Peptide, protein complex comprising said peptide, and t cell receptor

Abstract

The present disclosure provides a peptide, a protein complex containing said peptide, a T cell receptor, etc. that can be used in antigen-specific immunosuppressive therapy for suppressing autoimmunity.　The present invention includes peptides of 25 or fewer amino acids in length that include any one amino acid sequence selected from the group consisting of core sequences represented by SEQ ID NO: 1 through 10 and SEQ ID NO: 301 through 303.

Description

Peptides, protein complexes containing the peptides, and T cell receptors 【0001】 This disclosure relates to peptides, protein complexes containing the peptides, and T cell receptors, etc. 【0002】 Among autoimmune diseases, immunological intractable diseases are particularly difficult to diagnose and treat, and the development of antibody drugs and molecularly targeted therapies is progressing. Some of these are effective across multiple immunological intractable diseases, but others suppress not only autoimmunity but also normal immunity. Furthermore, for immunological intractable diseases other than rheumatoid arthritis, such as Sjögren's syndrome (SS) and inflammatory muscle diseases, even molecular targets have not been established. Therefore, treatment for immunological intractable diseases is still insufficient, and immunosuppression is required for life. 【0003】 Sjögren's syndrome is an autoimmune disease characterized by lymphocyte infiltration of the salivary and lacrimal glands, leading to tissue destruction, dry mouth, and dry eyes. In some patients, it can cause systemic organ damage such as interstitial pneumonia, interstitial nephritis, vasculitis, and lymphoma. It is known that anti-SS-A antibodies appear in the serum of approximately 70% of patients. For example, it has been reported that approximately 30% of B cells infiltrating the salivary glands of Sjögren's syndrome patients with serum that is positive for anti-SS-A / SS-B antibodies produce anti-SS-A and anti-SS-B antibodies (Non-Patent Literature 1). On the other hand, regarding the antigens of T cells in Sjögren's syndrome, various proteins have been sporadically reported in papers since ancient times, but there is no established theory with reproducibility. 【0004】 Takeshita M et al. Ann Rheum Dis 2020; 79: 150-158 【0005】 While distinguishing between autoimmunity and normal immunity is necessary for developing treatments for intractable immunological diseases, the analysis of antigen specificity in systemic autoimmune diseases has not progressed. Although CAR-T cell therapy targeting only autoreactive B cells is being developed, it is unsuitable for non-lethal chronic diseases due to the cost of treatment and long-term safety concerns. 【0006】 The present disclosure provides peptides, protein complexes containing the peptides, T cell receptors, etc. that can be used in antigen-specific immunosuppressive therapies for suppressing autoimmunity. 【0007】 The inventors of the present invention have intensively studied to solve the above problems. As a result, they have found that the above problems can be solved by having the following configurations, and have completed the present invention. 【0008】 One aspect of the present disclosure relates to, for example, the following [1A] to [42A]. [1A] A peptide having 25 amino acids or less in length, containing any one amino acid sequence selected from the group consisting of core sequences represented by SEQ ID NOs: 1 to 10 respectively. [2A] The peptide according to [1A], consisting of an amino acid sequence represented by SEQ ID NOs: 11 to 51, or an amino acid sequence in which 1 or 2 amino acids are deleted, substituted, or added in the amino acid sequence other than the core sequence in the amino acid sequence. [3A] The peptide according to [1A] or [2A], wherein the peptide contains any one of the core sequences shown in Table 1 below, and the full length of the peptide consists of any one amino acid sequence of the amino acid sequences represented by the respective SEQ ID NOs containing the core sequence in Table 1. [4A] The peptide according to any one of [1A] to [3A], wherein the peptide can bind to an HLA class II protein. [5A] The peptide according to any one of [1A] to [4A], wherein the HLA class II protein is any one of the following HLA alleles 1 to 4 and 7. HLA allele 1: HLA-DRA * 01:01 (α chain) + DRB1 * 14:06 (β chain) HLA allele 2: HLA-DRA * 01:01 (α chain) + DRB1 * 15:01 (β chain) HLA allele 3: HLA-DQA * 01:02 (α chain) + DQB1 * 06:02 (β chain) HLA allele 4: HLA-DPA * 02:02 (α chain) + DPB1 * 05:01 (β chain) HLA allele 7: HLA-DRA * 01:01 (α chain) + DRB1 *15:02 (β chain) [6A] The peptide according to any one of [1A] to [5A], wherein the combination of the peptide and the HLA class II protein is a peptide consisting of an amino acid sequence represented by any one of the SEQ ID NOs: 11 to 21 and the HLA allele 1, a peptide consisting of an amino acid sequence represented by any one of the SEQ ID NOs: 22 to 35 and the HLA allele 2, a peptide consisting of an amino acid sequence represented by any one of the SEQ ID NOs: 36 to 45 and the HLA allele 3, a peptide consisting of an amino acid sequence represented by any one of the SEQ ID NOs: 46 to 51 and the HLA allele 4, or a peptide consisting of an amino acid sequence represented by any one of the SEQ ID NOs: 22 to 35 and the HLA allele 7. 【0009】 [7A] A protein complex comprising the peptide described in [1A] and an HLA class II protein. [8A] The protein complex according to [7A], wherein the HLA class II protein is one of the following HLA alleles 1 to 4. HLA allele 1: HLA-DRA * 01:01 (α chain) + DRB1 * 14:06 (β-chain) HLA allele 2: HLA-DRA * 01:01 (α chain) + DRB1 * 15:01 (β-chain) HLA allele 3: HLA-DQA * 01:02 (α chain) + DQB1 * 06:02 (β-chain) HLA allele 4: HLA-DPA * 02:02 (α chain) + DPB1 * 05:01 (β-chain) HLA allele 7: HLA-DRA * 01:01 (α chain) + DRB1 *15:02 (β-chain) [9A] The combination of the peptide and the HLA class II protein is a peptide consisting of an amino acid sequence represented by any one of SEQ ID NOs: 11 to 21 and the HLA allele 1, a peptide consisting of an amino acid sequence represented by any one of SEQ ID NOs: 22 to 35 and the HLA allele 2, a peptide consisting of an amino acid sequence represented by any one of SEQ ID NOs: 36 to 45 and the HLA allele 3, a peptide consisting of an amino acid sequence represented by any one of SEQ ID NOs: 46 to 51 and the HLA allele 4, or a peptide consisting of an amino acid sequence represented by any one of SEQ ID NOs: 22 to 35 and the HLA allele 7, the protein complex according to [7A] or [8A]. [10A] The protein complex according to any one of [7A] to [9A], which can bind to a T cell receptor. [11A] The protein complex according to [10A], wherein the T cell receptor is a T cell receptor expressed on T cells derived from a patient with an autoimmune disease. [12A] The protein complex according to [11A], wherein the autoimmune disease is an anti-SS-A antibody positive disease. [13A] The protein complex according to [11A], wherein the autoimmune disease is Sjögren's syndrome. 【0010】 [14A] A polynucleotide 1 containing a base sequence encoding the α-chain of HLA class II of the protein complex according to any one of [7A] to [13A], a polynucleotide 2 containing a base sequence encoding the β-chain of HLA class II of the protein complex according to any one of [7A] to [13A], and a polynucleotide 3 containing a base sequence encoding the peptide according to any one of [1A] to [6A], wherein none of the polynucleotides 1 to 3 are linked, or any two or three of the polynucleotides 1 to 3 are linked, polynucleotide. [15A] An expression vector containing the polynucleotide according to [14A]. [16A] A cell containing the polynucleotide according to [14A] or the expression vector according to [15A]. 【0011】[17A] A T cell receptor represented by T cell receptors (TCRs) I to X, wherein the amino acid sequences of the α-chain complementarity determining regions (CDRs) 1 to 3 and the β-chain CDRs 1 to 3 of the T cell receptors I to X include any of the amino acid sequences represented by the CDR group I to X in Table 6 described below. [18A] The T cell receptor according to [17A], wherein the T cell receptors I to X include an α-chain variable domain and a β-chain variable domain, which consist of the amino acid sequences represented by the respective CDRs in Table 7 described below, or an α-chain variable domain and / or a β-chain variable domain, which consist of an amino acid sequence in which one or two amino acids are deleted, substituted or added in a region other than the CDRs of the amino acid sequences represented by the respective CDRs in Table 7 described below, and which has a sequence identity of 90% or more with the amino acid sequences represented by the respective CDRs in Table 7 described below. [19A] The T cell receptor according to [17A] or [18A], wherein TCRI-X can bind to a protein complex comprising a peptide of 25 amino acids or less in length, which includes one of the core sequences 1-10, each consisting of an HLA allele represented in Table 8 described below and an amino acid sequence represented by SEQ ID NOs: 1-10. [20A] The T cell receptor according to [19A], wherein the peptide consists of one of the amino acid sequences represented by SEQ ID NOs: 11-51, or an amino acid sequence in which one or two amino acids are deleted, substituted, or added in an amino acid sequence other than the core sequence in the amino acid sequence. [21A] The T cell receptor according to [19A], wherein the full-length amino acid sequence of the peptide containing the core sequence consists of one of the amino acid sequences shown by each SEQ ID NO in Table 9 described below. 【0012】[22A] A polynucleotide comprising a base sequence encoding a T cell receptor as described in any of [17A] to [21A]. [23A] An expression vector comprising the polynucleotide described in [22A]. [24A] A cell comprising the polynucleotide described in [22A] or the expression vector described in [23A]. [25A] A binding substance that specifically binds to a peptide as described in any of [1A] to [6A] or a protein complex as described in any of [7A] to [13A]. [26A] The binding substance according to [25A], wherein the binding substance is an antibody, an antigen-binding fragment thereof, or an antibody-like substance. 【0013】 [27A] A pharmaceutical composition for use in the treatment or prevention of an autoimmune disease, comprising the binding substance described in [25A] or [26A]. [28A] The pharmaceutical composition according to [27A], wherein the autoimmune disease is an anti-SS-A antibody-positive disease. [29A] The pharmaceutical composition according to [27A], wherein the autoimmune disease is Sjögren's syndrome. [30A] A binding substance that specifically binds to a T cell receptor according to any one of [17A] to [21A]. [31A] The binding substance according to [30A], wherein the binding substance is an antibody or its antigen-binding fragment, or an antibody-like substance. [32A] A pharmaceutical composition for use in the treatment or prevention of an autoimmune disease, comprising the binding substance described in [30A] or [31A]. [33A] The pharmaceutical composition according to [32A], wherein the autoimmune disease is an anti-SS-A antibody-positive disease. [34A] The pharmaceutical composition according to [32A], wherein the autoimmune disease is Sjögren's syndrome. 【0014】[35A] A method for determining the applicability of the pharmaceutical composition described in [28A] to a person positive for anti-SS-A antibodies, comprising: step A1 of measuring a peptide described in any of [1A] to [6A] or a protein complex described in any of [7A] to [10A] contained in a sample taken from the person positive for anti-SS-A antibodies; and step A2 of determining that the pharmaceutical composition is suitable for application to a person positive for anti-SS-A antibodies if the measured value is within a range useful for disease application. [36A] A method for determining the applicability of the pharmaceutical composition described in [29A] to a patient with Sjögren's syndrome, comprising: step B1 of measuring a peptide described in any of [1A] to [6A] or a protein complex described in any of [7A] to [10A] contained in a sample taken from the patient with Sjögren's syndrome; and step B2 of determining that the pharmaceutical composition is suitable for application to a patient with Sjögren's syndrome if the measured value is within a range useful for disease application. [37A] A companion diagnostic composition or companion diagnostic kit for determining the applicability of the pharmaceutical composition described in [28A] to persons positive for anti-SS-A antibodies. [38A] A companion diagnostic composition or companion diagnostic kit for determining the applicability of the pharmaceutical composition described in [29A] to patients with Sjögren's syndrome. [39A] A method for determining the applicability of the pharmaceutical composition described in [33A] to persons positive for anti-SS-A antibodies, comprising: step C1 measuring a T cell receptor described in any of [17A] to [21A] contained in a sample taken from the person positive for anti-SS-A antibodies; and step C2 determining that the pharmaceutical composition is suitable for application to persons positive for anti-SS-A antibodies if the measured value is within a range useful for disease application. A method for determining the applicability of the pharmaceutical composition described in [40A] [34A] to patients with Sjögren's syndrome, comprising: step D1 measuring a T cell receptor described in any of [17A] to [21A] contained in a sample taken from the patient with Sjögren's syndrome; and step D2 determining that the pharmaceutical composition is suitable for application to patients with Sjögren's syndrome if the measured value is within a range useful for disease treatment.[41A] A companion diagnostic composition or companion diagnostic kit for determining the applicability of the pharmaceutical composition described in [33A] to individuals positive for anti-SS-A antibodies. [42A] A companion diagnostic composition or companion diagnostic kit for determining the applicability of the pharmaceutical composition described in [34A] to patients with Sjögren's syndrome. 【0015】 One aspect of the present disclosure relates, for example, to the following [1B] to [28B]. [1B] A peptide with a length of 25 amino acids or less, comprising any one amino acid sequence selected from the group consisting of core sequences represented by SEQ ID NOs. 301 to 303, respectively. [2B] The peptide according to [1B], comprising an amino acid sequence represented by SEQ ID NOs. 304 to 318, or an amino acid sequence in which one or two amino acids are deleted, substituted, or added in an amino acid sequence other than the core sequence in the amino acid sequence. [3B] The peptide according to [1B] or [2B], wherein the peptide comprises any one of the core sequences shown in Table 2 below, and the total length of the peptide consists of any one amino acid sequence shown in each SEQ ID NO in Table 2 that includes the core sequence. [4B] The peptide according to any one of [1B] to [3B], wherein the peptide can bind to an HLA class II protein. [5B] The peptide according to [4B], wherein the HLA class II protein is HLA allele 5 or 6. HLA allele 5: HLA-DRA * 01:01 (α chain) + DRB1 * 03:01 (β-chain) HLA allele 6: HLA-DRA * 01:01 (α chain) + DRB1 *13:01 (β chain) [6B] The peptide according to [5B], wherein the combination of the peptide and the HLA class II protein is a peptide consisting of an amino acid sequence represented by any one of the SEQ ID NOs. 304 to 308 and the HLA allele 5, a peptide consisting of an amino acid sequence represented by any one of the SEQ ID NOs. 304 to 308 and the HLA allele 6, a peptide consisting of an amino acid sequence represented by any one of the SEQ ID NOs. 309 to 313 and the HLA allele 5, or a peptide consisting of an amino acid sequence represented by any one of the SEQ ID NOs. 314 to 318 and the HLA allele 5. 