*01:91、DRB4*01:92、DRB4*01:93、DRB4*02:01N、DRB5*01:01:01:01、DRB5*01:01:01:02、DRB5*01:01:02、DRB5*01:01:03、DRB5*01:01:04、DRB5*01:02、DRB5*01:03、DRB5*01:04、DRB5*01:05、DRB5*01:06、DRB5*01:07、DRB5*01:08N、DRB5*01:09、DRB5*01:10N、DRB5*01:11、DRB5*01:12、DRB5*01:13、DRB5*01:14、DRB5*01:15、DRB5*01:16、DRB5*01:17、DRB5*01:18、DRB5*01:19、DRB5*01:20、DRB5*01:21、DRB5*01:22:01、DRB5*01:22:02、DRB5*01:23、DRB5*01:24、DRB5*01:25、DRB5*01:26、DRB5*01:27N、DRB5*01:28、DRB5*01:29、DRB5*01:30、DRB5*01:31、DRB5*01:32、DRB5*01:33、DRB5*01:34、DRB5*01:35、DRB5*01:36、DRB5*01:37、DRB5*01:38、DRB5*01:39、DRB5*01:40、DRB5*01:41、DRB5*01:42、DRB5*01:43、DRB5*01:44、DRB5*01:45、DRB5*01:46、DRB5*01:47、DRB5*01:48N、DRB5*01:49N、DRB5*01:50、DRB5*01:51、DRB5*01:52N、DRB5*01:53N、DRB5*01:54、DRB5*01:55、DRB5*02:02:01、DRB5*02:02:02、DRB5*02:02:03、DRB5*02:03、DRB5*02:04、DRB5*02:05、DRB5*02:06、DRB5*02:07、DRB5*02:08、DRB5*02:09、DRB5*02:10、DRB5*02:11、DRB5*02:12、DRB5*02:13、DRB5*02:14、DRB5*02:15、DRB5*02:16、DRB5*02:17、DRB5*02:18、DRB5*02:19N、DRB5*02:20、DRB5*02:21、DRB5*02:22、DRB5*02:23, DRB5*02:24, and any combination thereof.

[0205] In some aspects, the HLA class II molecule is a monomer. In some aspects, the HLA class II molecule is a dimer. In some aspects, the HLA class II molecule is a polymer. In some aspects, the HLA class II molecule is a trimer. In some aspects, the HLA class II molecule is a tetramer. In some aspects, the HLA class II molecule is a pentamer.

[0206] Certain aspects of this disclosure relate to antigen-presenting cells (APCs) that contain any of the HLA class II molecules disclosed herein. In some aspects, the APC expresses an HLA class II molecule on its surface. In some aspects, the APC contains more than one HLA class II molecule disclosed herein.

[0207] II.E. vaccine

[0208] Some aspects of this disclosure relate to a cancer vaccine comprising a peptide having an amino acid sequence as listed in SEQ ID NO:13. In some aspects, the cancer vaccine comprises a peptide consisting of an amino acid sequence listed in SEQ ID NO:13. In some aspects, the vaccine further comprises one or more excipients. In some aspects, the vaccine further comprises one or more other peptides. In some aspects, the one or more other peptides comprise one or more other epitopes.

[0209] III. The Method of This Disclosure

[0210] Some aspects of this disclosure relate to methods for treating cancer in subjects of need. Other aspects of this disclosure relate to methods for engineering cells that target antigens. Still other aspects of this disclosure relate to methods for enriching target T cell populations obtained from human subjects.

[0211] III.A. Methods of Treating Cancer

[0212] Some aspects of this disclosure relate to methods for treating cancer in a subject in need, the methods 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.

[0213] In some respects, cancers include melanoma, bone cancer, kidney cancer, prostate cancer, breast cancer, colon cancer, lung cancer, malignant melanoma of the skin or eye, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, 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), esophageal cancer, small bowel cancer, endocrine system cancers, thyroid cancer, parathyroid cancer, and adrenal cancer. Soft tissue sarcoma, urethral cancer, penile cancer, 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, kidney or ureter cancer, renal pelvis tumor, central nervous system (CNS) spurs, primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem gliomas, pituitary adenomas, 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 thereof. In some respects, the cancer is melanoma.

[0214] In some cases, cancer is recurrent. In others, it is refractory. In still others, it is advanced. In some of the times, it is metastatic.

[0215] In some aspects, the methods disclosed herein treat cancer in subjects. In some aspects, the methods disclosed herein reduce the severity of one or more cancer symptoms. In some aspects, the methods disclosed herein reduce the size or number of tumors originating from cancer. In some aspects, the methods disclosed herein increase overall survival in subjects compared to those not provided with the methods disclosed herein. In some aspects, the methods disclosed herein increase progression-free survival in subjects compared to those not provided with the methods disclosed herein. In some aspects, the methods disclosed herein elicit a partial response in subjects. In some aspects, the methods disclosed herein elicit a complete response in subjects.

