Chimeric receptor recognizing modification site of antibody

Abstract

To provide a more cost-effective therapeutic method for cancer patients using CAR-T cells, having sufficient therapeutic effects and having high safety.SOLUTION: The present disclosure provides a pharmaceutical composition for use in combination with administration of a mutated antibody having a mutation, including substitution, deletion, addition or modification, of at least one amino acid in a CH1 region, a CH2 region, a CH3 region, a CL region, or a framework region, wherein the pharmaceutical composition comprises a cell expressing a chimeric receptor, the mutated antibody is capable of binding to an extracellular binding domain of the chimeric receptor via a moiety having the mutation, and the extracellular binding domain does not bind to an antibody free of the mutation.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to chimeric receptors, cells expressing the chimeric receptors, and methods for treating diseases using the cells, particularly adoptive cell therapy, adoptive T cell therapy, CAR-T therapy, and T cell redirecting antibodies using the cells. [Background technology]

[0002] A chimeric antigen receptor (CAR) is a chimeric protein that artificially fuses an antibody that recognizes a cell surface antigen, such as a cancer cell, with a signaling domain that induces T cell activation. CAR-expressing T cells (hereinafter simply referred to as "CAR-T cells") are generated by introducing a gene encoding a CAR into normal peripheral blood T cells (peripheral blood T lymphocytes) that do not have antigen reactivity. CAR-expressing T cells generated in this manner are used in the treatment of diseases such as cancer through adoptive immunotherapy. Such CAR-T cells are reactive to target cells that express antigens and can induce target cell destruction without relying on interactions with major histocompatibility complex (MHC).

[0003] Clinical trials are being conducted worldwide on cancer immunotherapy using CAR-T cells, specifically, a therapy in which T cells are collected from a patient, transfected with a gene encoding a CAR, expanded, and then reintroduced into the patient (Non-Patent Document 1). Cancer immunotherapy using CAR-T cells has shown efficacy in hematopoietic malignancies such as leukemia and lymphoma. In 2017, Kymriah® (Novartis, tisagenlecleucel, CTL-019, CD3 zeta-CD137) and Yescarta® (KiTE, axicabtagene ciloleucel, CD3 zeta-CD28), which are CAR-T cells targeting CD19 as an antigen, were approved as pharmaceuticals in the United States.

[0004] The establishment of a technique for generating universal T cells capable of changing the antigens they recognize has important clinical significance for the widespread use of T cell-based therapies. Several reports on such research have been published (Patent Documents 1 to 6 and Non-Patent Documents 2 to 5).

[0005] Furthermore, as molecules that bind to multiple targets, research is being conducted on antibodies that bind to two or more antigens with a single molecule (bispecific antibodies). By improving natural IgG-type antibodies, it is possible to confer binding activity to two different antigens (first and second antigens) (Non-Patent Document 5). Therefore, in addition to the ability to bind to two or more antigens with a single molecule, antitumor activity can be enhanced by crosslinking cytotoxic cells with cancer cells.

[0006] T cell-redirecting antibodies, which are one type of bispecific antibody and whose antitumor effect is mediated by cytotoxicity, recruiting T cells as effector cells, have been known since the 1980s (Patent Document 7, Non-Patent Documents 6, 7, and 8). Unlike antibodies whose antitumor effect is mediated by ADCC, recruiting NK cells or macrophages as effector cells, T cell-redirecting antibodies are bispecific antibodies that contain a binding domain for one of the constituent subunits of the T cell receptor (TCR) complex on T cells, particularly a domain that binds to the CD3 epsilon chain, and a domain that binds to an antigen on the target cancer cell. Simultaneous binding of T cell-redirecting antibodies to the CD3 epsilon chain and tumor antigen allows T cells to approach cancer cells. As a result, the cytotoxic activity of T cells exerts an antitumor effect on cancer cells. Furthermore, from the viewpoint of reducing side effects, the creation of highly selective antibodies against target tissues has also been reported (Patent Document 8). [Prior art documents] [Patent documents]

[0007]

Patent Document 1

Patent document 2

Patent document 3

Patent document 4

Patent document 5

Patent document 6

Patent document 7

Patent document 8

Non-licensed literature

[0008]

Non-licensed literature 1

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

[0009] Despite the promise of CAR-T cell therapy for cancer patients, there are several limitations to its widespread clinical application. First, because a single tumor antigen is not universally expressed in all cancers, CAR antigen recognition sites must be engineered for each target tumor antigen. Second, the economic and labor costs associated with identifying and engineering CAR-T cells with antigen recognition sites for various tumor antigens present significant challenges. Third, tumor antigens targeted by CARs can undergo immunological evasion in response to treatment, such as by downregulation or mutation. In particular, current CAR-T cells only recognize a single target antigen, resulting in reduced or even complete elimination of therapeutic efficacy. Furthermore, if the tumor antigen of a T cell redirecting antibody is expressed in normal tissue, damage to the normal tissue occurs, inducing strong side effects, so it is important that the antibody is selectively active only in the target tissue. Research is being conducted on CAR-T cells and T cell redirecting antibodies, which can change the tumor antigens they recognize depending on the treatment stage, and on treatment methods using them. However, there is a need for cheaper treatments through the development of treatment methods that are sufficiently effective when administered to patients and highly safe, as well as universally applicable technologies. [Means for solving the problem]

[0010] In order to solve the above technical problems, the inventors conducted extensive research and found that CAR-T cells or T cell redirecting antibodies using chimeric receptors that recognize antibody modification sites are effective in treatment, and completed the present disclosure. In one aspect of the present disclosure, the following invention is provided.

[0011] [1] At least one of the CH1 region, CH2 region, CH3 region, CL region, or framework region 1. A pharmaceutical composition for use in combination with the administration of a mutant antibody having a mutation comprising a substitution, deletion, addition or modification of one amino acid, comprising: the pharmaceutical composition comprises a cell expressing the chimeric receptor; The chimeric receptor comprises an extracellular binding domain, a transmembrane domain, and an intracellular signaling domain, the mutated antibody is capable of binding to the extracellular binding domain of the chimeric receptor via the portion of the extracellular binding domain comprising the mutation; The pharmaceutical composition, wherein the extracellular binding domain does not specifically bind to an antibody that does not contain the mutation. [2] A pharmaceutical composition for use in combination with the administration of cells expressing a chimeric receptor, comprising: The pharmaceutical composition contains at least one nucleotide sequence in the CH1 region, CH2 region, CH3 region, CL region, or framework region. and variant antibodies having mutations comprising substitutions, deletions, additions or modifications of at least one amino acid, The chimeric receptor comprises an extracellular binding domain, a transmembrane domain, and an intracellular signaling domain, the mutated antibody is capable of binding to the extracellular binding domain of the chimeric receptor via the portion of the extracellular binding domain comprising the mutation; The pharmaceutical composition, wherein the extracellular binding domain does not specifically bind to an antibody that does not contain the mutation. [3] At least one of the CH1 region, CH2 region, CH3 region, CL region, or framework region 1. A pharmaceutical composition for use in combination with the administration of a mutant antibody having a mutation comprising a substitution, deletion, addition or modification of one amino acid, comprising: the pharmaceutical composition comprises a bispecific antibody; The bispecific antibody comprises (1) a domain containing an antibody variable region that specifically binds to the mutated antibody via the portion containing the mutation, and (2) a domain that has binding activity to a molecule expressed on the surface of T cells. The pharmaceutical composition comprises a domain containing an antibody variable region and does not specifically bind to an antibody that does not contain a mutation. [4] A pharmaceutical composition for use in combination with administration of a bispecific antibody, comprising: The pharmaceutical composition contains at least one nucleotide sequence in the CH1 region, CH2 region, CH3 region, CL region, or framework region. and variant antibodies having mutations comprising substitutions, deletions, additions or modifications of at least one amino acid, The bispecific antibody comprises (1) a domain containing an antibody variable region that specifically binds to the mutated antibody via the portion containing the mutation, and (2) a domain that has binding activity to a molecule expressed on the surface of T cells. The pharmaceutical composition comprises a domain containing an antibody variable region and does not specifically bind to an antibody that does not contain a mutation. [5] The mutated antibody contains the mutation in the CH2 region, and is mutated compared to a corresponding non-mutated antibody.

[0023] Any of [1] to [4], wherein the antibody has reduced binding activity to Fc gamma receptors and C1q. The pharmaceutical composition according to any one of the preceding claims. [6] In the EU numbering system, the mutant antibodies are 234, 235, 236, 237, 238, 265, 266, 267, 268, 269, 270, 271, 295, 296, 298, 300, 324, 325, 326, 327, 328, 329, 330, 331, 332, A pharmaceutical composition according to any one of [1] to [5], which has a mutation in the CH2 region at any of positions 333, 334, 335, 336, and 337, and the mutant antibody binds to the extracellular binding domain via the portion containing the mutation. [7] The CH2 region of the mutant antibody is, in EU numbering, The amino acid at position 235 is arginine. The amino acid at position 236 is arginine. The amino acid at position 239 is lysine. The amino acid at position 250 is valine. The amino acid at position 252 is tyrosine. The amino acid at position 297 is alanine. The amino acid at position 307 is glutamine. The amino acid at position 308 is proline. The amino acid at position 311 is alanine. the amino acid at position 434 is tyrosine, and The pharmaceutical composition according to any one of [1] to [6], wherein the mutated antibody has a mutation selected from the group consisting of: wherein the amino acid at position 436 is valine; and wherein the mutated antibody binds to the extracellular binding domain via the portion containing the mutation. [8] An isolated nucleic acid encoding a chimeric receptor or a bispecific antibody contained in the pharmaceutical composition according to any one of [1] to [7]. [9] A vector comprising the isolated nucleic acid described in [8].

[10] The vector according to [9], which can be operably linked to at least one regulatory element for expression of a chimeric receptor or a bispecific antibody.

[11] A cell transformed or transduced with the isolated nucleic acid of [8] or the vector of either [9] or

[10] .