【0016】 [7B] A protein complex comprising the peptide described in [1B] and an HLA class II protein. [8B] The protein complex according to [7B], wherein the HLA class II protein is HLA allele 5 or 6. HLA allele 5: HLA-DRA * 01:01 (α chain) + DRB1 * 03:01 (β-chain) HLA allele 6: HLA-DRA * 01:01 (α chain) + DRB1 *13:01 (β chain) [9B] The protein complex according to [8B], wherein the combination of the peptide and the HLA class II protein is a peptide consisting of an amino acid sequence represented by any one of the SEQ ID NOs. 304 to 308 and the HLA allele 5, a peptide consisting of an amino acid sequence represented by any one of the SEQ ID NOs. 304 to 308 and the HLA allele 6, a peptide consisting of an amino acid sequence represented by any one of the SEQ ID NOs. 309 to 313 and the HLA allele 5, or a peptide consisting of an amino acid sequence represented by any one of the SEQ ID NOs. 314 to 318 and the HLA allele 5. [10B] The protein complex according to any one of [7B] to [9B], which can bind to a T cell receptor. [11B] The protein complex according to [10B], wherein the T cell receptor is a T cell receptor expressed on T cells derived from a patient with an autoimmune disease. [12B] The protein complex according to [11B], wherein the autoimmune disease is an anti-SS-A antibody positive disease. [13B] The protein complex according to [11B], wherein the autoimmune disease is Sjögren's syndrome. [14B] The protein complex according to any one of [10B] to [13B], wherein the T cell receptor is any of the T cell receptors (TCR) XI to XIII, and the amino acid sequences of the α chain complementarity determining regions (CDRs) 1 to 3 and the β chain CDRs 1 to 3 of TCR XI to XIII include any of the amino acid sequences shown in the CDR group XI to XIII in Table 3 below. [15B] The protein complex according to [14B], wherein the TCRXI to XIII comprises an α-chain variable domain and a β-chain variable domain consisting of the amino acid sequences shown in each of the sequence numbers in Table 4 described below, or an α-chain variable domain and / or a β-chain variable domain consisting of an amino acid sequence in which one or two amino acids are deleted, substituted or added in a region other than the CDR of the amino acid sequence shown in each of the sequence numbers in Table 4, and the sequence identity with the amino acid sequence shown in each of the sequence numbers in Table 4 is 90% or more.[16B] The protein complex according to [14B], wherein a protein complex represented in Table 5 described below, comprising the HLA allele and a peptide of 25 amino acids or less in length, which includes one of the core sequences 11 to 13 consisting of the amino acid sequences represented by SEQ ID NOs. 301 to 303, can be bound to TCRXI to XIII in the combinations shown in Table 5. 【0017】 [17B] A polynucleotide comprising: polynucleotide 1 containing a base sequence encoding the α chain of HLA class II of the protein complex described in any of [7B] to [16B]; polynucleotide 2 containing a base sequence encoding the β chain of HLA class II of the protein complex described in any of [7B] to [16B]; and polynucleotide 3 containing a base sequence encoding the peptide described in any of [1B] to [6B], wherein none of the polynucleotides 1 to 3 are linked, or two or three of the polynucleotides 1 to 3 are linked. [18B] An expression vector containing the polynucleotide described in [17B]. [19B] A cell containing the polynucleotide described in [17B] or the expression vector described in [18B]. [20B] A binding substance that specifically binds to the peptide described in [1B] or the protein complex described in [7B]. [21B] The binding substance according to [20B], wherein the binding substance is an antibody, an antigen-binding fragment thereof, or an antibody-like substance. 【0018】[22B] A pharmaceutical composition for use in the treatment or prevention of an autoimmune disease, comprising the binding substance described in [20B]. [23B] The pharmaceutical composition according to [22B], wherein the autoimmune disease is an anti-SS-A antibody positive disease. [24B] The pharmaceutical composition according to [22B], wherein the autoimmune disease is Sjögren's syndrome. [25B] A method for determining the applicability of the pharmaceutical composition according to [23B] to an anti-SS-A antibody positive person, comprising: step A1 of measuring a peptide described in any of [1B] to [6B] or a protein complex described in any of [7B] to [16B] contained in a sample taken from the anti-SS-A antibody positive person; and step A2 of determining that the pharmaceutical composition is suitable for application to an anti-SS-A antibody positive person if the measured value is within a range useful for disease application. [26B] A method for determining the applicability of the pharmaceutical composition described in [24B] to patients with Sjögren's syndrome, comprising: step B1 measuring a peptide described in any of [1B] to [6B] or a protein complex described in any of [7B] to [16B] contained in a sample taken from the patient with Sjögren's syndrome; and step B2 determining that the pharmaceutical composition is suitable for application to patients with Sjögren's syndrome if the measured value is within a range useful for disease application. [27B] A companion diagnostic composition or companion diagnostic kit for determining the applicability of the pharmaceutical composition described in [23B] to persons positive for anti-SS-A antibodies. [28B] A companion diagnostic composition or companion diagnostic kit for determining the applicability of the pharmaceutical composition described in [24B] to patients with Sjögren's syndrome. 【0019】 One aspect of the present disclosure relates, for example, to the following [1C] to [3C]: [1C] A pharmaceutical composition comprising the peptide and immunosuppressant described in [1A] or [1B]. [2C] A pharmaceutical formulation comprising a drug delivery carrier encapsulating the pharmaceutical composition described in [1C]. [3C] A pharmaceutical composition comprising an antibody-drug conjugate in which an antibody that specifically binds to the peptide described in [1A] or [1B] or the protein conjugate described in [7A] or [7B] and an immunosuppressant are linked via a linker. 【0020】According to the present invention, it is possible to provide peptides, protein complexes containing the peptides, and T cell receptors, etc., that can be used in antigen-specific immunosuppressive therapy to suppress autoimmunity. 【0021】 Furthermore, the peptides, protein complexes containing the peptides, and T cell receptors of this disclosure can be used as therapeutic targets, therapeutic markers, and companion diagnostic kits for Sjögren's syndrome or other anti-SS-A antibody-positive diseases described later. 【0022】 Figure 1 shows the positive rate of expressed GFP when CD14-positive monocytes and an LB63-51 reporter were mixed and cultured under four conditions: unstimulated (negative control), SS-A antigen only (full-length peptide), an immune complex containing SS-A antigen, or an immune complex containing SS-A antigen and an anti-HLA-DR inhibitory antibody. Figure 2 shows the positive rate of expressed CD154 when 293 T cells overexpressing HLA-DRB1*15:01 as antigen-presenting cells and LB63-51 overexpressing CD4-positive T cells were mixed and cultured under four conditions: unstimulated (negative control), with Cytostim added (positive control), with reaction peptide added, or with reaction peptide and anti-HLA-DR inhibitory antibody added. 【0023】 The following describes preferred forms for implementing this disclosure. The embodiments described below are merely examples of typical embodiments of this disclosure and should not be interpreted as narrowing the scope of this disclosure. Unless otherwise specified, the numerical range "A to B" indicates a range of A or greater and B or less. For example, "1 to 5%" means 1% or greater and 5% or less. 【0024】In this specification, autoimmune diseases include Sjögren's syndrome; systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), rheumatoid arthritis, other collagen diseases, systemic sclerosis (SSc), and diseases other than Sjögren's syndrome such as polymyositis / dermatomyositis (PM / DM); and diseases other than those listed above in which anti-SS-A antibodies are positive in specimens collected from patients (hereinafter also referred to as "anti-SS-A antibody positive diseases"), preferably Sjögren's syndrome or anti-SS-A antibody positive diseases. Patients with anti-SS-A antibody positive diseases are also referred to as anti-SS-A antibody positive persons. T cell receptor (T Cell Receptor) may be abbreviated as "TCR". 【0025】 <Peptide> One embodiment of the present invention is a peptide (hereinafter referred to as "the peptide of this disclosure") having a length of 25 amino acids or less, comprising one amino acid sequence selected from the group consisting of core sequences 11 to 13, each represented by SEQ ID NOs: 1 to 10 and SEQ ID NOs: 301 to 303. 【0026】 The peptides of this disclosure are preferably 23 amino acid lengths or less, and more preferably 20 amino acid lengths. The peptides of this disclosure are preferably peptides derived from SS-A (Sjögren's-syndrome-related antigen A) protein. 【0027】 Peptides containing one of the core sequences 1 to 10 are preferably amino acid sequences represented by SEQ ID NOs: 11 to 51, or amino acid sequences in which one or two, more preferably one, amino acid is deleted, substituted, or added in an amino acid sequence other than the core sequence (non-core sequence) within the said amino acid sequence. 【0028】 Peptides containing one of the core sequences 11 to 13 are preferably amino acid sequences represented by sequence numbers 304 to 318, or amino acid sequences in which one or two, more preferably one, amino acid is deleted, substituted, or added in an amino acid sequence other than the core sequence (non-core sequence) within the said amino acid sequence. 【0029】A more preferred embodiment of the peptides of this disclosure is one of the core sequences 1 to 10 shown in Table 1 below, wherein the full length of the peptide is one of the amino acid sequences shown in each SEQ ID NO: 【0030】 【0031】 A more preferred embodiment of the peptides of this disclosure includes one of the core sequences 11 to 13 shown in Table 2 below, wherein the full length of the peptide is one of the amino acid sequences shown in each SEQ ID NO: 【0032】 【0033】 The peptides of this disclosure can be identified, for example, as follows: A protein containing the peptides of this disclosure is prepared by stacking peptides of a predetermined length, for example, peptides with 10 amino acids at each of the following positions from the N-terminus: 1-20 (peptide sample 1), 11-30 (peptide sample 2), 21-40 (peptide sample 3), etc., to create peptide samples with a length of 20 amino acids, thereby preparing a group of peptide samples that cover the entire length. 【0034】A predetermined cell expressing TCR (TCR reporter cell) derived from a Sjögren's syndrome patient or a patient with an anti-SS-A antibody-positive disease who has serum autoantibodies against the above protein, for example, one type of CD4-positive reporter cell that expresses GFP upon antigen presentation, and cells capable of presenting the above peptide sample on HLA, for example, LCL (Lymphoblastoid Cell Lines obtained by infecting with Epstein-Barr Virus) cells made from human peripheral blood mononuclear cells (PBMCs) of the same patient, are cultured with only one of the peptide samples prepared above added, and the reactivity between the TCR reporter cell and the peptide is measured by cytometry, for example, flow cytometry (FACS). The expression level of GFP is used as an indicator, and a positive result is defined as when the GFP expression level is 1.8 times or more, preferably 1.9 times or more, more preferably 2 times or more, compared to the negative control, and the GFP expression level is 1.8% or more, preferably 1.9% or more, more preferably 2% or more. 【0035】 By mixing TCR reporter cells that have been determined to be positive with cells capable of presenting a peptide sample on HLA, and adding only one of the peptide samples prepared above, the peptide sample that shows a positive result by flow cytometry as described above can be identified as the peptide of this disclosure. 【0036】Furthermore, a predetermined cell expressing TCR derived from a Sjögren's syndrome patient or a patient with an anti-SS-A antibody-positive disease who has serum autoantibodies against the above protein (TCR reporter cell), for example, one type of CD4-positive reporter cell that expresses GFP upon antigen presentation, and one type of HLA-expressing cell expressing HLA derived from the above patient, for example, a cell that does not have HLA II and has been transfected with a vector expressing the α and β chains of HLA class II, are cultured with only one of the peptide samples prepared above added, and the reactivity between the TCR reporter cell, peptide sample and HLA-expressing cell is measured by cytometry, for example, flow cytometry (FACS). The expression level of GFP is used as an indicator, and a positive result is defined as when the GFP expression level is 1.8 times or more, preferably 1.9 times or more, more preferably 2 times or more, compared to the negative control, and the GFP expression level is 1.8% or more, preferably 1.9% or more, more preferably 2% or more. The peptide sample that shows a positive result can be identified as the peptide of this disclosure. 【0037】 The peptides of this disclosure can be obtained from cells or tissues of patients with autoimmune diseases, preferably Sjögren's syndrome or anti-SS-A antibody-positive diseases, by known methods for purifying and isolating proteins. For example, they can be obtained by homogenizing the cells or tissues, extracting them with an acid, and then purifying and isolating the extract by a combination of chromatography methods such as reverse-phase chromatography, ion-exchange chromatography, or affinity chromatography. Alternatively, they can be obtained by the Differential Solubilization (DS) method (Kawashima Y. et al., J. Proteome Res., 9, 2010), in which all proteins and peptides in the serum are precipitated once with a high concentration of organic solvent, the carrier protein is completely denatured, and then the peptide is extracted. 【0038】In this specification, "isolation" refers to the artificial alteration of a substance from its natural state. For example, a peptide, protein, or polynucleotide present in a living organism is not isolated, but the same peptide, protein, or polypeptide separated from materials that naturally coexist together is isolated. 【0039】 Since the peptides disclosed herein are directly involved in the autoimmune response of autoimmune diseases, preferably Sjögren's syndrome or anti-SS-A antibody-positive diseases, by using a binding substance that specifically binds to the peptides disclosed herein, as described later, the binding of the peptides disclosed presented on HLA as described later to TCR as described later is suppressed, thereby suppressing autoimmunity. Therefore, the peptides disclosed herein can be used in autoimmune suppression therapy. 【0040】 For example, the peptides of this disclosure can be used in a companion diagnostic agent, which is one embodiment of this disclosure described later. 【0041】 [Core Sequence] The core sequences contained in the peptides of this disclosure are either core sequences 1 to 10 selected from the group consisting of amino acid sequences represented by SEQ ID NOs: 1 to 10, or core sequences 11 to 13 selected from the group consisting of amino acid sequences represented by SEQ ID NOs: 301 to 303, and each peptide of this disclosure contains one of either core sequences 1 to 10 or core sequences 11 to 13. 