TCR targeting molecules and uses thereof

Abstract

Disclosed herein, in some aspects, are methods of treating autoimmune diseases or conditions using TCR targeting molecules or cells expressing TCR targeting molecules. TCR targeting molecules can comprise a moiety that binds to a TCR variable beta chain (TCRBV) or a TCR variable alpha chain (TCRAV). TCR targeting molecules can further comprise one, two or all of: (ii) an immune cell engager; (iii) a cytokine inhibitor molecule; (iv) a cytotoxic agent; and / or (v) a death receptor signal enhancer. Additionally, disclosed herein, in some aspects, are nucleic acids encoding the same, and methods of producing the aforesaid molecules.

Description

WSGR Docket No.: 53676-780.601TCR TARGETING MOLECULES AND USES THEREOFCROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 698,981, filed September 25, 2024, and U.S. Provisional Application No. 63 / 702,901, filed October 3, 2024, each of which is incorporated herein by reference in its entirety.BACKGROUND

[0002] T cell mediated antigen recognition depends on the interaction of the T cell receptor (TCR) with the antigen-major histocompatibility complex (MHC). The heterodimeric TCRs consist of a combination of a and P chains (aP TCR) expressed by the majority of T cells, or y5 chains (y5 TCR) present only in about 1-5% of the T cells. A highly diverse TCR repertoire is a fundamental property of an effective immune system. However, the immune repertoire can change greatly with the onset and progression of diseases, such as cancer, autoimmune, inflammatory, and infectious diseases.

[0003] Autoimmunity may result from abnormal regulation of the immune system. This may be manifested by autoreactive TCR clones that attack a patient’s own cells. There is a need for improved therapies for autoimmune diseases.SUMMARY

[0004] In some aspects, the present disclosure provides a method of treating a disease or condition or reducing a risk of developing the disease or condition in a subject in need thereof, comprising administering to the subject a composition, wherein the composition comprises an agent comprising a moiety that binds to a TCR variable region, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor variable beta region (TCRPV), and wherein: (a) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily; (b) the disease or condition is acute anterior uveitis (UAA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; (c) the disease or condition is psoriatic arthritis (PsA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; (d) the disease or condition is type I narcolepsy, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily; (e) the disease or condition is amyotrophic lateral sclerosis (ALS), and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily; or (f) the disease or condition is UAA, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily.WSGR Docket No.: 53676-780.601

[0005] In some aspects, the present disclosure provides a method of treating a disease or condition or reducing a risk of developing the disease or condition in a subject in need thereof, comprising administering to the subject a composition, wherein the composition comprises an agent comprising a moiety that binds to a TCR variable region, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the agent is present in the composition at a concentration of at least about 0.001 mg / ml, and wherein: (a) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRa VI subfamily; (b) the disease or condition is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V2 subfamily; (c) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V4 subfamily; (d) the disease or condition is Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCRa V12 subfamily; (e) the disease or condition is Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily; (f) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V20 subfamily; (g) the disease or condition is ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily; (h) the disease or condition is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V22 subfamily; (i) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V26 subfamily;(j) the disease or condition is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V40 subfamily; (k) the disease or condition is joint implant failure, and the moiety that binds to the TCR variable region binds to a TCRa V41 subfamily; (1) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily; (m) the disease or condition is primary Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily; (n) the disease or condition is amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily; (o) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily; (p) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily; (q) the disease or condition is ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; (r) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP VI 0 subfamily; (s) the disease or condition is COVID-induced multisystem inflammatory syndrome in children, and the moiety that binds to the TCR variable region binds to a TCRP VI 1 subfamily; (t) the disease or condition is Type I diabetes, and the moiety that binds to the TCR variable region binds to aWSGR Docket No.: 53676-780.601TCRP V12 subfamily; (u) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP VI 0 subfamily; (v) the disease or condition is Amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V23 subfamily; (w) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V29 subfamily; (x) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily; (y) the disease or condition is acute anterior uveitis (UAA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; (z) the disease or condition is psoriatic arthritis (PsA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; (aa) the disease or condition is type I narcolepsy, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily; (bb) the disease or condition is amyotrophic lateral sclerosis (ALS), and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily; or (cc) the disease or condition is UAA, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily.

[0006] In some embodiments, the agent is present in the composition at a concentration of at least about 0.01 mg / ml. In some embodiments, the agent is present in the composition at a concentration of at least about 0.1 mg / ml. In some embodiments, the agent is present in the composition at a concentration of at least about 1.0 mg / ml.