[12] The pharmaceutical composition according to any one of [1] to [7], wherein the mutant antibody binds to a tumor antigen. [A1-1] A chimeric receptor comprising an extracellular binding domain, a transmembrane domain, and an intracellular signaling domain, The extracellular binding domain contains at least one amino acid substitution, deletion, addition or deletion in the CH2 region. The chimeric receptor is capable of specifically binding to a mutant antibody having a mutation containing a modification via the portion containing the mutation, and does not specifically bind to an antibody that does not contain the mutation. [A1-2] A chimeric receptor according to [A1-1], wherein the mutated antibody does not increase the occurrence of intercellular cross-linking with other immune cells compared to the corresponding non-mutated antibody. [A1-3] The mutant antibodies have higher FcγI, FcγIIA, and FcγIIB binding than the corresponding non-mutated antibodies. The chimeric receptor according to [A1-1] or [A1-2], which is an antibody having reduced binding activity to either the Fcγ receptor FcγIIIA or FcγIIIB. [A1-3-1] The mutation is at one or more positions selected from the group consisting of 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 264, 265, 266, 267, 269, 270, 295, 296, 297, 298, 299, 300, 325, 327, 328, 329, 330, 331, and 332, as indicated by EU numbering. The chimeric receptor according to any one of [A1-1] to [A1-3], which has a mutation at a position, and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A1-3-2] A chimeric receptor described in any one of [A1-1] to [A1-3], wherein the mutations include one or more mutations selected from the group consisting of 234A, 235A, and 297A, represented by the position according to EU numbering and the amino acid after the mutation, and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A1-3-3] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. , 349C, 356C, 366W or S, 368A, 407V. A chimeric receptor according to any one of [A1-1] to [A1-3], wherein the extracellular binding domain can bind to the mutated antibody via the portion containing the mutation. [A1-3-4] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. , a combination of: (1) 235R and 239K; (2) 235R and 236R; (3) 235R, 239K and 297A; (4) 235R, 236R and 239K; (5) 252Y and 434Y; (6) 235R, 239K, 252Y and 434Y; (7) 252Y, 434Y and 436V; (8) 235R, 239K, 252Y, 434Y and 436V; (9) 250V, 252Y, 307Q, 308P, 311A, 434Y, and 436V; and (10) 235R, 239K, 250V, 252Y, 307Q, 308P, 311A, 434Y and 436V the extracellular binding domain via the portion containing the mutation in one or more combinations selected from the above. The chimeric receptor according to any one of [A1-1] to [A1-3], which is capable of binding to a mutant antibody. [A1-3-5] A chimeric receptor described in any of [A1-1] to [A1-3], wherein the mutation is at one or more positions selected from the group consisting of 235, 236, and 239, as indicated by EU numbering, and the extracellular binding domain binds to the mutant antibody via the portion containing the mutation. [A1-4] The binding activity of mutant antibodies to FcγRIa compared to the corresponding non-mutated antibodies The chimeric receptor described in [A1-1], which is an antibody in which the above-mentioned expression level is enhanced. [A1-4-1] The mutation is one or more selected from the group consisting of 234, 235, 236, 237, 238, 265, 266, 267, 268, 269, 270, 271, 295, 296, 298, 300, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, and 337, which are represented by EU numbering positions. A chimeric receptor described in either [A1-1] or [A1-4], which has a mutation at position (A1-1) and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A1-5] The mutant antibodies have higher FcγI, FcγIIA, and FcγIIB binding than the corresponding non-mutated antibodies. The chimeric receptor according to [A1-1], which is an antibody having enhanced binding activity to any one of the Fcγ receptors, FcγIIIA and FcγIIIB. [A1-5-1] The mutation is at one or more positions selected from the group consisting of 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 265, 266, 267, 268, 269, 270, 271, 295, 296, 298, 300, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, and 337, as indicated by EU numbering, and the mutation is transmitted to the extracellular A chimeric receptor according to either [A1-1] or [A1-5], wherein the binding domain is capable of binding to a mutant antibody. [A1-5-2] The following combinations of mutations are indicated by their positions in EU numbering and the amino acids after mutation: (1) 234Y, 235Y, 236W, 268D, 270E and 298A; (2) 234Y, 235Q, 236W, 239M, 268D, 270E and 298A; (3) 234Y, 235Q, 236W, 239M, 268D, 270E and 298A; (4) 234Y, 235Y, 236W, 268D, 298A and 327D; (5) 234Y, 235Y, 236W, 239M, 268D, 298A and 327D; (6) 234Y, 235Y, 236W, 239M, 268D, 298A, 327D, 328W and 334L; (7) 326D, 330M and 334E; (8) 270E, 326D, 330M, and 334E; and (9) 270E, 326D, 330K and 334E and the extracellular binding domain is linked via the portion containing the mutation. A chimeric receptor described in either [A1-1] or [A1-5], wherein the receptor is capable of binding to a mutant antibody. [A1-5-3] The following combinations of mutations are indicated by their positions in EU numbering and the amino acids after mutation: (1) 234L, S, F, E, V, D, Q, I, M, T, A, G or H, 235Y or Q, 236W, 239M or I, 268D, and 298A; (2) 234L, S, F, E, V, D, Q, I, M, T, A, G or H, 235Y or Q, 236W, 239M or I, 268D, 298A and 327D; (3) 234F, E, D, S or L, 235Y or Q, 236W, 239M or I, 268D, 298A and 327D; (4) 270E, 326D, 330A, K, M, F, I, Y or H, and 334E; (5) 270E, 326D, 330A, K, M, F, I, Y or H, and 334E; (6) 270E, 326D, 330A, F or K, and 334E; (7) 234L, S, F, E, V, D, Q, I, M, T, A, G or H, 235Y or Q, 236W, 239M or I, 268D, 270E, and 298A and the extracellular binding domain is linked via the portion containing the mutation. The antibody can bind to either [A1-1] or [A1-5]. The chimeric receptor described. [A1-6] A chimeric receptor described in [A1-1], wherein the mutated antibody has maintained or decreased binding activity to both the H type and R type genetic polymorphisms of FcγRIIa, compared to the corresponding non-mutated antibody, and has enhanced binding activity to FcγRIIb. [A1-6-1] A chimeric receptor described in either [A1-1] or [A1-6], wherein the mutation is at one or more positions selected from the group consisting of 233, 234, 237, 238, 239, 267, 268, 296, 271, 323, 326, and 330, as indicated by EU numbering, and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A1-6-2] Mutations are indicated by their EU numbering positions and the mutated amino acids: 238D, 328E, 237W, 267V, 267Q, 268N, 271G, 326M, 239D, 267A, 234W, 237A, 237D, 237E, 237L, 237M, 237Y, 330K, 330R, 233D, 268D, 268E, 326D, 326S, 326T, 323I, 323L, 323M, 296D, 326A, 326N. A chimeric receptor described in either [A1-1] or [A1-6], which has one or more mutations selected from the group consisting of 330M, 330M, and wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A1-6-3] The following combinations of mutations are indicated by their positions according to EU numbering: (1) 238, 233, 237, 268, 271, 296 and 330; (2) 238, 237, 268, 271, 296 and 330; (3) 238, 233, 237, 268, 271, 296, 330 and 332; (4) 238, 233, 237, 264, 267, 268, 271 and 330; (5) 238, 233, 237, 267, 268, 271, 296, 330 and 332; (6) 238, 237, 267, 268, 271, 296, 330 and 332; (7) 238, 233, 237, 268, 271, 296, 327 and 330; (8) 238, 233, 237, 264, 267, 268 and 271; (9) 238, 233, 237, 264, 267, 268, 271, 296 and 330; (10) 238, 233, 237, 264, 267, 268, 271, 296, 330 and 396; (11) 238, 237, 264, 267, 268, 271 and 330; (12) 238, 237, 264, 267, 268, 271, 296 and 330; (13) 238, 264, 267, 268 and 271; (14) 238, 264, 267, 268, 271 and 296; (15) 238, 237, 267, 268, 271, 296 and 330; (16) 238, 233, 237, 264, 267, 268, 271, 330 and 396; (17) 238, 233, 237, 264, 267, 268, 271, 296, 327, 330 and 396; (18) 238, 233, 237, 264, 267, 268, 271, 272 and 296; (19) 238, 237, 264, 267, 268, 271, 272 and 330; (20) 238, 237, 264, 267, 268, 271, 272, 296 and 330; (21) 238, 233, 264, 267, 268 and 271; (21) 238, 237, 267, 268, 271, 296 and 330; (22) 238, 264, 267, 268, 271, 272 and 296; and (22) 238, 233, 264, 267, 268, 271 and 296 and the mutation is present at one or more positions selected from the group consisting of: A chimeric receptor according to either [A1-1] or [A1-6], wherein the extracellular binding domain is capable of binding to a mutant antibody. [A1-6-4] Mutation at position 238, where the mutation is represented by the EU numbering system. and mutations at one or more positions selected from 235, 237, 241, 268, 295, 296, 298, 323, 324, and 330, and the mutations reduce binding activity to all activating FcγRs. A chimeric receptor described in either [A1-1] or [A1-6], wherein the extracellular binding domain is capable of binding to the mutant antibody via the portion containing the mutation. [A1-6-5] Mutations at position 238 are indicated by EU numbering. (1) 241, 268, 296, and 324; (2) 237, 241, 296, and 330; (3) 235, 237, 2 41 and 296, and all mutations The binding activity of the activating FcγR of the IgG1 gene is reduced, and the IgG1 gene is transported extracellularly via the region containing the mutation. A chimeric receptor according to either [A1-1] or [A1-6], wherein the binding domain is capable of binding to a mutant antibody. [A1-6-6] The mutations include mutations at positions 238 and 271, as indicated by EU numbering, and mutations at one or more positions selected from 234, 235, 236, 237, 239, 265, 267, and 297, and the mutations reduce the binding activity to all activating FcγRs. A chimeric receptor described in either [A1-1] or [A1-6], wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A1-6-7] Mutations at positions selected from the group consisting of: (1) 233, 238, 264, 267, 268, and 271, (2) 233, 237, 238, 264, 267, 268, 271, 296, 297, 330, and 396, as indicated by EU numbering; and (3) 233, 238, 264, 267, 268, 271, and 296. The mutation reduces the binding activity to all activating FcγRs, and A chimeric receptor described in either [A1-1] or [A1-6], wherein the extracellular binding domain can bind to a mutant antibody via a portion containing the mutation. [A1-6-8] The mutation includes 238D, and one or more selected from 235F, 237Q or D, 241M or L, 268P, 295M or V, 296E, H, N or D, 298A or M, 323I, 324N or H, and 330H or Y, represented by the position according to EU numbering and the amino acid after the mutation. The antibody contains mutations that reduce binding activity to all activating FcγRs, A chimeric receptor according to either [A1-1] or [A1-6], wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A1-6-9] The mutation includes 238D, which is represented by the position and amino acid after mutation according to EU numbering, and a combination of mutations selected from the group consisting of: (1) 241M, 268P, 296E, and 324H; (2) 237Q or D, 241M, 296E, and 330H; and (3) 235F, 237Q or D, 241M, and 296E. The mutation reduces the binding activity to all activating FcγRs, and A chimeric receptor described in either [A1-1] or [A1-6], wherein the extracellular binding domain can bind to a mutant antibody via a portion containing the mutation. [A1-6-10] The mutations include 238D and 271G, which are represented by the positions according to EU numbering and the amino acids after the mutations, and two or more mutations selected from 234A, H, N, K or R, 235A, 236Q, 237R or K, 239K, 265K, N, R, S or V, 267K, R or Y, and 297A, and the mutations reduce the binding activity to all activating FcγRs, and the mutations A chimeric receptor according to either [A1-1] or [A1-6], wherein the extracellular binding domain can bind to a mutant antibody via a portion comprising the chimeric receptor. [A1-6-11] Mutations include 238D and 271G, represented by the EU numbering position and the mutated amino acid, and (1) 233D, 238D, 264I, 267R, 268E, and 271G; (2) 233D, 237D, 238D, 264I, 267A, 268E, 271G, 296D, 297A, 330R, and 396M; (3) 233D, 238D , 264I, 267R, 268P, 271G, and 296E, and the mutations reduce the binding activity to all activating FcγRs, and the FcγR-binding activity is reduced through the portion containing the mutations. A chimeric receptor according to either [A1-1] or [A1-6], wherein the extracellular binding domain is capable of binding to a mutant antibody. [A1-6-12] A chimeric receptor according to any one of [A1-6-1] to [A1-6-11], wherein the mutant antibody further has reduced complement binding. [A1-6-13] A chimeric receptor described in [A1-1] or [A1-2], wherein the mutation includes a mutation at one or more positions selected from the group consisting of 322, 327, 330, and 331, as indicated by EU numbering, and the mutation reduces binding to complement, and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A1-6-14] The mutation includes one or more mutations selected from the group consisting of 322A or E, 327G, 330S, and 331S, which are represented by the position and the amino acid after the mutation according to EU numbering, and the mutation A chimeric receptor according to [A1-1] or [A1-2], wherein the extracellular binding domain can bind to a mutant antibody via a portion containing the mutation. [A1-6-15] Mutations are indicated by EU numbering positions: 238, 271, 327, 330, 331, and the FcγRIIb-binding activity of the mutated antibody is maintained when compared with a non-mutated antibody having a native IgG Fc region, and the binding activity to all activating FcγRs is reduced by the mutations. A chimeric receptor according to [A1-1] or [A1-2], wherein the extracellular binding domain is capable of binding to the mutant antibody via the chimeric receptor. [A1-6-16] A chimeric receptor described in [A1-1] or [A1-6], which has one or more mutations selected from the group consisting of 238D, 271G, 327G, 330S, and 331S, represented by the position according to EU numbering and the amino acid after the mutation, and in which the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A1-6-17] The mutant antibody further comprises a member selected from the group 233D, 237D, 264I, 267A, 268D, or E. The chimeric receptor according to [A1-6-14], which contains one or more mutations selected from the following, and wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A1-6-18] A chimeric receptor according to [A1-1] or [A1-6], wherein the mutations include 238D and 271G, represented by the positions according to EU numbering and the amino acids after the mutation, and the mutations are at positions selected from the group consisting of: (1) 237D, 238D, 268D or E, 271G, 327G, 330S, and 331S; (2) 233D, 237D, 238D, 268D, 271G, 327G, 330S, and 331S; (3) 238D, 267A, 268E, 271G, 327G, 330S, and 331S; and (4) 238D, 264I, 267A, 271G, 327G, 330S, and 331S, and the extracellular binding domain is capable of binding to the mutant antibody via the portion containing the mutations. [A1-6-19] Mutations are indicated by EU numbering positions: 233, 238, 264, 267, 268, 271, 327, 330, and 331, and A chimeric receptor according to [A1-1] or [A1-6], wherein the extracellular binding domain is capable of binding to a mutant antibody via a portion comprising: [A1-6-20] The mutations are expressed by EU numbering at positions selected from the group consisting of: (1) 237, 238, 268, 271, 327, 330, and 331; (2) 233, 237, 238, 268, 271, 327, 330, and 331; (3) 238, 267, 268, 271, 327, 330, and 331; and (4) 238, 264, 267, 271, 327, 330, and 331. The mutations are expressed by the group consisting of: (1) 237, 238, 268, 271, 327, 330, and 331; (2) 233, 237, 238, 268, 271, 327, 330, and 331; and (4) 238, 264, 267, 271, 327, 330, and 331. A chimeric receptor according to [A1-1] or [A1-6], wherein the binding domain is capable of binding to a mutant antibody. [A1-7] A chimeric receptor according to [A1-1], wherein the mutated antibody has antigen-binding activity that changes depending on ion concentration conditions, compared to the corresponding non-mutated antibody, and has FcRn-binding activity under neutral pH conditions, but does not form a heterocomplex containing two FcRn molecules and one activating Fcγ receptor molecule under neutral pH conditions. [A1-7-1] A chimeric receptor described in [A1-1] or [A1-7], wherein the mutation comprises a mutation at one or more positions selected from the group consisting of 235, 237, 238, 239, 270, 298, 325 and 329, as indicated by EU numbering, and the extracellular binding domain can bind to the mutant antibody via the portion comprising the mutation. [A1-7-2] Mutations are indicated by their positions in EU numbering and the amino acids after mutation. and the fragment contains one or more mutations selected from the group consisting of 235K or R, 237K or R, 238K or R, 239L or R, 270F, 298G, 325G, and 329K or R, and is linked via the portion containing the mutation. A chimeric receptor according to [A1-1] or [A1-7], wherein the extracellular binding domain is capable of binding to the mutant antibody. [A2-1] A chimeric receptor comprising an extracellular binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular binding domain has at least one amino acid sequence in the CH3 region. The chimeric receptor is capable of specifically binding to a mutant antibody having a mutation including an amino acid substitution, deletion, addition or modification via the portion containing the mutation, but does not specifically bind to an antibody that does not contain the mutation. [A2-2] The mutated antibody improves the stability, homogeneity, immunogenicity, safety, manufacturing efficiency, and / or plasma retention of the mutated antibody compared to the corresponding non-mutated antibody. The chimeric receptor described. [A2-3] A chimeric receptor according to [A2-1] or [A2-2], wherein the mutant antibody is an antibody lacking an amino acid at either position 446 or 447 in the EU numbering system. [A2-3-1] A chimeric receptor described in any of [A2-1] to [A2-3], wherein the mutation is represented by a position according to EU numbering, and further includes a mutation at position 434, and the extracellular binding domain can bind to the mutant antibody via the mutation. [A2-3-2] A chimeric receptor according to any one of [A2-1] to [A2-3], wherein the mutations are represented by positions according to EU numbering and further comprise mutations at positions selected from the group consisting of 131, 133, 137, 138, 219, 268, 330, 331, 335, 339, 397, and 419, and wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A2-3-3] The gene further contains a mutation at a position selected from the group consisting of 131, 133, 137, 138, 214, 217, 219, 220, 221, 222, 233, 234, 235, 236, and 409 in the EU numbering system, and the mutation The chimeric receptor according to any one of [A2-1] to [A2-3], wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A2-4] A chimeric receptor described in [A2-1] or [A2-2], wherein the mutant antibody is an antibody that contains mutations in amino acid residues at the interface so that two or more amino acid residues that form the interface have the same charge. [A2-4-1] The mutant antibody is an antibody comprising two or more heavy chain CH3 regions, in which the amino acid residues in the first heavy chain are mutated to have the same charge, and the mutations are represented by positions according to EU numbering, in the following combinations: (1)356 and 439; (2) 357 and 370; and (3) 399 and 409 and a portion containing the mutation at one of the positions of one or more combinations selected from the above. A chimeric receptor according to [A2-1], [A2-2] or [A2-4], wherein the extracellular binding domain is capable of binding to a mutant antibody via a molecule. [A2-4-2] The mutation is at one or more positions selected from the group consisting of 356, 357, 370, 399, 409, and 439, which are represented by EU numbering, and the extracellular binding is inhibited through the portion containing the mutation. domain but Mutant antibodies The chimeric receptor according to [A2-1], [A2-2] or [A2-4], which is capable of binding to [A2-4-3] The mutations are indicated by their positions according to EU numbering, and further include amino acid residues 10, 12, 23, 39, 43, and 105 in the heavy chain variable region according to the Kabat numbering system, or amino acid residues 137, 196, 203, 214, and 217 in the heavy chain constant region according to the EU numbering system. , 233, 268, 274, 276 and 297, The chimeric receptor according to any one of [A2-4-1] to [A2-4-3], wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A2-5] A chimeric receptor according to [A2-1] or [A2-2], wherein the mutated antibody is an antibody that promotes heterodimerization of polypeptides under reducing conditions compared to the corresponding non-mutated antibody. [A2-5-1] The mutant antibody is an antibody comprising two or more heavy chain CH3 regions, in which the amino acid residues in the first heavy chain are mutated to have the same charge, and the mutations are represented by positions according to EU numbering, in the following combinations: (1)356 and 439; (2) 357 and 370; (3) 399 and 409; and (4) 399, 409, 356, and 439 and a portion containing the mutation at one of the positions of one or more combinations selected from the above. A chimeric receptor according to [A2-1], [A2-2] or [A2-5], wherein the extracellular binding domain is capable of binding to a mutant antibody via a molecule. [A2-5-2] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. , 397M, F or Y, 392D, E, T, V, or I, 356K, 397F or Y, 439E A chimeric receptor described in [A2-1], [A2-2] or [A2-5], which has one or more mutations that are selected from the group consisting of methyl, ... [A2-5-3] A mutant antibody comprising two or more types of heavy chain CH3 regions, and A chimeric receptor described in [A2-1], [A2-2], [A2-5] or [A2-5-1], wherein at least one amino acid residue at any of positions 349, 351, 354, 356, 394 and 407 in the ring is cysteine, and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A2-5-4] Either of the positions represented by 226 and / or 229 in the EU numbering system A chimeric receptor described in [A2-1], [A2-2] or [A2-5], which contains a mutation in one of the regions or a deletion in the core hinge region, and wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A2-5-5] The chimeric receptor according to [A2-5-4], wherein the mutant antibody is an antibody in which positions 220 to 225 (EU numbering) are further substituted with YGPP, or positions 219 to 229 (EU numbering) are deleted. [A2-6] A chimeric receptor described in [A2-1] or [A2-2], wherein the mutant antibody comprises a first polypeptide and a second polypeptide that are in contact at the interface, and the first polypeptide has a protrusion at its interface that can be positioned in a gap at the interface of the second polypeptide. [A2-6-1] A chimeric receptor described in [A2-1], [A2-2] or [A2-6], wherein the mutant antibody is an antibody comprising two or more types of heavy chain CH3 regions, and contains a mutation at one or more positions selected from the group consisting of 366, 394, 405 and 407 in EU numbering, and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A2-6-2] The mutant antibody is an antibody containing two or more types of heavy chain CH3 regions, and In the ring, mutations in the CH3 regions of the first and second heavy chains are shown. The following combinations, represented by the amino acid: (1) the first heavy chain CH3 region is 366Y and the second heavy chain CH3 region is 407T; (2) the first heavy chain CH3 region is 366W and the second heavy chain CH3 region is 497A; (3) the first heavy chain CH3 region is 405A and the second heavy chain CH3 region is 394W; (4) the first heavy chain CH3 region is 407T and the second heavy chain CH3 region is 366Y; (5) the first heavy chain CH3 region is 366Y and 405A, and the second heavy chain CH3 region is 394W and 407T; (6) the first heavy chain CH3 region is 366W and 405W, and the second heavy chain CH3 region is 394S and 407A; (7) the first heavy chain CH3 region is 405W and 407A, and the second heavy chain CH3 region is 366W and 394S; (8) The first heavy chain CH3 region is 405W and the second heavy chain CH3 region is 394S and the mutations are selected from the group consisting of one or more combinations of mutations, and the mutations are linked to extracellular space via the mutations. A chimeric receptor according to [A2-1], [A2-2] or [A2-6], wherein the binding domain is capable of binding to a mutant antibody. [A3-1] A chimeric receptor comprising an extracellular binding domain, a transmembrane domain, and an intracellular signaling domain, The extracellular binding domain contains at least one amino acid substitution, deletion, addition or deletion in the CH1 region. The chimeric receptor is capable of specifically binding to a mutant antibody having a mutation containing a modification via the portion containing the mutation, and does not specifically bind to an antibody that does not contain the mutation. [A3-2] A chimeric receptor according to [A3-1], wherein the mutated antibody is an antibody that has improved pharmacokinetics and hinge region heterogeneity compared to the corresponding non-mutated antibody. [A3-2-1] A chimeric receptor described in [A3-1] or [A3-2], wherein the mutation is at one or more positions selected from the group consisting of 131, 133, 137, and 138, as indicated by EU numbering, and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A3-2-2] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. A chimeric receptor described in [A3-1] or [A3-2], which contains one or more mutations selected from the group consisting of 131S, 133K, 220S, 137G, 138G, 268Q, 355Q and 419E, and wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A3-2-3] A chimeric receptor according to [A3-2-1] or [A3-2-2], wherein the mutations are represented by positions according to EU numbering, and further, the chimeric receptor contains mutations at one or more positions selected from the group consisting of 220, 268, 330, 331, 339, 355, 419, 446, and 447, and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A4-1] A chimeric receptor comprising an extracellular binding domain, a transmembrane domain, and an intracellular signaling domain, The chimeric receptor, wherein the extracellular binding domain is capable of specifically binding to a mutant antibody having a mutation in the hinge region that includes at least one amino acid substitution, deletion, addition, or modification, via the portion containing the mutation, but does not specifically bind to an antibody that does not contain the mutation. [A4-2] The mutant antibodies show increased activity against FcγI, FcγIIA, and FcγIIB antibodies compared to the corresponding unmutated antibodies. The chimeric receptor according to [A4-1], which is an antibody having enhanced binding activity to any one of the Fcγ receptors, FcγIIIA and FcγIIIB. [A4-2-1] The mutation includes a mutation at one or more positions selected from the group consisting of 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, and 230, which are represented by EU numbering. A chimeric receptor according to [A4-1] or [A4-2], wherein the extracellular binding domain can bind to the mutated antibody via the portion containing the mutation. [A4-2-2] The mutation is represented by the position according to EU numbering, and further, one or more selected from the group consisting of 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 264, 265, 266, 267, 269, 270, 295, 296, 297, 298, 299, 300, 325, 327, 328, 329, 330, 331, and 332 A chimeric receptor according to [A4-2-1], which contains a mutation at position (A4-2-3), and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A4-2-3] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. A chimeric receptor described in [A4-1] or [A4-2], which contains one or more mutations selected from the group consisting of 235R, 239K and 297A, and wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A4-2-4] Mutations are indicated by their positions according to EU numbering, and are further indicated as follows: 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 249, 250, 251, 252, 254, 255, 256, 257, 258, 260, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 278, 279, 280, 281, 282, 283, 284, 285, 286, 288, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 307, 308, 309, 311, 312, 313, 314, 315, 316, 317, 318, 320, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, One or more selected from the group consisting of 336, 337, 339, 341, 343, 375, 376, 377, 378, 379, 380, 382, ​​385, 386, 387, 389, 392, 396, 421, 423, 427, 428, 429, 430, 431, 433, 434, 436, 438, 440, and 442 A chimeric receptor according to any one of [A4-2-1] to [A4-2-3], which has a mutation at position (A4-2-3) and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A4-2-5] The mutations are indicated by the position in EU numbering and the amino acid after mutation: 221K or Y, 222F, W, E or Y, 223F, W, E or K, 224F, W, E or Y, 225E, K or W, 227E, G, K or Y, 228E, G, K or Y, 230A, E, G or Y, and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A4-3] The mutant antibodies show increased activity against FcγI, FcγIIA, and FcγIIB antibodies compared to the corresponding non-mutated antibodies. The chimeric receptor according to [A4-1], which is an antibody having reduced binding activity to any one of the Fcγ receptors, FcγIIIA and FcγIIIB. [A4-3-1] Mutations are indicated by EU numbering positions 220, 226, and 229 group, and a cell is A chimeric receptor according to [A4-1] or [A4-3], wherein the outer binding domain is capable of binding to a mutant antibody. [A5-1] A chimeric receptor comprising an extracellular binding domain, a transmembrane domain, and an intracellular signaling domain, The chimeric receptor, wherein the extracellular binding domain is capable of specifically binding to a mutant antibody having a mutation including at least one amino acid substitution, deletion, addition or modification in the CH2 region and CH3 region via the portion containing the mutation, but does not specifically bind to an antibody that does not contain the mutation. [A5-2] The chimeric receptor according to [A5-1], wherein the mutated antibody has enhanced binding activity to FcRn at acidic pH compared to the corresponding non-mutated antibody. [A5-2-1] The mutation is at one or more positions selected from the group consisting of 235, 236, 239, 327, 330, 331, 428, 434, 436, 438, and 440, as indicated by EU numbering. A chimeric receptor according to [A5-1] or [A5-2], wherein the extracellular binding domain can bind to the mutated antibody via the portion containing the mutation. [A5-2-2] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. A chimeric receptor described in [A5-1] or [A5-2], having one or more mutations selected from the group consisting of 235R, 236R, 239K, 327G, 330S, 331S, 428L, 434A, 436T, 438R, and 440E, and wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A5-2-2-1] A chimeric receptor described in [A5-1] or [A5-2], wherein the mutation is at one or more positions selected from the group consisting of 214, 235, 236, 239, 327, 330, 331, 446, and 447, as indicated by EU numbering, and the extracellular binding domain binds to the mutant antibody via the portion containing the mutation. [A5-2-3] Mutations are indicated by their EU numbering positions: 238, 244, 245, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 260, 262, 265, 270, 272, 279, 283, 285, 286, 288, 293, 303, 305, 307, 308, 309, 311, 312, 314, 316, 317, 318, 332, 339, 340, 341, 343, 356, 360, 362, A chimeric receptor according to [A5-1] or [A5-2], which has mutations at one or more positions selected from the group consisting of 375, 376, 377, 378, 380, 382, ​​385, 386, 387, 388, 389, 400, 413, 415, 423, 424, 427, 428, 430, 431, 433, 434, 435, 436, 438, 439, 440, 442, and 447, and wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutations. [A5-2-4] The mutation is indicated by the position in EU numbering and the amino acid after mutation. 238L, 244L, 245R, 249P, and 250Q or E, or 251R, D, E, or L, 252F, S, T, or Y, 254S or T, 255R, G, I, or L, 256A, R, N, D, Q, E, P, or T, 257A, I, M, N, S, or V, 258D, 260S, 262L, 270K, 272L, or R, 279A, D, G, H, M, N, Q, R, S, T, W, or Y, 283A, D, F, G, H, I, K, L, N, P, Q, R, S, T, W, or Y, 285N, 286F, 288N, or P, 293V, 307A, E, Q, or M, 311A, E, I, K, L, M, S, V, or W, 309P, 312A, D, or P, 314A or L, 316K, 317P, 318N, or T, 332F, H, K, L, M, R, S, or W, 339N, T, or W, 341P, 343E, H, K, Q, R, T, or Y, 375R, 376G, I, M, P, T, or V, 377K, 378D, N, or V, 380A, N, S, or T, 382F, H, I, K, L, M, N, Q, R, S, T, V, W, or Y, 385A, R, D, G, H, K, S, or T, 386R, D, I, K, M, P, S, or T, 387A, R, H, P, S, or T, 389N, P, or S, 423N, 427N, 428L, M, F, S, or T, 430A, F, G, H, I, K, L, M, N, Q, R, S, T, V, or Y, 431H, or N, 433R, Q, H, I, K, P, or S, 434A, G, H, F, S, W, or Y, 436R, N, H, I, L, K, M, or T, 438K, L, T, or W, 440K, and 442K, 308I, P, or T, A chimeric receptor described in [A5-1] or [A5-2], which contains one or more mutations selected from the following, and wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A5-3] The chimeric receptor according to [A5-1], wherein the mutated antibody has enhanced binding activity to FcRn at neutral pH compared to the corresponding non-mutated antibody. [A5-3-1] The mutation is at one or more positions selected from the group consisting of 248, 250, 252, 254, 255, 256, 257, 258, 265, 286, 289, 297, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 332, 334, 360, 376, 380, 382, ​​384, 385, 386, 387, 389, 424, 428, 433, 434, and 436, as indicated by EU numbering, and the portion containing the mutation A chimeric receptor according to [A5-1] or [A5-3], wherein the extracellular binding domain is capable of binding to a mutant antibody via [A5-3-2] Mutations are indicated by their position according to EU numbering and the amino acid after mutation: 237M, 248I, 250A, F, I, M, Q, S, V, W or Y, 252F, W or Y, 254T, 255E, 256D, E or Q, 257A, G, I, L, M, N, S, T or Y, 258H, 265A, 286A or E, 289H, 297A, 303A, 305A, 307A, D, F, G, H, I, K, L, M, N, P, Q, R, S, V, W or Y, 308A, F, I, L, M, P, Q or T, 309A, D, E, P or R, 311A, H or I, 312A or H. 314K or R, 315A, D or H, 317A, 332V, 334L, 360H, 376A, 380A, 382A, 384A, 385D or H, 386P, 387E, 389A or S, 424A, 428A, D, F, G, H, I, K, L, N, P, Q, S, T, V, W or Y, and 436H, I, L, or V, and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A5-3-3] The mutation is selected from the group consisting of 238, 250, 252, 254, 255, 258, 286, 307, 308, 309, 311, 315, 428, 433, 434, and 436, which are represented by EU numbering positions. A chimeric receptor described in [A5-1] or [A5-3], which contains mutations at one or more positions where the extracellular binding domain can bind to the mutant antibody via the portion containing the mutations. [A5-3-4] Mutations are indicated by their position in the EU numbering system and the amino acid residues after the mutation: 238D, 250V, 252Y, 254T, 255L, 256E, 258D or I, 286E, 307Q, 308P, 309E, 311A. or H, 315D, 428I, 433A, K, P, R or S, 434Y or W, and 436I, L, V, T or contains one or more mutations selected from the group of F, and A chimeric receptor according to [A5-1] or [A5-3], wherein the domain is capable of binding to a mutant antibody. [A5-4] A chimeric receptor according to [A5-1], wherein the mutated antibody has higher antigen-binding activity at neutral pH than at acidic pH, compared to the corresponding non-mutated antibody. [A5-4-1] Mutations are indicated by EU numbering positions 257, 308, 428, and and 434, and A chimeric receptor according to [A5-1] or [A5-4], wherein the extracellular binding domain is capable of binding to a mutant antibody. [A5-4-2] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. A chimeric receptor described in [A5-1] or [A5-4], which contains one or more mutations selected from the group consisting of 257A, 308P, 428L, and 434Y, and wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A5-5] A chimeric receptor according to [A5-1], wherein the mutated antibody is an antibody having enhanced FcγRIIb binding activity compared to the corresponding non-mutated antibody. [A5-5-1] A chimeric receptor described in [A5-1] or [A5-5], wherein the mutations are at one or more positions selected from the group consisting of 231, 232, 233, 234, 235, 236, 237, 238, 239, 264, 266, 267, 268, 271, 295, 298, 325, 326, 327, 328, 330, 331, 332, 334, and 396, as indicated by EU numbering, and wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutations. [A5-5-2] The mutation includes a mutation at 236, as well as (1) 231, 232, 233, 234, 235, 237, 238, 239, 264, 266, 267, 268, 271, 295, 298, 325, 326, 327, 328, 330, 331, 332, 334, and 396, as indicated by the EU numbering system; (2) 231, 232, 235, 239, 268, 295, 298, 326, 330, and 396; or (3) 268, 295, 326, and 330, and a mutation at one or more of the positions selected from the group consisting of 268, 295, 326, and 330. A chimeric receptor according to [A5-1] or [A5-5], wherein the extracellular binding domain can bind to the mutant antibody via the portion comprising the chimeric receptor. [A5-5-3] The mutation comprises a mutation at one or more positions selected from the group consisting of 285, 311, 312, 315, 318, 333, 335, 337, 341, 342, 343, 384, 385, 388, 390, 399, 400, 401, 402, 413, 420, 422, and 431, as indicated by EU numbering, and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. or a chimeric receptor described in [A5-5]. [A5-5-4] Mutations are indicated by their positions in EU numbering and the amino acids after mutation. combination of: (1) 231D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y; (2) 232A, D, E, F, G, H, I, K, L, M, N, Q, R, S, T, V, W, or Y; (3) 233D, (4) 234W or Y, (5) 235W, (6) 236A, D, E, H, I, L, M, N, Q, S, T, or V; (7) 237D or Y, (8) 238E, I, M, Q, or Y; (9) 239I, L, N, P, or V; (10) 264I, (11) 266F, (12) 267A, H, or L; (13) 268D or E, (14) 271D, E, or G; (15) 295L, (16) 298L, (17) 325E, F, I, or L; (18) 326T, (19) 327I or N, (20) 328T, (21) 330K, or R, (22) 331E, (23) 332D, (24) 334D, I, M, V, or Y, and (25) 396A, D, E, F, G, H, I, K, L, M, N, Q, R, S, T, V, W, or Y and the mutations are selected from the group consisting of one or more combinations of mutations, and the mutations are linked to extracellular space via the portion containing the mutations. A chimeric receptor according to [A5-1] or [A5-5], wherein the binding domain is capable of binding to a mutant antibody. [A5-5-5] Mutations are indicated by their positions according to EU numbering. (1) containing a mutation at one or more positions selected from 234, 238, 250, 264, 267, 307, and 330; (2) 285, 311, 312, 315, 318, 333, 335, 337, 341, 342, 343, 384, 385, 388, 390, Contains mutations at two or more positions selected from 399, 400, 401, 402, 413, 420, 422, and 431 A chimeric receptor according to [A5-1] or [A5-5], wherein the extracellular binding domain can bind to the mutated antibody via the portion containing the mutation. [A5-5-6] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. , a combination of: (1) 234, 238, 250, 264, 307, 311, 330 and 343; (2) 234, 238, 250, 264, 307, 311, 330, or 413; (3) 234, 238, 250, 264, 267, 307, 311, or 343; (4) 234, 238, 250, 264, 267, 307, 311, 330 and 413; (5) 234, 238, 250, 267, 307, 311, 330 and 343; (6) 234, 238, 250, 267, 307, 311, 330 and 413; (7) 234, 238, 250, 307, 311, 330 and 343; (8) 234, 238, 250, 307, 311, 330 and 413; (9) 238, 250, 264, 267, 307, 311, 330 and 343; (10) 238, 250, 264, 267, 307, 311, 330 and 413; (11) 238, 250, 264, 307, 311, 330 and 343; (12) 238, 250, 264, 307, 311, 330 and 413; (13) 238, 250, 267, 307, 311, 330 and 343; (14) 238, 250, 267, 307, 311, 330 and 413; (15) 238, 250, 307, 311, 330 and 343; and (16) 238, 250, 307, 311, 330, and 413 A chimeric receptor described in [A5-1] or [A5-5], which contains mutations at one or more combinations selected from the following, and wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutations. [A5-6] A chimeric receptor according to [A5-1], wherein the mutant antibody is an antibody whose stability has been improved by a mutation in the loop region of the Fc region. [A5-6-1] A chimeric receptor according to [A5-1] or [A5-6], wherein the mutations are at one or more positions selected from the group consisting of 234, 235, 236, 237, 238, 239, 247, 250, 265, 266, 267, 268, 269, 270, 271, 295, 296, 298, 300, 307, 309, 315, 324, 325, 326, 327, 329, 330, 333, 335, 337, 360, 385, 386, 387, 389, 428, and 433, as indicated by EU numbering, and wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutations. [A6-1] A chimeric receptor comprising an extracellular binding domain, a transmembrane domain, and an intracellular signaling domain, The chimeric receptor, wherein the extracellular binding domain is capable of specifically binding to a mutated antibody having a mutation in the framework region that includes at least one amino acid substitution, deletion, addition or modification, and does not specifically bind to an antibody that does not contain the mutation. [A6-2] The mutant antibodies have higher FcγI, FcγIIA, and FcγIIB activity than the corresponding non-mutated antibodies. The chimeric receptor according to [A6-1], which is an antibody having enhanced binding activity to any one of the Fcγ receptors, FcγIIIA and FcγIIIB. [A6-2-1] Mutations are indicated by Kabat numbering positions 10, 12, and 23. A chimeric receptor described in [A6-1] or [A6-2], which contains a mutation at one or more positions selected from the group consisting of 1, 39, 43 and 105, and wherein the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A6-2-2] Mutations are indicated by Kabat numbering positions 10, 12, and 23. , 39, 43, and 105, or 137, 196, 203, 214, 217, 233, 268, 274, 276, 297, 355, 392, 419, and 435 (EU numbering), wherein the extracellular binding domain is capable of binding to the mutant antibody via the portion containing the mutation. [A6-3] A chimeric receptor according to [A6-1], wherein the mutated antibody is an antibody that can bind to an antigen in a pH-dependent manner compared to the corresponding non-mutated antibody. [A6-3-1] Mutations are indicated by their positions according to the Kabat numbering system. (1) the heavy chain contains a mutation at one or more positions selected from 1, 3, 5, 8, 10, 12, 13, 15, 16, 18, 19, 23, 25, 26, 39, 41, 42, 43, 44, 46, 68, 71, 72, 73, 75, 76, 77, 81, 82, 82a, 82b, 83, 84, 85, 86, 105, 108, 110, and 112; (2) a mutation at one or more positions selected from 1, 3, 7, 8, 9, 11, 12, 16, 17, 18, 20, 22, 37, 38, 39, 41, 42, 43, 45, 46, 49, 57, 60, 63, 65, 66, 68, 69, 70, 74, 76, 77, 79, 80, 81, 85, 100, 103, 105, 106, 107, and 108 in the light chain; A chimeric receptor according to [A6-1] or [A6-3], wherein the extracellular binding domain can bind to the mutated antibody via the portion containing the mutation. [A6-3-2] Furthermore, mutations are indicated by their positions according to EU numbering, and are listed as follows: 196, 253, 254, 256, 258, 278, 280, 281, 282, 285, 286, 307, 309, 311, 315, 327, 330, 342, 343, 345, 356, 358, 359, 361, 362, 373, 382, ​​384, 385, 386, 387, 389, 399, 400, 401, 402, 413, 415, 418, 419, 421, 424, 430, 433, From groups 434 and 443 and the extracellular binding domain is linked via the portion containing the mutation. A chimeric receptor according to [A6-1] or [A6-3], wherein the receptor is capable of binding to a mutant antibody. [A7-1] A chimeric receptor comprising an extracellular binding domain, a transmembrane domain, and an intracellular signaling domain, The chimeric receptor, wherein the extracellular binding domain is capable of specifically binding to a mutant antibody having a mutation in the CL region that includes at least one amino acid substitution, deletion, addition or modification, but does not specifically bind to an antibody that does not contain the mutation. [A7-2] Mutant antibodies inhibit the association of CH1 and CL compared to the corresponding non-mutated antibodies The chimeric receptor described in [A7-1], which is an antibody. [A7-2-1] The mutation is at one or more positions selected from the group consisting of 123, 131, 160, and 180, which are represented by EU numbering, and the mutation is transmitted to the extracellular space through the portion containing the mutation. A chimeric receptor according to [A7-1] or [A7-2], wherein the binding domain is capable of binding to a mutant antibody. [A7-2-2] The mutations are represented by the EU numbering position and the mutated amino acid, in the following combinations: (1) amino acid 147 in CH1 and amino acid 180 in CL; (2) amino acid 147 in CH1 and amino acid 131 in CL; (3) amino acid 175 contained in CH1 and amino acid 160 contained in CL; (4) amino acid 213 in CH1 and amino acid 123 in CL; A chimeric receptor described in [A7-1] or [A7-2], which is an antibody having amino acid mutations at one of the positions selected from the combination of: wherein the amino acid residues in said combination have an electrical charge that repels each other, and wherein the extracellular binding domain can bind to the mutated antibody via the portion containing the mutation. [A1-3-5] A chimeric receptor described in any of [A1-1] to [A1-3], wherein the mutation is at one or more positions selected from the group consisting of 235, 236, and 239, as indicated by EU numbering, and the extracellular binding domain binds to the mutant antibody via the portion containing the mutation. [A8-1] A chimeric receptor according to any one of [A1-1] to [A1-7-2], [A2-1] to [A2-6-2], [A3-1] to [A3-2-3], [A4-1] to [A4-3-1], [A5-1] to [A5-6-1], [A6-1] to [A6-3-2], and [A7-1] to [A7-2-2], wherein the extracellular binding domain comprises an antibody single-chain Fv fragment, a CrossMab fragment, or an antibody single-chain Fab fragment. [A8-2] The chimeric receptor described in [A8-1], wherein the extracellular binding domain comprises a single-chain Fv fragment. [A8-3] The chimeric receptor described in [A8-1], wherein the extracellular binding domain comprises a CrossMab fragment. [A8-4] The chimeric receptor described in [A8-1], wherein the extracellular binding domain comprises an antibody single-chain Fab fragment. [A8-5] A chimeric receptor described in any one of [A1-1] to [A1-7-2], [A2-1] to [A2-6-2], [A3-1] to [A3-2-3], [A4-1] to [A4-3-1], [A5-1] to [A5-6-1], [A6-1] to [A6-3-2], and [A7-1] to [A7-2-2], wherein the intracellular signaling domain includes a stimulatory molecule signaling domain derived from a stimulatory molecule. [A8-6] A chimeric receptor described in any of [A8-5], wherein the intracellular signaling domain comprises a costimulatory molecule signaling domain derived from a costimulatory molecule and a functional signaling domain derived from a stimulatory molecule. [A8-7] A chimeric receptor described in either [A8-5] or [A8-6], wherein the intracellular signaling domain comprises a costimulatory molecule signaling domain derived from one or more costimulatory molecules and a stimulatory molecule signaling domain derived from a stimulatory molecule. [A8-8] The intracellular signaling domain is derived from one or more costimulatory molecules. A chimeric receptor described in [A8-5], which comprises a costimulatory molecule signaling domain, a stimulatory molecule signaling domain derived from a stimulatory molecule, and other functional domains and / or motifs. [A8-9] A chimeric receptor described in any one of [A8-1] to [A8-8], wherein the transmembrane domain is selected from the group consisting of the alpha chain, beta chain, or zeta chain of a T cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, and CD154. [A8-10] Antibodies containing mutations in the Fc gamma receptor binding domain of CH2 A chimeric receptor described in [A8-1], which comprises an extracellular binding domain capable of recognizing an antigen and which may comprise the amino acid sequences of SEQ ID NOs: 19 and 21. [A8-11] A chimeric receptor according to [A8-1] or [A8-10], comprising the hinge domain and transmembrane domain of CD8 alpha of SEQ ID NO: 22. [A8-12] A chimeric receptor according to any one of [A8-1], [A8-10], and [A8-11], which comprises a CD28 molecule of SEQ ID NO: 23. [A8-13] A chimeric receptor according to any one of [A8-1], [A8-10] to [A8-12], which comprises a costimulatory molecule signaling domain derived from the 4-1BB molecule of SEQ ID NO: 24. [A8-14] A chimeric receptor according to any one of [A8-1], [A8-10] to [A8-13], which comprises a stimulatory molecule signaling domain derived from the CD3 zeta molecule of SEQ ID NO: 25. [A8-15] A chimeric receptor described in any one of [A8-9], [A8-10], and [A8-12] to [A8-14], wherein the hinge domain and transmembrane domain of CD8 alpha contain the amino acid sequence of a CD8 alpha molecule encoded by the sequence of nucleotide sequence 1271 to 1519 (Genbank NM001768.6). [A8-16] The intracellular signaling domain is selected from the group consisting of the cytoplasmic domains of CD28, CD2, CD4, CD5, CD8 alpha, CD8 beta, CD134, CD137, IL-2Rb, OX40, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), and 4-1BB (CD137), or the binding domain of STAT3. A chimeric receptor described in [A8-1], which contains one or more costimulatory molecule signaling domains. [A8-17] The intracellular signaling domain is an amino acid sequence and / or a nucleotide sequence of the human CD28 molecule encoded by the sequence of nucleotides 760 to 882 (Genbank NM006139.2). A chimeric receptor according to [A8-1], comprising the 4-1BB molecule amino acid sequence encoded by the sequence of peptide sequence 760 to 882 (Genbank NM006139.2). [A8-18] The chimeric receptor described in [A8-1], wherein the intracellular signaling domain comprises one or more stimulatory molecule signaling domains selected from the group consisting of CD3 zeta, common FcR gamma (FCER1G), Fc gamma RIIa, FcR beta (Fc epsilon R1b), CD3 gamma, CD3 delta, CD3 epsilon, CD79a, CD79b, DAP10, and DAP12. [A8-19] The intracellular signaling domain is a CD3 zeta molecule amino acid sequence encoded by the nucleotide sequence 299 to 637 (Genbank NM000734.3), 2A peptide (F2A ), and the chimeric receptor described in [A8-1], which contains an eGFP molecule and is located at the C-terminus of the chimeric receptor. Mela receptor. [A8-20] A chimeric receptor according to [A8-1], which comprises part or all of the amino acid sequence of SEQ ID NO: 17. An isolated nucleic acid encoding a chimeric receptor described in any one of [A9-1], [A1-1] to [A1-7-2], [A2-1] to [A2-6-2], [A3-1] to [A3-2-3], [A4-1] to [A4-3-1], [A5-1] to [A5-6-1], [A6-1] to [A6-3-2], [A7-1] to [A7-2-2], and [A8-1] to [A8-20]. [A9-2] A vector comprising the isolated nucleic acid described in [A9-1]. [A9-3] A vector according to [A9-2], which can be operably linked to at least one regulatory element for expression of a chimeric receptor. [A9-4] The vector according to [A9-2] or [A9-3], selected from the group consisting of DNA, RNA, a plasmid, a lentiviral vector, an adenoviral vector, or a retroviral vector. [A9-5] A cell transformed or transduced with the isolated nucleic acid according to [A9-1] or the vector according to any one of [A9-2] to [A9-4]. [A9-6] The cell described in [A9-5], which is a T lymphocyte, a NK cell, or a macrophage. [A9-7] A cell described in [A9-5] or [A9-6], which is a T lymphocyte in which the expression of an endogenous T cell receptor has been blocked or eliminated. [A9-8] The cells according to any one of [A9-5] to [A9-7], which are cells activated and / or expanded ex vivo. [A9-9] Cells according to any one of [A9-5] to [A9-8], which are genetically modified cells obtained by retroviral transduction, lentiviral transduction, DNA electroporation and RNA electroporation, DNA or RNA transfection, or gene editing. [A9-10] A chimeric receptor according to any one of [A1-1] to [A1-7-2], [A2-1] to [A2-6-2], [A3-1] to [A3-2-3], [A4-1] to [A4-3-1], [A5-1] to [A5-6-1], [A6-1] to [A6-3-2], [A7-1] to [A7-2-2], and [A8-1] to [A8-20], wherein the mutant antibody is capable of binding to a tumor antigen. [A10-1] There are few amino acids in the CH1 region, CH2 region, CH3 region, CL region, or framework region. 1. A pharmaceutical composition for use in combination with the administration of a mutant antibody having a mutation comprising at least one amino acid substitution, deletion, addition or modification, comprising: the pharmaceutical composition comprises a cell expressing the chimeric receptor; The chimeric receptor comprises an extracellular binding domain, a transmembrane domain, and an intracellular signaling domain, the mutated antibody is capable of binding to the extracellular binding domain of the chimeric receptor via the portion containing the mutation; The pharmaceutical composition, wherein the extracellular binding domain does not specifically bind to an antibody that does not contain the mutation. [A10-2] A pharmaceutical composition for use in combination with the administration of cells expressing a chimeric receptor, comprising: The pharmaceutical composition contains at least one nucleotide sequence in the CH1 region, CH2 region, CH3 region, CL region, or framework region. and variant antibodies having mutations comprising substitutions, deletions, additions or modifications of at least one amino acid, The chimeric receptor comprises an extracellular binding domain, a transmembrane domain, and an intracellular signaling domain, the extracellular binding domain is capable of binding to the mutated antibody via the portion comprising said mutation; The pharmaceutical composition, wherein the extracellular binding domain does not specifically bind to an antibody that does not contain the mutation. [A10-3] The pharmaceutical composition according to [A10-1] or [A10-2], wherein the chimeric receptor is a chimeric receptor according to any one of [A1-1] to [A1-7-2], [A2-1] to [A2-6-2], [A3-1] to [A3-2-3], [A4-1] to [A4-3-1], [A5-1] to [A5-6-1], [A6-1] to [A6-3-2], [A7-1] to [A7-2-2], and [A8-1] to [A8-20]. [A10-4] The pharmaceutical composition according to any one of [A10-1] to [A10-3], wherein the cell is a cell according to any one of [A9-5] to [A9-9]. [A10-5] A pharmaceutical composition according to any one of [A10-1] to [A10-4], wherein the mutated antibody has a longer half-life in the blood or a higher isoelectric point than the corresponding non-mutated antibody. [A10-6] The mutant antibody has at least one amino acid substitution, deletion, addition, or deletion in the CH2 region. The pharmaceutical composition according to any one of [A10-1] to [A10-5], which has a mutation including a modification, and the extracellular binding domain can bind to the mutant antibody via the portion including the mutation. [A10-7] The mutation in the CH2 region is at any of the positions 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 264, 265, 266, 267, 269, 270, 295, 296, 297, 298, 299, 300, 325, 327, 328, 329, 330, 331, and 332 in the EU numbering system. [A10-6] Pharmaceutical Composition . [A10-8] The CH2 region of the mutant antibody is The pharmaceutical composition according to [A10-6] or [A10-7], which contains a mutation selected from the group consisting of 234A, 235A, and / or 297A, wherein the mutation positions are represented by EU numbering. [A10-9] The CH2 region of the mutant antibody is (1) 235R and 239K; (2) 235R and 236R; (3) 235R, 239K and 297A; (4) 235R, 236R and 239K; (5) 252Y and 434Y; (6) 235R, 239K, 252Y and 434Y; (7) 252Y, 434Y and 436V; (8) 235R, 239K, 252Y, 434Y and 436V; (9) 250V, 252Y, 307Q, 308P, 311A, 434Y, and 436V; and (10) 235R, 239K, 250V, 252Y, 307Q, 308P, 311A, 434Y and 436V The pharmaceutical composition according to either [A10-6] or [A10-7], comprising a combination of mutations selected from the group consisting of: wherein the mutation positions are represented by EU numbering. [A10-10] The CH2 region of the mutant antibody comprises the amino acid sequence of SEQ ID NO: 3. The pharmaceutical composition according to any one of [A10-6] to [A10-9]. [A10-11] The mutant antibody has at least one amino acid substitution, deletion, or addition in the CH1 region. or a mutation including a modification, wherein the extracellular binding domain can bind to the mutant antibody via the portion including the mutation. [A10-12] The pharmaceutical composition according to [A10-11], wherein the mutant antibody is a full-length antibody, Fab, or F(ab')2. [A10-13] CH1 mutations are represented by EU numbering 131, 133, 137, and 138. The pharmaceutical composition according to any one of [A10-10] to [A10-12], wherein the mutation is at any of the positions indicated above. [A10-14] The CH1 region of the mutant antibody is The pharmaceutical composition according to any one of [A10-10] to [A10-13], which contains a mutation selected from the group consisting of 131S, 133K, 220S, 137G and 138G, wherein the mutation positions are represented by EU numbering. [A10-16] The mutant antibody has at least one amino acid substitution, deletion, or addition in the CH3 region. or a mutation including a modification, wherein the extracellular binding domain can bind to the mutant antibody via the portion including the mutation. [A10-17] Mutations in the CH3 region are 349, 351, 354, 356, 357, 366, A chimeric receptor complex according to [A10-16], wherein the mutation is at any of the positions represented by 370, 394, 399, 405, 407, 409, 439, 446 and 447. [A10-18] The CH3 region of the mutant antibody is 397M, F or Y, 392D, E, T, V, or I, 356K, 397F or Y, 439E, 366Y, 366W, containing a mutation at a position selected from the group consisting of 394S, 394W, 405A, 405W, 407T, and 407A. The pharmaceutical composition according to [A10-16] or [A10-17], wherein the mutation positions are represented by EU numbering. [A10-19] The CH3 region of the mutant antibody is (1)356 and 439; (2) 357 and 370; (3) 399 and 409; and (4) 399, 409, 356, and 439 The pharmaceutical composition according to [A10-16] or [A10-17], which contains a mutation at one of the positions of a combination selected from the group consisting of: [A10-20] The mutant antibody lacks GK at the CH3 end. [A10-16]~[A1 0-19]. [A10-21] Any of [A10-1] to [A10-5], wherein the mutant antibody has a mutation in the CL region, including at least one amino acid substitution, deletion, addition, or modification, and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. Pharmaceutical Composition . [A10-22] The pharmaceutical composition according to [A10-21], wherein the mutant antibody is a full-length antibody, Fab, or F(ab')2. [A10-23] The pharmaceutical composition according to [A10-21] or [A10-22], wherein the mutation in the CL region is at any of positions 123, 131, 160, and 180 according to EU numbering. [A10-24] The mutant antibody according to any one of [A10-1] to [A10-5], wherein the mutant antibody has a mutation in the CH2 and CH3 regions, including substitution, deletion, addition, or modification of at least one amino acid, and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. Pharmaceutical Composition . [A10-25] The CH2 and CH3 regions of the mutant antibody are 397M, F or Y, 392D, E, T, V, or or I, 356K, 397F or Y, 439E, 366Y, 366W, 394S, 394W, 405A, 405W, 407T, 407A, and the mutation positions are represented by EU numbering, [A 10-24] A pharmaceutical composition according to the present invention. [A10-26] A pharmaceutical composition described in any of [A10-1] to [A10-5], wherein the mutant antibody has a mutation in the framework region that includes substitution, deletion, addition or modification of at least one amino acid, and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [A10-27] Mutations in the framework region are indicated by their positions according to Kabat numbering. The pharmaceutical composition according to [A10-26], wherein the mutation is at any of positions 10, 12, 23, 39, 43 and 105. [A10-28] The mutant antibody has a mutation in the hinge region, and the mutation position is 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, or 230 in EU numbering. The pharmaceutical composition according to any one of [A10-1] to [A10-27]. [A10-29] The hinge region of the mutant antibody is 221K or Y, 222F, W, E or Y, 223F, W, E or K, 224F, W, E or Y, 225E, K or W, 227E, G, K or Y, 228E, G, K or Y, or 230A, E, G or Y. [A10-30] The pharmaceutical composition according to any one of [A10-1] to [A10-29], wherein the cells are derived from allogeneic T lymphocytes, allogeneic NK cells, or allogeneic macrophages. [A10-31] The cells are autologous T lymphocytes or autologous NK cells isolated from the subject. Alternatively, the pharmaceutical composition according to any one of [A10-1] to [A10-30] is derived from autologous macrophages. [A10-32] The pharmaceutical composition according to any one of [A10-1] to [A10-31], wherein the mutant antibody further comprises a second mutation other than the mutation involved in binding to the extracellular binding domain. [A10-33] A pharmaceutical composition described in [A10-32], in which the mutant antibody having the second mutation has a longer half-life in the blood or a higher isoelectric point compared to a corresponding antibody not having the mutation. [A10-34] A pharmaceutical composition described in any of [A10-1] to [A10-33] for use in treatment or prevention of T lymphocyte or NK cell antibody-dependent cellular cytotoxicity (ADCC) or macrophage antibody-dependent cellular cytotoxicity (ADCP) in a subject. [A10-35] The pharmaceutical composition according to any one of [A10-1] to [A10-34], wherein the mutant antibody is capable of binding to a tumor antigen. [A10-36] The pharmaceutical composition according to any one of [A10-1] to [A10-35], for use in the treatment or prevention of cancer. [A10-37] The pharmaceutical composition according to [A10-36], wherein the cancer is selected from the group consisting of carcinoma, lymphoma, sarcoma, blastoma and leukemia. [A10-38] The pharmaceutical composition described in [A10-36], wherein the cancer is selected from the group consisting of B-cell lineage acute lymphoblastic leukemia, B-cell chronic lymphocytic leukemia, B-cell non-Hodgkin's lymphoma, breast cancer, gastric cancer, neuroblastoma, osteosarcoma, lung cancer, melanoma, prostate cancer, colon cancer, renal cell carcinoma, ovarian cancer, rhabdomyosarcoma, leukemia, and Hodgkin's lymphoma. [A10-39] A pharmaceutical composition according to any one of [A10-1] to [A10-37] for use in adoptive immune cell therapy, adoptive immune T cell therapy, or CAR-T therapy. [A11-1] A pharmaceutical composition described in any of [A10-1] to [A10-39], wherein the extracellular binding domain of the chimeric receptor is an extracellular binding domain whose binding activity to the mutant antibody changes depending on the concentration of a target tissue-specific compound. [A11-2] The pharmaceutical composition according to [A11-1], wherein the target tissue is cancer tissue. [A11-3] The pharmaceutical composition described in [A11-2], wherein the cancer tissue-specific compound is a cancer cell-specific metabolite, an immune cell-specific metabolite infiltrating cancer tissue, or a stromal cell-specific metabolite in cancer tissue. [A11-4] Target tissue inflamed tissue The pharmaceutical composition according to [A11-1], [A11-5] The inflamed tissue-specific compound inflamed tissue The pharmaceutical composition according to [A11-4], wherein the metabolite is a metabolic product specific to immune cells infiltrating into the inflamed tissue, or a metabolic product specific to normal cells damaged in the inflamed tissue. [A11-6] The pharmaceutical composition according to any one of [A11-1] to [A11-5], wherein the target tissue-specific metabolite is at least one compound selected from the group consisting of nucleosides having a purine ring structure, amino acids and their metabolites, lipids and their metabolites, primary metabolites of sugar metabolism, and nicotinamide and its metabolites. [A11-7] The target tissue-specific metabolite is adenosine, adenosine triphosphate, iodo ... The pharmaceutical composition according to any one of [A11-1] to [A11-6], wherein the compound is at least one compound selected from the group consisting of nicotinic acid, alanine, glutamic acid, aspartic acid, kynurenine, prostaglandin E2, succinic acid, citric acid, and 1-methylnicotinamide. [A12-1] A chimeric receptor described in any one of [A1-1] to [A1-7-2], [A2-1] to [A2-6-2], [A3-1] to [A3-2-3], [A4-1] to [A4-3-1], [A5-1] to [A5-6-1], [A6-1] to [A6-3-2], [A7-1] to [A7-2-2], and [A8-1] to [A8-20], wherein the extracellular binding domain is an extracellular binding domain whose binding activity to the mutant antibody changes depending on the concentration of a target tissue-specific compound. [A12-2] The chimeric receptor according to [A12-1], wherein the target tissue is a cancer tissue. [A12-3] The cancer tissue-specific compound is a cancer cell-specific metabolite, a compound that infiltrates into cancer tissue, The chimeric receptor according to [A12-2] is an immune cell-specific metabolite or a stromal cell-specific metabolite of cancer tissue. [A12-4] Target tissue inflamed tissue The chimeric receptor according to [A12-1], [A12-5] The inflamed tissue-specific compound inflamed tissue The chimeric receptor according to [A12-4], wherein the chimeric receptor is a metabolite specific to immune cells infiltrating into the body, or a metabolite specific to normal cells damaged in inflamed tissue. [A12-6] A chimeric receptor described in any one of [A12-1] to [A12-5], wherein the target tissue-specific metabolite is at least one compound selected from nucleosides having a purine ring structure, amino acids and their metabolites, lipids and their metabolites, primary metabolites of sugar metabolism, and nicotinamide and its metabolites. [A12-7] The target tissue-specific metabolites are adenosine, adenosine triphosphate, iodophosphate, and the like. A chimeric receptor according to any one of [A12-1] to [A12-6], which is at least one compound selected from the group consisting of nicotinic acid, alanine, glutamic acid, aspartic acid, kynurenine, prostaglandin E2, succinic acid, citric acid, and 1-methylnicotinamide. [A13-1] The pharmaceutical composition according to any one of [A10-1] to [A10-39], wherein the mutant antibody is an antibody whose antigen-binding activity changes depending on the concentration of a target tissue-specific compound. [A13-2] The pharmaceutical composition according to [A13-1], wherein the target tissue is cancer tissue. [A13-3] The pharmaceutical composition described in [A13-2], wherein the cancer tissue-specific compound is a cancer cell-specific metabolite, an immune cell-specific metabolite infiltrating cancer tissue, or a stromal cell-specific metabolite in cancer tissue. [A13-4] Target tissue inflamed tissue The pharmaceutical composition according to [A13-1], [A13-5] The inflammatory tissue-specific compound is inflamed tissue The pharmaceutical composition according to [A13-4], wherein the metabolite is a metabolic product specific to immune cells infiltrating into the inflamed tissue, or a metabolic product specific to normal cells damaged in the inflamed tissue. [A13-6] The pharmaceutical composition according to any one of [A13-1] to [A13-5], wherein the target tissue-specific metabolite is at least one compound selected from the group consisting of nucleosides having a purine ring structure, amino acids and their metabolites, lipids and their metabolites, primary metabolites of sugar metabolism, and nicotinamide and its metabolites. [A13-7] The target tissue-specific metabolites are adenosine, adenosine triphosphate, iodophosphate, and the like. The pharmaceutical composition according to any one of [A13-1] to [A13-6], wherein the compound is at least one compound selected from the group consisting of nicotinic acid, alanine, glutamic acid, aspartic acid, kynurenine, prostaglandin E2, succinic acid, citric acid, and 1-methylnicotinamide. [A14-1] A chimeric receptor described in any one of [A1-1] to [A1-7-2], [A2-1] to [A2-6-2], [A3-1] to [A3-2-3], [A4-1] to [A4-3-1], [A5-1] to [A5-6-1], [A6-1] to [A6-3-2], [A7-1] to [A7-2-2], and [A8-1] to [A8-20], wherein the mutant antibody is an antibody whose binding activity to an antigen changes depending on the concentration of a target tissue-specific compound. [A14-2] The chimeric receptor according to [A14-1], wherein the target tissue is a cancer tissue. [A14-3] A chimeric receptor described in [A14-2], wherein the cancer tissue-specific compound is a cancer cell-specific metabolite, an immune cell-specific metabolite infiltrating cancer tissue, or a stromal cell-specific metabolite of cancer tissue. [A14-4] Target tissue inflamed tissue The chimeric receptor according to [A14-1], [A14-5] The inflammatory tissue-specific