[0216] In some aspects, the methods disclosed herein include treating cancer in a subject of need, including administering to the subject cells described herein, wherein the cells comprise nucleic acid molecules disclosed herein, vectors disclosed herein, recombinant TCRs disclosed herein, and / or bispecific antibodies disclosed herein. In some aspects, the cells are T cells. In some aspects, the cells are cells modified to express CD4.

[0217] In some respects, the cells (e.g., T cells) are obtained from the subject. In other respects, the cells (e.g., T cells) are obtained from a donor other than the subject.

[0218] In some aspects, the subject undergoes pretreatment prior to cell administration. Pretreatment may include any substance that contributes to T cell function and / or survival. In some protocols, the pretreatment includes administering chemotherapy, cytokines, proteins, small molecules, or any combination thereof to the subject. In some aspects, the pretreatment includes administering interleukins. In some aspects, the pretreatment includes administering IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, or any combination thereof. In some aspects, the pretreatment includes administering cyclophosphamide, fludarabine, or both. In some aspects, the pretreatment includes administering vitamin C, AKT inhibitors, ATRA (vesanoid), rapamycin, or any combination thereof.

[0219] III.B. Methods for engineering cells targeting antigens

[0220] Certain aspects of this disclosure relate to methods for engineering cells targeting an antigen. In some aspects, the antigen is the CCND1 antigen. In some aspects, the method includes transducing cells using nucleic acid molecules or vectors disclosed herein. The cells can be any cells described herein. In some aspects, the cells are T cells as described herein. In some aspects, the cells are cells modified to express CD4 as described herein. In some aspects, the cells (e.g., T cells) are obtained from a subject requiring T cell therapy. In some aspects, the cells are obtained from a donor other than a subject requiring T cell therapy. In some aspects, the cells are T cells or natural killer cells.

[0221] III.C. Methods for enriching target T cell populations

[0222] Certain aspects of this disclosure relate to methods for enriching a population of target T cells obtained from human subjects. In some aspects, the method includes contacting T cells with the HLA class II molecules disclosed herein. In some aspects, the method includes contacting T cells with the APCs disclosed herein. In some aspects, after contact, the enriched population of T cells contains a higher number of T cells capable of binding HLA class II molecules compared to the number of T cells capable of binding HLA class II molecules before contact.

[0223] In some aspects, the method includes contacting T cells in vitro with a peptide, wherein the peptide comprises the amino acid sequence listed in SEQ ID NO:13. In some aspects, the method includes contacting T cells in vitro with a peptide, wherein the peptide consists of the amino acid sequence listed in SEQ ID NO:13. In some aspects, after contact, the enriched T cell population comprises a higher number of T cells capable of binding HLA class II molecules compared to the number of T cells capable of binding HLA class II molecules before contact.

[0224] Some aspects of this disclosure relate to a method for selecting T cells capable of targeting tumor cells. In some aspects, the method includes contacting a population of isolated T cells in vitro with a peptide, said peptide consisting of an amino acid sequence as listed in SEQ ID NO:13. In some aspects, the T cells are obtained from a human subject.

[0225] The T cells obtained from human subjects can be any T cells disclosed herein. In some aspects, the T cells obtained from human subjects are tumor-infiltrating lymphocytes (TILs).

[0226] In some aspects, the method further includes administering enriched T cells to a human subject. In some aspects, as described herein, the subject is pretreated prior to receiving the T cells.

[0227] All aspects, features, and choices described in this article can be combined in any and all variations.

[0228] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application is specifically and individually indicated to be incorporated by reference.

[0229] Having generally described the invention, further understanding can be obtained by referring to the embodiments provided herein. These embodiments are for illustrative purposes only and are not intended to be limiting.

[0230] Example

[0231] Example 1 - Method

[0232] cell

[0233] Peripheral 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 expressing defective HLA class I / II. Previously, K562-based artificial APCs (aAPCs) expressing various HLA class I genes as single HLA alleles bound to CD80 and CD83 have been reported (Butler et al., PloS One 7, e30229 (2012)). The Jurkat 76 cell line is a T-cell leukemia cell line lacking endogenous TCR, CD4, and CD8 expression. Jurkat 76 / CD4 cells were generated by retroviral transduction of the human CD4 gene. HEK293T cells and melanoma cell lines were grown in DMEM supplemented with 10% FBS and 50 μg / ml gentamicin (Thermo Fisher Scientific, Waltham, MA). K562 and Jurkat 76 cell lines were cultured in RPMI 1640 supplemented with 10% FBS and 50 μg / ml gentamicin.

[0234] peptides

[0235] CCND 1219-238 The synthetic peptides were purchased from Genscript (Piscataway, NJ) and dissolved in DMSO at a concentration of 50 μg / ml.

[0236] Gene

[0237] The novel TCR gene was cloned using the SMARTer RACE 5' / 3' kit (Takara Bio, Shiga, Japan) via 5'-rapid amplification (RACE) PCR of the cDNA ends and sequenced as previously described. All genes were cloned into the pMX retroviral vector and transduced into cell lines using a retroviral system based on 293GPG and PG13 cells.