[0007] In some aspects, the present disclosure provides a method of treating a disease or condition or reducing a risk of developing the disease or condition in a subject in need thereof, comprising administering to the subject a composition, wherein the composition comprises an agent comprising a moiety that binds to a TCR variable region, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the moiety binds to the TCR variable region with a KD of at most about 500 nM, and wherein: (a) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRa VI subfamily; (b) the disease or condition is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V2 subfamily; (c) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V4 subfamily; (d) the disease or condition is Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCRa V12 subfamily; (e) the disease or condition is Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCRa V13 subfamily; (f) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V20 subfamily; (g) the disease or condition is ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily; (h) the disease or condition is Crohn’s disease, and the moiety that binds to theWSGR Docket No.: 53676-780.601TCR variable region binds to a TCRa V22 subfamily; (i) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V26 subfamily; (j) the disease or condition is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V40 subfamily; (k) the disease or condition is joint implant failure, and the moiety that binds to the TCR variable region binds to a TCRa V41 subfamily; (1) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily; (m) the disease or condition is primary Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily; (n) the disease or condition is amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily; (o) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily; (p) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily; (q) the disease or condition is ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; (r) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP VI 0 subfamily; (s) the disease or condition is COVID-induced multisystem inflammatory syndrome in children, and the moiety that binds to the TCR variable region binds to a TCRP VI 1 subfamily; (t) the disease or condition is Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCRP V12 subfamily; (u) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP VI 0 subfamily; (v) the disease or condition is Amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V23 subfamily; (w) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V29 subfamily; (x) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily; (y) the disease or condition is acute anterior uveitis (UAA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; (z) the disease or condition is psoriatic arthritis (PsA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; (aa) the disease or condition is type I narcolepsy, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily; (bb) the disease or condition is amyotrophic lateral sclerosis (ALS), and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily; or (cc) the disease or condition is UAA, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily.

[0008] In some embodiments, the moiety binds to the TCR variable region with a KD of at most about 100 nM. In some embodiments, the moiety binds to the TCR variable region with a KD ofWSGR Docket No.: 53676-780.601 at most about 10 nM. In some embodiments, the moiety binds to the TCR variable region with a KD of at most about 1 nM.

[0009] In some embodiments, the administration of the composition inhibits or prevents activation or expansion of autoreactive T cells in the subject. In some embodiments, the autoreactive T cells target an autologous cell in the subject. In some embodiments, the autoreactive T cells express TCRaV and / or TCRPV. In some embodiments, the agent comprises an antibody molecule or antigen binding domain thereof.

[0010] In some embodiments, the antibody molecule comprises an Fc region. In some embodiments, the Fc region comprises a binding mutation. In some embodiments, the agent is functionally linked to a cytotoxic agent. In some embodiments, the cytotoxic agent comprises calicheamicin, monomethyl auristatin E, maytansine derivative, or exatecan derivative. In some embodiments, the Fc region comprises no binding mutation. In some embodiments, the cytotoxic agent mediates killing of the autoreactive T cells in the subject. In some embodiments, the Fc region has enhanced effector function. In some embodiments, the enhanced effector function comprises antibody dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement dependent cytotoxicity (CDC). In some embodiments, the enhanced effector function mediates killing of the autoreactive T cells in the subject.

[0011] In some embodiments, the agent comprises an another moiety. In some embodiments, the another moiety comprises aNK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In some embodiments, the another moiety comprises the NK cell engager, and wherein said NK cell engager binds to NKp30.In some embodiments, binding of the another moiety to NKp30 mediates killing of the autoreactive T cells in the subject.

[0012] In some embodiments, the NK cell engager comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) the VH comprises a heavy chain complementarity determining region 1 (HC CDR1), HC CDR 2, and HC CDR 3 comprising: (i) an amino acid sequence of SEQ ID NOs: 6000, 6001, and 6003, respectively; (ii) an amino acid sequence of SEQ ID NOs: 6007, 6008, and 6009, respectively; (iii) an amino acid sequence of SEQ ID NOs: 7313, 6001, and 6002, respectively; (iv) an amino acid sequence of SEQ ID NOs: 7313, 6008, and 6009, respectively; (v) an amino acid sequence of SEQ ID NOs: 7313, 7385, and 7315, respectively; (vi) an amino acid sequence of SEQ ID NOs: 7313, 7318, and 6009, respectively; (vii) an amino acid sequence of SEQ ID NOs: 7313, 6001, and 7315, respectively; or (viii) an amino acid sequence of SEQ ID NOs: 7383, 7380, and 7352, respectively; and / or (b) the VL comprises a light chain complementarity determining region (LC CDR1), LC CDR2, and LC CDR3 comprising: (i) an amino acid sequence of SEQ ID NOs: 6063, 6064, and 67293,WSGR Docket No.: 53676-780.601 respectively; (ii) an amino acid sequence of SEQ ID NOs: 6070, 6071, and 6072, respectively; (iii) an amino acid sequence of SEQ ID NOs: 6070, 6064, and 7321, respectively; or (iv) an amino acid sequence of SEQ ID NOs: 7326, 7327, and 7329, respectively.