compound is inflamed tissue The chimeric receptor according to [A14-4], wherein the chimeric receptor is a metabolite specific to immune cells infiltrating into the body, or a metabolite specific to normal cells damaged in inflamed tissue. [A14-6] A chimeric receptor described in any one of [A14-1] to [A14-5], wherein the target tissue-specific metabolite is at least one compound selected from nucleosides having a purine ring structure, amino acids and their metabolites, lipids and their metabolites, primary metabolites of sugar metabolism, and nicotinamide and its metabolites. [A14-7] The target tissue-specific metabolites are adenosine, adenosine triphosphate, iodophosphate, and the like. A chimeric receptor according to any one of [A14-1] to [A14-6], which is at least one compound selected from the group consisting of nicotinic acid, alanine, glutamic acid, aspartic acid, kynurenine, prostaglandin E2, succinic acid, citric acid, and 1-methylnicotinamide. [B1-1] (1) a domain containing an antibody variable region capable of specifically binding to a mutant antibody via a portion containing the mutation; and (2) a domain having binding activity to a molecule expressed on the surface of T cells. a bispecific antibody comprising a domain containing an antibody variable region having the following structure, wherein the domain (1) has a mutation in the CH2 region including at least one amino acid substitution, deletion, addition, or modification; The bispecific antibody is capable of specifically binding to a mutant antibody having the mutation via the portion containing the mutation, but does not specifically bind to an antibody that does not contain the mutation. [B1-2] The bispecific antibody according to [B1-1], wherein the mutated antibody does not increase the occurrence of intercellular cross-linking with other immune cells compared to the corresponding non-mutated antibody. [B1-3] The mutant antibodies have higher FcγI, FcγIIA, and FcγIIB binding than the corresponding non-mutated antibodies. The bispecific antibody according to [B1-1] or [B1-2], which is an antibody having reduced binding activity to either the Fcγ receptor FcγIIIA or FcγIIIB. [B1-3-1] The mutation is at one or more positions selected from the group consisting of 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 264, 265, 266, 267, 269, 270, 295, 296, 297, 298, 299, 300, 325, 327, 328, 329, 330, 331, and 332, as indicated by EU numbering. The bispecific antibody according to any one of [B1-1] to [B1-3], which comprises a mutation at a position (B1-1) whereby the domain (1) can bind to the mutant antibody via the portion comprising the mutation. [B1-3-2] The bispecific antibody according to any one of [B1-1] to [B1-3], wherein the mutation is one or more selected from the group consisting of 234A, 235A, and / or 297A, represented by the position according to EU numbering and the amino acid after the mutation, and wherein the domain (1) can bind to the mutated antibody via the portion containing the mutation. [B1-3-3] The mutation includes one or more mutations selected from the group consisting of 349C, 356C, 366W or S, 368A, and 407V, which are represented by the position and the amino acid after mutation according to EU numbering, The bispecific antibody according to any one of [B1-1] to [B1-3], wherein the domain (1) can bind to the mutant antibody via a portion containing the mutation. [B1-3-4] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. , a combination of: (1) 235R and 239K; (2) 235R and 236R; (3) 235R, 239K and 297A; (4) 235R, 236R and 239K; (5) 252Y and 434Y; (6) 235R, 239K, 252Y and 434Y; (7) 252Y, 434Y and 436V; (8) 235R, 239K, 252Y, 434Y and 436V; (9) 250V, 252Y, 307Q, 308P, 311A, 434Y and 436V; (10) 235R, 239K, 250V, 252Y, 307Q, 308P, 311A, 434Y and 436V The bispecific antibody according to any one of [B1-1] to [B1-3], which contains one or more combinations of mutations selected from the following, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutations. [B1-3-5] A bispecific antibody according to any one of [B1-1] to [B1-3], wherein the mutation is one or more selected from the group consisting of 235, 236, and 239, where the positions are represented by EU numbering, and the mutated antibody binds to the extracellular binding domain via the portion containing the mutation. [B1-4] The binding activity of mutant antibodies to FcγRIa compared with the corresponding non-mutated antibodies The bispecific antibody according to [B1-1], wherein the antibody has enhanced [B1-4-1] Mutations are indicated by EU numbering positions: 234, 235, 236, 2 The bispecific antibody according to [B1-1] or [B1-4], which comprises a mutation at one or more positions selected from the group consisting of 37, 238, 265, 266, 267, 268, 269, 270, 271, 295, 296, 298, 300, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, and 337, and wherein the domain of (1) can bind to the mutant antibody via the portion comprising the mutation. [B1-5] The mutant antibodies have higher FcγI, FcγIIA, and FcγIIB binding than the corresponding non-mutated antibodies. The bispecific antibody according to [B1-1], which is an antibody having enhanced binding activity to either an Fcγ receptor, FcγIIIA, or FcγIIIB. [B1-5-1] The bispecific antibody according to [B1-1] or [B1-5], wherein the mutations are at one or more positions selected from the group consisting of 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 265, 266, 267, 268, 269, 270, 271, 295, 296, 298, 300, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, and 337, as designated by EU numbering, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutations. [B1-5-2] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. , a combination of: (1) 234Y, 235Y, 236W, 268D, 270E and 298A; (2) 234Y, 235Q, 236W, 239M, 268D, 270E, and 298A; (3) 234Y, 235Q, 236W, 239M, 268D, 270E, and 298A; (4) 234Y, 235Y, 236W, 268D, 298A and 327D; (5) 234Y, 235Y, 236W, 239M, 268D, 298A and 327D; (6) 234Y, 235Y, 236W, 239M, 268D, 298A, 327D, 328W and 334L; (7) 326D, 330M and 334E; (8) 270E, 326D, 330M, and 334E; and (9) 270E, 326D, 330K and 334E and the mutations are selected from the combinations of one or more of the above. The bispecific antibody according to [B1-1] or [B1-5], wherein the domain of (I) is capable of binding to a mutant antibody. [B1-5-3] The mutations are represented by the EU numbering position and the mutated amino acid, in the following combinations: (1) 234L, S, F, E, V, D, Q, I, M, T, A, G or H, 235Y or Q, 236W, 239M or I, 268D, and 298A; (2) 234L, S, F, E, V, D, Q, I, M, T, A, G or H, 235Y or Q, 236W, 239M or I, 268D, 298A and 327D; (3) 234F, E, D, S or L, 235Y or Q, 236W, 239M or I, 268D, 298A and 327D; (4) 270E, 326D, 330A, K, M, F, I, Y or H, and 334E; (5) 270E, 326D, 330A, K, M, F, I, Y or H, and 334E; (6) 270E, 326D, 330A, F or K, and 334E; (7) 234L, S, F, E, V, D, Q, I, M, T, A, G or H, 235Y or Q, 236W, 239M or I, 268D, 270E, and 298A and the mutations are selected from the combinations of one or more of the above. The bispecific antibody according to [B1-1] or [B1-5], wherein the domain of (I) is capable of binding to a mutant antibody. [B1-6] The bispecific antibody according to [B1-1], wherein the mutated antibody has maintained or decreased binding activity to both the H-type and R-type genetic polymorphisms of FcγRIIa, and has enhanced binding activity to FcγRIIb, compared to the corresponding unmutated antibody. [B1-6-1] The method according to [B1-1] or [B1-6], wherein the mutation comprises a mutation at one or more positions selected from the group consisting of 233, 234, 237, 238, 239, 267, 268, 296, 271, 323, 326, and 330, as indicated by EU numbering, and the domain (1) can bind to the mutant antibody via the portion comprising the mutation. Bispecific antibodies. [B1-6-2] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. , 238D, 328E, 237W, 267V, 267Q, 268N, 271G, 326M, 239D, 267A, 234W, 237A, 237D, 237E, 237L, 237M, 237Y, 330K, 330R, 233D, 268D, 268E, 326D, 326S, 326T, 323I, 323L, 323M, 296D, 326A, 326N, 330M, and wherein the domain of (1) can bind to the mutant antibody via the portion containing the mutation. [B1-6-3] The following combinations of mutations are indicated by their positions according to EU numbering: (1) 238, 233, 237, 268, 271, 296 and 330; (2) 238, 237, 268, 271, 296 and 330; (3) 238, 233, 237, 268, 271, 296, 330 and 332; (4) 238, 233, 237, 264, 267, 268, 271 and 330; (5) 238, 233, 237, 267, 268, 271, 296, 330 and 332; (6) 238, 237, 267, 268, 271, 296, 330 and 332; (7) 238, 233, 237, 268, 271, 296, 327 and 330; (8) 238, 233, 237, 264, 267, 268 and 271; (9) 238, 233, 237, 264, 267, 268, 271, 296 and 330; (10) 238, 233, 237, 264, 267, 268, 271, 296, 330 and 396; (11) 238, 237, 264, 267, 268, 271 and 330; (12) 238, 237, 264, 267, 268, 271, 296 and 330; (13) 238, 264, 267, 268 and 271; (14) 238, 264, 267, 268, 271 and 296; (15) 238, 237, 267, 268, 271, 296 and 330; (16) 238, 233, 237, 264, 267, 268, 271, 330 and 396; (17) 238, 233, 237, 264, 267, 268, 271, 296, 327, 330 and 396; (18) 238, 233, 237, 264, 267, 268, 271, 272 and 296; (19) 238, 237, 264, 267, 268, 271, 272 and 330; (20) 238, 237, 264, 267, 268, 271, 272, 296 and 330; (21) 238, 233, 264, 267, 268 and 271; (22) 238, 237, 267, 268, 271, 296 and 330; (23) 238, 264, 267, 268, 271, 272 and 296; and (24) 238, 233, 264, 267, 268, 271 and 296 and the mutation is present at one or more positions selected from the combination of The bispecific antibody according to [B1-1] or [B1-6], wherein the domain (1) is capable of binding to a mutant antibody. [B1-6-4] Mutations are indicated by their positions in the EU numbering system, including mutations at 238. and one or more positions selected from 235, 237, 241, 268, 295, 296, 298, 323, 324, and 330, and the mutations reduce the binding activity to all activating FcγRs. The bispecific antibody according to [B1-1] or [B1-6], wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B1-6-5] Mutations are indicated by their positions in the EU numbering system, including mutations at 238. and (1) 241, 268, 296, and 324; (2) 237, 241, 296, and 330; (3) 235, 237, 241, and 296, and the mutations are at one or more combinations selected from the group consisting of The binding activity to all activating FcγRs is reduced, and the mutation The bispecific antibody according to [B1-1] or [B1-6], wherein the domain (1) is capable of binding to a mutant antibody. [B1-6-6] The mutations include mutations at positions 238 and 271, as indicated by EU numbering, and mutations at two or more positions selected from 234, 235, 236, 237, 239, 265, 267, and 297, and the mutations reduce the binding activity to all activating FcγRs. The domain (1) can bind to the mutated antibody via the portion containing the mutation. The bispecific antibody according to [B1-1] or [B1-6], [B1-6-7] The mutations are represented by positions according to EU numbering: (1) 233, 238, 264, 267, 268, and 271; (2) 233, 237, 238, 264, 267, 268, 271, 296, 297, 330, and 396; and (3) any combination selected from the group consisting of 233, 238, 264, 267, 268, 271, and 296. The mutations are present at the combination positions, and the binding activity to all activating FcγRs is enhanced by the mutations. The bispecific antibody according to [B1-1] or [B1-6], wherein the domain (1) is capable of binding to the mutant antibody via the portion containing the mutation. [B1-6-8] The mutation includes 238D, and one or more mutations selected from 235F, 237Q or D, 241M or L, 268P, 295M or V, 296E, H, N or D, 298A or M, 323I, 324N or H, and 330H or Y, which are represented by the position according to EU numbering and the amino acid after the mutation. The mutations reduce the binding activity to all activating FcγRs. The bispecific antibody according to [B1-1] or [B1-6], wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B1-6-9] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. , 238D mutations, and one or more selected from the group consisting of: (1) 241M, 268P, 296E, and 324H; (2) 237Q or D, 241M, 296E, and 330H; (3) 235F, 237Q or D, 241M, and 296E. The mutations reduce the binding activity to all activating FcγRs. The bispecific antibody according to [B1-1] or [B1-6], wherein the domain (1) is capable of binding to the mutant antibody via the portion containing the mutation. [B1-6-10] Mutations are indicated by their positions in EU numbering and the amino acids after the mutation. and one or more mutations selected from 234A, H, N, K or R, 235A, 236Q, 237R or K, 239K, 265K, N, R, S or V, 267K, R or Y, and 297A, and the mutations reduce the binding activity to all activating FcγRs, The bispecific antibody according to [B1-1] or [B1-6], wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B1-6-11] Mutations are indicated by their positions in EU numbering and the amino acids after the mutation. and (1) 233D, 238D, 264I, 267R, 268E, and 271G; (2) 233D, 237D, 238D, 264I, 267A, 268E, 271G, 296D, 297A, 330R, and 396M; and (3) 233D, 238D, 264I, 267R, 268P, 271G, and 296E. and the mutation reduces the binding activity to all activating FcγRs, The bispecific antibody according to [B1-1] or [B1-6], wherein the (1) domain can bind to the mutant antibody via the portion containing the mutation. [B1-6-12] The bispecific antibody according to any one of [B1-6-1] to [B1-6-11], wherein the mutant antibody further has reduced complement binding. [B1-6-13] Mutations are indicated by EU numbering positions: 322, 327, 330 and 331, wherein the mutations reduce binding to complement. The bispecific antibody according to [B1-1] or [B1-2], wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B1-6-14] The mutation includes one or more mutations selected from the group consisting of 322A or E, or 327G, 330S, and 331S, which are represented by the position and the amino acid after mutation according to EU numbering. The bispecific antibody according to [B1-1] or [B1-2], wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B1-6-15] A non-human IgG having an Fc region of a native IgG, wherein the mutation is at one or more positions selected from the group consisting of 238, 271, 327, 330, and 331, as indicated by EU numbering. When compared with the mutant antibody, the mutant antibody maintains its binding activity to FcγRIIb, and the mutation reduces its binding activity to all activating FcγRs. The bispecific antibody according to [B1-1] or [B1-2], wherein the (1) domain is capable of binding to the mutant antibody via a [B1-6-16] Mutations are indicated by their positions in EU numbering and the amino acids after the mutation. and one or more mutations selected from the group consisting of 238D, 271G, 327G, 330S, and 331S, The bispecific antibody according to [B1-1] or [B1-6], wherein the domain (1) is capable of binding to the mutant antibody via a moiety comprising: [B1-6-17] The mutant antibody further comprises a member selected from the group 233D, 237D, 264I, 267A, 268D, or E. wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B1-6-18] Mutations are indicated by their positions in EU numbering and the amino acids after the mutation. (1) 237D, 238D, 268D or E, 271G, 327G, 330S, and and 331S; (2) 233D, 237D, 238D, 268D, 271G, 327G, 330S, and 331S; (3) 238D, 267A, 268E, 271G, 327G, 330S, and 331S; (4) 238D, 264I, 267A, 271G, 327G, 330S, and 331S The bispecific antibody according to [B1-1] or [B1-6], which comprises one or more combinations of mutations selected from the group consisting of: [B1-6-19] Mutations are indicated by EU numbering positions: 233, 238, 264, and a mutation at one or more positions selected from the group consisting of 267, 268, 271, 327, 330, and 331, The bispecific antibody according to [B1-1] or [B1-6], wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B1-6-20] Mutations are designated by their EU numbering positions: (1) 237, 238, 268, 271, 327, 330, and 331; (2) 233, 237, 238, 268, 271, 327, 330, and 331; (3) 238, 267, 268, 271, 327, 330, and 331; (4) 238, 264, 267, 271, 327, 330, and 331. and the mutation is contained in one or more combinations of positions selected from the above, and the mutation is contained in the portion containing the mutation. A bispecific antibody according to [B1-1] or [B1-6], wherein the domain (1) is capable of binding to a mutant antibody. [B1-7] The bispecific antibody according to [B1-1], wherein the mutated antibody has antigen-binding activity that changes depending on ion concentration conditions, compared to the corresponding non-mutated antibody, and has FcRn-binding activity in the neutral pH range, but does not form a heterocomplex containing two FcRn molecules and one activating Fcγ receptor molecule in the neutral pH range. [B1-7-1] The mutation includes a mutation at one or more positions selected from the group consisting of 235, 237, 238, 239, 270, 298, 325 and 329, which are represented by EU numbering, and the mutation The bispecific antibody according to [B1-1] or [B1-7], wherein the domain (1) can bind to the mutant antibody via a moiety comprising [B1-7-2] The bispecific antibody according to [B1-1] or [B1-7], wherein the mutations include one or more mutations selected from the group consisting of 235K or R, 237K or R, 238K or R, 239L or R, 270F, 298G, 325G, or 329K or R, represented by the position and amino acid after the mutation according to EU numbering, and wherein the domain (1) can bind to the mutated antibody via the portion containing the mutation. [B2-1] (1) a domain containing an antibody variable region capable of specifically binding to a mutant antibody via the portion containing the mutation; and (2) a domain having binding activity to a molecule expressed on the surface of T cells. A bispecific antibody comprising a domain comprising an antibody variable region having The domain (1) has at least one amino acid substitution, deletion, addition or deletion in the CH3 region. a bispecific antibody capable of specifically binding to a mutant antibody having a mutation containing the mutation or modification via the portion containing the mutation, and not specifically binding to an antibody not containing the mutation. [B2-2] The bispecific antibody according to [B2-1], wherein the mutated antibody improves the stability, homogeneity, immunogenicity, safety, production efficiency, and / or plasma retention of the mutated antibody compared to the corresponding non-mutated antibody. [B2-3] The mutant antibody has one of the amino acids at positions 446 and 447 in the EU numbering system. The bispecific antibody according to [B2-1] or [B2-2], wherein the antibody is deficient in any one of the above. [B2-3-1] The mutation is represented by the position according to EU numbering, and further represented by 434. The bispecific antibody according to any one of [B2-1] to [B2-3], which comprises a mutation at a position where the domain (1) is located, and which is capable of binding to the mutant antibody via the mutation. [B2-3-2] Mutations are indicated by their positions according to the EU numbering system, and furthermore, 131, 133, The bispecific antibody according to any one of [B2-1] to [B2-3], which contains a mutation at one or more positions selected from the group consisting of 137, 138, 219, 268, 330, 331, 335, 339, 397, and 419, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B2-3-3] The bispecific antibody according to any one of [B2-1] to [B2-3], further comprising a mutation at one or more positions selected from the group consisting of 131, 133, 137, 138, 214, 217, 219, 220, 221, 222, 233, 234, 235, 236, and 409, according to EU numbering, wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B2-4] The bispecific antibody according to [B2-1] or [B2-2], wherein the mutant antibody is an antibody in which mutations have been introduced into amino acid residues at the interface so that two or more amino acid residues forming the interface have the same charge. [B2-4-1] A mutant antibody is an antibody comprising two or more heavy chain CH3 regions, wherein the amino acid residues in the first heavy chain are mutated to have the same charge, and the mutations are located at positions (positions) according to the EU numbering system. The following combinations, denoted by: (1)356 and 439; (2) 357 and 370; and (3) 399 and 409 The bispecific antibody according to [B2-1], [B2-2], or [B2-4], which contains a mutation at one of the positions in one or more combinations selected from the following: [B2-4-2] The mutation is at one or more positions selected from the group consisting of 356, 357, 370, 399, 409, and 439, which are represented by EU numbering, and the mutation is transmitted through the portion containing the mutation. The bispecific antibody according to [B2-1], [B2-2], or [B2-4], wherein the domain (1) is capable of binding to a mutant antibody. [B2-4-3] The mutation further comprises 10 mutations in the heavy chain variable region according to the Kabat numbering system. , 12, 23, 39, 43 and 105 amino acid residues, or from the group of 137, 196, 203, 214, 217, 233, 268, 274, 276 and 297 in EU numbering in the heavy chain constant region. The bispecific antibody according to any one of [B2-4-1] to [B2-4-3], which comprises a mutation at one or more positions selected from the above, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B2-5] The bispecific antibody according to [B2-1] or [B2-2], wherein the mutated antibody is an antibody that promotes heterodimerization of polypeptides under reducing conditions compared to the corresponding non-mutated antibody. [B2-5-1] A mutant antibody is an antibody comprising two or more heavy chain CH3 regions, wherein the first heavy chain amino acid residues are mutated to have the same charge, and the mutations are located at positions according to EU numbering. The following combinations, expressed as: (1) 356 and 439; (2) 357 and 370; (3) 399 and 409; and (4) 399, 409, 356, and 439 The bispecific antibody according to [B2-1], [B2-2], or [B2-5], which contains a mutation at one of the positions in one or more combinations selected from the following, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B2-5-2] The mutation is selected from the group consisting of 397M, F or Y, 392D, E, T, V or I, 356K, 397F or Y, and 439E, represented by the position according to EU numbering and the amino acid after mutation. The bispecific antibody according to [B2-1], [B2-2], or [B2-5], which contains one or more mutations that are mutated in the mutated antibody, and wherein the domain (1) can bind to the mutated antibody via the portion containing the mutation. [B2-5-3] A mutant antibody comprising two or more types of heavy chain CH3 regions, and A bispecific antibody according to [B2-1], [B2-2], [B2-5] or [B2-5-1], wherein at least one amino acid residue at any of positions 349, 351, 354, 356, 394 and 407 in the ring is cysteine, and the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B2-5-4] Either of the positions represented by 226 and / or 229 in the EU numbering system The bispecific antibody according to [B2-1], [B2-2], or [B2-5], which comprises a mutation in one or more of the amino acid sequences or a deletion in the core hinge region, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B2-5-5] The bispecific antibody according to [B2-5-4], wherein the mutant antibody is an antibody in which positions 220 to 225 (EU numbering) are further substituted with YGPP, or positions 219 to 229 (EU numbering) are deleted. [B2-6] A bispecific antibody according to [B2-1] or [B2-2], wherein the mutant antibody comprises a first polypeptide and a second polypeptide that are in contact at their interface, and the first polypeptide has a protrusion at its interface that can be positioned in a gap at the interface of the second polypeptide. [B2-6-1] A bispecific antibody according to [B2-1], [B2-2] or [B2-6], wherein the mutant antibody comprises two or more types of heavy chain CH3 regions, and contains a mutation at one or more positions selected from the group consisting of 366, 394, 405 and 407, EU numbering, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B2-6-2] A mutant antibody comprising two or more types of heavy chain CH3 regions, and In the ring, mutations in the CH3 regions of the first and second heavy chains are shown. The following combinations, represented by the amino acid: (1) the first heavy chain CH3 region is 366Y and the second heavy chain CH3 region is 407T; (2) the first heavy chain CH3 region is 366W and the second heavy chain CH3 region is 497A; (3) the first heavy chain CH3 region is 405A and the second heavy chain CH3 region is 394W; (4) the first heavy chain CH3 region is 407T and the second heavy chain CH3 region is 366Y; (5) the first heavy chain CH3 region is 366Y and 405A, and the second heavy chain CH3 region is 394W and 407T; (6) the first heavy chain CH3 region is 366W and 405W, and the second heavy chain CH3 region is 394S and 407A; (7) the first heavy chain CH3 region is 405W and 407A, and the second heavy chain CH3 region is 366W and 394S; (8) The first heavy chain CH3 region is 405W and the second heavy chain CH3 region is 394S The bispecific antibody according to [B2-1], [B2-2], or [B2-6], which contains one or more combinations of mutations selected from the following, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutations. [B3-1] (1) a domain containing an antibody variable region capable of specifically binding to a mutant antibody via the portion containing the mutation; and (2) a domain having binding activity to a molecule expressed on the surface of T cells. A bispecific antibody comprising a domain comprising an antibody variable region having The domain (1) has at least one amino acid substitution, deletion, addition or deletion in the CH1 region. a bispecific antibody capable of specifically binding to a mutant antibody having a mutation containing the mutation or modification via the portion containing the mutation, and not specifically binding to an antibody not containing the mutation. [B3-2] The bispecific antibody according to [B3-1], wherein the mutated antibody has improved pharmacokinetics and hinge region heterogeneity compared to the corresponding non-mutated antibody. [B3-2-1] The mutation includes a mutation at one or more positions selected from the group consisting of 131, 133, 137, and 138, which are represented by positions according to EU numbering, and the ( The bispecific antibody according to [B3-1] or [B3-2], wherein the domain 1) is capable of binding to the mutant antibody. [B3-2-2] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. The bispecific antibody according to [B3-1] or [B3-2], which contains one or more mutations selected from the group consisting of 131S, 133K, 220S, 137G, 138G, 268Q, 355Q, and 419E, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B3-2-3] The mutation is represented by a position according to EU numbering, and further includes a mutation at one or more positions selected from the group consisting of 220, 268, 330, 331, 339, 355, 419, 446, and 447; The bispecific antibody according to any one of [B3-2-1] to [B3-2-2], wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B4-1] (1) A method for specifically binding to a mutant antibody via the portion containing the mutation. and (2) a domain containing an antibody variable region that binds to a molecule expressed on the surface of T cells. a bispecific antibody comprising a domain containing an antibody variable region that The bispecific antibody, wherein the domain (1) is capable of specifically binding to a mutant antibody having a mutation in the hinge region comprising substitution, deletion, addition, or modification of at least one amino acid, via the portion containing the mutation, but does not specifically bind to an antibody that does not contain the mutation. [B4-2] The mutant antibodies show increased activity against FcγI, FcγIIA, and FcγIIB antibodies compared to the corresponding unmutated antibodies. The bispecific antibody according to [B4-1], which is an antibody having enhanced binding activity to either the Fcγ receptor FcγIIIA or FcγIIIB. [B4-2-1] The bispecific antibody according to [B4-1] or [B4-2], wherein the mutation is at one or more positions selected from the group consisting of 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, and 230, as indicated by EU numbering, and wherein the domain (1) can bind to the mutated antibody via the portion containing the mutation. [B4-2-2] Mutations are indicated by their positions according to the EU numbering system, and also by 231, 232. , 233, 234, 235, 236, 237, 238, 239, 240, 264, 265, 266, 267, 269, 270, 295, 296, 297, 298, 299, 300, 325, 327, 328, 329, 330, 331, and 332. The bispecific antibody according to [B4-2-1], which comprises a mutation at one or more positions, and wherein the domain (1) can bind to the mutant antibody via the portion comprising the mutation. [B4-2-3] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. , 235R, 239K, and 297A, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B4-2-4] Mutations are indicated by their positions according to EU numbering, and are further indicated as follows: 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 249, 250, 251, 252, 254, 255, 256, 257, 258, 260, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 278, 279, 280, 281, 282, 283, 284, 285, 286, 288, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 307, 308, 309, 311, 312, 313, 314, 315, 316, 317, 318, 320, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, The bispecific antibody according to any one of [B4-2-1] to [B4-2-3], which contains a mutation at one or more positions selected from the group consisting of 336, 337, 339, 341, 343, 375, 376, 377, 378, 379, 380, 382, ​​385, 386, 387, 389, 392, 396, 421, 423, 427, 428, 429, 430, 431, 433, 434, 436, 438, 440, and 442, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B4-2-5] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. , 221K or Y, 222F, W, E or Y, 223F, W, E or K, 224F, W, E or Y, 225E, K or W, 227E, G, K or Y, 228E, G, K or Y, 230A, E, G or Y, and wherein the domain of (1) above can bind to the mutant antibody via the portion containing the mutation. [B4-3] The mutant antibodies show increased activity against FcγI, FcγIIA, and FcγIIB antibodies compared to the corresponding unmutated antibodies. The bispecific antibody according to [B4-1], which is an antibody having reduced binding activity to either the Fcγ receptor FcγIIIA or FcγIIIB. [B4-3-1] Mutations are indicated by their EU numbering positions, 220, 226, and 229. The bispecific antibody according to [B4-1] or [B4-3], which contains one or more mutations selected from the group (1) above, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B5-1] (1) An antibody that specifically binds to a mutant antibody via a portion containing the mutation. (2) a domain containing the human variable region, and (3) a domain that has binding activity to a molecule expressed on the surface of T cells 1. A bispecific antibody comprising a domain comprising an antibody variable region, The domain (1) has at least one amino acid substitution or deletion in the CH2 region and the CH3 region. The bispecific antibody is capable of specifically binding to a mutant antibody having a mutation including a deletion, addition, or modification via the portion containing the mutation, but does not specifically bind to an antibody that does not contain the mutation. [B5-2] The bispecific antibody according to [B5-1], wherein the mutated antibody has enhanced FcRn-binding activity at acidic pH compared to the corresponding non-mutated antibody. [B5-2-1] The mutation is at one or more positions selected from the group consisting of 235, 236, 239, 327, 330, 331, 428, 434, 436, 438, and 440, which are represented by EU numbering. The bispecific antibody according to [B5-1] or [B5-2], wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B5-2-2] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. , 235R, 236R, 239K, 327G, 330S, 331S, 428L, 434A, 436T, 438R, and 440E, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B5-2-2-1] The bispecific antibody according to [B5-1] or [B5-2], wherein the mutation is one or more selected from the group consisting of 214, 235, 236, 239, 327, 330, 331, 446, and 447, where the positions are represented by EU numbering, and the mutated antibody binds to the extracellular binding domain via the portion containing the mutation. [B5-2-3] Mutations are indicated by their positions in the EU numbering system: 238, 244, 245, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 260, 262, 265, 270, 272, 279, 283, 285, 286, 288, 293, 303, 305, 307, 308, 309, 311, 312, 314, 316, 317, 318, 332, 339, 340, 341, 343, 356, 360, 362, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, 386, 388, 389, 390, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 44 The bispecific antibody according to [B5-1] or [B5-2], which comprises a mutation at one or more positions selected from the group consisting of 76, 377, 378, 380, 382, ​​385, 386, 387, 388, 389, 400, 413, 415, 423, 424, 427, 428, 430, 431, 433, 434, 435, 436, 438, 439, 440, 442, and 447, and wherein the domain (1) can bind to the mutant antibody via the portion comprising the mutation. [B5-2-4] The mutation is indicated by the position in EU numbering and the amino acid after the mutation. 238L, 244L, 245R, 249P, 250Q or E or 251R, D, E, or L, 252F, S, T, or Y, 254S or T, 255R, G, I, or L, 256A, R, N, D, Q, E, P, or T, 257A, I, M, N, S, or V, 258D, 260S, 262L, 270K, 272L, or R, 279A, D, G, H, M, N, Q, R, S, T, W, or Y, 283A, D, F, G, H, I, K, L, N, P, Q, R, S, T, W, or Y, 285N, 286F, 288N, or P, 293V, 307A, E, Q, or M, 311A, E, I, K, L, M, S, V, or W, 309P, 312A, D, or P, 314A or L, 316K, 317P, 318N, or T, 332F, H, K, L, M, R, S, or W, 339N, T, or W, 341P, 343E, H, K, Q, R, T, or Y, 375R, 376G, I, M, P, T, or V, 377K, 378D, N, or V, 380A, N, S, or T 382F, H, I, K, L, M, N, Q, R, S, T, V, W, or Y, 385A, R, D, G, H, K, S, or T, 386R, D, I, K, M, P, S, or T, 387A, R, H, P, S, or T, 389N, P, or S, 423N, 427N, 428L, M, F, S, or T, 430A, F, G, H, I, K, L, M, N, Q, R, S, T, V, or Y, 431H, or N, 433R, Q, H, I, K, P, or S, 434A, G, H, F, S, W, or Y, 436R, N, H, I, L, K, M, or T, 438K, L, T, or W, 440K, and 442K, 308I, P, or T, The bispecific antibody according to [B5-1] or [B5-2], which contains one or more mutations selected from the following, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B5-3] The bispecific antibody according to [B5-1], wherein the mutated antibody has enhanced FcRn-binding activity at neutral pH compared to the corresponding non-mutated antibody. [B5-3-1] The bispecific antibody according to [B5-1] or [B5-3], wherein the mutations are at one or more positions selected from the group consisting of 248, 250, 252, 254, 255, 256, 257, 258, 265, 286, 289, 297, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 332, 334, 360, 376, 380, 382, ​​384, 385, 386, 387, 389, 424, 428, 433, 434, and 436, as expressed by EU numbering, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutations. [B5-3-2] Mutations are indicated by their EU numbering position and the mutated amino acid: 237M, 248I, 250A, F, I, M, Q, S, V, W or Y, 252F, W or Y, 254T, 255E, 256D, E or Q, 257A, G, I, L, M, N, S, T or Y, 258H, 265A, 286A or E, 289H, 297A, 303A, 305A, 307A, D, F, G, H, I, K, L, M, N, P, Q, R, S, V, W or Y, 308A, F, I, L, M, P, Q or T, 309A, D, E, P or R, 311A, H or I, 312A or H. 314K or R, 315A, D or H, 317A, 332V, 334L, 360H, 376A, 380A, 382A, 384A, 385D or H, 386P, 387E, 389A or S, 424A, 428A, D, F, G, H, I, K, L, N, P, Q, S, T, V, W or Y, and 436H, I, L, V, wherein the domain of (1) can bind to the mutant antibody via the portion containing the mutation. [B5-3-3] The mutation is selected from the group consisting of 238, 250, 252, 254, 255, 258, 286, 307, 308, 309, 311, 315, 428, 433, 434, or 436, represented by EU numbering. The bispecific antibody according to [B5-1] or [B5-3], which comprises a mutation at one or more positions where the mutation is present, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B5-3-4] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. , 238D, 250V, 252Y, 254T, 255L, 256E, 258D or I, 286E, 307Q, 308P, 309E, 311A or H, 315D, 428I, 433A, K, P, R or S, 434Y or W, and 436I, L, V, T or contains one or more mutations selected from the group F, and the (1) The bispecific antibody according to [B5-1] or [B5-3], wherein the domain is capable of binding to a mutant antibody. [B5-4] The bispecific antibody according to [B5-1], wherein the mutated antibody has higher antigen-binding activity at neutral pH than at acidic pH, compared to the corresponding non-mutated antibody. [B5-4-1] Mutations are indicated by EU numbering positions 257, 308, 428, and and 434, and The bispecific antibody according to [B5-1] or [B5-4], wherein the domain (1) is capable of binding to a mutant antibody. [B5-4-2] Mutations are indicated by their position in EU numbering and the amino acid after the mutation. , 257A, 308P, 428L, 434Y, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B5-5] The bispecific antibody according to [B5-1], wherein the mutated antibody has enhanced FcγRIIb binding activity compared to the corresponding non-mutated antibody. [B5-5-1] The bispecific antibody according to [B5-1] or [B5-5], wherein the mutation is at one or more positions selected from the group consisting of 231, 232, 233, 234, 235, 236, 237, 238, 239, 264, 266, 267, 268, 271, 295, 298, 325, 326, 327, 328, 330, 331, 332, 334, and 396, as expressed by EU numbering, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B5-5-2] The mutation includes a mutation at position 236, as indicated by EU numbering, and (1) 231, 232, 233, 234, 235, 237, 238, 239, 264, 266, 267, 268, 271, 295, 298, 325, 326, 327, 328, 330, 331, 332, 334, and 396; (2) 231, 232, 235, 239, 268, 295, 298, 326, 330, and 396; or (3) 268, 295, 326, and 330, and a mutation at one or more of the positions selected from the group consisting of 268, 295, 326, and 330. The bispecific antibody according to [B5-1] or [B5-5], wherein the domain (1) can bind to the mutant antibody via a portion containing the amino acid sequence. [B5-5-3] The bispecific antibody according to [B5-1] or [B5-5], wherein the mutations are at one or more positions selected from the group consisting of 285, 311, 312, 315, 318, 333, 335, 337, 341, 342, 343, 384, 385, 388, 390, 399, 400, 401, 402, 413, 420, 422, and 431, as indicated by EU numbering, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutations. [B5-5-4] The mutations are represented by the EU numbering position and the mutated amino acid, in the following combinations: (1) 231D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y; (2) 232A, D, E, F, G, H, I, K, L, M, N, Q, R, S, T, V, W, or Y; (3) 233D, (4) 234W or Y, (5) 235W, (6) 236A, D, E, H, I, L, M, N, Q, S, T, or V; (7) 237D or Y, (8) 238E, I, M, Q, or Y; (9) 239I, L, N, P, or V; (10) 264I, (11) 266F, (12) 267A, H, or L; (13) 268D or E, (14) 271D, E, or G; (15) 295L, (16) 298L, (17) 325E, F, I, or L; (18) 326T, (19) 327I or N, (20) 328T, (21) 330K, or R, (22) 331E, (23) 332D, (24) 334D, I, M, V, or Y, and (25) 396A, D, E, F, G, H, I, K, L, M, N, Q, R, S, T, V, W, or Y The bispecific antibody according to [B5-1] or [B5-5], which contains one or more mutations selected from the following, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutations. [B5-5-5] Mutations are indicated by their positions according to EU numbering. (1) containing a mutation at one or more positions selected from 234, 238, 250, 264, 267, 307, and 330; (2) 285, 311, 312, 315, 318, 333, 335, 337, 341, 342, 343, 384, 385, 388, 390, Contains mutations at two or more positions selected from 399, 400, 401, 402, 413, 420, 422, and 431 The bispecific antibody according to [B5-1] or [B5-5], wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B5-5-6] The mutations are represented by the EU numbering position and the mutated amino acid, in the following combinations: (1) 234, 238, 250, 264, 307, 311, 330 and 343; (2) 234, 238, 250, 264, 307, 311, 330, or 413; (3) 234, 238, 250, 264, 267, 307, 311, or 343; (4) 234, 238, 250, 264, 267, 307, 311, 330 and 413; (5) 234, 238, 250, 267, 307, 311, 330 and 343; (6) 234, 238, 250, 267, 307, 311, 330 and 413; (7) 234, 238, 250, 307, 311, 330 and 343; (8) 234, 238, 250, 307, 311, 330 and 413; (9) 238, 250, 264, 267, 307, 311, 330 and 343; (10) 238, 250, 264, 267, 307, 311, 330 and 413; (11) 238, 250, 264, 307, 311, 330 and 343; (12) 238, 250, 264, 307, 311, 330 and 413; (13) 238, 250, 267, 307, 311, 330 and 343; (14) 238, 250, 267, 307, 311, 330 and 413; (15) 238, 250, 307, 311, 330 and 343; and (16) 238, 250, 307, 311, 330, and 413 and the mutation is present at one or more positions selected from the combination of A bispecific antibody according to [B5-1] or [B5-5], wherein the domain (1) is capable of binding to a mutant antibody. [B5-6] The bispecific antibody according to [B5-1], wherein the mutant antibody is an antibody whose stability has been improved by a mutation in a loop region of the Fc region. [B5-6-1] The bispecific antibody according to [B5-1] or [B5-6], wherein the mutations are at one or more positions selected from the group consisting of 234, 235, 236, 237, 238, 239, 247, 250, 265, 266, 267, 268, 269, 270, 271, 295, 296, 298, 300, 307, 309, 315, 324, 325, 326, 327, 329, 330, 333, 335, 337, 360, 385, 386, 387, 389, 428, and 433, as expressed by EU numbering, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B6-1] (1) An antibody that specifically binds to a mutant antibody via a portion containing the mutation. (2) a domain containing the human variable region, and (3) a domain that has binding activity to a molecule expressed on the surface of T cells 1. A bispecific antibody comprising a domain comprising an antibody variable region, The bispecific antibody, wherein the domain (1) is capable of specifically binding to a mutant antibody having a mutation in the framework region comprising at least one amino acid substitution, deletion, addition, or modification, but does not specifically bind to an antibody that does not contain the mutation. [B6-2] The mutant antibodies show increased activity against FcγI, FcγIIA, and FcγIIB antibodies compared to the corresponding unmutated antibodies. The bispecific antibody according to [B6-1], which is an antibody having enhanced binding activity to either the Fcγ receptor FcγIIIA or FcγIIIB. [B6-2-1] Mutations are indicated by Kabat numbering positions 10, 12, and 23. 39, 43 and 105, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B6-2-2] Mutations are indicated by Kabat numbering positions 10, 12, and 23. , 39, 43, and 105, or 137, 196, 203, 214, 217, 233, 268, 274, 276, 297, 355, 392, 419, and 435 (EU numbering), wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B6-3] The bispecific antibody according to [B6-1], wherein the mutated antibody is an antibody that can bind to an antigen in a pH-dependent manner compared to the corresponding non-mutated antibody. [B6-3-1] Mutations are indicated by their positions according to the Kabat numbering system. (1) Heavy chains: 1, 3, 5, 8, 10, 12, 13, 15, 16, 18, 19, 23, 25, 26, 39, 41, 42, 43, 44, 46, 68, 71, 72, 73, 75, 76, 77, 81, 82, 82a, 82b, 83, 84, 85, 86, 105, 108, 110, and 112; (2) Light chains 1, 3, 7, 8, 9, 11, 12, 16, 17, 18, 20, 22, 37, 38, 39, 41, 42, 43, 45, 46, 49, 57, 60, 63, 65, 66, 68, 69, 70, 74, 76, 77, 79, 80, 81, 85, 100, 103, 105, 106, 107, and 108 The bispecific antibody according to [B6-1] or [B6-3], wherein the domain (1) can bind to the mutant antibody via a portion containing a mutation at any of the positions represented by: [B6-3-2] Furthermore, mutations are indicated by their positions according to EU numbering: 196, 253, 254, 256, 258, 278, 280, 281, 282, 285, 286, 307, 309, 311, 315, 327, 330, 342, 343, 345, 356, 358, 359, 361, 362, 373, 382, ​​384, 385, 386, 387, 389, 399, 400, 401, 402, 413, 415, 418, 419, 421, 424, 430, 433, From groups 434, and 443 A bispecific antibody according to [B6-1] or [B6-3], which contains a mutation at one or more selected positions, and wherein the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B7-1] (1) An antibody that specifically binds to a mutant antibody via a portion containing the mutation. (2) a domain containing the human variable region, and (3) a domain that has binding activity to a molecule expressed on the surface of T cells 1. A bispecific antibody comprising a domain comprising an antibody variable region, The bispecific antibody, wherein the domain (1) is capable of specifically binding to a mutant antibody having a mutation in the CL region comprising at least one amino acid substitution, deletion, addition, or modification, but does not specifically bind to an antibody that does not contain the mutation. [B7-2] Mutant antibodies inhibit the association of CH1 and CL compared to the corresponding non-mutated antibodies The bispecific antibody described in [B7-1], which is an antibody. [B7-2-1] The mutation comprises a mutation at one or more positions selected from the group consisting of 123, 131, 160, and 180, which are represented by EU numbering, and the ( The bispecific antibody according to [B7-1] or [B7-2], wherein the domain 1) is capable of binding to the mutant antibody. [B7-2-2] The mutations are expressed by their positions according to EU numbering, in the following combinations: (1) amino acid 147 in CH1 and amino acid 180 in CL; (2) amino acid 147 in CH1 and amino acid 131 in CL; (3) amino acid 175 contained in CH1 and amino acid 160 contained in CL; (4) amino acid 213 in CH1 and amino acid 123 in CL; a bispecific antibody according to [B7-1] or [B7-2], which comprises an amino acid mutation at one of the positions selected from the combination of (a) and (b) above, where the amino acid residues in said combination have an electrical charge that repels each other, and the domain (1) above can bind to the mutated antibody via the portion containing the mutation. [B8-1] The molecules expressed on the surface of T cells are CD3, CD2, CD4, CD5, CD6, CD8, CD16, CD28, and CD44. [B1-1]~[B1-7-2], [B2-1]~[B2-6-2] ] and a bispecific antibody according to any one of [B3-1] to [B3-2-3], [B4-1] to [B4-3-1], [B5-1] to [B5-6-1], [B6-1] to [B6-3-2], and [B7-1] to [B7-2-2]. An isolated nucleic acid encoding a bispecific antibody according to any one of [B9-1], [B1-1] to [B1-7-2], [B2-1] to [B2-6-2], [B3-1] to [B3-2-3], [B4-1] to [B4-3-1], [B5-1] to [B5-6-1], [B6-1] to [B6-3-2], [B7-1] to [B7-2-2], and [B8-1]. [B9-2] A vector comprising the isolated nucleic acid described in [B9-1]. [B9-3] The vector according to [B9-2], which can be operably linked to at least one regulatory element for expression of a bispecific antibody. [B9-4] The vector according to [B9-2] or [B9-3], which is selected from the group consisting of DNA, RNA, a plasmid, a lentiviral vector, an adenoviral vector, or a retroviral vector. [B9-5] A cell transformed or transduced with the isolated nucleic acid according to [B9-1] or the vector according to any one of [B9-2] to [B9-4]. [B9-6] The cell according to [B9-5], which is a T lymphocyte, a NK cell, or a macrophage. [B9-7] The cell according to [B9-5] or [B9-6], which is a T lymphocyte in which the expression of an endogenous T cell receptor has been blocked or eliminated. [B9-8] The cells according to any one of [B9-5] to [B9-7], which are cells activated and / or expanded ex vivo. [B9-9] Cells according to any one of [B9-5] to [B9-8], which are genetically modified cells obtained by retroviral transduction, lentiviral transduction, DNA electroporation and RNA electroporation, DNA or RNA transfection, or gene editing. [B9-10] A bispecific antibody according to any one of [B1-1] to [B1-7-2], [B2-1] to [B2-6-2], [B3-1] to [B3-2-3], [B4-1] to [B4-3-1], [B5-1] to [B5-6-1], [B6-1] to [B6-3-2], [B7-1] to [B7-2-2], and [B8-1], wherein the mutant antibody is capable of binding to a tumor antigen. [B10-1] A small amount of nucleotides in the CH1 region, CH2 region, CH3 region, CL region, or framework region 1. A pharmaceutical composition for use in combination with the administration of a mutant antibody having a mutation comprising at least one amino acid substitution, deletion, addition or modification, comprising: the pharmaceutical composition comprises a bispecific antibody; A bispecific antibody comprises (1) a domain containing an antibody variable region that can specifically bind to a mutated antibody via the portion containing the mutation, and (2) a domain that binds to a molecule expressed on the surface of a T cell. The pharmaceutical composition comprises a domain containing an antibody variable region having activity, and does not specifically bind to an antibody that does not contain a mutation. [B10-2] A pharmaceutical composition for use in combination with administration of a bispecific antibody, comprising: The pharmaceutical composition contains at least one nucleotide sequence in the CH1 region, CH2 region, CH3 region, CL region, or framework region. and variant antibodies having mutations comprising substitutions, deletions, additions or modifications of at least one amino acid, A bispecific antibody comprises (1) a domain containing an antibody variable region that can specifically bind to a mutated antibody via the portion containing the mutation, and (2) a domain that binds to a molecule expressed on the surface of a T cell. The pharmaceutical composition comprises a domain containing an antibody variable region having activity, and does not specifically bind to an antibody that does not contain a mutation. [B10-3] A pharmaceutical composition wherein the bispecific antibody is any one of [B1-1] to [B1-7-2], [B2-1] to [B2-6-2], [B3-1] to [B3-2-3], [B4-1] to [B4-3-1], [B5-1] to [B5-6-1], [B6-1] to [B6-3-2], [B7-1] to [B7-2-2], and [B8-1]. [B10-4] The pharmaceutical composition according to any one of [B10-1] to [B10-3], wherein the cell is a cell according to any one of [B9-5] to [B9-9]. [B10-5] A pharmaceutical composition according to any one of [B10-1] to [B10-4], wherein the mutated antibody has a longer half-life in the blood or a higher isoelectric point than the corresponding non-mutated antibody. [B10-6] The mutant antibody has at least one amino acid substitution, deletion, addition, or deletion in the CH2 region. The pharmaceutical composition according to any one of [B10-1] to [B10-5], which has a mutation including a modification, and the domain (1) can bind to the mutant antibody via the portion including the mutation. [B10-7] The method according to [B10-6], wherein the mutation in the CH2 region is at any of positions 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 264, 265, 266, 267, 269, 270, 295, 296, 297, 298, 299, 300, 325, 327, 328, 329, 330, 331, and 332 according to the EU numbering system. Pharmaceutical Composition . [B10-8] The CH2 region of the mutant antibody is The pharmaceutical composition according to [B10-6] or [B10-7], which contains a mutation selected from the group consisting of 234A, 235A, and / or 297A, wherein the mutation positions are represented by EU numbering. [B10-9] The CH2 region of the mutant antibody is (1) 235R and 239K; (2) 235R and 236R; (3) 235R, 239K and 297A; (4) 235R, 236R and 239K; (5) 252Y and 434Y; (6) 235R, 239K, 252Y and 434Y; (7) 252Y, 434Y and 436V; (8) 235R, 239K, 252Y, 434Y and 436V; (9) 250V, 252Y, 307Q, 308P, 311A, 434Y and 436V; (10) A pharmaceutical composition according to either [B10-6] or [B10-7], comprising a combination of mutations selected from the group consisting of 235R, 239K, 250V, 252Y, 307Q, 308P, 311A, 434Y and 436V, wherein the mutation positions are represented by EU numbering. [B10-10] The CH2 region of the mutant antibody comprises the amino acid sequence of SEQ ID NO: 3. The pharmaceutical composition according to any one of [B10-6] to [B10-9]. [B10-11] The mutant antibody has at least one amino acid substitution, deletion, or addition in the CH1 region. or a mutation including a modification, and the domain (1) can bind to the mutant antibody via the portion including the mutation. [B10-12] The pharmaceutical composition according to [B10-11], wherein the mutant antibody is a full-length antibody, Fab, or F(ab')2. [B10-13] CH1 mutations are represented by EU numbering 131, 133, 137, and 138. The pharmaceutical composition according to any one of [B10-10] to [B10-12], wherein the mutation is at any of the positions indicated above. [B10-14] The CH1 region of the mutant antibody is The pharmaceutical composition according to any one of [B10-10] to [B10-13], which contains a mutation selected from the group consisting of 131S, 133K, 220S, 137G and 138G, wherein the mutation positions are represented by EU numbering. [B10-16] The mutant antibody has at least one amino acid substitution, deletion, or addition in the CH3 region. or a mutation including a modification, and the domain (1) can bind to the mutant antibody via the portion including the mutation. [B10-17] CH3 mutations are present in the EU numbering system 349, 351, 354, 356, 357, 366, The pharmaceutical composition according to [B10-16], wherein the mutation is at any of the positions represented by 370, 394, 399, 405, 407, 409, 439, 446 and 447. [B10-18] The CH3 region of the mutant antibody is 397M, F or Y, 392D, E, T, V, or I, 356K, 397F or Y, 439E, 366Y, 366W, The mutations are selected from the group consisting of 394S, 394W, 405A, 405W, 407T, and 407A, and the mutations at the positions The pharmaceutical composition according to [B10-16] or [B10-17], wherein the positions are represented by EU numbering. [B10-19] The CH3 region of the mutant antibody is (1)356 and 439; (2) 357 and 370; (3) 399 and 409; and (4) 399, 409, 356, and 439 The pharmaceutical composition according to [B10-16] or [B10-17], which comprises a mutation at one of the positions of a combination selected from the group consisting of: [B10-20] The mutant antibody lacks GK at the end of the CH3 region, [B10-16]~[ B10-19]. [B10-21] A pharmaceutical composition according to any one of [B10-1] to [B10-5], wherein the mutant antibody has a mutation in the CL region that includes at least one amino acid substitution, deletion, addition or modification, and the extracellular binding domain is capable of binding to the mutant antibody via the portion containing the mutation. [B10-22] The pharmaceutical composition according to [B10-21], wherein the mutant antibody is a full-length antibody, Fab, or F(ab')2. [B10-23] The pharmaceutical composition according to [B10-21] or [B10-22], wherein the mutation in the CL region is at any of positions 123, 131, 160, and 180 according to EU numbering. [B10-24] A pharmaceutical composition described in any of [B10-1] to [B10-5], wherein the mutant antibody has a mutation in the CH2 and CH3 regions that includes at least one amino acid substitution, deletion, addition or modification, and the extracellular binding domain can bind to the mutant antibody via the portion containing the mutation. [B10-25] The CH2 and CH3 regions of the mutant antibody are 397M, F or Y, 392D, E, T, V, or or a mutation selected from the group consisting of I, 356K, 397F or Y, 439E, 366Y, 366W, 394S, 394W, 405A, 405W, 407T, and 407A, wherein the mutation positions are represented by EU numbering. [B10-26] A pharmaceutical composition described in any of [B10-1] to [B10-5], wherein the mutant antibody has a mutation in the framework region that includes at least one amino acid substitution, deletion, addition or modification, and the domain (1) can bind to the mutant antibody via the portion containing the mutation. [B10-27] Mutations in the framework region are indicated by their positions according to the Kabat numbering system. The pharmaceutical composition according to [B10-26], wherein the mutation is at any of positions 10, 12, 23, 39, 43 and 105. [B10-28] The mutant antibody has a mutation in the hinge region, and the mutation position is any of 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, and 230 in the EU numbering system. The pharmaceutical composition according to any one of [B10-1] to [B10-27]. [B10-29] The hinge region of the mutant antibody is The pharmaceutical composition according to any one of [B10-1] to [B10-28], which contains any of the mutations represented by 221K or Y, 222F, W, E or Y, 223F, W, E or K, 224F, W, E or Y, 225E, K or W, 227E, G, K or Y, 228E, G, K or Y, and 230A, E, G or Y. [B10-30] The pharmaceutical composition according to any one of [B10-1] to [B10-29], wherein the mutant antibody further comprises a second mutation other than the mutation involved in binding to the bispecific antibody. [B10-31] A pharmaceutical composition described in [B10-30], in which the mutant antibody having the second mutation has an extended half-life in the blood or a higher isoelectric point compared to a corresponding antibody not having the mutation. [B10-32] A pharmaceutical composition according to any one of [B10-1] to [B10-31] for use in treatment or prevention of T lymphocyte or NK cell antibody-dependent cellular cytotoxicity (ADCC) or macrophage antibody-dependent cellular cytotoxicity (ADCP) in a subject. [B10-33] The pharmaceutical composition according to any one of [B10-1] to [B10-32], wherein the mutant antibody is capable of binding to a tumor antigen. [B10-34] The pharmaceutical composition according to any one of [B10-1] to [B10-33], for use in the treatment or prevention of cancer. [B10-35] The pharmaceutical composition according to [B10-34], wherein the cancer is selected from the group consisting of carcinoma, lymphoma, sarcoma, blastoma, and leukemia. [B10-36] Cancers include B-cell lineage acute lymphoblastic leukemia, B-cell chronic lymphocytic leukemia, B-cell non-Hodgkin's lymphoma, breast cancer, gastric cancer, neuroblastoma, osteosarcoma, lung cancer, melanoma, and pre- The pharmaceutical composition according to [B10-35], wherein the cancer is selected from the group consisting of prostate cancer, colon cancer, renal cell carcinoma, ovarian cancer, rhabdomyosarcoma, leukemia, and Hodgkin's lymphoma. [B11-1] The pharmaceutical composition according to any one of [B10-1] to [B10-31], wherein the domain (1) of the bispecific antibody is the domain (1) whose binding activity to the mutant antibody changes depending on the concentration of a target tissue-specific compound. [B11-2] The pharmaceutical composition according to [B11-1], wherein the target tissue is cancer tissue. [B11-3] The pharmaceutical composition according to [B11-2], wherein the cancer tissue-specific compound is a cancer cell-specific metabolite, an immune cell-specific metabolite infiltrating cancer tissue, or a stromal cell-specific metabolite in cancer tissue. [B11-4] Target tissue inflamed tissue The pharmaceutical composition according to [B11-1], [B11-5] The inflamed tissue-specific compound inflamed tissue The pharmaceutical composition according to [B11-4], wherein the metabolite is a metabolic product specific to immune cells infiltrating into the inflamed tissue, or a metabolic product specific to normal cells damaged in the inflamed tissue. [B11-6] The target tissue-specific metabolite is at least one compound selected from the group consisting of nucleosides having a purine ring structure, amino acids and their metabolites, lipids and their metabolites, primary metabolites of sugar metabolism, and nicotinamide and its metabolites [B11-1] to [B11 -5] The pharmaceutical composition according to any one of the preceding claims. [B11-7] The target tissue-specific metabolites are adenosine, adenosine triphosphate, iodophosphate, and the like. The pharmaceutical composition according to any one of [B11-1] to [B11-6], wherein the compound is at least one compound selected from the group consisting of nicotinic acid, alanine, glutamic acid, aspartic acid, kynurenine, prostaglandin E2, succinic acid, citric acid, and 1-methylnicotinamide. [B12-1] A bispecific antibody according to any one of [B1-1] to [B1-7-2], [B2-1] to [B2-6-2], [B3-1] to [B3-2-3], [B4-1] to [B4-3-1], [B5-1] to [B5-6-1], [B6-1] to [B6-3-2], [B7-1] to [B7-2-2], and [B8-1], wherein the domain (1) of the bispecific antibody is a domain (1) whose binding activity to a mutant antibody changes depending on the concentration of a target tissue-specific compound. [B12-2] The bispecific antibody according to [B12-1], wherein the target tissue is a cancer tissue. [B12-3] The bispecific antibody according to [B12-2], wherein the cancer tissue-specific compound is a cancer cell-specific metabolite, a metabolite specific to immune cells infiltrating cancer tissue, or a metabolite specific to stromal cells of cancer tissue. [B12-4] Target tissue inflamed tissue The bispecific antibody according to [B12-1], [B12-5] The inflamed tissue-specific compound inflamed tissue the bispecific antibody according to [B12-4], wherein the metabolic product is a metabolic product specific to immune cells infiltrating into the body, or a metabolic product specific to normal cells damaged in inflamed tissue. [B12-6] The bispecific antibody according to any one of [B12-1] to [B12-5], wherein the target tissue-specific metabolite is at least one compound selected from the group consisting of nucleosides having a purine ring structure, amino acids and their metabolites, lipids and their metabolites, primary metabolites of sugar metabolism, and nicotinamide and its metabolites. [B12-7] The target tissue-specific metabolites are adenosine, adenosine triphosphate, iodophosphate, and the like. The bispecific antibody according to any one of [B12-1] to [B12-6], wherein the amino acid residue is at least one compound selected from the group consisting of nicotinic acid, alanine, glutamic acid, aspartic acid, kynurenine, prostaglandin E2, succinic acid, citric acid, and 1-methylnicotinamide. [B13-1] The pharmaceutical composition according to any one of [B10-1] to [B10-31], wherein the mutant antibody is an antibody whose antigen-binding activity changes depending on the concentration of a target tissue-specific compound. [B13-2] The pharmaceutical composition according to [B13-1], wherein the target tissue is cancer tissue. [B13-3] The pharmaceutical composition according to [B13-2], wherein the cancer tissue-specific compound is a cancer cell-specific metabolite, an immune cell-specific metabolite infiltrating cancer tissue, or a stromal cell-specific metabolite of cancer tissue. [B13-4] Target tissue inflamed tissue The pharmaceutical composition according to [B13-1], [B13-5] The inflamed tissue-specific compound inflamed tissue The pharmaceutical composition according to [B13-4], wherein the metabolite is a metabolic product specific to immune cells infiltrating into the inflamed tissue, or a metabolic product specific to normal cells damaged in the inflamed tissue. [B13-6] The pharmaceutical composition according to any one of [B13-1] to [B13-5], wherein the target tissue-specific metabolite is at least one compound selected from the group consisting of nucleosides having a purine ring structure, amino acids and their metabolites, lipids and their metabolites, primary metabolites of sugar metabolism, and nicotinamide and its metabolites. [B13-7] The target tissue-specific metabolites are adenosine, adenosine triphosphate, iodo ... The pharmaceutical composition according to any one of [B13-1] to [B13-6], wherein the compound is at least one compound selected from the group consisting of nicotinic acid, alanine, glutamic acid, aspartic acid, kynurenine, prostaglandin E2, succinic acid, citric acid, and 1-methylnicotinamide. [B14-1] Mutant antibodies are antibodies whose binding activity to antigens changes depending on the concentration of target tissue-specific compounds, [B1-1] to [B1-7-2], [B2-1] to [B2-6-2], [B3-1] to [B3-2-3], [B4-1] to [B4-3-1], [B5-1] to [B5-6-1], [B6-1] to [B6-3-2], [B7-1] to [B7- 2-2] and [B8-1]. [B14-2] The bispecific antibody according to [B14-1], wherein the target tissue is a cancer tissue. [B14-3] The bispecific antibody according to [B14-2], wherein the cancer tissue-specific compound is a cancer cell-specific metabolite, a metabolite specific to immune cells infiltrating cancer tissue, or a metabolite specific to stromal cells of cancer tissue. [B14-4] Target tissue inflamed tissue The bispecific antibody according to [B14-1], [B14-5] The inflamed tissue-specific compound inflamed tissue a metabolite specific to immune cells infiltrating into the body, or a metabolite specific to normal cells damaged in inflamed tissues. [B14-6] The bispecific antibody according to any one of [B14-1] to [B14-5], wherein the target tissue-specific metabolite is at least one compound selected from the group consisting of nucleosides having a purine ring structure, amino acids and their metabolites, lipids and their metabolites, primary metabolites of sugar metabolism, and nicotinamide and its metabolites. [B14-7] The target tissue-specific metabolites are adenosine, adenosine triphosphate, iodophosphate, and the like. The bispecific antibody according to any one of [B14-1] to [B14-6], wherein the amino acid residue is at least one compound selected from the group consisting of nicotinic acid, alanine, glutamic acid, aspartic acid, kynurenine, prostaglandin E2, succinic acid, citric acid, and 1-methylnicotinamide. [C1-1] A method for treating a subject in need of treatment, comprising: At least one in the CH1 region, CH2 region, CH3 region, CL region, or framework region administering to a subject a therapeutically effective amount of a mutant antibody having mutations including amino acid substitutions, deletions, additions or modifications, and administering to a subject a therapeutically effective amount of cells expressing a chimeric receptor; the extracellular binding domain is capable of binding to the extracellular binding domain of the chimeric receptor via the portion of the mutant antibody comprising the mutation; The method, wherein the extracellular binding domain does not specifically bind to an antibody that does not contain the mutation. The method according to [C1-1], wherein the pharmaceutical composition according to any one of [C1-2] and [A10-1] to [A10-39] is administered to a subject. [C1-3] A method for treating a subject in need of treatment, comprising: At least one in the CH1 region, CH2 region, CH3 region, CL region, or framework region administering to a subject a therapeutically effective amount of a mutant antibody having mutations that include amino acid substitutions, deletions, additions, or modifications, and administering to a subject a therapeutically effective amount of a bispecific antibody; A bispecific antibody comprises (1) a domain containing an antibody variable region that can specifically bind to a mutated antibody via the portion containing the mutation, and (2) a domain that binds to a molecule expressed on the surface of a T cell. The method according to any one of claims 1 to 4, wherein the domain comprises an antibody variable region having activity and does not specifically bind to an antibody that does not contain the mutation. The method according to [C1-3], wherein the pharmaceutical composition according to any one of [C1-4] and [B10-1] to [B10-36] is administered to a subject. [C1-5] The method according to any one of [C1-1] to [C1-4] for use in the treatment or prevention of cancer. [C1-5] The method according to [C1-4], wherein the cancer is selected from the group consisting of carcinoma, lymphoma, sarcoma, blastoma, and leukemia. [C1-6] The method according to [C1-4], wherein the cancer is selected from the group consisting of B-cell lineage acute lymphoblastic leukemia, B-cell chronic lymphocytic leukemia, B-cell non-Hodgkin's lymphoma), breast cancer, gastric cancer, neuroblastoma, osteosarcoma, lung cancer, melanoma, prostate cancer, colon cancer, renal cell carcinoma, ovarian cancer, rhabdomyosarcoma, leukemia, and Hodgkin's lymphoma. [C1-7] The method according to [C1-1], wherein the pharmaceutical composition according to any one of [A11-1] to [A11-7] and [A13-1] to [A13-7] is administered to a subject. The method according to [C1-3], wherein the pharmaceutical composition according to any one of [C1-8], [B11-1] to [B11-7] and [B13-1] to [B13-7] is administered to a subject. [C1-9] For use in the treatment or prevention of cancer, [C1-7] or [C1 -8]. [C1-10] The method according to [C1-9], wherein the cancer is selected from the group consisting of carcinoma, lymphoma, sarcoma, blastoma, and leukemia. [C1-11] The method according to [C1-9], wherein the cancer is selected from the group consisting of B-cell lineage acute lymphoblastic leukemia, B-cell chronic lymphocytic leukemia, B-cell non-Hodgkin's lymphoma), breast cancer, gastric cancer, neuroblastoma, osteosarcoma, lung cancer, melanoma, prostate cancer, colon cancer, renal cell carcinoma, ovarian cancer, rhabdomyosarcoma, leukemia, and Hodgkin's lymphoma. [Brief explanation of the drawings]