[0238] Antibody

[0239] The following antibody was used for flow cytometry analysis: APC-Cy7 conjugated anti-CD4 (RPA-T4, Biolegend, San Diego, CA). 44Anti-His tags conjugated with PE (AD1.1.10, Abcam, Cambridge, MA). Dead cells were identified using the Live / Dead Fixable Near-Infrared Dead Cell Staining Kit 465 (Thermo Fisher Scientific, Waltham, MA). Stained cells were analyzed using Canto II or LSR Tortessa X-20 (BD Biosciences, Franklin Lakes, NJ). Cell sorting was performed using FACS Aria II (BD Biosciences, Franklin Lakes, NJ). Data analysis was performed using FlowJo software (Tree Star, Ashland, OR).

[0240] The following antibodies were used for immunoblotting analysis: anti-β-actin (C4, Santa Cruz Biotechnology, Santa Cruz, CA), anti-CCND1 (EPR2241, Abcam, Cambridge, MA), HRP-conjugated goat anti-mouse IgG (H+L) secondary antibody (Promega, Fitchburg, WI), and HRP-conjugated anti-rabbit IgG (H+L) secondary antibody (Promega, Fitchburg, WI), where applicable.

[0241] TCR transduction into primary T cells

[0242] CD3 + and CD4 + T cells were isolated using a whole T cell isolation kit (Miltenyi Biotec, Bergisch Gladbach, Germany) and CD4+. + T cell division kit (Miltenyi Biotec, Bergisch Gladbach, Germany) was used for purification. Purified T cells were stimulated with 200 Gy of irradiated aAPC / mOKT3 at an E:T ratio of 20:1. Starting the second day, activated T cells were transduced with a cloned TCR gene or retrovirus using retroviruses coated with retroviruses (Takara Bio, Shiga, Japan) after centrifugation at 1,000 × g for 1 hour at 32°C for 3 consecutive days. On the second day, 100 IU / ml IL-2 and 10 ng / ml IL-15 were added to the TCR-transduced T cells. Culture medium was replenished every 2–3 days.

[0243] Production of HLA class II monomers and dimers

[0244] The extracellular domain of the wild-type class II α gene was fused to an acidic leucine zipper via a GGGS linker, followed by fusion to a 6xHis tag via a GS linker (see SEQ ID NO:15; Table 5). The extracellular domain of the mutant class II β gene (see SEQ ID NO:14) was similarly fused to a basic leucine zipper via a GGGS linker (see SEQ ID NO:14). HEK293T and A375 cells were transfected with the α and β genes using a 293GPG cell-based retroviral system and cultured in DMEM supplemented with 10% FBS and 50 μg / ml gentamicin. For DP4 dimer staining, soluble DP4 was stably secreted. L112W / V141M HEK293T cells containing the protein were grown until confluence, and the medium was replaced with serum-free 293SFM II medium (Thermo Fisher Scientific, Waltham, MA). After 48 hours, the conditioned medium was harvested and concentrated using an Amicon Ultra filter (molecular weight cutoff (MWCO) 10 kDa) (Millipore Sigma, Burlington, MA). The supernatant containing soluble HLA class II peptides was then mixed with 100 μg / ml of the target peptide at 37°C for 20–24 hours for in vitro peptide exchange. Monomers not subjected to peptide exchange served as controls. Monomer concentrations were measured by specific ELISA using nickel-coated plates (XPressBio, Frederick, MD) and anti-His-tagged biotinylated mAbs (AD1.1.10, R&D Systems, Minneapolis, MN). Soluble HLA class II monomers were dimerized at 4°C for 1.5 hours using PE-conjugated anti-His mAb (AD1.1.10, Abcam, Cambridge, MA) at a molar ratio of 2:1 for staining.

[0245] Table 5: HLA-DP Class II Molecules

[0246]

[0247] DP4-restricted antigen-specific CD4 + T cell stimulation

[0248] CD4 + T cells use CD4 +T cell purification was performed using a T cell isolation kit (Miltenyi Biotec, Bergisch Gladbach, Germany). Purified T cells were stimulated with DP4-expressing aAPCs irradiated with a DP4-restricted peptide at a pulse of 10 μg / ml and an E:T ratio of 20:1 at 200 Gy. Forty-eight hours later, 10 IU / ml IL-2 and 10 ng / ml IL-15 were added to CD4. + T cells were supplemented with culture medium containing IL-2 (10 IU / ml) and IL-15 (10 ng / ml) every 2-3 days. After 2 weeks of stimulation, T cells were subjected to DP4... L112W / V141M Dimer staining.

[0249] HLA class II dimer staining

[0250] Primary T cells and Jurkat 76 / CD4 T cells transduced with endogenous TCR gene were pretreated with 50 nM dasatinib (LC Laboratories, Woburn, MA) at 37°C for 30 minutes. 46 The cells were stained with 5-15 μg / ml class II dimers at room temperature for 4-5 hours. After washing, the cell surface molecules were counterstained with APC-Cy7 conjugated anti-CD4 mAb.

[0251] ELISPOT measurement

[0252] As previously reported, the cytokine ELISPOT assay was performed (see, for example, Yamashita et al., Nat. Commun. 8:15244 (2017); and Anczurowski et al., Sci. Rep. 8:4804 (2018)).