【0042】 The position of the core sequence in the peptide of the disclosure is not particularly limited. The core sequence may be positioned so that its N-terminus is the N-terminus of the peptide of the disclosure, or so that its C-terminus is the C-terminus of the peptide of the disclosure, or the core sequence may be positioned so as not to include either end of the peptide of the disclosure. 【0043】The core sequence can be identified, for example, as follows: Synthesize a peptide of 14 to 20 amino acids in length by shifting one amino acid each to the N-terminus and / or C-terminus of the amino acid sequence containing part or all of the peptide identified above. In the same manner as when identifying the peptide above, add one type of the synthesized peptide each to TCR reporter cells and cells capable of presenting the peptide on HLA, and obtain a synthetic peptide in which the expression level of GFP is higher than a predetermined threshold (Cut-off value). Identify the common sequence contained in the obtained synthetic peptide as the core sequence. 【0044】 The above thresholds vary depending on the type of TCR, HLA, and peptide, but are set to be 1.8 times or more, preferably 1.9 times or more, more preferably 2 times or more, the reactivity of the negative control, and the reactivity to be 1.8% or more, preferably 1.9% or more, more preferably 2% or more. 【0045】 The core sequence may include a sequence in which one or two amino acids are added to the N-terminal and C-terminal ends of the core sequence. For example, as described later in the examples, in a sequence in which S (serine) is added to the N-terminal end and D (aspartic acid) is added to the C-terminal end of the core sequence of SEQ ID NO: 9, the peptide containing the added sequence shows significantly higher reactivity with the T cell receptor (GFP expression level) than the negative control, so the added sequence is also included in the core sequence. 【0046】 [HLA Class II Protein] The peptides of this disclosure are preferably capable of binding to HLA class II proteins. 【0047】 The HLA class II protein that binds to the peptide of this disclosure is not particularly limited, but for example, HLA-DRA * 01:01 (α chain) + DRB1 * 14:06 (β chain) (hereinafter also referred to as "HLA allele 1"), HLA-DRA * 01:01 (α chain) + DRB1 * 15:01 (β-chain) (hereinafter also referred to as "HLA allele 2"), HLA-DQA * 01:02 (α chain) + DQB1 *06:02 (β-chain) (hereinafter also referred to as "HLA allele 3"), HLA-DPA * 02:02 (α chain) + DPB1 * 05:01 (β chain) (hereinafter also referred to as "HLA allele 4"), HLA-DRA * 01:01 (α chain) + DRB1 * 03:01 (β chain) (hereinafter also referred to as "HLA allele 5"), HLA-DRA * 01:01 (α chain) + DRB1 * 13:01 (β chain) (hereinafter also referred to as "HLA allele 6"), HLA-DRA * 01:01 (α chain) + DRB1 * 15:02 (β chain) (hereinafter also referred to as "HLA allele 7"), HLA-DRA * 01:01 (α chain) + DRB1 * 03:01 (β chain), HLA-DQA1 * 05:01 (α chain) + DQB1 * 02:01 (β chain), HLA-DQA1 * 03:01 (α chain) + DQB1 * 03:02 (β chain), HLA-DRA * 01:01 (α chain) + HLA-DRB1 * 04:05 (β chain), HLA-DQA1 * 03:01 (α chain) + HLA-DQB1 * 04:01 (β chain), HLA-DRA * 01:01 (α chain) + HLA-DRB1 * 08:03 (β chain), HLA-DQA1 * 01:03 (α chain) + HLA-DQB1 * 06:01 (β chain), HLA-DRA * 01:01 (α chain) + HLA-DRB1 * 15:02 (β chain), HLA-DRA * 01:01 (α chain) + HLA-DRB1 * 03:01 (β chain), HLA-DRA * 01:01 (α chain) + HLA-DRB3 * 01:01 (β chain), HLA-DQA1 * 05:01 (α chain) + HLA-DQB1 * 02:01 (β chain), HLA-DQA1* 05:01 (α chain) + HLA-DQB1 * 03:01 (β chain), HLA-DQA1 * 01:02 (α chain) + HLA-DQB1 * 06:02 (β chain), HLA-DRA * 01:01 (α chain) + HLA-DRB1 * Examples include 11:04 (β-chain). Of these, when the peptide of this disclosure is a peptide of 25 amino acids or less in length and containing one amino acid sequence selected from the group consisting of core sequences represented by SEQ ID NOs: 1 to 10, the HLA class II protein that binds to the peptide is preferably one of HLA allele 1, HLA allele 2, HLA allele 3, HLA allele 4, or HLA allele 7. When the peptide of this disclosure is a peptide of 25 amino acids or less in length and containing one amino acid sequence selected from the group consisting of core sequences represented by SEQ ID NOs: 301 to 303, the HLA class II protein that binds to the peptide is preferably HLA allele 5 or HLA allele 6. 【0048】 The HLA class II protein to which the peptide of this disclosure binds is not particularly limited, but if it is a peptide of 25 amino acids or less in length that includes one amino acid sequence selected from the group consisting of core sequences represented by SEQ ID NOs: 1 to 10, then the following combinations are preferred from the viewpoint of reactivity with T cell receptors described later: a peptide consisting of the amino acid sequence represented by any one of SEQ ID NOs: 11 to 21 and HLA allele 1; a peptide consisting of the amino acid sequence represented by any one of SEQ ID NOs: 22 to 35 and HLA allele 2; a peptide consisting of the amino acid sequence represented by any one of SEQ ID NOs: 36 to 45 and HLA allele 3; a peptide consisting of the amino acid sequence represented by any one of SEQ ID NOs: 46 to 51 and HLA allele 4; or a peptide consisting of the amino acid sequence represented by any one of SEQ ID NOs: 22 to 35 and the HLA allele 7. 【0049】When a peptide is 25 amino acids or less in length and contains one amino acid sequence selected from the group consisting of core sequences represented by SEQ ID NOs. 301 to 303, the following combinations of HLA class II proteins to which the peptide binds are preferred from the viewpoint of reactivity with the T cell receptor described later: a peptide consisting of an amino acid sequence represented by any one of SEQ ID NOs. 304 to 308 and HLA allele 5; a peptide consisting of an amino acid sequence represented by any one of SEQ ID NOs. 304 to 308 and HLA allele 6; a peptide consisting of an amino acid sequence represented by any one of SEQ ID NOs. 309 to 313 and HLA allele 5; or a peptide consisting of an amino acid sequence represented by any one of SEQ ID NOs. 314 to 318 and HLA allele 5. 【0050】 The combination of HLA alleles and peptides can be identified, for example, as follows: Cells capable of presenting peptide samples on HLA (e.g., LCL cells) are treated with inhibitory antibodies for HLA-DR, HLA-DQ, and HLA-DP, along with the peptide identified above. These cells are then mixed with TCR reporter cells, and the type of HLA allele is identified from the inhibitory antibodies whose GFP positivity rate decreases. The positivity rate can be calculated, for example, using flow cytometry, by visually setting an upper limit for GFP in the negative population with low GFP signals observed in the group treated with the negative control peptide CLIP (amino acid sequence: PVSKMRMATPLLMQA), and counting cells above that upper limit as positive cells. 【0051】 For the identified HLA alleles, genes derived from HLA-DR, HLA-DQ, and HLA-DP are transfected into cells lacking HLA class II using a vector or the like, and cells are prepared in which the α and β chains of each HLA are forced to express. The peptide identified above is added to these cells to cause the peptide to be displayed on the HLA, and when this is mixed with a predetermined TCR reporter cell, the combination that becomes GFP positive can be identified as an HLA allele and peptide combination, and the TCR that can bind to these combinations can also be identified. 【0052】<Protein Complex> One embodiment of the present invention is a protein complex (hereinafter referred to as the "Protein Complex of the Present Disclosure") comprising the peptide of the present disclosure and an HLA class II protein. The definitions of the peptide and HLA class II protein of the present disclosure, including combinations thereof, are the same as the definitions given in the <Peptide> section above. 【0053】 The protein complex of the disclosed herein may consist of the peptide and the HLA class II protein, but may also include a linker that connects them. The linker is not particularly limited, but examples include linkers of 5 to 20 amino acid residues such as GSGSGS, GGGSGSGSGS, GKPGSGEGSTKG, (GGGGGS)n, (G)n, (PAPAP)n, (AAAA)n, and (EAAAK)n. Here, n is an integer of 1 or more that represents the number of repetitions. 【0054】 The protein complexes of this disclosure can be produced by methods known in the art, such as chemical synthesis based on amino acid sequences or recombinant methods. For example, the target protein complex can be obtained by transforming a host such as E. coli using an expression vector containing the polynucleotide encoding the protein complex of this disclosure, and then culturing the resulting recombinant in an appropriate liquid medium, after which the target protein complex can be isolated from the cultured cells. Alternatively, the target protein complex can also be obtained by transfecting eukaryotic cells using an expression vector containing the polynucleotide encoding the protein complex of this disclosure, and then culturing the resulting transgenic cells under appropriate conditions, after which the target protein complex can be isolated from the cultured cells. 【0055】The protein complex of this disclosure can bind to a TCR in a preferred embodiment. Preferably, the TCR is expressed on T cells derived from patients with autoimmune diseases, and more preferably, on T cells derived from patients with systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), rheumatoid arthritis, other collagen diseases, systemic sclerosis (SSc), or polymyositis / dermatomyositis (PM / DM), or on T cells derived from patients with anti-SS-A antibody-positive diseases, or on T cells derived from patients with Sjögren's syndrome. 【0056】 Preferred combinations of TCRs that can bind to the protein complex of this disclosure are those shown in Table 5 of the section on <T cell receptor 1> and Table 8 of the section on <T cell receptor 2>, described later. 【0057】 The binding of the protein complex of this disclosure to TCR can be confirmed, for example, by using TCR reporter cells that highly express GFP upon TCR stimulation, as shown in the examples described later. 【0058】 Similar to the peptides described herein, by using the protein complexes described herein, for example, a binding substance that specifically binds to the peptide-HLA binding site in the protein complex, the binding of the protein complexes described herein to the TCR described later is suppressed, thereby suppressing autoimmunity. Therefore, the protein complexes described herein can be used in autoimmune suppression therapy. 【0059】<Polynucleotides of Protein Complexes, Expression Vectors, and Cells> One embodiment of the present invention includes a polynucleotide (hereinafter referred to as "Polynucleotide C of the present disclosure") comprising a polynucleotide 1 comprising a nucleotide sequence encoding the α chain of the HLA class II of the protein complex of the present disclosure as shown in the <Protein Complex> section above, a polynucleotide 2 comprising a nucleotide sequence encoding the β chain of the HLA class II of the protein complex of the present disclosure, and a polynucleotide 3 comprising a nucleotide sequence encoding the peptide of the present disclosure, wherein none of the polynucleotides 1 to 3 are linked, or any two or three of the polynucleotides 1 to 3 are linked, an expression vector comprising Polynucleotide C of the present disclosure (hereinafter referred to as "Expression Vector C of the present disclosure"), and a cell comprising Polynucleotide C of the present disclosure or Expression Vector C of the present disclosure (hereinafter referred to as "Cell C of the present disclosure"). 【0060】 [Polynucleotide C] Polynucleotide C of this disclosure comprises polynucleotides 1 to 3, wherein none of the polynucleotides 1 to 3 are linked, or two or three of any two or three of the polynucleotides 1 to 3 are linked. Polynucleotides 1 to 3 and polynucleotide C may be DNA, RNA, or DNA / RNA chimeras, but are preferably DNA, and include cDNA and synthetic DNA. 【0061】 Polynucleotide C may be double-stranded or single-stranded, and if double-stranded, it may be double-stranded DNA, double-stranded RNA, or a DNA:RNA hybrid. 【0062】 The polynucleotide C of this disclosure includes (a) a polynucleotide comprising a nucleotide sequence that is 90% or more identical to the nucleotide sequence encoding the protein complex of this disclosure, (b) a polynucleotide comprising a nucleotide sequence in which 3 to 12 (multiples of 3) bases are deleted or added, or 1 to 12 bases are substituted, in the nucleotide sequence encoding the protein complex of this disclosure, or (c) a polynucleotide comprising a degenerate isomer of the nucleotide sequence encoding the protein complex of this disclosure. 【0063】The polynucleotide C of this disclosure includes, for example, polynucleotide 1 containing a base sequence encoding the α chain of HLA class II obtained by identifying a patient's HLA type, polynucleotide 2 containing a base sequence encoding the β chain of HLA class II, and polynucleotide 3 containing a base sequence encoding the peptide sequence of this disclosure. These polynucleotides 1 to 3 are included in polynucleotide C in the following manner: (1) polynucleotides 1 to 3 are not linked to each other, (2) any two of polynucleotides 1 to 3 are linked and the remaining one is not linked to them, or (3) all three polynucleotides 1 to 3 are linked together. 【0064】 Examples of the embodiments of (2) above include an embodiment in which polynucleotide 1 and polynucleotide 2 are linked and polynucleotide 3 is not linked thereto, an embodiment in which polynucleotide 1 and polynucleotide 3 are linked and polynucleotide 2 is not linked thereto, or an embodiment in which polynucleotide 2 and polynucleotide 3 are linked and polynucleotide 1 is not linked thereto. 【0065】 In the embodiment of (3) described above, there are no particular restrictions on the order in which polynucleotides 1 to 3 are linked, but the order from the 5' end is preferably polynucleotide 1, polynucleotide 3, and polynucleotide 2. 【0066】 When linking polynucleotides 1 to 3 in the embodiments of (2) and (3) above, polynucleotides containing a base sequence encoding a linker sequence may be added between them. 【0067】 If the protein complex of the present disclosure includes a linker, the polynucleotide C of the present disclosure includes a polynucleotide containing a base sequence encoding the linker. Examples include polynucleotides containing the base sequences represented by SEQ ID NOs. 252 and 253. 【0068】[Expression Vector C] Expression vector C of the present disclosure is not particularly limited as long as it is a known vector that contains a polynucleotide encoding the protein complex of the present disclosure and is replicable in a host cell. Examples of vectors include plasmids, bacteriophages, viruses, and artificial chromosomes (including linear nucleic acid molecules). If the host cell is E. coli, for example, pUC vectors, pET vectors, pBlueScript vectors, and pCold vectors can be used. If the host cell is yeast, for example, pPICZ vectors and pYD1 vectors can be used. 【0069】 The expression vector C preferably contains regulatory elements such as a transcription promoter, a ribosome binding site, a terminator, and optionally an operator, and more preferably contains replication initiation sites, selection markers, restriction enzyme sites, etc., for autonomous replication in host cells. 【0070】 The expression vector C disclosed herein can also be used in cell therapy. Cell therapy can be performed, for example, by taking cells from the body of a subject, introducing genes into regulatory T cells (Treg) using the expression vector C disclosed herein to express TCRs, and then returning these cells to the body. 