TCR-targeted molecules and their uses

Abstract

In some embodiments, methods for treating autoimmune diseases or conditions using TCR-targeting molecules or cells expressing TCR-targeting molecules are disclosed herein. TCR-targeting molecules may include a moiety that binds to a variable TCR beta chain (TCRBV) or a variable TCR alpha chain (TCRAV). TCR-targeting molecules may further include one, two, or all of the following: (ii) immune cell engagers, (iii) cytokine inhibitors, (iv) cytotoxic agents, and / or (v) death receptor signal enhancers. Furthermore, in some embodiments herein, encoding nucleic acids and methods for producing the aforementioned molecules are disclosed herein.

Description

[Background technology]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 491,399, filed on 21 March 2023, the entire contents of which said application are incorporated herein by reference.

[0002] T cell-mediated antigen recognition relies on the interaction between T cell receptors (TCRs) and antigen-major histocompatibility complexes (MHCs). Heterodimeric TCRs consist of either an α- and β-chain combination (αβ TCR) expressed by the majority of T cells, or a γδ-chain combination (γδ TCR) present in only about 1-5% of T cells. A highly diverse TCR repertoire is a characteristic that underlies an effective immune system. However, the immune repertoire can change significantly with the onset and progression of diseases such as cancer, autoimmune diseases, inflammatory diseases, and infections.

[0003] Autoimmunity can arise from abnormal regulation of the immune system. Autoimmunity can manifest through autoreactive TCR clones that attack the patient's own cells. Improved treatments for autoimmune diseases are needed. [Overview of the project]

[0004] In some embodiments, methods for treating a disease or condition, or for reducing the risk of developing a disease or condition, in subjects where such treatment is necessary, are disclosed herein, and such methods include administering to the subject a therapeutically effective amount of an agent comprising a portion that binds to a TCR variable region. The TCR variable region in question is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV). (a) The disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCRα V1 subfamily. (b) The disease or condition is Crohn's disease, and the portion that binds to the TCR variable region binds to the TCRα V2 subfamily, (c) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRα V4 subfamily. (d) The disease or condition is type 1 diabetes, and the portion that binds to the variable region of the TCR binds to the TCRα V12 subfamily. (e) The disease or condition is Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCRα V13 subfamily, (f) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRα V20 subfamily. (g) The disease or condition is ankylosing spondylitis, and the portion that binds to the variable region of the TCR binds to the TCRα V21 subfamily. (h) The disease or condition is Crohn's disease, and the portion that binds to the TCR variable region binds to the TCRα V22 subfamily, (i) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRα V26 subfamily, (j) The disease or condition is Crohn's disease, and the portion that binds to the TCR variable region binds to the TCRα V40 subfamily. (k) The disease or condition is a malfunction of the joint implant, and the portion that binds to the TCR variable region binds to the TCRα V41 subfamily, (l) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRβ V4 subfamily. (m) The disease or condition is primary Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCRβ V6 subfamily. (n) The disease or condition is amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V7 subfamily. (o) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRβ V7 subfamily. (p) The disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V7 subfamily. (q) The disease or condition is ankylosing spondylitis, and the portion that binds to the variable region of the TCR binds to the TCRβ V9 subfamily, (r) The disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V10 subfamily. (s) The disease or condition is a COVID-associated multisystem inflammatory syndrome in children, and the portion that binds to the TCR variable region binds to the TCRβ V11 subfamily. (t) The disease or condition is type 1 diabetes, and the portion that binds to the TCR variable region binds to the TCRβ V12 subfamily. (u) The disease or condition is multiple sclerosis, and the portion that binds to the variable region of the TCR binds to the TCRβ V10 subfamily. (v) The disease or condition is amyotrophic lateral sclerosis, and the portion that binds to the variable region of the TCR binds to the TCRβ V23 subfamily, or (w) The disease or condition is multiple sclerosis, and the portion that binds to the variable region of the TCR binds to the TCRβ V29 subfamily.

[0005] In some embodiments, the activation or expansion of autoreactive T cells in a subject is inhibited or prevented by administering a therapeutically effective dose of the agent.

[0006] In some embodiments, autoreactive T cells target the target self-cell.

[0007] In some embodiments, autoreactive T cells express TCRαV and / or TCRβV.

[0008] In some embodiments, the agent comprises an antibody molecule or its antigen-binding domain.

[0009] In some embodiments, the antibody molecule includes an Fc region.

[0010] In some embodiments, the Fc region comprises a binding mutation.

[0011] In some embodiments, the agent is functionally linked to a cytotoxic agent.

[0012] In some embodiments, the cytotoxic agent comprises calicheamicin, monomethyl auristatin E, maytansine derivative, or exatecan derivative.

[0013] In some embodiments, the Fc region does not comprise a binding mutation.

[0014] In some embodiments, the cytotoxic agent mediates the killing of autoreactive T cells in a subject.

[0015] In some embodiments, the Fc region has enhanced effector function.

[0016] In some embodiments, the enhanced effector function includes antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC).

[0017] In some embodiments, the enhanced effector function mediates the killing of autoreactive T cells in a subject.

[0018] In some embodiments, the agent contains another moiety.

[0019] In some embodiments, the another moiety includes an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

[0020] In some embodiments, the another moiety includes an NK cell engager, and the NK cell engager binds to NKp30.

[0021] In some embodiments, the other part binds to NKp30, thereby mediating the death of the target autoreactive T cells.

[0022] In some embodiments, the other part includes a T cell engager, which binds to an antigen expressed on CD8+ and / or CD4+ T cells.

[0023] In some embodiments, the other part includes a T cell engager that binds to TCRαV or TCRβV.

[0024] In some embodiments, the TCRαV or TCRβV comprises a TCRαV or TCRβV that is different from the TCR variable region to which the portion of the agent binds.

[0025] In some embodiments, the other part includes a T cell engager, which binds to CD3.

[0026] In some embodiments, the T cell engager mediates the death of the target self-reactive T cells by binding to CD8+ and / or CD4+ T cells.

[0027] In some embodiments, the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRαV1-1 or TCRαV1-2.

[0028] In some embodiments, the disease or condition is type 1 diabetes, and the portion that binds to the TCR variable region binds to TCRαV12-3.

[0029] In some embodiments, the disease or condition is Sjögren's syndrome, and the portion that binds to the TCR variable region binds to TCRαV13-1 or TCRαV13-2.

[0030] In some embodiments, the disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to TCRαV26-1 or TCRαV26-2.

[0031] In some embodiments, the disease or condition is primary Sjögren's syndrome, and the portion that binds to the TCR variable region binds to TCRβV6-1, TCRβV6-2 / 3, or TCRβV6-5.

[0032] In some embodiments, the disease or condition is amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to TCRβV7-1 or TCRβV7-8 / 9.

[0033] In some embodiments, the disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to TCRβV7-1 or TCRβV7-8 / 9.

[0034] In some embodiments, the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRβV7-1 or TCRβV7-8 / 9.

[0035] In some embodiments, the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRβV10-3.

[0036] In some embodiments, the disease or condition is COVID-related multisystem inflammatory syndrome, and the portion that binds to the TCR variable region binds to TCRβV11-2.

[0037] In some embodiments, the subjects are children.

[0038] In some embodiments, the disease or condition is type 1 diabetes, and the portion that binds to the TCR variable region binds to TCRβV12-3 / 4.

[0039] In some embodiments, the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRβV20-1.

[0040] In some embodiments, the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRβV29-1.

[0041] In some embodiments, compositions comprising a recombinant T cell receptor or a chimeric antigen receptor (CAR) including a portion that binds to the TCR variable region are disclosed herein.

[0042] In some embodiments, compositions comprising T cells containing recombinant T cell receptors or chimeric antigen receptors (CARs) are disclosed herein, wherein the recombinant T cell receptor or CAR includes a portion that binds to the TCR variable region.

[0043] In some embodiments, recombinant T cell receptors or CARs are (a) Extracellular domain including a portion that binds to the TCR variable region, (b) transmembrane domain, and (c) Includes an intracellular domain containing an intracellular signaling domain.

[0044] In some embodiments, the extracellular domain includes a CD8 or CD28 extracellular domain.

[0045] In some embodiments, the transmembrane domain includes a CD8 or CD28 transmembrane domain.

[0046] In some embodiments, the intracellular domain includes a CD3 zeta intracellular signaling domain.

[0047] In some embodiments, the portion coupled to the TCR variable region is the TCRα V1 subfamily, TCRα V2 subfamily, TCRα V3 subfamily, TCRα V4, TCRα V5 subfamily, TCRα V6 subfamily, TCRα V7 subfamily, TCRα V8 subfamily, TCRα V9 subfamily, TCRα V10 subfamily, TCRα V12 subfamily, TCRα V13 subfamily, TCRα V14 subfamily, TCRα V16 subfamily, TCRα V17 subfamily, TCRα V18 subfamily, TCRα V19 subfamily, TCRα V20 subfamily, TCRα V21 subfamily, TCRα V22 subfamily, TCRα V23 subfamily, TCRα V24 subfamily, TCRα V25 subfamily, TCRα V26 subfamily, TCRα V27 subfamily, TCRα V29 subfamily, TCRα V30 subfamily, TCRα The TCRαV subfamily is selected from the group consisting of the V34 subfamily, TCRα V35 subfamily, TCRα V36 subfamily, TCRα V38 subfamily, TCRα V39 subfamily, TCRα V40 subfamily, and TCRα V41 subfamily, as well as the family members of those subfamilies and their variants.

[0048] In some embodiments, the portion that binds to the TCR variable region binds to a TCRβV subfamily selected from the group consisting of the TCRβ V2 subfamily, TCRβ V3 subfamily, TCRβ V4 subfamily, TCRβ V5 subfamily, TCRβ V6 subfamily, TCRβ V9 subfamily, TCRβ V10 subfamily, TCRβ V11 subfamily, TCRβ V12 subfamily, TCRβ V13 subfamily, TCRβ V16 subfamily, TCRβ V19 subfamily, TCRβ V21 subfamily, TCRβ V23 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V29 subfamily, and TCRβ V30 subfamily, as well as family members of the subfamily and their variants.

[0049] In another embodiment, pharmaceutical compositions comprising compositions disclosed herein and pharmaceutically acceptable diluents, carriers, excipients, or stabilizers are provided herein.

[0050] In another embodiment, this specification discloses methods for treating a disease or condition, or for reducing the risk of developing a disease or condition, in a subject where such treatment is necessary, and such methods include administering a therapeutically effective amount of a pharmaceutical composition disclosed herein to the subject.

[0051] In some embodiments, the disease or condition is an autoimmune disease.

[0052] In some embodiments, autoimmune diseases include amyotrophic lateral sclerosis (ALS), celiac disease (CD), ankylosing spondylitis (AS), Covid-associated multisystem inflammatory syndrome (MIS-C) in children, primary Sjögren's syndrome (PSS), Churg-Strauss syndrome, sarcoidosis, systemic lupus erythematosus (SLE), type 1 diabetes, autoimmune hepatitis (e.g., type 1 or type 2), primary sclerosing cholangitis, primary biliary cholangitis, multiple sclerosis, Guillain-Barré syndrome, and AMAN (axonal and neuronal neuropathy), chronic Inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis, Trosa Hunt syndrome (THS), Devic's disease (neuromyelitis optica), paraneoplastic cerebellar degeneration (PCD), Lambert-Eaton syndrome, psoriasis, scleroderma, CREST (calcification, Raynaud's phenomenon, esophageal motility disorders, finger sclerosis, and telangiectasia) syndrome, herpetiform dermatitis, dermatomyositis, bullous pemphigoid, scarring pemphigoid / benign mucosal pemphigoid, pemphigoid of pregnancy, rheumatoid arthritis (RA), psoriatic arthritis, relapsing polychondritis, chronic relapsing polymyelitis (CRMO) The following conditions are selected from the group consisting of recurrent multifocal osteomyelitis, vasculitis, Kawasaki disease, granulomatosis with polyangiitis (GPA), Behçet's disease (vasculitis), Takayasu's arteritis, polyarteritis nodosa, microscopic polyangiitis (MPA), leukocytoclastic vasculitis, Cogan's syndrome, uveitis, peripheral uveitis (tonsillar), scleritis, autoimmune inner ear disease (AIED), Crohn's disease, ulcerative colitis (UC), Dressler's syndrome, rheumatic fever, Evans syndrome, paroxysmal nocturnal hemoglobinuria (PNH), hemolytic anemia, thrombocytopenic purpura (TTP), polymyositis, juvenile myositis (JM), including juvenile dermatomyositis (JDM) and juvenile polymyositis (JPM), ocular scarring pemphigoid, or Hashimoto's thyroiditis.

[0053] In some embodiments: (a) The disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCRα V1 subfamily. (b) The disease or condition is Crohn's disease, and the portion that binds to the TCR variable region binds to the TCRα V2 subfamily, (c) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRα V4 subfamily. (d) The disease or condition is type 1 diabetes, and the portion that binds to the variable region of the TCR binds to the TCRα V12 subfamily. (e) The disease or condition is Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCRα V13 subfamily, (f) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRα V20 subfamily. (g) The disease or condition is ankylosing spondylitis, and the portion that binds to the variable region of the TCR binds to the TCRα V21 subfamily. (h) The disease or condition is Crohn's disease, and the portion that binds to the TCR variable region binds to the TCRα V22 subfamily, (i) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRα V26 subfamily, (j) The disease or condition is Crohn's disease, and the portion that binds to the TCR variable region binds to the TCRα V40 subfamily. (k) The disease or condition is a malfunction of the joint implant, and the portion that binds to the TCR variable region binds to the TCRα V41 subfamily, (l) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRβ V4 subfamily. (m) The disease or condition is primary Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCRβ V6 subfamily. (n) The disease or condition is amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V7 subfamily. (o) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRβ V7 subfamily. (p) The disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V7 subfamily. (q) The disease or condition is ankylosing spondylitis, and the portion that binds to the variable region of the TCR binds to the TCRβ V9 subfamily, (r) The disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V10 subfamily. (s) The disease or condition is a COVID-associated multisystem inflammatory syndrome in children, and the portion that binds to the TCR variable region binds to the TCRβ V11 subfamily. (t) The disease or condition is type 1 diabetes, and the portion that binds to the TCR variable region binds to the TCRβ V12 subfamily. (u) The disease or condition is multiple sclerosis, and the portion that binds to the variable region of the TCR binds to the TCRβ V10 subfamily. (v) The disease or condition is amyotrophic lateral sclerosis, and the portion that binds to the variable region of the TCR binds to the TCRβ V23 subfamily, or (w) The disease or condition is multiple sclerosis, and the portion that binds to the variable region of the TCR binds to the TCRβ V29 subfamily.

[0054] In some embodiments, the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRαV1-1 or TCRαV1-2.

[0055] In some embodiments, the disease or condition is type 1 diabetes, and the portion that binds to the TCR variable region binds to TCRαV12-3.

[0056] In some embodiments, the disease or condition is Sjögren's syndrome, and the portion that binds to the TCR variable region binds to TCRαV13-1 or TCRαV13-2.

[0057] In some embodiments, the disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to TCRαV26-1 or TCRαV26-2.

[0058] In some embodiments, the disease or condition is primary Sjögren's syndrome, and the portion that binds to the TCR variable region binds to TCRβV6-1, TCRβV6-2 / 3, or TCRβV6-5.

[0059] In some embodiments, the disease or condition is amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to TCRβV7-1 or TCRβV7-8 / 9.

[0060] In some embodiments, the disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to TCRβV7-1 or TCRβV7-8 / 9.

[0061] In some embodiments, the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRβV7-1 or TCRβV7-8 / 9.

[0062] In some embodiments, the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRβV10-3.

[0063] In some embodiments, the disease or condition is COVID-related multisystem inflammatory syndrome, and the portion that binds to the TCR variable region binds to TCRβV11-2.

[0064] In some embodiments, the subjects are children.

[0065] In some embodiments, the disease or condition is type 1 diabetes, and the portion that binds to the TCR variable region binds to TCRβV12-3 / 4.

[0066] In some embodiments, the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRβV20-1.

[0067] In some embodiments, the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRβV29-1.

[0068] In some embodiments, the methods provided herein further include administering a second therapeutic agent or treatment to a target.

[0069] In some embodiments, the second therapeutic agent or treatment method includes chemotherapeutic agents, biologics, immunosuppressants, or radiation.

[0070] In some embodiments, a second therapeutic agent or treatment is administered sequentially, simultaneously, or in parallel in combination with an agent, composition, or pharmaceutical composition provided herein.

[0071] In some embodiments, the Specified Public Service provides a method for inhibiting or preventing the activation and / or expansion of autoreactive T cells in a subject where such action is required, the method comprising administering to the subject a therapeutically effective dose of an agent comprising a portion that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject, wherein the TCR variable region is the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), the autoreactive T cells target the subject's own cells, the autoreactive T cells express TCRαV and / or TCRβV, and (a) the subject suffers from multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V1 subfamily, (b) the subject suffers from Crohn's disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V2 subfamily, (c) the subject suffers from celiac disease, and the portion that binds to the TCR variable region is TCRα (d) The subject has type 1 diabetes, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V12 subfamily, (e) The subject has Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V13 subfamily, (f) The subject has celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V20 subfamily, (g) The subject has ankylosing spondylitis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V21 subfamily, (h) The subject has Crohn's disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V22 subfamily, (i) The subject has celiac disease, and the portion that binds to the TCR variable region is TCRα (j) The subject suffers from Crohn's disease, and the portion that binds to the TCR variable region is TCRα. (k) The subject exhibits joint implant malfunction, and the portion that binds to the TCR variable region is TCRα.(l) The subject suffers from celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V4 subfamily; (m) The subject suffers from primary Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V6 subfamily; (n) The subject suffers from amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V7 subfamily; (o) The subject suffers from celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V7 subfamily; (p) The subject suffers from multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V7 subfamily; (q) The subject suffers from ankylosing spondylitis, and the portion that binds to the TCR variable region is TCRβ (r) The subject has multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V10 subfamily, (s) The subject has COVID-associated multisystem inflammatory syndrome in children, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V11 subfamily, (t) The subject has type 1 diabetes, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V12 subfamily, (u) The subject has multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V10 subfamily, (v) The subject has amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V23 subfamily, or (w) The subject has multiple sclerosis, and the portion that binds to the TCR variable region is TCRβ It binds to the TCR variable region of the V29 subfamily.

[0072] In some embodiments, methods are provided herein for reducing or depleting autoreactive T cells in subjects where such reduction is needed, the method comprising administering to the subject a therapeutically effective dose of an agent comprising a portion that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject, wherein the TCR variable region is the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), the autoreactive T cells target the subject's own cells, the autoreactive T cells express TCRαV and / or TCRβV, and (a) the subject suffers from multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V1 subfamily, (b) the subject suffers from Crohn's disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V2 subfamily, (c) the subject suffers from celiac disease, and the portion that binds to the TCR variable region is TCRα (d) The subject has type 1 diabetes, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V12 subfamily, (e) The subject has Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V13 subfamily, (f) The subject has celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V20 subfamily, (g) The subject has ankylosing spondylitis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V21 subfamily, (h) The subject has Crohn's disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V22 subfamily, (i) The subject has celiac disease, and the portion that binds to the TCR variable region is TCRα (j) The subject suffers from Crohn's disease, and the portion that binds to the TCR variable region is TCRα. (k) The subject exhibits joint implant malfunction, and the portion that binds to the TCR variable region is TCRα.(l) The subject suffers from celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V4 subfamily; (m) The subject suffers from primary Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V6 subfamily; (n) The subject suffers from amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V7 subfamily; (o) The subject suffers from celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V7 subfamily; (p) The subject suffers from multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V7 subfamily; (q) The subject suffers from ankylosing spondylitis, and the portion that binds to the TCR variable region is TCRβ (r) The subject has multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V10 subfamily, (s) The subject has COVID-associated multisystem inflammatory syndrome in children, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V11 subfamily, (t) The subject has type 1 diabetes, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V12 subfamily, (u) The subject has multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V10 subfamily, (v) The subject has amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V23 subfamily, or (w) The subject has multiple sclerosis, and the portion that binds to the TCR variable region is TCRβ It binds to the TCR variable region of the V29 subfamily.

[0073] In some embodiments, the method further includes determining that the subject has multiple sclerosis associated with a biased TCR clonal type, which includes a TCR variable region of the TCRα V1 subfamily, TCRβ V7 subfamily, TCRβ V10 subfamily, TCRβ V20 subfamily, or TCRβ V29 subfamily, in which case the portion binding to the TCR variable region binds to the TCR variable domain of the TCRα V1 subfamily, TCRβ V7 subfamily, TCRβ V10 subfamily, TCRβ V20 subfamily, or TCRβ V29 subfamily.

[0074] In some embodiments, the method further includes determining that the subject has amyotrophic lateral sclerosis associated with a biased TCR clonal type, which includes a TCR variable region of the TCRβ V7 subfamily or the TCRβ V23 subfamily, wherein the portion binding to the TCR variable region binds to the TCR variable domain of the TCRβ V7 subfamily or the TCRβ V23 subfamily.

[0075] In some embodiments, the method further includes determining that the subject has celiac disease associated with a biased TCR clonal type, which includes a TCR variable region of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily, in which case the portion binding to the TCR variable region binds to the TCR variable domain of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily.

[0076] In some embodiments, the method further includes determining that the subject has ankylosing spondylitis associated with a biased TCR clonal type, which includes a TCR variable region of the TCRα V21 subfamily or the TCRβ V9 subfamily, wherein the portion binding to the TCR variable region binds to the TCR variable domain of the TCRα V21 subfamily or the TCRβ V9 subfamily.

[0077] In some embodiments, the method further comprises determining that the subject has a pediatric COVID-associated multisystem inflammatory syndrome associated with a biased TCR clonal type, which includes a TCR variable region of the TCRβ V11 subfamily, wherein the portion binding to the TCR variable region binds to the TCR variable domain of the TCRβ V11 subfamily.

[0078] In some embodiments, the method further includes determining that the subject has primary Sjögren's syndrome associated with a biased TCR clonal type, which includes a TCR variable region of the TCRβ V6 subfamily, wherein the portion binding to the TCR variable region binds to the TCR variable domain of the TCRβ V6 subfamily.

[0079] In some embodiments, the method further includes determining that the subject has type 1 diabetes associated with a biased TCR clonal type, which includes a TCR variable region of the TCRα V12 subfamily or the TCRβ V12 subfamily, wherein the portion binding to the TCR variable region binds to the TCR variable domain of the TCRα V12 subfamily or the TCRβ V12 subfamily.

[0080] In some embodiments, the agent comprises an antibody molecule or an antigen-binding fragment thereof. In some embodiments, the antibody molecule comprises an Fc region.

[0081] In some embodiments, the Fc region includes a binding mutation. In some embodiments, the agent is functionally linked to a cytotoxic agent. In some embodiments, the cytotoxic agent includes calicheamycin, monomethyl auristatin E, a maytansine derivative, or an exatecan derivative.

[0082] In some embodiments, the Fc region does not contain mutations that affect the binding of the Fc region to the Fc receptor. In some embodiments, the cytotoxic agent mediates the death of autoreactive T cells in the subject. In some embodiments, the Fc region contains amino acid mutations that enhance effector function. In some embodiments, effector function includes antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC). In some embodiments, the effector function mediates the death of autoreactive T cells in the subject.

[0083] In some embodiments, the agent contains another part. In some embodiments, the other part includes an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In some embodiments, the other part includes an NK cell engager, which binds to an antigen selected from the group consisting of NKp30, NKp40, NKp44, NKp46, NKG2D, DNAM1, DAP10, CD16, CRTAM, CD27, PSGL1, CD96, CD100 (SEMA4D), NKp80, CD244 (also known as SLAMF4 or 2B4), SLAMF6, SLAMF7, KIR2DS2, KIR2DS4, KIR3DS1, KIR2DS3, KIR2DS5, KIR2DS1, CD94, NKG2C, NKG2E, and CD160. In some embodiments, the other part activates NK cells by binding to NKp30, thereby mediating the death of autoreactive T cells in the target. In some embodiments, the other part includes an NK cell engager, which binds to the KIR receptor and / or CD94-NKG2A. In some embodiments, the binding of the other part to the KIR receptor and / or CD94-NKG2A derepresses NK cells, mediating the death of autoreactive T cells in the target.

[0084] In some embodiments, the other portion comprises a T cell engager, which binds to an antigen expressed on CD8+ and / or CD4+ T cells. In some embodiments, the other portion comprises a T cell engager, which binds to TCRαV or TCRβV. In some embodiments, the TCRαV or TCRβV to which the T cell engager binds is different from the TCR variable region to which the portion of the agent binds. In some embodiments, the other portion that binds to TCRαV or TCRβV binds to TCRαV of a subfamily selected from the group consisting of: TCRα V1 subfamily, TCRα V2 subfamily, TCRα V3 subfamily, TCRα V4, TCRα V5 subfamily, TCRα V6 subfamily, TCRα V7 subfamily, TCRα V8 subfamily, TCRα V9 subfamily, TCRα V10 subfamily, TCRα V12 subfamily, TCRα V13 subfamily, TCRα V14 subfamily, TCRα V16 subfamily, TCRα V17 subfamily, TCRα V18 subfamily, TCRα V19 subfamily, TCRα V20 subfamily, TCRα V21 subfamily, TCRα V22 subfamily, TCRα V23 subfamily, TCRα V24 subfamily, TCRα V25 subfamily, TCRα V26 subfamily, TCRα The V27 subfamily, TCRα V29 subfamily, TCRα V30 subfamily, TCRα V34 subfamily, TCRα V35 subfamily, TCRα V36 subfamily, TCRα V38 subfamily, TCRα V39 subfamily, TCRα V40 subfamily, and TCRα V41 subfamily, as well as the family members of said subfamilies, and their variants.

[0085] In some embodiments, the other portion that binds to TCRαV or TCRβV binds to TCRβV of a subfamily selected from the group consisting of: TCRβ V2 subfamily, TCRβ V3 subfamily, TCRβ V4 subfamily, TCRβ V5 subfamily, TCRβ V6 subfamily, TCRβ V9 subfamily, TCRβ V10 subfamily, TCRβ V11 subfamily, TCRβ V12 subfamily, TCRβ V13 subfamily, TCRβ V16 subfamily, TCRβ V19 subfamily, TCRβ V21 subfamily, TCRβ V23 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V29 subfamily, and TCRβ V30 subfamily, as well as family members of the subfamily, and their variants.

[0086] In some embodiments, the other part includes a T cell engager, which binds to CD3.

[0087] In some embodiments, the T cell engager mediates the death of the target self-reactive T cells by binding to CD8+ and / or CD4+ T cells.

[0088] In some embodiments, the subject suffers from multiple sclerosis, in which case the portion that binds to the TCR variable region binds to the TCR variable region of the TCRαV1-1 or TCRαV1-2 family. In some embodiments, the subject suffers from type 1 diabetes, in which case the portion that binds to the TCR variable region binds to the TCR variable region of the TCRαV12-3 family. In some embodiments, the subject suffers from Sjögren's syndrome, in which case the portion that binds to the TCR variable region binds to the TCR variable region of the TCRαV13-1 or TCRαV13-2 family. In some embodiments, the subject suffers from celiac disease, in which case the portion that binds to the TCR variable region binds to the TCR variable region of the TCRαV26-1 or TCRαV26-2 family. In some embodiments, the subject suffers from primary Sjögren's syndrome, in which case the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV6-1, TCRβV6-2 / 3, or TCRβV6-5 family. In some embodiments, the subject has amyotrophic lateral sclerosis (ALS), in which case the portion that binds to the TCR variable region binds to the TCRβV7-1 or TCRβV7-8 / 9 family TCR variable region. In some embodiments, the subject has celiac disease, in which case the portion that binds to the TCR variable region binds to the TCRβV7-1 or TCRβV7-8 / 9 family TCR variable region. In some embodiments, the subject has multiple sclerosis, in which case the portion that binds to the TCR variable region binds to the TCRβV7-1 or TCRβV7-8 / 9 family TCR variable region. In some embodiments, the subject has multiple sclerosis, in which case the portion that binds to the TCR variable region binds to the TCRβV10-3 family TCR variable region. In some embodiments, the subject has COVID-related multisystem inflammatory syndrome, in which case the portion that binds to the TCR variable region binds to the TCRβV11-2 family TCR variable region. In some embodiments, the subject is a child. In some embodiments, the subject suffers from type 1 diabetes, in which case the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV12-3 / 4 family.In some embodiments, the subject suffers from multiple sclerosis, and in this case, the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV20-1 family. In some embodiments, the subject suffers from multiple sclerosis, and in this case, the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV29-1 family.

[0089] In some embodiments, methods are provided herein for inhibiting or preventing the activation and / or expansion of autoreactive T cells in a subject where such action is required, the method comprising administering a therapeutically effective dose of an agent containing a portion that binds to a TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject, wherein the TCR variable region is the T cell receptor alpha variable region (TCRαV) or the T cell receptor beta variable region (TCRβV), and the autoreactive T cells are The study targets the subject's own cells, and the autoreactive T cells express TCRαV and / or TCRβV, and (a) the subject is identified as having or exhibiting symptoms of multiple sclerosis associated with a biased TCR clonal type including the TCR variable region of the TCRαV1 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRαV1 subfamily, and (b) the subject has multiple sclerosis associated with a biased TCR clonal type including the TCR variable region of the TCRβV7 subfamily, (c) The subject is identified as having symptoms of multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV7 subfamily, (d) The subject is identified as having multiple sclerosis associated with a biased TCR clonal type, including the TCR variable region of the TCRβV10 subfamily, or having symptoms of multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV10 subfamily, (c) The subject is identified as having multiple sclerosis associated with a biased TCR clonal type, including the TCR variable region of the TCRβV20 subfamily (e) The subject is identified as having or exhibiting symptoms of multiple sclerosis associated with a lone type, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV20 subfamily, or (e) the subject is identified as having or exhibiting symptoms of multiple sclerosis associated with a biased TCR clonal type, including the TCR variable region of the TCRβV29 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV29 subfamily, and in this case, the portionIt does not bind to different TCRαV and / or TCRβV subfamilies.

[0090] In some embodiments, methods are provided herein for reducing and / or depleting autoreactive T cells in a subject where such reduction is necessary, comprising administering a therapeutically effective dose of an agent comprising a portion that binds to a TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject, wherein the TCR variable region is the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), and the autoreactive T cells target the subject's own cells. The autoreactive T cells express TCRαV and / or TCRβV, and (a) the subject is identified as having or exhibiting symptoms of multiple sclerosis associated with a biased TCR clonal type including the TCR variable region of the TCRαV1 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRαV1 subfamily, and (b) the subject is identified as having or exhibiting symptoms of multiple sclerosis associated with a biased TCR clonal type including the TCR variable region of the TCRβV7 subfamily. (c) The portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV7 subfamily, and the subject is identified as having multiple sclerosis associated with a biased TCR clonal type, including the TCR variable region of the TCRβV10 subfamily, or having symptoms of multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV10 subfamily, and (d) The subject has multiple sclerosis associated with a biased TCR clonal type, including the TCR variable region of the TCRβV20 subfamily, or has symptoms of multiple sclerosis (e) A subject is identified as having symptoms of the disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV20 subfamily, or (e) a subject is identified as having or having symptoms of multiple sclerosis associated with a biased TCR clonal type, including the TCR variable region of the TCRβV29 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV29 subfamily, and in this case, the portion does not bind to different TCRαV and / or TCRβV subfamilies.

[0091] In some embodiments, the Specified herein provides a method for inhibiting or preventing the activation and / or expansion of autoreactive T cells in a subject where such action is required, the method comprising administering to the subject a therapeutically effective dose of an agent comprising a portion that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject, wherein the TCR variable region is the T cell receptor alpha variable region (TCRαV) or the T cell receptor beta variable region (TCRβV), the autoreactive T cells target the subject's own cells, the autoreactive T cells express TCRαV and / or TCRβV, and (a) the subject is identified as having amyotrophic lateral sclerosis associated with a biased TCR clonal type, including a TCR variable region of the TCRβ V7 subfamily or the TCRβ V23 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V7 subfamily or the TCRβ V23 subfamily, or (b) the subject is identified as having TCRβ Identified as having or exhibiting symptoms of amyotrophic lateral sclerosis associated with a biased TCR clonal type, including a TCR variable region of the V7 subfamily or TCRβ V23 subfamily, wherein the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V7 subfamily or TCRβ V23 subfamily, and in this case, the portion does not bind to any other different TCRαV and / or TCRβV subfamilies.

[0092] In some embodiments, the Specified herein provides a method for reducing or depleting autoreactive T cells in a subject where such reduction is needed, the method comprising administering to the subject a therapeutically effective dose of an agent comprising a portion that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject, wherein the TCR variable region is the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), the autoreactive T cells target the subject's own cells, the autoreactive T cells express TCRαV and / or TCRβV, and (a) the subject is identified as having amyotrophic lateral sclerosis (ALS) associated with a biased TCR clonal type, including a TCR variable region of the TCRβ V7 subfamily or the TCRβ V23 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V7 subfamily or the TCRβ V23 subfamily, or (b) the subject is identified as having TCRβ Identified as having or exhibiting symptoms of amyotrophic lateral sclerosis associated with a biased TCR clonal type, including a TCR variable region of the V7 subfamily or TCRβ V23 subfamily, wherein the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V7 subfamily or TCRβ V23 subfamily, and in this case, the portion does not bind to any other different TCRαV and / or TCRβV subfamilies.