[0253] Immunoblotting

[0254] Immunoblot analysis was performed as previously reported (see, for example, Yamashita et al., Nat. Commun. 8:15244 (2017); and Anczurowski et al., Sci. Rep. 8:4804 (2018)).

[0255] Statistical analysis

[0256] Statistical analyses were performed using GraphPad Prism 6.0 software (GraphPad Software, San Diego, CA). Unpaired two-tailed Student's t-tests were used for comparisons of two samples. No statistical methods were used to predetermine sample size. Researchers were nonblinded during the experiment and outcome evaluation. The experiment was not randomized.

[0257] Example 2 – CCND1219-238 Characterization of TCR

[0258] From six DP4 + Primary CD4 isolated from melanoma patients + T cells were stimulated only once with DP4-aAPC, which was pulsed with a peptide fragment of CCND1 (219-238) and homologous DP4. L112W / V141M Dimer staining. A weak stimulation condition was used to avoid potential in vitro priming. CCND1 was detected by dimer staining. 219-238 It is immunogenic (data not shown).

[0259] To verify the dimer staining results, a clone of CCND1 was cloned from dimer-positive T cells. 219-238 DP4-specific TCR gene ( Figure 1A-1B (and Table 6) When in human CD4 + During clonal recombination in TCR-deficient T cells, CCND1 219-238 TCR is associated with DP4 L112W / V141M The dimer was successfully stained. Figure 2A-2D ), and functions in a DP4-restrictive and antigen-specific manner ( Figure 3 ).

[0260] TCR 03-CCND1 219-238 It can recognize homologous peptides that are endogenously processed and presented by DP4 (Figures 4A-4E and 5A-5B).