【0071】 [Cell C] Cell C of the present disclosure comprises the polynucleotide C of the present disclosure or the expression vector C of the present disclosure. The cell is not particularly limited as long as it is a cell that can be transfected, but a cell line that is easy to transfect and easy to culture is preferred, for example, 293T cells are preferred. 【0072】<T Cell Receptor 1> An example of a combination with a T cell receptor that can bind to a protein complex, which is one embodiment of the present disclosure, is a T cell receptor represented by TCRXI to XIII, wherein the amino acid sequences of the α-chain complementarity determining regions (CDRs) 1 to 3 and the β-chain CDRs 1 to 3 of TCRXI to XIII include any of the amino acid sequences shown by the CDR group I to X in Table 3 below, and a combination with a protein complex in which the peptide is 25 amino acid length or less, and the peptide includes any one amino acid sequence selected from the group consisting of core sequences represented by SEQ ID NOs. 301 to 303, and the HLA class II protein is HLA allele 5 or 6 as described below. HLA allele 5: HLA-DRA * 01:01 (α chain) + DRB1 * 03:01 (β-chain) HLA allele 6: HLA-DRA * 01:01 (α chain) + DRB1 * 13:01 (β chain) is one example. 【0073】 【0074】 In Table 3, for example, TCRXI includes, as CDR group I, an α-chain CDR having the amino acid sequence shown in SEQ ID NO: 319 for the complementarity-determining region (CDR) 1 of the α-chain, the amino acid sequence shown in SEQ ID NO: 322 for CDR2, and the amino acid sequence shown in SEQ ID NO: 325 for CDR3, as well as a β-chain CDR having the amino acid sequence shown in SEQ ID NO: 328 for CDR1 of the β-chain, the amino acid sequence shown in SEQ ID NO: 331 for CDR2, and the amino acid sequence shown in SEQ ID NO: 334 for CDR3. 【0075】 The above TCRXI to XIII may include an α-chain variable domain and a β-chain variable domain consisting of the amino acid sequences shown in each of the sequence numbers in Table 4 below. In Table 4, for example, TCRXI includes an α-chain variable domain consisting of the amino acid sequence shown in sequence number 337 and a β-chain variable domain consisting of the amino acid sequence shown in sequence number 340. 【0076】 【0077】 Furthermore, TCRXI to XIII may include an α-chain variable domain and / or a β-chain variable domain, which consist of an amino acid sequence in which one or two, preferably one amino acid, is deleted, substituted, or added in the non-CDR region (non-CDR region) of the amino acid sequence shown in each sequence number in Table 4, and the sequence identity with the amino acid sequence shown in each sequence number in Table 4 is 90% or more, preferably 91% or more, more preferably 92% or more, even more preferably 93% or more, particularly preferably 94% or more, and most preferably 95% or more. 【0078】 For example, TCRXI may include an α-chain variable domain in which one or two amino acids are deleted, substituted, or added in the amino acid sequence of a region other than CDR1 (shown in SEQ ID NO: 319), CDR2 (shown in SEQ ID NO: 322), and CDR3 (shown in SEQ ID NO: 325) within the α-chain variable domain shown in SEQ ID NO: 337, resulting in an amino acid sequence with 90% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 337. Alternatively, TCRXI may include a β-chain variable domain in which one or two amino acids are deleted, substituted, or added in the amino acid sequence of a region other than CDR1 (shown in SEQ ID NO: 328), CDR2 (shown in SEQ ID NO: 331), and CDR3 (shown in SEQ ID NO: 334) within the α-chain variable domain shown in SEQ ID NO: 340, resulting in an amino acid sequence with 90% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 340. TCRXI may include both an α-chain variable domain and a β-chain variable domain, both consisting of amino acid sequences with 90% or more sequence identity in the non-CDR sequences. 【0079】 TCRXI to XIII can preferably be bound to a protein complex containing a peptide of 25 amino acids or less in length, which includes an HLA allele represented in Table 5 below and a core sequence 11 to 13 consisting of amino acid sequences represented by SEQ ID NOs. 301 to 303, in combination with the combinations shown in Table 5 below. 【0080】 【0081】Regarding the combinations of TCR and protein complexes in Table 5, for example, TCRXI can bind to a protein complex that includes HLA5 and a peptide with a length of 25 amino acids or less, which includes a core sequence 11 consisting of the amino acid sequence represented by SEQ ID NO: 301. 【0082】 The full-length amino acid sequences of the α-chain and β-chain in TCRXI to XIII are as shown in the amino acid sequences represented by SEQ ID NOs. 343 to 348 in Table 10 below. In the amino acid sequences of the α-chain and β-chain regions other than CDR1 to 3, amino acids 1, 2, 3, 4, or 5 may be deleted, substituted, or added. 【0083】 【0084】 <T cell receptor 2> One embodiment of the present invention is a T cell receptor represented by TCRI to X, wherein the amino acid sequences of the α chain complementarity determining regions (CDRs) 1 to 3 and the β chain CDRs 1 to 3 of TCRI to X include any of the amino acid sequences shown by the CDR group I to X in Table 6 below, and is referred to as "TCR2 of the present disclosure". 【0085】 【0086】 In Table 6, for example, TCRI includes, as CDR group I, an α-chain CDR having the amino acid sequence shown in SEQ ID NO: 52 for the complementarity-determining region (CDR) 1 of the α-chain, the amino acid sequence shown in SEQ ID NO: 62 for CDR2, and the amino acid sequence shown in SEQ ID NO: 72 for CDR3, and a β-chain CDR having the amino acid sequence shown in SEQ ID NO: 82 for CDR1 of the β-chain, the amino acid sequence shown in SEQ ID NO: 92 for CDR2, and the amino acid sequence shown in SEQ ID NO: 102 for CDR3. 【0087】One preferred embodiment of TCR2 in this disclosure is that TCRI to X include an α-chain variable domain and a β-chain variable domain, each consisting of the amino acid sequences shown in the respective sequence numbers in Table 7 below. In Table 7, for example, TCRI includes an α-chain variable domain consisting of the amino acid sequence shown in sequence number 112 and a β-chain variable domain consisting of the amino acid sequence shown in sequence number 122. 【0088】 【0089】 Furthermore, TCRI to X may also include an α-chain variable domain and / or a β-chain variable domain, which consist of an amino acid sequence in which one or two, preferably one amino acid, is deleted, substituted, or added in the non-CDR region (non-CDR region) of the amino acid sequence shown in each sequence number in Table 7, and the sequence identity with the amino acid sequence shown in each sequence number in Table 7 below is 90% or more, preferably 91% or more, more preferably 92% or more, even more preferably 93% or more, particularly preferably 94% or more, and most preferably 95% or more. 【0090】 For example, TCRI may include an α-chain variable domain in which one or two amino acids are deleted, substituted, or added in the amino acid sequence of a region other than CDR1 (shown in SEQ ID NO: 52), CDR2 (shown in SEQ ID NO: 62), and CDR3 (shown in SEQ ID NO: 72) within the α-chain variable domain shown in SEQ ID NO: 112, resulting in an amino acid sequence with 90% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 112. Alternatively, TCRI may include a β-chain variable domain in which one or two amino acids are deleted, substituted, or added in the amino acid sequence of a region other than CDR1 (shown in SEQ ID NO: 82), CDR2 (shown in SEQ ID NO: 92), and CDR3 (shown in SEQ ID NO: 102) within the α-chain variable domain shown in SEQ ID NO: 122, resulting in an amino acid sequence with 90% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 122. TCRI may include both an α-chain variable domain and a β-chain variable domain, both consisting of amino acid sequences with 90% or more sequence identity in the non-CDR sequences. 【0091】One preferred embodiment of TCR2 in this disclosure is that TCRI to X can bind to a protein complex containing a peptide of 25 amino acids or less in length, which includes an HLA allele represented in Table 8 below and core sequences 1 to 10 consisting of amino acid sequences represented by SEQ ID NOs: 1 to 10. The definition of protein complex is the same as that given in the section <Protein Complex> above. 【0092】 【0093】 Regarding the combinations of TCR and protein complexes in Table 8, for example, TCRI can bind to a protein complex containing HLA1 and a peptide with a length of 25 amino acids or less that includes a core sequence 1 consisting of the amino acid sequence represented by Sequence ID No. 1. 【0094】 In one further preferred embodiment, the full-length amino acid sequence of the peptide containing the core sequence is one of the amino acid sequences shown in each of the sequence numbers in Table 9 below. For example, TCRI can bind to a protein complex containing HLA1 and a peptide consisting of an amino acid sequence represented by one of sequence numbers 11 to 21, for example, a protein complex containing HLA1 and a peptide consisting of an amino acid sequence represented by sequence number 11. 【0095】 【0096】 The full-length amino acid sequences of the α-chain and β-chain in TCRI-X are as shown in the amino acid sequences represented by SEQ ID NOs. 132-151 in Table 11 below. In the amino acid sequences of the α-chain and β-chain regions other than CDR1-3, amino acids 1, 2, 3, 4, or 5 may be deleted, substituted, or added. 【0097】 【0098】The TCR2 disclosed herein can be used as a marker for autoimmune diseases, preferably Sjögren's syndrome or anti-SS-A antibody-positive diseases, similar to the peptide disclosed herein. Furthermore, by using a binding substance that specifically binds to the TCR2 disclosed herein, as described later, the binding of the peptide or protein complex disclosed to the TCR2 disclosed herein is suppressed, thereby suppressing autoimmunity. Therefore, the TCR2 disclosed herein can be used in autoimmune suppression therapy. 【0099】 <T cell receptor polynucleotide, expression vector, and cell> One embodiment of the present invention includes a polynucleotide comprising a nucleotide sequence encoding the TCR2 of the present disclosure (hereinafter referred to as "the polynucleotide T of the present disclosure"), an expression vector comprising the polynucleotide T of the present disclosure (hereinafter referred to as "the expression vector T of the present disclosure"), and a cell comprising the polynucleotide T of the present disclosure or the expression vector T of the present disclosure (hereinafter referred to as "the cell T of the present disclosure"). 【0100】 [Polynucleotide T] The polynucleotide T of the present disclosure is a polynucleotide comprising a base sequence encoding TCR2 of the present disclosure, and may be DNA, RNA, or a DNA / RNA chimera, but is preferably DNA. Examples of DNA comprising a base sequence encoding TCR2 of the present disclosure include cDNA and synthetic DNA. 【0101】 Polynucleotide T may be double-stranded or single-stranded, and if double-stranded, it may be double-stranded DNA, double-stranded RNA, or a DNA:RNA hybrid. 【0102】The nucleotide sequences encoding TCR2 in this disclosure preferably include nucleotide sequences of the CDR group represented by SEQ ID NOs. 82 to 111, which encode the amino acid sequences of the α-chain CDR1 to 3 and β-chain CDR1 to 3 of the T cell receptor represented by SEQ ID NOs. 52 to 111 in Table 6, respectively. More preferably, the nucleotide sequences encoding the α-chain variable domain represented by SEQ ID NOs. 112 to 121 in Table 3, which include the α-chain CDR1 to 3, and the β-chain variable domain represented by SEQ ID NOs. 122 to 131 in Table 3, which include the β-chain CDR1 to 3, are included. Even more preferably, the nucleotide sequences encoding the full-length α-chain represented by SEQ ID NOs. 132 to 141 in Table 6, and the nucleotide sequences encoding the full-length β-chain represented by SEQ ID NOs. 142 to 151 are included. 【0103】 The polynucleotide T of this disclosure includes (a) a polynucleotide comprising a base sequence that is 90% or more identical to the base sequences represented by SEQ ID NOs. 132 to 151, (b) a polynucleotide comprising a base sequence in which 1, 2, 3, 4, or 5 bases are deleted, substituted, or added in the base sequences represented by SEQ ID NOs. 132 to 151, or (c) a polynucleotide comprising a degenerate isomer of the base sequences represented by SEQ ID NOs. 132 to 151. 【0104】 The polynucleotide T of this disclosure can be obtained, for example, by identifying a TCR sequence that is proliferating in the affected area of ​​a diseased patient and chemically synthesizing it. 【0105】 [Expression Vector T] The expression vector T of the present disclosure is not particularly limited as long as it is a known vector that contains a polynucleotide encoding the TCR2 of the present disclosure and is replicable in a host cell. Examples of vectors include plasmids, bacteriophages, viruses, and artificial chromosomes (including linear nucleic acid molecules). If the host cell is E. coli, for example, pUC vectors, pET vectors, pBlueScript vectors, and pCold vectors can be used. If the host cell is yeast, for example, pPICZ vectors and pYD1 vectors can be used. 【0106】The expression vector T preferably contains regulatory elements such as a transcription promoter, a ribosome binding site, a terminator, and optionally an operator, and more preferably contains replication initiation sites, selection markers, restriction enzyme sites, etc., for autonomous replication in host cells. 【0107】 Expression vector T, as disclosed herein, can also be used in cell therapy, similar to expression vector C, disclosed herein. 【0108】 [Cell T] The cell T of the present disclosure is not particularly limited as long as it includes the polynucleotide T of the present disclosure or the expression vector T of the present disclosure, but T cells that can bind to the peptide, protein complex, or cell C of the present disclosure are preferred. 【0109】 <Binding Substances> One embodiment of the present disclosure is a binding substance that specifically binds to the peptides or protein complexes of the present disclosure. One embodiment of the present disclosure is a binding substance that specifically binds to TCR1 or TCR2 of the present disclosure. 【0110】 The binding substances of this disclosure are not particularly limited as long as they can inhibit binding to the peptides, protein complexes, TCR1 or TCR2 (hereinafter referred to as "peptides, etc.") of this disclosure. Examples include antibodies against peptides, etc., their antigen-binding fragments, as well as HLA monomers, HLA multimers, TCR monomers, TCR multimers, aptamers, Affibody, Affilin, Anticalin, Atrimer, Avimer, Affirmer, Bicyclopeptide, Cys-knot, DARPin, FN3, Fynomer, and Kunitz. Examples include antibody-like substances such as domains and OBody for peptides. Of these, antibodies or antigen-binding fragments for peptides are preferred as the binding substance. 【0111】Antibodies may be produced by immunizing animals such as mice, or by screening antibody libraries such as phage libraries. Antibodies include chimeric antibodies, humanized antibodies, and fully human antibodies. Monoclonal antibodies that specifically bind to peptides are preferred. 【0112】 An antigen-binding fragment is a protein containing a portion of an antibody that can bind to an antigen. Examples of antigen-binding fragments include F(ab')2, Fab', Fab, Fv (variable fragment of antibody), disulfide-bonded Fv, single-chain antibodies (scFv), VHH antibodies, and polymers thereof. 【0113】 Examples of aptamers include nucleic acid aptamers and peptide aptamers. 【0114】 The binding substances of this disclosure can inhibit the binding of the peptide or protein complex of this disclosure to TCR1 or TCR2 of this disclosure, and can therefore be used for the treatment or prevention of autoimmune diseases, preferably Sjögren's syndrome or anti-SS-A antibody-positive diseases. 