[0013] In some embodiments, the VH comprises a sequence with 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 6121-6134, 7295, 7297, 7298, 7300-7304, and 7384; and / or the VL comprises a sequence with 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 6136-6147, 7294, 7296, 7299, and 7305-7309. In some embodiments, the VH comprises an amino acid sequence of any one of SEQ ID NOs: 6121- 6134, 7295, 7297, 7298, 7300-7304, and 7384; and / or the VL comprises an amino acid sequence of any one of SEQ ID NOs: 6136-6147, 7294, 7296, 7299, and 7305-7309. In some embodiments, the NK cell engager that binds to NKp30 comprises an amino acid sequence as set forth in SEQ ID NO: 7310, 7311, 7400, 7401, 7402, 7403, 7404, 7405, 7406, 7407, or 7369.

[0014] In some embodiments, the another moiety comprises the T cell engager, and wherein said T cell engager binds to an antigen expressed on a CD8+ and / or CD4+ T cell. In some embodiments, the another moiety comprises the T cell engager, and wherein said T cell engager binds to a TCRaV or a TCRPV. In some embodiments, the TCRaV or a TCRPV comprises a different TCRaV or a TCRPV from the TCR variable region that the moiety of the agent binds to. In some embodiments, the another moiety comprises the T cell engager, and wherein said T cell engager binds to CD3. In some embodiments, binding of the T cell engager to a CD8+ and / or CD4+ T cell mediates killing of the autoreactive T cells in the subject.

[0015] In some embodiments, the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRaVl-1 or TCRaVl-2. In some embodiments, the disease or condition is type I diabetes, and wherein the moiety that binds to the TCR variable region binds to TCRaV12-3. In some embodiments, the disease or condition is Sjogren's syndrome, and wherein the moiety that binds to the TCR variable region binds to TCRaV13-l or TCRaV13-2. In some embodiments, the disease or condition is celiac disease, and wherein the moiety that binds to the TCR variable region binds to TCRaV26-l or TCRaV26-2. In some embodiments, the disease or condition is primary Sjogren’s syndrome, and wherein the moiety that binds to the TCR variable region binds to TCRPV6-1, TCRPV6-2 / 3, or TCRPV6-5. In some embodiments, the disease or condition is amyotrophic lateral sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV7-1 or TCRPV7-8 / 9. In some embodiments, the disease or condition is celiac disease, and wherein the moiety that binds to the TCR variable region binds to TCRPV7-1 or TCRPV7-8 / 9. In some embodiments, the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV7-1 or TCRPV7-8 / 9. In some embodiments, the disease orWSGR Docket No.: 53676-780.601 condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRpV10-3. In some embodiments, the disease or condition is COVID-induced multisystem inflammatory syndrome, and wherein the moiety that binds to the TCR variable region binds to TCRPV11-2. In some embodiments, the subject is a child. In some embodiments, the disease or condition is type I diabetes, and wherein the moiety that binds to the TCR variable region binds to TCRPV12-3 / 4. In some embodiments, the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV20-1. In some embodiments, the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV29-1.

[0016] In some embodiments, the agent comprising the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of WINAYTGTPTYADDFEG. In some embodiments, the VH comprises a HC CDR3 comprising the amino acid sequence SWRRGIRGIGFDY. In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of GYTFTDYIVH. In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQHNEYPPT. In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of AGSTLQS. In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of KASKSINKYLA. In some embodiments, the moiety comprises: a HC CDR2 comprising the amino acid sequence of WINAYTGTPTYADDFEG, a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY, a HC CDR1 comprising the amino acid sequence of GYTFTDYIVH, a LC CDR3 comprising the amino acid sequence of QQHNEYPPT, a LC CDR2 comprising the amino acid sequence of AGSTLQS, and a LC CDR1 comprising the amino acid sequence of KASKSINKYLA.