[0093] In some embodiments, this specification provides a method for inhibiting or preventing the activation and / or expansion of autoreactive T cells in a subject where such action is needed, the method comprising administering a therapeutically effective dose of an agent containing a portion that binds to a TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject, wherein the TCR variable region is the T cell receptor alpha variable region (TCRαV) or the T cell receptor beta variable region (TCRβV), the autoreactive T cells target the subject's own cells, the autoreactive T cells express TCRαV and / or TCRβV, and (a) the subject is identified as having celiac disease associated with a biased TCR clonal type, or having symptoms of celiac disease, including the TCR variable region of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily, and the portion that binds to the TCR variable region is the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ (b) The subject is identified as having celiac disease associated with a biased TCR clonal type, including the TCR variable region of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily, in which case the portion does not bind to any other different TCRαV and / or TCRβV subfamily.

[0094] In some embodiments, the Specified herein provides a method for reducing or depleting autoreactive T cells in a subject where such reduction is needed, the method comprising administering to the subject a therapeutically effective dose of an agent comprising a portion that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject, wherein the TCR variable region is the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), the autoreactive T cells target the subject's own cells, the autoreactive T cells express TCRαV and / or TCRβV, and (a) the subject is identified as having celiac disease associated with a biased TCR clonal type, or having symptoms of celiac disease, comprising the TCR variable region of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily, and the portion that binds to the TCR variable region is the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ (b) The subject is identified as having celiac disease associated with a biased TCR clonal type, including the TCR variable region of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily, in which case the portion does not bind to any other different TCRαV and / or TCRβV subfamily.

[0095] In some embodiments, the Specified herein provides a method for inhibiting or preventing the activation and / or expansion of autoreactive T cells in a subject where such action is needed, the method comprising administering to the subject a therapeutically effective dose of an agent comprising a portion that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject, wherein the TCR variable region is the T cell receptor alpha variable region (TCRαV) or the T cell receptor beta variable region (TCRβV), the autoreactive T cells target the subject's own cells, the autoreactive T cells express TCRαV and / or TCRβV, and (a) the subject is identified as having or exhibiting symptoms of ankylosing spondylitis associated with a biased TCR clonal type comprising a TCR variable region of the TCRα V21 subfamily or the TCRβ V9 subfamily, the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRα V21 subfamily or the TCRβ V9 subfamily, or (b) the subject is identified as having TCRα Identified as having or exhibiting symptoms of ankylosing spondylitis associated with a biased TCR clonal type, including the TCR variable region of the V21 subfamily or the TCRβ V9 subfamily, wherein the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRα V21 subfamily or the TCRβ V9 subfamily, in which case the portion does not bind to any other different TCRαV and / or TCRβV subfamilies.

[0096] In some embodiments, this specification provides a method for reducing or depleting autoreactive T cells in a subject where such reduction is needed, the method comprising administering to the subject a therapeutically effective dose of an agent comprising a portion that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject, wherein the TCR variable region is the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), the autoreactive T cells target the subject's own cells, the autoreactive T cells express TCRαV and / or TCRβV, and (a) the subject is identified as having or exhibiting symptoms of ankylosing spondylitis associated with a biased TCR clonal type comprising a TCR variable region of the TCRα V21 subfamily or the TCRβ V9 subfamily, the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRα V21 subfamily or the TCRβ V9 subfamily, or (b) the subject is identified as having TCRα Identified as having or exhibiting symptoms of ankylosing spondylitis associated with a biased TCR clonal type, including the TCR variable region of the V21 subfamily or the TCRβ V9 subfamily, wherein the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRα V21 subfamily or the TCRβ V9 subfamily, in which case the portion does not bind to any other different TCRαV and / or TCRβV subfamilies.

[0097] In some embodiments, the Specified herein provides a method for inhibiting or preventing the activation and / or expansion of autoreactive T cells in a subject where such action is needed, the method comprising administering to the subject a therapeutically effective dose of an agent comprising a portion that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRαV) or a T cell receptor beta variable region (TCRβV), the autoreactive T cells target the subject's own cells, the autoreactive T cells express TCRαV and / or TCRβV, and (a) the subject is identified as having or exhibiting symptoms of pediatric COVID-related multisystem inflammatory syndrome associated with a biased TCR clonal type including a TCR variable region of the TCRβ V11 subfamily, the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V11 subfamily, or (b) the subject is identified as having TCRβ Identified as having or presenting with symptoms of COVID-related multisystem inflammatory syndrome in children associated with a biased TCR clonal type, including the TCR variable region of the V11 subfamily, wherein the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V11 subfamily, and in this case, the portion does not bind to any other different TCRαV and / or TCRβV subfamilies.

[0098] In certain embodiments, the Specified provides a method for reducing or depleting autoreactive T cells in a subject where such reduction is needed, the method comprising administering to the subject a therapeutically effective dose of an agent comprising a portion that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRαV) or a T cell receptor variable beta region (TCRβV), the autoreactive T cells target the subject's own cells, the autoreactive T cells express TCRαV and / or TCRβV, and (a) the subject is identified as having or exhibiting symptoms of pediatric COVID-related multisystem inflammatory syndrome associated with a biased TCR clonal type comprising a TCR variable region of the TCRβ V11 subfamily, the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V11 subfamily, or (b) the subject is identified as having TCRβ Identified as having or presenting with symptoms of COVID-related multisystem inflammatory syndrome in children associated with a biased TCR clonal type, including the TCR variable region of the V11 subfamily, wherein the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V11 subfamily, and in this case, the portion does not bind to any other different TCRαV and / or TCRβV subfamilies.

[0099] In some embodiments, this specification provides a method for inhibiting or preventing the activation and / or expansion of autoreactive T cells in a subject where such action is needed, the method comprising administering to the subject a therapeutically effective dose of an agent comprising a portion that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject, wherein the TCR variable region is the T cell receptor alpha variable region (TCRαV) or the T cell receptor beta variable region (TCRβV), the autoreactive T cells target the subject's own cells, the autoreactive T cells express TCRαV and / or TCRβV, and (a) the subject is identified as having primary Sjögren's syndrome associated with a biased TCR clonal type including a TCR variable region of the TCRβ V6 subfamily, the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V6 subfamily, or (b) the subject is identified as having TCRβ Identified as having or exhibiting symptoms of primary Sjögren's syndrome associated with a biased TCR clonal type including a TCR variable region of the V6 subfamily, the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V6 subfamily, in which case the portion does not bind to any other different TCRαV and / or TCRβV subfamilies.

[0100] In certain embodiments, the Specified provides a method for reducing or depleting autoreactive T cells in a subject where such reduction is needed, the method comprising administering to the subject a therapeutically effective dose of an agent comprising a portion that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject, wherein the TCR variable region is the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), the autoreactive T cells target the subject's own cells, the autoreactive T cells express TCRαV and / or TCRβV, and (a) the subject is identified as having primary Sjögren's syndrome associated with a biased TCR clonal type comprising the TCR variable region of the TCRβ V6 subfamily, the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V6 subfamily, or (b) the subject is identified as having TCRβ Identified as having or exhibiting symptoms of primary Sjögren's syndrome associated with a biased TCR clonal type including a TCR variable region of the V6 subfamily, the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V6 subfamily, in which case the portion does not bind to any other different TCRαV and / or TCRβV subfamilies.

[0101] In some embodiments, the Specified herein provides a method for inhibiting or preventing the activation and / or expansion of autoreactive T cells in a subject where such action is needed, the method comprising administering to the subject a therapeutically effective dose of an agent comprising a portion that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject, wherein the TCR variable region is the T cell receptor alpha variable region (TCRαV) or the T cell receptor beta variable region (TCRβV), the autoreactive T cells target the subject's own cells, the autoreactive T cells express TCRαV and / or TCRβV, and (a) the subject is identified as having type 1 diabetes associated with a biased TCR clonal type comprising the TCRβ V12 subfamily or the TCR variable region of the TCRα V12 subfamily, the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V12 subfamily or the TCRα V12 subfamily, or (b) the subject is identified as having TCRβ Identified as having type 1 diabetes associated with a biased TCR clonal type including the TCR variable region of the V12 subfamily or the TCRα V12 subfamily, and the portion that binds to said TCR variable region binds to the TCR variable domain of the TCRβ V12 subfamily or the TCRα V12 subfamily, in which case the portion does not bind to any other different TCRαV and / or TCRβV subfamilies.

[0102] In some embodiments, the Specified Information provides a method for reducing or depleting autoreactive T cells in a subject where such reduction is needed, the method comprising administering to the subject a therapeutically effective dose of an agent comprising a portion that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject, wherein the TCR variable region is the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), the autoreactive T cells target the subject's own cells, the autoreactive T cells express TCRαV and / or TCRβV, and (a) the subject is identified as having type 1 diabetes associated with a biased TCR clonal type comprising the TCRβ V12 subfamily or the TCRα V12 subfamily, the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V12 subfamily or the TCRα V12 subfamily, or (b) the subject is identified as having type 1 diabetes associated with a biased TCR clonal type comprising the TCRβ V12 subfamily or the TCR variable region of the TCRα Identified as having type 1 diabetes associated with a biased TCR clonal type including a TCR variable region of the V12 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V12 subfamily or the TCRα V12 subfamily, in which case the portion does not bind to any other different TCRαV and / or TCRβV subfamilies.

[0103] Reference All published documents, patents, and patent applications referenced herein are incorporated herein by reference to the same extent that each individual published document, patent, or patent application is specifically and individually incorporated by reference. [Brief explanation of the drawing]

[0104] The novelty of this disclosure is described in detail in the attached claims. A deeper understanding of the characteristics and advantages of this disclosure will be obtained by referring to the following detailed description, which describes exemplary embodiments in which the principles of this disclosure are utilized, and to the attached drawings below.

[0105] [Figure 1A] Figures 1A and 1B show the structures and sequences of eight TCRβV proteins derived from the following seven different subfamilies: the TCRβV6 subfamily (showing TCRβV6-5 and TCRβV6-4), the TCRβV28 subfamily, the TCRβV19 subfamily, the TCRβV9 subfamily, the TCRβV5 subfamily, the TCRβV20 subfamily, and the TCRβV12 subfamily. Figure 1A shows the structural alignment of various TCRβV proteins. The circled regions represent outward-facing regions containing proposed binding sites for the anti-TCRβV antibodies described herein. [Figure 1B] Figure 1B shows the amino acid sequence alignment of the proteins shown in Figure 1A (sequence numbers 3449-3456, in order of appearance). Although various TCRβV proteins (derived from seven different TCRβV subfamilies) have diverse sequences, they share conserved (similar) structures and functions. [Figure 2] Figure 2 shows an exemplary embodiment of an anti-TCRαV molecule that binds to autoreactive T cells, such as T cells expressing TCRαV associated with autoimmune diseases, and inhibits the activation of or kills such autoreactive T cells. [Figure 3] Figure 3 shows an exemplary embodiment of an anti-TCRαV molecule functionally linked to a cytotoxic agent. The derivatized molecule can bind to target autoreactive T cells, such as T cells expressing TCRαV associated with autoimmune diseases, and initiate the death of these target autoreactive T cells. [Figure 4]Figure 4 shows an exemplary embodiment of a multifunctional molecule engineered to contain a natural killer (NK) cell engager that binds to TCRαV on target autoreactive T cells and further binds to NKp30 expressed on NK cells. [Figure 5] Figure 5 shows exemplary embodiments of a multispecific molecule containing a T cell engager that binds to TCRαV or TCRβV on target autoreactive T cells, and further binds to the CD3 complex on healthy effector T cells in the subject. [Figure 6] Figure 6 shows exemplary embodiments of antibody molecules specific to TCRαV and / or TCRβV, having Fc mutations to enhance effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), and / or complement-dependent cytotoxicity (CDC). [Figure 7] Figure 7 shows a diagram of CAR T cells that have antigen recognition domains for TCRαV and / or TCRβV on targeted autoreactive T cells, and the T cells express TCRαV and / or TCRβV associated with autoimmune diseases. [Figure 8] Figure 8 shows the frequency of transcript counts for TRBV13-1, 13-2, and 13-3 compared to all TRBV counts. Two animals were administered at each time point. [Modes for carrying out the invention]

[0106] In some embodiments, methods for treating autoimmune diseases or conditions using TCR-targeting molecules or cells expressing TCR-targeting molecules are disclosed herein. TCR-targeting molecules may include a moiety that binds to a variable TCR beta chain (TCRBV) or a variable TCR alpha chain (TCRAV). TCR-targeting molecules may further include one, two, or all of the following: (ii) immune cell engagers, (iii) cytokine inhibitors, (iv) cytotoxic agents, and / or (v) death receptor signal enhancers.

[0107] While we do not wish to be bound by theory, TCR bias may exist in autoimmune diseases. This bias may be associated with a dominant autoreactive TCR clone that is disease-causing or associated with symptoms. For example, by removing or depleting T cells containing the autoreactive clone, thereby restoring the balance of the TCR repertoire, it may be possible to treat the associated autoimmune disease and / or reduce the symptoms of the autoimmune disease. Therefore, the multispecific or multifunctional molecules disclosed herein are expected to target (e.g., localize, crosslink, and / or activate) immune cells (e.g., immune effector cells selected from NK cells, T cells, B cells, dendritic cells, or macrophages) with target cells (e.g., T cells containing a biased TCRAV or TCRBV clone, or T cells containing a TCRAV antigen or TCRBV antigen corresponding to a biased TCRAV or TCRBV clone). By increasing the proximity and / or activity of immune cells using the polyspecific molecules described herein, it is predicted that the immune response against target cells (e.g., T cells containing TCRAV or TCRBV, e.g., TCRAV antigen or TCRBV antigen corresponding to a biased clonal type of TCRAV or TCRBV) will be enhanced, thereby providing more effective treatments (e.g., more effective treatments for autoimmune diseases). While not bound by theory, targeted, local immune responses against target cells (e.g., T cells containing a biased clonal type of TCRAV or TCRBV) are thought to reduce the systemic toxic effects of the polyspecific molecules described herein. Targeted immune responses against autoreactive T cell populations with a lower degree of targeting of non-autoreactive T cells (e.g., not targeting non-autoreactive T cells) are thought to be less harmful than systemically ablating all T cells.

[0108] Accordingly, this specification provides, in particular, a TCR-targeting molecule (e.g., a multispecific antibody molecule or a multifunctional antibody molecule) including the aforementioned portion, an encoding nucleic acid, a method for producing the aforementioned molecule, and a method for treating autoimmune diseases using the aforementioned molecule. Also provided this specification are an anti-TCRαV antibody molecule or an anti-TCRβV antibody molecule, an encoding nucleic acid, a method for producing the aforementioned molecule, and a method for treating autoimmune diseases using the anti-TCRαV antibody molecule or an anti-TCRβV antibody molecule.

[0109] Furthermore, methods are provided for depleting biased TCRBV clonal types (e.g., in vivo depletion) in the context of autoimmune diseases, for example, with multispecific molecules or anti-TCRαV antibody molecules or anti-TCRβV antibody molecules. In some embodiments, the method includes identifying, for example, a clonal bias in the use of TCRAV or TCRBV associated with an autoreactive subpopulation in a patient, and, in response to such analysis, administering a multifunctional molecule targeting the TCRAV antigen or TCRBV antigen corresponding to the biased clonal type of TCRAV or TCRBV to reduce, for example, eliminate, and promote, for example, establish a normal TCRBV distribution.

[0110] Accordingly, in one embodiment, the present disclosure features a multifunctional molecule comprising (i) a first antigen-binding domain that binds to, for example, a TCRAV receptor variable alpha (TCRAV), such as a TCRAV antigen, such as selectively; (ii) one, two, or all of the following: (a) an immune cell engager selected from NK cell engagers, T cell engagers, B cell engagers, dendritic cell engagers, or macrophage cell engagers; (b) a cytokine molecule or cytokine inhibitor molecule; and (c) a death receptor signaling engager.

[0111] In another aspect, the present disclosure features a multifunctional molecule comprising (i) a first antigen-binding domain that binds, for example, a variable T cell receptor beta (TCRBV) antigen, for example, selectively; (ii) one, two, or all of the following: (a) an immune cell engager selected from NK cell engagers, T cell engagers, B cell engagers, dendritic cell engagers, or macrophage cell engagers; (b) a cytokine molecule or cytokine inhibitor molecule; and (c) a death receptor signaling engager.

[0112] In some embodiments, the first antigen-binding domain includes, for example, an anti-TCRαV antibody molecule as described herein.

[0113] In some embodiments, the first antigen-binding domain includes, for example, an anti-TCRβV antibody molecule as described herein.

[0114] In another aspect, the present disclosure features nucleic acid molecules encoding the multifunctional molecules disclosed herein.

[0115] In another aspect, the present disclosure features a vector comprising nucleic acid molecules disclosed herein, for example, an expression vector.

[0116] In another aspect, the present disclosure features a host cell containing a nucleic acid molecule or vector disclosed herein.

[0117] In another aspect, the disclosure features, for example, a method for producing the multifunctional molecules disclosed herein, the method comprising culturing the host cells disclosed herein under preferred conditions, for example, conditions preferred for gene expression and / or conditions preferred for homodimerization or heterodimerization.

[0118] In another aspect, the present disclosure features a pharmaceutical composition comprising a multifunctional molecule disclosed herein.

[0119] In another aspect, the disclosure features a method for treating TCR bias, the method comprising administering a multifunctional molecule disclosed herein to a subject in need, the multifunctional molecule being administered in an amount effective for treating TCR bias.

[0120] In another aspect, the disclosure features a method for treating an autoimmune disease (e.g., an autoimmune disease associated with TCR bias), the method comprising administering a multifunctional molecule disclosed herein to a subject in need, the multifunctional molecule being administered in an amount effective for treating the autoimmune disease.

[0121] In another aspect, the Disclosure features a method for identifying subjects in need of treatment for TCR bias or autoimmune diseases (e.g., associated with TCR bias) using the multifunctional molecules disclosed herein, the method comprising determining whether the subject has TCR bias (e.g., a clonal variant of biased TCRAV or TCRBV) and / or an autoimmune disease associated with such bias (e.g., by determining directly or by determining indirectly, such as by obtaining relevant information), in which case, in response to the determination that the subject has TCR bias (e.g., a clonal variant of biased TCRAV or TCRBV) and / or an autoimmune disease associated with such bias, the subject is identified as a candidate for treatment using a multifunctional molecule containing an antigen-binding domain that binds to a TCRAV antigen or a TCRBV antigen.

[0122] In another aspect, the Disclosure features a method for evaluating subjects in need of treatment for TCR bias (e.g., biased TCRBV or clonal type of TCRBV) and / or autoimmune diseases associated with such R bias, the method comprising determining whether the subject has TCR bias (e.g., biased TCRAV or clonal type of TCRBV) (e.g., by direct determination or by indirect determination such as obtaining relevant information).

[0123] In yet another embodiment, this specification discloses a method for treating an autoimmune disease (e.g., an autoimmune disease associated with TCR bias) in a subject where such treatment is necessary, the method comprising administering to the subject an effective amount, e.g., a therapeutically effective amount, of an antibody molecule that binds (e.g., specifically binds) to the T cell receptor alpha variable region (TCRαV) (anti-TCRαV antibody molecule) or the T cell receptor beta variable region (TCRβV) (anti-TCRβV antibody molecule), thereby treating the disorder.

[0124] In another aspect, the disclosure provides a method for depleting a population of T cells in a subject having an autoimmune disorder (e.g., an autoimmune disease associated with TCR bias), the method comprising contacting the T cell population with an effective amount of an antibody molecule that binds (e.g., specifically binds) to the T cell receptor alpha variable region (TCRαV) (an anti-TCRαV antibody molecule) or the T cell receptor beta variable region (TCRβV) (an anti-TCRβV antibody molecule).

[0125] In another embodiment, the present disclosure features nucleic acid molecules encoding an anti-TCRαV antibody molecule or an anti-TCRβV antibody molecule disclosed herein.

[0126] In another aspect, the present disclosure features a vector comprising nucleic acid molecules disclosed herein, for example, an expression vector.

[0127] In another aspect, the present disclosure features a host cell containing a nucleic acid molecule or vector disclosed herein.

[0128] In another aspect, the present disclosure features, for example, a method for producing an anti-TCRαV antibody molecule or an anti-TCRβV antibody molecule as disclosed herein, the method comprising culturing a host cell as disclosed herein under suitable conditions, for example, conditions suitable for gene expression and / or conditions suitable for homodimerization or heterodimerization.

[0129] In another embodiment, the present disclosure features a pharmaceutical composition comprising an anti-TCRβV antibody molecule disclosed herein.

[0130] In some embodiments, TCR-targeting molecules are disclosed herein that include an antigen-binding domain that binds to, for example, a variable T cell receptor beta (TCRBV), such as a TCRBV antigen, for example, selectively. In some examples, the TCR-targeting molecule includes an Fc region containing one or more binding mutations that enhance the effector function of the Fc region, such as, for example, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC). In some examples, the TCR-targeting molecule includes an Fc region that does not contain binding mutations.

[0131] In certain embodiments of this specification, TCR targeting molecules (also referred to herein as multifunctional molecules or multispecific molecules) having multiple (e.g., two or more) functions (or binding specificities) are disclosed, such molecules comprising (i) a variable T cell receptor beta (TCRBV), for example, an antigen-binding domain that binds to a TCRBV antigen, for example, a selectively binding antigen-binding domain, and (ii) (a) an immune cell engager selected from T cell engagers, NK cell engagers (e.g., molecules that bind to NKp30, NKp46, NKG2D, or CD16), B cell engagers, dendritic cell engagers, or macrophage cell engagers, (b) a cytokine inhibitor molecule, (c) a cytotoxic agent, or (d) a death receptor signaling engager.

[0132] In one embodiment, the TCR targeting molecule is a bispecific (or bifunctional) molecule, a trispecific (or trifunctional) molecule, or a tetraspecific (or tetrafunctional) molecule.

[0133] In some embodiments, the TCR-targeting molecule includes an antigen-binding domain that binds to a TCRAV antigen or TCRBV antigen on the surface of lymphocytes, such as T cells. In some embodiments, the TCRAV antigen or TCRBV antigen corresponds to a clonal variant of TCRAV or TCRBV. For example, a TCR containing the TCRAV antigen or TCRBV antigen may be overexpressed in the TCR repertoire or lymphocyte (e.g., T cell) pool of a subject (e.g., a subject with an autoimmune disease associated with TCR bias), or may be expressed at levels higher than in other subjects (e.g., subjects with non-autoimmune diseases).

[0134] While not bound by theory, the TCR-targeting molecules disclosed herein are expected to localize (e.g., cross-link) and / or activate immune cells (e.g., immune effector cells selected from T cells, NK cells, B cells, dendritic cells, or macrophages) expressing TCRAV antigen or TCRBV antigen (e.g., TCRAV antigen or TCRBV antigen corresponding to a biased clonal type of TCRAV or TCRBV) to immune cells (e.g., immune effector cells selected from T cells, NK cells, B cells, dendritic cells, or macrophages) in the presence of cells expressing TCRAV antigen or TCRBV antigen (e.g., T cells) on the cell surface, for example. Using the TCR-targeting molecules described herein, it is anticipated that an immune response to target cells will be enhanced by increasing the proximity and / or activity of immune cells in the presence of cells (e.g., lymphocytes such as T cells) expressing TCRAV antigen or TCRBV antigen (e.g., TCRAV antigen or TCRBV antigen corresponding to a biased clonal type of TCRAV or TCRBV), thereby providing a more effective therapeutic approach (e.g., by reducing the level of biased TCR and / or by reducing the level of T cells expressing biased TCR). In another embodiment, it is thought that targeting cells (e.g., lymphocytes such as T cells) expressing TCRAV antigen or TCRBV antigen (e.g., TCRAV antigen or TCRBV antigen corresponding to a biased clonal type of TCRAV or TCRBV) using a TCR-targeting molecule further comprising a cell death-inducing moiety (e.g., a death receptor signaling engager) will promote the death of target cells (e.g., by reducing the level of biased TCR and / or by reducing the level of T cells expressing biased TCR).

[0135] While not bound by theory, it is predicted that in some embodiments, by utilizing TCR-targeting molecules that are specific to a particular TCRAV antigen or TCRBV antigen (e.g., a TCRAV antigen or TCRBV antigen corresponding to a biased TCRAV or TCRBV clone) but not specific to other types or all types of the T cell repertoire, adverse effects from broadly increasing the proximity or activity of immune cells to T cells, or adverse effects from broadly promoting cell death in T cells, may be mitigated. Thus, it is thought that by using the TCR-targeting molecules disclosed herein, it may be possible to increase the proximity or activity of immune cells to cells containing a TCRAV antigen or TCRBV antigen corresponding to a biased TCRAV or TCRBV clone without necessarily increasing the proximity or activity of immune cells to T cells, or to promote cell death in cells containing a TCRAV antigen or TCRBV antigen corresponding to a biased TCRAV or TCRBV clone without necessarily increasing cell death in T cells.

[0136] Accordingly, in particular, this specification provides a TCR-targeting molecule (e.g., a multifunctional antibody molecule) including the aforementioned portion, a nucleic acid encoding the aforementioned molecule, a method for producing the aforementioned molecule, and a method for treating a disease or disorder, such as an autoimmune disease or TCR bias, using the aforementioned molecule.

[0137] Specific terms Certain specific details of this specification are provided to provide a complete understanding of the various embodiments. However, those skilled in the art will understand that this disclosure can be carried out without these details. In other examples, known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments.

[0138] Unless otherwise required by context, throughout the following specification and claims, the term “comprise” and its variations, such as “comprises” and “comprising,” shall be interpreted as having an open and comprehensive meaning, i.e., “including, but not limited to.” Furthermore, the headings provided herein are for convenience only and do not describe the scope or meaning of the claimed disclosure.

[0139] As used herein and in the appended claims, singular nouns such as “a,” “an,” and “the” include plural nouns unless the context otherwise clearly indicates. As used herein in conjunction with the term “comprising,” the use of the words “a” or “an” may mean “one,” but also coincides with the meanings of “one or more,” “at least one,” and “two or more.”

[0140] It should also be noted that, unless otherwise explicitly stated in the context, the term "or" is generally used to mean "and / or".

[0141] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the field to which this disclosure belongs. Similar or equivalent methods and materials may be used in the implementation or testing of this disclosure, but preferred methods and materials are listed below.

[0142] For example, when referring to measurable values ​​such as quantity or duration, the term “about” means to include a variation of ±20%, in some cases ±10%, in some cases ±5%, in some cases ±1%, and in some cases ±0.1% from the specified value, provided that the variation required to implement the disclosed method is appropriate. As used herein, “about” and “approximately” generally mean the degree of error that is acceptable for the measured quantity, given the nature or precision of the measurement. An exemplary degree of error is within 20 percent (%) of a given range of values, typically within 10%, and more typically within 5%.

[0143] As used herein, the terms “obtain” or “acquire” mean to acquire ownership of a physical entity (e.g., a sample, polypeptide, nucleic acid, or sequence) or a value (e.g., a numerical value) by “directly obtaining” or “indirectly obtaining” it. “Directly obtaining” means performing a process to obtain a physical entity or value (e.g., performing a synthesis or analytical method). “Indirectly obtaining” means receiving a physical entity or value from another party or source (e.g., a third laboratory that directly obtained the physical entity or value). Directly obtaining a physical entity includes performing a process that involves a physical change in a physical substance, e.g., an initial material. Directly obtaining a value includes performing a process that involves a physical change in a sample or another substance, e.g., performing an analytical process that involves a physical change in a substance such as a sample.

[0144] As used herein, “antibody molecule” means a protein, e.g., an immunoglobulin chain or a fragment thereof, comprising the structure and / or sequence of at least one immunoglobulin variable domain. Antibody molecules encompass antibodies (e.g., full-length antibodies) and antibody fragments. In some embodiments, an antibody molecule includes a full-length antibody or an antigen-binding or functional fragment of a full-length immunoglobulin chain. For example, a full-length antibody is an immunoglobulin (Ig) molecule (e.g., an IgG antibody) that is naturally occurring or formed by the usual recombination processes of immunoglobulin gene fragments. In several embodiments, an antibody molecule refers to an immunoactive antigen-binding portion of an immunoglobulin molecule, such as an antibody fragment. An antibody fragment, e.g., a functional fragment, is a portion of an antibody, e.g., Fab, Fab', F(ab')2, F(ab)2, a variable fragment (Fv), a domain antibody (dAb), or a single-stranded variable fragment (scFv). A functional antibody fragment binds to the same antigen recognized by an intact antibody (e.g., a full-length antibody). The terms “antibody fragment” or “functional fragment” also include isolated fragments consisting of variable regions, such as “Fv” fragments, which consist of variable regions of heavy and light chains, or recombinant single-chain polypeptide molecules (scFv proteins) in which the variable regions of light and heavy chains are linked by a peptide linker. In some embodiments, antibody fragments do not contain antibody moieties that do not have antigen-binding activity, such as Fc fragments or single amino acid residues. Exemplary antibody molecules include full-length antibodies and antibody fragments, such as dAb (domain antibodies), single-chain, Fab, Fab', and F(ab')2 fragments, and single-chain variable fragments (scFv). In some embodiments, the antibody molecule is an antibody mimetic. In some embodiments, the antibody molecule is an antibody-like framework or scaffold, or includes such a framework or scaffold, such as fibronectin, ankyrin repeats (e.g., engineered ankyrin repeat proteins (DARPins)), avimers, afibodies, affinity ligands, anticalin, or affilin molecules.

[0145] As used herein, the term “human-like antibody molecule” refers to a humanized antibody molecule, a human antibody molecule, or an antibody molecule having at least 95% sequence identity with a framework region of a non-mouse germline, e.g., FR1, FR2, FR3, and / or FR4. In some embodiments, the human-like antibody molecule includes a framework region having at least 95% sequence identity with a framework region of a human germline, e.g., FR1, FR2, FR3, and / or FR4 of a human germline framework region. In some embodiments, the human-like antibody molecule is a recombinant antibody. In some embodiments, the human-like antibody molecule is a humanized antibody molecule. In some embodiments, the human-like antibody molecule is a human antibody molecule. In some embodiments, the human-like antibody molecule is a phage-display antibody molecule or a yeast-display antibody molecule. In some embodiments, the human-like antibody molecule is a chimeric antibody molecule. In some embodiments, the human-like antibody molecule is a CDR-transplanted antibody molecule.

[0146] As used herein, “immunoglobulin variable domain sequence” refers to an amino acid sequence capable of forming the structure of an immunoglobulin variable domain. For example, a sequence may include all or part of the amino acid sequence of a native variable domain. For example, a sequence may include or not include one, two or more N-terminal or C-terminal amino acids, or may include other modifications that are compatible with the formation of a protein structure.

[0147] In several embodiments, the antibody molecule is monospecific, for example, having binding specificity to one epitope. In some embodiments, the antibody molecule is polyspecific. For example, the antibody molecule comprises multiple immunoglobulin variable domain sequences, in which case the first immunoglobulin variable domain sequence has binding specificity to a first epitope, and the second immunoglobulin variable domain sequence has binding specificity to a second epitope. In some embodiments, the antibody molecule is a bispecific antibody molecule. As used herein, a "bispecific antibody molecule" means an antibody molecule having specificity to two or more (e.g., 2, 3, 4 or more) epitopes and / or antigens.

[0148] As used herein, “antigen (Ag)” refers to a molecule that can induce an immune response, for example, the activation of specific immune cells and / or antibody production. Any macromolecule, including virtually any protein or peptide, can be an antigen. Antigens can also be derived from genomic recombination or DNA. For example, any DNA containing a nucleotide sequence or partial nucleotide sequence that codes for a protein capable of eliciting an immune response codes for an “antigen.” In some embodiments, an antigen does not have to be coded solely by a full-length nucleotide sequence of a gene, nor does it have to be coded by a gene at all. As used herein, “immune cell antigen” includes any molecule present on or associated with immune cells that can elicit an immune response.

[0149] The "antigen-binding site" or "binding region" of an antibody molecule refers to a part of the antibody molecule, such as an immunoglobulin (Ig) molecule, that is involved in antigen binding. In several embodiments, the antigen-binding site is formed by amino acid residues in the variable (V) regions of the heavy (H) and light (L) chains. Three highly divergent regions within the variable regions of the heavy and light chains, called hypervariable regions, are located between more conserved adjacent regions called "framework regions" (FRs). FRs are naturally occurring amino acid sequences between and adjacent to the hypervariable regions of immunoglobulins. In several embodiments, in an antibody molecule, the three hypervariable regions of the light chain and the three hypervariable regions of the heavy chain are arranged in three-dimensional space to form an antigen-binding surface. The antigen-binding surface is complementary to the three-dimensional surface of the antigen to which it is bound. The three hypervariable regions of the heavy and light chains are referred to as "complementarity-determining regions" or "CDRs." Framework regions and CDRs are defined and described, for example, in Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USD Department of Health and Human Services, NIH Publication No. 91-3242, and Chothia, C. et al. (1987) J. Mol. Biol. 196: 901-917. Each variable chain (e.g., variable heavy chain and variable light chain) typically consists of three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus in the following amino acid order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0150] As used herein, “immune cells” refers to any of the various cells that function in the immune system, such as, for example, defense against infectious agents or foreign substances. In several embodiments, the term includes leukocytes, e.g., neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Leukocytes of the innate immune system include phagocytes (e.g., macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells. Leukocytes of the innate immune system identify pathogens and eliminate larger pathogens by attacking them by contact, or eliminate microorganisms by engulfing and then killing them. These leukocytes are mediators of the activation of adaptive immune responses. Cells of the adaptive immune system are a special type of leukocyte called lymphocytes. B cells and T cells are important lymphocytes that are derived from hematopoietic stem cells in the bone marrow. B cells are involved in humoral immune responses, while T cells are involved in cell-mediated immune responses. The term “immune cells” includes immune effector cells.