[0012] [Figure 1] Figure 1 shows the format of a generic TRAB using an antibody that specifically binds to a modified Fc, and a generic CAR-T having an extracellular binding domain that specifically binds to a modified Fc. X indicates a modification that does not bind to Fc gamma R, as an example of a modified Fc. [Figure 2] FIG. 2 is a graph showing the results of a binding affinity test of the prepared antibodies to antigens. [Figure 3-1] Figure 3-1 is a graph showing the results of an evaluation test of T cell activation by generic TRAB that binds to silent Fc antibodies. The horizontal axis represents the concentration of generic TRAB, and the vertical axis represents the luminescence intensity of luciferase. [Figure 3-2] 3-2 is a graph showing the results of an evaluation test of T cell activation by generic TRAB that binds to deltaGK-Fc antibody. The horizontal axis represents the concentration of generic TRAB, and the vertical axis represents the luminescence intensity of luciferase. [Figure 4] FIG. 4 is a schematic diagram showing the vector construct and the order of components arranged in frame from the 5′ end to the 3′ end. [Figure 5-1] Figure 5-1 is a graph showing the results of an in vitro cytotoxicity test, showing the percentage of remaining cancer cells 48 hours after mixing GPC3-negative cancer cells SK-Hep1 with CAR-T cells. Each data point is shown as the mean ± SD for n=3. [Figure 5-2]Figure 5-2 is a graph showing the results of an in vitro cytotoxicity test, showing the percentage of remaining cancer cells 48 hours after mixing GPC3-positive cancer cells SK-Pca60 with CAR-T cells. Each data point is shown as the mean ± SD for n=3. [Figure 6] 6 is a graph showing the results of a test to confirm antitumor effect in mice. The horizontal axis shows the number of days since the first administration of the primary antibody, with the day being set as 0. DETAILED DESCRIPTION OF THE INVENTION