【0115】 Furthermore, by adding immunosuppressants, anticancer agents, etc., the binding substances of this disclosure can deliver substances containing these drugs to disease-specific lymphocytes or antigen-presenting cells. Therefore, they can be used for the treatment or prevention of autoimmune diseases, preferably Sjögren's syndrome or anti-SS-A antibody-positive diseases. 【0116】 <Pharmaceutical Compositions for the Treatment or Prevention of Autoimmune Diseases> One embodiment of the present invention is a pharmaceutical composition for the treatment or prevention of autoimmune diseases, preferably Sjögren's syndrome or anti-SS-A antibody-positive diseases, comprising a binding substance that specifically binds to the peptide or protein complex of the present disclosure. One embodiment of the present invention is a pharmaceutical composition for the treatment or prevention of autoimmune diseases, comprising a binding substance that specifically binds to TCR1 or TCR2 of the present disclosure. The pharmaceutical composition for the treatment or prevention of autoimmune diseases described above is also referred to as "Pharmaceutical Composition 1 of the present disclosure". 【0117】The pharmaceutical composition 1 of this disclosure may consist only of the above-mentioned binding substance and a pharmaceutically acceptable carrier, or it may contain any other components. Examples of acceptable carriers include diluents, excipients, binders, stabilizers, pH adjusters, thickeners, antioxidants, isotonic agents, buffers, solubilizers, suspending agents, preservatives, freeze-drying protectants, freeze-drying protectants, and antibacterial agents. 【0118】 The method of administering the pharmaceutical composition 1 of this disclosure to a subject, the content of the binding substance 1 of this disclosure contained in the pharmaceutical composition, the amount of the pharmaceutical composition administered to the subject, etc., are not particularly limited as long as the activity of the binding substance contained in the pharmaceutical composition can be exerted, and can be appropriately determined depending on the type of disease the subject has, the degree of the disease, the symptoms, the age of the subject, weight, etc. 【0119】 The dosage form of the pharmaceutical composition 1 of this disclosure can be appropriately selected depending on the route of administration, etc. For example, in the case of oral administration, it can be formulated as a solid preparation such as tablets, granules, powders, and capsules; or as a liquid preparation such as a solution, syrup, suspension, or emulsion. In the case of parenteral administration, it can be formulated as an injection, liquid preparation, suspension, etc., and these dosage forms of pharmaceutical compositions can be administered to the target via routes of administration such as intra-arterial, intravenous, intramedullary, intrathecal, or intestinal. 【0120】 <Determination Method> One embodiment of the present invention is a method for determining the applicability of a pharmaceutical composition for use in the treatment or prevention of an anti-SS-A antibody-positive autoimmune disease, which includes a binding substance that specifically binds to the peptide or protein complex of the present disclosure, to an anti-SS-A antibody-positive person, comprising: step A1 of measuring the peptide or protein complex of the present disclosure contained in a sample taken from the anti-SS-A antibody-positive person; and step A2 of determining that the pharmaceutical composition is suitable for application to an anti-SS-A antibody-positive person if the measured value is within a range useful for disease application. Hereinafter, this determination method will also be referred to as "Determination Method A of the present disclosure". 【0121】One embodiment of the present invention is a method for determining the applicability of a pharmaceutical composition for use in the treatment or prevention of Sjögren's syndrome to a patient with Sjögren's syndrome, the composition comprising: step B1 measuring the peptide or protein complex of the present disclosure contained in a sample taken from the patient with Sjögren's syndrome; and step B2 determining that the pharmaceutical composition is suitable for application to the patient with Sjögren's syndrome if the measured value falls within a range useful for disease application. Hereinafter, this determination method will also be referred to as "Determination Method B of the Present Disclosure". 【0122】 One embodiment of the present invention is a method for determining the applicability of a pharmaceutical composition for use in the treatment or prevention of an anti-SS-A antibody-positive autoimmune disease, comprising a binding substance that specifically binds to TCR1 or TCR2 of the present disclosure, to an anti-SS-A antibody-positive person, comprising: step C1 measuring TCR1 or TCR2 of the present disclosure contained in a sample taken from the anti-SS-A antibody-positive person; and step C2 determining that the pharmaceutical composition is suitable for application to the anti-SS-A antibody-positive person if the measured value is within a range useful for disease application. Hereinafter, this determination method will also be referred to as "Determination Method C of the present disclosure". 【0123】 One embodiment of the present invention is a method for determining the applicability of a pharmaceutical composition for use in the treatment or prevention of Sjögren's syndrome to a patient with Sjögren's syndrome, comprising a binding substance that specifically binds to TCR1 or TCR2 of the present disclosure, the method comprising: step D1 measuring TCR1 or TCR2 of the present disclosure contained in a sample taken from the patient with Sjögren's syndrome; and step D2 determining that the pharmaceutical composition is suitable for application to the patient with Sjögren's syndrome if the measured value falls within a range useful for disease application. Hereinafter, this determination method will also be referred to as "Determination Method D of the Present Disclosure". 【0124】 In the determination methods A to D of this disclosure described above, the specimens collected from the patient are not particularly limited, but examples include serum, plasma, whole blood, urine, saliva, peripheral blood mononuclear cells (PBMCs), and biopsy tissue. Of these, PBMCs and biopsy tissue are preferred specimens collected from the patient. 【0125】 In steps A1 and B1 described above, the method for measuring peptides and protein complexes is not limited to any specific embodiment, as long as it is a method capable of detecting them. Immunological methods can be used for detection, and examples include flow cytometry, enzyme-linked immunosorbent assay (ELISA), chemiluminescent enzyme immunoassay (CLEIA), immunoprecipitation (IPP), immunoblotting (IB), latex agglutination, immunochromatography, indirect immunofluorescence assay (IF), and radioimmunoassay (RIA). Furthermore, when tissue is collected from the affected area during surgery, the complex can also be detected by immunohistochemistry (IHC). Specifically, an antibody that recognizes the complex can be labeled with fluorescence, and the complex that may be present in the patient sample can be detected by flow cytometry. Alternatively, instead of an antibody that recognizes the peptide-protein complex, detection may be performed using a TCR that binds to the peptide-protein complex, preferably a fluorescently labeled TCR monomer, more preferably a fluorescently labeled TCR tetramer or multimer, and even more preferably the TCR reporter cells of this disclosure. 【0126】 In steps C1 and D1 described above, the method for measuring TCR is not limited to any specific embodiment, as long as it is capable of detecting clonal expansion of TCR. Examples include flow cytometry and immunohistochemistry (IHC). For example, tetramers or multimers of the HLA-peptide complex paired in the subset of this disclosure can be fluorescently labeled, and the complex that may be present in the patient sample can be detected by flow cytometry. Alternatively, clonal expansion may be detected by TCR repertoire analysis using next-generation sequencing technology based on information of the TCR gene obtained from the human genome sequence. 【0127】If the measured value obtained in step A2 or step B2 above falls within a range useful for disease application, it can be determined that the pharmaceutical composition is suitable for application to individuals positive for anti-SS-A antibodies. The range useful for disease application can be set as appropriate, but for example, it can be set as the range in which the measured value exceeds a predetermined threshold. The threshold can be determined by using the above measurement results obtained from samples from healthy individuals and individuals positive for anti-SS-A antibodies, for example, using an ROC curve (Receiver Operating Characteristic Curve) to set the optimal point of sensitivity and specificity. 【0128】 If the measured value obtained in step C2 or step D2 above falls within a range useful for disease application, it can be determined that the pharmaceutical composition is suitable for application to patients with Sjögren's syndrome. The range useful for disease application can be set as appropriate, but for example, it can be set as the range in which the measured value exceeds a predetermined threshold. To determine the threshold, the above measurement results obtained from samples from healthy individuals and patients with Sjögren's syndrome can be set from the point of optimal sensitivity and specificity using, for example, an ROC curve (Receiver Operating Characteristic Curve). 【0129】 <Companion Diagnostic Composition or Companion Diagnostic Kit> One embodiment of the present invention is a companion diagnostic composition or companion diagnostic kit for determining whether to apply either of the following two pharmaceutical compositions to a person positive for anti-SS-A antibodies: (1) A pharmaceutical composition for use in the treatment or prevention of autoimmune diseases, comprising a binding substance that specifically binds to the peptide or protein complex of the present disclosure. (2) A pharmaceutical composition for use in the treatment or prevention of autoimmune diseases, comprising a binding substance that specifically binds to TCR1 or TCR2 of the present disclosure. 【0130】One embodiment of the present invention is a companion diagnostic composition or companion diagnostic kit for determining whether to apply either of the following two pharmaceutical compositions to a patient with Sjögren's syndrome: (1) A pharmaceutical composition for use in the treatment or prevention of an autoimmune disease, comprising a binding substance that specifically binds to a peptide or protein complex of the present disclosure; (2) A pharmaceutical composition for use in the treatment or prevention of an autoimmune disease, comprising a binding substance that specifically binds to TCR1 or TCR2 of the present disclosure. 【0131】 The companion diagnostic compositions of the present disclosure include reagents such as antibodies, probes, and labeled molecules necessary to measure the peptide, protein complex, TCR1, or TCR2 of the present disclosure contained in a sample taken from a person positive for anti-SS-A antibody or a patient with Sjögren's syndrome, for example, by the method described in step A1, step B1, step C1, or step D1. 【0132】 The kit of this disclosure may include the companion diagnostic composition described above, and may also include a manual describing how to use the companion diagnostic composition and the test procedure. The kit of this disclosure may also include instruments for sample collection, such as cotton swabs, syringes, and blood collection tubes, and necessary containers, such as test tubes. The kit of this disclosure may also include instructions describing the criteria for application to patients with Sjögren's syndrome, such as the thresholds described in steps A2, B2, C2, or D2 described above. 【0133】 <Pharmaceutical Composition Containing a Peptide and an Immunosuppressant> One embodiment of the present invention is a pharmaceutical composition containing the peptide and an immunosuppressant of the present disclosure. This pharmaceutical composition is also referred to as "Pharmaceutical Composition 2 of the present disclosure". 【0134】The immunosuppressant is not particularly limited as long as it has an effect of suppressing the immune response, but examples include those that can suppress the differentiation, maturation, or activation of immune cells such as dendritic cells, B cells, T cells, and macrophages. Preferred immunosuppressants include vitamin D (active vitamin D), rapamycin, dexamethasone, cyclosporine A, tacrolimus, prezonisone, methotrexate, azathioprine, mycophenolate mofetil, leflunomide, cyclophosphamide, hydroxychloroquine, and abatacept. 【0135】 There are no particular limitations on the combination of the peptides of this disclosure with immunosuppressants, and one or more of the peptides of this disclosure can be arbitrarily combined with one or more immunosuppressants. 【0136】 Pharmaceutical composition 2 of this disclosure may consist only of the peptide and the immunosuppressant described above, as well as a pharmaceutically acceptable carrier, or it may contain any other components. The acceptable carrier is the same as in the case of pharmaceutical composition 1 of this disclosure. 【0137】 The method of administering the pharmaceutical composition 2 of this disclosure to a subject, the amount of immunosuppressant contained in the pharmaceutical composition, the amount of the pharmaceutical composition administered to the subject, etc., are not particularly limited as long as the activity of the binding substance contained in the pharmaceutical composition can be exerted, and can be appropriately determined depending on the type of disease the subject has, the severity of the disease, the symptoms, the age of the subject, weight, etc. 【0138】 The dosage form of the pharmaceutical composition 2 of this disclosure can be appropriately selected depending on the route of administration, etc. For example, in the case of oral administration, it can be formulated as a solid preparation such as tablets, granules, powders, or capsules; or as a liquid preparation such as a solution, syrup, suspension, or emulsion. In the case of parenteral administration, it can be formulated as an injection, liquid preparation, suspension, etc., and these dosage forms of pharmaceutical compositions can be administered to the target via routes of administration such as intra-arterial, intra-venous, intramedullary, intrathecal, or intestinal. It may also be a preparation encapsulated in a drug delivery carrier as described later. 【0139】 <Pharmaceutical Formulation> One embodiment of the present invention is a pharmaceutical formulation comprising a drug delivery carrier containing the pharmaceutical composition 2 of the present disclosure. 【0140】 A drug delivery carrier refers to a carrier (support) for effectively delivering the pharmaceutical composition 2 of this disclosure to a target site. Examples of drug delivery carrier forms include known liposomes (vesicles consisting of a phospholipid bilayer), nanoparticles (polymer nanoparticles and lipid nanoparticles (including those prepared by combining ionizable lipids, cholesterol, neutral lipids, and PEG-modified lipids, etc.)), emulsions (emulsified liquids, microemulsions, nanoemulsions, etc.), and polymer micelles (polymer micelles). Lipid nanoparticles are preferred as drug delivery carriers. 