[0151] When used herein, “immune effector cells” refer to cells involved in an immune response, such as promoting an immune effector response. Examples of immune effector cells, but not limited to, include T cells, e.g., alpha / beta T cells and gamma / delta T cells, B cells, natural killer (NK) cells, natural killer T (NKT) cells, and mast cells.

[0152] The terms "effector function" and "effector response" refer to specific functions of cells. The effector function of T cells can be, for example, cytolytic activity or helper activity, including cytokine secretion.

[0153] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein (in the case of a single chain) to refer to amino acid polymers of any length. The polymers may be linear or branched, may contain modified amino acids, and may have non-amino acid intercalations. The terms also encompass modified amino acid polymers, such as those subjected to any other operation, including disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or conjugation with a labeling component. Polypeptides may be isolated from natural sources, prepared by recombination techniques from eukaryotic or prokaryotic hosts, or be products of synthetic methods.

[0154] The terms “nucleic acid,” “nucleic acid sequence,” “nucleotide sequence,” or “polynucleotide sequence,” and “polynucleotide” are interchangeable. They refer to polymeric forms of nucleotides of any length, either deoxyribonucleotides, ribonucleotides, or their analogues. Polynucleotides may be single-stranded or double-stranded, and if single-stranded, they may be coding or non-coding (antisense) strands. Polynucleotides may contain modified nucleotides, such as methylated nucleotides and nucleotide analogs. Nucleic acid sequences may have non-nucleotide components interspersed. Polynucleotides may be further modified after polymerization, such as by conjugation with labeling components. Nucleic acids may be recombinant polynucleotides or genomic polynucleotides, or semi-synthetic or synthetic cDNAs linked to other polynucleotides in configurations not found in nature or that do not exist in nature.

[0155] As used herein, the term “isolated” refers to a substance that has been removed from its original environment or its natural environment (e.g., the natural environment, if it exists naturally). For example, a naturally occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide that has been separated by human intervention from some or all of the substances that coexisted with it in a natural system is isolated. Such a polynucleotide may be part of a vector, and / or such a polynucleotide or polypeptide may be part of a composition, and furthermore, such a vector or composition may be isolated in that it is not part of the environment in which it exists in nature. An isolated polynucleotide (ribonucleic acid (RNA), deoxyribonucleic acid (DNA)), or polypeptide does not contain adjacent genes / nucleic acids or sequences / amino acids in its natural state.

[0156] The compositions and methods of the present invention include polypeptides and nucleic acids having a specified sequence, or sequences that are substantially identical or similar thereto, for example, sequences that are at least 80%, 85%, 90%, 95%, or more identical to the specified sequence. In the context of amino acid sequences, the term “substantially identical” means herein that a first amino acid sequence contains a sufficient or minimum number of amino acid residues that are i) identical to or ii) conserved substitutions of aligned amino acid residues in a second amino acid sequence, thereby allowing the first and second amino acid sequences to have a common structural domain and / or common functional activity. For example, there are amino acid sequences containing a common structural domain that have at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity with respect to a reference sequence, for example, a sequence provided herein. In the context of nucleotide sequences, the term “substantially identical” means a first nucleic acid sequence containing a sufficient or minimum number of nucleotides that are identical to the aligned nucleotides in a second nucleic acid sequence, thereby encoding a polypeptide having common functional activity, or a polypeptide domain of common structure or a polypeptide of common functional activity. For example, there are nucleotide sequences that have at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity with respect to a reference sequence, e.g., the sequence provided herein.

[0157] The term "variant" refers to a polypeptide having an amino acid sequence substantially identical to a reference amino acid sequence, or a polypeptide encoded by a substantially identical nucleotide sequence. In some embodiments, the variant is a functional variant. In some embodiments, the TCRβV variant can bind to TCRα and form a TCRα:β complex.

[0158] The term "functional variant" refers to a polypeptide having an amino acid sequence substantially identical to a reference amino acid sequence, or a polypeptide encoded by a substantially identical nucleotide sequence, which can possess one or more activities of the reference amino acid sequence.

[0159] The calculation of homology or sequence identity between sequences (these terms are used interchangeably herein) is carried out as follows: The sequences are aligned for optimal comparison purposes to determine the percentage of identity between two amino acid sequences or two nucleic acid sequences (for example, gaps may be introduced in one or both of the first and second amino acid sequences or nucleic acid sequences for optimal alignment, and non-homologous sequences may be ignored for comparison purposes). In a preferred embodiment, the length of the reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, or 100% of the length of the reference sequence. The amino acid residues or nucleotides at the corresponding amino acid or nucleotide positions are then compared. If the position of the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position of the second sequence, the molecules are identical at that position (as used herein, "identity" of amino acids or nucleic acids is equivalent to "homology" of amino acids or nucleic acids).

[0160] The percentage of identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap that were necessary to introduce for the optimal alignment of the two sequences. The comparison of sequences and the determination of the percentage of identity between two sequences can be achieved using mathematical algorithms. In a preferred embodiment, the percentage of identity between two amino acid sequences is determined using the algorithm of Needleman and Wunsch ((1970) J.Mol.Biol.48:444-453). This algorithm is incorporated into the GAP program of the GCG software package (available at http: / / www.gcg.com) and uses either a Blossum 62 matrix or a PAM250 matrix, with gap weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percentage of identity between two nucleotide sequences is determined using the GAP program of the GCG software package (available at http: / / www.gcg.com) with the NWSgapdna.CMP matrix and gap weights of 40, 50, 60, 70, or 80 and length weights of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and parameters to be used unless otherwise specified) is the Blossum 62 scoring matrix, with a gap penalty of 12, a gap elongation penalty of 4, and a frameshift gap penalty of 5.

[0161] The percentage of identity between two amino acid sequences or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17). This algorithm is incorporated into the ALIGN program (version 2.0) and uses the PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. The nucleic acid and protein sequences described herein can be used as "query sequences" to perform searches against public databases to identify, for example, sequences of other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. A BLAST nucleotide search can be performed using the NBLAST program with a score of 100 and a word length of 12 to obtain nucleotide sequences homologous to the nucleic acid molecules of the present invention. By performing a BLAST protein search using an XBLAST program with a score of 50 and a word length of 3, amino acid sequences homologous to the protein molecule of the present invention can be obtained. To obtain gapped alignment for comparison purposes, Gapped BLAST can be used as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402. When using the BLAST and Gapped BLAST programs, the default parameters of each program (e.g., XBLAST and NBLAST) can be used.

[0162] The molecules of the present invention may have additional conservative amino acid substitutions or non-essential amino acid substitutions, and it should be understood that these substitutions have no substantial effect on the function.

[0163] The term "amino acid" is intended to encompass all molecules, whether natural or synthetic, that include both amino- and acid-functional properties and can be found in polymers of natural amino acids. Exemplary amino acids include natural amino acids, their analogues, derivatives and cognates, amino acid analogues with variant side chains, and all of the aforementioned stereoisomers. As used herein, the term "amino acid" includes both D-optical isomers or L-optical isomers, and peptide mimetic compounds.

[0164] A "conservative amino acid substitution" is a substitution in which an amino acid residue is replaced by an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains are defined in this art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), amino acids with acidic side chains (e.g., aspartic acid, glutamic acid), amino acids with non-loading side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), amino acids with nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), amino acids with beta-branched side chains (e.g., threonine, valine, isoleucine), and amino acids with aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0165] As used herein, the term “molecule,” as used in relation to, for example, antibody molecules, cytokine molecules, receptor molecules, etc., includes full-length native molecules as well as variants (e.g., cleaved forms, fragments, mutant forms (e.g., substantially similar sequences) or derivative forms thereof), such as functional variants, provided that they retain at least one function and / or activity of the unmodified (e.g., native) molecule.

[0166] As used herein, the term “mutation” refers to a change in the nucleotide sequence of an organism’s genome, virus, or extrachromosomal DNA. In some embodiments, mutations may be large mutations, such as amplification (or gene duplication) or repetition of a chromosomal segment, deletion of a large chromosomal region, rearrangement of a chromosome (e.g., chromosomal translocation, chromosomal inversion, crossover of non-homologous chromosomes, and deletion of an intermediate region), and loss of heterozygosity. In some embodiments, mutations may be small mutations, such as insertions, deletions, and substitution mutations. As used herein, the term “substitution mutation” refers to a change in which one nucleotide is exchanged for another nucleotide.

[0167] In some embodiments, the agent is a TCR-targeting molecule provided herein.

[0168] Human T cell receptor (TCR) complex The TCR is a disulfide-linked, membrane-immobilized heterodimer protein consisting of highly variable alpha (α) and beta (β) chains, expressed as part of a complex with the invariant CD3 chain molecule. The TCR on αβ T cells is formed by a heterodimer of one alpha chain and one beta chain. Each alpha or beta chain consists of a constant domain and a highly variable domain, and is classified as an immunoglobulin superfamily (IgSF) fold. The TCRβV chain can be further classified into 30 subfamilies (TRBV1-30). Despite high structural and functional homology, the amino acid sequence homology of the TRBV gene is very low. Only 4 out of approximately 95 amino acids are identical, and 10 more amino acids are conserved across all subfamilies (see Table 8 for TCR amino acid sequence alignment). Nevertheless, TCRs formed between alpha and beta chains with highly diverse sequences exhibit remarkable structural homology (Figures 1A and 1B) and induce similar functions, such as T cell activation.

[0169] T cell receptors (TCRs) can be present on the surface of T cells. TCRs recognize antigens, such as peptides, which are presented by binding to tumor histocompatibility complex (MHC) molecules on the surface of cells, such as antigen-presenting cells. TCRs are heterodimeric molecules and may contain alpha, beta, gamma, or delta chains. TCRs containing alpha and beta chains are also called TCRαβ. The TCR beta chain consists of the following regions (also known as segments): variable region (V), diversity region (D), binding region (J), and constant region (C) (see Mayer G. and Nyland J. (2010) Chapter 10: Major Histocompatibility Complex and T-cell Receptors-Role in Immune Responses. In: Microbiology and Immunology online, University of South Carolina School of Medicine). The TCR alpha chain consists of the V, J, and C regions. Somatic recombination of the T cell receptor (TCR) in its V (variability), D (diversity), J (binding), and C (constant) regions is a critical event in T cell development and maturation. TCR gene rearrangement occurs within the thymus.

[0170] The TCR may include a receptor complex known as the TCR complex, which comprises a TCR heterodimer containing alpha and beta chains, and a dimeric signaling molecule, such as a CD3 coreceptor, such as CD3δ / ε and / or CD3γ / ε.

[0171] As used herein, the terms “T cell receptor alpha variable chain,” “TCRαV,” or “TRAV” refer to the extracellular region of the T cell receptor alpha chain, which may include a portion of the antigen-recognition domain of the T cell receptor. The term TCRαV includes mammalian isoforms, human species homologs, and analogs containing at least one epitope common to TCRαV, such as human TCRαV. Human TCRαV includes, but is not limited to, gene families containing subfamilies such as: TCRα V1 subfamily, TCRα V2 subfamily, TCRα V3 subfamily, TCRα V4, TCRα V5 subfamily, TCRα V6 subfamily, TCRα V7 subfamily, TCRα V8 subfamily, TCRα V9 subfamily, TCRα V10 subfamily, TCRα V12 subfamily, TCRα V13 subfamily, TCRα V14 subfamily, TCRα V16 subfamily, TCRα V17 subfamily, TCRα V18 subfamily, TCRα V19 subfamily, TCRα V20 subfamily, TCRα V21 subfamily, TCRα V22 subfamily, TCRα V23 subfamily, TCRα V24 subfamily, TCRα V25 subfamily, TCRα V26 subfamily, TCRα V27 subfamily, TCRα The V29 subfamily, TCRα V30 subfamily, TCRα V34 subfamily, TCRα V35 subfamily, TCRα V36 subfamily, TCRα V38 subfamily, TCRα V39 subfamily, TCRα V40 subfamily, or TCRα V41 subfamily, as well as the family members of said subfamily, and their variants (e.g., their structural variants or functional variants).

[0172] In some embodiments, the TCRαV1 subfamily includes TCRαV1-1 or TCRαV1-2, or variants thereof.

[0173] In some embodiments, the TCRαV8 subfamily includes TCRαV8-1, TCRαV8-2, TCRαV8-3, TCRαV8-4, or TCRαV8-6, or variants thereof.

[0174] In some embodiments, the TCRαV9 subfamily includes TCRαV9-1 or TCRαV9-2, or variants thereof.

[0175] In some embodiments, the TCRαV12 subfamily includes TCRαV12-1, TCRαV12-2, or TCRαV12-3, or variants thereof.

[0176] In some embodiments, the TCRαV13 subfamily includes TCRαV13-1 or TCRαV13-2, or variants thereof.

[0177] In some embodiments, the TCRαV14 subfamily includes TCRαV14 / DV4 or its variants.

[0178] In some embodiments, the TCRαV23 subfamily includes TCRαV23 / DV6 or its variants.

[0179] In some embodiments, the TCRαV26 subfamily includes TCRαV26-1 or TCRαV26-2, or variants thereof.

[0180] In some embodiments, the TCRαV29 subfamily includes TCRαV29 / DV5 or its variants.

[0181] In some embodiments, the TCRαV36 subfamily includes TCRαV236 / DV7 or its variants.

[0182] In some embodiments, the TCRαV38 subfamily includes TCRαV38-1 or TCRαV38-2 / DV8, or variants thereof.

[0183] As used herein, the terms “T cell receptor beta variable chain” or “TCRβV” refer to the extracellular region of the T cell receptor beta chain, which includes the antigen-recognition domain of the T cell receptor. The term TCRβV includes mammalian isoforms, human species homologs, and analogs containing at least one epitope common to TCRβV, such as human TCRβV. Human TCRβV includes, but is not limited to, gene families containing subfamilies such as: TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, TCRβ V29 subfamily, TCRβ V1 subfamily, TCRβ V17 subfamily, TCRβ The V21 subfamily, the TCRβ V23 subfamily, or the TCRβ V26 subfamily, as well as family members of said subfamily, and their variants (e.g., their structural or functional variants). In some embodiments, the TCRβV6 subfamily includes TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01, or TCRβ V6-1*01. In some embodiments, TCRβV includes TCRβ V6-5*01, or its variants, e.g., variants having 85%, 90%, 95%, 99%, or more identity with the native sequence.TCRβ V6-5*01 is also known as TRBV65, TCRBV6S5, TCRBV13S1, or TCRβ V13.1. The amino acid sequence of TCRβ V6-5*01, for example, human TCRβ V6-5*01, is publicly known in the art and is provided, for example, by IMGT ID L36092. In some embodiments, TCRβ V6-5*01 is encoded by the nucleic acid sequence of SEQ ID NO: 43, or a sequence having 85%, 90%, 95%, 99% or more identity therewith. In some embodiments, TCRβ V6-5*01 includes the amino acid sequence of SEQ ID NO: 44, or a sequence having 85%, 90%, 95%, 99% or more identity therewith.

[0184] Sequence ID 43 ATGAGCATCGGCCTCCTGTGCTGTGCAGCCTTGTCTCTCCTGGGCAGGTCCAGTGAATGCTGGTGTCACTCAGACCCCAAAATTCCAGGTCCTGAAGACAGGACAGAGCATGACACTGCAGTGTGCCCAGGATATGAACCATGAATACATGTCCTGGTATCGACAAGACC CAGGCATGGGGCTGAGGCTGATTCATTACTCAGTTGGTGCTGGTATCACTGACCAAGGAGAAGTCCCCAATGGCTACAATGTCTCCAGATCAACCACAGAGGATTTCCCGCTCAGGCTGCTGTCGGCTGCTCCCTCCCAGACATCTGTGTACTTCTGTGCCAGCAGTTACTC

[0185] Sequence ID 44 MSIGLCCAALSLLWAGPVNAGVTQTPKFQVLKTGQSMTLQCAQDMNHEYMSWYRQDPGMGLRLIHY-SVGAGITDQGEVPNGYNVSRSTTEDFPLRLLSAAPSQTSVYFCASSY

[0186] TCR Alpha V (TCRαV) Diversity in the immune system enables defense against a wide variety of pathogens. Because the size of the germ cell genome is limited, diversity is achieved not only through the V(D)J recombination process, but also through deletions of nucleotide junctions (the junctions between the VD and DJ segments) and the addition of pseudo-random pseudo-template nucleotides. The TCR alpha gene forms diversity through gene rearrangement.

[0187] The TCR V-alpha repertoire varies between individuals and populations, for example, due to seven frequently occurring inactivation polymorphisms in functional gene segments and a large insertion / deletion-associated polymorphism encompassing two V-alpha gene segments.

[0188] In particular, this specification provides antibody molecules and fragments that bind, for example, specifically to the human TCR alpha V chain (TCRαV), for example, the TCRαV gene family (also called the group), for example, the TCRαV subfamily (also called the subgroup), as described herein. The TCR alpha V family and subfamily are known in the art and are described, for example, Yassai et al., (2009) Immunogenetics 61(7) pp:493-502; Wei S. and Concannon P. (1994) Human Immunology 41(3) pp:201-206. The antibodies described herein may be recombinant antibodies, for example, recombinant non-mouse antibodies, for example, recombinant human antibodies or humanized antibodies.

[0189] The terms TCRAV, TCRVA, TRAV, TCRαV, TCRVα, or TRαV are used interchangeably herein and refer, for example, to the TCR alpha-V chain as described herein.

[0190] In some embodiments, the Specified Information provides anti-TCRαV antibody molecules that bind to human TCRαV, for example, the TCRαV family, for example, its gene family or variant.

[0191] Examples of amino acid sequences for TCRαV subfamily members can be found on the ImMunoGeneTics Information System website: www.imgt.org or similar resources.

[0192] TCR beta-V (TCRβV) Diversity in the immune system enables defense against a wide variety of pathogens. Because the germ cell genome is limited in size, diversity is achieved not only through the V(D)J recombination process, but also through deletions of nucleotide junctions (the junctions between the VD and DJ segments) and the addition of pseudorandom pseudotemplate nucleotides. The TCR beta gene forms diversity through gene rearrangement.

[0193] The TCR V-beta repertoire varies between individuals and populations, for example, due to seven frequently occurring inactivation polymorphisms in functional gene segments and large insertion / deletion-associated polymorphisms encompassing two V-beta gene segments.

[0194] In particular, this specification provides antibody molecules and fragments thereof that bind, for example, specifically to the human TCR beta-V chain (TCRβV), for example, the TCRβV gene family (also called the group), for example, the TCRβV subfamily (also called the subgroup), as described herein. The TCR beta-V family and subfamily are known in the art and are described, for example, Yassai et al., (2009) Immunogenetics 61(7) pp:493-502; Wei S. and Concannon P. (1994) Human Immunology 41(3) pp:201-206. The antibodies described herein may be recombinant antibodies, for example, recombinant non-mouse antibodies, for example, recombinant human antibodies or humanized antibodies.

[0195] The terms TCRBV, TCRVB, TRBV, TCRβV, TCRVβ, or TRβV are used interchangeably herein and refer, for example, to the TCR beta-V chain as described herein.

[0196] In some embodiments, anti-TCRβV antibody molecules are provided herein that bind to human TCRβV, for example, the TCRβV family, for example, the gene family or variant thereof. In some embodiments, the TCRβV gene family includes, for example, one or more subfamilies listed herein in Table 6 or Table 7. In some embodiments, the TCRβV gene family includes: TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, TCRβ V29 subfamily, TCRβ V1 subfamily, TCRβ V17 subfamily, TCRβ V21 subfamily, TCRβ The V23 subfamily, or the TCRβ V26 subfamily.

[0197] In some embodiments, the TCRβ V6 subfamily is also known as TCRβ V13.1. In some embodiments, the TCRβV6 subfamily includes TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01, or TCRβ V6-1*01, or their variants. In some embodiments, TCRβ V6 includes TCRβ V6-4*01 or its variants. In some embodiments, TCRβ V6 includes TCRβ V6-4*02 or its variants. In some embodiments, TCRβ V6 includes TCRβ V6-9*01 or its variants. In some embodiments, TCRβ V6 includes TCRβ V6-8*01 or a variant thereof. In some embodiments, TCRβ V6 includes TCRβ V6-5*01 or a variant thereof. In some embodiments, TCRβ V6 includes TCRβ V6-6*02 or a variant thereof. In some embodiments, TCRβ V6 includes TCRβ V6-6*01 or a variant thereof. In some embodiments, TCRβ V6 includes TCRβ V6-2*01 or a variant thereof. In some embodiments, TCRβ V6 includes TCRβ V6-3*01 or a variant thereof. In some embodiments, TCRβ V6 includes TCRβ V6-1*01 or a variant thereof.

[0198] In some embodiments, TCRβ V6 includes TCRβ V6-5*01 or a variant thereof. In some embodiments, TCRβ V6, for example, TCRβ V6-5*01, is recognized by SEQ ID NO: 1 and / or SEQ ID NO: 2, and is, for example, bound to them. In some embodiments, TCRβ V6, for example, TCRβ V6-5*01, is recognized by SEQ ID NO: 9 and / or SEQ ID NO: 10, and is, for example, bound to them. In some embodiments, TCRβ V6 is recognized by SEQ ID NO: 9 and / or SEQ ID NO: 11, and is, for example, bound to them.

[0199] In some embodiments, the TCRβ V10 subfamily is also known as TCRβ V12. In some embodiments, the TCRβV10 subfamily includes TCRβ V10-1*01, TCRβ V10-1*02, TCRβ V10-3*01, or TCRβ V10-2*01, or variants thereof.

[0200] In some embodiments, the TCRβ V12 subfamily is also known as TCRβ V8.1. In some embodiments, the TCRβV12 subfamily includes TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01, or variants thereof. In some embodiments, TCRβ V12 is recognized by SEQ ID NO: 15 and / or SEQ ID NO: 16, and is bound to them, for example. In some embodiments, TCRβ V12 is recognized by any one of SEQ ID NOs: 23-25 ​​and / or any one of SEQ ID NOs: 26-30, and is bound to them, for example.

[0201] In some embodiments, the TCRβ V5 subfamily is selected from TCRβ V5-5*01, TCRβ V5-6*01, TCRβ V5-4*01, TCRβ V5-8*01, TCRβ V5-1*01, or variants thereof.

[0202] In some embodiments, the TCRβ V7 subfamily includes TCRβ V7-7*01, TCRβ V7-6*01, TCRβ V7-8*02, TCRβ V7-4*01, TCRβ V7-2*02, TCRβ V7-2*03, TCRβ V7-2*01, TCRβ V7-3*01, TCRβ V7-9*03, or TCRβ V7-9*01, or variants thereof.

[0203] In some embodiments, the TCRβV11 subfamily includes TCRβ V11-1*01, TCRβ V11-2*01, or TCRβ V11-3*01, or their variants. In some embodiments, the TCRβ V14 subfamily includes TCRβ V14*01 or its variants. In some embodiments, the TCRβ V16 subfamily includes TCRβ V16*01 or its variants. In some embodiments, the TCRβ V18 subfamily includes TCRβ V18*01 or its variants. In some embodiments, the TCRβ V9 subfamily includes TCRβ V9*01 or TCRβ V9*02, or their variants. In some embodiments, the TCRβ V13 subfamily includes TCRβ V13*01 or its variants. In some embodiments, the TCRβ V4 subfamily includes TCRβ V4-2*01, TCRβ V4-3*01, or TCRβ V4-1*01, or their variants. In some embodiments, the TCRβ V3 subfamily includes TCRβ V3-1*01 or its variants. In some embodiments, the TCRβ V2 subfamily includes TCRβ V2*01 or its variants. In some embodiments, the TCRβ V15 subfamily includes TCRβ V15*01 or its variants. In some embodiments, the TCRβ V30 subfamily includes TCRβ V30*01 or TCRβ V30*02, or their variants. In some embodiments, the TCRβ V19 subfamily includes TCRβ V19*01 or TCRβ V19*02, or their variants. In some embodiments, the TCRβ V27 subfamily includes TCRβ V27*01 or its variants. In some embodiments, the TCRβ V28 subfamily includes TCRβ V28*01 or a variant thereof. In some embodiments, the TCRβ V24 subfamily includes TCRβ V24-1*01 or a variant thereof. In some embodiments, the TCRβ V20 subfamily includes TCRβ V20-1*01 or TCRβ V20-1*02 or a variant thereof.In some embodiments, the TCRβ V25 subfamily includes TCRβ V25-1*01 or its variants. In some embodiments, the TCRβ V29 subfamily includes TCRβ V29-1*01 or its variants.

[0204] Examples of amino acid sequences for TCRβV subfamily members can be found on the ImMunoGeneTics Information System website: www.imgt.org or similar resources.

[0205] Target treatment Any of the compositions provided herein may be administered to an organism. “Organization” may be used interchangeably with “Subject” or “Patient.” An organism may be a mammal, e.g., a human, or an animal, e.g., a non-human primate, rodent, rabbit, rat, mouse, horse, donkey, goat, cat, dog, cow, pig, or sheep. In some embodiments, the organism is a human. In some embodiments, the organism is a fetus, embryo, or child. In other embodiments, the organism may be another eukaryote, e.g., a plant. In some embodiments, the compositions provided herein are administered to cells in vitro.

[0206] In some embodiments, the compositions provided herein are administered to an individual as a method for treating a disease or disorder. In some embodiments, the individual has a genetic disorder, such as one of the diseases described herein. In some embodiments, the individual is at risk of having a disease, such as one of the diseases described herein. In some embodiments, the individual is at high risk of having a disease or disorder caused by a deficiency in the amount or activity of a protein. If the individual is at "high risk" of having a disease or disorder caused by a deficiency in the amount or activity of a protein, the method includes preventive or prophylactic treatment. For example, an individual may be at high risk of having such a disease or disorder due to a family history of the disease. Typically, an individual at high risk of having such a disease or disorder would benefit from prophylactic treatment (e.g., benefit from preventing or delaying the onset or progression of the disease or disorder). In some embodiments, a fetus is treated in utero by administering, for example, a multifunctional or multispecific molecule or composition described herein directly or indirectly (e.g., via the mother) to the fetus.

[0207] The preferred route for administering the molecules or compositions described herein may vary depending on the cell type to which the molecule or composition is to be delivered. The molecules or compositions described herein may be administered parenterally to patients, for example, by intrathecal injection, intraventricular injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, or intravenous injection.

[0208] In some embodiments, the molecules or compositions described herein are administered together with one or more agents capable of facilitating the penetration of the molecules or compositions described herein into the target area across the blood-brain barrier by methods known in the art. For example, the delivery of an agent by administration of an adenovirus vector to motor neurons in muscle tissue is described in U.S. Patent No. 6,632,427, “Adenoviral-vector-mediated gene transfer into medullary motor neurons,” which is incorporated herein by reference. The direct delivery of vectors to the brain, such as the striatum, thalamus, hippocampus, or substantia nigra, is described, for example, in U.S. Patent No. 6,756,523, “Adenovirus vectors for the transfer of foreign genes into cells of the central nervous system particularly in brain,” which is incorporated herein by reference.

[0209] In some embodiments, the molecules or compositions described herein are linked to or conjugated to an agent that provides desired pharmaceutical or pharmacological properties. In some embodiments, the molecules or compositions described herein are linked to substances known in the art that facilitate penetration or transport across the blood-brain barrier, such as antibodies against transferrin receptors. In some embodiments, the molecules or compositions described herein are linked to a viral vector.

[0210] In some embodiments, the object treated using the method and composition is evaluated for improvement in condition using any method known and reported in the art.

[0211] Terms such as “to treat,” “to treat,” and “treatment” are used herein generally to mean obtaining a desired pharmacological and / or physiological effect. The effect may be preventive in that it prevents or partially prevents a disease or its symptoms or condition, and / or therapeutic in that it is a partial or complete cure of a disease, a condition resulting from a disease, symptoms or adverse effects. Where used herein, the term “treatment” encompasses any treatment of a disease in a mammal, in particular a human, and includes (a) preventing the development of a disease in a subject that may be prone to developing the disease but has not yet been diagnosed with the disease, (b) inhibiting the disease, i.e., stopping its development, and (c) alleviating the disease, i.e., reducing or improving the disease and / or its symptoms or condition. Where used herein, the term “prevention” is used herein to mean measures taken for the prevention or partial prevention of a disease or condition. In some embodiments, where used herein, the terms “condition,” “disease,” or “disorder” are interchangeable.

[0212] "Treating or preventing a disease or disorder" means improving any of the conditions, signs, or symptoms associated with the disease or disorder before or after its onset. Compared to an equivalent untreated control, the degree of such reduction or prevention is at least 3%, 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100%, as measured by any standard technique. Patients treated for a disease or disorder are those diagnosed by a healthcare professional as having the condition. The diagnosis may be made by any appropriate means. Diagnosis and monitoring include, for example, detecting the presence of diseased cells in a biological sample (e.g., tissue biopsy, blood test, or urine test), detecting levels of surrogate markers for the disorder in a biological sample, or detecting symptoms associated with the disorder. Patients whose onset of the disorder is prevented may or may not have received such a diagnosis. Those skilled in the art will understand that these patients may be subject to the same standard tests as described above, or may be identified as high-risk due to the presence of one or more risk factors (e.g., family history or genetic predisposition) without verification.

[0213] Treatment method In this specification, in certain embodiments, methods for treating diseases or conditions in subjects requiring such treatment are described, comprising administering to the subject a therapeutically effective amount of an antibody molecule, a multifunctional or multispecific molecule, a nucleic acid molecule, a vector, a cell, a pharmaceutical composition, or a combination thereof, as described herein, in such case, the administration is effective in treating the condition or disease of the subject. Any condition or disease associated with TCRαV and / or TCRβV may be subject to the therapeutic methods disclosed herein. For example, a condition or disease can be treated with CAR-T cells containing CARs having anti-TCRαV-binding domains and / or anti-TCRβV-binding domains that bind to TCRαV and / or TCRβV expressed by the subject's autoreactive T cells expressing TCRαV and / or TCRβV. Examples of TCRαV-related diseases and TCRβV-related diseases are, but are not limited to, those listed in Table 5.

[0214] In some embodiments, the condition or disease is an autoimmune disease. In some embodiments, autoimmune diseases include amyotrophic lateral sclerosis (ALS), celiac disease (CD), ankylosing spondylitis (AS), Covid-associated multisystem inflammatory syndrome (MIS-C) in children, primary Sjögren's syndrome (PSS), Churg-Strauss syndrome, sarcoidosis, systemic lupus erythematosus (SLE), type 1 diabetes, autoimmune hepatitis (e.g., type 1 or type 2), primary sclerosing cholangitis, primary biliary cholangitis, multiple sclerosis, Guillain-Barré syndrome, and AMAN (axonal and neuronal neuropathy), chronic Inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis, Trosa Hunt syndrome (THS), Devic's disease (neuromyelitis optica), paraneoplastic cerebellar degeneration (PCD), Lambert-Eaton syndrome, psoriasis, scleroderma, CREST (calcification, Raynaud's phenomenon, esophageal motility disorders, finger sclerosis, and telangiectasia) syndrome, herpetiform dermatitis, dermatomyositis, bullous pemphigoid, scarring pemphigoid / benign mucosal pemphigoid, pemphigoid of pregnancy, rheumatoid arthritis (RA), psoriatic arthritis, relapsing polychondritis, chronic relapsing polymyelitis (CRMO) The following are selected from the group of autoimmune diseases, including recurrent multifocal osteomyelitis, vasculitis, Kawasaki disease, granulomatosis with polyangiitis (GPA), Behçet's disease (vasculitis), Takayasu's arteritis, polyarteritis nodosa, microscopic polyangiitis (MPA), leukocytoclastic vasculitis, Cogan's syndrome, uveitis, peripheral uveitis (tonsillar), scleritis, autoimmune inner ear disease (AIED), Crohn's disease, ulcerative colitis (UC), Dressler's syndrome, rheumatic fever, Evans syndrome, paroxysmal nocturnal hemoglobinuria (PNH), hemolytic anemia, thrombocytopenic purpura (TTP), polymyositis, juvenile myositis (JM), including juvenile dermatomyositis (JDM) and juvenile polymyositis (JPM), ocular pemphigoid, or Hashimoto's thyroiditis.

[0215] In some embodiments, the molecules or compositions disclosed herein (e.g., antibody molecules or polyspecific molecules (or pharmaceutical compositions) provided herein, nucleic acid molecules described herein, vectors described herein, cells described herein, pharmaceutical compositions described herein, or combinations thereof) are administered in a manner appropriate to the disease being treated or prevented. The amount and frequency of administration are determined by factors such as the patient's condition, as well as the type and severity of the patient's disease. The appropriate dose may be determined by clinical trials. For example, where indicated as “effective dose” or “therapeutic dose,” the exact amount of the molecules or compositions disclosed herein to be administered may be determined by a physician, taking into account individual differences in the severity / characteristics of the immune disorder, the degree of infection or metastasis, the subject's age, weight, and condition.