[0013] Other features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples indicating preferred embodiments of the present disclosure are given by way of illustration only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description. Embodiments of the present disclosure will now be described with reference to the drawings.

[0014] The terms "substantially," "about," or "approximately" refer to a reasonable amount of deviation from the modified word that does not significantly alter the final result, i.e., within an acceptable error range for a particular value as determined by one of ordinary skill in the art. For example, "about" can refer to an acceptable standard deviation according to practice in the art. Alternatively, "about" can mean up to ±20%, preferably up to ±10%, more preferably up to ±5%, and even more preferably up to ±1% of a value. Alternatively, particularly in biological systems or processes, the term can mean within an order of magnitude, preferably within two-fold, of a value. When a particular value is described in the specification and claims, unless otherwise specified, the term "about" is implied and, in this context, means within an acceptable error range for the particular value.

[0015] When used in the English translation of this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used within its meaning, including "and / or," unless the content clearly dictates otherwise.

[0016] In this disclosure, the recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5). It should also be understood that all numbers and fractions may be modified by the term "about." However, where it is clear that the numbers recited in a numerical range refer to integers, the numerical range should be interpreted as a definitive recitation of the integers subsumed within the range. In such cases, for example, 1 to 5, or 1 to 5, should be interpreted as a definitive recitation of 1, 2, 3, 4, and 5.

[0017] Furthermore, definitions and embodiments described in a particular section are intended to apply to other embodiments described herein that are described as preferred, as would be understood by one skilled in the art. For example, in the following paragraphs, various aspects of the present disclosure are defined in more detail. Each aspect so defined may be combined with any one or more other aspects, unless expressly stated otherwise. In particular, any feature indicated as being preferred or advantageous may be combined with any one or more other features indicated as being preferred or advantageous.

[0018] The term "chimeric receptor" refers to a recombinant polypeptide that contains at least an extracellular binding domain, a transmembrane domain, and an intracellular signaling domain, which, when expressed in an immune effector cell, confers specificity for a target cell, e.g., a cancer cell, and intracellular signal production. The term "chimeric antigen receptor" or "CAR" refers to a chimeric receptor in which the extracellular binding domain binds to an antigen. The term "extracellular binding domain" refers to any proteinaceous molecule or a portion thereof that can specifically bind to a molecule such as a predetermined antigen, and includes, for example, a single-chain antibody (scFv) in which the light chain (VL) and heavy chain (VH) of the variable region of a monoclonal antibody specific to a tumor antigen or the like are linked in tandem. The extracellular binding domain can also be referred to as an extracellular recognition domain. The term "transmembrane domain" includes a polypeptide that is located between the extracellular binding domain and the intracellular signaling domain and has the function of spanning a cell membrane. The term "intracellular signaling domain" refers to any oligopeptide or polypeptide domain known to function in transmitting signals that cause the activation or inhibition of biological processes within a cell, for example, the activation of immune cells such as T cells or NK cells, and includes a "stimulatory molecule signaling domain" derived from at least one T cell stimulatory molecule, as described below, and a "costimulatory molecule signaling domain" derived from at least one T cell costimulatory molecule, as described below. In the present disclosure, antibodies with mutations in the IgG1, IgG2, IgG3, or IgG4 sequence at sites other than the antigen recognition site may be referred to as "adapter antibodies" or "primary antibodies." Furthermore, the extracellular binding domain of a chimeric receptor or a T cell redirecting antibody that recognizes the mutated site of an adapter antibody may be referred to as a "secondary antibody."

[0019] In one embodiment, the extracellular binding domain and the intracellular signaling domain may comprise an extracellular hinge domain and a transmembrane domain. The term "extracellular hinge domain" refers to a domain that connects the extracellular binding domain and the transmembrane domain. The extracellular hinge domain is not particularly limited as long as it can connect the extracellular binding domain and the transmembrane domain. It may be derived from a natural protein or may be artificially designed. The extracellular hinge domain may be composed of, for example, approximately 10 to 300 amino acids, preferably approximately 20 to 100 amino acids. It is preferable that the extracellular hinge domain does not interfere with the binding ability of the extracellular binding domain to the Fc region of the Fc region variant antibody of the present disclosure and does not interfere with signal transduction via the intracellular signaling domain. The term "transmembrane domain" is not particularly limited as long as it is a polypeptide located between the extracellular binding domain and the intracellular signaling domain and has the function of penetrating the cell membrane. The transmembrane domain may be derived from a natural protein or may be artificially designed. Transmembrane domains derived from natural proteins can be obtained from any membrane-bound or transmembrane protein.

[0020] In one embodiment, examples of the extracellular hinge domain include the extracellular hinge domains of CD8 alpha, CD8 beta, CD28, CD4, NKp30, NKp44, NKp46, etc. Alternatively, the hinge region of an immunoglobulin (e.g., IgG4, etc.) may be used.

[0021] In one embodiment, proteins from which the transmembrane domain is derived include, for example, the alpha and beta chains of the T cell receptor, CD3 zeta, CD28, CD3 epsilon, CD45, CD4, CD5, CD8 alpha, CD8 beta, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, ICOS, CD154, GITR, NKp30, NKp44, and NKp46.

[0022] In one embodiment, the chimeric receptor is a molecule comprising the domains defined below. In one embodiment, the chimeric receptor comprises a chimeric fusion protein comprising an extracellular binding domain, an extracellular hinge domain, a transmembrane domain, and an intracellular signaling domain comprising a stimulatory molecule signaling domain derived from a stimulatory molecule. In one embodiment, the chimeric receptor comprises a chimeric fusion protein comprising an extracellular binding domain, an extracellular hinge domain, a transmembrane domain, and an intracellular signaling domain comprising a costimulatory molecule signaling domain derived from a costimulatory molecule and a functional signaling domain derived from a stimulatory molecule. In one embodiment, the chimeric receptor comprises a chimeric fusion protein comprising an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain comprising two functional signaling domains derived from one or more costimulatory molecules and a functional signaling domain derived from a stimulatory molecule. In one embodiment, the chimeric receptor comprises a chimeric fusion protein comprising an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain comprising at least two costimulatory molecule signaling domains derived from one or more costimulatory molecules, a stimulatory molecule signaling domain derived from a stimulatory molecule, and other functional domains and / or motifs. In one embodiment, the chimeric receptors described herein can be used as chimeric antigen receptors (CARs).

[0023] In one embodiment, the chimeric receptor contains an additional leader sequence at the amino terminus (N-terminus) of the chimeric receptor fusion protein. In one embodiment, the chimeric receptor further comprises a leader sequence at the N-terminus of the extracellular antigen-recognition domain, wherein the leader sequence may be cleaved from the antigen-recognition domain (e.g., scFV) during cellular processing and localization of the chimeric receptor to the cell membrane.

[0024] As used in this disclosure, "domain" refers to a region of a polypeptide that, for example, folds into a particular structure and / or has a particular function independently of other regions. A domain can be, for example, the cytoplasmic portion of a molecule or a portion thereof. As used in this disclosure, the "cytoplasmic domain" of a molecule refers to the full-length cytoplasmic domain or a portion thereof that transmits an intracellular signal when activated.

[0025] The term "scFv" refers to a fusion protein comprising at least one antibody fragment comprising a light chain variable region and at least one antibody fragment comprising a heavy chain variable region. In one embodiment, an scFv refers to a fusion protein in which the light chain variable region and the heavy chain variable region are contiguously linked, e.g., via a synthetic linker, e.g., a short, flexible polypeptide linker, such that the fusion protein can be expressed as a single polypeptide chain, yet the scFv retains the specificity of the antibody from which it was derived. Unless otherwise specified, in the present disclosure, an scFv may have the light chain variable region (VL) and the heavy chain variable region (VH) in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide, the scFv may comprise a VL-linker-VH or a VH-linker-VL. Various methods for preparing scFvs are known, including those described in U.S. Pat. No. 4,694,778, Science, vol. 242, pp. 423-442 (1988), Nature, vol. 334, p. 54454 (1989), and Science, vol. 242, pp. 1038-1041 (1988).

[0026] The term "flexible polypeptide linker" or "linker," when used in reference to an scFv, refers to a peptide linker composed of amino acids such as glycine and / or serine residues, used alone or in combination, to link the variable heavy and variable light chain regions together. In one embodiment, the flexible polypeptide linker is a Gly / Ser linker, having the amino acid sequence (Gly-Gly-Gly-Ser). nwherein n is an integer equal to or greater than 1. For example, n=1, n=2, n=3, n=4, n=5, n=6, n=7, n=8, n=9, and n=10. In one embodiment, flexible polypeptide linkers include, but are not limited to, (Gly4Ser)5, (Gly4Ser)4, or (Gly4Ser)3. In another embodiment, the linker comprises multiple repeats of (Gly2Ser), (GlySer), or (Gly3Ser). Linkers described in WO2012 / 138475, incorporated herein by reference, are also encompassed within the scope of the present disclosure.

[0027] The term "stimulation" refers to a primary response induced by the binding of a stimulatory molecule (e.g., a TCR / CD3 complex or a CAR) with its cognate ligand (or tumor antigen in the case of a CAR), thereby mediating a signaling event, such as, but not limited to, signaling through the TCR / CD3 complex or through an appropriate NK receptor or signaling domain of the CAR. Stimulation may also mediate altered expression of certain molecules.

[0028] The term "stimulatory molecule" refers to a molecule expressed by an immune cell, e.g., a T cell, NK cell, or B cell, that provides a cytoplasmic signaling sequence that regulates immune cell activation in a stimulatory manner with respect to at least some aspects of an immune cell signaling pathway. In one embodiment, the signal is a primary signal initiated, e.g., by binding of the TCR / CD3 complex to a peptide-presenting MHC molecule, which results in mediation of T cell responses, including, but not limited to, proliferation, activation, differentiation, and allogeneic responses. The primary cytoplasmic signaling sequence (also referred to as a "primary signaling domain") that acts in a stimulatory manner may contain a signaling motif, known as an immunoreceptor tyrosine-based activation motif or ITAM. Examples of ITAMs containing cytoplasmic signaling sequences that have particular use in the present disclosure include, but are not limited to, those derived from CD3 zeta, common FcR gamma (FCER1G), Fc gamma RIIa, FcR beta (Fc epsilon R1b), CD3 gamma, CD3 delta, CD3 epsilon, CD22, CD79a, CD79b, CD278 ("ICOS"), Fc epsilon RI, CD66d, CD32, DAP10, DAP12, CLEC2, CLEC7A (Dectin1), CLEC9A, EZRIN, RADIXIN, and MOESIN. In certain chimeric receptors of the present disclosure, the intracellular signaling domain in any one or more chimeric receptors of the present disclosure comprises an intracellular signaling sequence, e.g., the primary signaling sequence of CD3-zeta.

[0029] The term "CD3 zeta," as used in this disclosure, refers to the cluster of differentiation 3 (CD3) T-cell coreceptor of all mammalian species, preferably humans. In mammals, CD3 comprises the CD3 zeta chain, the CD3 delta chain, and two CD3 epsilon chains. The CD3 zeta chain (e.g., NCBI RefSeq: NP_932170.1) comprises an intracellular signaling domain that can be used to engineer chimeric receptors. In certain chimeric receptors of this disclosure, the primary signaling sequence of CD3 zeta is the full-length or partial cytoplasmic region sequence (nucleotide sequence 299-634) of Genbank NM000734.3, or equivalent residues from non-human species, such as mice, rodents, monkeys, apes, and the like.

[0030] In one embodiment, the intracellular signaling domain may comprise the cytoplasmic domain of an interleukin receptor chain.

[0031] In one embodiment, a chimeric receptor is disclosed comprising an intracellular segment comprising: i) an extracellular domain capable of binding to a predetermined antigen; ii) a transmembrane domain; and iii) one or more intracellular signaling domains selected from a cytoplasmic costimulatory domain and / or the cytoplasmic domain of an interleukin receptor chain; and a CD3 zeta intracellular signaling domain comprising an exogenous STAT3-associated motif, wherein the intracellular segment comprises an endogenous or exogenous JAK-binding motif and a STAT5-associated motif. In one embodiment, these domains are optionally fused directly or indirectly in the above order, starting from the N-terminus. In one embodiment, these domains within the intracellular segment are fused in the reverse order.

[0032] The term "signaling domain" refers to a functional portion of a protein that acts by transmitting intracellular signals to regulate cellular activity through defined signaling pathways by generating second messengers or functioning as an effector in response to such messengers.

[0033] As used in the present disclosure, the term "intracellular signaling domain" refers to the intracellular portion of a molecule. The intracellular signaling domain can generate a signal that promotes the immune effector function of a cell containing a chimeric receptor such as a CAR, e.g., a CART cell. Examples of immune effector functions, for example, in a CART cell, include cytolytic activity and helper activity, such as cytokine secretion. In embodiments, the intracellular signaling domain is a portion of a protein that transmits an effector function signal and allows the cell to perform a specialized function. While the entire intracellular signaling domain may be employed, in many cases, it is not necessary to use the entire chain. To the extent that a truncated portion of the intracellular signaling domain is used, such a truncated portion can be used in place of the intact chain as long as it transmits the effector function signal. Thus, the term intracellular signaling domain is meant to encompass any truncated portion of the intracellular signaling domain sufficient to transmit the effector function signal.

[0034] In some embodiments, the intracellular signaling domain may comprise a primary intracellular signaling domain. Exemplary primary intracellular signaling domains include those derived from molecules involved in primary stimulation or antigen-dependent stimulation. In some embodiments, the intracellular signaling domain may comprise a costimulatory intracellular domain. Exemplary costimulatory intracellular signaling domains include those derived from molecules involved in costimulatory signals or antigen-independent stimulation. For example, in the case of CART, the primary intracellular signaling domain may comprise a cytoplasmic sequence of a T cell receptor, and the costimulatory intracellular signaling domain may comprise a cytoplasmic sequence from a coreceptor or costimulatory molecule.