[0017] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWINAYTG TPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK. In some embodiments, the VH comprises the amino acid sequence of QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWINAYTGWSGR Docket No.: 53676-780.601TPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises the amino acid sequence ofDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK.

[0018] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINAYTGT PTYADDFEGQFTFSLDASISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK. In some embodiments, the VH comprises the amino acid sequence ofELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINAYTGT PTYADDFEGQFTFSLDASISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises the amino acid sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK.

[0019] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceQVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINAYTG TPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK. In some embodiments, the VH comprises the amino acid sequence ofQVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINAYTG TPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises the amino acid sequence ofDIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK.

[0020] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINAYTGTWSGR Docket No.: 53676-780.601PTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK. In some embodiments, the VH comprises the amino acid sequence of EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINAYTGT PTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK.

[0021] In some embodiments, the agent comprising the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VL comprises: a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of AGSTLQS. In some embodiments, the VL comprises a LC CDR3 comprising the amino acid sequence of QQHNEYPPT. In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of KASKSINKYLA. In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SWRRGIRGIGFDY. In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence WINAYTGTPTYADDFEG. In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of GYTFTDYIVH. In some embodiments, the moiety comprises: a HC CDR2 comprising the amino acid sequence of WINAYTGTPTYADDFEG, a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY, a HC CDR1 comprising the amino acid sequence of GYTFTDYIVH, a LC CDR3 comprising the amino acid sequence of QQHNEYPPT, a LC CDR2 comprising the amino acid sequence of AGSTLQS, and a LC CDR1 comprising the amino acid sequence of KASKSINKYLA.

[0022] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWINAYTG TPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK. In someWSGR Docket No.: 53676-780.601 embodiments, the VH comprises the amino acid sequence of QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWINAYTG TPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises the amino acid sequence ofDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK.

[0023] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINAYTGT PTYADDFEGQFTFSLDASISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK. In some embodiments, the VH comprises the amino acid sequence ofELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINAYTGT PTYADDFEGQFTFSLDASISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises the amino acid sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK.

[0024] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceQVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINAYTG TPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK. In some embodiments, the VH comprises the amino acid sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINAYTGTPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises the amino acid sequence ofDIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK.WSGR Docket No.: 53676-780.601

[0025] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINAYTGT PTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK. In some embodiments, the VH comprises the amino acid sequence of EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINAYTGT PTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK.

[0026] In some embodiments, the agent comprising the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of YFDGYLDY. In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of GFTFSSFGMH. In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of YISSGSSNIQYADTMKG. In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQWSSNPLT. In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of SVSSSVSYVH. In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of LTFNLAS. In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of YFDGYLDY, a HC CDR2 comprising the amino acid sequence of YISSGSSNIQYADTMKG, a HC CDR1 comprising the amino acid sequence of GFTFSSFGMH, a LC CDR3 comprising the amino acid sequence of QQWSSNPLT, a LC CDR2 comprising the amino acid sequence of LTFNLAS, and a LC CDR1 comprising the amino acid sequence of SVSSSVSYVH.

[0027] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVESGGGL VQPGGSRKLSC VVSGFTFS SFGMHWVRQAPEKGLEWVAYIS SGS SNIQ YADTMKGRFTISRDNPKNTLFLQMTSLRSEDTAMYYCARYFDGYLDYWGQGTTLTVSS . In some embodiments, the VL comprises a sequence with at least 80% sequence identity to theWSGR Docket No.: 53676-780.601 sequenceQIVLTHSPTIMS ASPGEK VTMTC S VS S S VS YVHW YQQKPGS SPRLWIYLTFNL ASGVPGR FSGSGSGTSYSLSISSMEAEDAATYYCQQWSSNPLTFGAGTKLELK. In some embodiments, the VH comprises the amino acid sequence ofEVQLVESGGGL VQPGGSRKLSC VVSGFTFS SFGMHWVRQAPEKGLEWVAYIS SGS SNIQ YADTMKGRFTISRDNPKNTLFLQMTSLRSEDTAMYYCARYFDGYLDYWGQGTTLTVSS . In some embodiments, the VL comprises the amino acid sequence ofQIVLTHSPTIMS ASPGEK VTMTC S VS S S VS YVHW YQQKPGS SPRLWIYLTFNL ASGVPGR FSGSGSGTSYSLSISSMEAEDAATYYCQQWSSNPLTFGAGTKLELK.