【0141】 "Encompassing" is synonymous with "encapsulating," "supporting," or "containing," and encompasses all forms of containing or holding a pharmaceutical composition within a drug delivery carrier. For example, it is not limited to the form of incorporating the pharmaceutical composition 2 of this disclosure inside the drug delivery carrier, but broadly refers to all means of including the pharmaceutical composition 2 of this disclosure in a drug delivery carrier. Examples include encapsulating (sealing) the pharmaceutical composition 2 of this disclosure in the hollow portion or internal matrix of the drug delivery carrier, adsorbing or binding the pharmaceutical composition 2 of this disclosure to the surface of the drug delivery carrier, and mixing and holding the pharmaceutical composition 2 of this disclosure within the constituent materials of the drug delivery carrier. 【0142】 There are no particular limitations on the method for encapsulating the pharmaceutical composition 2 of this disclosure in a drug delivery carrier, but examples include a method of encapsulating a hydrophilic drug in the aqueous phase inside a liposome, a method of dissolving and dispersing a hydrophobic drug in the core of nanoparticles, a method of adsorbing a drug into the pores of porous microparticles, and a microencapsulation method of dispersing and mixing a drug in a resin matrix. 【0143】 There are no particular restrictions on the method of formulating the above-mentioned drug delivery carrier, but as an example, an LNP formulation using lipid nanoparticles (LNPs) is given below. 【0144】When the formulation is an injectable preparation, for example, an ionizable cationic lipid, phospholipid, sterol such as cholesterol, and PEG-binding lipid (PEG lipid) can be dissolved in an organic solvent and rapidly mixed with an aqueous buffer containing the peptide and immunosuppressant of this disclosure to prepare a suspension of LNPs containing the active ingredient by self-assembly of amphiphilic lipids. After removing the organic solvent from the obtained LNP suspension, it is subjected to dialysis or ultrafiltration. Next, it is aseptically filtered (e.g., through a 0.22 μm filter) and dispensed into a sterile vial while maintaining sterility. After dispensing, the solution in the vial is freeze-dried to remove water and obtain a freeze-dried powder containing LNPs. The above operations are performed under sterile conditions, and after freeze-drying, the vial is sealed with a rubber stopper or the like to prepare the formulation. When using the preparation, sterile distilled water or physiological saline can be added to dissolve and suspend it to prepare an injectable solution. 【0145】 If the formulation is an oral preparation, for example, an LNP suspension is prepared in the same manner as for the injectable preparation described above, and then powdered by freeze-drying or spray-drying to obtain a dry powder of LNP containing the peptide and immunosuppressant of this disclosure. A predetermined amount of the obtained powder is filled into hard capsules together with a filler, and the surface of the capsules is coated with an enteric polymer coating. The coating can be performed, for example, by immersing the capsules in an enteric coating solution and drying, or by a fluidized bed coating method. Alternatively, the powder may be mixed with an excipient and directly compressed into tablets, and the resulting tablets may be coated with an enteric coating. 【0146】 <Pharmaceutical Composition Containing an Antibody-Drug Conjugate> One embodiment of the present invention is a pharmaceutical composition comprising an antibody-drug conjugate in which an antibody that specifically binds to the peptide or protein complex of the present disclosure and an immunosuppressant are linked via a linker. The antibody-drug conjugate is also referred to as "Pharmaceutical Composition 3 of the present disclosure". 【0147】 The antibodies constituting the antibody-drug conjugate contained in the pharmaceutical composition 3 of this disclosure may be those described in the section on <binding substance> above, as appropriate. 【0148】The immunosuppressant constituting the antibody-drug conjugate contained in the pharmaceutical composition 3 of this disclosure may be one of those described in the section above, "<Pharmaceutical composition containing peptide and immunosuppressant>", as appropriate. 【0149】 There are no particular restrictions on the linker in the antibody-drug conjugate described above, but for example, one that is stable in the blood is preferred. Examples of linkers include peptide-based linkers such as Val-Cit (valine-citrulline), Phe-Lys (phenylalanine-lysine), and Val-Ala (valine-alanine); disulfide bond-type linkers that include a disulfide bond in the covalent bond connecting the antibody and the drug, such as SPDB (N-suxinimidyl-4-(2-pyridyldithio)butanoic acid) linker; and hydrazone linkers that have a reversible bond (hydrazone bond) that is cleaved in response to pH. 【0150】 The method for producing the antibody-drug conjugate described above is not particularly limited, and known methods can be used. For example, a method utilizing nucleophilic functional groups present in the amino acid side chains of the antibody can be used, such as a method using the ε-amino group of a lysine (Lys) residue or the thiol group of a cysteine ​​(Cys) residue as a reaction site. 【0151】 In the former lysine-binding type, a linker reagent containing an NHS ester (active ester) is used to acylate (form an amide bond) the lysine on the antibody surface, and then an immunosuppressant can be bound to the other end of the linker. 【0152】 In the latter cysteine-linked form, the disulfide bonds of the antibody (between H chains and L chains, or between H chains) are partially reduced to expose the thiol group, which can then be reacted with a solution containing an immunosuppressant or linker with a maleimide group to form a stable thioether bond. 【0153】 The pharmaceutical composition 3 of this disclosure may consist only of a pharmaceutically acceptable carrier in addition to the antibody-drug conjugate described above, or it may contain any other components. The acceptable carrier is the same as in the case of pharmaceutical composition 1 of this disclosure. 【0154】The method of administering the pharmaceutical composition 3 of this disclosure to a subject, the amount of immunosuppressant contained in the pharmaceutical composition, the amount of the pharmaceutical composition administered to the subject, etc., are not particularly limited as long as the activity of the binding substance contained in the pharmaceutical composition can be exerted, and can be appropriately determined depending on the type of disease the subject has, the severity of the disease, the symptoms, the age of the subject, weight, etc. 【0155】 The dosage form of the pharmaceutical composition 3 of this disclosure can be appropriately selected depending on the route of administration, etc. For example, in the case of oral administration, it can be formulated as a solid preparation such as tablets, granules, powders, and capsules; or as a liquid preparation such as a solution, syrup, suspension, or emulsion. In the case of parenteral administration, it can be formulated as an injection, liquid preparation, suspension, etc., and these dosage forms of pharmaceutical compositions can be administered to the target via routes of administration such as intra-arterial, intravenous, intramedullary, intrathecal, or intestinal. 【0156】 The present disclosure will be described in more detail below based on examples, but the present disclosure is not limited to these examples and can be modified as appropriate without changing its essence. 【0157】 [Example 1] [Preparation of Reporter Cells] Salivary gland tissue was obtained from seven patients with Sjögren's syndrome who were positive for serum anti-SS-A antibodies. The obtained salivary gland tissue was finely chopped and shaken for 30 minutes under 10 mg / ml Type 2 collagenase (Worthingon) and 100 U / ml DNase I (Merck). The treated material was passed through a 40 μm cell strainer (Greiner Japan) and stained with fluorescently labeled antibodies against CD3, CD19, CD45, and CD326 (Biolegend). CD3-positive T cells, CD19-positive B cells, CD45-positive, CD3-negative, CD19-negative immune cells (monocytes, NK cells, etc.), and CD326-positive salivary gland epithelial cells were sorted using FACS Aria III (Becton Dickinson). 【0158】The obtained cells were used to prepare libraries for gene expression analysis and immunorepertoire analysis using the Chromium Next GEM Single Cell 5' Kit v2 for Dual Index (10x Genomics), and sequencing was performed at 150 bp pair-end using HiSeqX (Illumina) by Macrogen. 【0159】 The sequencing results were subjected to primary analysis using CellRanger (ver. 7.0.0) to extract the gene expression matrix and TCR sequences. Noise in the gene expression matrix was removed using CellBender (ver. 0.3.0), and gene expression analysis was performed using Seurat package (ver. 5.0.1). For filtering, genes with fewer than 200 expressed genes or those mapped to mitochondria by more than 20% were removed, and doublets were removed using scDblFinder. Data standardization was performed using NormalizeData, and the top 2000 differentially expressed genes were identified using FindVariableFeatures. Furthermore, batch effects were reduced using Harmony package. 【0160】 Principal component analysis (PCA) was performed on the obtained data, and Louvain clustering was performed using the top 20 principal components, resulting in the following components: PTPRC (Protein Tyrosine Phosphate Receptor type C) (HGNC: 9666), CD3E (HGNC: 1674), CD19 (HGNC: 1633), CD4 (HGNC: 1678), CD8A (HGNC: 1706), CD8B (HGNC: 1707), MS4A1 (Membrane Spanning 4-domains A1) (HGNC: 7315), CD14 (HGNC: 1628), and NCAM1 (Neural Cell Adhesion). CD4-positive T cell clusters were identified based on the expression levels of Molecule 1 (HGNC: 7656) and EPCAM (Epitis Cell Adhesion Molecule) (HGNC: 11529). 【0161】The TCR sequences were analyzed using Change-O and scRepertoire to remove sequences found in multiple cells or sequences unexpressible as proteins. The TCR sequences were then integrated with the gene expression matrix and output as a list of CD4-positive T cell TCR sequences. From this list, TCRs exhibiting clonal expansion in each patient were selected. The double-stranded DNA of the variable regions of the top approximately 150 TCR sequences exhibiting clonal expansion was synthesized by GenScript Japan. This DNA was then inserted into retroviral vectors (described later) using NEBuilder® HiFi DNA Assembly Master Mix (manufactured by New England Biolabs) to obtain TCR expression vectors. 【0162】 The obtained TCR expression vector was introduced into Plat-GP cells (Cell Biolabs) using PEI MAX® (Polyscience) along with a pCMV-VSV-G vector (Cell Biolabs), and the culture supernatant was concentrated by centrifugation to obtain a TCR forced-expression retrovirus. 【0163】 The obtained TCR forced-expression retrovirus was used to infect CD4-positive TCR reporter cells, as described later. CD4-positive TCR reporter cells that highly expressed TCR and NGFR (Nerve Growth Factor Receptor) (HGNC: 7809) were labeled with fluorescent antibodies (Biolegend) against CD3E, NGFR, and TCRa / b. These cells were then sorted twice using FACS Aria III (Becton Dickinson) to obtain CD4-positive reporter cells expressing TCR derived from the patient. 【0164】[Retroviral Vector Construction] The retroviral vectors having the sequence pMX-signal sequence-TCRβ sequence-linker-P2A sequence-signal sequence-TCRα sequence-linker-P2A sequence-NGFR, or pMX-signal sequence-TCRβ sequence-linker-P2A sequence-signal sequence-TCRα sequence-linker-P2A sequence-NGFR-IRES-Blasticidin resistance gene sequence, were constructed by inserting a TCR sequence produced by a double-stranded DNA synthesis service (AZENTA, USA) into pMX (Cell Biolabs, USA) using NEBbuilder® HiFi DNA Assembly Master Mix. 【0165】 [Preparation of CD4-positive TCR reporter cells] Vectorbuilder Inc. was commissioned to produce a virus (pLV-Puromycin resistance gene-NFAT response sequence x 6-minimal promoter sequence-EGF) that expresses EGFP in response to NFAT stimulation located downstream of TCR stimulation. 【0166】 The prepared virus was used to infect JKT-beta-del cells (obtained from the JCRB cell bank; this T cell line lacks the TCRβ chain gene, resulting in no TCR / CD3 complex expression on the cell surface. It is characterized by the ability to express the TCR / CD3 complex on the cell surface by introducing the TCRβ chain gene) and puromycin was added to obtain bulk virus-infected cells. Furthermore, these cells were infected with a human CD4 forced-expression retrovirus prepared using pMX-CD4, and CD4-high-expression cells were obtained using FACS Aria III (Becton Dickinson). The obtained cells were cloned using the limiting dilution method, and clones that highly expressed CD4, highly expressed TCR upon introduction of the TCR forced-expression retrovirus, and highly expressed GFP upon TCR stimulation were selected and designated as CD4-positive TCR reporter cells. 【0167】 [Example 2] [Preparation of LCL cells] Peripheral blood was collected from the same seven Sjögren's syndrome patients as in Example 1, and PBMCs were obtained by specific gravity centrifugation using Lymphoprep (manufactured by STEMCELL Technologies). 【0168】 LCL cell lines were created from the obtained PBMCs according to the protocol described in the literature (Joyce Hui-Yuen et al. "Establishment of Epstein-Barr virus growth-transformed lymphoblastoid cell lines", J Vis Exp 2011 Nov 8:(57):3321). These LCL cell lines constitutively express HLA class I and class II molecules derived from the above-mentioned patients and can be used as antigen-presenting cells for the peptides described later. 【0169】 [Example 3] [Preparation of Peptide Mix] DNA was extracted from the PBMC obtained in Example 1 using Nucleospin Blood QuickPure (Takara Bio, Japan), and HLA typing was performed by an HLA laboratory. 【0170】 HLA class II proteins have a structure with a groove between the α and β chains. A core sequence of approximately 7-9 amino acids, along with amino acids approximately 12-20 amino acids in length, binds to this groove and is presented to T cells. The SS-A protein (HGNC: 11313) has a total length of 538 amino acids. Since it is unknown which portion is cleaved and presented to HLA, 53 peptides covering the full length were synthesized by stacking 10 amino acids in increments of 10 (1-20, 11-30, 21-40, etc.) from the N-terminus, creating 20-amino acid peptides (commissioned to GenScript Japan). The peptides were dissolved in DMSO (manufactured by Fujifilm Wako Pure Chemical Industries), and 5-10 peptides were mixed to create six peptide mixes. In subsequent stimulation experiments, each peptide was used at a final concentration of 10 μg / ml. 【0171】 [Example 4] The peptide that reacts with the antigen-specific TCR and the HLA presenting the peptide in the protein complex that reacts with the TCR were identified as follows. 【0172】[Peptide Identification] Eight wells were prepared on a round bottom 96-well plate (Thermo Fisher Scientific) containing one type of CD4-positive reporter cell expressing patient-derived TCR and an LCL cell line prepared from the same patient's PBMC. One well was left without peptide addition (negative control), one well was treated with Cytostim (Miltenyi Biotec, Germany, a reagent that forcibly binds TCR and HLA, positive control), and one peptide mix (amounts that result in a final concentration of 10 μg / ml for each peptide) was added to the remaining six wells. The mixtures were left standing at 37°C for one day. The following day, anti-CD4 antibody (Biolegend) and anti-NGFR antibody (Biolegend) were added, and reporter cells were gated using FACS Verse (Becton Dickinson) to separate the fractions that were positive for anti-CD4 antibody and anti-NGFR antibody. The expression level of GFP was then measured. Among the cells to which the test peptide was added, those with a reactivity of more than twice the GFP expression level of the negative control and a reactivity of 2% or more were determined to be positive. 