[0035] The term "costimulatory molecule" refers to the cognate binding partner on a T cell that specifically binds to a costimulatory ligand and thereby mediates a costimulatory response by the T cell, such as, but not limited to, proliferation (secondary signal). Costimulatory molecules are cell surface molecules other than antigen receptors or their ligands that contribute to an efficient immune response. The term "costimulatory intracellular signaling domain" refers to the intracellular portion of a costimulatory molecule. The intracellular signaling domain may comprise the entire intracellular portion, or the entire native intracellular signaling domain of the molecule from which it is derived, or a functional fragment or derivative thereof.Costimulatory molecules include, but are not limited to, MHC class I molecules, TNF receptor proteins, immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocyte activation molecules (SLAM proteins), activating NK cell receptors, BTLA, Toll ligand receptors, OX40 (CD134), CD2, CD7, CD27, CD28, CD30, CD40, CD5, ICAM-1, LFA-1 (CD11a / CD18), 4 -1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD5, CD8 alpha, CD8 beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D , ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB 2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE / RANKL, DNAM1(CD226), SLAMF4(CD244, 2B4), CD84, CD96(Tactile), C Ligands that specifically bind to EACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, CD19a, CD154, and CD83 are included.

[0036] In one embodiment, the costimulatory molecule is selected from, for example, 4-1BB (ie, CD137), CD27, CD28 and / or OX40, and enhances T cell receptor stimulation.

[0037] The term "4-1BB" refers to a member of the TNFR superfamily having the amino acid sequence provided as GenBank Accession No. AAA62478.2, or equivalent residues from non-human species such as mice, rodents, monkeys, apes, and the like, and a "4-1BB costimulatory domain" is defined as amino acid residues 214-255 of GenBank Accession No. AAA62478.2, or equivalent residues from non-human species such as mice, rodents, monkeys, apes, and the like. In one embodiment, the "4-1BB costimulatory domain" is the full length or a portion of the nucleotide sequence 886-1026 of Genbank Accession No. NM001561.5, or equivalent residues from non-human species such as mice, rodents, monkeys, apes, and the like.

[0038] The term "T cell-redirecting antibody (TRAB)" refers to an antibody whose antitumor effect is mediated by cytotoxicity, which recruits T cells as effector cells (Nature (1985) 314 (6012), 628-31., Int J Cancer (1988) 41 (4), 609-15., Proc Natl Acad Sci USA (1986) 83 (5), 1453-7). T cell-redirecting antibodies are bispecific antibodies that contain a binding domain for one of the constituent subunits of the T cell receptor (TCR) complex on T cells, particularly the CD3 epsilon chain, and a domain that binds to an antigen on target cancer cells. The simultaneous binding of T cell-redirecting antibodies to the CD3 epsilon chain and tumor antigens allows T cells to approach cancer cells. Consequently, the cytotoxic activity of T cells is thought to exert an antitumor effect on cancer cells.

[0039] The TRAB of the present disclosure is a bispecific antibody that contains a domain that binds to a constituent subunit of the T cell receptor complex and a domain that binds to a site containing a mutation in the antibody.

[0040] In the present disclosure, a "domain comprising an antibody variable region having T cell receptor complex-binding activity" refers to a portion of a T cell receptor complex antibody comprising a region that specifically binds to and is complementary to a part or all of a T cell receptor complex. The T cell receptor complex may be the T cell receptor itself, or an adaptor molecule that forms the T cell receptor complex together with the T cell receptor. A preferred adaptor is CD3.

[0041] A "domain comprising an antibody variable region having CD3-binding activity" refers to a portion of an anti-CD3 antibody comprising a region that specifically binds to and is complementary to a part or all of CD3. Preferably, the domain comprises the light chain variable region (VL) of an anti-CD3 antibody and the heavy chain variable region (VH) of an anti-CD3 antibody. Suitable examples of such domains include "scFv (single chain Fv)," "single chain antibody," "Fv," "scFv2 (single chain Fv 2)," "Fab," and "F(ab')2."

[0042] The domains comprising antibody variable regions with CD3-binding activity according to the present disclosure may bind to any epitope present in the gamma, delta, or epsilon chain sequences constituting human CD3. In the present disclosure, a domain comprising a light chain variable region (VL) and a heavy chain variable region (VH) of an anti-CD3 antibody that binds to an epitope present in the extracellular domain of the epsilon chain of the human CD3 complex is preferably used. Examples of such domains include the light chain variable region (VL) and heavy chain variable region (VH) of an anti-CD3 antibody described in the Examples, as well as CD3-binding domains comprising the light chain variable region (VL) and heavy chain variable region (VH) of an OKT3 antibody (Proc. Natl. Acad. Sci. USA (1980) 77, 4914-4917) and various other known CD3 antibodies. Alternatively, a domain containing an antibody variable region derived from an anti-CD3 antibody having desired properties obtained by immunizing a desired animal with the gamma, delta, or epsilon chains constituting human CD3 by the above-described method can be used as appropriate. As described above, an appropriate humanized or human antibody can be used as the anti-CD3 antibody from which the domain containing the antibody variable region with CD3-binding activity is derived. The polynucleotide sequences of the gamma, delta, or epsilon chains constituting CD3 are represented by RefSeq accession numbers NM_000073.2, NM_000732.4, and M_000733.3, and the polypeptide sequences are represented by RefSeq accession numbers NP_000064.1, NP_000723.1, and NP_000724.1.

[0043] The term "mutation" refers to the substitution, deletion, addition, or modification of one or several to multiple amino acids, or any combination thereof. The purpose of creating an antibody containing mutations can be to achieve any desired characteristic, such as reducing or enhancing binding to Fc receptors, improving the pharmacokinetics of the antibody, reducing heterogeneity, improving commercial productivity, or being recognized by the TRAB and / or chimeric receptors of the present disclosure. Furthermore, as long as the mutant retains substantially the same function as the original sequence, it also includes molecules modified by commonly known conservative substitutions. Deletions and insertions in the amino acid sequence include amino- and / or carboxy-terminal deletions and insertions of amino acids. Specific amino acid mutations are referred to as "mutations" herein. Mutations also include substitutions with unnatural amino acids or naturally occurring amino acid derivatives of the 20 standard amino acids. Amino acid mutations can be generated using genetic or chemical methods well known in the art. Genetic methods include site-directed mutagenesis, PCR, gene synthesis, and the like. Methods other than genetic engineering, such as chemical modification, may also be useful. The mutations may be at least one in the regions specified in this disclosure, and may include up to 50, 40, 30, 20, 10, or 5 amino acid deletions and / or conservative substitutions in other regions. In this disclosure, intentionally introducing mutations is referred to as "modification," regardless of whether or not a characteristic is acquired. When a secondary antibody specifically binds to a primary antibody via the portion containing the mutation, the secondary antibody may recognize and bind to the modified amino acid and its surrounding area of ​​the primary antibody (mutated antibody) as an epitope on the antigen. In the present disclosure, the phrase "modified amino acid and its surrounding area" may include a sequence of amino acids, most usually at least five, e.g., about 8 to about 10, or 6 to 20, containing the modified amino acid, as in a linear epitope of the antigen, or may include the three-dimensional structure surrounding the modified amino acid of the primary antibody that is recognized by the secondary antibody, as in a conformational epitope of the antigen.

[0044] The term "antigen" or "Ag" refers to a molecule that elicits an immune response. This immune response may involve either antibody production or activation of specific immunocompetent cells, or both. Any macromolecule, including virtually any protein or peptide, can serve as an antigen. Furthermore, antigens may be derived from recombinant or genomic DNA. Any DNA containing a nucleotide sequence or a partial nucleotide sequence encoding a protein that elicits an immune response will therefore encode an "antigen," as the term is used in this disclosure. Furthermore, antigens are not necessarily encoded solely by the full-length nucleotide sequence of a gene. It is readily understood that the present disclosure encompasses, but is not limited to, the use of partial nucleotide sequences from more than one gene, and that these nucleotide sequences may be arranged in various combinations to encode a polypeptide that elicits a desired immune response. Furthermore, antigens do not necessarily have to be encoded by a "gene." Antigens may be generated or synthesized, derived from a biological sample, or may be macromolecules other than polypeptides. Such biological samples may include, but are not limited to, tissue samples, tumor samples, and fluids containing cells or other biological components. When a chimeric receptor that is a secondary antibody of the present disclosure has an antibody-derived amino acid sequence as part of its extracellular binding domain, the molecule to which the extracellular binding domain binds can also be referred to as an antigen.Furthermore, the primary antibody to which a bispecific antibody (TRAB) that is a secondary antibody of the present disclosure binds can also be referred to as an antigen.

[0045] In one embodiment, suitable examples of the antigen include receptors, tumor antigens, MHC antigens, and differentiation antigens.

[0046] Examples of receptors include receptors belonging to receptor families such as the hematopoietic factor receptor family, cytokine receptor family, tyrosine kinase receptor family, serine / threonine kinase receptor family, TNF receptor family, G protein-coupled receptor family, GPI-anchored receptor family, tyrosine phosphatase receptor family, adhesion factor family, and hormone receptor family. The receptors belonging to these receptor families and their characteristics are described in numerous publications, for example, Cooke BA., King RJB., van der Molen HJ. ed. New Comprehesive Biochemistry Vol. 18B "Hormones and their Actions Part II" pp. 1-46 (1988) Elsevier Science Publishers BV., or Miyasaka Masayuki (ed.), Cell Engineering Special Edition Handbook Series "Handbook of Adhesion Factors" (1994) (Shujunsha, Tokyo, Japan), as well as reviews by Patthy (Cell (1990) 61 (1), 13-14), Ullrich et al. (Cell (1990) 61 (2), 203-212), Massague (e has an acute accent mark) (Cell (1992) 69 (6), 1067-1070), Miyajima et al. (Annu. Rev. Immunol. (1992) 10, 295-331), Taga et al. (FASEB J. (1992) 6, 3387-3396), Fantl et al. (Annu. Rev. Biochem. (1993), 62, 453-481), Smith et al. (Cell (1994) 76 (6) 959-962), Flower DR. Biochim. Biophys. Acta, Flower (Biochim. Biophys. Acta (1999) 1422 (3) 207-234, etc. Specific examples of receptors belonging to the above receptor families include human or mouse erythropoietin (EPO) receptor (Blood (1990) 76 (1), 31-35, Cell (1989) 57 (2), 277-285), human or mouse granulocyte colony-stimulating factor (G-CSF) receptor (Proc. Natl. Acad. Sci. USA. (1990) 87 (22), 8702-8706, mG-CSFR, Cell (1990) 61 (2), 341-350), human or mouse thrombopoietin (TPO) receptor (Proc Natl Acad Sci USA. (1992) 89 (12), 5640-5644, EMBO J. (1993) 12 (7), 2645-53), and human or mouse insulin receptor (Nature (1985) 313 (6005), 756-761), human or mouse Flt-3 ligand receptor (Proc. Natl. Acad. Sci. USA. (1994) 91 (2), 459-463), human or mouse platelet-derived growth factor (PDGF) receptor (Proc. Natl. Acad. Sci. USA. (1988) 85 (10) 3435-3439), human or mouse interferon (IFN)-alpha, beta receptor (Cell (1990) 60 (2), 225-234. and Cell (1994) 77 (3), 391-400), human or mouse leptin receptor, human or mouse growth hormone (GH) receptor, human or mouse interleukin (IL)-10 receptor, human or mouse insulin-like growth factor (IGF)-I receptor, human or mouse leukemia inhibitory factor (LIF) receptor, human or mouse ciliary neurotrophic factor (CNTF) receptor, etc.

[0047] The term "tumor antigen" refers to an antigen expressed on cancer cells, and refers to an antigenic biological molecule whose expression is recognized in association with malignant changes in cells. Tumor antigens of the present disclosure include tumor-specific antigens (antigens present only in tumor cells and not found in other normal cells) and tumor-associated antigens (antigens also present in other organs and tissues or heterogeneous and allogeneic normal cells, or antigens expressed during development and / or differentiation). Abnormal glycans that appear on cell surfaces or protein molecules when cells become cancerous are also tumor antigens, and are also called cancer glycan antigens.

[0048] Examples of tumor antigens include GPC3 (Int J Cancer. (2003) 103 (4), 455-65), which belongs to the GPI-anchored receptor family and is expressed in several cancers including liver cancer, and EpCAM (Proc Natl Acad Sci U S A. (1989) 86 (1), 27-31) (the polynucleotide sequence is listed in RefSeq Accession No. NM_002354.2, and the polypeptide sequence is listed in RefSeq Accession No. NP_002345.2, respectively), EGFR, CA19-9, CA15-3, cerebrospinal fluid leukemia antigen (SSEA-1), Her2, prostate stem cell antigen (PSCA), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), tumor antigen-125 (CA-125), calretinin, MUC-1, MUC-16, epithelial membrane protein (EMA), epithelial tumor antigen (ETA), tyrosinase, melanoma-associated antigen (MAGE), chromogranin, cytokeratin, desmin, glial fibrillary acidic protein (GFAP), gross cystic disease fluid protein (GRDF), and HER2. protein) (GCDFP-15), HMB-45 antigen, protein melan-A (melanoma antigen recognized by T lymphocytes; MART-1), myo-D1, muscle-specific actin (MSA), neurofilament, neuron-specific enolase (NSE), placental alkaline phosphatase, synaptophysin, thyroglobulin, thyroid transcription factor-1, dimeric form of pyruvate kinase isoenzyme type M2 (tumor M2-PK), GD2 (ganglioside G2), EGFRvIII (epidermal growth factor variant III), sperm protein 17 (Sp17), mesothelin, PAP (prostatic acid phosphatase), prostein, TARP (T cell receptor gamma alternate reading frame protein), Trp-p8, STEAP1 (six-transmembrane epithelial antigen of prostate 1), TROP-2, Claudin 6, RNF43a, abnormal ras protein, abnormal p53 protein, integrin alpha v beta 3 (CD61), galectin, K-Ras (V-Ki-ras2 Kirsten rat sarcoma viral oncogene), or Ral-B.

[0049] Furthermore, thyroid-stimulating hormone receptor (TSHR); CD171; CS-1 (CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); Tn antigen (Tn Ag); T antigen (T Ag); Fms-like tyrosine kinase 3 (FLT3); CD38; CD44v6; B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha-2 (IL-13Ra2); interleukin-11 receptor alpha (IL-11Ra); interleukin-2 receptor alpha (IL-2Ra); prostate stem cell antigen (PSCA); protease serine 21 (PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2) Lewis (Y) antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-beta); stage-specific embryonic antigen-4 (SSEA-4); neural cell adhesion molecule (NCAM); carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunit, beta, 9 (LMP2); ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bDGal p(1-4)bDGlcp(1-1)Cer; TGS5; high-molecular-weight melanoma-associated antigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); G protein-coupled receptor class C group 5, member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97 ;CD179a;anaplastic lymphoma kinase (ALK);polysialic acid;placenta-specific 1 (PLAC1);hexasaccharide moiety of globoH glycoceramide (GloboH);mammary differentiation antigen (NY-BR-1);uroplakin 2 (UPK2);hepatitis A virus cellular receptor 1 (HAVCR1);adrenergic receptor beta 3 (ADRB3);pannexin 3 (PANX3);G protein-coupled receptor 20 (GPR20);lymphocyte antigen 6 complex, locus K9 (LY6K);Olfactory receptor 51E2 (OR51E2); TCR gamma alternative reading frame protein (TARP); Wilms tumor protein (WT1); ETS translocation mutant gene 6 located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X antigen family, member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie 2); melanoma cancer testis antigen-1 (MAD-CT-1); melanoma cancer testis antigen-2 (MAD-CT-2); Fos-related antigen 1; p53 mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; v-myc avian myelocytoma viral oncogene neuroblastoma-derived homolog (MYCN); Ras homolog family member C (RhoC); cytochrome P450 1B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS); squamous cell tumor antigen recognized by T cells 3 (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein p32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X breakpoint 2 (SSX2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); IgA receptor Also included are Fc fragment of the human leukocyte immunoglobulin-like receptor (FCAR); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1).

[0050] "MHC antigens" are gene products of the major histocompatibility complex (MHC), and glycoproteins expressed on cell membranes are primarily classified into MHC class I and MHC class II antigens. MHC class I antigens include HLA-A, -B, -C, -E, -F, -G, and -H, while MHC class II antigens include HLA-DR, -DQ, and -DP. These MHC antigens also include tumor antigen-derived peptides presented by these MHC antigens. Tumor antigens such as GP100, MART-1, and MAGE-1, as well as complexes with MHC presenting mutant portions of RAS and p53, are also considered tumor antigens.

[0051] "Differentiation antigens" is a general term for cell surface molecules that appear and disappear as macrophages, T cells, B cells, etc. differentiate from bone marrow stem cells. Differentiation antigens include CD1, CD2, CD4, CD5, CD6, CD7, CD8, CD10, CD11a, CD11b, CD11c, CD13, CD14, CD15s, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD27, CD28, CD29, CD30, CD32, CD33, CD34, CD35, CD38, CD40, CD41a, CD41b, CD42a, CD42b, and CD4 3, CD44, CD45, CD45RO, CD48, CD49a, CD49b, CD49c, CD49d, CD49e, CD49f, CD51, CD54, CD55, CD56, CD57, CD58, CD61, CD62E, CD62L, CD62P, CD64, CD69, CD70, CD71, CD73, CD95, CD99, CD102, CD106, CD117, CD122, CD126, and CDw130.

[0052] In one embodiment, the extracellular binding domain of the chimeric receptor is and / or comprises the antigen-binding region of an antibody capable of binding to a given antigen via a specific antibody containing mutations in the CH1, CH2, CH3, CL, or FR regions of the antibody.

[0053] In one embodiment, the extracellular binding domain of the chimeric receptor binds via a portion of an antibody that binds to a predetermined antigen, such as a receptor, tumor antigen, MHC antigen, or differentiation antigen.

[0054] In one embodiment, the TRAB ("T cell-redirecting antibody") used as the secondary antibody of the present disclosure can bind to a specific antigen via a specific antibody (primary antibody) containing mutations in its CH1, CH2, CH3, CL, or FR regions. As a result, compared to a bispecific antibody containing a domain that binds to one of the constituent subunits of the T cell receptor (TCR) complex on T cells and a domain that binds to an antigen on cancer cells, which is one of the targets, the TRAB binds more strongly to the target antigen via the primary antibody and brings the cancer cells and T cells into close proximity, thereby exerting a stronger immune effect. In one embodiment, the extracellular binding domain of the chimeric receptor of the present disclosure or the domain of the TRAB of the present disclosure that binds to a primary antibody may be a domain whose binding activity to an antibody that binds to a predetermined antigen (primary antibody) changes depending on the concentration of a target tissue-specific compound. See, for example, WO2013 / 180200 and US2019 / 0359704. As used herein, the term "core hinge region" refers to a region sandwiched between at least two cysteine ​​residues that form an inter-heavy chain disulfide bond in the hinge region, and in IgG1 and IgG4, for example, refers to a region consisting of amino acids at positions 226 to 229 (EU numbering) in the antibody heavy chain. For example, the core hinge region in human IgG1 refers to a region consisting of Cys at position 226, Pro at position 227, Pro at position 228, and Cys at position 229 (EU numbering) in the antibody heavy chain.

[0055] The domain that recognizes the site containing the antibody mutation The TRAB and chimeric receptor of the present disclosure have a "domain that recognizes the site containing the mutation in the antibody," which refers to a portion that can specifically bind to the portion of the primary antibody containing the mutated amino acid. The domain containing the antibody variable region is provided by one or more antibody variable domains, and preferably, the domain containing the antibody variable region contains an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH). Suitable examples of such domains containing antibody variable regions include "scFv (single chain Fv)," "single chain antibody," "Fv," "scFv2 (single chain Fv 2)," "Fab," and "F(ab')2."

[0056] The term "specific" refers to a state in which a specifically binding molecule does not exhibit the same binding activity to molecules other than the one or more partner molecules, or the binding activity is significantly reduced. It is also used when a domain containing an antibody variable region is specific to a specific epitope among multiple epitopes contained in a certain antigen. Furthermore, when the epitopes bound by a domain containing an antibody variable region are contained in multiple different antigens, an antigen-binding molecule having the domain containing the antibody variable region can bind to various antigens containing the epitope. For example, in some embodiments, the term "does not specifically bind" refers to the ability to bind to an epitope containing a mutant amino acid that is present in IgG1 or IgG4 but not in their variants, or that is absent in IgG1 or IgG4 but present in their variants, at different concentrations (e.g., higher or lower) compared to the site without the mutation. For example, a chimeric receptor or TRAB of the present disclosure exhibits the same binding activity as a primary antibody containing a mutant amino acid and a primary antibody containing the site without the mutation, at concentrations that are at least 10-fold, at least 100-fold, at least 1,000-fold, at least 10,000-fold, or more, with increasing concentrations extending up to infinity. In another embodiment, the term refers to a relationship in which a primary antibody containing a mutant amino acid and a primary antibody containing the site without the mutation do not compete with each other.

[0057] The terms "compete" or "cross-compete" are used interchangeably in the present disclosure to refer to the ability of an antibody molecule. Interference with binding can be direct or indirect (e.g., by allosteric modification of the antibody molecule or the target). The degree to which an antibody molecule can interfere with the binding of another antibody molecule to a target and therefore can be said to compete with it can be determined using a competitive binding assay, for example, as described in the present disclosure. In some embodiments, the competitive binding assay is a quantitative competitive assay. In some embodiments, a first antibody molecule is said to compete with a second antibody molecule for binding to a target if binding of the first antibody molecule to the target is reduced by 10% or more, e.g., 20% or more, 30% or more, 40% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more in a competitive binding assay (e.g., a competitive assay described in this disclosure).

[0058] As used in this disclosure, the term "epitope" refers to a component of an antigen that specifically interacts with an antibody molecule. Such a component typically includes or is a portion of an element such as an amino acid side chain or a sugar side chain. Epitopes can be defined, for example, by methods known in the art or disclosed in this disclosure, such as by crystallography or hydrogen-deuterium exchange. At least one or some of the components on an antibody molecule that specifically interact with the epitope are typically located within a CDR. Typically, an epitope has specific three-dimensional structural characteristics. Typically, an epitope has specific charge characteristics. Some epitopes are linear epitopes, while others are conformational epitopes. An epitope can also be defined by the binding activity of an antibody molecule that recognizes the epitope to an antigen. When the antigen is a peptide or polypeptide, the epitope can also be identified by the amino acid residues that constitute the epitope. When the epitope is a glycan, the epitope can also be identified by a specific glycan structure. When the chimeric receptor of the present disclosure has an antibody-derived amino acid sequence as part of its extracellular binding domain, the binding site of the molecule to which the extracellular binding domain binds can also be referred to as an epitope. A linear epitope is an epitope that contains a recognized primary amino acid sequence. A linear epitope typically includes at least 3, and most usually at least 5, for example, about 8 to about 10, 6 to 20 amino acids in a unique sequence. Conformational epitopes, in contrast to linear epitopes, are epitopes in which the primary sequence of amino acids comprising the epitope is not the single defining component of the recognized epitope (e.g., an epitope in which the primary sequence of amino acids is not necessarily recognized by the antibody that defines the epitope). Conformational epitopes may encompass an increased number of amino acids relative to linear epitopes. In recognizing conformational epitopes, antibodies recognize the three-dimensional structure of a peptide or protein. For example, when a protein molecule folds to form a three-dimensional structure, certain amino acids and / or polypeptide backbones that form a conformational epitope are juxtaposed, allowing the antibody to recognize the epitope. Methods for determining the conformation of an epitope include, for example, X-ray crystallography, two-dimensional nuclear magnetic resonance spectroscopy, and site-specific spectroscopy. These include, but are not limited to, spin labeling and electromagnetic paramagnetic resonance spectroscopy. See, e.g., Epitope Mapping Protocols in Methods in Molecular Biology (1996), Vol. 66, Morris (ed.). The term "target tissue-specific compound" refers to a compound that is differentially present in target tissue compared to non-target tissue. For example, in some embodiments, a target tissue-specific compound can be a compound that is defined by qualitative target tissue specificity, such as being present in target tissue but not in non-target tissue, or being absent in target tissue but present in non-target tissue. The term "cancer tissue-specific compound" refers to a compound that is differentially present in cancer tissue compared to non-cancerous tissue. For example, in some embodiments, a cancer tissue-specific compound may be a compound that is defined by qualitative cancer tissue specificity, such as being present in cancer tissue but not in non-cancerous tissue, or being absent in cancer tissue but present in non-cancerous tissue. In another embodiment, the cancer tissue-specific compound can be a compound that is defined by quantitative cancer tissue specificity, such as being present at a different concentration (e.g., higher or lower concentration) in cancer tissue compared to non-cancerous tissue. For example, the cancer tissue-specific compound is differentially present at a given concentration. Generally, however, the cancer tissue specific compound can be present in increasing concentrations of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150%, at least 2-fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 103-fold, at least 104-fold, at least 105-fold, at least 106-fold, or more, up to infinity (i.e., absent in non-cancerous tissue), or generally at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% (i.e., representing absence). The cancer tissue-specific compound is preferably differentially present at a statistically significant concentration (i.e., a p-value of less than 0.05 and / or a q-value of less than 0.10, as determined using either Welch's t-test or Wilcoxon rank sum test). Non-limiting examples of cancer tissue-specific compounds include compounds that are cancer tissue-specific metabolites (cancer tissue-specific metabolites; cancer cell-specific metabolites, cancer tissue-infiltrating immune cell-specific metabolites, cancer stromal cell-specific metabolites) produced by metabolic activity specific to cancer cells, immune cells, and stromal cells contained in cancer tissue, such as: The term "metabolism" refers to chemical changes that occur within the tissues of an organism, and includes "anabolism" and "catabolism." Anabolism refers to the biosynthesis or accumulation of molecules, while catabolism refers to the breakdown of molecules. A "metabolite" is an intermediate or product resulting from metabolism. A "primary metabolite" refers to a metabolic product that is directly involved in the growth or reproduction process of a cell or organism. Suitable, non-limiting embodiments of the cancer tissue-specific compound or cancer tissue-specific metabolite used in the present disclosure include at least one compound selected from the following compounds: (1) Primary metabolic products of glycolysis or the Krebs cycle, such as lactate, succinate, and citrate (2) Amino acids such as alanine, glutamic acid, and aspartic acid that accumulate in high concentrations in cancer tissues due to glutamine degradation, etc. (3) Kinure D and its metabolites, such as anthranilic acid, 3-hydroxykynurenine, and kynurenic acid, (4) Prostaglandin E2, thromboxane A2 (TXA2), etc. Arachidonic acid metabolites (5) Purine nucleotides with a purine ring structure, such as adenosine, adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and methylthioadenosine (MTA; CAS number: 2457-80-9), accumulate in high concentrations in cancer tissues due to the metabolism of purine nucleotides. Nucleosides and their degradation products such as inosine (6)Uric acid (7) 1-methylnicotinamide accumulates in high concentrations in cancer tissues due to the metabolism of nicotinamide. Chinamide etc. The term "inflammatory tissue-specific compound" refers to a compound that is differentially present in inflamed tissue compared to non-inflamed tissue. As used herein, "inflamed tissue" refers to Multiple sclerosis, asthenia gravis, and nerve and muscle tissue such as myelin sheaths in multiple sclerosis Joints in rheumatoid arthritis and osteoarthritis Lungs (alveoli) in bronchial asthma and COPD Digestive tract in inflammatory bowel disease, Crohn's disease, ulcerative colitis or colorectal cancer Fibrotic tissue in liver, kidney, and lung fibrosis Tissues undergoing rejection (including graft-versus-host disease) in organ transplants and skin grafts Blood vessels and heart (myocardium) in hemophilia A, arteriosclerosis or heart failure, myocarditis, and pericarditis Visceral fat in metabolic syndrome Skin tissue in atopic dermatitis and other dermatitis Spinal nerves in herniated discs and chronic lower back pain Burkitt lymphoma, sarcoma, or prostate cancer has spread to abdominal lymph nodes, connective tissue, or internal organs Tissues where infectious diseases such as smallpox are occurring Suitable examples include: Preferred examples of cells attacked by the CAR-T cells or TRAB of the present disclosure include autoantibody-producing B cells, fibrotic cells, and myofibroblasts, and preferred examples of antigens include CD19, CD20, desmoglein 3, MuSK, TNP (2,4,5-trinitrophenol), CEA, MOG (myelin oligodendrocyte glycoprotein), FAP, PDGFR, FVIII, vimentin, integrin, adiponectin, CD26, desmin, and HLA-A2 (see Front Immunol. 2018; 9: 2359). The term "inflammatory tissue-specific metabolites" refers to metabolites that are produced in high amounts by immune cells infiltrating inflammatory tissues, and metabolites that are produced in high amounts specifically by normal cells that are damaged in inflammatory tissues. Examples of infiltrating immune cells include effector T cells, mature dendritic cells, Examples of such compounds include neutrophils, granulocytes (mast cells), and basophils. Metabolites in the present disclosure also include compounds that are released from inside to outside of cells when cells (immune cells, normal cells) present in inflamed tissue die due to apoptosis, necrosis, or the like. Suitable, non-limiting examples of the inflamed tissue-specific compound or inflamed tissue-specific metabolite used in the present disclosure include at least one compound selected from the following compounds: (1) Arachidonic acid metabolites such as prostaglandin E2 (2) Purine nucleotides with a purine ring structure, such as adenosine, adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and methylthioadenosine (MTA; CAS number: 2457-80-9), accumulate in high concentrations in inflamed tissues through the metabolism of purine nucleotides. Nucleosides and their degradation products such as inosine (3)Uric acid In one embodiment of the present disclosure, the cancer tissue-specific compound, cancer tissue-specific metabolite, inflamed tissue-specific compound, or inflamed tissue-specific compound includes ATP, adenosine, inosine, MTA, prostaglandin E2, succinic acid, lactic acid, or kynurenine.

[0059] The term "antibody," as used in this disclosure, refers to a protein or polypeptide sequence derived from an immunoglobulin molecule that specifically binds to an antigen. It is intended to include monoclonal antibodies, polyclonal antibodies, and mouse-human chimeric antibodies, humanized antibodies, as well as murine, bovine, rabbit, rat, goat, camel, shark, human antibodies, and antibodies of other organisms. Antibodies may be derived from recombinant sources and / or produced in transgenic animals. Antibodies may also be synthetic.

[0060] The term "antibody fragment" refers to at least a portion of an antibody that retains the ability to specifically interact with an epitope of an antigen (e.g., by binding, steric hindrance, stabilization / destabilization, spatial distribution). As used herein, this term includes, but is not limited to, Fab, Fab', F(ab')2, scFv, dsFv, ds-scFv, Fd fragments consisting of the VH and CH1 domains, linear antibodies, single-domain antibodies such as sdAb (either VL or VH); camelized VHH domains; multispecific antibodies formed from antibody fragments such as bivalent fragments comprising two Fab fragments linked by a disulfide bridge at the hinge region; and isolated CDRs or other epitope-binding fragments of antibodies. Antigen-binding fragments may also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NARs, and bis-scFvs (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005). Antigen-binding fragments can also be grafted onto polypeptide-based scaffolds, such as fibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide minibodies). Fab, Fab' and F(ab')2, scFv, dsFv, ds-scFv, dimers, minibodies, diabodies, bispecific antibody fragments, and other fragments can also be synthesized by recombinant techniques.

[0061] The term "antibody heavy chain" refers to the larger of the two types of polypeptide chains present in antibody molecules in their naturally occurring conformations. The antibody heavy chain usually determines the class to which the antibody belongs.

[0062] The term "antibody light chain" refers to the smaller of the two types of polypeptide chains present in antibody molecules in their naturally occurring conformations. Kappa (κ) and lambda (λ) light chains refer to the two major antibody light chain isotypes.