[0028] In some embodiments, the agent comprising the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of YYRDDVNYAMDY. In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of GFNIKDTHMH. In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of RTDPASGDIKYDPKFQG. In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQYNTYPYT. In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of KASQNVGSNVA. In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of SSSFRYS. In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of YYRDDVNYAMDY, a HC CDR2 comprising the amino acid sequence of RTDPASGDIKYDPKFQG, a HC CDR1 comprising the amino acid sequence of GFNIKDTHMH, a LC CDR3 comprising the amino acid sequence of QQYNTYPYT, a LC CDR2 comprising the amino acid sequence of SSSFRYS, and a LC CDR1 comprising the amino acid sequence of KASQNVGSNVA.

[0029] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLQQSGAELVKPGASVKLSCTASGFNIKDTHMHWVKQRPEQGLEWIGRTDPASGDI KYDPKFQGKATITADTSSNTAYLHLSSLTSEDTAVYYCAHYYRDDVNYAMDYWGQGT SVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSQKFLSTSVGDRVSVTCKASQNVGSNVAWYQQKPGQSPKSLIYSSSFRYSGVP DRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNTYPYTFGGGTELEIR. In some embodiments, the VH comprises the amino acid sequence of EVQLQQSGAELVKPGASVKLSCTASGFNIKDTHMHWVKQRPEQGLEWIGRTDPASGDIWSGR Docket No.: 53676-780.601KYDPKFQGKATITADTSSNTAYLHLSSLTSEDTAVYYCAHYYRDDVNYAMDYWGQGT SVTVSS. In some embodiments, the VL comprises the amino acid sequence of DIVMTQSQKFLSTSVGDRVSVTCKASQNVGSNVAWYQQKPGQSPKSLIYSSSFRYSGVP DRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNTYPYTFGGGTELEIR.

[0030] In some aspects, the present disclosure provides a composition comprising a recombinant T cell receptor or a chimeric antigen receptor (CAR) comprising a moiety that binds to a TCR variable region, wherein the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH), wherein the VH comprises a heavy chain complementarity determining region 3 (HC CDR3) comprising an amino acid sequence as set forth in SEQ ID NOs: 4602 or 4615.

[0031] In some aspects, the present disclosure provides a composition comprising a recombinant T cell receptor or a chimeric antigen receptor (CAR) comprising a moiety that binds to a TCR variable region, wherein the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH), wherein the VH comprises a heavy chain complementarity determining region 2 (HC CDR2) comprising an amino acid sequence as set forth in SEQ ID NOs: 4601, 4614, or 4626.

[0032] In some aspects, the present disclosure provides a composition comprising a T cell comprising a recombinant T cell receptor or a chimeric antigen receptor (CAR), wherein the recombinant T cell receptor or the CAR comprises a moiety that binds to a TCR variable region, wherein the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH), wherein the VH comprises a heavy chain complementarity determining region 3 (HC CDR3) comprising an amino acid sequence as set forth in SEQ ID NOs: 4602 or 4615.

[0033] In some aspects, the present disclosure provides a composition comprising a T cell comprising a recombinant T cell receptor or a chimeric antigen receptor (CAR), wherein the recombinant T cell receptor or the CAR comprises a moiety that binds to a TCR variable region, wherein the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH), wherein the VH comprises a heavy chain complementarity determining region 2 (HC CDR2) comprising an amino acid sequence as set forth in SEQ ID NOs: 4601, 4614, or 4626.

[0034] In some embodiments, the recombinant T cell receptor or the CAR comprises an extracellular domain comprising the moiety that binds to the TCR variable region, a transmembrane domain; and an intracellular domain comprising a intracellular signaling domain. In some embodiments, the extracellular domain comprises a CD8 or CD28 extracellular domain. In some embodiments, the transmembrane domain comprises a CD8 or CD28 transmembraneWSGR Docket No.: 53676-780.601 domain. In some embodiments, the intracellular domain comprises a CD3 zeta intracellular signaling domain.