【0173】 For TCR reporters that showed a positive reaction with the peptide mix, experiments were conducted in the same manner as above, mixing them with LCL cells and adding 5 to 10 different peptides individually, one peptide per well, to identify the peptides that reacted. The results are shown in Table 12. 【0174】 【0175】 [Identification of HLA Alleles] To identify the HLA alleles in the HLA peptide complexes that TCR reacts with, inhibitory antibodies (manufactured by Biolegend) for HLA-DR, HLA-DQ, and HLA-DP were added at a final concentration of 10 μg / ml. Then, the reaction peptide was added to LCL cells and mixed with a TCR reporter. The type of HLA allele was identified by determining which inhibitory antibody caused a decrease in the GFP positivity rate. 【0176】Regarding the identified HLA alleles, each individual possesses 2 to 4 types of DR genes and 2 types of DQ and DP genes. Therefore, the next step was to determine which gene-derived HLA the TCR was reacting with. 293T cells (obtained from Riken Cell Bank) lacking HLA class II were transfected using PEI MAX® with a vector that forces the expression of the α and β chains of HLA class II, thereby preparing cells expressing only one type of HLA class II from each individual's collection. Two days after transfection, a peptide that reacts with the 293T cells was added and mixed with TCR reporter cells to identify one HLA allele that was GFP-positive. The results are shown in Table 7. 【0177】 [Identification of Core Sequence] The peptides used so far are 20-amino acid peptides with 10-amino acid shifts. It is presumed that the core sequence and the bilateral sequences necessary for the reaction are contained within these 20 amino acids, but it is unclear which part is important. Therefore, in order to identify the core sequence, 15-amino acid peptides were synthesized with 1-amino acid shifts around the reacted peptide, and one of each was added to TCR reporter cells and LCL cells to confirm which peptides cause GFP positivity. The results are shown in Tables 13-24. In the tables, the common sequence included when the reaction rate between TCR and peptide is higher than a predetermined threshold (Cut-off value) is underlined as the core sequence. Reactivity is expressed as the percentage of cells with GFP expression levels above an upper limit set for the GFP expression level of the negative population based on the flow cytometry results. 【0178】 【0179】 【0180】 【0181】 【0182】 【0183】 【0184】 【0185】 【0186】 【0187】 【0188】 【0189】 【0190】 [Example 5] [Verification experiment of identified peptides] Experiments using reporter cells identified several TCRs that react to complexes of specific HLAs and specific peptides, but the peptides were chemically synthesized. Therefore, we investigated whether the experimental system could be reproduced by mimicking conditions closer to those in vivo. 【0191】 As an example, we targeted "LB63-51" (TCR VIII), which reacts to HLA-DRB1*15:01. PBMCs were obtained from HLA-DRB1*15:01-positive individuals as antigen-presenting cells, and CD14-positive monocytes were enriched using CD14 microbeads (Miltenyi Biotec). As antigens, we simulated a patient's body with anti-SS-A antibodies in the serum, and prepared immunocomplexes (final concentrations of 20 μg / ml and 2 μg / ml, respectively) by mixing serum-derived IgG (purified from serum using Ab-capcher Mag 2 (ProteNova)) and SS-A protein (BBI solutions) from serum-positive anti-SS-A antibody patients, allowing them to stand at 4°C for 1 hour. 【0192】 CD14-positive monocytes and LB63-51 reporter cells were mixed, and the reaction was observed using FACS Verse (Becton Dickinson) under the following conditions: no stimulation (negative control), SS-A antigen (SS-A protein) only, an immune complex containing SS-A antigen, and an immune complex containing SS-A antigen and an anti-HLA-DR inhibitory antibody. The results showed that GFP was expressed in LB63-51 when an immune complex containing SS-A antigen was added, and that the majority of this reaction was suppressed by the inhibitory antibody (see Figure 1). 【0193】This means that when SS-A protein is released from dead cells in the patient's serum, it reacts with anti-SS-A antibodies in the serum to form an immune complex. When antigen-presenting cells phagocytose this complex, a peptide that LB63-51 can react with is cleaved within the antigen-presenting cell and presented on the cell membrane. The peptide identified in this study was confirmed to be cleaved within antigen-presenting cells and presented on the cell membrane to act as an antigen in vivo. 【0194】 [Example 6] [Verification experiment of identified TCRs] Experiments using reporter cells identified several TCRs that react to specific HLA and specific peptide complexes. However, the reporter cells themselves were artificial cells created from leukemia cell lines. Therefore, we investigated whether the experimental system could be reproduced by mimicking conditions closer to those in vivo. 【0195】 PBMCs were collected from the peripheral blood of healthy individuals, and CD4-positive T cells were obtained using the CD4+ T Cell Isolation Kit (Miltenyi Biotec). 【0196】Based on the methods described in the literature (Kenji Sugata et al., “Affinity-matured HLA class II dimers for robust staining of antibody-specific CD4+ T cells”, Nature Biotechnology, vol. 39, August 2021, 958-967), CD4-positive T cells were stimulated using K562 cells (obtained from Riken Cell Bank) that overexpressed anti-CD3 antibody (clone OKT3) and CD80 (HGNC: 1700). Two days after stimulation, retronectin (registered trademark) (Takara Cells were infected with LB63-51 forced-expression retrovirus using Bio-based cells. After 2-3 days, virus-infected cells were sorted based on NGFR expression, and LB63-51 forced-expression CD4-positive T cells were proliferated by stimulation with anti-CD3 antibody and anti-CD28 antibody (Biolegend) as needed, and by adding IL-2 at a final concentration of 5 ng / ml (R&D systems, USA). 293 T cells were forced to express HLA-DRB1*15:01 as antigen-presenting cells and mixed with LB63-51 forced-expression CD4-positive T cells. 【0197】 A mixture of antigen-presenting cells and LB63-51 overexpressing CD4-positive T cells was cultured for 2.5–3 hours under four conditions: no stimulation (negative control), addition of Cytostim (positive control), addition of reaction peptide, and addition of reaction peptide and anti-HLA-DR inhibitory antibody. Brefeldin A (Biolegend) was added, and the cells were cultured for another 2.5–3 hours. The expression level of CD154 protein in the cytoplasm of CD4-positive T cells was then checked using FACS Verse (Becton Dickinson). (CD154 protein is rapidly expressed when antigen-specific stimulation from the TCR is received, but when Brefeldin A is added, it cannot be expressed outside the cell and remains in the cytoplasm, thus allowing for the confirmation of cytoplasmic CD154 protein.) The results are shown in Figure 2. 【0198】Upon addition of the LB63-51 reaction peptide, an increase in the expression level of the CD154 protein (HGNC: 11935) was observed, and this reaction was inhibited by an anti-HLA-DR antibody. This confirmed that the TCR identified in this study also functions in primary T cells in vivo. 【0199】 [Example 7] [HLA-linker-SS-A antigen complex] HLA-DRA represented by SEQ ID NO: 292, SS-A(70-84)-linker1(GSGSGS)-HLA-DRB1 represented by SEQ ID NO: 252 * SS-A(70-84)-linker2(GGGSGSGSGS)-HLA-DRB1, as indicated by 15:01 and Sequence ID No. 253. * Vector 15:01 was constructed as follows: Each HLA sequence was cloned from a healthy individual, and the linker and peptide sequences were synthesized using a double-stranded DNA synthesis service (Thermo Fisher Scientific). These sequences were then inserted into pcDNA3.4 using NEBuilder® HiFi DNA Assembly Master Mix (New England Biolabs). Subsequently, 293T cells lacking HLA class II were transfected with the vector, which linked the α chain of HLA class II and the antigen peptide and β chain, using PEI MAX®. After two days, the vector was mixed with TCR reporter cells (LB63-51), and the percentage of reporters that became GFP-positive was examined using FACS Verse (Becton Dickinson). The results are shown in Table 25 below. 【0200】 【0201】 From the above results, it was confirmed that even protein complexes having a linker between the peptide and HLA of this disclosure exhibit reactivity with TCR. 【0202】[Example 8] [Preparation of Reporter Cells] Based on the nucleotide sequence information of the α and β chains of TCR obtained from cloned CD4+ T cells collected from the salivary glands of 10 Caucasian patients or patients of mixed Caucasian and Native American descent with Sjögren's syndrome, as disclosed in Table 3 of Reference A (Michelle L. Joachims et. al., “Single-cell analysis of glandular T cell receptors in Sjögren's syndrome”, JCI Insight. 2016;1(8):e85609.), double-stranded DNA of the variable region of the TCR sequence was synthesized by GenScript Japan, and inserted into a retroviral vector described later using NEBuilder® HiFi DNA Assembly Master Mix (manufactured by New England Biolabs) to obtain a TCR expression vector. 【0203】 The obtained TCR expression vector was introduced into Plat-GP cells (Cell Biolabs) using PEI MAX® (Polyscience) along with a pCMV-VSV-G vector (Cell Biolabs), and the culture supernatant was concentrated by centrifugation to obtain a TCR forced-expression retrovirus. 【0204】 The obtained TCR forced-expression retrovirus was used to infect CD4-positive TCR reporter cells, as described later. CD4-positive TCR reporter cells that highly expressed TCR and NGFR (Nerve Growth Factor Receptor) (HGNC: 7809) were then labeled with fluorescent antibodies (Biolegend) against CD3 (a complex of CD3E (HGNC: 1674), CD3G (HGNC: 1673), CD3D (HGNC: 1672), and CD247 (HGNC: 1670)), NGFR, and TCRa / b. The cells were then sorted twice using FACS Aria III (Becton Dickinson) to obtain CD4-positive reporter cells expressing the TCR described in reference A above. 【0205】[Retroviral Vector Construction] The retroviral vectors having the sequence pMX-signal sequence-TCRβ sequence-linker-P2A sequence-signal sequence-TCRα sequence-linker-P2A sequence-NGFR, or pMX-signal sequence-TCRβ sequence-linker-P2A sequence-signal sequence-TCRα sequence-linker-P2A sequence-NGFR-IRES-Blasticidin resistance gene sequence, were constructed by inserting a TCR sequence produced by a double-stranded DNA synthesis service (AZENTA, USA) into pMX (Cell Biolabs, USA) using NEBbuilder® HiFi DNA Assembly Master Mix. 【0206】 [Production of CD4-positive TCR reporter cells] Vectorbuilder Inc. was commissioned to produce a virus (pLV-Puromycin resistance gene-NFAT response sequence x 6-minimal promoter sequence-EGF) that expresses EGFP in response to NFAT stimulation located downstream of TCR stimulation. 【0207】 The prepared virus was used to infect JKT-beta-del cells (obtained from the JCRB cell bank; this T cell line lacks the TCRβ chain gene, resulting in no TCR / CD3 complex expression on the cell surface. It is characterized by the ability to express the TCR / CD3 complex on the cell surface by introducing the TCRβ chain gene) and puromycin was added to obtain bulk virus-infected cells. Furthermore, these cells were infected with a human CD4 forced-expression retrovirus prepared using pMX-CD4, and CD4-high-expression cells were obtained using FACS Aria III (Becton Dickinson). The obtained cells were cloned using the limiting dilution method, and clones that highly expressed CD4, highly expressed TCR upon introduction of the TCR forced-expression retrovirus, and highly expressed GFP upon TCR stimulation were selected and designated as CD4-positive TCR reporter cells. 【0208】[Example 9] [Preparation of HLA-expressing cells] 293T cells (obtained from Riken Cell Bank) lacking HLA class II were transfected with a vector that forcibly expresses the α and β chains of HLA class II, based on the HLA allele information described in Supplementary Table 1 of Reference A, using PEI MAX®, thereby producing HLA-expressing cells that express only one type of HLA class II. 【0209】 [Example 10] [Preparation of Peptide Mix] HLA class II has a structure with a groove between the α and β chains, to which amino acids approximately 12 to 20 amino acids in length, including a core sequence approximately 7 to 9 amino acids in length, are bound and presented to T cells. The SS-A protein (HGNC: 11313) has a total length of 538 amino acids, and it is unknown which part is cleaved and presented to HLA. Therefore, 53 peptides covering the full length were synthesized by stacking 10 amino acids at a time from the N-terminus, starting from 1 to 20, 11 to 30, and 21 to 40, to create peptides of 20 amino acids in length (commissioned to GenScript Japan). The peptides were dissolved in DMSO (manufactured by Fujifilm Wako Pure Chemical Industries), and 5 to 10 peptides were mixed together to create six peptide mixes. In subsequent stimulation experiments, the final concentration of each peptide was 10 μg / ml. 【0210】 [Example 11] A peptide that reacts with an antigen-specific TCR and an HLA presenting the peptide in a protein complex that reacts with the TCR were identified as follows. 【0211】[Peptide Identification] Eight wells were prepared on a round bottom 96-well plate (Thermo Fisher Scientific) containing one type of CD4-positive reporter cell prepared in Example 1 and one type of HLA-expressing cell prepared in Example 2. One well was left without peptide addition (negative control), one well was treated with Cytostim (Miltenyi Biotec, Germany, a reagent that forcibly binds TCR and HLA, positive control), and one peptide mix (amounts that result in a final concentration of 10 μg / ml for each peptide) was added to the remaining six wells. The mixtures were left standing at 37°C for one day. The following day, anti-CD4 antibody (Biolegend) and anti-NGFR antibody (Biolegend) were added, and reporter cells were gated using FACS Verse (Becton Dickinson) to separate the fractions that were positive for anti-CD4 antibody and anti-NGFR antibody. The expression level of GFP was then measured. Among the cells to which the test peptide was added, those with a reactivity of more than twice the GFP expression level of the negative control and a reactivity of 2% or more were determined to be positive. 【0212】 For CD4-positive TCR reporter cells that showed a positive reaction with the peptide mix, experiments were conducted by mixing them with HLA-expressing cells, as described above, and adding 5 to 10 different peptides individually, one peptide per well, to identify the peptides that reacted. The results are shown in Table 26. 【0213】 【0214】[Identification of Core Sequence] The peptides used so far are 20-amino acid peptides with a 10-amino acid shift. It is presumed that the core sequence and the bilateral sequences necessary for the reaction are contained within these 20 amino acids, but it is unclear which part is important. Therefore, in order to identify the core sequence, 15-amino acid peptides were synthesized with a 1-amino acid shift around the reacted peptide. One of these peptides was added to the CD4-positive reporter cells obtained in Example 1 and the HLA-expressing cells obtained in Example 2, and it was confirmed which peptides caused GFP positivity. The results are shown in Tables 27-30. In the tables, the common sequence included when the reaction rate between TCR and peptide is higher than a predetermined threshold (Cut-off value) is underlined as the core sequence. Reactivity is expressed as the percentage of cells with GFP expression levels above an upper limit set for the GFP expression level in the negative population based on the flow cytometry results. 【0215】 【0216】 【0217】 【0218】 【0219】[Example 12] [Study of reactivity between TCR and protein complex] 293T cells lacking HLA class II (obtained from Riken Cell Bank) were transfected with vectors that forcibly express the α chain (DRA, DQA, or DPA) and β chain (DRB, DQB, or DPB) of HLA class II in predetermined combinations as described in Tables 31-33 below, using PEI MAX® to prepare cells expressing each HLA class II. Two days after transfection, the peptides from Table 31 synthesized in Examples 3 and 10, which react with the 293T cells, were added and mixed with TCR reporter cells expressing each TCR described in Tables 31-33, which were prepared in the same manner as in Example 1. Reactivity is determined from flow cytometry results and represents the percentage of cells with GFP expression levels above the upper limit set for the negative population of "DRA1*01:01 only" as described in Tables 31-33. In Table 33, the combinations of α and β chains in DQ set1, DQ set2, and DP set1 are as described in Table 34. 【0220】 【0221】 【0222】 【0223】