[0261] Table 6: DP4-Restricted TCR

[0262] sequence list <110> University Health Network <120> T-cell receptors and their usage <130> 4285.013PC01 / C-K / BMD <150> US 62 / 880,504 <151> 2019-07-30 <160> 28 <170> PatentIn version 3.5 <210> 1 <211> 248 <212> PRT <213> Artificial Sequence <220> <223> synthetic construction <400> 1 Lys Asp Gln Val Phe Gln Pro Ser Thr Val Ala Ser Ser Glu Gly Ala 1 5 10 15 Val Val Glu Ile Phe Cys Asn His Ser Val Ser Asn Ala Tyr Asn Phe 20 25 30 Phe Trp Tyr Leu His Phe Pro Gly Cys Ala Pro Arg Leu Leu Val Lys 35 40 45 Gly Ser Lys Pro Ser Gln Gln Gly Arg Tyr Asn Met Thr Tyr Glu Arg 50 55 60 Phe Ser Ser Ser Leu Leu Ile Leu Gln Val Arg Glu Ala Asp Ala Ala 65 70 75 80 Val Tyr Tyr Cys Ala Val Cys Thr Leu Tyr Asn Phe Asn Lys Phe Tyr 85 90 95 Phe Gly Ser Gly Thr Lys Leu Asn Val Lys Pro Asn Ile Gln Asn Pro 100 105 110 Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser 115 120 125 Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser 130 135 140 Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val Leu Asp Met Arg 145 150 155 160 Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser 165 170 175 Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp 180 185 190 Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val Lys Leu Val Glu 195 200 205 Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn Leu Ser Val 210 215 220 Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu 225 230 235 240 Met Thr Leu Arg Leu Trp Ser Ser 245 <210> 2 <211> 288 <212> PRT <213> Artificial Sequence <220> <223> Synthetic construct <400> 2 Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu Lys Thr Gly Gln Ser 1 5 10 15 Met Thr Leu Gln Cys Ala Gln Asp Met Asn His Glu Tyr Met Ser Trp 20 25 30 Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu Ile His Tyr Ser Val 35 40 45 Gly Ala Gly Ile Thr Asp Gln Gly Glu Val Pro Asn Gly Tyr Asn Val 50 55 60 Ser Arg Ser Thr Thr Glu Asp Phe Pro Leu Arg Leu Leu Ser Ala Ala 65 70 75 80 Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser Leu Thr Asp Asn Asn 85 90 95 Glu Gln Phe Phe Gly Pro Gly Thr Arg Leu Thr Val Leu Glu Asp Leu 100 105 110 Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro Ser Glu Ala 115 120 125 Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu Ala Thr Gly 130 135 140 Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu 145 150 155 160 Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu Lys Glu Gln Pro 165 170 175 Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser 180 185 190 Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln 195 200 205 Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp Arg Ala Lys 210 215 220 Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys 225 230 235 240 Gly Phe Thr Ser Glu Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile 245 250 255 Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val 260 265 270 Ser Ala Leu Val Leu Met Ala Met Val Lys Arg Lys Asp Ser Arg Gly 275 280 285 <210> 3 <400> 3 000 <210> 4 <400> 4 000 <210> 5 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic construct <400> 5 Val Ser Asn Ala Tyr Asn 1 5 <210> 6 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Synthetic constructs <400> 6 Gly Ser Lys Pro 1 <210> 7 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Synthetic constructs <400> 7 Cys Ala Val Cys Thr Leu Tyr Asn Phe Asn Lys Phe Tyr Phe 1 5 10 <210> 8 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic constructs <400> 8 Met Asn His Glu Tyr 1 5 <210> 9 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic constructs <400> 9 Ser Val Gly Ala Gly Ile 1 5 <210> 10 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic constructs <400> 10 Cys Ala Ser Leu Thr Asp Asn Asn Glu Gln Phe Phe 1 5 10 <210> 11 <400> 11 000 <210> 12 <400> 12 000 <210> 13 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> Synthetic constructs <400> 13 Ser Pro Asn Asn Phe Leu Ser Tyr Tyr Arg Leu Thr Arg Phe Leu Ser 1 5 10 15 Arg Val Ile Lys 20 <210> 14 <211> 265 <212> PRT <213> Artificial Sequence <220> <223> Synthetic constructs <400> 14 Met Met Arg Pro Ile Val Leu Val Leu Leu Phe Ala Thr Ser Ala Leu 1 5 10 15 Ala Arg Ala Thr Pro Glu Asn Tyr Leu Phe Gln Gly Arg Gln Glu Cys 20 25 30 Tyr Ala Phe Asn Gly Thr Gln Arg Phe Leu Glu Arg Tyr Ile Tyr Asn 35 40 45 Arg Glu Glu Phe Ala Arg Phe Asp Ser Asp Val Gly Glu Phe Arg Ala 50 55 60 Val Thr Glu Leu Gly Arg Pro Ala Ala Glu Tyr Trp