[0035] In some embodiments, the moiety that binds to the TCR variable region binds a TCRaV subfamily selected from the group consisting of: a TCRa VI subfamily, a TCRa V2 subfamily, a TCRa V3 subfamily, a TCRa V4, a TCRa V5 subfamily, a TCRa V6 subfamily, a TCRa V7 subfamily, a TCRa V8 subfamily, a TCRa V9 subfamily, a TCRa V10 subfamily, a TCRa V12 subfamily, a TCRa V13 subfamily, a TCRa V14 subfamily, a TCRa V16 subfamily, a TCRa VI 7 subfamily, a TCRa VI 8 subfamily, a TCRa VI 9 subfamily, a TCRa V20 subfamily, a TCRa V21 subfamily, a TCRa V22 subfamily, a TCRa V23 subfamily, a TCRa V24 subfamily, TCRa V25 subfamily, a TCRa V26 subfamily, a TCRa V27 subfamily, a TCRa V29 subfamily, a TCRa V30 subfamily, a TCRa V34 subfamily, a TCRa V35 subfamily, a TCRa V36 subfamily, a TCRa V38 subfamily, a TCRa V39 subfamily, a TCRa V40 subfamily, a TCRa V41 subfamily, a TCRP V2 subfamily, a TCRP V3 subfamily, a TCRP V4 subfamily, a TCRP V5 subfamily, a TCRP V6 subfamily, a TCRP V9 subfamily, a TCRP VI 0 subfamily, a TCRP VI 1 subfamily, a TCRP V12 subfamily, a TCRP V13 subfamily, a TCRP V16 subfamily, a TCRP VI 9 subfamily, a TCRP V21 subfamily, a TCRP V23 subfamily, a TCRP V27 subfamily, a TCRP V28 subfamily, TCRP V29 subfamily, and TCRP V30 subfamily, as well as family members of said subfamilies, and variants thereof.

[0036] In some aspects, the present disclosure provides a pharmaceutical composition comprising the composition described herein, and a pharmaceutically acceptable diluent, carrier, excipient, or stabilizer.

[0037] In some aspects, the present disclosure provides a method of treating a disease or condition, or reducing a risk of developing the disease or condition in a subject in need thereof comprising administering a therapeutically effective amount of the pharmaceutical composition described herein to the subject.

[0038] In some embodiments, the disease or condition is an autoimmune disease. In some embodiments, the autoimmune disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), coeliac disease (CD), ankylosing spondylitis (AS), Covid-induced multisystem inflammatory syndrome in children (MIS-C), primary Sjogren’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 cirrhosis, multiple sclerosis, Guillain-Barre syndrome and the AMAN (axonal & neuronal neuropathy), chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis, Tolosa-Hunt syndrome (THS), Devic’s disease (neuromyelitis optica), paraneoplastic cerebellardegeneration (PCD), Lambert-Eaton syndrome, psoriasis, scleroderma, CRESTWSGR Docket No.: 53676-780.601(calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome, dermatitis herpetiformis, dermatomyositis, bullous pemphigoid, cicatricial pemphigoid / benign mucosal pemphigoid, pemphigoid gestationis, rheumatoid arthritis (RA), psoriatic arthritis, relapsing polychondritis, chronic recurrent multifocal osteomyelitis (CRMO), vasculitis, Kawasaki disease, granulomatosis with polyangiitis (GPA), Behcet’s disease (vasculitis), Takayasu’s arteritis, polyarteritis nodosa, microscopic polyangiitis (MPA), leukocytoclastic vasculitis, Cogan’s syndrome, uveitis, peripheral uveitis (Pars planitis), scleritis, autoimmune inner ear disease (AIED), Crohn’s, ulcerative colitis (UC), Dressier’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 cicatricial pemphigoid, or Hashimoto’s thyroiditis.

[0039] In some embodiments: the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRa VI subfamily; the disease or condition is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V2 subfamily; the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V4 subfamily; the disease or condition is Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCRa V12 subfamily; the disease or condition is Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily; the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V20 subfamily; the disease or condition is ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily; the disease or condition is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V22 subfamily; the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V26 subfamily; the disease or condition is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V40 subfamily; the disease or condition is joint implant failure, and the moiety that binds to the TCR variable region binds to a TCRa V41 subfamily; the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily; the disease or condition is primary Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily; the disease or condition is amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily; the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily; the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily; the disease or condition isWSGR Docket No.: 53676-780.601 ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V10 subfamily; the disease or condition is COVID-induced multisystem inflammatory syndrome in children, and the moiety that binds to the TCR variable region binds to a TCRP VI 1 subfamily; the disease or condition is Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCRP V12 subfamily; the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP VI 0 subfamily; the disease or condition is Amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V23 subfamily; or the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V29 subfamily.