[0216] In some embodiments, the binding of the molecules or compositions disclosed herein results in cell death, such as the death of target cells, including the death of autoreactive T cells. In some embodiments, the autoreactive T cells are CD4+ T cells. In some embodiments, the autoreactive T cells are CD8+ T cells. In some embodiments, the binding of the molecules or compositions disclosed herein results in cell death in vitro or in vivo.

[0217] In several embodiments, the molecules or compositions disclosed herein are administered to subjects parenterally. In several embodiments, the cells disclosed herein are administered to subjects intravenously, subcutaneously, intranodally, intramuscularly, intradermally, or intraperitoneally. In several embodiments, the cells are administered by infusion (e.g., as described in Rosenberg et al., New Eng. J. of Med. 319:1676, 1988) or by intravenous injection. In several embodiments, the cells are administered as an injectable depot formulation.

[0218] In multiple embodiments, the subject is a mammal. In multiple embodiments, the subject is a human, monkey, pig, dog, cat, cow, sheep, goat, rabbit, rat, or mouse. In multiple embodiments, the subject is a human. In multiple embodiments, the subject is a child subject, for example, under 18 years of age, for example, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 year of age or younger. In multiple embodiments, the subject is an adult, for example, at least 18 years of age, for example, at least 19, 20, 21, 22, 23, 24, 25, 25-30, 30-35, 35-40, 40-50, 50-60, 60-70, 70-80, or 80-90 years of age.

[0219] While we do not wish to be bound by any particular theory, the immune response induced by anti-TCRVα TCR-targeting molecules and / or anti-TCRβV TCR-targeting molecules may be an active or passive immune response. In one embodiment, the anti-TCRVα TCR-targeting molecules and / or anti-TCRβV TCR-targeting molecules of this disclosure may be some kind of vaccine for in vitro immunization and / or in vivo treatment in mammals. With respect to in vitro immunization, before administering cells to a mammal, at least one of the following occurs in vitro: i) cell expansion, ii) introduction of nucleic acids encoding anti-TCRVα TCR and / or anti-TCRβV TCR-targeting molecules into the cells, or iii) cryopreservation of the cells.

[0220] In vitro methods are known in this field and will be discussed in detail below. Briefly, cells are isolated from mammals (e.g., humans) and genetically modified (i.e., transfected in vitro) with vectors expressing the anti-TCRVα TCR targeting molecule and / or anti-TCRβV TCR targeting molecule disclosed herein.

[0221] Methods described herein include treating a target autoimmune disease by using a molecule or composition disclosed herein, for example, by using a pharmaceutical composition described herein. Methods for reducing or improving the symptoms of a target autoimmune disease are also provided. In some embodiments, methods described herein restore balance to the T cell repertoire in a subject (for example, by reducing or depleting autoreactive T cells and maintaining healthy T cells to establish a T cell repertoire similar to that of a person without an autoimmune disease).

[0222] This specification discloses a method for reducing the symptoms of autoimmune diseases in subjects where such reduction is needed, the method comprising administering a therapeutically effective dose of an agent containing a portion that binds to a TCR variable region (e.g., the TCRVα region and / or the TCRβV region) to the subject, thereby inhibiting or preventing the activation or expansion of autoreactive T cells in the subject. In some embodiments, the agent comprises an anti-TCRαV antibody containing a variant Fc region. In some embodiments, the agent comprises an anti-TCRβV antibody containing a variant Fc region. In some embodiments, the variant Fc region has increased binding to C1q complement. In some embodiments, the variant Fc region has increased effector function (e.g., antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC)).

[0223] This specification discloses methods for treating a disease or condition in subjects where such treatment is needed, comprising administering a therapeutically effective dose of an agent containing a portion that binds to a TCR variable region (e.g., the TCRVα region and / or the TCRβV region) to the subject, thereby inhibiting or preventing the activation or expansion of autoreactive T cells in the subject. In some embodiments, the agent comprises an anti-TCRαV antibody containing a variant Fc region. In some embodiments, the agent comprises an anti-TCRβV antibody containing a variant Fc region. In some embodiments, the variant Fc region has increased binding to C1q complement. In some embodiments, the variant Fc region has increased effector function (e.g., antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC)). In some embodiments, the disease or condition is an autoimmune disease.

[0224] This specification discloses methods for reducing symptoms of autoimmune diseases in subjects where such reduction is needed, the methods comprising administering a therapeutically effective dose of an agent containing a portion that binds to the TCR variable region (e.g., the TCRVα region and / or the TCRβV region) to the subject. In some embodiments, the agent comprises an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate comprises a TCRαV antigen-binding domain. In some embodiments, the antibody-drug conjugate comprises a TCRβV antigen-binding domain. In some embodiments, the antibody-drug conjugate does not have mutations in the Fc region. In some embodiments, the antibody-drug conjugate is functionally linked to a cytotoxic agent. In some embodiments, the cytotoxic agent is a tubulin polymerization inhibitor. In some embodiments, the cytotoxic agent is selected from the group consisting of meitansine, drastatin, auristatin drug analogs, duocalmycin derivatives (e.g., CC-1065 analogs and duocalmycin), esperamycin, calicheamicin, and pyrrolobenzodiazepines (PBDs).

[0225] In this specification, methods for treating a disease or condition in a subject where such treatment is needed are disclosed, the methods comprising administering a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region (e.g., the TCRVα region and / or the TCRβV region) to the subject. In some embodiments, the agent comprises an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate comprises a TCRαV antigen-binding domain. In some embodiments, the antibody-drug conjugate comprises a TCRβV antigen-binding domain. In some embodiments, the antibody-drug conjugate does not have mutations in the Fc region. In some embodiments, the antibody-drug conjugate is functionally linked to a cytotoxic agent. In some embodiments, the cytotoxic agent is a tubulin polymerization inhibitor. In some embodiments, the cytotoxic agent is selected from the group consisting of meitansine, drastatin, auristatin drug analogs, duocalmycin derivatives (e.g., CC-1065 analogs and duocalmycin), esperamycin, calicheamicin, and pyrrolobenzodiazepines (PBDs). In some embodiments, the disease or condition is an autoimmune disease.

[0226] This specification discloses methods for reducing symptoms of autoimmune diseases in subjects where such reduction is needed, the methods comprising administering a therapeutically effective dose of an agent comprising a portion that binds to a TCR variable region (e.g., the TCRVα region and / or the TCRβV region) to the subject. In some embodiments, the agent is a CAR T cell comprising a CAR having an anti-TCRαV binding domain that binds to TCRαV expressed by autoreactive T cells. In some embodiments, the agent is a CAR T cell comprising a CAR having an anti-TCRβV binding domain that binds to TCRβV expressed by autoreactive T cells. In some embodiments, the CAR comprises a transmembrane domain provided herein. In some embodiments, the CAR comprises an intracellular domain provided herein.

[0227] In this specification, methods for treating a disease or condition in subjects where such treatment is needed are disclosed, the methods comprising administering a therapeutically effective amount of an agent comprising a portion that binds to a TCR variable region (e.g., the TCRVα region and / or the TCRβV region) to the subject. In some embodiments, the agent is a CAR T cell comprising a CAR having an anti-TCRαV binding domain that binds to TCRαV expressed by autoreactive T cells. In some embodiments, the agent is a CAR T cell comprising a CAR having an anti-TCRβV binding domain that binds to TCRβV expressed by autoreactive T cells. In some embodiments, the CAR comprises a transmembrane domain provided herein. In some embodiments, the CAR comprises an intracellular domain provided herein. In some embodiments, the disease or condition is an autoimmune disease.

[0228] This specification discloses methods for reducing the symptoms of autoimmune diseases in subjects where such reduction is needed, and these methods include administering a therapeutically effective dose of an agent containing a portion that binds to a TCR variable region (e.g., the TCRVα region and / or the TCRβV region) to the subject. In some embodiments, the subject is administered a polyspecific molecule containing a TCRVα binding region and an NK cell engager. In some embodiments, the NK cell engager is selected from antigen-binding domains or ligands that bind to (e.g., activate) the following: NKp30, NKp40, NKp44, NKp46, NKG2D, DNAM1, DAP10, CD16 (e.g., CD16a, CD16b, or both), CRTAM, CD27, PSGL1, CD96, CD100 (SEMA4D), NKp80, CD244 (also known as SLAMF4 or 2B4), SLAMF6, SLAMF7, KIR2DS2, KIR2DS4, KIR3DS1, KIR2DS3, KIR2DS5, KIR2DS1, CD94, NKG2C, NKG2E, or CD160. In some embodiments, the NK cell engager is a ligand for CD16, and a CD16a / b ligand, e.g., a CD16a / b ligand further comprising an antibody Fc region. In some embodiments, the NK cell engager is an agonist of the NK activating receptor. In some embodiments, the NK cell engager is an antagonist of the NK inhibitory receptor. In some embodiments, the polyspecific molecule does not have mutations in the Fc region.

[0229] In this specification, methods for treating a disease or condition in subjects where such treatment is necessary are disclosed, the methods comprising administering a therapeutically effective amount of an agent containing a portion that binds to a TCR variable region (e.g., the TCRVα region and / or the TCRβV region) to the subject. In some embodiments, the subject is administered a polyspecific molecule containing a TCRVα binding region and an NK cell engager. In some embodiments, the NK cell engager is selected from antigen-binding domains or ligands that bind to (e.g., activate) the following: NKp30, NKp40, NKp44, NKp46, NKG2D, DNAM1, DAP10, CD16 (e.g., CD16a, CD16b, or both), CRTAM, CD27, PSGL1, CD96, CD100 (SEMA4D), NKp80, CD244 (also known as SLAMF4 or 2B4), SLAMF6, SLAMF7, KIR2DS2, KIR2DS4, KIR3DS1, KIR2DS3, KIR2DS5, KIR2DS1, CD94, NKG2C, NKG2E, or CD160. In some embodiments, the NK cell engager is a ligand for CD16, and a CD16a / b ligand, e.g., a CD16a / b ligand further comprising an antibody Fc region. In some embodiments, the NK cell engager is an agonist of the NK activating receptor. In some embodiments, the NK cell engager is an antagonist of the NK inhibitory receptor. In some embodiments, the polyspecific molecule does not have mutations in the Fc region. In some embodiments, the subject has an autoimmune disease.

[0230] This specification discloses methods for reducing symptoms of autoimmune diseases in subjects where such reduction is needed, the methods comprising administering a therapeutically effective dose of an agent to the subject that includes a portion that binds to the TCR variable region (e.g., the TCRVα region and / or the TCRβV region). In some embodiments, the subject is administered an agent comprising a polyspecific molecule containing an antigen-binding domain that binds to TCRVα and a T cell engager. In some embodiments, the subject is administered an agent comprising a polyspecific molecule containing an antigen-binding domain that binds to TCRVβ and a T cell engager. In some embodiments, the T cell engager is selected from antigen-binding domains or ligands that bind to (e.g., are activated in some embodiments) one or more of CD3, TCRα, TCRβ, TCRγ, TCRζ, ICOS, CD28, CD27, HVEM, LIGHT, CD40, 4-1BB, OX40, DR3, GITR, CD30, TIM1, SLAM, CD2, or CD226. In some embodiments, the T cell engager binds to (e.g., activates) CD4+ T cells and / or CD8+ T cells. In some embodiments, the T cell engager binds to (e.g., activates) CD4+ T cells. In some embodiments, the T cell engager binds to (e.g., activates) CD8+ T cells. In some embodiments, the disease or condition is an autoimmune disease.

[0231] Alternatively, the Specified Publication may also describe a method for treating a subject having an autoimmune disease, the method comprising determining the status of one or more TCRαV molecules and / or TCRβV molecules in a sample derived from the subject, and determining that the one or more TCRαV molecules and / or TCRβV molecules are expressed in an autoreactive T cell population in the sample derived from the subject, the method comprising, in accordance with the determination, administering to the subject an effective amount of an anti-TCRαV antibody molecule and / or anti-TCRβV antibody molecule as described herein, for example, an agonist anti-TCRαV antibody molecule and / or an agonist anti-TCRβV antibody molecule.

[0232] In some embodiments, determining the state of one or more TCRαV molecules and / or TCRβV molecules, such as their presence, levels, and / or activity, involves determining the T cell receptor (TCR) repertoire of the sample. In some embodiments, the values ​​include determining the clonal type of the T cell population in the sample.

[0233] In some embodiments, values ​​relating to the state of one or more TCRαV molecules and / or TCRβV molecules are obtained, for example, using an assay described in Wang CY, et al., Int J Oncol. (2016) 48(6):2247-56, which is incorporated herein by reference in its entirety.

[0234] In some embodiments, values ​​relating to the state of one or more TCRαV molecules and / or TCRβV molecules are obtained, for example, by flow cytometry.

[0235] In some embodiments, subjects are administered a multifunctional polypeptide molecule described herein, which includes an anti-TCRαV binding moiety and / or an anti-TCRβV binding moiety.

[0236] In some embodiments, a method for treating a subject suffering from amyotrophic lateral sclerosis (ALS) is provided, comprising administering a TCR-targeting molecule, a nucleic acid molecule encoding a TCR-targeting molecule, or cells expressing a TCR-targeting molecule (e.g., CAR-T cells disclosed herein) that specifically binds to a TCRβV7 subfamily molecule. In some embodiments, the TCRβV7 subfamily molecule includes the TCRβV7-1 molecule. In some embodiments, a method for treating a subject suffering from amyotrophic lateral sclerosis (ALS) is provided, comprising administering a TCR-targeting molecule, a nucleic acid molecule encoding a TCR-targeting molecule, or cells expressing a TCR-targeting molecule (e.g., CAR-T cells disclosed herein) that specifically binds to a TCRβV23 subfamily molecule.

[0237] In some embodiments, a method for treating a subject suffering from celiac disease is provided herein, comprising administering a TCR-targeting molecule disclosed herein, a nucleic acid molecule encoding a TCR-targeting molecule, or cells expressing a TCR-targeting molecule (e.g., CAR-T cells disclosed herein) that specifically binds to a TCRβV4 subfamily molecule. In some embodiments, a method for treating a subject suffering from celiac disease is provided herein, comprising administering a TCR-targeting molecule disclosed herein, a nucleic acid molecule encoding a TCR-targeting molecule, or cells expressing a TCR-targeting molecule (e.g., CAR-T cells disclosed herein) that specifically binds to a TCRβV7 subfamily molecule. In some embodiments, a method for treating a subject suffering from celiac disease is provided herein, comprising administering a TCR-targeting molecule disclosed herein, a nucleic acid molecule encoding a TCR-targeting molecule, or cells expressing a TCR-targeting molecule (e.g., CAR-T cells disclosed herein) that specifically binds to a TCRαV4 subfamily molecule. In some embodiments, a method is provided herein for treating a subject suffering from celiac disease, comprising administering a TCR-targeting molecule disclosed herein, a nucleic acid molecule encoding a TCR-targeting molecule, or cells expressing a TCR-targeting molecule (e.g., CAR-T cells disclosed herein) that specifically binds to a TCRαV26 subfamily molecule.

[0238] In some embodiments, a method for treating a subject suffering from ankylosing spondylitis is provided herein, comprising administering a TCR-targeting molecule disclosed herein, a nucleic acid molecule encoding a TCR-targeting molecule, or cells expressing a TCR-targeting molecule (e.g., CAR-T cells disclosed herein) that specifically binds to a TCRβV9 subfamily molecule. In some embodiments, a method for treating a subject suffering from ankylosing spondylitis is provided herein, comprising administering a TCR-targeting molecule disclosed herein, a nucleic acid molecule encoding a TCR-targeting molecule, or cells expressing a TCR-targeting molecule (e.g., CAR-T cells disclosed herein) that specifically binds to a TCRαV21 subfamily molecule. In some embodiments, a method is provided herein for treating a subject suffering from Covid-associated multisystem inflammatory syndrome (MIS-C) in children, comprising administering a TCR-targeting molecule, a nucleic acid molecule encoding a TCR-targeting molecule, or cells expressing a TCR-targeting molecule (e.g., CAR-T cells disclosed herein) that specifically binds to a TCRβV11 subfamily molecule. In some embodiments, the TCRβV11 subfamily molecule includes the TCRβV11-2 molecule. In some embodiments, a method is provided herein for treating a subject suffering from primary Sjögren's syndrome, comprising administering a TCR-targeting molecule, a nucleic acid molecule encoding a TCR-targeting molecule, or cells expressing a TCR-targeting molecule (e.g., CAR-T cells disclosed herein) that specifically binds to a TCRβV6 subfamily molecule. In some embodiments, the TCRβV6 subfamily molecule includes the TCRβV6-1 molecule, the TCRβV6-2 / 3 molecule, or the TCRβV6-5 molecule.

[0239] In some embodiments, a method for treating a subject suffering from multiple sclerosis is provided herein, comprising administering a TCR-targeting molecule, a nucleic acid molecule encoding a TCR-targeting molecule, or cells expressing a TCR-targeting molecule (e.g., CAR-T cells disclosed herein) that specifically binds to a TCRβV20 subfamily molecule. In some embodiments, the TCRβV20 subfamily molecule is the TCRβV20-1 molecule. In some embodiments, a method for treating a subject suffering from multiple sclerosis is provided herein, comprising administering a TCR-targeting molecule, a nucleic acid molecule encoding a TCR-targeting molecule, or cells expressing a TCR-targeting molecule (e.g., CAR-T cells disclosed herein) that specifically binds to a TCRβV29 subfamily molecule. In some embodiments, the TCRβV20 subfamily molecule is the TCRβV29-1 molecule. In some embodiments, a method for treating a subject suffering from multiple sclerosis is provided herein, comprising administering a TCR-targeting molecule, a nucleic acid molecule encoding a TCR-targeting molecule, or cells expressing a TCR-targeting molecule (e.g., CAR-T cells disclosed herein) that specifically binds to a TCRβV7 subfamily molecule. In some embodiments, the TCRβV7 subfamily molecule is the TCRβV7-8 / 9 molecule. In some embodiments, a method for treating a subject suffering from multiple sclerosis is provided herein, comprising administering a TCR-targeting molecule, a nucleic acid molecule encoding a TCR-targeting molecule, or cells expressing a TCR-targeting molecule (e.g., CAR-T cells disclosed herein) that specifically binds to a TCRβV10 subfamily molecule. In some embodiments, the TCRβV10 subfamily molecule is the TCRβV10-3 molecule.

[0240] In some embodiments, a method for treating a subject suffering from type 1 diabetes is provided, comprising administering a TCR-targeting molecule, a nucleic acid molecule encoding a TCR-targeting molecule, or cells expressing a TCR-targeting molecule (e.g., CAR-T cells disclosed herein) that specifically binds to a TCRβV12 subfamily molecule. In some embodiments, the TCRβV12 subfamily molecule includes the TCRβV12-3 / 4 molecule. In some embodiments, a method for treating a subject suffering from type 1 diabetes is provided, comprising administering a TCR-targeting molecule, a nucleic acid molecule encoding a TCR-targeting molecule, or cells expressing a TCR-targeting molecule (e.g., CAR-T cells disclosed herein) that specifically binds to a TCRαV12 subfamily molecule. In some embodiments, the TCRαV12 subfamily molecule includes the TCRαV12-3 molecule.

[0241] In some embodiments, subjects have amyotrophic lateral sclerosis (ALS). In some embodiments, subjects with ALS have a population of autoreactive T cells expressing the TCRβV7 subfamily, including TCRβV7-1. In some embodiments, subjects are administered agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, including anti-TCRβV molecules that bind to one or more members of the TCRβV7 subfamily. In some embodiments, administration of agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein inhibits or prevents the activation and / or expansion of the autoreactive T cell population expressing one or more members of the TCRβV7 subfamily. In some embodiments, administration of agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein reduces or depletes the autoreactive T cell population expressing one or more members of the TCRβV7 subfamily. In some embodiments, subjects with ALS have a population of autoreactive T cells expressing the TCRβV23 subfamily. In some embodiments, subjects are administered agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, including anti-TCRβV molecules that bind to one or more members of the TCRβV23 subfamily. In some embodiments, administration of agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein inhibits or prevents the activation and / or expansion of an autoreactive T cell population expressing one or more members of the TCRβV23 subfamily. In some embodiments, administration of agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein reduces or depletes an autoreactive T cell population expressing one or more members of the TCRβV23 subfamily.

[0242] In some embodiments, subjects have celiac disease. In some embodiments, subjects with celiac disease have a population of autoreactive T cells expressing the TCRβV4 subfamily. In some embodiments, subjects are administered agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, including anti-TCRβV molecules that bind to one or more members of the TCRβV4 subfamily. In some embodiments, by administering agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, the activation and / or expansion of the autoreactive T cell population expressing one or more members of the TCRβV4 subfamily is inhibited or prevented. In some embodiments, by administering agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, the autoreactive T cell population expressing one or more members of the TCRβV4 subfamily is reduced or depleted. In some embodiments, subjects with celiac disease have a population of autoreactive T cells expressing the TCRβV7 subfamily. In some embodiments, subjects are administered agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, including anti-TCRβV molecules that bind to one or more members of the TCRβV7 subfamily. In some embodiments, by administering agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, the activation and / or expansion of an autoreactive T cell population expressing one or more members of the TCRβV7 subfamily is inhibited or prevented. In some embodiments, by administering agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, the autoreactive T cell population expressing one or more members of the TCRβV7 subfamily is reduced or depleted. In some embodiments, subjects with celiac disease have a population of autoreactive T cells expressing the TCRαV4 subfamily. In some embodiments, subjects are administered agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, including anti-TCRαV molecules that bind to one or more members of the TCRαV4 subfamily.In some embodiments, administration of the agents, antibody molecules, multispecific molecules, and / or multifunctional molecules described herein inhibits or prevents the activation and / or expansion of an autoreactive T cell population expressing one or more members of the TCRαV4 subfamily. In some embodiments, administration of the agents, antibody molecules, multispecific molecules, and / or multifunctional molecules described herein reduces or depletes the autoreactive T cell population expressing one or more members of the TCRαV4 subfamily. In some embodiments, subjects with celiac disease have a population of autoreactive T cells expressing the TCRαV26 subfamily. In some embodiments, subjects are administered the agents, antibody molecules, multispecific molecules, and / or multifunctional molecules described herein, including an anti-TCRαV molecule that binds to one or more members of the TCRαV26 subfamily. In some embodiments, administration of the agents, antibody molecules, multispecific molecules, and / or multifunctional molecules described herein inhibits or prevents the activation and / or expansion of an autoreactive T cell population expressing one or more members of the TCRαV26 subfamily. In some embodiments, administration of agents, antibody molecules, multispecific molecules, and / or multifunctional molecules described herein reduces or depletes an autoreactive T cell population expressing one or more members of the TCRαV26 subfamily.

[0243] In some embodiments, the subjects have ankylosing spondylitis. In some embodiments, the subjects with ankylosing spondylitis have a population of autoreactive T cells expressing the TCRβV9 subfamily. In some embodiments, the subjects are administered agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, including anti-TCRβV molecules that bind to one or more members of the TCRβV9 subfamily. In some embodiments, by administering agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, the activation and / or expansion of the autoreactive T cell population expressing one or more members of the TCRβV9 subfamily is inhibited or prevented. In some embodiments, by administering agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, the autoreactive T cell population expressing one or more members of the TCRβV9 subfamily is reduced or depleted. In some embodiments, the subjects with ankylosing spondylitis have a population of autoreactive T cells expressing the TCRαV21 subfamily. In some embodiments, subjects are administered agents, antibody molecules, multispecific molecules, and / or multifunctional molecules described herein, including anti-TCRαV molecules that bind to one or more members of the TCRαV21 subfamily. In some embodiments, administration of agents, antibody molecules, multispecific molecules, and / or multifunctional molecules described herein inhibits or prevents the activation and / or expansion of an autoreactive T cell population expressing one or more members of the TCRαV21 subfamily. In some embodiments, administration of agents, antibody molecules, multispecific molecules, and / or multifunctional molecules described herein reduces or depletes an autoreactive T cell population expressing one or more members of the TCRαV21 subfamily.

[0244] In some embodiments, subjects have childhood COVID-related multisystem inflammatory syndrome (MIS-C). In some embodiments, subjects with MIS-C have a population of autoreactive T cells expressing the TCRβV11 subfamily, including TCRβV11-2. In some embodiments, subjects are administered agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, including anti-TCRβV molecules that bind to one or more members of the TCRβV11 subfamily. In some embodiments, administration of agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein inhibits or prevents the activation and / or expansion of the autoreactive T cell population expressing one or more members of the TCRβV11 subfamily. In some embodiments, administration of agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein reduces or depletes the autoreactive T cell population expressing one or more members of the TCRβV11 subfamily.

[0245] In some embodiments, subjects have primary Sjögren's syndrome. In some embodiments, subjects with primary Sjögren's syndrome have a population of autoreactive T cells expressing the TCRβV6 subfamily, including TCRβV6-1, TCRβV6-2 / 3, or TCRβV6-5. In some embodiments, subjects are administered agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, including anti-TCRβV molecules that bind to one or more members of the TCRβV6 subfamily. In some embodiments, administration of agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein inhibits or prevents the activation and / or expansion of the autoreactive T cell population expressing one or more members of the TCRβV6 subfamily. In some embodiments, administration of agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein reduces or depletes the autoreactive T cell population expressing one or more members of the TCRβV6 subfamily.

[0246] In some embodiments, subjects have multiple sclerosis. In some embodiments, subjects with multiple sclerosis have a population of autoreactive T cells expressing the TCRβV20 subfamily, including TCRβV20-1. In some embodiments, subjects are administered agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, including anti-TCRβV molecules that bind to one or more members of the TCRβV20 subfamily. In some embodiments, by administering agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, the activation and / or expansion of the autoreactive T cell population expressing one or more members of the TCRβV20 subfamily is inhibited or prevented. In some embodiments, by administering agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, the autoreactive T cell population expressing one or more members of the TCRβV20 subfamily is reduced or depleted. In some embodiments, subjects with multiple sclerosis have a population of autoreactive T cells expressing the TCRβV29 subfamily, including TCRβV29-1. In some embodiments, subjects are administered agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, including anti-TCRβV molecules that bind to one or more members of the TCRβV29 subfamily. In some embodiments, administration of agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein inhibits or prevents the activation and / or expansion of the autoreactive T cell population expressing one or more members of the TCRβV29 subfamily. In some embodiments, administration of agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein reduces or depletes the autoreactive T cell population expressing one or more members of the TCRβV29 subfamily. In some embodiments, subjects with multiple sclerosis have a population of autoreactive T cells expressing the TCRβV7 subfamily, including TCRβV7-8 / 9.In some embodiments, subjects are administered agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, including anti-TCRβV molecules that bind to one or more members of the TCRβV7 subfamily. In some embodiments, by administering agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, the activation and / or expansion of an autoreactive T cell population expressing one or more members of the TCRβV7 subfamily is inhibited or prevented. In some embodiments, by administering agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, the autoreactive T cell population expressing one or more members of the TCRβV7 subfamily is reduced or depleted. In some embodiments, subjects with multiple sclerosis have a population of autoreactive T cells expressing the TCRβV10 subfamily, including TCRβV10-3. In some embodiments, subjects are administered agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, including anti-TCRβV molecules that bind to one or more members of the TCRβV10 subfamily. In some embodiments, administration of the agents, antibody molecules, multispecific molecules, and / or multifunctional molecules described herein inhibits or prevents the activation and / or expansion of an autoreactive T cell population expressing one or more members of the TCRβV10 subfamily. In some embodiments, administration of the agents, antibody molecules, multispecific molecules, and / or multifunctional molecules described herein reduces or depletes an autoreactive T cell population expressing one or more members of the TCRβV10 subfamily.

[0247] In some embodiments, the subjects have type 1 diabetes. In some embodiments, the subjects with type 1 diabetes have a population of autoreactive T cells expressing the TCRβV12 subfamily, including TCRβV12-3 / 4. In some embodiments, the subjects are administered agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, including anti-TCRβV molecules that bind to one or more members of the TCRβV12 subfamily. In some embodiments, by administering agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, the activation and / or expansion of the autoreactive T cell population expressing one or more members of the TCRβV12 subfamily is inhibited or prevented. In some embodiments, by administering agents, antibody molecules, polyspecific molecules, and / or multifunctional molecules described herein, the autoreactive T cell population expressing one or more members of the TCRβV12 subfamily is reduced or depleted. In some embodiments, the subjects with type 1 diabetes have a population of autoreactive T cells expressing the TCRαV12 subfamily, including TCRαV12-3. In some embodiments, subjects are administered agents, antibody molecules, multispecific molecules, and / or multifunctional molecules described herein, including anti-TCRαV molecules that bind to one or more members of the TCRαV12 subfamily. In some embodiments, administration of agents, antibody molecules, multispecific molecules, and / or multifunctional molecules described herein inhibits or prevents the activation and / or expansion of an autoreactive T cell population expressing one or more members of the TCRαV12 subfamily. In some embodiments, administration of agents, antibody molecules, multispecific molecules, and / or multifunctional molecules described herein reduces or depletes an autoreactive T cell population expressing one or more members of the TCRαV12 subfamily.

[0248] In some embodiments, the disclosure provides a method for depleting or reducing T cells in a subject where such depletion is needed. In some embodiments, the T cells are autoreactive T cells. In some embodiments, the autoreactive T cells target the subject's own T cells. In some embodiments, the autoreactive T cells express TCRαV, TCRβV, or any combination thereof. In some embodiments, the subject suffers from an autoimmune disease. In some embodiments, the method comprises administering an agent containing the fraction to the subject. In some embodiments, the fraction binds to the TCR variable region.

[0249] In some embodiments, the administration of the agent depletes the T cell population in a subject by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or more than about 99% compared to a baseline measurement of the T cell population (e.g., a measurement of the T cell population before administration of the agent). In some embodiments, administering the agent depletes the T cell population in a subject to a maximum of approximately 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, or less than 20% compared to a baseline measurement of the T cell population (e.g., a measurement of the T cell population before administration of the agent).

[0250] In some embodiments, administering the agent depletes the T cell population in a subject by approximately 20% to approximately 99% compared to a baseline measurement of the T cell population (e.g., a measurement of the T cell population before administration of the agent). In some embodiments, administering the agent depletes the T cell population in a subject by approximately 20% to approximately 30%, approximately 20% to approximately 40%, approximately 20% to approximately 50%, approximately 20% to approximately 60%, approximately 20% to approximately 70%, approximately 20% to approximately 75%, approximately 20% to approximately 80%, approximately 20% to approximately 85%, approximately 20% to approximately 90%, approximately 20% to approximately 95%, and approximately 20% to approximately 99% compared to a baseline measurement of the T cell population (e.g., a measurement of the T cell population before administration of the agent). %, approximately 30%~40%, approximately 30%~50%, approximately 30%~60%, approximately 30%~70%, approximately 30%~75%, approximately 30%~80%, approximately 30%~85%, approximately 30%~90%, approximately 30%~95%, approximately 30%~99%, approximately 40%~50%, approximately 40%~60%, approximately 40%~70%, approximately 40%~75%, approximately 40%~80%, approximately 40%~85%, approximately 40%~90%, approximately 40%~95%, approximately 40%~ Approximately 99%, approximately 50% to 60%, approximately 50% to 70%, approximately 50% to 75%, approximately 50% to 80%, approximately 50% to 85%, approximately 50% to 90%, approximately 50% to 95%, approximately 50% to 99%, approximately 60% to 70%, approximately 60% to 75%, approximately 60% to 80%, approximately 60% to 85%, approximately 60% to 90%, approximately 60% to 95%, approximately 60% to 99%, approximately 70% to 75%, approximately 70% to 80%, approximately 70% to 85%, approximately Deplete 70% to approximately 90%, approximately 70% to approximately 95%, approximately 70% to approximately 99%, approximately 75% to approximately 80%, approximately 75% to approximately 85%, approximately 75% to approximately 90%, approximately 75% to approximately 95%, approximately 75% to approximately 99%, approximately 80% to approximately 85%, approximately 80% to approximately 90%, approximately 80% to approximately 95%, approximately 80% to approximately 99%, approximately 85% to approximately 90%, approximately 85% to approximately 95%, approximately 85% to approximately 99%, approximately 90% to approximately 95%, approximately 90% to approximately 99%, or approximately 95% to approximately 99%.

[0251] In some embodiments, administering the agent to a target in need provides a sustained reduction and / or depletion of targeted T cells or T cell populations. In some embodiments, administering the agent to a target in need can deplete T cells for at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 12 hours, at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, or beyond about 6 months.