Claims

A peptide with a length of 25 amino acids or less, containing one amino acid sequence selected from the group consisting of core sequences represented by SEQ ID NOs: 1-10 and SEQ ID NOs: 301-303, respectively. 　 Amino acid sequences represented by Sequence IDs 11 to 51, which include one amino acid sequence selected from the group consisting of core sequences having the core sequences represented by Sequence IDs 1 to 10, An amino acid sequence represented by sequence numbers 304 to 318, which includes any one amino acid sequence selected from the group consisting of core sequences represented by sequence numbers 301 to 303, or The peptide according to claim 1, comprising an amino acid sequence in which one or two amino acids are deleted, substituted, or added in an amino acid sequence other than the core sequence within the amino acid sequence. 　 The peptide according to claim 1, wherein the peptide comprises one of the core sequences shown in Table 1 or Table 2 below, and the total length of the peptide consists of one of the amino acid sequences shown in each sequence number containing the core sequence in Table 1 or Table 2. The peptide according to claim 1, wherein the peptide can bind to an HLA class II protein. 　 The peptide according to claim 4, wherein the peptide is a peptide of 25 amino acids or less in length, comprising one amino acid sequence selected from the group consisting of core sequences represented by SEQ ID NOs: 1 to 10, and the HLA class II protein is one of the following HLA alleles 1 to 4 and 7. 　 HLA allele 1: HLA-DRA * 01:01 (α chain) + DRB1 * 14:06 (β chain) HLA allele 2: HLA-DRA * 01:01 (α chain) + DRB1 * 15:01 (β chain) HLA allele 3: HLA-DQA * 01:02 (α chain) + DQB1 * 06:02 (β chain) HLA allele 4: HLA-DPA * 02:02 (α chain) + DPB1 * 05:01 (β chain) HLA allele 7: HLA-DRA * 01:01 (α chain) + DRB1 * 15:02 (β chain) The combination of the peptide and the HLA class II protein is A peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 11 to 21 and the above HLA allyl 1, A peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 22 to 35 and the above HLA allyl 2, A peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 36 to 45, and the above HLA allyl 3, A peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 46 to 51 and the above HLA allyl 4, or The peptide according to claim 5, comprising a peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 22 to 35 and the HLA allyl 7. 　 The peptide according to claim 4, wherein the peptide is a peptide with a length of 25 amino acids or less, comprising one amino acid sequence selected from the group consisting of core sequences represented by SEQ ID NOs. 301 to 303, and the HLA class II protein is HLA allele 5 or 6 as described below. 　 HLA allele 5: HLA-DRA * 01:01 (α chain) + DRB1 * 03:01 (β chain) HLA allele 6: HLA-DRA * 01:01 (α chain) + DRB1 * 13:01 (β chain) The combination of the peptide and the HLA class II protein is A peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 304 to 308 and the above HLA allyl 5, A peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 304 to 308, and the above HLA allyl 6, A peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 309 to 313 and the above HLA allyl 5, or The peptide according to claim 7, comprising a peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 314 to 318 and the HLA allyl 5. 　 A protein complex comprising the peptide described in claim 1 and an HLA class II protein. 　 The protein complex according to claim 9, wherein the peptide is a peptide with a length of 25 amino acids or less, comprising any one amino acid sequence selected from the group consisting of core sequences represented by SEQ ID NOs: 1 to 10, and the HLA class II protein is any of the following HLA alleles 1 to 4 and 7. 　 HLA allele 1: HLA-DRA * 01:01 (α chain) + DRB1 * 14:06 (β chain) HLA allele 2: HLA-DRA * 01:01 (α chain) + DRB1 * 15:01 (β chain) HLA allele 3: HLA-DQA * 01:02 (α chain) + DQB1 * 06:02 (β chain) HLA allele 4: HLA-DPA * 02:02 (α chain) + DPB1 * 05:01 (β chain) HLA allele 7: HLA-DRA * 01:01 (α chain) + DRB1 * 15:02 (β chain) The combination of the peptide and the HLA class II protein is A peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 11 to 21 and the above HLA allyl 1, A peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 22 to 35 and the above HLA allyl 2, A peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 36 to 45 and the above HLA allyl 3 A peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 46 to 51 and the above HLA allyl 4, or The protein complex according to claim 10, comprising a peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 22 to 35 and the HLA allyl 7. 　 The protein complex according to claim 9, wherein the peptide is a peptide with a length of 25 amino acids or less, comprising any one amino acid sequence selected from the group consisting of core sequences represented by SEQ ID NOs. 301 to 303, and the HLA class II protein is HLA allele 5 or 6. 　 HLA allele 5: HLA-DRA * 01:01 (α chain) + DRB1 * 03:01 (β chain) HLA allele 6: HLA-DRA * 01:01 (α chain) + DRB1 * 13:01 (β chain) The combination of the peptide and the HLA class II protein is A peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 304 to 308 and the above HLA allyl 5, A peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 304 to 308, and the above HLA allyl 6, A peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 309 to 313 and the above HLA allyl 5, or The protein complex according to claim 12, comprising a peptide consisting of an amino acid sequence represented by any one of the above sequence numbers 314 to 318 and the HLA allyl 5. 　 The protein complex according to claim 9, which can bind to a T cell receptor. 　 The protein complex according to claim 14, wherein the T cell receptor is a T cell receptor expressed on T cells derived from a patient with an autoimmune disease. 　 The protein complex according to claim 15, wherein the autoimmune disease is an anti-SS-A antibody-positive disease. 　 The protein complex according to claim 15, wherein the autoimmune disease is Sjögren's syndrome. 　 The protein complex according to claim 14, wherein the T cell receptor is any of the T cell receptors (TCRs) XI to XIII, and the amino acid sequences of the α-chain complementarity determining regions (CDRs) 1 to 3 and the β-chain CDRs 1 to 3 of the TCRs XI to XIII include any of the amino acid sequences shown by the CDR group XI to XIII in Table 3 below, and the peptide is a peptide of 25 amino acids or less in length, which includes any one amino acid sequence selected from the group consisting of core sequences represented by SEQ ID NOs. 301 to 303, and the HLA class II protein is HLA allele 5 or 6 below. 　 HLA allele 5: HLA-DRA * 01:01 (α chain) + DRB1 * 03:01 (β chain) HLA allele 6: HLA-DRA * 01:01 (α chain) + DRB1 * 13:01 (β chain) The aforementioned TCRX1 to XIII are, The α-chain variable domain and β-chain variable domain consist of the amino acid sequences shown in each sequence number in Table 4 below, or The protein complex according to claim 18, comprising an α-chain variable domain and / or a β-chain variable domain, wherein one or two amino acids are deleted, substituted, or added in the region other than the CDR of the amino acid sequence shown in each sequence number in Table 3 below, and the sequence identity with the amino acid sequence shown in each sequence number in Table 3 below is 90% or more. 　 The protein complex according to claim 18, wherein a protein complex represented in Table 5 below, comprising the HLA allele and a peptide with a length of 25 amino acids or less, which includes one of the core sequences 11 to 13 consisting of the amino acid sequences represented by SEQ ID NOs. 301 to 303, can be bound to TCRXI to XIII in the combinations shown in Table 5 below. A polynucleotide comprising: polynucleotide 1 containing a base sequence encoding the α chain of the HLA class II protein complex described in claim 9; polynucleotide 2 containing a base sequence encoding the β chain of the HLA class II protein complex described in claim 7; and polynucleotide 3 containing a base sequence encoding the peptide described in claim 1, wherein none of the polynucleotides 1 to 3 are linked, or any two or three of the polynucleotides 1 to 3 are linked. 　 An expression vector comprising the polynucleotide described in claim 21. 　 A cell comprising the polynucleotide described in claim 21 or the expression vector described in claim 22. 　 A binding substance that specifically binds to the peptide described in claim 1 or the protein complex described in claim 9. 　 The binding substance according to claim 24, wherein the binding substance is an antibody, an antigen-binding fragment thereof, or an antibody-like substance. 　 A pharmaceutical composition for use in the treatment or prevention of an autoimmune disease, comprising the binding substance described in claim 24. 　 The pharmaceutical composition according to claim 26, wherein the autoimmune disease is an anti-SS-A antibody-positive disease. 　 The pharmaceutical composition according to claim 26, wherein the autoimmune disease is Sjögren's syndrome. 　 A method for determining the applicability of the pharmaceutical composition described in claim 27 to a person positive for anti-SS-A antibodies, Step A1: Measuring the peptide according to claim 1 or the protein complex according to claim 9 contained in a sample taken from a person positive for anti-SS-A antibody. The process includes step A2, in which, if the measured values ​​fall within a range useful for disease application, it is determined that the pharmaceutical composition is suitable for application to individuals positive for anti-SS-A antibodies. Judgment method. 　 A method for determining the applicability of the pharmaceutical composition described in claim 28 to a patient with Sjögren's syndrome, Step B1: Measuring the peptide according to claim 1 or the protein complex according to claim 9 contained in a sample taken from the patient with Sjögren's syndrome. The process includes step B2, which determines that the pharmaceutical composition is suitable for application to patients with Sjögren's syndrome if the measured values ​​fall within a range useful for disease application. Judgment method. 　 A companion diagnostic composition or kit for determining the applicability of the pharmaceutical composition described in claim 27 to a person positive for anti-SS-A antibodies. 　 A companion diagnostic composition or kit for determining the applicability of the pharmaceutical composition according to claim 28 to patients with Sjögren's syndrome. A T cell receptor (TCR) represented by T cell receptors (TCRs) I to X, wherein the amino acid sequences of the α-chain complementarity-determining regions (CDRs) 1 to 3 and the β-chain CDRs 1 to 3 of TCRs I to X include any of the amino acid sequences shown by the CDR group I to X in Table 6 below. The aforementioned TCRI-X are, The α-chain variable domain and β-chain variable domain consist of the amino acid sequences shown in each sequence number in Table 7 below, or An α-chain variable domain and / or β-chain variable domain consisting of an amino acid sequence in which one or two amino acids are deleted, substituted, or added in the region other than the CDR of the amino acid sequence shown in each sequence number in Table 7 below, and the sequence identity with the amino acid sequence shown in each sequence number in Table 7 below is 90% or more. The T cell receptor according to claim 33, comprising: The aforementioned TCRI-X are, The T cell receptor according to claim 33, which can bind to a protein complex comprising an HLA allele represented in Table 8 below and a peptide with a length of 25 amino acids or less, which comprises one of the core sequences 1 to 10, each consisting of an amino acid sequence represented by SEQ ID NOs. 1 to 10. The peptide is an amino acid sequence represented by SEQ ID NOs: 11-51, or The T cell receptor according to claim 35, comprising one of the amino acid sequences in which one or two amino acids are deleted, substituted, or added in an amino acid sequence other than the core sequence within the amino acid sequence. 　 The T cell receptor according to claim 35, wherein the full-length amino acid sequence of the peptide containing the core sequence consists of one of the amino acid sequences shown in each sequence number in Table 9 below. A polynucleotide comprising a nucleotide sequence encoding the α chain of the T cell receptor according to claim 33 and a nucleotide sequence encoding the β chain of the T cell receptor according to claim 33. 　 An expression vector comprising the polynucleotide described in claim 38. 　 A cell comprising the polynucleotide described in claim 38, or the expression vector described in claim 39. 　 A binding substance that specifically binds to the T cell receptor according to claim 33. 　 The binding substance according to claim 41, wherein the binding substance is an antibody or its antigen-binding fragment, or an antibody-like substance. 　 A pharmaceutical composition for use in the treatment or prevention of an autoimmune disease, comprising the binding substance described in claim 41. 　 The pharmaceutical composition according to claim 43, wherein the autoimmune disease is an anti-SS-A antibody-positive disease. 　 The pharmaceutical composition according to claim 43, wherein the autoimmune disease is Sjögren's syndrome. 　 A method for determining the applicability of the pharmaceutical composition described in claim 44 to a person positive for anti-SS-A antibodies, Step C1, which involves measuring the T cell receptor according to claim 33 contained in a sample taken from a person positive for anti-SS-A antibody, The process includes step C2, which determines that the pharmaceutical composition is suitable for application to individuals positive for anti-SS-A antibodies if the measured values ​​fall within a range useful for disease application. Judgment method. 　 A method for determining the applicability of the pharmaceutical composition described in claim 45 to a patient with Sjögren's syndrome, Step D1: Measuring the T cell receptor according to claim 33 contained in a sample taken from the aforementioned Sjögren's syndrome patient. The process includes step D2, which determines that the pharmaceutical composition is suitable for application to patients with Sjögren's syndrome if the measured values ​​fall within a range useful for disease application. Judgment method. 　 A companion diagnostic composition or kit for determining the applicability of the pharmaceutical composition described in claim 44 to persons positive for anti-SS-A antibodies. 　 A companion diagnostic composition or kit for determining the applicability of the pharmaceutical composition according to claim 45 to patients with Sjögren's syndrome. 　 A pharmaceutical composition comprising the peptide and immunosuppressant described in claim 1. 　 A pharmaceutical formulation comprising a drug delivery carrier containing the pharmaceutical composition described in claim 50. 　 A pharmaceutical composition comprising an antibody-drug conjugate in which an antibody that specifically binds to the peptide described in claim 1 or the protein conjugate described in claim 9 and an immunosuppressant are linked via a linker.

Images