[0040] In some embodiments, the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRaVl-1 or TCRaVl-2. In some embodiments, the disease or condition is type I diabetes, and wherein the moiety that binds to the TCR variable region binds to TCRaV12-3. In some embodiments, the disease or condition is Sjogren's syndrome, and wherein the moiety that binds to the TCR variable region binds to TCRaV13-l or TCRaV13-2. In some embodiments, the disease or condition is celiac disease, and wherein the moiety that binds to the TCR variable region binds to TCRaV26-l or TCRaV26-2. In some embodiments, the disease or condition is primary Sjogren’s syndrome, and wherein the moiety that binds to the TCR variable region binds to TCRPV6-1, TCRPV6-2 / 3, or TCRPV6-5. In some embodiments, the disease or condition is amyotrophic lateral sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV7-1 or TCRPV7-8 / 9. In some embodiments, the disease or condition is celiac disease, and wherein the moiety that binds to the TCR variable region binds to TCRPV7-1 or TCRPV7-8 / 9. In some embodiments, the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV7-1 or TCRPV7-8 / 9. In some embodiments, the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRP VI 0-3. In some embodiments, the disease or condition is COVID-induced multisystem inflammatory syndrome, and wherein the moiety that binds to the TCR variable region binds to TCRPV11-2. In some embodiments, the subject is a child. In some embodiments, the disease or condition is type I diabetes, and wherein the moiety that binds to the TCR variable region binds to TCRPV12-3 / 4. In some embodiments, the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV20-1. In some embodiments, the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV29-1.WSGR Docket No.: 53676-780.601

[0041] In some embodiments, the method further comprises administering a second therapeutic agent or therapy to the subject. In some embodiments, the second therapeutic agent or therapy comprises a chemotherapeutic agent, a biologic agent, an immunosuppressive agent, or radiation. In some embodiments, the second therapeutic agent or therapy is administered in combination with the agent described herein, the composition described herein or the pharmaceutical composition described herein, sequentially, simultaneously, or concurrently.

[0042] In some aspects, the present disclosure provides a method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a composition, wherein the composition comprises an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI subfamily; the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V2 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V4 subfamily; the subject suffers from Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI 2 subfamily; the subject suffers from Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI 3 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V20 subfamily; the subject suffers from ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V21 subfamily; the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V22 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V26 subfamily; the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V40 subfamily; the subject suffers from joint implant failure, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V41 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V4 subfamily; the subject suffers from primary Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds toWSGR Docket No.: 53676-780.601 a TCR variable region in TCRP V6 subfamily; the subject suffers from amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily; the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily; the subject suffers from ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V9 subfamily; the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP VI 0 subfamily; the subject suffers from COVID-induced multisystem inflammatory syndrome in children, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP VI 1 subfamily; the subject suffers from Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V12 subfamily; the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP VI 0 subfamily; the subject suffers from Amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V23 subfamily; the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V29 subfamily; the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily; the disease or condition is acute anterior uveitis (UAA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; the disease or condition is psoriatic arthritis (PsA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; the disease or condition is type I narcolepsy, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily; the disease or condition is amyotrophic lateral sclerosis (ALS), and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily; or the disease or condition is UAA, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily.

[0043] In some aspects, the present disclosure provides a method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a composition, wherein the composition comprises an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein a concentration of the agent is at least about 0.001WSGR Docket No.: 53676-780.601 mg / ml, and wherein: the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI subfamily; the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V2 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V4 subfamily; the subject suffers from Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V12 subfamily; the subject suffers from Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI 3 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V20 subfamily; the subject suffers from ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V21 subfamily; the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V22 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V26 subfamily; the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V40 subfamily; the subject suffers from joint implant failure, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V41 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V4 subfamily; the subject suffers from primary Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V6 subfamily; the subject suffers from amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily; the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily; the subject suffers from ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V9 subfamily; the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP VI 0 subfamily; the subject suffers from COVID-induced multisystem inflammatory syndrome in children, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP VI 1 subfamily; the subject suffers from Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V12 subfamily; the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP VI 0 subfamily; the subject suffers fromWSGR Docket No.: 53676-780.601Amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V23 subfamily; the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V29 subfamily; the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily; the disease or condition is acute anterior uveitis (UAA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; the disease or condition is psoriatic arthritis (PsA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; the disease or condition is type I narcolepsy, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily; the disease or condition is amyotrophic lateral sclerosis (ALS), and the moiety that binds to the TCR variable region binds to a TCRa V13 subfamily; or the disease or condition is UAA, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily.

[0044] In some embodiments, the agent is present in the composition at a concentration of at least about 0.01 mg / ml. In some embodiments, the agent is present in the composition at a concentration of at least about 0.1 mg / ml. In some embodiments, the agent is present in the composition at a concentration of at least about 1.0 mg / ml.