[0252] The methods described herein may also provide subject identification based on TCR clonal type. Subject identification may include genotyping of subjects suffering from a disease or condition. The disease may be an autoimmune disease. Autoimmune diseases include amyotrophic lateral sclerosis (ALS), celiac disease (CD), ankylosing spondylitis (AS), Covid-associated multisystem inflammatory syndrome (MIS-C) in children, primary Sjögren's syndrome (PSS), Churg-Strauss syndrome, sarcoidosis, systemic lupus erythematosus (SLE), type 1 diabetes, autoimmune hepatitis (e.g., type 1 or type 2), primary sclerosing cholangitis, primary biliary cholangitis, multiple sclerosis, Guillain-Barré syndrome, and AMAN (axonal and neuronal neuropathy), and chronic inflammatory demyelination. Polyneuritis optica (CIDP), transverse myelitis, Trosa Hunt syndrome (THS), Devic's disease (neuromyelitis optica), paraneoplastic cerebellar degeneration (PCD), Lambert-Eaton syndrome, psoriasis, scleroderma, CREST (calcification, Raynaud's phenomenon, esophageal motility disorder, finger sclerosis, and telangiectasia) syndrome, herpetiform dermatitis, dermatomyositis, bullous pemphigoid, scarring pemphigoid / benign mucosal pemphigoid, pemphigoid of pregnancy, rheumatoid arthritis (RA), psoriatic arthritis, relapsing polychondritis, chronic relapsing polymyelitis (CRMO) The following conditions may be selected from the group consisting of recurrent multifocal osteomyelitis, vasculitis, Kawasaki disease, granulomatosis with polyangiitis (GPA), Behçet's disease (vasculitis), Takayasu's arteritis, polyarteritis nodosa, microscopic polyangiitis (MPA), leukocytoclastic vasculitis, Cogan's syndrome, uveitis, peripheral uveitis (tonsillar), scleritis, autoimmune inner ear disease (AIED), Crohn's disease, ulcerative colitis (UC), Dressler's syndrome, rheumatic fever, Evans syndrome, paroxysmal nocturnal hemoglobinuria (PNH), hemolytic anemia, thrombocytopenic purpura (TTP), polymyositis, juvenile myositis (JM), including juvenile dermatomyositis (JDM) and juvenile polymyositis (JPM), ocular scarring pemphigoid, or Hashimoto's thyroiditis.

[0253] The sample may be obtained from the subject and sequenced to determine the TCR clone type associated with the autoimmune disease. The TCR clone type may include the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV). In some embodiments, the genotype may be determined. In some embodiments, commercially available techniques for genotyping, such as SNP genotyping, may be used, but are not limited to: TaqMan genotyping assays (Applied Biosystems), SNPlex platforms (Applied Biosystems), gel electrophoresis, capillary electrophoresis, size exclusion chromatography, mass spectrometry, such as the MassARRAY system (Sequenom), mini-sequencing, real-time polymerase chain reaction (PCR), Bio-Plex system (BioRad), CEQ and SNPstream systems (Beckman), array hybridization techniques, such as Affymetrix GeneChip (Perlegen), bead array techniques, such as Illumina GoldenGate and Infinium assays, array tagging techniques, and Multiplex Ligation-dependent Probe Amplification. Examples include MLPA (Invader assay using non-amplified or amplified genome, or non-amplified total RNA, or non-amplified cDNA or amplified cDNA; Third Wave / Hologic).

[0254] Combination therapy In some embodiments, the methods described herein further include administering a second therapeutic agent or treatment to a target.

[0255] In some embodiments, the second therapeutic agent or treatment method includes chemotherapeutic agents, biologics, hormone therapy, radiation, or surgery.

[0256] In some embodiments, the present invention may be used in combination with immunosuppressants such as cyclosporine, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunosuppressants, such as CAM PATH, anti-CD3 antibodies or other antibody therapies, cytoxane, fludarabine, cyclosporine, FK506, rapamycin, mycophenolate, steroids, FR901228, cytokines, and irradiation. These agents inhibit the calcium-dependent phosphatase calcineurin (cyclosporine and FK506) or inhibit p70S6 kinase (rapamycin), which is important for growth factor-induced signaling. (Liu et al., Cell 66:807-815, 1991; Henderson et al., Immun. 73:316-321, 1991; Bierer et al., Curr. Opin. Immun. 5:763-773, 1993). In some embodiments, the compositions and pharmaceutical compositions of the present invention are administered to a patient in conjunction with (e.g., before, concurrently with, or after) bone marrow transplantation, chemotherapy agents such as fludarabine, external beam radiation therapy (XRT), cyclophosphamide, or T cell depletion therapy using antibodies such as OKT3 or CAMPATH. For example, in one embodiment, the subject may receive standard treatment with high-dose chemotherapy followed by peripheral blood stem cell transplantation. In certain embodiments, after transplantation, the subject receives an infusion of the expanded immune cells of the present invention. In additional embodiments, the expanded cells are administered before or after surgery.

[0257] In some embodiments, a second therapeutic agent or treatment is administered sequentially, simultaneously, or in parallel in combination with the agents, nucleic acid molecules, vectors, cells, or pharmaceutical compositions described herein.

[0258] The molecules or compositions described herein may be used in combination with a second therapeutic agent or method.

[0259] In some embodiments, the molecule or composition described herein and the second therapeutic agent or method are administered / implemented after the subject has been diagnosed with an autoimmune disease, for example, before the autoimmune disease has disappeared from the subject. In some embodiments, the molecule or composition described herein and the second therapeutic agent or method are administered / implemented simultaneously or in parallel. For example, the delivery of one treatment is still occurring when the second delivery is initiated, resulting in, for example, an overlap in the administration of treatments. In other embodiments, the molecule or composition described herein and the second therapeutic agent or method are administered / implemented sequentially. For example, the delivery of one treatment is completed before the delivery of the other treatment begins.

[0260] In some embodiments, combination therapy can provide more effective treatment than monotherapy with either drug alone. In some embodiments, a combination of the first and second therapies is more effective than the first or second therapy alone (e.g., a greater reduction in symptoms and / or autoreactive T cells). In some embodiments, combination therapy allows for the use of lower doses of the first or second therapy compared to the dose of the first or second therapy that would normally be required to achieve a similar effect when administered as monotherapy. In some embodiments, combination therapy exhibits a partial additive effect, a total additive effect, or a greater additive effect.

[0261] In some embodiments, anti-TCRαV antibodies and / or anti-TCRβV antibodies, multispecific molecules, or multifunctional molecules are administered in combination with, for example, treatments for autoimmune diseases (e.g., one or more of immunotherapy, photodynamic therapy (PDT), surgery, and / or radiation). The terms “chemotherapy,” “chemotherapeutic agent,” and “anticancer agent” are used interchangeably herein. The administration of multispecific molecules or multifunctional molecules with treatments such as, for example, treatments for autoimmune diseases, may be continuous (with or without overlap) or simultaneous. The administration of anti-TCRαV antibodies and / or anti-TCRβV antibodies, multispecific molecules, or multifunctional molecules may be continuous or intermittent throughout the course of treatment (e.g., treatment of autoimmune diseases).

[0262] Methods described herein include treating an autoimmune disease of interest by using a molecule or composition described herein, for example, by using a pharmaceutical composition described herein. Methods are also provided for reducing or improving the symptoms of an autoimmune disease in an interest, as well as for inhibiting or preventing the activation and / or expansion of autoreactive T cells, and / or for reducing, depleting, or killing one or more autoreactive T cells. In some embodiments, methods described herein reduce the number of autoreactive T cells in an interest administered with a pharmaceutical composition described herein or herein.

[0263] In some embodiments, the molecules or compositions described herein (or pharmaceutical compositions described herein) are administered in a manner appropriate to the disease being treated or prevented. The amount and frequency of administration are determined by factors such as the patient's condition, as well as the type and severity of the patient's disease. The appropriate dose may be determined by clinical trials. For example, where indicated as “effective dose” or “therapeutic dose,” the exact amount of pharmaceutical composition (or polyspecific or multifunctional molecule) to be administered may be determined by a physician, taking into account the degree of symptoms of the disease in question, age, weight, and individual differences in condition. In some embodiments, the pharmaceutical compositions described herein are 10 4 ~10 9 Cells / kg of body weight, for example, 10 5 ~10 6 The pharmaceutical compositions can be administered in doses of cells / kg body weight (including all integer values ​​within that range). In some embodiments, the pharmaceutical compositions described herein can be administered multiple times in these doses. In some embodiments, the pharmaceutical compositions described herein can be administered using the infusion techniques described in immunotherapy (see, for example, Rosenberg et al., New Eng. J. of Med. 319:1676, 1988).

[0264] Antibodies against the TCR variable region Anti-TCRαV antibody The currently designed bispecific constructs utilize antibody fragments (Fab, scFv, VH, single-domain antibodies, etc.) derived from monoclonal antibodies (mAbs) against the CD3e subunit of the T cell receptor (TCR). However, this approach has limitations and may hinder a complete understanding of the therapeutic potential of such bispecific constructs. Previous studies have shown that even low “activating” doses of anti-CD3e mAbs can induce long-term T cell dysfunction and exert immunosuppressive effects. Furthermore, anti-CD3e mAbs have been associated with side effects resulting from large-scale T cell activation. Numerous activated T cells secrete significant amounts of cytokines, the most important of which is interferon-gamma (IFNγ). This excess IFNγ then activates macrophages, which subsequently overproduce pro-inflammatory cytokines such as IL-1 beta, IL-6, IL-10, and TNF-alpha, triggering a "cytokine storm" known as cytokine release syndrome (CRS) (Shimabukuro-Vornhagen et al., J Immunother Cancer. 2018 Jun 15;6(1):56; the relevant paper is incorporated herein by reference in its entirety). Therefore, there is a need for the development of antibodies that can bind to and activate only a subset of effector T cells, for example, antibodies that can reduce CRS and / or neurotoxicity (NT).

[0265] This specification describes molecules and methods for targeting the TCRαV chain of the TCR. While we do not wish to be bound by theory, such molecules may bind to, activate, and / or expand only a subset of T cells, thereby evading or reducing the CRS and / or NT, and minimizing the potential immunosuppressive effects of anti-CD3 mAbs.

[0266] As used herein, certain antibodies, namely, anti-TCRαV antibody molecules described herein, are described, which antibodies recognize regions, such as domains, that are structurally conserved but sequence-variable on the TCRαV protein, and have similar functions (e.g., activation of T cells and similar cytokine profiles as described herein), despite low sequence similarity (e.g., low sequence identity among various antibody molecules that recognize various TCRαV subfamilies). Thus, the anti-TCRαV antibody molecules described herein share structure-function relationships.

[0267] In some embodiments, the anti-TCRαV antibody molecules described herein do not recognize, e.g., do not bind to, the interface of the TCRβV:TCR alpha complex. In some embodiments, the anti-TCRαV antibody molecules described herein do not recognize, e.g., do not bind to, the constant region of the TCRβV protein. In some embodiments, the anti-TCRαV antibody molecules described herein do not recognize, e.g., do not bind to, one or more (e.g., all) of the complementarity-determining regions (e.g., CDR1, CDR2, and / or CDR3) of the TCRβV protein.

[0268] In particular, this specification provides antibodies against the variable chain of the alpha subunit of the TCR (TCR alpha V), the antibody molecule which binds to a subset of T cells and, for example, activates them. The anti-TCRαV antibody molecules described herein reduce or completely suppress the production of CRS-related cytokines, such as IL-6, IL-1 beta, IL-10, and TNF alpha, and enhance and / or delay the production of IL-2 and IFNγ. In some embodiments, the anti-TCRαV antibodies described herein have a cytokine profile different from that of a T cell engager that binds to receptors or molecules other than the TCRαV region (non-TCRαV-binding T cell engager), for example, the cytokine profile described herein. In some embodiments, the non-TCRαV-binding T cell engager includes an antibody that binds to a CD3 molecule (e.g., a CD3 epsilon (CD3e) molecule) or a TCR alpha (TCRα) molecule. In some embodiments, the non-TCRαV-binding T cell engager is an OKT3 antibody or an SP34-2 antibody.

[0269] In some embodiments, the anti-TCRαV antibodies described herein result in the expansion of TCRαV+ T cells, such as a subset of memory effector T cells known as TEMRA. While we do not wish to be bound by theory, in some embodiments, TEMRA cells are thought to promote the lysis of tumor cells, but CRS cannot. Accordingly, methods for producing the anti-TCRαV antibody molecule and its use are provided herein. Also described herein are polyspecific molecules, such as bispecific molecules containing the anti-TCRαV antibody molecule. In some embodiments, compositions containing the anti-TCRαV antibody molecule of this disclosure can be used, for example, to (1) inhibit or prevent the activation and / or expansion of autoreactive T cells, and / or to reduce or deplete autoreactive T cells. In some embodiments, compositions containing the anti-TCRαV antibody molecule described herein limit the adverse side effects of CRS and / or NT, such as CRS and / or NT associated with anti-CD3e targeting.

[0270] In some embodiments, the anti-TCRαV antibody molecule is a full antibody or a fragment thereof (e.g., Fab, F(ab’)2, Fv, single domain antibody, or single chain Fv fragment (scFv)). In multiple embodiments, the anti-TCRαV antibody molecule is a monoclonal antibody or a monospecific antibody. In some embodiments, the anti-TCRαV antibody molecule may be a humanized antibody molecule, a chimeric antibody molecule, a camelid antibody molecule, a shark antibody molecule, or an in vitro generated antibody molecule. In some embodiments, the anti-TCRαV antibody molecule is a humanized antibody molecule. The heavy and light chains of the anti-TCRαV antibody molecule may be full length (e.g., the antibody can include at least one, preferably two complete heavy chains and at least one, preferably two complete light chains), or may include antigen-binding fragments (e.g., Fab, F(ab’)2, Fv, single chain Fv fragment, single domain antibody, diabody (dAb), bispecific or bispecific antibody or fragment thereof, single domain variants thereof, or camelid antibodies).

[0271] In some embodiments, the anti-TCRαV antibody molecule is in the form of a multispecific molecule, such as a bispecific molecule described herein.

[0272] In some embodiments, the anti-TCRαV antibody molecule has a heavy chain constant region (Fc) selected from, for example, the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE. In some embodiments, the Fc region is selected from the heavy chain constant regions of IgG!1, IgG2, IgG3 and IgG4. In some embodiments, the Fc region is selected from the heavy chain constant regions of IgG1 or IgG2 (e.g., human IgG1 or IgG2). In some embodiments, the heavy chain constant region is human IgG1. In some embodiments, the Fc region includes, for example, Fc region variants described herein.

[0273] In some embodiments, the anti-TCRαV antibody molecule has a light chain constant region selected from, for example, a kappa or lambda light chain constant region, preferably a kappa (e.g., human kappa) light chain constant region. In some embodiments, the constant region is modified, for example, mutated, to alter the properties of the anti-TCRαV antibody molecule (e.g., to increase or decrease one or more of the following: Fc receptor binding, antibody glycosylation, number of cysteine ​​residues, effector cell function, or complement function). For example, the constant region is mutated at positions 296 (M to Y), 298 (S to T), 300 (T to E), 477 (H to K), and 478 (N to F) relative to human IgG1, altering Fc receptor binding (for example, the mutated positions correspond to positions 132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K), and 314 (N to F) in sequence numbers 212 or 214, or to positions 135 (M to Y), 137 (S to T), 139 (T to E), 316 (H to K), and 317 (N to F) in sequence numbers 215, 216, 217, or 218).

[0274] Various TCRαV subfamilies and / or members of subfamilies can be expressed at varying levels in individuals, such as healthy individuals, as disclosed in Kitaura K. et al (2016), BMC Immunology vol 17:38. The entire contents of that document are incorporated herein by reference.

[0275] In some embodiments, the anti-TCRαV antibody molecule is a non-mouse antibody molecule, such as a human antibody molecule or a humanized antibody molecule. In some embodiments, the anti-TCRαV antibody molecule is a human antibody molecule. In some embodiments, the anti-TCRαV antibody molecule is a humanized antibody molecule.

[0276] In some embodiments, the anti-TCRαV antibody molecule is isolated or recombinant.

[0277] In some embodiments, the anti-TCRαV antibody molecule includes the heavy chain constant region of IgG4, for example, human IgG4. In yet another embodiment, the anti-TCRαV antibody molecule includes the heavy chain constant region of IgG1, for example, human IgG1. In some embodiments, the heavy chain constant region includes an amino acid sequence listed in Table 1, or a sequence substantially identical thereto (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical).

[0278] In some embodiments, the anti-TCRαV antibody molecule includes a kappa light chain constant region, for example, the human kappa light chain constant region. In some embodiments, the light chain constant region includes an amino acid sequence listed in Table 1, or a sequence substantially identical thereto (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical thereto).

[0279] In some embodiments, for example, embodiments including a variable region, a CDR (e.g., a combined CDR, a Chothia CDR, or a Kabat CDR), or other sequences referred to herein, the antibody molecule is a monospecific antibody molecule, a dispecific antibody molecule, a bivalent antibody molecule, a diparatope antibody molecule, or an antibody molecule comprising an antigen-binding fragment of an antibody, such as a half-antibody or an antigen-binding fragment of a half-antibody. In certain embodiments, the antibody molecule includes a polyspecific molecule, such as a dispecific molecule as described herein.

[0280] In some embodiments, the anti-TCRαV antibody molecule is a non-mouse antibody molecule, such as a human antibody molecule or a humanized antibody molecule. In some embodiments, the anti-TCRαV antibody molecule is a human antibody molecule. In some embodiments, the anti-TCRαV antibody molecule is a humanized antibody molecule.

[0281] In some embodiments, the anti-TCRαV antibody molecule is isolated or recombinant.

[0282] In some embodiments, the anti-TCRαV antibody molecule may contain any combination of CDR or hypervariable loops, according to the Kabat and Chothia definitions.

[0283] In some embodiments, for example, embodiments including a variable region, a CDR (e.g., a combined CDR, a Chothia CDR, or a Kabat CDR), or other sequences referred to herein, the antibody molecule is a monospecific antibody molecule, a dispecific antibody molecule, a bivalent antibody molecule, a diparatope antibody molecule, or an antibody molecule comprising an antigen-binding fragment of an antibody, such as a half-antibody or an antigen-binding fragment of a half-antibody. In certain embodiments, the antibody molecule includes a polyspecific molecule, such as a dispecific molecule as described herein.

[0284] In some embodiments, the anti-TCRαV antibody molecule comprises a light chain variable domain including (a) a framework region 1 (FR1) containing changes such as substitutions (e.g., conservative substitutions) at one or more (e.g., all) positions described herein according to Kabat numbering, and (b) a framework region 3 (FR3) containing changes such as substitutions (e.g., conservative substitutions) at one or more (e.g., all) positions described herein according to Kabat numbering. In some embodiments, the substitutions are for the light chain framework region sequence of human germline cells.

[0285] In some embodiments, the anti-TCRαV antibody molecule is a complete antibody or a fragment thereof (e.g., Fab, F(ab')2, Fv, or a single-chain Fv fragment (scFv)). In several embodiments, the anti-TCRαV antibody molecule is a monoclonal antibody or a monospecific antibody. In some embodiments, the anti-TCRαV antibody molecule may be a humanized antibody molecule, a chimeric antibody molecule, a camelid antibody molecule, a shark antibody molecule, or an in vitro produced antibody molecule. In some embodiments, the anti-TCRαV antibody molecule is a humanized antibody molecule. The heavy and light chains of the anti-TCRαV antibody molecule may be full-length (e.g., the antibody may contain at least one, preferably two, complete heavy chains and at least one, preferably two, complete light chains) or may contain antigen-binding fragments (e.g., Fab, F(ab')2, Fv, a single-chain Fv fragment, a single-domain antibody, a diabody (dAb), a bivalent antibody or a bispecific antibody or fragment thereof, their single-domain variants, or a camelid antibody).

[0286] In some embodiments, the anti-TCRαV antibody molecule is a polyspecific molecule, for example, a bispecific molecule as described herein.

[0287] In some embodiments, the anti-TCRαV antibody molecule has a heavy chain constant region (Fc) selected from, for example, the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE. In some embodiments, the Fc region is selected from the heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4. In some embodiments, the Fc region is selected from the heavy chain constant region of IgG1 or IgG2 (e.g., human IgG1 or IgG2). In some embodiments, the heavy chain constant region is human IgG1.

[0288] In some embodiments, the anti-TCRαV antibody molecule has a light chain constant region selected from, for example, a kappa or lambda light chain constant region, preferably a kappa (e.g., human kappa) light chain constant region. In some embodiments, the constant region is altered, e.g., mutated, to modify the properties of the anti-TCRαV antibody molecule (e.g., to increase or decrease one or more of Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function or complement function). For example, the constant region is mutated at, for example, positions 296 (M to Y), 298 (S to T), 300 (T to E), 477 (H to K) and 478 (N to F) such that Fc receptor binding (e.g., the positions at which the mutation occurs correspond to positions 132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K), and 314 (N to F) of SEQ ID NO: 212 or 214, or correspond to positions 135 (M to Y), 137 (S to T), 139 (T to E), 316 (H to K), and 317 (N to F) of SEQ ID NO: 215, 216, 217, or 218) is changed.

[0289] Anti-TCRα V12 antibody In one aspect, provided herein are anti-TCRαV antibody molecules that bind to human TCRα V12 subfamily members. In some embodiments, the TCRα V12 subfamily is also known as TCRα V12. In some embodiments, the TCRαV12 subfamily includes TCRα V12-1, TCRα V12-2 or TCRα V12-3, or variants thereof.

[0290] Anti-TCRα V4 antibody In one aspect, provided herein are anti-TCRαV antibody molecules that bind to human TCRα V4 subfamily members. In some embodiments, the TCRα V4 subfamily is also known as TCRα V4.

[0291] Anti-TCRα V21 antibody In one embodiment, an anti-TCRαV antibody molecule that binds to a member of the human TCRα V21 subfamily is provided herein. In some embodiments, the TCRα V21 subfamily is also known as TCRα V21.

[0292] Anti-TCRα V26 antibody In one embodiment, an anti-TCRαV antibody molecule that binds to a member of the human TCRα V26 subfamily is provided herein. In some embodiments, the TCRα V26 subfamily is also known as TCRα V26. In some embodiments, the TCRαV26 subfamily includes TCRα V26-1, TCRα V26-2, or variants thereof.

[0293] Antibodies against TCRβV This specification describes molecules and methods for targeting the TCRβV chain of the TCR. While we do not wish to be bound by theory, such molecules can bind to, suppress, and / or eliminate only a subset of T cells and reduce the immune response directly or indirectly mediated by the T cells bound by such molecules.

[0294] In this specification, certain antibodies, namely anti-TCRβV antibody molecules described herein, recognize structurally conserved yet sequence-variable regions on the TCRβV protein, such as domains (indicated by the circled region in Figure 1A), despite low sequence similarity (e.g., low sequence identity among various antibody molecules that recognize different TCRβV subfamilies), and have similar functions (e.g., T cell activation and similar cytokine profiles described herein). Therefore, the anti-TCRβV antibody molecules described herein share a common structure-function relationship.

[0295] While we do not wish to be constrained by theory, in some embodiments, the anti-TCRβV antibody molecules described herein bind to outward-facing epitopes of the TCRβV protein when complexed with the TCR alpha protein, for example, as shown in the circled region in Figure 1A. In some embodiments, the anti-TCRβV antibody molecules described herein recognize (e.g., bind) domains (e.g., epitopes) on the TCRβV protein that (1) are structurally conserved between different TCRβV subfamilies, and (2) have minimal sequence identity between different TCRβV subfamilies. As shown in Table 8, TCRβV proteins from different TCRβV subfamilies share minimal sequence similarity. However, as shown in Figures 1A-1B, TCRβV proteins with minimal sequence similarity share similar 3D configurations and structures.

[0296] The alignment of TCRBV amino acid sequences in Table 8 highlights the diversity of TCR sequences. In particular, TRBV sequences originating from different subfamilies are quite different from one another.

[0297] In some embodiments, the anti-TCRβV antibody molecules described herein do not recognize, for example, the TCRβV:TCR alpha complex interface and therefore do not bind. In some embodiments, the anti-TCRβV antibody molecules described herein do not recognize, for example, the constant region of the TCRβV protein and therefore do not bind. An example of an antibody that binds to the constant region of the TCRβV region is JOVI.1, described in Viney et al., (Hybridoma. 1992 Dec;11(6):701-13). In some embodiments, the anti-TCRβV antibody molecules described herein do not recognize, for example, the complementarity-determining regions of the TCRβV protein (e.g., CDR1, CDR2, and / or CDR3) and therefore do not bind.

[0298] In particular, this specification provides antibodies against the variable chain (TCR alpha V) of the beta subunit of the TCR (TCRβV), which bind to a subset of T cells and, for example, suppress or eliminate them. The anti-TCRβV antibody molecules described herein reduce or completely suppress the production of cytokines associated with CRS, such as IL-6, IL-1 beta, IL-10, and TNF alpha, and enhance and / or delay the production of IL-2 and IFNγ. In some embodiments, the non-TCRβV-binding T cell engager includes an antibody that binds to a CD3 molecule (e.g., a CD3 epsilon (CD3e) molecule) or a TCR alpha (TCRα) molecule. In some embodiments, the non-TCRβV-binding T cell engager is an OKT3 antibody or an SP34-2 antibody.

[0299] In some embodiments, the anti-TCRβV antibodies described herein result in the inhibition or depletion of clonal types containing the TCRBV antigen corresponding to a biased TCRβV+ clone or a biased TCRBV clone. While we do not wish to be bound by theory, TCR bias may exist in autoimmune diseases. This bias may be associated with a dominant autoreactive TCR clone that is disease-causing or associated with symptoms. For example, by removing or depleting T cells containing the autoreactive clone, the balance of the TCR repertoire may be restored, thereby treating the associated autoimmune disease and / or reducing the symptoms of the autoimmune disease. Accordingly, methods for producing such anti-TCRβV antibody molecules and their use are provided herein.

[0300] In some embodiments, the anti-TCRβV antibody molecule is TRBV2, TRBV3-1, TRBV4-1, TRBV4-2, TRBV4-3, TRBV5-1, TRBV5-4, TRBV5-5, TRBV5-6, TRBV5-8, TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8, TRBV6-9, TRBV7-2, TRBV7-3, TRBV7-4, TRBV7-6, TRBV7-7, TRBV7-8 It combines with one or more of the following: TRBV7-9, TRBV9, TRBV10-1, TRBV10-2, TRBV10-3, TRBV11-1, TRBV11-2, TRBV11-3, TRBV12-3, TRBV12-4, TRBV12-5, TRBV13, TRBV14, TRBV15, TRBV16, TRBV18, TRBV19, TRBV20-1, TRBV24-1, TRBV25-1, TRBV27, TRBV28, TRBV29-1, and TRBV30. In some embodiments, the anti-TCRβV antibody molecule binds to one or more of TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8, and TRBV6-9. In some embodiments, the anti-TCRβV antibody molecule is anti-TRBV2, anti-TRBV3-1, anti-TRBV4-1, anti-TRBV4-2, anti-TRBV4-3, anti-TRBV5-1, anti-TRBV5-4, anti-TRBV5-5, anti-TRBV5-6, anti-TRBV5-8, anti-TRBV 6-1, anti-TRBV6-2, anti-TRBV6-3, anti-TRBV6-4, anti-TRBV6-5, anti-TRBV6-6, anti-TRBV6-8, anti-TRBV6-9, anti-TRBV7-2, anti-TRBV7-3, anti-TRBV7-4, anti-TRBV7-6, anti-TRBV7-7, anti-TR These are anti-TRBV7-8, anti-TRBV7-9, anti-TRBV9, anti-TRBV10-1, anti-TRBV10-2, anti-TRBV10-3, anti-TRBV11-1, anti-TRBV11-2, anti-TRBV11-3, anti-TRBV12-3, anti-TRBV12-4, anti-TRBV12-5, anti-TRBV13, anti-TRBV14, anti-TRBV15, anti-TRBV16, anti-TRBV18, anti-TRBV19, anti-TRBV20-1, anti-TRBV24-1, anti-TRBV25-1, anti-TRBV27, anti-TRBV28, anti-TRBV29-1, or anti-TRBV30.Examples of anti-TCRβV antibody molecules and the corresponding TCRβV subfamilies recognized by these anti-TCRβV antibody molecules are disclosed in Table 9.

[0301] In some embodiments, the anti-TCRβV antibody molecule is TRBV2, TRBV3-1, TRBV4-1, TRBV4-2, TRBV4-3, TRBV5-1, TRBV5-4, TRBV5-5, TRBV5-6, TRBV5-8, TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8, TRBV6-9, TRBV7-2, TRBV7-3, TRBV7-4, TRBV7-6, TRBV7-7, TRBV7 It specifically binds to TRBV-8, TRBV7-9, TRBV9, TRBV10-1, TRBV10-2, TRBV10-3, TRBV11-1, TRBV11-2, TRBV11-3, TRBV12-3, TRBV12-4, TRBV12-5, TRBV13, TRBV14, TRBV15, TRBV16, TRBV18, TRBV19, TRBV20-1, TRBV24-1, TRBV25-1, TRBV27, TRBV28, TRBV29-1, or TRBV30. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV6-1. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV6-2. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV6-3. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV6-4. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV6-5. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV6-6. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV6-8. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV6-9.

[0302] In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBVs associated with autoimmune diseases, such as TRBV4, TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-5, TRBV6-2 / 3, TRBV7.1, TRBV7, TRBV7-8, TRBV7-9, TRBV7-8 / 9, TRBV9, TRBV10-3, TRBV11-2, TRBV12-3, TRBV12-4, TRBV12-3 / 4, TRBV20-1, TRBV23, or TRBV29-1. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV4. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV6-1. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV6-2. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV6-3. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV6-5. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV6-2 / 3. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV7.1. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV7. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV7-8. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV7-9. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV7-8 / 9. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV9. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV10-3. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV11-2. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV12-3. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV12-4. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV12-3 / 4. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV20-1. In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV23.In some embodiments, the anti-TCRβV antibody molecule specifically binds to TRBV29-1.

[0303] In some embodiments, an anti-TCRβV antibody molecule, such as an anti-TCRβV6 (e.g., anti-TCRβV6-5*01) antibody molecule, includes a light chain variable domain containing a framework region, such as framework region 1 (FR1), which includes a change at position 10, such as a substitution (e.g., a conservative substitution), according to Kabat numbering. In some embodiments, FR1 includes phenylalanine at position 10, such as a substitution from serine to phenylalanine. In some embodiments, the substitution is relative to the light chain framework region sequence of human germline cells.

[0304] In some embodiments, an anti-TCRβV antibody molecule, e.g., an anti-TCRβV6 (e.g., anti-TCRβV6-5*01) antibody molecule, includes a light chain variable domain, including a framework region such as framework region 2 (FR2), which includes changes such as substitutions (e.g., conservative substitutions) at positions described herein according to Kabat numbering. In some embodiments, FR2 includes histidine at position 36, e.g., a substitution at position 36 according to Kabat numbering, e.g., a substitution from tyrosine to histidine. In some embodiments, FR2 includes alanine at position 46, e.g., a substitution at position 46 according to Kabat numbering, e.g., a substitution from arginine to alanine. In some embodiments, the substitution is relative to the light chain framework region sequence of human germline cells.

[0305] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβV6 (e.g., anti-TCRβV6-5*01) antibody molecule, includes a light chain variable domain, such as framework region 3 (FR3), which includes changes such as substitutions (e.g., conservative substitutions) at positions described herein according to Kabat numbering. In some embodiments, FR3 includes phenylalanine at position 87, for example, a substitution at position 87 according to Kabat numbering, such as a substitution from tyrosine to phenylalanine. In some embodiments, the substitution is relative to the light chain framework region sequence of human germline cells.

[0306] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule includes, for example, a light chain variable domain, as shown in the amino acid sequence of SEQ ID NO: 10, comprising: (a) a framework region 1 (FR1) containing phenylalanine at position 10, for example, a substitution at position 10 according to Kabat numbering, for example, a substitution from serine to phenylalanine; (b) a framework region 2 (FR2) containing histidine at position 36, for example, a substitution at position 36 according to Kabat numbering, for example, a substitution from tyrosine to histidine, and alanine at position 46, for example, a substitution at position 46 according to Kabat numbering, for example, a substitution from arginine to alanine; and (c) a framework region 3 (FR3) containing phenylalanine at position 87, for example, a substitution at position 87 according to Kabat numbering, for example, a substitution from tyrosine to phenylalanine. In some embodiments, the substitution is for the light chain framework region sequence of human germline cells.

[0307] In some embodiments, an anti-TCRβV antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule includes, for example, a light chain variable domain, including (a) a framework region 2 (FR2) containing histidine at position 36, e.g., a substitution at position 36 according to Kabat numbering, e.g., a substitution from tyrosine to histidine, and alanine at position 46, e.g., a substitution at position 46 according to Kabat numbering, e.g., an arginine to alanine substitution, as shown in the amino acid sequence of SEQ ID NO: 11, and (b) a framework region 3 (FR3) containing phenylalanine at position 87, e.g., a substitution at position 87 according to Kabat numbering, e.g., a substitution from tyrosine to phenylalanine. In some embodiments, the substitutions are relative to the light chain framework region sequence of human germline cells.

[0308] In some embodiments, an anti-TCRβV antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes a light chain variable domain comprising: (a) a framework region 1 (FR1) including changes such as substitutions (e.g., conservative substitutions) at one or more (e.g., all) positions described herein according to Kabat numbering; (b) a framework region 2 (FR2) including changes such as substitutions (e.g., conservative substitutions) at one or more (e.g., all) positions described herein according to Kabat numbering; and (c) a framework region 3 (FR3) including changes such as substitutions (e.g., conservative substitutions) at one or more (e.g., all) positions described herein according to Kabat numbering. In some embodiments, the substitutions are relative to the light chain framework region sequence of human germline cells.

[0309] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes a heavy chain framework region 1 of AH.1 or AH.2. In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes a heavy chain framework region 2 of AH.1 or AH.2. In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes a heavy chain framework region 3 of AH.1 or AH.2. In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes a heavy chain framework region 4 of AH.1 or AH.2.