Asn Ser Gln Lys 65 70 75 80 Asp Ile Leu Glu Glu Lys Arg Ala Val Pro Asp Arg Met Cys Arg His 85 90 95 Asn Tyr Glu Leu Gly Gly Pro Met Thr Leu Gln Arg Arg Val Gln Pro 100 105 110 Arg Val Asn Val Ser Pro Ser Lys Lys Gly Pro Leu Gln His His Asn 115 120 125 Trp Leu Val Cys His Val Thr Asp Phe Tyr Pro Gly Ser Ile Gln Val 130 135 140 Arg Trp Phe Leu Asn Gly Gln Glu Glu Thr Ala Gly Val Met Ser Thr 145 150 155 160 Asn Leu Ile Arg Asn Gly Asp Trp Thr Phe Gln Ile Leu Val Met Leu 165 170 175 Glu Met Thr Pro Gln Gln Gly Asp Val Tyr Thr Cys Gln Val Glu His 180 185 190 Thr Ser Leu Asp Ser Pro Val Thr Val Glu Trp Lys Ala Gln Ser Asp 195 200 205 Ser Ala Arg Ser Lys Gly Gly Gly Gly Ser Leu Glu Ile Glu Ala Ala 210 215 220 Phe Leu Glu Arg Glu Asn Thr Ala Leu Glu Thr Arg Val Ala Glu Leu 225 230 235 240 Arg Gln Arg Val Gln Arg Leu Arg Asn Arg Val Ser Gln Tyr Arg Thr 245 250 255 Arg Tyr Gly Pro Leu Gly Gly Gly Lys 260 265 <210> 15 <211> 269 <21​​​​​​​​​​​​​​​​​​​​​​​​​​ 65 70 75 80 Ala Ile Leu Asn Asn Asn Leu Asn Thr Leu Ile Gln Arg Ser Asn His 85 90 95 Thr Gln Ala Thr Asn Asp Pro Pro Glu Val Thr Val Phe Pro Lys Glu 100 105 110 Pro Val Glu Leu Gly Gln Pro Asn Thr Leu Ile Cys His Ile Asp Lys 115 120 125 Phe Phe Pro Pro Val Leu Asn Val Thr Trp Leu Cys Asn Gly Glu Leu 130 135 140 Val Thr Glu Gly Val Ala Glu Ser Leu Phe Leu Pro Arg Thr Asp Tyr 145 150 155 160 Ser Phe His Lys Phe His Tyr Leu Thr Phe Val Pro Ser Ala Glu Asp 165 170 175 Phe Tyr Asp Cys Arg Val Glu His Trp Gly Leu Asp Gln Pro Leu Leu 180 185 190 Lys His Trp Glu Ala Gln Glu Pro Ile Gln Met Pro Glu Thr Thr Glu 195 200 205 Thr Gly Gly Gly Gly Ser Leu Glu Ile Arg Ala Ala Phe Leu Arg Gln 210 215 220 Arg Asn Thr Ala Leu Arg Thr Glu Val Ala Glu Leu Glu Gln Glu Val 225 230 235 240 Gln Arg Leu Glu Asn Glu Val Ser Gln Tyr Glu Thr Arg Tyr Gly Pro 245 250 255 Leu Gly Gly Gly Lys Gly Ser His His His His His His 260 265 <210> 16 <211> 295 <212> PRT <213> Artificial Sequence <220><​​​​​​​​​​​​​​​​​​​​​​​​​​​​Ser Arg Leu Gln Leu Leu Gly Ala Thr Cys Met Phe Val Ala Ser Lys 100 105 110 Met Lys Glu Thr Ile Pro Leu Thr Ala Glu Lys Leu Cys Ile Tyr Thr 115 120 125 Asp Asn Ser Ile Arg Pro Glu Glu Leu Leu Gln Met Glu Leu Leu Leu 130 135 140 Val Asn Lys Leu Lys Trp Asn Leu Ala Ala Met Thr Pro His Asp Phe 145 150 155 160 Ile Glu His Phe Leu Ser Lys Met Pro Glu Ala Glu Glu Asn Lys Gln 165 170 175 Ile Ile Arg Lys His Ala Gln Thr Phe Val Ala Leu Cys Ala Thr Asp 180 185 190 Val Lys Phe Ile Ser Asn Pro Pro Ser Met Val Ala Ala Gly Ser Val 195 200 205 Val Ala Ala Val Gln Gly Leu Asn Leu Arg Ser Pro Asn Asn Phe Leu 210 215 220 Ser Tyr Tyr Arg Leu Thr Arg Phe Leu Ser Arg Val Ile Lys Cys Asp 225 230 235 240 Pro Asp Cys Leu Arg Ala Cys Gln Glu Gln Ile Glu Ala Leu Leu Glu 245 250 255 Ser Ser Leu Arg Gln Ala Gln Gln Asn Met Asp Pro Lys Ala Ala Glu 260 265 270 Glu Glu Glu Glu Glu Glu Glu Glu Val Asp Leu Ala Cys Thr Pro Thr 275 280 285[[ID=⑧]] Asp Val Arg Asp Val Asp Ile 290 295 <210> 17 <211> 458 <212> PRT <213> Artificial Sequence <220> <223> Synthetic construct <400> 17 Met Asn Arg Gly Val Pro Phe Arg His Leu Leu Leu Val Leu Gln Leu 1 5 10 15 Ala Leu Leu Pro Ala Ala Thr Gln Gly Lys Lys Val Val Leu Gly Lys 20 25 30 Lys Gly Asp Thr Val Glu Leu Thr Cys Thr Ala Ser Gln Lys Lys Ser 35 40 45 Ile Gln Phe His Trp Lys Asn Ser Asn Gln Ile Lys Ile Leu Gly Asn 50 55 60 Gln Gly Ser Phe Leu Thr Lys Gly Pro Ser Lys Leu Asn Asp Arg Ala 65 70 75 80 ]>Asp Ser Arg Arg Ser Leu Trp Asp Gln Gly Asn Phe Pro Leu Ile Ile 85 90 95 Lys Asn Leu Lys Ile Glu Asp Ser Asp Thr Tyr Ile Cys Glu Val Glu 100 105 110 Asp Gln Lys Glu Glu Val Gln Leu Leu Val Phe Gly Leu Thr Ala Asn 115 120 125 Ser Asp Thr His Leu Leu Gln Gly Gln Ser Leu Thr Leu Thr Leu Glu 130 135 140 Ser Pro Pro Gly Ser Ser Pro Ser Val Gln Cys Arg Ser Pro Arg Gly 145 150 155 160 Lys Asn Ile Gln Gly Gly Lys Thr Leu Ser Val Ser Gln Leu Glu Leu 165 170 175 Gln Asp Ser Gly Thr Trp Thr Cys Thr Val Leu Gln Asn Gln Lys Lys 180 185 190 Val Glu Phe Lys Ile Asp Ile Val Val Leu Ala Phe Gln Lys Ala Ser 195 200 205 Ser Ile Val Tyr Lys Lys Glu Gly Glu Gln Val Glu Phe Ser Phe Pro 210 215 220 Leu Ala Phe Thr Val Glu Lys Leu Thr Gly Ser Gly Glu Leu Trp Trp 225 230 235 240 Gln Ala Glu Arg Ala Ser Ser Ser Lys Ser Trp Ile Thr Phe Asp Leu 245 250 255 Lys Asn Lys Glu Val Ser Val Lys Arg Val Thr Gln Asp Pro Lys Leu 260 265 270 Gln Met Gly Lys Lys Leu Pro Leu His Leu Thr Leu Pro Gln Ala Leu 275 280 285 Pro Gln Tyr