[0063] The term "recombinant antibody" refers to an antibody produced using recombinant DNA technology, such as, for example, an antibody expressed in a bacteriophage or yeast expression system. The term shall also be taken to mean an antibody produced by synthesis of a DNA molecule encoding the antibody (which DNA molecule expresses the antibody protein), or an amino acid sequence specifying the antibody, where the DNA or amino acid sequence is obtained using recombinant DNA or amino acid sequence technology available and well known in the art.

[0064] "Humanized" forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof [e.g., Fv, Fab, Fab', F(ab')] that contain minimal sequence derived from non-human immunoglobulin. 2or other antigen-binding subsequences of antibodies. For the most part, humanized antibodies and antibody fragments thereof are human immunoglobulins (recipient antibody or antibody fragment) in which residues from a complementarity-determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity. In some cases, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies / antibody fragments may comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences. These modifications may further refine and optimize antibody or antibody fragment performance. In general, humanized antibodies or antibody fragments thereof will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or a significant portion of the FR regions are those of a human immunoglobulin sequence. The humanized antibody or antibody fragment may also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature, 321: 522-525, 1986; Reichmann et al., Nature, 332: 323-329, 1988; Presta, Curr. Op. Struct. Biol., 2: 593-596, 1992.

[0065] The term "fully human" refers to an immunoglobulin, such as an antibody or antibody fragment, where the entire molecule is of human origin or consists of an amino acid sequence identical to a human form of the antibody or immunoglobulin.

[0066] The present disclosure will enable those skilled in the art to employ conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art, such techniques being fully explained in the literature. For example, Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York (herein “Sambrook et al., 1989”); DNA Cloning: A practical Approach, Volumes I and II (DN Glover ed. 1985); Oligonucleotide Synthesis (MJ. Gait ed. 1984); Nucleic Acid Hybridization (BD Hames & SJ Higgins eds.(1985); Transcription and Translation (BD Hames & SJ Higgins, eds. (1984); Animal Cell Culture (RI Freshney, ed. (1986); Immobilized Cells and Enzymes (IRL Press, (1986); B. Perbal, A practical Guide To Molecular Cloning (1984); FM Ausubel et al. (eds.), Current Protocols in Molecular Biology, John See Wiley & Sons, Inc. (1994).

[0067] Methods for producing antibodies are known in the art. To produce human monoclonal antibodies and / or binding fragments thereof, antibody-producing cells (lymphocytes) can be taken from cancer-bearing humans and fused with myeloma cells by standard somatic cell fusion procedures, thus immortalizing these cells and resulting in hybridoma cells. Such techniques are well known in the art (e.g., the hybridoma technique first developed by Kohler and Milstein (Nature 256:495-497 (1975)) as well as other techniques such as the human B-cell hybridoma technique (Kozbor et al., Immunol. Today 4:72 (1983)), the EBV-hybridoma technique for producing human monoclonal antibodies (Cole et al., Methods Enzymol, 121:140-67 (1986)), and screening of combinatorial antibody libraries (Huse et al., Science 246:1275 (1989)). Hybridoma cells can be screened immunochemically for the production of antibodies specifically reactive with cancer cells, and monoclonal antibodies can be isolated.

[0068] In this disclosure, "variable region" or "VR" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The heavy and light chain variable domains (VH and VL, respectively) of natural antibodies typically have similar structures, with each domain containing four conserved framework regions (FR) and three hypervariable regions (HVR). (See, e.g., Kindt et al., Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a specific antigen may be isolated by screening a complementary library of VL or VH domains, respectively, using a VH or VL domain from an antibody that binds to that antigen. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0069] The term "hypervariable region" or "HVR" as used in this disclosure refers to each region of an antibody variable domain that is hypervariable in sequence (the "complementarity determining region" or "CDR"), and / or forms structurally defined loops (the "hypervariable loops"), and / or contains antigen-contacting residues (the "antigen contacts"). Typically, antibodies contain six HVRs: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). Exemplary HVRs in the present disclosure include: (a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)); (b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) antigenic contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)); and (d) combinations of (a), (b), and / or (c), including HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3), and 94-102 (H3).

[0070] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain typically consists of four FR domains: FR1, FR2, FR3, and FR4. Accordingly, the HVR and FR sequences typically appear in VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0071] "Percent (%) amino acid sequence identity" in this disclosure relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after aligning the sequences to achieve the maximum percent sequence identity and introducing gaps, if necessary, and excluding any conservative substitutions from the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved by a variety of methods within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms necessary to achieve maximum alignment over the entire length of the sequences being compared. However, for purposes of this disclosure, % amino acid sequence identity values ​​are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program is the copyright of Genentech, Inc., and its source code, together with user documentation, has been filed with the U.S. Copyright Office, Washington, DC, 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code. The ALIGN-2 program is compiled for use on UNIX operating systems, including Digital UNIX® V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0072] In situations where ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (alternatively, one can say that a given amino acid sequence A has or contains a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X / Y, where X is the number of amino acid residues scored by the sequence alignment program ALIGN-2 as identical matches in that program's alignment of A and B, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless otherwise specified, all % amino acid sequence identity values ​​used in this disclosure are obtained using the ALIGN-2 computer program as described in the immediately preceding paragraph.

[0073] In this disclosure, the term "Fc region" is used to define the C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. This term includes native-sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226 or from Pro230 to the carboxyl terminus of the heavy chain, except that the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified in this disclosure, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system (also referred to as the EU index) as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD 1991.

[0074] A "variant Fc region" in the present disclosure comprises an amino acid sequence that differs from that of a native-sequence Fc region by at least one amino acid mutation (alteration), preferably one or more amino acid substitutions or deletions. Preferably, a variant Fc region has at least one amino acid substitution or deletion in the native-sequence Fc region or in the Fc region of the parent polypeptide, compared to the native-sequence Fc region or the Fc region of the parent polypeptide. amino acid substitutions, for example, about 1 to about 10 amino acid substitutions, preferably about 1 to about 5 amino acid substitutions The variant Fc regions of the present disclosure preferably have at least about 80% homology to a native sequence Fc region and / or the Fc region of a parent polypeptide, most preferably at least about 90% homology thereto, and more preferably at least about 95% homology thereto. In one embodiment of the present disclosure, the mutated Fc region includes a mutated Fc region that does not increase the occurrence of intercellular cross-linking with other immune cells compared to a corresponding non-mutated Fc region. FcγRIIA, FcγRIIB, FcγRIIIA and / or FcγRIIIB. In one embodiment of the present disclosure, the mutant Fc region comprises an antibody Fc region deleted at any of positions 446 and 447 in the EU numbering system. In the present disclosure, the mutant antibody has reduced binding activity to all activating FcγRs due to mutations. When the mutated antibody is expressed as a β-actin-binding antibody, the binding activity of the mutated antibody to all activating FcγRs is significantly increased compared to the unmutated antibody. The decrease in activity can be confirmed by assays using methods well known to those skilled in the art. Similarly, the decrease in activity of the mutated antibody relative to the corresponding non-mutated antibody can be confirmed by assays using methods well known to those skilled in the art. and the mutated antibody has enhanced binding activity to any one of Fcγ receptors FcγI, FcγIIA, FcγIIB, FcγIIIA, and FcγIIIB compared to the corresponding unmutated antibody. The altered binding activity of the mutated antibody, e.g., an antibody with enhanced binding activity, can be confirmed by comparing it with the corresponding unmutated antibody by assays using methods well known to those skilled in the art. In the present disclosure, "antigen-binding activity at acidic pH" refers to antigen-binding activity at pH 4.0 to pH 6.5, preferably at pH 5.5 to pH 6.5, and particularly preferably at pH 5.8 to pH 6.0, which is close to the pH in early endosomes in vivo. Furthermore, "antigen-binding activity at neutral pH" refers to antigen-binding activity at pH 6.7 to pH 10.0. The term "antigen-binding activity" refers to the original binding activity, preferably at pH 7.0 to pH 8.0, and particularly preferably at pH 7.4, which is close to the pH of plasma in vivo. In the present disclosure, an "interface" comprises "contact" amino acid residues of a first polypeptide that interact with one or more "contact" amino acid residues of an interface of a second polypeptide. A preferred interface is a region (or part thereof) of an immunoglobulin, such as a variable region or constant region. A preferred interface is preferably from an IgG antibody, most preferably a human IgG1 It contains the CH3 region of an immunoglobulin derived from an antibody. In the present disclosure, a "protrusion" refers to at least one amino acid side chain that protrudes from the interface of a first polypeptide and can thus be positioned within a compensatory cavity in the adjacent interface (i.e., the interface of a second polypeptide) to stabilize heteromultimers, thereby, for example, favoring heteromultimer formation over homomultimer formation. The protrusion may be present at the original interface or may be synthetically introduced (e.g., by altering the nucleic acid encoding the interface). Typically, the nucleic acid encoding the interface of the first polypeptide is altered to encode the protrusion. To achieve this, nucleic acid encoding at least one "original" amino acid residue in the interface of the first polypeptide is replaced with nucleic acid encoding at least one "introduced" amino acid residue having a side chain volume larger than that of the original amino acid residue. It will be recognized that there can be more than one original and corresponding introduced residue. The upper limit of the number of original residues that can be replaced is the total number of residues in the interface of the first polypeptide. Various amino acids can be introduced. acid The side chain volumes of the residues are shown in the table below. Preferred introduced residues for protrusion formation are generally naturally occurring amino acid residues, preferably selected from arginine (R), phenylalanine (F), tyrosine (Y) and tryptophan (W). Most preferred are tryptophan and tyrosine. In a preferred embodiment, the original residue for protrusion formation is one with a small side chain volume, such as alanine, asparagine, aspartic acid, glycine, serine, threonine or valine. In the present disclosure, a "void" refers to at least one amino acid side chain recessed from the interface of a second polypeptide, thus accommodating a corresponding protrusion in the adjacent interface of a first polypeptide. The gap may be present in the original interface or may be introduced synthetically (e.g., by altering the nucleic acid encoding the interface). Typically, the nucleic acid encoding the interface of the second polypeptide is altered to encode the gap. To accomplish this, the nucleic acid encoding at least one "original" amino acid residue in the interface of the second polypeptide is replaced with DNA encoding at least one "introduced" amino acid residue having a smaller side chain volume than the original amino acid residue. It will be recognized that there may be more than one original and one introduced residue. The upper limit of the number of original residues to be replaced is the total number of residues in the interface of the second polypeptide. Various amino acids may be introduced. acid The side chain volumes of the residues are shown in Section 1 above. Preferred introduced residues for cavities are usually naturally occurring amino acid residues, preferably selected from alanine (A), serine (S), threonine (T) and valine (V). Most preferred are serine, alanine or threonine. In a preferred embodiment, the original residue for protrusion formation has a large side chain volume, such as tyrosine, arginine, phenylalanine or tryptophan.

[0075] In this disclosure, the terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the originally transformed cell and progeny derived from that cell regardless of the number of passages. The progeny may not be completely identical in nucleic acid content to the parent cell and may contain mutations. Mutant progeny that have the same function or biological activity as that for which the original transformed cell was screened or selected are also included in this disclosure.

[0076] As used herein, a "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes vectors as self-replicating nucleic acid structures and vectors that integrate into the genome of a host cell into which they are introduced. Certain vectors are capable of effecting expression of nucleic acids to which they are operatively linked. Such vectors are also referred to as "expression vectors" in this disclosure.

[0077] The monoclonal antibodies of this disclosure may be made using the hybridoma method first described by Kohler et al., Nature, 256:495 (1975), or may be made using recombinant DNA methods (U.S. Pat. No. 4,816,565). It can be made by the method of In the hybridoma method, mice or other suitable host animals, such as hamsters, are immunized to induce lymphocytes that produce or are capable of producing antibodies that specifically bind to the protein (antigen) used for immunization. Antibodies are generally raised in animals by multiple subcutaneous (sc) or intraperitoneal (ip) injections of antigen and adjuvant. In one embodiment, animals are immunized with an antigen fused to the Fc portion of an immunoglobulin heavy chain. In a preferred embodiment, animals are immunized with an antigen-IgG1 fusion protein. Typically, animals are immunized with monophosphorylated lipid A (MPL) / trehalose dicrynomycolate (TDM) (Ribi Immunochem. Research, Inc., Hamilton, MT) to enhance the immunogenicity of the antigen. The animals are immunized against the adjuvant or derivative and the solution is injected subcutaneously at multiple sites. Two weeks later, the animals are boosted. immunity After 7-14 days, the animals are bled and the serum is assayed for antibody titer. Additional animals are added until the antibody titer plateaus. immunity do.

[0078] Alternatively, lymphocytes can be immunized in vitro. The lymphocytes are then fused with myeloma cells using a suitable fusing agent, such as polyethylene glycol, to form hybridoma cells (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986)). Alternatively, a DNA immunization method is also known in which an expression control region is operably linked to a cDNA encoding a mutant antigen, and the cDNA is then used to immunize animals. DNA immunization does not require the purification of the immunogen. The hybridoma cells thus prepared are plated and grown in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, parental myeloma cells. For example, if the parental myeloma cells are deficient in the enzyme hypoxanthine guanidine phosphoribosyltransferase (HGPRT or HPRT), the culture medium for the hybridomas will typically contain hypoxanthine, aminopterin, and thymidine, substances that prevent the growth of HGPRT-deficient cells (HAT medium).

[0079] Preferred myeloma cells are those that fuse efficiently, support stable high-level antibody production by selected antibody-producing cells, and are sensitive to a medium such as HAT medium. Among these, preferred myeloma cell lines are those derived from mouse myeloma lines, such as MOPC-21 and MPC-11 mouse tumors available from the Salk Institute Cell Distribution Center, San Diego, California, USA, and SP-2 or X63-Ag8-653 cells available from the American Type Culture Collection, Rockville, Maryland, USA. Human myeloma and mouse-human heteromyeloma cell lines have also been described for the production of human monoclonal antibodies (Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987)).

[0080] Alternatively, cDNA encoding antibody variable regions can be obtained directly from antibody-producing cells of an immunized animal. For example, a known method involves limiting dilution of B cells from an immunized rabbit and culturing them with feeder cells. The specificities of antibodies produced in the culture medium can be compared in advance, and cDNA encoding the antibody variable regions can be recovered from cells producing the desired antibody by techniques such as PCR. By incorporating the recovered cDNA into an appropriate expression system, it is possible to obtain monoclonal antibodies without the need for hybridomas.

[0081] The culture medium in which the hybridoma cells are growing is assayed for production of monoclonal antibodies. Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson et al., Anal. Biochem., 107:220 (1980).

[0082] After hybridoma cells producing antibodies of the desired specificity, affinity, and / or activity are identified, the clones can be subcloned by limiting dilution and grown by standard methods (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986)). Suitable media for this purpose include, for example, D-MEM or RPMI-1640 medium. Additionally, the hybridoma cells can be grown in vivo as ascites tumors in animals.

[0083] The monoclonal antibodies secreted by the subclones are preferably separated from the culture medium, ascites fluid, or serum by conventional immunoglobulin purification procedures such as, for example, protein A-SEPHAROSE, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography. Antibodies encompassed by the present disclosure can be identified using combinatorial libraries to screen for synthetic antibody clones with the desired activity. In principle, synthetic antibody clones are selected by screening phage libraries containing phage displaying various fragments of antibody variable regions (Fv) fused to phage coat proteins. Such phage libraries are then selected by affinity chromatography against the desired antigen. Clones expressing Fv fragments capable of binding to the desired antigen are absorbed to the antigen, thereby separating them from non-binding clones in the library. The binding clones can then be eluted from the antigen and further enriched by additional cycles of antigen absorption / elution. Any antibody of the present disclosure can be obtained by designing an appropriate antigen screening method to select a phage clone of interest, followed by construction of a full-length antibody clone using the Fv sequence from the phage clone of interest and appropriate constant region (Fc) sequences as described in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda, MD (1991), vols. 1-3.

[0084] The antigen-binding domain of an antibody is formed by two variable (V) regions of approximately 110 amino acids, a light (VL) and a heavy (VH) chain, each of which contains three hypervariable loops or complementarity-determining regions (CDRs). The variable domains can be functionally displayed on phage either as single-chain Fv (scFv) fragments in which the VH and VL are covalently linked via a short, flexible peptide, as described in Winter et al., Ann. Rev. Immunol., 12: 433-455 (1994), or as Fab fragments in which the VH and VL are fused to constant domains and interact noncovalently. As used herein, scFv-encoding phage clones and Fab-encoding phage clones are collectively referred to as "Fv phage clones" or "Fv clones." Repertoires of VH and VL genes can be isolated and cloned by polymerase chain reaction (PCR) and randomly recombined in phage libraries, which can be screened for antigen-binding clones as described in Winter et al., Ann. Rev. Immunol., 12: 433-455 (1994). Libraries from immunized sources provide high-affinity antibodies to immunogens without the need to construct hybridomas. Alternatively, natural repertoires can be cloned to provide a single source of human antibodies against a wide range of non-self and self antigens without any immunization, as described in Griffiths et al., EMBO J., 12: 725-734 (1993). Finally, natural libraries can also be generated synthetically by cloning unrearranged V gene segments from stem cells and using PCR primers with random sequences to encode the hypervariable CDR3 regions and complete the rearrangement in vitro, as described by Hoogenboom and Winter, J. Mol. Biol. 227: 381-388 (1992).

[0085] Filamentous phage have been used to display antibody fragments by fusion to the minor coat protein pill. The antibody fragments can be displayed as single-chain Fv fragments in which the VH and VL domains are linked on the same polypeptide chain by a flexible polypeptide spacer, e.g., as described in Marks et al., J. Mol. Biol. 222:581-597 (1991), or as Fab fragments secreted into the periplasm of bacterial host cells upon assembly of the Fab coat protein structure, one chain fused to pill and the other chain displayed on the phage surface by replacing some of the wild-type coat protein, e.g., as described in Hoogenboom et al., Nucl. Acids. Res., 19:4133-4137 (1991).

[0086] Generally, nucleic acids encoding antibody gene fragments are obtained from immune cells collected from humans or animals. If a library biased in favor of desired clones is desired, an individual is immunized with an antigen to generate an antibody response, and circulating B cells, such as spleen cells and / or other peripheral blood lymphocytes (PBLs), are collected for library construction.

[0087] Further enrichment of the antigen-reactive cell population can be obtained by isolating B cells expressing antigen-specific membrane-bound antibodies using appropriate screening techniques, for example, cell separation by affinity chromatography using the antigen, or fluorescent dye labeling, adsorption of cells to the antigen followed by fluorescence activated cell sorting (FACS).

[0088] Alternatively, the use of spleen cells and / or B cells or other PBLs from unimmunized donors provides a better representation of the potential antibody repertoire and allows the construction of antibody libraries using any animal species (human or non-human) with different immunogens. For libraries incorporating in vitro antibody gene constructs, stem cells are collected from an individual to provide nucleic acids encoding unrearranged antibody gene segments. The subject's immune cells can be obtained from a variety of animal species, including humans, mice, rats, lagomorphs, wolves, canines, felines, porcines, cattle, horses, and avian species.

[0089] Nucleic acids encoding antibody variable gene segments (including VH and VL segments) are recovered and amplified from cells of interest. In the case of rearranged VH and VL gene libraries, the desired DNA can be obtained by isolating genomic DNA or mRNA from lymphocytes and performing polymerase chain reaction (PCR) with primers corresponding to the 5' and 3' ends of the rearranged VH and VL genes, as described in Orlandi et al., Proc. Natl. Acad. Sci. (USA), 86: 3833-3837 (1989), thereby generating a diverse V gene repertoire for expression. The V genes can be amplified from cDNA and genomic DNA using a back primer at the 5' end of the exon encoding the mature V domain and a forward primer based on the J segment, as described in Orlandi et al., (1989) and Ward et al., Nature, 341: 544-546 (1989). However, for amplification from cDNA, back primers can also be based on leader exons as described by Jones et al., Biotechnol., 9:88-89 (1991), and forward primers can be based within the constant region as described by Sastry et al., Proc. Natl. Acad. Sci. (USA) 86:5728-5732 (1989). To maximize complementarity, degeneracy can be incorporated into the primers as described by Orlandi et al. (1989) or Sastry et al. (1989). Preferably, PCR primers targeted to each V gene family are used to amplify all available VH and VL sequences present in a nucleic acid sample of immune cells, maximizing the diversity of the library, as described, for example, in the method of Marks et al., J. Mol. Biol., 222: 581-597 (1991) or in the method of Orum et al., Nucleic Acids Res., 21: 4491-4498 (1993).For cloning of the amplified DNA into an expression vector, a rare restriction site can be introduced as a tag at one end within the PCR primer as described in Orlandi et al. (1989) or by further PCR amplification with tagged primers as described in Clackson et al., Nature, 352: 624-628 (1991).

[0090] Synthetically rearranged V gene repertoires can be derived in vivo from V gene segments. Most human VH gene segments have been cloned and sequenced (as reported in Tomlinson et al., J. Mol. Biol. 227:776-798 (1992)) and mapped (Matsuda et al., Nature Genet. 3:88-94 (1993)); these cloned segments (containing all major conformations of the H1 and H2 loops) are used to generate diverse VH gene repertoires using PCR primers encoding H3 loops of various sequences and lengths, as described in Hoogenboom and Winter, J. Mol. Biol. 227:381-388 (1992). VH repertoires can also be generated with all sequence diversity focused on a single, long H3 loop, as described by Barbas et al., Proc. Natl. Acad. Sci. USA, 89: 4457-4461 (1992). Human Vκ and Vλ segments have been cloned and sequenced (Williams and Winter, Eur. J. Immunol., 23: 1456-1461 (1993)) and can be used to generate synthetic light chain repertoires. Synthetic V gene repertoires based on a range of VH and VL folds and L3 and H3 lengths encode antibodies with considerable structural diversity. Following amplification of DNA-encoded V gene segments, germline V gene segments can be rearranged in vitro according to the method of Hoogenboom and Winter, J. Mol. Biol. 227: 381-388 (1992).

[0091] Antibody fragment repertoires can be constructed by combining VH and VL gene repertoires together in several ways. Each repertoire can be generated in a different vector, which can be generated in vitro, for example, as described by Hogrefe et al., Gene, 128: 119-126 (1993), or in vivo by combinatorial infection, for example, the loxP system described by Waterhouse et al., Nucl. Acids Res., 21: 2265-2266 (1993). This in vivo recombination approach utilizes Fab fragments of two-chain species to overcome the library size limitations imposed by the transformation efficiency of E. coli. Naive VH and VL repertoires are cloned separately, one into a phagemid and the other into a phage vector. The two libraries are then combined by phage infection of phagemid-containing bacteria, such that each cell contains a different combination and the size of the library is limited only by the number of cells present (approximately 10 clones). Both vectors contain in vivo recombination signals, allowing the VH and VL genes to be recombined into a single replicon and co-packaged into phage virions. These large libraries provide many diverse antibodies with good affinity (Kd of approximately 10 M).

[0092] Alternatively, the repertoire can be assembled by sequential cloning into the same vector, as described, for example, in Barbas et al., Proc. Natl. Acad. Sci. USA 88:7978-7982 (1991), or by PCR followed by cloning, as described in Clarkson et al., Nature, 352:624-628 (1991). PCR assembly can also be used to link VH and VL DNA with DNA encoding a flexible peptide spacer to form single-chain Fv (scFv) repertoires. In yet another technique, "in cellular PCR assembly" is used to combine VH and VL genes in lymphocytes by PCR, followed by cloning the repertoire of linked genes, as described in Embleton et al., Nucl. Acids Res., 20:3831-3837 (1992).

[0093] Antibodies produced by naive libraries (either natural or synthetic) have moderate affinity (approximately 10 6 ~10 7 M -1 Kd -1 ), but Winter et al. (1994), supra Affinity maturation can also be mimicked in vitro by constructing and isolating a second library as described above. Mutations can be randomly introduced in vitro, for example, by using an error-prone polymerase (as reported in Leung et al., Technique, 1:11-15 (1989)) in the manner of Hawkins et al., J. Mol. Biol. 226:889-896 (1992) or Gram et al., Proc. Natl. Acad. Sci. USA, 89:3576-3580 (1992). Furthermore, affinity maturation can be performed by randomly mutating one or more CDRs, for example, by PCR with primers containing random sequences spanning the CDRs of interest in selected individual Fv clones, and screening for higher affinity clones. International Publication No. 9607754 (published March 14, 1996) describes a method for generating a library of light chain genes by directing mutagenesis into the complementarity-determining regions of immunoglobulin light chains. Another effective approach is to recombine VH or VL domains selected by phage display with a repertoire of naturally occurring V domain variants obtained from unimmunized donors, and screen for higher affinity in several rounds of chain shuffling, as described by Marks et al., Biotechnol. 10: 779-783 (1992). This technique has been used for over 10 -9 This allows the production of antibodies and antibody fragments with a range of affinities.

[0094] Nucleic acid and amino acid sequences of antigens, such as tumor antigens encompassed by this disclosure, are known in the art. A nucleic acid sequence encoding a target antigen can be designed using the amino acid sequence of the desired region of the antigen.

[0095] Nucleic acids encoding target antigens can be prepared by a variety of methods known in the art. These methods include, but are not limited to, chemical synthesis by any of the methods described in Engels et al., Agnew. Chem. Int. Ed. Engl., 28: 716-734 (1989), such as triester, phosphite, phosphoramidite, and H-phosphonate methods. In one embodiment, codons preferred by the expression host cell are used to design the antigen-encoding DNA. Alternatively, antigen-encoding DNA can be isolated from a genomic or cDNA library.

[0096] Following construction of a DNA molecule encoding an antigen, the DNA molecule is operably linked to an expression control sequence of an expression vector, such as a plasmid, which control sequence is recognized by a host cell transformed with the vector. Generally, plasmid vectors contain replication and control sequences derived from a species compatible with the host cell. The vector usually contains a replication site as well as sequences encoding proteins that are capable of providing phenotypic selection in transformed cells. Vectors suitable for expression in prokaryotic and eukaryotic host cells are known in the art, and some are further described herein. Prokaryotes, such as yeast, or cells derived from multicellular organisms, such as mammals, can be used. In some cases, the DNA encoding the antigen is operably linked to a secretory leader sequence that causes secretion of the expression product into the culture medium by the host cell. Examples of secretory leader sequences include stII, ecotin, lamB, herpes GD, lpp, alkaline phosphatase, invertase, and alpha factor. Also suitable for use herein is the 36 amino acid leader sequence of protein A (Abrahmsen et al., EMBO J., 4:3901 (1985)).

[0097] Host cells are transfected, or preferably transformed, with the above-described expression or cloning vectors of this invention and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying genes encoding the desired sequences.

[0098] Transfection refers to the uptake of an expression vector by a host cell, which may or may not actually express any coding sequences. Many methods of transfection are known to those of ordinary skill in the art, such as CaPO precipitation and electroporation. Successful transfection is generally recognized when there is evidence of the vector functioning within the host cell.

[0099] Transformation means introducing DNA into an organism so that the DNA is replicable, either as an extrachromosomal element or by chromosomal integration. Depending on the host cell used, transformation is performed using basic techniques appropriate to the cell. Transformation methods are known in the art, some of which are further described herein.

[0100] Prokaryotic host cells used to produce the antigen may generally be cultured as described in Sambrook et al., supra. The mammalian host cells used to produce the antigen may be cultured in a variety of media, which are well known in the art, some of which are described herein. The host cells referred to in this disclosure include cells in in vitro culture as well as cells within a host animal. Purification of the antigen is carried out using art-recognized methods, some of which are described herein.

[0101] Affinity chromatographic separation of phage display clones For use in affinity chromatography separation of phage-displayed clones, purified antigen proteins can be attached to suitable substrates such as agarose beads, acrylamide beads, glass beads, cellulose, various acrylic copolymers, hydroxyl methacrylic gels, polyacrylic and polymethacrylic copolymers, nylon, neutral and ionic carriers, etc. Attachment of antigen proteins to substrates can be accomplished by the method described in Methods in Enzymology, Vol. 44 (1976). A widely used technique for attaching protein ligands to polysaccharide substrates such as agarose, dextran, or cellulose involves activation of the support with cyanogen halide, followed by coupling of the primary aliphatic or aromatic amine of the peptide ligand to the activated substrate. Alternatively, antigens can be used to coat the wells of absorbent plates, expressed on host cells attached to absorbent plates or used in cell sorting, or conjugated with biotin for capture by streptavidin-coated beads, or any other method known in the art for panning phage display libraries. A sample of the phage library is contacted with the immobilized antigen under conditions suitable for binding of at least a portion of the phage particles to the adsorbent. Conditions, including pH, ionic strength, and temperature, are typically selected to mimic physiological conditions. The bound phage are washed and then eluted with acid, as described, for example, in Barbas et al., Proc. Natl. Acad. Sci. USA, 88:7978-7982 (1991), or alkali, as described, for example, in Marks et al., J. Mol. Biol., 222:581-597 (1991), or by a technique similar to the antigen competition method described, for example, in Clackson et al., Nature, 352:624-628 (1991). Phage can be enriched 20- to 1,000-fold after the first round of selection. Furthermore, the enriched phage can be grown in bacterial culture and subjected to additional rounds of selection.

[0102] The efficiency of selection depends on many factors, including the kinetics of dissociation during washing and whether multiple antibody fragments on a single phage can simultaneously engage with antigen. Antibodies with first-order dissociation constants (and weak binding affinity) can be retained by using short washes, multivalent phage display, and high coating densities of antigen on the solid phase. High density not only stabilizes phage through multivalent interactions, but also favors rebinding of dissociated phage. Selection of antibodies with slow dissociation kinetics (and good binding affinity) can be facilitated by using long washes and monovalent phage display, as described in Bass et al., Proteins, 8: 309-314 (1990) and WO 92 / 09690, and by using low coating densities of antigen, as described in Marks et al., Biotechnol., 10: 779-783 (1992). Even slight differences in affinity make it possible to select among phage antibodies with different affinities for an antigen. However, random mutation of a selected antibody (e.g., as performed in some of the affinity maturation techniques described above) is likely to generate many mutations, most of which bind to the antigen and a few with higher affinity. Limiting the antigen allows rare high-affinity phage to be competed out. To retain all higher-affinity mutations, phage can be incubated with an excess of biotinylated antigen, but at a molar concentration lower than the target molar affinity constant for the antigen. High-affinity binding phage can then be captured by streptavidin-coated paramagnetic beads. Such "equilibrium capture" allows for the selection of antibodies according to binding affinity, with sensitivity enabling the isolation of mutant clones with only two-fold higher affinity from an excess of low-affinity phage. The conditions used to wash phage bound to the solid phase can also be manipulated to allow discrimination based on dissociation constants.

[0103] DNA encoding the monoclonal antibodies from hybridomas or phage-displayed Fv clones of the present disclosure is readily isolated and sequenced using conventional methods (e.g., by using oligonucleotide primers designed to specifically amplify the heavy and light chain or phage DNA template encoding the region of interest in the hybridoma). Once isolated, the DNA can be placed into an expression vector, which can then be transfected into host cells such as E. coli cells, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce antibody protein, to obtain synthesis of the monoclonal antibody in the recombinant host cells. Review articles on recombinant bacterial expression of antibody-encoding DNA include Skerra et al., Curr. Opinion in Immunol., 5:256-262 (1993) and Pluckthun, Immunol. Revs. 130: 151-188 (1992).