[0310] In some embodiments, an anti-TCRβV antibody molecule, e.g., an anti-TCRβV6 (e.g., anti-TCRβV6-5*01) antibody molecule, includes a heavy chain variable domain including a framework region, such as framework region 3 (FR3), which includes changes such as substitutions (e.g., conservative substitutions) at positions described herein according to Kabat numbering. In some embodiments, FR3 includes threonine at position 73, e.g., a substitution at position 73, e.g., a substitution from glutamate to threonine, e.g., according to Kabat numbering. In some embodiments, FR3 includes glycine at position 94, e.g., a substitution at position 94, e.g., a substitution from arginine to glycine, e.g., according to Kabat numbering. In some embodiments, the substitution is relative to the heavy chain framework region sequence of human germline cells.

[0311] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes a heavy chain variable domain comprising a framework region 3 (FR3), which includes threonine at position 73, for example, as shown in the amino acid sequence of SEQ ID NO: 10, and includes a substitution at position 73, for example, such as a substitution from glutamic acid to threonine according to Kabat numbering, and glycine at position 94, for example, such as a substitution from arginine to glycine according to Kabat numbering.

[0312] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes heavy chain framework regions 1-4 of AH.1 or AH.2, for example, SEQ ID NO: 9. In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes light chain framework regions 1-4 of AH.1, for example, SEQ ID NO: 10. In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes light chain framework regions 1-4 of AH.2, for example, SEQ ID NO: 11. In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes heavy chain framework regions 1-4 of AH.1, such as SEQ ID NO: 9, and light chain framework regions 1-4 of AH.1, such as SEQ ID NO: 10. In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes heavy chain framework regions 1-4 of AH.2, such as SEQ ID NO: 9, and light chain framework regions 1-4 of AH.2, such as SEQ ID NO: 11.

[0313] In some embodiments, the heavy chain variable domain or light chain variable domain of an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes an amino acid sequence that is substantially identical to the amino acids described herein, such as an antibody selected from any one of AH.1 to AH.85, for example, an antibody selected from any one of AH.1, AH.2, or AH.68, or an antibody listed in Table 1, or an antibody encoded by the nucleotide sequence in Table 1, or an antibody encoded by a nucleotide sequence that is at least 1 or 5 residues different from the variable region of an antibody described herein, but less than 40, 30, 20, or 10 residues.

[0314] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes at least one, two, three, or four antigen-binding regions, such as variable regions having amino acid sequences listed in Table 1, or substantially identical thereto (e.g., sequences identical by at least about 85%, 90%, 95%, 99% or more, or sequences that differ from the sequences shown in Table 1 by 1, 2, 5, 10, or 15 amino acid residues or less). In another embodiment, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises a VH domain and / or VL domain encoded by a nucleic acid having a nucleotide sequence listed in Table 1, or a nucleotide sequence substantially identical thereto (e.g., a sequence identical to them by at least about 85%, 90%, 95%, 99%, or more, or a sequence that differs from the sequences shown in Table 1 by 3, 6, 15, 30, or 45 nucleotides or less).

[0315] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a VH domain containing the amino acid sequence of SEQ ID NO: 9, an amino acid sequence that is at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 9, or an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 9 by 1, 2, 5, 10, or 15 amino acid residues or less, and / or a VL domain containing the amino acid sequence of SEQ ID NO: 10, an amino acid sequence that is at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 10 by 1, 2, 5, 10, or 15 amino acid residues or less.

[0316] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes a VH domain comprising the amino acid sequence of SEQ ID NO: 9, an amino acid sequence that is at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 9, or an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 9 by 1, 2, 5, 10, or 15 amino acid residues or less, and / or a VL domain comprising the amino acid sequence of SEQ ID NO: 11, an amino acid sequence that is at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 11, or an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 11 by 1, 2, 5, 10, or 15 amino acid residues or less.

[0317] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a complete antibody or a fragment thereof (e.g., Fab, F(ab')2, Fv, single-domain antibody, or single-stranded Fv fragment (scFv)). In several embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a monoclonal antibody or a monospecific antibody. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, may be a humanized antibody molecule, a chimeric antibody molecule, a camelid antibody molecule, a shark antibody molecule, or an antibody molecule produced in vitro. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a humanized antibody molecule. The heavy and light chains of an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, may be full-length (e.g., an antibody may contain at least one, preferably two, complete heavy chains and at least one, preferably two, complete light chains), or they may contain antigen-binding fragments (e.g., Fab, F(ab')2, Fv, single-chain Fv fragment, single-domain antibody, diabody (dAb), bivalent antibody or bispecific antibody or fragment thereof, single-domain variants thereof, or camelid antibody).

[0318] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is in the form of a TCR-targeting molecule, for example, a bispecific molecule described herein.

[0319] In some embodiments, an anti-TCRβV antibody molecule, such as an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, has a heavy chain constant region (Fc) selected from, for example, the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE. In some embodiments, the Fc region is selected from the heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4. In some embodiments, the Fc region is selected from the heavy chain constant region of IgG1 or IgG2 (e.g., human IgG1 or IgG2). In some embodiments, the heavy chain constant region is human IgG1. In some embodiments, the Fc region includes, for example, the Fc region variants described herein.

[0320] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, has a light chain constant region selected from, for example, the kappa or lambda light chain constant region, preferably the kappa (e.g., human kappa) light chain constant region. In some embodiments, the constant region is modified, for example, mutated, to alter the properties of the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule (e.g., to increase or decrease one or more of the following: Fc receptor binding, antibody glycosylation, number of cysteine ​​residues, effector cell function, or complement function). For example, the constant region is mutated at positions 296 (M to Y), 298 (S to T), 300 (T to E), 477 (H to K), and 478 (N to F) relative to human IgG1, altering Fc receptor binding (for example, the mutated positions correspond to positions 132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K), and 314 (N to F) in sequence numbers 212 or 214, or to positions 135 (M to Y), 137 (S to T), 139 (T to E), 316 (H to K), and 317 (N to F) in sequence numbers 215, 216, 217, or 218).

[0321] Antibody AH.1 contains a heavy chain containing the amino acid sequence of SEQ ID NO: 3278 and a light chain containing the amino acid sequence of SEQ ID NO: 72. Antibody AH.2 contains a heavy chain containing the amino acid sequence of SEQ ID NO: 3278 and a light chain containing the amino acid sequence of SEQ ID NO: 3279. Antibody AH.68 contains the amino acid sequence of SEQ ID NO: 1337, or a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity thereto. Antibody AH.69 contains the amino acid sequence of SEQ ID NO: 1500, or a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity thereto.

[0322] Additional exemplary humanized anti-TCRB V6 antibodies are provided in Table 1. In some embodiments, the anti-TCRβ V6 is antibody A provided in Table 1, e.g., humanized antibody A (antibody AH). In some embodiments, the anti-TCRβV antibody includes one or more (e.g., all three) of LC CDR1, LC CDR2, and LC CDR3 provided in Table 1, and / or one or more (e.g., all three) of HC CDR1, HC CDR2, and HC CDR3 provided in Table 1, or a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity to them. In some embodiments, antibody A comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 1, or a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity to them.

[0323] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule is AH.1, AH.2, AH.3, AH.4, AH.5, AH.6, AH.7, AH.8, AH.9, AH.10, AH.11, AH.12, AH.13, AH.14, AH.15, AH.16, AH.17, AH.18, AH.19, AH.20, AH.21, AH.22, AH.23, AH.2 4, AH.25, AH.26, AH.27, AH.28, AH.29, AH.30, AH.31, AH.32, AH.33, AH.34, AH.35, AH.36 , AH.37, AH.38, AH.39, AH.40, AH.1, AH.42, AH.43, AH.44, AH.45, AH.46, AH.47, AH.48, AH .49, AH.50, AH.51, AH.52, AH.53, AH.54, AH.55, AH.56, AH.57, AH.58, AH.59, AH.60, AH. 61, AH.62, AH.63, AH.64, AH.65, AH.66, AH.67, AH.68, AH.69, AH.70, AH.71, AH.72, AH.73 , AH.74, AH.75, AH.76, AH.77, AH.78, AH.79, AH.80, AH.81, AH.82, AH.83, AH.84, or VH of AH.85, or sequences having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more identity to them.

[0324] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule is AH.1, AH.2, AH.3, AH.4, AH.5, AH.6, AH.7, AH.8, AH.9, AH.10, AH.11, AH.12, AH.13, AH.14, AH.15, AH.16, AH.17, AH.18, AH.19, AH.20, AH.21, AH.22, AH.23, AH.2 4, AH.25, AH.26, AH.27, AH.28, AH.29, AH.30, AH.31, AH.32, AH.33, AH.34, AH.35, AH.36 , AH.37, AH.38, AH.39, AH.40, AH.1, AH.42, AH.43, AH.44, AH.45, AH.46, AH.47, AH.48, AH .49, AH.50, AH.51, AH.52, AH.53, AH.54, AH.55, AH.56, AH.57, AH.58, AH.59, AH.60, AH. 61, AH.62, AH.63, AH.64, AH.65, AH.66, AH.67, AH.68, AH.69, AH.70, AH.71, AH.72, AH.73 , including the VL of AH.74, AH.75, AH.76, AH.77, AH.78, AH.79, AH.80, AH.81, AH.82, AH.83, AH.84, or AH.85, or sequences having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more identity to them.

[0325] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule is AH.1, AH.2, AH.3, AH.4, AH.5, AH.6, AH.7, AH.8, AH.9, AH.10, AH.11, AH.12, AH.13, AH.14, AH.15, AH.16, AH.17, AH.18, AH.19, AH.20, AH.21, AH.22, AH.23, AH.24, AH.25, AH.26, AH.27, AH.28, AH.29, AH.30, AH.31, AH.32, AH.33, AH. 34, AH.35, AH.36, AH.37, AH.38, AH.39, AH.40, AH.1, AH.42, AH.43, AH.44, AH.45, AH.46, AH.47, AH.48, AH.49, AH.50, AH.51 ,AH.52,AH.53,AH.54,AH.55,AH.56,AH.57,AH.58,AH.59,AH.60,AH.61,AH.62,AH.63,AH.64,AH.65,AH.66,AH.67,AH.68,A The sequence includes H.69, AH.70, AH.71, AH.72, AH.73, AH.74, AH.75, AH.76, AH.77, AH.78, AH.79, AH.80, AH.81, AH.82, AH.83, AH.84, or VH of AH.85, or sequences having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more identity to them, and AH.1, AH.2, AH.3, AH.4, AH.5, AH .6, AH.7, AH.8, AH.9, AH.10, AH.11, AH.12, AH.13, AH.14, AH.15, AH.16, AH.17, AH.18, AH.19, AH.20, AH.21, AH.22, AH.23, A H.24, AH.25, AH.26, AH.27, AH.28, AH.29, AH.30, AH.31, AH.32, AH.33, AH.34, AH.35, AH.36, AH.37, AH.38, AH.39, AH.40, AH.1, AH.42, AH.43, AH.44, AH.45, AH.46, AH.47, AH.48, AH.49, AH.50, AH.51, AH.52, AH.53, AH.54, AH.55 , AH.56, AH.57, AH.58, AH.59, AH.60, AH.61, AH.62, AH.63, AH.64, AH.65, AH.66, AH.67, AH.68, AH.69, The sequence contains the VL of AH.70, AH.71, AH.72, AH.73, AH.74, AH.75, AH.76, AH.77, AH.78, AH.79, AH.80, AH.81, AH.82, AH.83, AH.84, or AH.85, or sequences having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or higher identity to them.

[0326] Examples of anti-TCRβV antibody molecules and the corresponding TCRβV subfamilies recognized by these anti-TCRβV antibody molecules are disclosed in Table 9.

[0327] Various TCRβV subfamilies and / or members of subfamilies can be expressed at varying levels in individuals, such as healthy individuals, as disclosed in Kitaura K. et al (2016), BMC Immunology vol 17:38. The entire contents of that document are incorporated herein by reference. For example, TCRβ V6-5 appears in approximately 3–6% of healthy donors. Anti-TCRβ V6 antibody

[0328] In one embodiment, the Specified Reference Indicators provides anti-TCRβV antibody molecules that bind to human TCRβ V6, such as the TCRβ V6 subfamily, which includes, for example, TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01, or TCRβ V6-1*01. In some embodiments, the TCRβ V6 subfamily includes TCRβ V6-5*01 or a variant thereof. In some embodiments, TCRβ V6 includes TCRβ V6-4*01 or a variant thereof. In some embodiments, TCRβ V6 includes TCRβ V6-4*02 or a variant thereof. In some embodiments, TCRβ V6 includes TCRβ V6-9*01 or a variant thereof. In some embodiments, TCRβ V6 includes TCRβ V6-8*01 or a variant thereof. In some embodiments, TCRβ V6 includes TCRβ V6-5*01 or a variant thereof. In some embodiments, TCRβ V6 includes TCRβ V6-6*02 or a variant thereof. In some embodiments, TCRβ V6 includes TCRβ V6-6*01 or a variant thereof. In some embodiments, TCRβ V6 includes TCRβ V6-2*01 or a variant thereof. In some embodiments, TCRβ V6 includes TCRβ V6-3*01 or a variant thereof. In some embodiments, TCRβ V6 includes TCRβ V6-1*01 or a variant thereof.

[0329] In some embodiments, TCRβ V6-5*01 is encoded by the nucleic acid sequence of SEQ ID NO: 43, or a sequence having 85%, 90%, 95%, 99%, or more identity thereto. In some embodiments, TCRβ V6-5*01 includes the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence having 85%, 90%, 95%, 99%, or more identity thereto.

[0330] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a non-mouse antibody molecule, for example, a human antibody molecule or a humanized antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a human antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a humanized antibody molecule.

[0331] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is isolated or recombinant.

[0332] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes at least one antigen-binding region, such as a variable region or antigen-binding fragment derived from an antibody molecule described herein, for example, an antibody selected from any one of AH.1 to AH.85, for example, AH.1, AH.2, or AH.68, or an antibody listed in Table 1, or an antibody encoded by the nucleotide sequence in Table 1, or an antibody encoded by a sequence substantially identical to any of the above sequences (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical).

[0333] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes at least one, two, three, or four variable regions derived from antibody molecules described herein, for example, antibodies selected from AH.1 to AH.85, for example, AH.1, AH.2, or AH.68, or antibodies listed in Table 1, or antibodies encoded by the nucleotide sequences in Table 1, or antibodies encoded by sequences substantially identical to any of the sequences described above (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical).

[0334] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes at least one or two heavy chain variable regions derived from an antibody molecule described herein, for example, an antibody selected from any one of AH.1 to AH.85, for example, AH.1, AH.2, or AH.68, or an antibody molecule listed in Table 1, or an antibody encoded by a nucleotide sequence in Table 1, or an antibody encoded by a sequence substantially identical to any of the sequences described above (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical).

[0335] In some embodiments, the anti-TCRβV antibody molecule includes a heavy chain variable region (VH) having the consensus sequence of SEQ ID NO: 231 or 3290.

[0336] SEQ ID NO: 231 - Consensus VHQVQLVQSGAEVKKPGSSVKVSCKASGH / T / G / YD / T / SFH / R / D / K / TL / D / K / T / NW / F / T / I / Y / GYIHWVRQAPGQGLEWM GR / WV / I / FF / S / YA / PGSGN / ST / V / Y / IK / RYNEKFKGRVTITADTSTSTAYMELSSLRSEDTAVYYCAG / VSY / IYSY / AD / GVLDYWGQGTTVTVSS

[0337] Accession No. 3290 - Consensus VHQVQLVQSGAEVKKPGSSVKVSCKASGX1X2FX3X4X5YIHWVRQAPGQGLEWMGX6X7X8X9GSGX 10 X 11 X 12 YNEKFKGRVTITADTSTSTAYMELSSLRSEDTAVYYCAX 13 SX 14 YSX 15 X 16 VLDYWGQGTTVTVSS, wherein X1 is H or T or G or Y, X2 is D or T or S, X3 is H or R or D or K or T, X4 is L or D or K or T or N, X5 is W or F or T or I or Y or G, X6 is R or W, X7 is V or I or F, X8 is F or S or Y, X9 is A or P, X10 is N or S, X11 is T or V or Y or I, X12 is K or R, X13 is G or V, X14 is Y or I, X15 is Y or A, and X16 is D or G.

[0338] In some embodiments, an anti - TCRβV antibody molecule, e.g., an anti - TCRβ V6 (e.g., anti - TCRβ V6 - 5*01) antibody molecule, comprises at least one or two light - chain variable regions derived from an antibody selected from any one of the antibody molecules described herein, e.g., A - H.1 to A - H.85, e.g., A - H.1, A - H.2 or A - H.68, or an antibody described in Table 1, or an antibody encoded by the nucleotide sequence of Table 1, or an antibody encoded by a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical) to any of the above - mentioned sequences.

[0339] In some embodiments, an anti - TCRβV antibody molecule comprises a light - chain variable region (VL) having the consensus sequence of Accession No. 230 or 3289.

[0340] Sequence ID 230 - Consensus VLDIQMTQSPSFLSASVGDRVTITCKASQNVG / E / A / DN / DR / KVAWY / HQQKPGKAPKALIYSSSHRYK / SGVPSRFSGSGSGTEFTLTISSLQPEDFATYFCQQFKSYPLTFGQGTKLEIK

[0341] Sequence ID 3289 - Consensus VLDIQMTQSPSFLSASVGDRVTITCKASQNVX1X2X3VAWX4QQKPGKAPKALIYSSSHRYX5GVPSRFSGSGSGTEFTLTISSLQPEDFATYFCQQFKSYPLTFGQGTKLEIK, where X1 is G, E, A or D, X2 is N or D, X3 is R or K, X4 is Y or H, and X5 is K or S.

[0342] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes the heavy chain constant region of IgG4, such as human IgG4. In yet another embodiment, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes the heavy chain constant region of IgG1, such as human IgG1. In some embodiments, the heavy chain constant region includes an amino acid sequence listed in Table 3, or a sequence substantially identical thereto (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical).

[0343] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes a kappa light chain constant region, for example, the human kappa light chain constant region. In some embodiments, the light chain constant region includes an amino acid sequence listed in Table 3, or a sequence substantially identical thereto (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical).

[0344] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes at least one, two, or three complementarity-determining regions (CDRs) derived from the heavy chain variable region (VH) of an antibody molecule described herein, for example, an antibody selected from any one of AH.1 to AH.85, for example, AH.1, AH.2, or AH.68, or an antibody listed in Table 1, or an antibody encoded by the nucleotide sequence in Table 1, or an antibody encoded by a sequence substantially identical to any of the sequences described above (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical).

[0345] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, contains at least one, two, or three (or collectively all of the CDRs) derived from a heavy chain variable region containing the amino acid sequence shown in Table 1, or a heavy chain variable region encoded by the nucleotide sequence shown in Table 1. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six, or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or to the amino acid sequence encoded by the nucleotide sequence shown in Table 1.

[0346] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes at least one, two, or three complementarity-determining regions (CDRs) derived from the light chain variable region of an antibody molecule described herein, for example, an antibody selected from any one of AH.1 to AH.85, e.g., AH.1, AH.2, or AH.68, or an antibody listed in Table 1, or an antibody encoded by a nucleotide sequence in Table 1, or an antibody encoded by a sequence substantially identical to any of the above sequences (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical).

[0347] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, contains at least one, two, or three (or collectively all of the CDRs) derived from a light chain variable region containing the amino acid sequence shown in Table 1, or a light chain variable region encoded by the nucleotide sequence shown in Table 1. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six, or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or to the amino acid sequence encoded by the nucleotide sequence shown in Table 1.

[0348] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule contains at least one, two, three, four, five, or six (or collectively all of the CDRs) derived from the variable regions of the heavy and light chains containing the amino acid sequences shown in Table 1, or the variable regions of the heavy and light chains encoded by the nucleotide sequences shown in Table 1. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six, or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequences shown in Table 1, or the amino acid sequences encoded by the nucleotide sequences shown in Table 1.

[0349] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a CDR derived from an antibody described herein, for example, any one of AH.1 to AH.85, for example, an antibody selected from AH.1, AH.2 or AH.68, or an antibody listed in Table 1, or an antibody encoded by the nucleotide sequence in Table 1, or a closely related CDR, for example, an identical CDR, or all six CDRs having at least one but two, three or four or fewer amino acid changes (e.g., substitution, deletion or insertion, for example, conservative substitution). In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule may contain any CDR described herein.

[0350] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes at least one, two, or three sequences (e.g., at least one, two, or three CDRs according to the Kabat definitions listed in Table 1) that are substantially identical to any of the above sequences, or sequences derived from the heavy chain variable region of the antibodies described herein, for example, one selected from AH.1 to AH.85, for example, an antibody selected from AH.1, AH.2, or AH.68, or a CDR according to the Kabat definitions listed in Table 1, or sequences that are substantially identical to any of the sequences described above (e.g., sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical), or sequences that have at least one but no more than two, three, or four amino acid changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to one, two, or three CDRs according to the Kabat definitions listed in Table 1.

[0351] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes at least one, two, or three sequences (e.g., at least one, two, or three CDRs according to the Kabat definitions listed in Table 1) that are substantially identical to any of the above sequences, or sequences derived from the light chain variable region of the antibodies described herein, for example, one selected from AH.1 to AH.85, for example, an antibody selected from AH.1, AH.2, or AH.68, or a CDR according to the Kabat definitions listed in Table 1, or sequences that are substantially identical to any of the sequences described above (e.g., sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical), or sequences that have at least one but no more than two, three, or four amino acid changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to one, two, or three CDRs according to the Kabat definitions listed in Table 1.

[0352] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule is derived from the antibodies described herein, for example, an antibody selected from any one of AH.1 to AH.85, for example, an antibody selected from AH.1, AH.2 or AH.68, or a sequence encoded by a Kabat et al.-compliant CDR or nucleotide sequence in Table 1, derived from the variable regions of the heavy and light chains of the antibodies listed in Table 1, or a sequence substantially identical to any of the sequences described above (e.g., a sequence that is at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical), or one, two, three, four, five or six CDRs according to Kabat et al. shown in Table 1. The sequence comprises at least one, two, three, four, or six sequences (for example, at least one, two, three, four, or six CDRs according to the Kabat definitions listed in Table 1) each having at least one, but no more than two, three, or four, amino acid changes (e.g., substitutions, deletions, or insertions, such as conservative substitutions).

[0353] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes all six sequences (e.g., all six CDRs according to the Kabat definitions listed in Table 1) that are substantially identical to any of the above sequences (e.g., sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) of all six CDRs according to the Kabat definitions listed in Table 1, which are derived from the variable regions of the heavy and light chains of the antibodies listed in Table 1, or sequences encoded by the nucleotide sequences in Table 1, or sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical to any of the above sequences, or sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical to any of the above sequences, or sequences that are at least 2, 3, or 4 amino acid changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) of all six CDRs according to the Kabat definitions listed in Table 1. In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, may include any CDR described herein.

[0354] In some embodiments, an anti-TCRβV antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one, two, or three hypervariable loops, the loops having the same canonical structure as the corresponding hypervariable loop of any of the antibodies described herein, e.g., AH.1 to AH.85, e.g., selected from AH.1, AH.2, or AH.68, e.g., the loops having the same canonical structure as at least loop 1 and / or loop 2 of the variable domains of the heavy and / or light chains of the antibodies described herein. For example, for a description of the canonical structure of the hypervariable loops, see Chothia et al., (1992) J.Mol.Biol.227:799-817; Tomlinson et al., (1992) J.Mol.Biol.227:776-798. These structures can be determined by examining the tables provided in these references.

[0355] In some embodiments, an anti-TCRβV antibody molecule, for example, anti-TCRβ V6 (for example, anti-TCRβ V6-5*01) The antibody molecule comprises at least one, two, or three sequences (for example, at least one, two, or three CDRs according to the Chothia definition as shown in Table 1) that are substantially identical to any of the above sequences, or sequences that are substantially identical to any of the above sequences, or sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical to any of the above sequences, or sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical to any of the above sequences, or sequences that are at least one, but not more than two, three, or four amino acid changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to one, two, or three CDRs according to the Chothia definition as shown in Table 1.

[0356] In some embodiments, an anti-TCRβV antibody molecule, for example, anti-TCRβ V6 (for example, anti-TCRβ V6-5*01) The antibody molecule comprises at least one, two, or three sequences (for example, at least one, two, or three CDRs according to the Chothia definition as shown in Table 1) that are substantially identical to any of the above sequences, or sequences that are substantially identical to any of the above sequences, or sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical to any of the above sequences, or sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical to any of the above sequences, or sequences that are at least one, but not more than two, three, or four amino acid changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to one, two, or three CDRs according to the Chothia definition as shown in Table 1.

[0357] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule is derived from the antibodies described herein, for example, an antibody selected from any one of AH.1 to AH.85, for example, an antibody selected from AH.1, AH.2 or AH.68, or a sequence encoded by a Chothia et al. CDR or nucleotide sequence in Table 1, derived from the variable regions of the heavy and light chains of the antibodies listed in Table 1, or a sequence substantially identical to any of the sequences described above (e.g., a sequence that is at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical), or one, two, three, four, five or six CDRs according to Chothia et al. shown in Table 1. The sequence comprises at least one, two, three, four, or six sequences (for example, at least one, two, three, four, or six CDRs according to the Chothia definition listed in Table 1) each having at least one, but no more than two, three, or four, amino acid changes (e.g., substitutions, deletions, or insertions, such as conservative substitutions).

[0358] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is derived from the antibodies described herein, for example, an antibody selected from any one of AH.1 to AH.85, for example, an antibody selected from AH.1, AH.2 or AH.68, or a sequence encoded by a Chothia et al. CDR or nucleotide sequence in Table 1, derived from the variable regions of the heavy and light chains of the antibodies listed in Table 1, or a sequence substantially identical to any of the sequences described above (e.g., a sequence that is at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical), or all six CDRs according to Chothia et al. shown in Table 1. The six sequences (for example, all six CDRs according to the Chothia definitions listed in Table 1) each have at least one, but no more than two, three, or four, amino acid changes (e.g., substitutions, deletions, or insertions, such as conservative substitutions). In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, may contain any CDR described herein.

[0359] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes a combination of CDRs or hypervariable loops as defined according to Kabat et al., Chothia et al., or as listed in Table 1.

[0360] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, may contain any combination of CDR or hypervariable loops according to the definitions of Kabat and Chothia.

[0361] In some embodiments, the integrated CDRs listed in Table 1 are CDRs that include Kabat CDRs and Chothia CDRs.

[0362] In some embodiments, the anti-TCRβV antibody molecule, e.g., the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes a combination of CDRs or hypervariable loops, as identified as the integrated CDR in Table 1. In some embodiments, the anti-TCRβV antibody molecule, e.g., the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule may contain any combination of CDRs or hypervariable loops according to the "integrated" CDR listed in Table 1.

[0363] In some embodiments, for example, embodiments including a variable region, a CDR (e.g., a combined CDR, a Chothia CDR, or a Kabat CDR), or other sequences referenced herein, such as in Table 1, the antibody molecule is a monospecific antibody molecule, a dispecific antibody molecule, a bivalent antibody molecule, a diparatope antibody molecule, or an antibody molecule containing an antigen-binding fragment of an antibody, such as a half-antibody or an antigen-binding fragment of a half-antibody. In certain embodiments, the antibody molecule includes a TCR-targeting molecule, such as a dispecific molecule as described herein.

[0364] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes (i) one, two, or all of the light chain complementarity determination region 1 (LC CDR1), light chain complementarity determination region 2 (LC CDR2), and light chain complementarity determination region 3 (LC CDR3) of SEQ ID NO: 2, SEQ ID NO: 10, or SEQ ID NO: 11, and / or (ii) one, two, or all of the heavy chain complementarity determination region 1 (HC CDR1), heavy chain complementarity determination region 2 (HC CDR2), and heavy chain complementarity determination region 3 (HC CDR3) of SEQ ID NO: 1 or SEQ ID NO: 9.

[0365] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 2, and HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 1.

[0366] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 10, and HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 9.

[0367] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 11, and HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 9.

[0368] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes (i) the LC CDR1 amino acid sequence of SEQ ID NO: 6, the LC CDR2 amino acid sequence of SEQ ID NO: 7, or the LC CDR3 amino acid sequence of SEQ ID NO: 8, and / or (ii) the HC CDR1 amino acid sequence of SEQ ID NO: 3, the HC CDR2 amino acid sequence of SEQ ID NO: 4, or the HC CDR3 amino acid sequence of SEQ ID NO: 5.

[0369] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes (i) a light chain variable region (VL) comprising the LC CDR1 amino acid sequence of SEQ ID NO: 6, the LC CDR2 amino acid sequence of SEQ ID NO: 7, or the LC CDR3 amino acid sequence of SEQ ID NO: 8, and / or (ii) a heavy chain variable region (VH) comprising the HC CDR1 amino acid sequence of SEQ ID NO: 3, the HC CDR2 amino acid sequence of SEQ ID NO: 4, or the HC CDR3 amino acid sequence of SEQ ID NO: 5.

[0370] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes (i) the LC CDR1 amino acid sequence of SEQ ID NO: 51, the LC CDR2 amino acid sequence of SEQ ID NO: 52, or the LC CDR3 amino acid sequence of SEQ ID NO: 53, and / or (ii) the HC CDR1 amino acid sequence of SEQ ID NO: 45, the HC CDR2 amino acid sequence of SEQ ID NO: 46, or the HC CDR3 amino acid sequence of SEQ ID NO: 47.

[0371] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes (i) a light chain variable region (VL) comprising the LC CDR1 amino acid sequence of SEQ ID NO: 51, the LC CDR2 amino acid sequence of SEQ ID NO: 52, or the LC CDR3 amino acid sequence of SEQ ID NO: 53, and / or (ii) a heavy chain variable region (VH) comprising the HC CDR1 amino acid sequence of SEQ ID NO: 45, the HC CDR2 amino acid sequence of SEQ ID NO: 46, or the HC CDR3 amino acid sequence of SEQ ID NO: 47.

[0372] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes (i) the LC CDR1 amino acid sequence of SEQ ID NO: 54, the LC CDR2 amino acid sequence of SEQ ID NO: 55, or the LC CDR3 amino acid sequence of SEQ ID NO: 56, and / or (ii) the HC CDR1 amino acid sequence of SEQ ID NO: 48, the HC CDR2 amino acid sequence of SEQ ID NO: 49, or the HC CDR3 amino acid sequence of SEQ ID NO: 50.

[0373] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes (i) a light chain variable region (VL) comprising the LC CDR1 amino acid sequence of SEQ ID NO: 54, the LC CDR2 amino acid sequence of SEQ ID NO: 55, or the LC CDR3 amino acid sequence of SEQ ID NO: 56, and / or (ii) a heavy chain variable region (VH) comprising the HC CDR1 amino acid sequence of SEQ ID NO: 48, the HC CDR2 amino acid sequence of SEQ ID NO: 49, or the HC CDR3 amino acid sequence of SEQ ID NO: 50.

[0374] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, contains the VH and / or VL of the antibodies listed in Table 1, or sequences having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0375] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes sequences having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the antibodies listed in Table 1.

[0376] In some embodiments, the anti-TCRVb antibody described herein has an antigen-binding domain having a VL having the consensus sequence of SEQ ID NO: 230, in which case the 30th position is G, E, A, or D, the 31st position is N or D, the 32nd position is R or K, the 36th position is Y or H, and / or the 56th position is K or S.

[0377] In some embodiments, the anti-TCRVb antibody described herein has an antigen-binding domain having VH having the consensus sequence of SEQ ID NO: 231, in which position 27 is H, T, G, or Y; position 28 is D, T, or S; position 30 is H, R, D, K, or T; position 31 is L, D, K, T, or N; position 32 is W, F, T, I, Y, or G; position 49 is R or W; position 50 is V, I, or F; position 51 is F, S, or Y; position 52 is A or P; position 56 is N or S; position 57 is T, V, Y, or I; position 58 is K or R; position 97 is G or V; position 99 is Y, or I; position 102 is Y, or A; and / or position 103 is D, or G.

[0378] Anti-TCRβ V12 antibody In one embodiment, the Specified Reference Indicators provides anti-TCRβV antibody molecules that bind to human TCRβ V12, such as the TCRβ V12 subfamily, which includes, for example, TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01. In some embodiments, the TCRβ V12 subfamily includes TCRβ V12-4*01. In some embodiments, the TCRβ V12 subfamily includes TCRβ V12-3*01.

[0379] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, is a non-mouse antibody molecule, for example, a human antibody molecule or a humanized antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, is a human antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, is a humanized antibody molecule.

[0380] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, is isolated or recombinant.

[0381] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes at least one antigen-binding region, such as a variable region or antigen-binding fragment derived from an antibody molecule described herein, for example, an antibody listed in Table 2, or an antibody encoded by the nucleotide sequence in Table 2, or an antibody encoded by a sequence substantially identical to any of the above sequences (for example, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical).

[0382] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes at least one, two, three, or four variable regions derived from antibody molecules described herein, for example, the antibodies listed in Table 2, or antibodies encoded by the nucleotide sequences in Table 2, or antibodies encoded by sequences substantially identical to any of the sequences described above (for example, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical).