Ala Gly Ser Gly Asn Leu Thr Leu Ala Leu Glu Ala Lys 290 295 300 Thr Gly Lys Leu His Gln Glu Val Asn Leu Val Val Met Arg Ala Thr 305 310 315 320 Gln Leu Gln Lys Asn Leu Thr Cys Glu Val Trp Gly Pro Thr Ser Pro 325 330 335 Lys Leu Met Leu Ser Leu Lys Leu Glu Asn Lys Glu Ala Lys Val Ser 340 345 350 Lys Arg Glu Lys Ala Val Trp Val Leu Asn Pro Glu Ala Gly Met Trp 355 360 365 Gln Cys Leu Leu Ser Asp Ser Gly Gln Val Leu Leu Glu Ser Asn Ile 370 375 380 Lys Val Leu Pro Thr Trp Ser Thr Pro Val Gln Pro Met Ala Leu Ile 385 390 395 400 Val Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile 405 410 415 Phe Phe Cys Val Arg Cys Arg His Arg Arg Arg Gln Ala Glu Arg Met 420 425 430 Ser Gln Ile Lys Arg Leu Leu Ser Glu Lys Lys Thr Cys Gln Cys Pro 435 440 445 His Arg Phe Gln Lys Thr Cys Ser Pro Ile 450 455 <210> 18 <211> 744 <212> DNA <213> Artificial Sequence <220> <223> Synthetic construct <400> 18 aaggaccaag tgtttcagcc ttccacagtg gcatcttcag agggagctgt ggtggaaatc 60 ttctgtaatc actctgtgtc caatgcttac aacttcttct ggtaccttca cttcccggga 120 tgtgcaccaa gactccttgt taaaggctca aagccttctc agcagggacg atacaacatg 180 acctatgaac ggttctcttc atcgctgctc atcctccagg tgcgggaggc agatgctgct 240 gtttactact gtgctgtctg caccttatac aacttcaaca aattttactt tggatctggg 300 accaaactca atgtaaaacc aaatatccag aaccctgacc ctgccgtgta ccagctgaga 360 gactctaaat ccagtgacaa gtctgtctgc ctattcaccg attttgattc tcaaacaaat 420 gtgtcacaaa gtaaggattc tgatgtgtat atcacagaca aaactgtgct agacatgagg 480 tctatggact tcaagagcaa cagtgctgtg gcctggagca acaaatctga ctttgcatgt 540 gcaaacgcct tcaacaacag cattattcca gaagacacct tcttccccag cccagaaagt 600 tcctgtgatg tcaagctggt cgagaaaagc tttgaaacag atacgaacct aaactttcaa 660 aacctgtcag tgattgggtt ccgaatcctc ctcctgaaag tggccgggtt taatctgctc 720 atgacgctgc ggctgtggtc cagc 744 <210> 19 <211> 864 <212> DNA <213> Artificial Sequence <220> <223> Synthetic construct <400> 19 ggtgtcactc agaccccaaa attccaggtc ctgaagacag gacagagcat gacactgcag 60 tgtgcccagg atatgaacca tgaatacatg tcctggtatc gacaagaccc aggcatgggg 120 ctgaggctga ttcattactc agttggtgct ggtatcactg accaaggaga agtccccaat 180 ggctacaatg tctccagatc aaccacagag gatttcccgc tcaggctgct gtcggctgct 240 ccctcccaga catctgtgta cttctgtgcc agcctgacag ataacaatga gcagttcttc 300 gggccaggga cacggctcac cgtgctagag gacctgaaga acgtgttccc cccagaggtg 360 gccgtgttcg agccttctga ggccgagatc agccacaccc agaaagccac cctcgtgtgt 420 ctggccaccg gcttctaccc cgaccatgtg gaactgtctt ggtgggtcaa cggcaaagag 480 gtgcacagcg gagtgtccac cgacccccag cctctgaaag aacagcccgc cctgaacgac 540 agccggtact gcctgagcag cagactgaga gtgtccgcca ccttctggca gaacccccgg 600 aaccacttca gatgccaggt gcagttctac ggcctgagcg agaacgacga gtggacccag 660 gacagagcca agcccgtgac ccagatcgtg tctgccgaag cctggggcag agccgattgc 720 ggctttacca gcgagagcta ccagcagggc gtgctgagcg ccaccatcct gtacgagatt 780 ctgctgggca aggccaccct gtacgctgtg ctggtgtcag ccctggtgct gatggccatg 840 gtcaagcgga aggacagcag aggc 864 <210> 20 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic constructs <400> 20 Met Met Arg Pro Ile Val Leu Val Leu Leu Phe Ala Thr Ser Ala Leu 1 5 10 15 Ala <210> twenty one <211> 25 <212> PRT <213> Artificial Sequence <220> <223> Synthetic constructs <400> twenty one Met Ala Leu Gln Ser Thr Leu Gly Ala Val Trp Leu Gly Leu Leu Leu 1 5 10 15 Asn Ser Leu Trp Lys Val Ala Glu Ser 20 25 <210> twenty two <211> twenty one <212> PRT <213> Artificial Sequence <220> <223> Synthetic constructs <400> twenty two Met Ser Ile Gly Leu Leu Cys Cys Ala Ala Leu Ser Leu Leu Trp Ala 1 5 10 15 Gly Pro Val Asn Ala 20 <210> twenty three <211> 75 <212> DNA <213> Artificial Sequence <220> <223> Synthetic constructs <400> twenty three atggctttgc agagcactct gggggcggtg tggctagggc ttctcctcaa ctctctctgg 60 aaggttgcag aaagc 75 <210> twenty four <211> 63 <212> DNA <213> Artificial Sequence <220> <223> Synthetic constructs <400> twenty four atgagcatcg gcctcctgtg ctgtgcagcc ttgtctctcc tgtgggcagg tccagtgaat 60 gct 63 <210> 25 <211> twenty one <212> DNA <213> Artificial Sequence <220> <223> Synthetic constructs <400> 25 guaaggauuc ugauguguat t 21 <210> 26 <211> twenty one <212> DNA <213> Artificial Sequence <220> <223> Synthetic constructs <400> 26 uacacaucag aauccuuact t 21 <210> 27 <211> twenty one <212> DNA <213> Artificial Sequence <220> <223> Synthetic constructs <400> 27 ccaccauccu cuaugagaut t 21 <210> 28 <211> twenty one <212> DNA <213> Artificial Sequence <220> <223> Synthetic constructs <400> 28 aucucauaga ggaugguggt t 21