[0104] DNA encoding the Fv clones of the present disclosure can be combined with known DNA sequences encoding heavy and / or light chain constant regions (e.g., suitable DNA sequences can be obtained from Kabat et al., supra) to form clones encoding full-length or partial heavy and / or light chains. It will be understood that constant regions of any isotype can be used for this purpose, e.g., IgG, IgM, IgA, IgD, and IgE constant regions. Such constant regions can be derived from any human or animal species. Fv clones derived from variable domain DNA of one animal (e.g., human) species and then fused to constant region DNA of another animal species to form "hybrid" full-length heavy and / or light chain coding sequences are included in the definition of "chimeric" and "hybrid" antibodies as used herein. In a preferred embodiment, Fv clones derived from human variable DNA are fused to human constant region DNA to form fully human, full-length, or partial heavy and / or light chain coding sequences.

[0105] DNA encoding antibodies derived from hybridomas of the present disclosure can also be modified, for example, by substituting coding sequences for human heavy and light chain constant domains for the homologous murine sequences derived from the hybridoma clone (e.g., by the method of Morrison et al., Proc. Nat. Acad. Sci. USA, 81:6851 (1984)). DNA encoding antibodies or antibody fragments derived from hybridomas or Fv clones can be further modified by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. In this manner, "chimeric" or "hybrid" antibodies can be prepared that have the binding specificity of antibodies derived from the Fv clones or hybridoma clones of the present disclosure.

[0106] The present disclosure encompasses antibody fragments. In certain cases, there are advantages to using antibody fragments rather than whole antibodies. The smaller size of the fragments may allow for faster clearance and improved access to solid tumors.

[0107] Various techniques have been developed for the production of antibody fragments. Traditionally, these fragments were derived via proteolytic digestion of intact antibodies (see, e.g., Morimoto et al., Journal of Biochemical and Biophysical Methods 24:107-117 (1992) and Brennan et al., Science 229:81 (1985)). However, these fragments can now be produced directly by recombinant host cells. For example, Fab, Fv, and ScFv antibody fragments can all be expressed in and secreted from E. coli, facilitating large-scale production of these fragments. Antibody fragments can be isolated from the antibody phage libraries discussed above. Alternatively, Fab'-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab')2 fragments (Carter et al., Bio / Technology 10:163-167 (1992)). In another approach, F(ab')2 fragments can be directly isolated from recombinant host cell culture. Fab and F(ab')2 fragments containing salvage receptor-binding epitope residues and exhibiting increased in vivo half-lives are described in U.S. Pat. No. 5,869,046. Other methods for producing antibody fragments will be apparent to those skilled in the art. In another embodiment, the antibody of choice is a single-chain Fv fragment (scFv). See WO 93 / 16185; U.S. Pat. No. 5,571,894; and U.S. Pat. No. 5,587,458. Fv and sFv are the only species with intact binding sites that lack constant regions; therefore, they are suitable for reducing nonspecific binding during in vivo use. sFv fusion proteins can be constructed to allow fusion of effector proteins at either the amino or carboxy terminus of sFv. See Antibody Engineering, ed. Borrebaeck, supra. Antibody fragments may also be "linear antibodies," e.g., as described in U.S. Pat. No. 5,641,870. Such linear fragments may be monospecific or bispecific.

[0108] The present disclosure encompasses humanized antibodies. Various methods for humanizing non-human antibodies are well known in the art. For example, a humanized antibody has one or more amino acid residues introduced into it from a non-human source. These non-human amino acid residues are often referred to as "import" residues, typically from an "import" variable domain. Humanization can be performed using the method of Winter and coworkers (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)) by substituting the appropriate hypervariable region sequences of essentially a human antibody. Such "humanized" antibodies are thus chimeric antibodies (U.S. Pat. No. 4,816,567) in which substantially less than an intact human variable domain has been substituted by the appropriate sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some hypervariable region residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.

[0109] To reduce antigenicity, the selection of human variable domains, both light and heavy, to be used in generating humanized antibodies is crucial. In the "best-fit" method, the sequence of the variable domain of a rodent antibody is screened against the entire library of known human variable domain sequences. The human sequence that is closest to that of the rodent is then accepted as the human framework region of the humanized antibody (Sims et al., J. Immunol., 151:2296 (1993); Chothia et al., J. Mol. Biol., 196:901 (1987)). Another method uses a particular framework region derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains. The same framework can be used for several different humanized antibodies (Carter et al., Proc. Natl. Acad. Sci. USA, 89:4285 (1992); Presta et al., J. Immunol., 151:2623 (1993)).

[0110] It is also important that antibodies be humanized with retention of high affinity for the antigen and other favorable biological properties. To achieve this goal, one method involves the preparation of humanized antibodies by a process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are commercially available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., analysis of residues that influence the ability of the candidate immunoglobulin to bind to its antigen. In this way, FR residues can be selected and combined from the recipient and import sequences so that the desired antibody characteristic, such as increased affinity for the target antigen, is achieved. In general, hypervariable region residues are directly and most substantially involved in influencing antigen binding.

[0111] Antibodies encompassed by the present disclosure can be constructed by combining Fv clone variable domain sequences selected from a human-derived phage display library with known human constant domain sequences, as described above. Alternatively, human monoclonal antibodies of the present disclosure can be produced by hybridoma technology. Human myeloma and mouse myeloma cells can be used to generate human monoclonal antibodies. - Human heteromyeloma cell lines are described, for example, in Kozbor, J. Immunol. 133, 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147: 86 (1991).

[0112] It is now possible to produce transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production. For example, it has been described that the homozygous deletion of the antibody heavy-chain joining region (JH) gene in chimeric and germ-line mutant mice results in complete inhibition of endogenous antibody production. Transfer of human germ-line immunoglobulin gene sequences in such germ-line mutant mice results in the production of human antibodies upon antigen challenge. See, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. USA 90, 2551-255 (1993); Jakobovits et al., Nature 362, 255-258 (1993).

[0113] Gene shuffling can also be used to derive human antibodies from nonhuman, e.g., rodent, antibodies, if the human antibodies have similar affinities and properties to the starting nonhuman, e.g., rodent, antibody. This method, also known as "epitope imprinting," involves replacing either the heavy or light chain variable region genes of nonhuman antibody fragments obtained by the above-described phage display technology with a repertoire of human V domain genes, generating a population of nonhuman / human chain chimeric scFvs or Fabs. Antigen selection results in the isolation of nonhuman / human chain chimeric scFvs or Fabs in which the human chain restores the antigen-binding site disrupted by removal of the matching nonhuman chain in the initial phage display clone; i.e., the epitope governs (imprints) the selection of the human chain partner. Repeating this process to replace the remaining nonhuman chains yields human antibodies (see PCT Patent Application WO 93 / 06213, published April 1, 1993). Unlike traditional humanization of non-human antibodies by CDR grafting, this technique provides completely human antibodies, which have no FR or CDR residues of non-human origin.

[0114] Bispecific antibodies are monoclonal antibodies, preferably human or humanized, that have binding specificities for at least two different epitopes. In this case, one binding specificity is for a specific antigen and the other is for any other antigen. Exemplary bispecific antibodies can bind to two different epitopes of a single antigen. Bispecific antibodies can also be used to localize cytotoxic activity to cells expressing the antigen. These antibodies combine an antigen-binding arm and a CD3-binding arm to exert T-cell-dependent cytotoxic activity. Bispecific antibodies can be prepared as full-length antibodies or antibody fragments (e.g., F(ab')2 bispecific antibodies).

[0115] In the present disclosure, a "domain comprising an antibody variable region having T cell receptor complex-binding activity" refers to a portion of a T cell receptor complex antibody comprising a region that specifically binds to and is complementary to a part or all of a T cell receptor complex. The T cell receptor complex may be the T cell receptor itself, or an adaptor molecule that forms the T cell receptor complex together with the T cell receptor. A preferred adaptor is CD3.

[0116] In the present disclosure, a "domain comprising an antibody variable region having T cell receptor binding activity" refers to a portion of a T cell receptor antibody comprising a region that specifically binds to and is complementary to part or all of a T cell receptor. The portion of the T cell receptor to which the domain of the present disclosure binds may be a variable region or a constant region, but preferably an epitope present in the constant region. Examples of constant region sequences include the T cell receptor α chain (RefSeq Accession No. CAA26636.1) (SEQ ID NO: 64), the T cell receptor β chain (RefSeq Accession No. C25777) (SEQ ID NO: 65), the T cell receptor γ1 chain (RefSeq Accession No. A26659) (SEQ ID NO: 66), the T cell receptor γ2 chain (RefSeq Accession No. AAB63312.1) (SEQ ID NO: 67), and the T cell receptor δ chain (RefSeq Accession No. AAA61033.1) (SEQ ID NO: 68).

[0117] In the present disclosure, a "domain comprising an antibody variable region having CD3-binding activity" refers to a portion of an anti-CD3 antibody comprising a region that specifically binds to and is complementary to a part or all of CD3. Preferably, the domain comprises the light chain variable region (VL) of an anti-CD3 antibody and the heavy chain variable region (VH) of an anti-CD3 antibody. Suitable examples of such domains include "scFv (single chain Fv)," "single chain antibody," "Fv," "scFv2 (single chain Fv 2)," "Fab," and "F(ab')2."

[0118] The domains comprising antibody variable regions with CD3-binding activity according to the present disclosure may bind to any epitope present in the gamma, delta, or epsilon chain sequences constituting human CD3. In the present disclosure, a domain comprising a light chain variable region (VL) and a heavy chain variable region (VH) of an anti-CD3 antibody that binds to an epitope present in the extracellular domain of the epsilon chain of the human CD3 complex is preferably used. Examples of such domains include the light chain variable region (VL) and heavy chain variable region (VH) of an anti-CD3 antibody described in the Examples, as well as CD3-binding domains comprising the light chain variable region (VL) and heavy chain variable region (VH) of an OKT3 antibody (Proc. Natl. Acad. Sci. USA (1980) 77, 4914-4917) and various other known CD3 antibodies. Alternatively, a domain containing an antibody variable region derived from an anti-CD3 antibody having desired properties obtained by immunizing a desired animal with the gamma, delta, or epsilon chain constituting human CD3 using the aforementioned method may be used. As described above, a humanized or human antibody may be used as the anti-CD3 antibody from which the domain containing the antibody variable region having CD3-binding activity is derived. The polynucleotide sequences of the gamma, delta, or epsilon chains constituting CD3 are registered in RefSeq under accession numbers NM_000073.2, NM_000732.4, and NM_000733.3, and the polypeptide sequences thereof are registered under RefSeq accession numbers NP_000064.1, NP_000723.1, and NP_000724.1.

[0119] Methods for generating bispecific antibodies are known in the art. Traditional recombinant production of bispecific antibodies is based on the coexpression of two immunoglobulin heavy-light chain pairs, where the two heavy chains have different specificities (Millstein et al., Nature, 305:537-539 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (tetrahybrids) produce a potential mixture of 10 different antibody molecules, of which only one has the correct bispecific structure. Purification of the correct molecule, usually by affinity chromatography steps, is quite cumbersome and results in low product yields. Similar methods are disclosed in WO 93 / 08829, published May 13, 1993, and Traunecker et al., EMBO J. 10:3655-3659 (1991).

[0120] In a different, more preferred approach, antibody variable domains with the desired binding specificities (antibody-antigen combining sites) are fused to immunoglobulin constant domain sequences. The fusions are preferably to immunoglobulin heavy-chain constant domains, comprising at least part of the hinge, CH2, and CH3 regions. The first heavy-chain constant region (CH1), containing the site necessary for light-chain binding, is preferably present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors and co-transfected into a suitable host organism. This allows for great flexibility in adjusting the relative proportions of the three polypeptide fragments in embodiments where unequal ratios of the three polypeptide chains used in the construct provide optimal yields. However, when expression of at least two polypeptide chains in equal ratios results in high yields, or when the ratio is not particularly critical, it is possible to insert the coding sequences for two or all three polypeptide chains into a single expression vector. In a preferred embodiment of this approach, the bispecific antibody consists of a hybrid immunoglobulin heavy chain with a first binding specificity in one arm and a hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) in the other arm. This asymmetric structure has been found to facilitate separation of the desired bispecific compound from unwanted immunoglobulin chain combinations, since the presence of an immunoglobulin light chain in only half of the bispecific molecule provides a facile separation method. This approach is disclosed in International Publication No. 94 / 04690. For further details on producing bispecific antibodies, see, e.g., Suresh et al., Methods in Enzymology, 121:210 (1986).

[0121] According to another approach, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH3 domain of the antibody constant domain. In this method, one or more small amino acid side chains from the interface of a first antibody molecule are replaced with larger side chains (e.g., tyrosine or tryptophan). A complementary "cavity" of identical or similar size to the large side chain(s) is created at the interface of the second antibody molecule by replacing the large amino acid side chain with a smaller one (e.g., alanine or threonine). This provides a mechanism for increasing the yield of heterodimers over other unwanted end-products such as homodimers. In the present disclosure, the term "interface" generally refers to the surface at which association (interaction) occurs, and the amino acid residues that form the interface generally refer to one or more amino acid residues contained in the polypeptide region involved in the association, more preferably amino acid residues that come close to each other during association and are involved in the interaction. Specific examples of such interactions include those formed by hydrogen bonds, electrostatic interactions, salt bridges, etc., between amino acid residues that come close to each other during association. In the present disclosure, "amino acid residues forming an interface" refers, more specifically, to amino acid residues contained in a polypeptide region that constitutes the interface. For example, a polypeptide region that forms an interface refers to a polypeptide region that is responsible for selective intermolecular binding in antibodies, ligands, receptors, substrates, etc. Specific examples of such polypeptide regions in antibodies include heavy chain constant regions, heavy chain variable regions, light chain constant regions, and light chain variable regions. In the present disclosure, the terms "controlling the association" and "the association is controlled" refer to controlling the association to a desired state, and more specifically, to controlling the association to prevent the formation of an undesirable association between a heavy chain and a light chain.

[0122] two heavy Specific antibodies include cross-linked antibodies and "heteroconjugate antibodies." For example, one antibody in a heteroconjugate may be conjugated to avidin and the other to biotin. Such antibodies have been used, for example, to target immune system cells to unwanted cells (U.S. Pat. No. 4,676,980) and to treat HIV infection (WO 91 / 00360, WO 92 / 00373, and EP 03089). etc. Uses have been proposed. Heteroconjugate antibodies can be made using appropriate cross-linking methods. Suitable cross-linking agents are known in the art; several cross-linking methods are described, for example, in U.S. Patent No. 4,676,980.

[0123] The chimeric receptors of the present disclosure can be engineered to contain an extracellular domain with an antigen-binding domain fused to the intracellular signaling domain of the T cell antigen receptor complex zeta chain (e.g., CD3 zeta). The CARs of the present disclosure, when expressed in T cells, can redirect antigen recognition based on antigen-binding specificity.

[0124] With respect to the transmembrane domain, a chimeric receptor can be designed to contain a transmembrane domain fused to its extracellular domain. In one embodiment, the transmembrane domain naturally associated with one of the domains in the chimeric receptor is used. In some cases, the transmembrane domain can be selected or modified by amino acid substitution to avoid binding of such domain to the transmembrane domain of the same or a different surface membrane protein, in order to minimize interaction with other members of the receptor complex. The transmembrane domain may be derived from either natural or synthetic sources. If the source is natural, the domain may be derived from any membrane-bound or transmembrane protein. Transmembrane regions of particular utility in the present disclosure may be derived from (i.e., including at least the transmembrane regions of) the alpha, beta, or zeta chains of the T cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, or CD154. Alternatively, the transmembrane domain may be synthetic, in which case it will primarily comprise hydrophobic residues such as leucine and valine. Preferably, triplets of phenylalanine, tryptophan, and valine will be found at each end of the synthetic transmembrane domain. Optionally, a short oligopeptide or polypeptide linker, preferably 2-10 amino acids in length, may form the link between the transmembrane and cytoplasmic signaling domains of the chimeric receptor. A glycine-serine doublet is a particularly suitable linker.

[0125] The cytoplasmic domain, or alternatively, the intracellular signaling domain, of the chimeric receptor of the present disclosure is responsible for activating at least one of the normal effector functions of an immune cell expressing the chimeric receptor. The term "effector function" refers to a specialized function of a cell. For example, the effector function of a T cell may be cytolytic activity or helper activity, including cytokine secretion. Thus, the term "intracellular signaling domain" refers to the portion of a protein that transmits an effector function signal to direct the cell to carry out a specialized function. While the entire intracellular signaling domain can usually be used, in many cases it is not necessary to use the entire chain. To the extent that a truncated portion of the intracellular signaling domain is used, such a truncated portion can be used in place of the intact chain, so long as it transmits the effector function signal. The term intracellular signaling domain, therefore, is intended to include any truncated portion of the intracellular signaling domain sufficient to transmit the effector function signal. Preferred examples of intracellular signaling domains for use in the chimeric receptors of the present disclosure include the cytoplasmic sequences of the T cell receptor (TCR) and coreceptors that act cooperatively to initiate signal transduction following engagement of the receptor with an antigen, as well as any derivatives or variants of these sequences and any synthetic sequences that have the same functional capabilities. It is known that signals generated through the TCR alone are insufficient for full activation of T cells, and that secondary or costimulatory signals are also required. Thus, T cell activation can be said to be mediated by two distinct classes of cytoplasmic signaling sequences: those that initiate antigen-dependent primary activation through the TCR (primary cytoplasmic signaling sequences), and those that act in an antigen-independent manner to provide secondary or costimulatory signals (secondary cytoplasmic signaling sequences).

[0126] Prior to the expansion and genetic modification of T cells of the present disclosure, a source of T cells is obtained from a subject. T cells can be obtained from numerous sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from an infection site, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present disclosure, any of the various T cell lines available in the art can be used. In certain embodiments of the present disclosure, T cells are obtained from a blood unit collected from a subject using any of a variety of techniques known to those skilled in the art, such as Ficoll™ separation. In a preferred embodiment, cells from an individual's shed blood are obtained by apheresis. The apheresis product typically contains lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and platelets. In one embodiment, cells collected by apheresis can be washed to remove the plasma fraction, and then placed in an appropriate buffer or medium for subsequent processing steps. In one embodiment of the present disclosure, the cells are washed with phosphate-buffered saline (PBS). In an alternative embodiment, the wash solution is calcium-free and magnesium-free, or free of many, but not all, divalent cations. Surprisingly, an initial activation step in the absence of calcium also results in enhanced activation. As those skilled in the art will readily appreciate, the wash step can be accomplished by methods known in the art, such as by using a semi-automated "flow-through" centrifuge (e.g., a Cobe 2991 cell processor, a Baxter CytoMate, or a Haemonetics Cell Saver 5) according to the manufacturer's instructions. After washing, the cells can be resuspended in various biocompatible buffers, such as Ca2+-free, Mg2+-free PBS, PlasmaLyte A, or other saline solutions with or without buffering agents. Alternatively, undesirable components of the apheresis sample can be removed and the cells resuspended directly in culture medium.

[0127] either before or after genetic modification of T cells to express the desired chimeric receptor In this regard, T cells can generally be activated and expanded using methods described in, for example, U.S. Patent Nos. 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041; and U.S. Patent Application Publication No. 20060121005. Generally, T cells of the present disclosure are expanded by contact with a surface bearing an agent that stimulates a CD3 / TCR complex-associated signal and a ligand that stimulates a costimulatory molecule on the surface of the T cells. In particular, the T cell population can be expanded by contact with a surface bearing an agent that stimulates a CD3 / TCR complex-associated signal and a ligand that stimulates a costimulatory molecule on the surface of the T cells, e.g., a surface-bound T cell population, as described herein. by contact with an immobilized anti-CD3 antibody or antigen-binding fragment thereof or anti-CD2 antibody, or a protein kinase C activator (e.g., with a calcium ionophore). The antigens on the surface of T cells can be stimulated by contact with antibodies (antigens, bryostatin, etc.). For costimulation of accessory molecules, a ligand that binds the accessory molecule is used. For example, a population of T cells can be treated with anti-CD3 antibody and an anti-CD3 antibody under conditions suitable for stimulating T cell proliferation. and an anti-CD28 antibody. To stimulate the proliferation of either CD4+ T cells or CD8+ T cells, an anti-CD3 antibody and an anti-CD28 antibody are used. Examples of anti-CD28 antibodies include 9.3, B-T3, and XR-CD28 (Diaclone, Besancon, France), and are commonly known in the art. This method can be used in conjunction with other methods (Berg et al., Transplant Proc. 30(8):3975-3977, 1998; Haanen et al., J. Exp. Med. 190(9):1319). -1328, 1999; Garland et al., J. Immunol Meth. 227(1-2):53-63, 1999).

[0128] The present disclosure encompasses cells (e.g., T cells) transduced with lentiviral vectors (LVs). For example, the LVs encode chimeric receptors that combine the antigen recognition domain of a specific antibody with the intracellular domain of CD3-zeta, CD28, 4-1BB, or any combination thereof. Thus, in some cases, the transduced T cells are capable of eliciting T cell responses mediated by the chimeric receptor. The present disclosure provides the use of CAR to redirect the specificity of primary T cells toward tumor antigens. Thus, the present disclosure also provides a method for stimulating a T cell-mediated immune response against a target cell population or tissue in a mammal, comprising administering a T cell expressing a CAR to the mammal, wherein the CAR comprises a binding moiety that specifically interacts with a predetermined target, such as a zeta chain portion comprising the intracellular domain of human CD3ζ, and a costimulatory signaling region. In one embodiment, the present disclosure includes a type of cell therapy in which T cells are genetically modified to express chimeric receptors, and the CAR-T cells are infused into recipients in need thereof. The infused cells can kill tumor cells in the recipients. Unlike antibody therapy, CAR-T cells can replicate in vivo, resulting in long-term persistence that can lead to sustained tumor control.

[0129] Techniques for generating bispecific antibodies from antibody fragments have also been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science, 229:81 (1985) described a procedure for proteolytic cleavage of intact antibodies to produce F(ab')2 fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The fragments are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab'-TNB derivatives is then reconverted to the Fab'-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab'-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.

[0130] Recently, it has become easier to directly recover Fab'-SH fragments from E. coli, which can then be chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med., 175: 217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab')2 molecule. Each Fab' fragment was separately secreted from E. coli and chemically coupled in vitro. The resulting bispecific antibody not only binds to HER2-overexpressing cells and normal human T cells, but also binds to human breast cancer cells. It could trigger the lytic activity of human cytotoxic lymphocytes against tumor targets.

[0131] Various methods for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers (Kostelny et al., J. Immunol., 148(5):1547-1553 (1992)). Leucine zipper peptides from the Fos and Jun proteins were attached to the Fab' portions of two different antibodies by gene fusion. Antibody homodimers were reduced at the hinge region to form monomers and then reoxidized to form antibody heterodimers. This method can also be used for the production of antibody homodimers. The "diabody" technology described by Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993) provided another mechanism for generating bispecific antibody fragments. The fragments consist of a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) by a linker short enough to allow pairing between the two domains on the same chain. Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See Gruber et al., J. Immunol., 152:5368 (1994). More than bivalent antibodies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991).

[0132] Multivalent antibodies may be internalized (and / or catabolized) more quickly than bivalent antibodies by cells expressing the antigen to which the antibody binds. The antibodies of the present disclosure may be multivalent antibodies (other than IgM class) with three or more binding sites (e.g., tetravalent antibodies), which can be easily produced by recombinant expression of nucleic acids encoding antibody polypeptide chains. Multivalent antibodies have a dimerization domain and three or more antigen-binding sites. A preferred dimerization domain comprises (or consists of) an Fc region or hinge region. In this scenario, the antibody would have an Fc region and three or more antigen-binding sites at the amino terminus of the Fc region. Here, preferred multivalent antibodies have (or consist of) three to eight, preferably four, antigen-binding sites. Multivalent antibodies have at least one polypeptide chain (preferably two polypeptide chains), and the polypeptide chain(s) have two or more variable domains. For example, the polypeptide chain(s) may comprise VD1-(X1). n -VD2-(X2) n -Fc, where VD1 is a first variable domain and VD2 is a second variable domain, Fc is one of the polypeptide chains of the Fc region, X1 and X2 represent amino acids or polypeptides, and n is 0 or 1. For example, the polypeptide chain(s) may have: VH-CH1-flexible linker-VH-CH1-Fc region chain; or VH-CH1-VH-CH1-Fc region chain. The multivalent antibody herein preferably further comprises at least two (preferably four) light chain variable domain polypeptides. The multivalent antibody herein comprises, for example, about two to about eight light chain variable domain polypeptides. The light chain variable domain polypeptides discussed herein comprise a light chain variable domain and, optionally, further comprise a CL domain.

[0133] In some embodiments, amino acid sequence modification(s) of the antibodies disclosed herein are contemplated. For example, it may be desirable to improve the binding affinity and / or biological properties of the antibody. Amino acid sequence variants of the antibodies are prepared by introducing appropriate nucleotide changes into the antibody nucleic acid, or by peptide synthesis. Such modifications include, for example, deletion, or insertion or substitution of residues within the antibody amino acid sequence. Any combination of deletion, insertion, or substitution may be used, provided that the final construct possesses the desired characteristics. Amino acid changes may be introduced into the subject antibody amino acid sequence as the sequence is generated.

[0134] A useful method for identifying specific residues or regions of an antibody that are preferred locations for mutagenesis is called "alanine scanning mutagenesis," as disclosed by Cunningham and Wells in Science, 244:1081-1085 (1989). In this method, a target residue or set of residues is identified (e.g., charged residues such as arg, asp, his, lys, and glu) and substituted with neutral or negatively charged amino acids (most preferably alanine or polyalanine) to affect the amino acid's interaction with the antigen. Those amino acid locations demonstrating functional sensitivity to the substitutions are then refined by introducing further or other mutations at, or for, the sites of substitution. In this way, while the sites for introducing amino acid sequence variation are predetermined, the nature of the mutation per se need not be predetermined. For example, to analyze the function of mutations at any site, ala scanning or random mutagenesis is conducted at the target codon or region and the expressed immunoglobulins are screened for the desired activity. Amino acid sequence insertions include amino- and / or carboxy-terminal fusions ranging in length from one residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue or the antibody fused to a cytotoxic polypeptide. Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g., for ADEPT), or a polypeptide which increases the serum half-life of the antibody.

[0135] Glycosylation of polypeptides is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine (where X is any amino acid except proline) are the recognition sequences for enzymatic attachment of a carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.

[0136] Addition of glycosylation sites to the antibody is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites). The alteration may also be made by adding, or substituting, one or more serine or threonine residues to the sequence of the original antibody (for O-linked glycosylation sites). If the antibody contains an Fc region, the carbohydrate attached thereto may be altered. For example, antibodies with a mature carbohydrate structure lacking fucose attached to the Fc region of the antibody are described in U.S. Patent Publication No. 2003 / 0157108 (Presta, L.). See also U.S. Patent Publication No. 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd.). Antibodies with bisecting N-acetylglucosamine (GlcNAc) in the carbohydrate attached to the Fc region of the antibody are referenced in International Publication No. 03 / 011878 (Jean-Mairet et al.) and U.S. Patent No. 6,602,684 (Umana et al.). Antibodies with at least one galactose residue in the oligosaccharide attached to the Fc region of the antibody are reported in International Publ...

Claims

1. A pharmaceutical composition for use in combination with the administration of a mutant antibody having a mutation in a CH1 region, a CH2 region, a CH3 region, a CL region, or a framework region, the mutation comprising at least one amino acid substitution, deletion, addition, or modification, comprising: The pharmaceutical composition comprises a cell expressing the chimeric receptor, The chimeric receptor comprises an extracellular binding domain, a transmembrane domain, and an intracellular signaling domain, the mutated antibody is capable of binding to the extracellular binding domain of the chimeric receptor via a portion of the extracellular binding domain that contains said mutation; The pharmaceutical composition, wherein the extracellular binding domain does not specifically bind to an antibody that does not contain the mutation.

2. 1. A pharmaceutical composition for use in combination with the administration of cells expressing a chimeric receptor, comprising: The pharmaceutical composition comprises a mutant antibody having a mutation in a CH1 region, a CH2 region, a CH3 region, a CL region, or a framework region, the mutation comprising at least one amino acid substitution, deletion, addition, or modification, The chimeric receptor comprises an extracellular binding domain, a transmembrane domain, and an intracellular signaling domain, the mutated antibody is capable of binding to the extracellular binding domain of the chimeric receptor via a portion of the extracellular binding domain that contains said mutation; The pharmaceutical composition, wherein the extracellular binding domain does not specifically bind to an antibody that does not contain the mutation.

3. A pharmaceutical composition for use in combination with the administration of a mutant antibody having a mutation in a CH1 region, a CH2 region, a CH3 region, a CL region, or a framework region, the mutation comprising at least one amino acid substitution, deletion, addition, or modification, comprising: The pharmaceutical composition comprises a bispecific antibody, The bispecific antibody comprises (1) a domain comprising an antibody variable region that specifically binds to a mutated antibody via a portion containing the mutation, and (2) a domain comprising an antibody variable region that has binding activity to a molecule expressed on the surface of T cells, and does not specifically bind to an antibody that does not contain the mutation.

4. 1. A pharmaceutical composition for use in combination with the administration of a bispecific antibody, comprising: The pharmaceutical composition comprises a mutant antibody having a mutation in a CH1 region, a CH2 region, a CH3 region, a CL region, or a framework region, the mutation comprising at least one amino acid substitution, deletion, addition, or modification, The bispecific antibody comprises (1) a domain comprising an antibody variable region that specifically binds to a mutated antibody via a portion containing the mutation, and (2) a domain comprising an antibody variable region that has binding activity to a molecule expressed on the surface of T cells, and does not specifically bind to an antibody that does not contain the mutation.

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the mutated antibody comprises the mutation in the CH2 region, and the mutated antibody has reduced binding activity to Fc gamma receptor and C1q compared to the corresponding non-mutated antibody.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the mutated antibody has a mutation in the CH2 region at any of positions 234, 235, 236, 237, 238, 265, 266, 267, 268, 269, 270, 271, 295, 296, 298, 300, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, and 337 according to EU numbering, and the mutated antibody binds to the extracellular binding domain via the portion containing the mutation.

7. The CH2 region of the mutant antibody is, in EU numbering, The amino acid at position 235 is arginine; The amino acid at position 236 is arginine; The amino acid at position 239 is lysine; The amino acid at position 250 is valine. The amino acid at position 252 is tyrosine; The amino acid at position 297 is alanine; The amino acid at position 307 is glutamine. The amino acid at position 308 is proline; The amino acid at position 311 is alanine; the amino acid at position 434 is tyrosine; and and wherein the mutated antibody binds to the extracellular binding domain via a portion containing the mutation.

8. An isolated nucleic acid encoding a chimeric receptor or a bispecific antibody contained in the pharmaceutical composition of any one of claims 1 to 7.

9. A vector comprising the isolated nucleic acid of claim 8.

10. 10. The vector of claim 9 , which is operably linked to at least one regulatory element for expression of a chimeric receptor or a bispecific antibody.

11. 11. A cell transformed or transduced with an isolated nucleic acid according to claim 8 or a vector according to any of claims 9 or 10.

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