[0383] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes at least one or two heavy chain variable regions derived from antibody molecules described herein, for example, the antibodies listed in Table 2, or antibodies encoded by the nucleotide sequences in Table 2, or antibodies encoded by sequences substantially identical to any of the above sequences (for example, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical).

[0384] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes at least one or two light chain variable regions derived from antibody molecules described herein, for example, the antibodies listed in Table 2, or antibodies encoded by the nucleotide sequences in Table 2, or antibodies encoded by sequences substantially identical to any of the above sequences (for example, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical).

[0385] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes the heavy chain constant region of IgG4, such as human IgG4. In yet another embodiment, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes the heavy chain constant region of IgG1, such as human IgG1. In some embodiments, the heavy chain constant region includes an amino acid sequence listed in Table 3, or a sequence substantially identical thereto (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical).

[0386] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes a kappa light chain constant region, for example, the human kappa light chain constant region. In some embodiments, the light chain constant region includes an amino acid sequence listed in Table 3, or a sequence substantially identical thereto (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical thereto).

[0387] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes at least one, two, or three complementarity-determining regions (CDRs) derived from the heavy chain variable region of an antibody molecule described herein, for example, an antibody listed in Table 2, or an antibody encoded by the nucleotide sequence in Table 2, or an antibody encoded by a sequence substantially identical to any of the above sequences (for example, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical).

[0388] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, contains at least one, two, or three (or collectively all of the CDRs) derived from a heavy chain variable region containing the amino acid sequence shown in Table 2, or a heavy chain variable region encoded by the nucleotide sequence shown in Table 2. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six, or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 2, or to the amino acid sequence encoded by the nucleotide sequence shown in Table 2.

[0389] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes at least one, two, or three complementarity-determining regions (CDRs) derived from the light chain variable region of an antibody molecule described herein, for example, an antibody listed in Table 2, or an antibody encoded by the nucleotide sequence in Table 2, or an antibody encoded by a sequence substantially identical to any of the sequences described above (for example, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical).

[0390] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, contains at least one, two, or three (or collectively all of the CDRs) derived from a light chain variable region containing the amino acid sequence shown in Table 2, or a light chain variable region encoded by the nucleotide sequence shown in Table 2. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six, or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 2, or to the amino acid sequence encoded by the nucleotide sequence shown in Table 2.

[0391] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, contains at least one, two, three, four, five, or six (or collectively all of the CDRs) derived from the variable regions of the heavy and light chains containing the amino acid sequences shown in Table 2, or the variable regions of the heavy and light chains encoded by the nucleotide sequences shown in Table 2. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six, or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequences shown in Table 2, or the amino acid sequences encoded by the nucleotide sequences shown in Table 2.

[0392] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, comprises CDRs derived from antibodies described herein, for example, antibodies listed in Table 2, or antibodies encoded by the nucleotide sequences in Table 2, or closely related CDRs, for example, identical CDRs, or all six CDRs having at least one but two, three, or four or fewer amino acid changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions). In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, may contain any CDRs described herein.

[0393] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, comprises at least one, two, or three sequences (for example, at least one, two, or three CDRs according to the Kabat definitions listed in Table 2) that are substantially identical to any of the above sequences, or sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical to any of the antibodies described herein, for example, CDRs according to Kabat et al. derived from the heavy chain variable region of a selected antibody, or sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical to any of the sequences described above, or sequences that have at least one, but not more than two, three, or four, amino acid changes (e.g., substitutions, deletions, or insertions, such as conservative substitutions) to one, two, or three CDRs according to Kabat et al. shown in Table 2.

[0394] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, comprises at least one, two, or three sequences (for example, at least one, two, or three CDRs according to the Kabat definitions listed in Table 2) that are substantially identical to any of the above sequences, or sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical, or sequences that have at least one but no more than two, three, or four amino acid changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to one, two, or three CDRs according to the Kabat definitions listed in Table 2.

[0395] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, comprises at least one, two, three, four, five, or six sequences (for example, at least one, two, three, four, or six CDRs according to the Kabat definitions listed in Table 2) that are substantially identical to any of the above sequences, derived from the variable regions of the heavy and light chains of antibodies described herein, for example, the antibodies listed in Table 2, or antibodies encoded by the nucleotide sequences in Table 2, or sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical, or sequences that have at least one, but no more than two, three, or four, amino acid changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to one, two, three, or six CDRs according to the Kabat definitions listed in Table 2.

[0396] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, comprises a Kabat et al.-based CDR derived from an antibody described herein, for example, an antibody listed in Table 2, or an antibody encoded by the nucleotide sequence in Table 2, or the light chain variable region of the heavy and light chains of an antibody encoded by the nucleotide sequence in Table 2, or a sequence substantially identical to any of the above sequences (e.g., a sequence identical by at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more), or all six sequences having at least one, but two, three or four or fewer, amino acid changes (e.g., substitutions, deletions or insertions, e.g., conservative substitutions) to all six Kabat et al.-based CDRs shown in Table 2 (e.g., all six CDRs according to the Kabat definitions listed in Table 2). In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, may contain any CDR described herein.

[0397] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, comprises at least one, two, or three hypervariable loops, the loops having the same canonical structure as the corresponding hypervariable loops of the antibodies described herein, for example, the antibodies listed in Table 2, and having the same canonical structure as at least loop 1 and / or loop 2 of the variable domains of the heavy and / or light chains of the antibodies described herein. For example, see Chothia et al., (1992) J.Mol.Biol.227:799-817; Tomlinson et al., (1992) J.Mol.Biol.227:776-798. These structures can be determined by examining the tables listed in these references.

[0398] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, comprises at least one, two, or three sequences (for example, at least one, two, or three CDRs according to the Chothia definitions listed in Table 2) that are substantially identical to any of the antibodies described herein, for example, CDRs according to Chothia et al. derived from the heavy chain variable region of the selected antibody, or sequences that are substantially identical to any of the sequences described above (e.g., sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical), or sequences that have at least one but no more than two, three, or four amino acid changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to one, two, or three CDRs according to Chothia et al. shown in Table 2 (e.g., at least one, two, or three CDRs according to the Chothia definitions listed in Table 2).

[0399] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, comprises at least one, two, or three sequences (for example, at least one, two, or three CDRs according to the Chothia definition as shown in Table 2) that are substantially identical to any of the above sequences, or sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical, or sequences that have at least one but no more than two, three, or four amino acid changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to one, two, or three CDRs according to the Chothia definition as shown in Table 2.

[0400] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, comprises at least one, two, three, four, five, or six sequences (for example, at least one, two, three, four, or six CDRs according to the Chothia definitions listed in Table 2) that are substantially identical to any of the above sequences, derived from the variable regions of the heavy and light chains of antibodies described herein, for example, the antibodies listed in Table 2, or antibodies encoded by the nucleotide sequences in Table 2, or sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical, or sequences that have at least one, but no more than two, three, or four, amino acid changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to one, two, three, or six CDRs according to the Chothia definitions listed in Table 2.

[0401] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, comprises a Chothia et al.-based CDR derived from an antibody described herein, for example, an antibody listed in Table 2, or an antibody encoded by the nucleotide sequence in Table 2, or the light chain variable region of the heavy and light chains of an antibody encoded by the nucleotide sequence in Table 2, or a sequence substantially identical to any of the above sequences (e.g., a sequence identical by at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more), or all six sequences having at least one, but two, three or four or fewer, amino acid changes (e.g., substitutions, deletions or insertions, e.g., conservative substitutions) for all six CDRs according to Chothia et al. shown in Table 2 (e.g., all six CDRs according to the Chothia definitions listed in Table 2). In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, may contain any CDR described herein.

[0402] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, comprises at least one, two, or three sequences (for example, at least one, two, or three CDRs according to the definition of an integrated CDR as described herein, e.g., an integrated CDR derived from the heavy chain variable region of an antibody listed in Table 2 and selected, or a sequence substantially identical to any of the sequences described above (e.g., sequences identical by at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more), or one, two, or three sequences having at least one but no more than two, three, or four amino acid changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to one, two, or three CDRs according to the integrated CDR definition shown in Table 2.

[0403] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, comprises at least one, two, or three sequences (for example, at least one, two, or three CDRs according to the integrated CDR definitions in Table 2) having at least one, but not more than two, three, or four, amino acid changes (e.g., substitutions, deletions, or insertions, such as conservative substitutions) derived from the light chain variable region of an antibody described herein, for example, an antibody listed in Table 2, or a sequence substantially identical to any of the sequences described above (e.g., sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical), or at least one CDR according to the integrated CDRs shown in Table 2, but with respect to one, two, or three CDRs according to the integrated CDR definitions shown in Table 2.

[0404] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, comprises at least one, two, three, four, five, or six sequences (for example, at least one, two, three, four, or six CDRs according to the definition of an integrated CDR as shown in Table 2) derived from the variable regions of the heavy and light chains of an antibody described herein, for example, an antibody listed in Table 2, or an antibody encoded by the nucleotide sequences in Table 2, which are substantially identical to any of the sequences described above (e.g., sequences that are at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical), or sequences having at least one, but no more than two, three, or four, amino acid changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to one, two, three, four, or six CDRs according to the integrated CDR definition shown in Table 2.

[0405] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, comprises an antibody described herein, for example, an antibody listed in Table 2, or an antibody encoded by the nucleotide sequence in Table 2, or a CDR according to the integrated CDRs derived from the light chain variable region of the heavy and light chains of an antibody encoded by the nucleotide sequence in Table 2, or a sequence substantially identical to any of the above sequences (e.g., a sequence identical by at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more), or all six sequences having at least one, but no more than two, three, or four, amino acid changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to all six CDRs according to the integrated CDRs shown in Table 2 (e.g., all six CDRs according to the integrated CDR definitions listed in Table 2). In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, may contain any CDR described herein.

[0406] In some embodiments, the integrated CDRs listed in Table 1 are CDRs that include Kabat CDRs and Chothia CDRs.

[0407] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes a combination of CDRs or hypervariable loops, which are identified as the integrated CDR in Table 1. In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, may contain any combination of CDRs or hypervariable loops that conform to the “integrated” CDR listed in Table 1.

[0408] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes a combination of CDR or hypervariable loop as defined according to Kabat et al., Chothia et al., or as listed in Table 1.

[0409] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, may contain any combination of CDR or hypervariable loops according to the Kabat and Chothia definitions.

[0410] In some embodiments, for example, embodiments including a variable region, a CDR (e.g., a combined CDR, a Chothia CDR, or a Kabat CDR), or other sequences referred to herein, such as in Table 2, the antibody molecule is a monospecific antibody molecule, a dispecific antibody molecule, a bivalent antibody molecule, a diparatope antibody molecule, or an antibody molecule containing an antigen-binding fragment of an antibody, such as a half-antibody or an antigen-binding fragment of a half-antibody. In certain embodiments, the antibody molecule includes a TCR-targeting molecule, such as a dispecific molecule as described herein.

[0411] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes (i) one, two, or all of the light chain complementarity determination region 1 (LC CDR1), light chain complementarity determination region 2 (LC CDR2), and light chain complementarity determination region 3 (LC CDR3) of SEQ ID NO: 16, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30, and / or (ii) one, two, or all of the heavy chain complementarity determination region 1 (HC CDR1), heavy chain complementarity determination region 2 (HC CDR2), and heavy chain complementarity determination region 3 (HC CDR3) of SEQ ID NO: 15, SEQ ID NO: 23, SEQ ID NO: 24, or SEQ ID NO: 25.

[0412] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes (i) the LC CDR1 amino acid sequence of SEQ ID NO: 20, the LC CDR2 amino acid sequence of SEQ ID NO: 21, or the LC CDR3 amino acid sequence of SEQ ID NO: 22, and / or (ii) the HC CDR1 amino acid sequence of SEQ ID NO: 17, the HC CDR2 amino acid sequence of SEQ ID NO: 18, or the HC CDR3 amino acid sequence of SEQ ID NO: 19.

[0413] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes (i) a light chain variable region (VL) comprising the LC CDR1 amino acid sequence of SEQ ID NO: 20, the LC CDR2 amino acid sequence of SEQ ID NO: 21, and the LC CDR3 amino acid sequence of SEQ ID NO: 2, and / or (ii) a heavy chain variable region (VH) comprising the HC CDR1 amino acid sequence of SEQ ID NO: 17, the HC CDR2 amino acid sequence of SEQ ID NO: 18, and the HC CDR3 amino acid sequence of SEQ ID NO: 19.

[0414] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, comprises (i) the LC CDR1 amino acid sequence of SEQ ID NO: 63, the LC CDR2 amino acid sequence of SEQ ID NO: 64, or the LC CDR3 amino acid sequence of SEQ ID NO: 65, and / or (ii) the HC CDR1 amino acid sequence of SEQ ID NO: 57, the HC CDR2 amino acid sequence of SEQ ID NO: 58, or the HC CDR3 amino acid sequence of SEQ ID NO: 59.

[0415] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, comprises (i) a light chain variable region (VL) including the LC CDR1 amino acid sequence of SEQ ID NO: 63, the LC CDR2 amino acid sequence of SEQ ID NO: 64, or the LC CDR3 amino acid sequence of SEQ ID NO: 65, and / or (ii) a heavy chain variable region (VH) including the HC CDR1 amino acid sequence of SEQ ID NO: 57, the HC CDR2 amino acid sequence of SEQ ID NO: 58, or the HC CDR3 amino acid sequence of SEQ ID NO: 59.

[0416] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes (i) the LC CDR1 amino acid sequence of SEQ ID NO: 66, the LC CDR2 amino acid sequence of SEQ ID NO: 67, or the LC CDR3 amino acid sequence of SEQ ID NO: 68, and / or (ii) the HC CDR1 amino acid sequence of SEQ ID NO: 60, the HC CDR2 amino acid sequence of SEQ ID NO: 61, or the HC CDR3 amino acid sequence of SEQ ID NO: 62.

[0417] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, comprises (i) a light chain variable region (VL) including the LC CDR1 amino acid sequence of SEQ ID NO: 63, the LC CDR2 amino acid sequence of SEQ ID NO: 64, or the LC CDR3 amino acid sequence of SEQ ID NO: 65, and / or (ii) a heavy chain variable region (VH) including the HC CDR1 amino acid sequence of SEQ ID NO: 57, the HC CDR2 amino acid sequence of SEQ ID NO: 58, or the HC CDR3 amino acid sequence of SEQ ID NO: 59.

[0418] In some embodiments, the variable light and heavy chain framework of an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule (e.g., a region encompassing at least FR1, FR2, FR3 and optionally FR4) is (a) a variable light or heavy chain framework comprising at least 80%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, or 100% of amino acid residues derived from a human variable light or heavy chain framework, such as a human mature antibody, a human germline sequence, or a human consensus sequence; and (b) a variable human light or heavy chain The framework may be selected from (c) a variable light chain or heavy chain framework containing 20% ​​to 80%, 40% to 60%, 60% to 90%, and 70% to 95% of amino acid residues derived from, for example, a mature human antibody, a human germline sequence, or a variable light chain or heavy chain framework residue derived from a human consensus sequence; (c) a non-human framework (e.g., a rodent framework); or (d) a modified non-human framework from which, for example, antigenic determinants or cytotoxic determinants have been removed, for example, a deimmunized or partially humanized non-human framework. In some embodiments, the variable light chain or heavy chain framework region (particularly FR1, FR2 and / or FR3) includes a variable light chain or heavy chain framework sequence that is identical to, or at least 70%, 75%, 80%, 85%, 87%, 88%, 90%, 92%, 94%, 95%, 96%, 97%, 98%, and 99% identical to, the framework of the VL or VH segment of a human germline gene.

[0419] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes a heavy chain variable domain having at least 1, 2, 3, 4, 5, 6, 7, 10, 15, 20, or more changes, such as amino acid substitutions or deletions, from the amino acid sequence of the FR region in the entire variable region, as listed in Table 2, for example, SEQ ID NOs. 23-25.

[0420] Alternatively, in combination with the heavy chain substitutions described herein, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes a light chain variable domain having at least 1, 2, 3, 4, 5, 6, 7, 10, 15, 20, or more amino acid changes, such as amino acid substitutions or deletions, from the amino acid sequence of the FR region in the entire variable region, as described herein, for example, SEQ ID NOs. 26-30.

[0421] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, comprises 1, 2, 3, or 4 heavy chain framework regions, or a sequence substantially identical thereto.

[0422] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes 1, 2, 3, or 4 light chain framework regions, or a sequence substantially identical thereto. In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes light chain framework region 1. In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes light chain framework region 2. In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes light chain framework region 3. In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes light chain framework region 4.

[0423] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβV12 antibody molecule, includes a light chain containing a framework region, such as framework region 1 (FR1), at one or more positions, for example, all positions, according to Kabat numbering, including changes such as substitutions (e.g., conservative substitutions). In some embodiments, FR1 includes aspartic acid at position 1, for example, a substitution at position 1, for example, a substitution from arginine to aspartic acid, according to Kabat numbering. In some embodiments, FR1 includes asparagine at position 2, for example, a substitution at position 2, for example, a substitution from isoleucine to asparagine, a substitution from serine to asparagine, or a substitution from tyrosine to asparagine, according to Kabat numbering. In some embodiments, FR1 includes leucine at position 4, for example, a substitution at position 4, for example, a substitution from methionine to leucine, according to Kabat numbering.

[0424] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes a light chain comprising a framework region, and for example, a light chain comprising a framework region 1 (FR1) including a substitution at position 1 according to Kabat numbering, such as a substitution from alanine to aspartic acid; a substitution at position 2 according to Kabat numbering, such as a substitution from isoleucine to asparagine, serine to asparagine, or tyrosine to asparagine; and a substitution at position 4 according to Kabat numbering, such as a substitution from methionine to leucine. In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes a light chain containing a framework region, for example, a substitution at position 1 according to Kabat numbering, such as a substitution from alanine to aspartic acid, and a substitution at position 2 according to Kabat numbering, such as a substitution from isoleucine to asparagine, serine to asparagine, or tyrosine to asparagine. In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes a light chain containing a framework region, and for example, a light chain containing framework region 1 (FR1) which includes a substitution at position 2 according to Kabat numbering, such as a substitution from isoleucine to asparagine, a substitution from serine to asparagine, or a substitution from tyrosine to asparagine, and a substitution at position 4 according to Kabat numbering, such as a substitution from methionine to leucine. In some embodiments, the substitutions are relative to the light chain framework region sequence of human germline cells.

[0425] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes a light chain containing a framework region, such as framework region 3 (FR3), at one or more positions, for example, all positions, as described herein according to Kabat numbering, including substitutions (e.g., conservative substitutions). In some embodiments, FR3 includes glycine at position 66, for example, a substitution at position 66, for example, a substitution from lysine to glycine, or a substitution from serine to glycine, according to Kabat numbering. In some embodiments, FR3 includes asparagine at position 69, for example, a substitution at position 69, for example, a substitution from tyrosine to asparagine, according to Kabat numbering. In some embodiments, FR3 includes tyrosine at position 71, for example, a substitution at position 71, for example, a substitution from phenylalanine to tyrosine, or a substitution from alanine to tyrosine, according to Kabat numbering.

[0426] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes a light chain containing a framework region, for example, a substitution at position 66 according to Kabat numbering, such as a substitution from lysine to glycine or a substitution from serine to glycine, and a substitution at position 69 according to Kabat numbering, such as a substitution from tyrosine to asparagine. In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes a light chain containing a framework region, for example, a substitution at position 69 according to Kabat numbering, for example, a substitution from tyrosine to asparagine, and at position 71 according to Kabat numbering, for example, a substitution from phenylalanine to tyrosine, or a substitution from alanine to tyrosine, and includes a light chain containing a framework region 3 (FR3). In some embodiments, the substitution is for the light chain framework region sequence of human germline cells.

[0427] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes a light chain comprising a framework region 1 (FR1) containing a substitution at position 2 according to Kabat numbering, such as an isoleucine to asparagine substitution, and a framework region 3 (FR3) containing a substitution at position 69 according to Kabat numbering, such as a tyrosine to asparagine substitution, and at position 71 according to Kabat numbering, such as a phenylalanine to tyrosine substitution. In some embodiments, the substitutions are relative to the light chain framework region sequence of human germline cells.

[0428] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes a light chain comprising: (a) a framework region 1 (FR1) comprising a substitution at position 1 according to Kabat numbering, such as a substitution from alanine to asparagine, and a substitution at position 2 according to Kabat numbering, such as a substitution from isoleucine to asparagine; and (b) a framework region 3 (FR3) comprising a substitution at position 69 according to Kabat numbering, such as a substitution from threonine to asparagine, and a substitution at position 71 according to Kabat numbering, such as a substitution from phenylalanine to tyrosine. In some embodiments, the substitutions are for the light chain framework region sequence of human germline.

[0429] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes a light chain comprising: (a) a framework region 1 (FR1) including a substitution at position 2 according to Kabat numbering, such as a substitution from serine to asparagine, and a substitution at position 4 according to Kabat numbering, such as a substitution from methionine to leucine; and (b) a framework region 3 (FR3) including a substitution at position 69 according to Kabat numbering, such as a substitution from threonine to asparagine, and a substitution at position 71 according to Kabat numbering, such as a substitution from phenylalanine to tyrosine. In some embodiments, the substitutions are for the light chain framework region sequence of human germline.

[0430] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes a light chain comprising (a) a framework region 1 (FR1) including a substitution at position 2 according to Kabat numbering, such as a substitution from serine to asparagine, and (b) a framework region 3 (FR3) including a substitution at position 66 according to Kabat numbering, such as a substitution from lysine to glycine, at position 69 according to Kabat numbering, such as a substitution from threonine to asparagine, and at position 71 according to Kabat numbering, such as a substitution from alanine to tyrosine. In some embodiments, the substitutions are relative to the light chain framework region sequence of human germline cells.

[0431] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes a light chain comprising (a) a framework region 1 (FR1) including a substitution at position 2 according to Kabat numbering, such as a substitution from tyrosine to asparagine, and (b) a framework region 3 (FR3) including a substitution at position 66 according to Kabat numbering, such as a substitution from serine to glycine, at position 69 according to Kabat numbering, such as a substitution from threonine to asparagine, and at position 71 according to Kabat numbering, such as a substitution from alanine to tyrosine. In some embodiments, the substitutions are relative to the light chain framework region sequence of human germline cells.

[0432] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes a light chain variable domain comprising (a) a framework region 1 (FR1) including changes such as substitutions (e.g., conservative substitutions) at one or more (e.g., all) positions described herein according to Kabat numbering, and (b) a framework region 3 (FR3) including changes such as substitutions (e.g., conservative substitutions) at one or more (e.g., all) positions described herein according to Kabat numbering. In some embodiments, the substitutions are relative to the light chain framework region sequence of human germline cells.

[0433] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes heavy chain framework region 1. In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes heavy chain framework region 2. In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes heavy chain framework region 3. In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes heavy chain framework region 4. In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes heavy chain framework regions 1 to 4, such as SEQ ID NOs. 20 to 23. In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes light chain framework regions 1 to 4, such as SEQ ID NOs. 26 to 30.

[0434] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes heavy chain framework regions 1-4, such as SEQ ID NOs. 23-25, and light chain framework regions 1-4, such as SEQ ID NOs. 26-30.

[0435] In some embodiments, the heavy chain variable domain or light chain variable domain of an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, includes an amino acid sequence that is substantially identical to the amino acids described herein, such as being at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, or more identical to the variable region of an antibody described herein, such as an antibody described herein, for example, an antibody described in Table 2, or an antibody encoded by the nucleotide sequence in Table 2, or an antibody encoded by a nucleotide sequence that is at least 1 or 5 residues different from the variable region of an antibody described herein, but less than 40, 30, 20, or 10 residues.

[0436] In some embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes at least one, two, three, or four antigen-binding regions, including a variable region having an amino acid sequence listed in Table 2, or an amino acid sequence substantially identical thereto (e.g., a sequence identical by at least about 85%, 90%, 95%, 99%, or more, or a sequence that differs from the sequences shown in Table 2 by 1, 2, 5, 10, or 15 amino acid residues or less). In other embodiments, the anti-TCRβV antibody molecule, for example, the anti-TCRβ V12 antibody molecule, includes a VH domain and / or VL domain encoded by a nucleic acid having a nucleotide sequence listed in Table 2, or a nucleotide sequence substantially identical thereto (e.g., a sequence identical by at least about 85%, 90%, 95%, 99%, or more, or a sequence that differs from the sequences shown in Table 2 by 3, 6, 15, 30, or 45 nucleotides or less).

[0437] In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ The V12 antibody molecule includes a VH domain containing the amino acid sequence of SEQ ID NO: 23, SEQ ID NO: 24, or SEQ ID NO: 25, an amino acid sequence that is at least approximately 85%, 90%, 95%, 99%, or more identical to the amino acid sequence of SEQ ID NO: 23, SEQ ID NO: 24, or SEQ ID NO: 25, or an amino acid sequence selected from amino acid sequences that differ from the amino acid sequence of SEQ ID NO: 23, SEQ ID NO: 24, or SEQ ID NO: 25 by 1, 2, 5, 10, or 15 amino acid residues or less, and / or a VL domain containing the amino acid sequence of SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30, an amino acid sequence that is at least approximately 85%, 90%, 95%, 99%, or more identical to the amino acid sequence of SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30, or an amino acid sequence selected from amino acid sequences that differ from the amino acid sequence of SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30 by 1, 2, 5, 10, or 15 amino acid residues or less. In some embodiments, an anti-TCRβV antibody molecule, for example, an anti-TCRβ V12 antibody molecule, comprises a VH domain containing the amino acid sequence of SEQ ID NO: 23, an amino acid sequence that is at least about 85%, 90%, 95%, 99%, or more identical to the amino acid sequ...

Claims

1. A method for treating a disease or condition, or for reducing the risk of developing such a disease or condition, wherein the method comprises administering to the subject a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region. The TCR variable region is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), and (a) The disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCRα V1 subfamily. (b) The disease or condition is Crohn's disease, and the portion that binds to the TCR variable region binds to the TCRα V2 subfamily, (c) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRα V4 subfamily. (d) The disease or condition is type 1 diabetes, and the portion that binds to the TCR variable region binds to the TCRα V12 subfamily, (e) The disease or condition is Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCRα V13 subfamily, (f) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRα V20 subfamily, (g) The disease or condition is ankylosing spondylitis, and the portion that binds to the TCR variable region binds to the TCRα V21 subfamily. (h) The disease or condition is Crohn's disease, and the portion that binds to the TCR variable region binds to the TCRα V22 subfamily, (i) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRα V26 subfamily, (j) The disease or condition is Crohn's disease, and the portion that binds to the TCR variable region binds to the TCRα V40 subfamily. (k) The disease or condition is a malfunction of the joint implant, and the portion that binds to the TCR variable region is bound to the TCRα V41 subfamily. (l) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRβ V4 subfamily, (m) The disease or condition is primary Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCRβ V6 subfamily. (n) The disease or condition is amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V7 subfamily. (o) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRβ V7 subfamily, (p) The disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V7 subfamily. (q) The disease or condition is ankylosing spondylitis, and the portion that binds to the TCR variable region binds to the TCRβ V9 subfamily, (r) The disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V10 subfamily. (s) The disease or condition is a COVID-related multisystem inflammatory syndrome in a child, wherein the portion that binds to the TCR variable region binds to the TCRβ V11 subfamily, (t) The disease or condition is type 1 diabetes, and the portion that binds to the TCR variable region binds to the TCRβ V12 subfamily, (u) The disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V10 subfamily. (v) The disease or condition is amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V23 subfamily, or (w) The disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V29 subfamily.

2. The method according to claim 1, wherein the activation or expansion of autoreactive T cells in the subject is inhibited or prevented by administering the therapeutically effective amount of the agent.

3. The method according to claim 2, wherein the self-reactive T cells target self cells in the subject.

4. The method according to claim 2 or 3, wherein the autoreactive T cells express TCRαV and / or TCRβV.

5. The method according to any one of claims 1 to 4, wherein the agent comprises an antibody molecule or its antigen-binding domain.

6. The method according to claim 5, wherein the antibody molecule includes an Fc region.

7. The method according to claim 6, wherein the Fc region includes a binding mutation.

8. The method according to any one of claims 1 to 7, wherein the agent is functionally linked to a cytotoxic agent.

9. The method according to claim 8, wherein the cytotoxic agent comprises calicheamycin, monomethyl auristatin E, a meitansine derivative, or an exatecan derivative.

10. The method according to claim 6, wherein the Fc region does not contain binding mutations.

11. The method according to any one of claims 8 to 10, wherein the cytotoxic agent mediates the death of the autoreactive T cells in the subject.

12. The method according to claim 6, wherein the Fc region has an enhanced effector function.

13. The method according to claim 12, wherein the enhanced effector function includes antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC).

14. The method according to claim 12 or 13, wherein the enhanced effector function mediates the death of the autoreactive T cells in the subject.

15. The method according to any one of claims 1 to 4, wherein the agent comprises another portion.

16. The method according to claim 15, wherein the other part comprises an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

17. The method according to claim 16, wherein the other part comprises the NK cell engager, the NK cell engager binds to NKp30.

18. The method according to claim 17, wherein the binding of the other portion to NKp30 mediates the death of the autoreactive T cells in the subject.

19. The method according to claim 16, wherein the other part comprises the T cell engager, the T cell engager binds to an antigen expressed on CD8+ and / or CD4+ T cells.

20. The method according to claim 19, wherein the other part comprises the T cell engager, the T cell engager binds to TCRαV or TCRβV.

21. The method according to claim 19, wherein the TCRαV or TCRβV comprises a TCRαV or TCRβV different from the TCR variable region to which the portion of the agent is bound.

22. The method according to claim 16, wherein the other part comprises the T cell engager, the T cell engager binds to CD3.

23. The method according to any one of claims 19 to 22, wherein the binding of the T cell engager to CD8+ and / or CD4+ T cells mediates the death of the autoreactive T cells in the subject.

24. The method according to any one of claims 19 to 23, wherein the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRαV1-1 or TCRαV1-2.

25. The method according to any one of claims 19 to 23, wherein the disease or condition is type 1 diabetes, and the portion that binds to the TCR variable region binds to TCRαV12-3.

26. The method according to any one of claims 19 to 23, wherein the disease or condition is Sjögren's syndrome, and the portion that binds to the TCR variable region binds to TCRαV13-1 or TCRαV13-2.

27. The method according to any one of claims 19 to 23, wherein the disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to TCRαV26-1 or TCRαV26-2.

28. The method according to any one of claims 19 to 23, wherein the disease or condition is primary Sjögren's syndrome, and the portion that binds to the TCR variable region binds to TCRβV6-1, TCRβV6-2 / 3, or TCRβV6-5.

29. The method according to any one of claims 19 to 23, wherein the disease or condition is amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to TCRβV7-1 or TCRβV7-8 / 9.

30. The method according to any one of claims 19 to 23, wherein the disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to TCRβV7-1 or TCRβV7-8 / 9.

31. The method according to any one of claims 19 to 23, wherein the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRβV7-1 or TCRβV7-8 / 9.

32. The method according to any one of claims 19 to 23, wherein the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRβV10-3.

33. The method according to any one of claims 19 to 23, wherein the disease or condition is COVID-related multisystem inflammatory syndrome, and the portion that binds to the TCR variable region binds to TCRβV11-2.

34. The method according to claim 33, wherein the subject is a child.

35. The method according to any one of claims 19 to 23, wherein the disease or condition is type 1 diabetes, and the portion that binds to the TCR variable region binds to TCRβV12-3 / 4.

36. The method according to any one of claims 19 to 23, wherein the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRβV20-1.

37. The method according to any one of claims 19 to 23, wherein the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRβV29-1.

38. A composition comprising a recombinant T cell receptor or a chimeric antigen receptor (CAR) including a portion that binds to the TCR variable region.

39. A composition comprising T cells containing a recombinant T cell receptor or a chimeric antigen receptor (CAR), wherein the recombinant T cell receptor or the CAR includes a portion that binds to the TCR variable region.

40. The recombinant T cell receptor or the CAR, (a) Extracellular domain including the portion that binds to the TCR variable region, (b) Transmembrane domain, and (c) The composition according to claim 38 or 39, comprising an intracellular domain including an intracellular signaling domain.

41. The composition according to claim 40, wherein the extracellular domain comprises the extracellular domain of CD8 or CD28.

42. The composition according to claim 40 or 41, wherein the transmembrane domain comprises a transmembrane domain of CD8 or CD28.

43. The composition according to any one of claims 40 to 42, wherein the intracellular domain comprises the intracellular signaling domain of CD3 zeta.

44. The portion coupled to the TCR variable region is the TCRα V1 subfamily, TCRα V2 subfamily, TCRα V3 subfamily, TCRα V4, TCRα V5 subfamily, TCRα V6 subfamily, TCRα V7 subfamily, TCRα V8 subfamily, TCRα V9 subfamily, TCRα V10 subfamily, TCRα V12 subfamily, TCRα V13 subfamily, TCRα V14 subfamily, TCRα V16 subfamily, TCRα V17 subfamily, TCRα V18 subfamily, TCRα V19 subfamily, TCRα V20 subfamily, TCRα V21 subfamily, TCRα V22 subfamily, TCRα V23 subfamily, TCRα V24 subfamily, TCRα The composition according to any one of claims 40 to 43, wherein the TCRα V subfamily is bonded to the V25 subfamily, TCRα V26 subfamily, TCRα V27 subfamily, TCRα V29 subfamily, TCRα V30 subfamily, TCRα V34 subfamily, TCRα V35 subfamily, TCRα V36 subfamily, TCRα V38 subfamily, TCRα V39 subfamily, TCRα V40 subfamily, and TCRα V41 subfamily, as well as family members of the subfamilies and variants thereof, selected from the group.