Claims

1. A nucleic acid molecule comprising (i) a first nucleotide sequence, which encodes an anti-CCNDl TCR, which is a recombinant T cell receptor (TCR) or antigen binding portion thereof, which specifically binds to an epitope of human G1 / S-specific cyclin D1 (CCNDl) consisting of the amino acid sequence of SEQ ID NO: 13, wherein the epitope is complexed with an HLA class II molecule HLA-DP allele; wherein the anti-CCNDl TCR comprises an alpha chain and a beta chain, wherein the alpha chain comprises a variable domain comprising an alpha chain CDR1, an alpha chain CDR2, and an alpha chain CDR3; and wherein the beta chain comprises a variable domain comprising a beta chain CDR1, a beta chain CDR2, and a beta chain CDR3; and wherein: (a) the amino acid sequence of the beta chain CDR3 of the anti-CCNDl TCR is set forth in SEQ ID NO: 10; (b) the amino acid sequence of the beta chain CDR2 of the anti-CCNDl TCR is set forth in SEQ ID NO: 9; (c) the amino acid sequence of the beta chain CDR1 of the anti-CCNDl TCR is set forth in SEQ ID NO: 8; (d) the amino acid sequence of the alpha chain CDR3 of the anti-CCNDl TCR is set forth in SEQ ID NO: 7; (e) the amino acid sequence of the alpha chain CDR2 of the anti-CCNDl TCR is set forth in SEQ ID NO: 6; and (f) the amino acid sequence of the alpha chain CDR1 of the anti-CCNDl TCR is set forth in SEQ ID NO: 5; and (ii) a second nucleotide sequence, wherein the second nucleotide sequence or a polypeptide encoded by the second nucleotide sequence inhibits expression of an endogenous TCR.

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

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

4. The nucleic acid molecule of any one of claims 1 to 3, wherein the alpha chain of the anti-CCNDl TCR further comprises a constant region, wherein the alpha chain constant region comprises the amino acid sequence of a constant region present in the amino acid sequence set forth in SEQ ID NO:

1.

5. The nucleic acid molecule of any one of claims 1 to 3, wherein the beta chain of the anti-CCNDl TCR further comprises a constant region, wherein the beta chain constant region comprises an amino acid sequence of a constant region present in the amino acid sequence set forth in SEQ ID NO:

2.

6. The nucleic acid molecule of any one of claims 1 to 3, wherein (i) the amino acid sequence of the alpha chain of the anti-CCNDl TCR is as set forth in SEQ ID NO: 1; (ii) the amino acid sequence of the beta chain of the anti-CCNDl TCR is as set forth in SEQ ID NO: 2; or (iii) both (i) and (ii).

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

8. The nucleic acid molecule of claim 7, wherein the one or more siRNAs comprise one or more nucleotide sequences selected from the group consisting of SEQ ID NOs: 53-56.

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

10. The vector of claim 9, which is a viral vector, a mammalian vector, or a bacterial vector.

11. The vector of claim 9, which is a retroviral vector.

12. The vector of claim 9, which 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 papovaviral vector, a vaccinia virus vector, a herpes simplex virus vector, a hybrid vector, and an adeno-associated virus (AAV) vector.

13. The vector of claim 9, which is a lentivirus.

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

15. A cell comprising the nucleic acid molecule of any one of claims 1 to 8, the vector of any one of claims 9 to 13, or the TCR of claim 14.

16. The cell of claim 15, which further expresses CD3.

17. The cell of claim 15 or 16, which is a T cell.

18. The cell of claim 15 or 16, which is a natural killer (NK) cell, a natural killer T (NKT) cell, or an ILC cell.

19. Use of the cell of any one of claims 15 to 18 in the manufacture of a medicament for treating melanoma in a subject in need thereof.

20. The use of claim 19, wherein the melanoma is relapsed or refractory.

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

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

23. The use of claim 19, wherein the melanoma is metastatic.

24. The use of claim 19, wherein the cells are obtained from the subject.

25. The use of claim 19, wherein the cells are obtained from a donor other than the subject.

26. A method of engineering a cell targeting an antigen, the method comprising transducing a cell collected from a subject in need of a T cell therapy with the nucleic acid molecule of any one of claims 1 to 9 or the vector of any one of claims 10 to 13.

27. The method of claim 26, wherein the cell targeting an antigen further expresses CD4.

28. The method of claim 26, wherein the cell is a T cell.

29. The method of claim 26, wherein the cell is a natural killer (NK) cell.

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