45. The composition according to any one of claims 40 to 43, wherein the portion bound to the TCR variable region is bound to a TCRβV subfamily selected from the group consisting of the TCRβ V2 subfamily, TCRβ V3 subfamily, TCRβ V4 subfamily, TCRβ V5 subfamily, TCRβ V6 subfamily, TCRβ V9 subfamily, TCRβ V10 subfamily, TCRβ V11 subfamily, TCRβ V12 subfamily, TCRβ V13 subfamily, TCRβ V16 subfamily, TCRβ V19 subfamily, TCRβ V21 subfamily, TCRβ V23 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V29 subfamily, and TCRβ V30 subfamily, as well as family members of the subfamilies and their variants.

46. A pharmaceutical composition comprising the composition according to any one of claims 38 to 45, and a pharmaceutically acceptable diluent, carrier, excipient, or stabilizer.

47. A method for treating a disease or condition, or for reducing the risk of developing such a disease or condition, in a subject who needs such treatment, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition described in claim 46.

48. The method according to claim 47, wherein the disease or condition is an autoimmune disease.

49. The aforementioned autoimmune diseases include amyotrophic lateral sclerosis (ALS), celiac disease (CD), ankylosing spondylitis (AS), Covid-associated multisystem inflammatory syndrome in children (MIS-C), primary Sjögren's syndrome (PSS), Churg-Strauss syndrome, sarcoidosis, systemic lupus erythematosus (SLE), type 1 diabetes, autoimmune hepatitis (e.g., type 1 or type 2), primary sclerosing cholangitis, primary biliary cholangitis, multiple sclerosis, Guillain-Barré syndrome, and AMAN (axonal and neuronal neuropathy), and chronic inflammatory bowel disease. Polyneuropathy myelin (CIDP), transverse myelitis, Trosa Hunt syndrome (THS), Devic's disease (neuromyelitis optica), paraneoplastic cerebellar degeneration (PCD), Lambert-Eaton syndrome, psoriasis, scleroderma, CREST syndrome (calcification, Raynaud's phenomenon, esophageal motility disorders, finger sclerosis, and telangiectasia), herpetiform dermatitis, dermatomyositis, bullous pemphigoid, scarring pemphigoid / benign mucosal pemphigoid, pemphigoid of pregnancy, rheumatoid arthritis (RA), psoriatic arthritis, relapsing polychondritis, chronic relapsing polymyelitis (CRMO) The method according to claim 48, selected from the group consisting of osteomyelitis, vasculitis, Kawasaki disease, granulomatosis with polyangiitis (GPA), Behçet's disease (vasculitis), Takayasu's arteritis, polyarteritis nodosa, microscopic polyangiitis (MPA), leukocytoclastic vasculitis, Cogan's syndrome, uveitis, peripheral uveitis (tonsillar), scleritis, autoimmune inner ear disease (AIED), Crohn's disease, ulcerative colitis (UC), Dressler syndrome, rheumatic fever, Evans syndrome, paroxysmal nocturnal hemoglobinuria (PNH), hemolytic anemia, thrombocytopenic purpura (TTP), polymyositis, juvenile myositis (JM), including juvenile dermatomyositis (JDM) and juvenile polymyositis (JPM), ocular scarring pemphigoid, or Hashimoto's thyroiditis.

50. (a) The disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCRα V1 subfamily. (b) The disease or condition is Crohn's disease, and the portion that binds to the TCR variable region binds to the TCRα V2 subfamily, (c) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRα V4 subfamily. (d) The disease or condition is type 1 diabetes, and the portion that binds to the TCR variable region binds to the TCRα V12 subfamily, (e) The disease or condition is Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCRα V13 subfamily, (f) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRα V20 subfamily, (g) The disease or condition is ankylosing spondylitis, and the portion that binds to the TCR variable region binds to the TCRα V21 subfamily. (h) The disease or condition is Crohn's disease, and the portion that binds to the TCR variable region binds to the TCRα V22 subfamily, (i) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRα V26 subfamily, (j) The disease or condition is Crohn's disease, and the portion that binds to the TCR variable region binds to the TCRα V40 subfamily. (k) The disease or condition is a malfunction of the joint implant, and the portion that binds to the TCR variable region is bound to the TCRα V41 subfamily. (l) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRβ V4 subfamily, (m) The disease or condition is primary Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCRβ V6 subfamily. (n) The disease or condition is amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V7 subfamily. (o) The disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to the TCRβ V7 subfamily, (p) The disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V7 subfamily. (q) The disease or condition is ankylosing spondylitis, and the portion that binds to the TCR variable region binds to the TCRβ V9 subfamily, (r) The disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V10 subfamily. (s) The disease or condition is a COVID-related multisystem inflammatory syndrome in a child, wherein the portion that binds to the TCR variable region binds to the TCRβ V11 subfamily, (t) The disease or condition is type 1 diabetes, and the portion that binds to the TCR variable region binds to the TCRβ V12 subfamily, (u) The disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V10 subfamily. (v) The disease or condition is amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V23 subfamily, or (w) The disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCRβ V29 subfamily, according to claim 47.

51. The method according to any one of claims 47 to 50, wherein the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRαV1-1 or TCRαV1-2.

52. The method according to any one of claims 47 to 50, wherein the disease or condition is type 1 diabetes, and the portion that binds to the TCR variable region binds to TCRαV12-3.

53. The method according to any one of claims 47 to 50, wherein the disease or condition is Sjögren's syndrome, and the portion that binds to the TCR variable region binds to TCRαV13-1 or TCRαV13-2.

54. The method according to any one of claims 47 to 50, wherein the disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to TCRαV26-1 or TCRαV26-2.

55. The method according to any one of claims 47 to 50, wherein the disease or condition is primary Sjögren's syndrome, and the portion that binds to the TCR variable region binds to TCRβV6-1, TCRβV6-2 / 3, or TCRβV6-5.

56. The method according to any one of claims 47 to 50, wherein the disease or condition is amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to TCRβV7-1 or TCRβV7-8 / 9.

57. The method according to any one of claims 47 to 50, wherein the disease or condition is celiac disease, and the portion that binds to the TCR variable region binds to TCRβV7-1 or TCRβV7-8 / 9.

58. The method according to any one of claims 47 to 50, wherein the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRβV7-1 or TCRβV7-8 / 9.

59. The method according to any one of claims 47 to 50, wherein the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRβV10-3.

60. The method according to any one of claims 47 to 50, wherein the disease or condition is COVID-related multisystem inflammatory syndrome, and the portion that binds to the TCR variable region binds to TCRβV11-2.

61. The method according to claim 60, wherein the subject is a child.

62. The method according to any one of claims 47 to 50, wherein the disease or condition is type 1 diabetes, and the portion that binds to the TCR variable region binds to TCRβV12-3 / 4.

63. The method according to any one of claims 47 to 50, wherein the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRβV20-1.

64. The method according to any one of claims 47 to 50, wherein the disease or condition is multiple sclerosis, and the portion that binds to the TCR variable region binds to TCRβV29-1.

65. The method according to any one of claims 1 to 37 or 47 to 50, further comprising administering a second therapeutic agent or treatment to the subject.

66. The method according to claim 65, wherein the second therapeutic agent or treatment method comprises a chemotherapeutic agent, a biologic, an immunosuppressant, or radiation.

67. The method according to claim 65 or 66, wherein the second therapeutic agent or treatment method is administered in combination with the agent according to any one of claims 1 to 37, the composition according to any one of claims 38 to 45, or the pharmaceutical composition according to claim 46, and administered sequentially, simultaneously, or in parallel.

68. A method for inhibiting or preventing the activation and / or expansion of autoreactive T cells in a subject where such need exists, comprising administering a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject. The TCR variable region is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), The aforementioned self-reactive T cells target the self cells in the subject, The aforementioned self-reactive T cells express TCRαV and / or TCRβV, and (a) The subject is suffering from multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V1 subfamily, (b) The subject is suffering from Crohn's disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V2 subfamily, (c) The subject is suffering from celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V4 subfamily, (d) The subject is suffering from type 1 diabetes, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V12 subfamily, (e) The subject is suffering from Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V13 subfamily, (f) The subject is suffering from celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V20 subfamily, (g) The subject is suffering from ankylosing spondylitis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V21 subfamily, (h) The subject is suffering from Crohn's disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V22 subfamily, (i) The subject is suffering from celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V26 subfamily, (j) The subject is suffering from Crohn's disease, and the portion that binds to the TCR variable region is bound to the TCR variable region of the TCRα V40 subfamily, (k) The subject exhibits a malfunction of the joint implant, and the portion that connects to the TCR variable region is connected to the TCR variable region of the TCRα V41 subfamily. (l) The subject is suffering from celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V4 subfamily, (m) The subject is suffering from primary Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V6 subfamily, (n) The subject is suffering from amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V7 subfamily, (o) The subject is suffering from celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V7 subfamily, (p) The subject is suffering from multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V7 subfamily, (q) The subject suffers from ankylosing spondylitis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V9 subfamily, (r) The subject is suffering from multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V10 subfamily, (s) The subject is a child suffering from COVID-related multisystem inflammatory syndrome, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V11 subfamily, (t) The subject is suffering from type 1 diabetes, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V12 subfamily, (u) The subject is suffering from multiple sclerosis, and the portion that binds to the TCR variable region is bound to the TCR variable region of the TCRβ V10 subfamily, (v) The subject is suffering from amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V23 subfamily, or (w) The subject is a person suffering from multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V29 subfamily.

69. A method for reducing or depleting autoreactive T cells in a subject where such reduction is necessary, comprising administering a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject. The TCR variable region is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), The aforementioned self-reactive T cells target the self cells in the subject, The aforementioned self-reactive T cells express TCRαV and / or TCRβV, and (a) The subject is suffering from multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V1 subfamily, (b) The subject is suffering from Crohn's disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V2 subfamily, (c) The subject is suffering from celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V4 subfamily, (d) The subject is suffering from type 1 diabetes, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V12 subfamily, (e) The subject is suffering from Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V13 subfamily, (f) The subject is suffering from celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V20 subfamily, (g) The subject is suffering from ankylosing spondylitis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V21 subfamily, (h) The subject is suffering from Crohn's disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V22 subfamily, (i) The subject is suffering from celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V26 subfamily, (j) The subject is suffering from Crohn's disease, and the portion that binds to the TCR variable region is bound to the TCR variable region of the TCRα V40 subfamily, (k) The subject exhibits a malfunction of the joint implant, and the portion that connects to the TCR variable region is connected to the TCR variable region of the TCRα V41 subfamily. (l) The subject is suffering from celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V4 subfamily, (m) The subject is suffering from primary Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V6 subfamily, (n) The subject is suffering from amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V7 subfamily, (o) The subject is suffering from celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V7 subfamily, (p) The subject is suffering from multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V7 subfamily, (q) The subject suffers from ankylosing spondylitis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V9 subfamily, (r) The subject is suffering from multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V10 subfamily, (s) The subject is a child suffering from COVID-related multisystem inflammatory syndrome, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V11 subfamily, (t) The subject is suffering from type 1 diabetes, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V12 subfamily, (u) The subject is suffering from multiple sclerosis, and the portion that binds to the TCR variable region is bound to the TCR variable region of the TCRβ V10 subfamily, (v) The subject is suffering from amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V23 subfamily, or (w) The subject is a person suffering from multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V29 subfamily.

70. The method according to claim 68 or 69, further comprising determining that the subject is suffering from multiple sclerosis associated with a biased TCR clonal type, comprising the TCR variable region of the TCRα V1 subfamily, TCRβ V7 subfamily, TCRβ V10 subfamily, TCRβ V20 subfamily, or TCRβ V29 subfamily, wherein the portion binding to the TCR variable region binds to the TCR variable domain of the TCRα V1 subfamily, TCRβ V7 subfamily, TCRβ V10 subfamily, TCRβ V20 subfamily, or TCRβ V29 subfamily.

71. The method according to claim 68 or 69, further comprising determining that the subject is suffering from amyotrophic lateral sclerosis associated with a biased TCR clonal type comprising the TCR variable region of the TCRβ V7 subfamily or the TCRβ V23 subfamily, wherein the portion binding to the TCR variable region binds to the TCR variable domain of the TCRβ V7 subfamily or the TCRβ V23 subfamily.

72. The method according to claim 68 or 69, further comprising determining that the subject has celiac disease associated with a biased TCR clonal type, comprising the TCR variable region of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily, wherein the portion binding to the TCR variable region binds to the TCR variable domain of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily.

73. The method according to claim 68 or 69, further comprising determining that the subject is suffering from ankylosing spondylitis associated with a biased TCR clonal type comprising the TCR variable region of the TCRα V21 subfamily or the TCRβ V9 subfamily, wherein the portion binding to the TCR variable region binds to the TCR variable domain of the TCRα V21 subfamily or the TCRβ V9 subfamily.

74. The method according to claim 68 or 69, further comprising determining that the subject is suffering from a childhood COVID-related multisystem inflammatory syndrome associated with a biased TCR clonal type comprising the TCR variable region of the TCRβ V11 subfamily, wherein the portion binding to the TCR variable region binds to the TCR variable domain of the TCRβ V11 subfamily.

75. The method according to claim 68 or 69, further comprising determining that the subject suffers from primary Sjögren's syndrome associated with a biased TCR clonal type comprising the TCR variable region of the TCRβ V6 subfamily, wherein the portion binding to the TCR variable region binds to the TCR variable domain of the TCRβ V6 subfamily.

76. The method according to claim 68 or 69, further comprising determining that the subject suffers from type 1 diabetes associated with a biased TCR clonal type, wherein the portion binding to the TCR variable region is bound to the TCR variable domain of the TCRα V12 subfamily or the TCRβ V12 subfamily.

77. The method according to any one of claims 68 to 76, wherein the agent comprises an antibody molecule or an antigen-binding fragment thereof.

78. The method according to claim 77, wherein the antibody molecule includes an Fc region.

79. The method according to claim 78, wherein the Fc region includes a binding mutation.

80. The method according to any one of claims 68 to 79, wherein the agent is functionally linked to a cytotoxic agent.

81. The method according to claim 80, wherein the cytotoxic agent comprises calicheamycin, monomethyl auristatin E, a maytansine derivative, or an exatecan derivative.

82. The method according to claim 78, wherein the Fc region does not contain a mutation that affects the binding of the Fc region to the Fc receptor.

83. The method according to any one of claims 80 to 82, wherein the cytotoxic agent mediates the death of the autoreactive T cells in the subject.

84. The method according to claim 78 or 79, wherein the Fc region includes an amino acid mutation that enhances the effector function.

85. The method according to claim 84, wherein the effector function includes antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC).

86. The method according to claim 84 or 85, wherein the effector function mediates the death of the autoreactive T cells in the subject.

87. The method according to any one of claims 68 to 86, wherein the agent comprises another portion.

88. The method according to claim 87, wherein the other part comprises an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

89. The method according to claim 88, wherein the other portion comprises the NK cell engager, and the NK cell engager binds to an antigen selected from the group consisting of NKp30, NKp40, NKp44, NKp46, NKG2D, DNAM1, DAP10, CD16, CRTAM, CD27, PSGL1, CD96, CD100 (SEMA4D), NKp80, CD244 (also known as SLAMF4 or 2B4), SLAMF6, SLAMF7, KIR2DS2, KIR2DS4, KIR3DS1, KIR2DS3, KIR2DS5, KIR2DS1, CD94, NKG2C, NKG2E, and CD160.

90. The method according to claim 89, wherein the binding of the other portion to NKp30 activates NK cells and mediates the death of the target autoreactive T cells.

91. The method according to claim 88, wherein the other part comprises the NK cell engager, the NK cell engager binds to the KIR receptor and / or CD94-NKG2A.

92. The method according to claim 91, wherein the binding of the other portion to the KIR receptor and / or CD94-NKG2A deinhibits NK cells and mediates the death of the autoreactive T cells in the subject.

93. The method according to claim 88, wherein the other part comprises the T cell engager, the T cell engager binds to an antigen expressed on CD8+ and / or CD4+ T cells.

94. The method according to claim 93, wherein the other part comprises the T cell engager, the T cell engager binds to TCRαV or TCRβV.

95. The method according to claim 94, wherein the TCRαV or TCRβV to which the T cell engager binds is different from the TCR variable region to which the portion of the agent binds.

96. The other portion that binds to TCRαV or TCRβV is the TCRα V1 subfamily, TCRα V2 subfamily, TCRα V3 subfamily, TCRα V4, TCRα V5 subfamily, TCRα V6 subfamily, TCRα V7 subfamily, TCRα V8 subfamily, TCRα V9 subfamily, TCRα V10 subfamily, TCRα V12 subfamily, TCRα V13 subfamily, TCRα V14 subfamily, TCRα V16 subfamily, TCRα V17 subfamily, TCRα V18 subfamily, TCRα V19 subfamily, TCRα V20 subfamily, TCRα V21 subfamily, TCRα V22 subfamily, TCRα V23 subfamily, TCRα The method according to claims 94 to 95, wherein the TCRαV of a subfamily selected from the group consisting of the V24 subfamily, the TCRα V25 subfamily, the TCRα V26 subfamily, the TCRα V27 subfamily, the TCRα V29 subfamily, the TCRα V30 subfamily, the TCRα V34 subfamily, the TCRα V35 subfamily, the TCRα V36 subfamily, the TCRα V38 subfamily, the TCRα V39 subfamily, the TCRα V40 subfamily, and the TCRα V41 subfamily, as well as family members of the subfamilies and their variants.

97. The method according to claims 94 to 95, wherein the other portion that binds to TCRαV or TCRβV binds to TCRβV of a subfamily selected from the group consisting of the TCRβ V2 subfamily, TCRβ V3 subfamily, TCRβ V4 subfamily, TCRβ V5 subfamily, TCRβ V6 subfamily, TCRβ V9 subfamily, TCRβ V10 subfamily, TCRβ V11 subfamily, TCRβ V12 subfamily, TCRβ V13 subfamily, TCRβ V16 subfamily, TCRβ V19 subfamily, TCRβ V21 subfamily, TCRβ V23 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V29 subfamily, and TCRβ V30 subfamily, as well as family members of the subfamily and variants thereof.

98. The method according to claim 88, wherein the other part comprises the T cell engager, the T cell engager binds to CD3.

99. The method according to any one of claims 93 to 98, wherein the binding of the T cell engager to the CD8+ and / or CD4+ T cells mediates the death of the autoreactive T cells in the subject.

100. The method according to any one of claims 68 to 99, wherein the subject is suffering from multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRαV1-1 or TCRαV1-2 family.

101. The method according to any one of claims 68 to 99, wherein the subject is suffering from type 1 diabetes, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRαV12-3 family.

102. The method according to any one of claims 68 to 99, wherein the subject suffers from Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRαV13-1 or TCRαV13-2 family.

103. The method according to any one of claims 68 to 99, wherein the subject is suffering from celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRαV26-1 or TCRαV26-2 family.

104. The method according to any one of claims 68 to 99, wherein the subject suffers from primary Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV6-1, TCRβV6-2 / 3, or TCRβV6-5 family.

105. The method according to any one of claims 68 to 99, wherein the subject is suffering from amyotrophic lateral sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of TCRβV7-1 or the TCRβV7-8 / 9 family.

106. The method according to any one of claims 68 to 99, wherein the subject is suffering from celiac disease, and the portion that binds to the TCR variable region binds to the TCR variable region of TCRβV7-1 or the TCRβV7-8 / 9 family.

107. The method according to any one of claims 68 to 99, wherein the subject is suffering from multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV7-1 or TCRβV7-8 / 9 family.

108. The method according to any one of claims 68 to 99, wherein the subject is suffering from multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV10-3 family.

109. The method according to any one of claims 68 to 99, wherein the subject is suffering from COVID-related multisystem inflammatory syndrome, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV11-2 family.

110. The method according to claim 109, wherein the subject is a child.

111. The method according to any one of claims 68 to 99, wherein the subject is suffering from type 1 diabetes, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV12-3 / 4 family.

112. The method according to any one of claims 68 to 99, wherein the subject is suffering from multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV20-1 family.

113. The method according to any one of claims 68 to 99, wherein the subject is suffering from multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβV29-1 family.

114. A method for inhibiting or preventing the activation and / or expansion of autoreactive T cells in a subject where such need exists, comprising administering a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject. The TCR variable region is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor beta variable region (TCRβV), The aforementioned self-reactive T cells target the self cells in the subject, The aforementioned autoreactive T cells express TCRαV and / or TCRβV, (a) The subject is identified as having multiple sclerosis associated with a biased TCR clonal type including the TCR variable region of the TCRα V1 subfamily, or having symptoms of multiple sclerosis, wherein the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V1 subfamily, (b) The subject is identified as having multiple sclerosis associated with a biased TCR clonal type including the TCR variable region of the TCRβ V7 subfamily, or having symptoms of multiple sclerosis, wherein the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V7 subfamily, (c) The subject is identified as having multiple sclerosis associated with a biased TCR clonal type including the TCR variable region of the TCRβ V10 subfamily, or having symptoms of multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V10 subfamily, (d) The subject is identified as having multiple sclerosis associated with a biased TCR clonal type including the TCR variable region of the TCRβ V20 subfamily, or having symptoms of multiple sclerosis, wherein the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V20 subfamily, or (e) The subject is identified as having multiple sclerosis associated with a biased TCR clonal type including the TCR variable region of the TCRβ V29 subfamily, or having symptoms of multiple sclerosis, wherein the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V29 subfamily, and A method wherein the aforementioned portion does not bind to different TCRαV and / or TCRβV subfamilies.

115. A method for reducing or depleting autoreactive T cells in a subject where such reduction is necessary, comprising administering a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject. The TCR variable region is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), The aforementioned self-reactive T cells target the self cells in the subject, The aforementioned self-reactive T cells express TCRαV and / or TCRβV, and (a) The subject is identified as having multiple sclerosis associated with a biased TCR clonal type including the TCR variable region of the TCRα V1 subfamily, or having symptoms of multiple sclerosis, wherein the portion that binds to the TCR variable region binds to the TCR variable region of the TCRα V1 subfamily, (b) The subject is identified as having multiple sclerosis associated with a biased TCR clonal type including the TCR variable region of the TCRβ V7 subfamily, or having symptoms of multiple sclerosis, wherein the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V7 subfamily, (c) The subject is identified as having multiple sclerosis associated with a biased TCR clonal type including the TCR variable region of the TCRβ V10 subfamily, or having symptoms of multiple sclerosis, and the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V10 subfamily, (d) The subject is identified as having multiple sclerosis associated with a biased TCR clonal type including the TCR variable region of the TCRβ V20 subfamily, or having symptoms of multiple sclerosis, wherein the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V20 subfamily, or (e) The subject is identified as having multiple sclerosis associated with a biased TCR clonal type including the TCR variable region of the TCRβ V29 subfamily, or having symptoms of multiple sclerosis, wherein the portion that binds to the TCR variable region binds to the TCR variable region of the TCRβ V29 subfamily, and A method wherein the aforementioned portion does not bind to different TCRαV and / or TCRβV subfamilies.

116. A method for inhibiting or preventing the activation and / or expansion of autoreactive T cells in a subject where such need exists, comprising administering a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject. The TCR variable region is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor beta variable region (TCRβV), The aforementioned self-reactive T cells target the self cells in the subject, The aforementioned autoreactive T cells express TCRαV and / or TCRβV, (a) The subject is identified as having amyotrophic lateral sclerosis associated with a biased TCR clonal type, which includes the TCR variable region of the TCRβ V7 subfamily or the TCRβ V23 subfamily, or having symptoms of amyotrophic lateral sclerosis, wherein the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V7 subfamily or the TCRβ V23 subfamily, or (b) The subject is identified as having amyotrophic lateral sclerosis associated with a biased TCR clonal type, which includes the TCR variable region of the TCRβ V7 subfamily or the TCRβ V23 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V7 subfamily or the TCRβ V23 subfamily, and A method wherein the portion does not bind to any other different TCRαV and / or TCRβV subfamily.

117. A method for reducing or depleting autoreactive T cells in a subject where such reduction is necessary, comprising administering a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject. The TCR variable region is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), The aforementioned self-reactive T cells target the self cells in the subject, The aforementioned self-reactive T cells express TCRαV and / or TCRβV, and (a) The subject is identified as having amyotrophic lateral sclerosis associated with a biased TCR clonal type, which includes the TCR variable region of the TCRβ V7 subfamily or the TCRβ V23 subfamily, or having symptoms of amyotrophic lateral sclerosis, wherein the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V7 subfamily or the TCRβ V23 subfamily, or (b) The subject is identified as having amyotrophic lateral sclerosis associated with a biased TCR clonal type, which includes the TCR variable region of the TCRβ V7 subfamily or the TCRβ V23 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V7 subfamily or the TCRβ V23 subfamily, and A method wherein the portion does not bind to any other different TCRαV and / or TCRβV subfamily.

118. A method for inhibiting or preventing the activation and / or expansion of autoreactive T cells in a subject where such need exists, comprising administering a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject. The TCR variable region is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor beta variable region (TCRβV), The aforementioned self-reactive T cells target the self cells in the subject, The aforementioned autoreactive T cells express TCRαV and / or TCRβV, (a) The subject is identified as having celiac disease associated with a biased TCR clonal type, or having symptoms of celiac disease, which includes the TCR variable region of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily, or (b) The subject is identified as having celiac disease associated with a biased TCR clonal type, or having symptoms of celiac disease, which includes the TCR variable region of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily, and A method wherein the portion does not bind to any other different TCRαV and / or TCRβV subfamily.

119. A method for reducing or depleting autoreactive T cells in a subject where such reduction is necessary, comprising administering a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject. The TCR variable region is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), The aforementioned self-reactive T cells target the self cells in the subject, The aforementioned self-reactive T cells express TCRαV and / or TCRβV, and (a) The subject is identified as having celiac disease associated with a biased TCR clonal type, or having symptoms of celiac disease, which includes the TCR variable region of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily, or (b) The subject is identified as having celiac disease associated with a biased TCR clonal type, or having symptoms of celiac disease, which includes the TCR variable region of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRα V26 subfamily, TCRα V4 subfamily, TCRβ V7 subfamily, or TCRβ V4 subfamily, and A method wherein the portion does not bind to any other different TCRαV and / or TCRβV subfamily.

120. A method for inhibiting or preventing the activation and / or expansion of autoreactive T cells in a subject where such need exists, comprising administering a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject. The TCR variable region is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor beta variable region (TCRβV), The aforementioned self-reactive T cells target the self cells in the subject, The aforementioned autoreactive T cells express TCRαV and / or TCRβV, (a) The subject is identified as having ankylosing spondylitis associated with a biased TCR clone type, which includes the TCR variable region of the TCRα V21 subfamily or the TCRβ V9 subfamily, or having symptoms of ankylosing spondylitis, wherein the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRα V21 subfamily or the TCRβ V9 subfamily, or (b) The subject is identified as having ankylosing spondylitis associated with a biased TCR clone type, which includes the TCR variable region of the TCRα V21 subfamily or the TCRβ V9 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRα V21 subfamily or the TCRβ V9 subfamily, and A method wherein the portion does not bind to any other different TCRαV and / or TCRβV subfamily.

121. A method for reducing or depleting autoreactive T cells in a subject where such reduction is necessary, comprising administering a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject. The TCR variable region is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), The aforementioned self-reactive T cells target the self cells in the subject, The aforementioned self-reactive T cells express TCRαV and / or TCRβV, and (a) The subject is identified as having ankylosing spondylitis associated with a biased TCR clone type, which includes the TCR variable region of the TCRα V21 subfamily or the TCRβ V9 subfamily, or having symptoms of ankylosing spondylitis, wherein the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRα V21 subfamily or the TCRβ V9 subfamily, or (b) The subject is identified as having ankylosing spondylitis associated with a biased TCR clone type, which includes the TCR variable region of the TCRα V21 subfamily or the TCRβ V9 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRα V21 subfamily or the TCRβ V9 subfamily, and A method wherein the portion does not bind to any other different TCRαV and / or TCRβV subfamily.

122. A method for inhibiting or preventing the activation and / or expansion of autoreactive T cells in a subject where such need exists, comprising administering a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject. The TCR variable region is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor beta variable region (TCRβV), The aforementioned self-reactive T cells target the self cells in the subject, The aforementioned autoreactive T cells express TCRαV and / or TCRβV, (a) The subject is identified as having or having symptoms of childhood COVID-related multisystem inflammatory syndrome associated with a biased TCR clonal type including the TCR variable region of the TCRβ V11 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V11 subfamily, or (b) The subject is identified as having or having symptoms of childhood COVID-related multisystem inflammatory syndrome associated with a biased TCR clonal type including the TCR variable region of the TCRβ V11 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V11 subfamily, and A method wherein the portion does not bind to any other different TCRαV and / or TCRβV subfamily.

123. A method for reducing or depleting autoreactive T cells in a subject where such reduction is necessary, comprising administering a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject. The TCR variable region is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), The aforementioned self-reactive T cells target the self cells in the subject, The aforementioned self-reactive T cells express TCRαV and / or TCRβV, and (a) The subject is identified as having or having symptoms of childhood COVID-related multisystem inflammatory syndrome associated with a biased TCR clonal type including the TCR variable region of the TCRβ V11 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V11 subfamily, or (b) The subject is identified as having or having symptoms of childhood COVID-related multisystem inflammatory syndrome associated with a biased TCR clonal type including the TCR variable region of the TCRβ V11 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V11 subfamily, and A method wherein the portion does not bind to any other different TCRαV and / or TCRβV subfamily.

124. A method for inhibiting or preventing the activation and / or expansion of autoreactive T cells in a subject where such need exists, comprising administering a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject. The TCR variable region is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor beta variable region (TCRβV), The aforementioned self-reactive T cells target the self cells in the subject, The aforementioned autoreactive T cells express TCRαV and / or TCRβV, (a) The subject is identified as having primary Sjögren's syndrome associated with a biased TCR clonal type including the TCR variable region of the TCRβ V6 subfamily, or having symptoms of primary Sjögren's syndrome, wherein the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V6 subfamily, or (b) The subject is identified as having primary Sjögren's syndrome associated with a biased TCR clonal type including the TCR variable region of the TCRβ V6 subfamily, or having symptoms of primary Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V6 subfamily, and A method wherein the portion does not bind to any other different TCRαV and / or TCRβV subfamily.

125. A method for reducing or depleting autoreactive T cells in a subject where such reduction is necessary, comprising administering a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject. The TCR variable region is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), The aforementioned self-reactive T cells target the self cells in the subject, The aforementioned self-reactive T cells express TCRαV and / or TCRβV, and (a) The subject is identified as having primary Sjögren's syndrome associated with a biased TCR clonal type including the TCR variable region of the TCRβ V6 subfamily, or having symptoms of primary Sjögren's syndrome, wherein the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V6 subfamily, or (b) The subject is identified as having primary Sjögren's syndrome associated with a biased TCR clonal type including the TCR variable region of the TCRβ V6 subfamily, or having symptoms of primary Sjögren's syndrome, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V6 subfamily, and A method wherein the portion does not bind to any other different TCRαV and / or TCRβV subfamily.

126. A method for inhibiting or preventing the activation and / or expansion of autoreactive T cells in a subject where such need exists, comprising administering a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject. The TCR variable region is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor beta variable region (TCRβV), The aforementioned self-reactive T cells target the self cells in the subject, The aforementioned autoreactive T cells express TCRαV and / or TCRβV, (a) The subject is identified as having type 1 diabetes associated with a biased TCR clonal type including the TCR variable region of the TCRβ V12 subfamily or the TCRα V12 subfamily, or having symptoms of type 1 diabetes, wherein the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V12 subfamily or the TCRα V12 subfamily, or (b) The subject is identified as having type 1 diabetes associated with a biased TCR clonal type including the TCR variable region of the TCRβ V12 subfamily or the TCRα V12 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V12 subfamily or the TCRα V12 subfamily, and A method wherein the portion does not bind to any other different TCRαV and / or TCRβV subfamily.

127. A method for reducing or depleting autoreactive T cells in a subject where such reduction is necessary, comprising administering a therapeutically effective amount of an agent containing a portion that binds to the TCR variable region to the subject, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject. The TCR variable region is either the T cell receptor alpha variable region (TCRαV) or the T cell receptor variable beta region (TCRβV), The aforementioned self-reactive T cells target the self cells in the subject, The aforementioned self-reactive T cells express TCRαV and / or TCRβV, and (a) The subject is identified as having type 1 diabetes associated with a biased TCR clonal type including the TCR variable region of the TCRβ V12 subfamily or the TCRα V12 subfamily, or having symptoms of type 1 diabetes, wherein the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V12 subfamily or the TCRα V12 subfamily, or (b) The subject is identified as having type 1 diabetes associated with a biased TCR clonal type including the TCR variable region of the TCRβ V12 subfamily or the TCRα V12 subfamily, and the portion that binds to the TCR variable region binds to the TCR variable domain of the TCRβ V12 subfamily or the TCRα V12 subfamily, and A method wherein the portion does not bind to any other different TCRαV and / or TCRβV subfamily.

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