[0045] In some aspects, the present disclosure provides a method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a composition, wherein the composition comprises an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the moiety binds to the TCR variable region with a KD of at most about 500 nM, and wherein: the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI subfamily; the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V2 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V4 subfamily; the subject suffers from Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V12 subfamily; the subject suffers from Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI 3 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V20 subfamily; the subject suffers from ankylosing spondylitis, and the moietyWSGR Docket No.: 53676-780.601 that binds to the TCR variable region binds to a TCR variable region in TCRa V21 subfamily; the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V22 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V26 subfamily; the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V40 subfamily; the subject suffers from joint implant failure, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V41 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V4 subfamily; the subject suffers from primary Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V6 subfamily; the subject suffers from amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily; the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily; the subject suffers from ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V9 subfamily; the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP VI 0 subfamily; the subject suffers from COVID-induced multisystem inflammatory syndrome in children, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP VI 1 subfamily; the subject suffers from Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V12 subfamily; the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP VI 0 subfamily; the subject suffers from Amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V23 subfamily; the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V29 subfamily; the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily; the disease or condition is acute anterior uveitis (UAA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; the disease or condition is psoriatic arthritis (PsA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; the disease or condition is type I narcolepsy, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily; the disease or condition is amyotrophic lateral sclerosis (ALS), and the moiety that binds to the TCR variable region binds to a TCRa VI 3WSGR Docket No.: 53676-780.601 subfamily; or the disease or condition is UAA, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily.

[0046] In some aspects, the present disclosure provides a method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a composition, wherein the composition comprises an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the moiety binds to the TCR variable region with a KD of at most about 500 nM, and wherein: the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI subfamily; the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V2 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V4 subfamily; the subject suffers from Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI 2 subfamily; the subject suffers from Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI 3 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V20 subfamily; the subject suffers from ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V21 subfamily; the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V22 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V26 subfamily; the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V40 subfamily; the subject suffers from joint implant failure, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V41 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V4 subfamily; the subject suffers from primary Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V6 subfamily; the subject suffers from amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily; the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily; the subject suffersWSGR Docket No.: 53676-780.601 from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily; the subject suffers from ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V9 subfamily; the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP VI 0 subfamily; the subject suffers from COVID-induced multisystem inflammatory syndrome in children, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP VI 1 subfamily; the subject suffers from Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V12 subfamily; the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP VI 0 subfamily; the subject suffers from Amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V23 subfamily; the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V29 subfamily; the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily; the disease or condition is acute anterior uveitis (UAA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; the disease or condition is psoriatic arthritis (PsA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; the disease or condition is type I narcolepsy, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily; the disease or condition is amyotrophic lateral sclerosis (ALS), and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily; or the disease or condition is UAA, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily.

[0047] In some embodiments, the moiety binds to the TCR variable region with a KD of at most about 100 nM. In some embodiments, the moiety binds to the TCR variable region with a KD of at most about 10 nM. In some embodiments, the moiety binds to the TCR variable region with a KD of at most about 1 nM.

[0048] In some embodiments, the method further comprises determining that the subject suffers from multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa VI subfamily, TCRP V7 subfamily, TCRP VI 0 subfamily, TCRP V20 subfamily or TCRP V29 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa VI subfamily, TCRP V7 subfamily, TCRP VI 0 subfamily, TCRP V20 subfamily or TCRP V29 subfamily.

[0049] In some embodiments, the method further comprises determining that the subject suffers from amyotrophic lateral sclerosis that is associated with a biased TCR clonotype that comprisesWSGR Docket No.: 53676-780.601 the TCR variable region in TCRP V7 subfamily, TCRa VI 3 subfamily, or TCRP V23 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V7 subfamily, TCRa VI 3 subfamily, or TCRP V23 subfamily. In some embodiments, the method further comprises determining that the subject suffers from celiac disease that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily.

[0050] In some embodiments, the method further comprises determining that the subject suffers from ankylosing spondylitis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V21 subfamily or TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V21 subfamily or TCRP V9 subfamily. In some embodiments, the method further comprises determining that the subject suffers from COVID-induced multisystem inflammatory syndrome in children that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP VI 1 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP VI 1 subfamily. In some embodiments, the method further comprises determining that the subject suffers from primary Sjogren’s syndrome that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V6 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V6 subfamily. In some embodiments, the method further comprises determining that the subject suffers from Type I diabetes that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V12 subfamily or TCRP V12 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V12 subfamily or TCRP V12 subfamily. In some embodiments, the method further comprises determining that the subject suffers from acute anterior uveitis (UAA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily or TCRa V21 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily or TCRa V21 subfamily. In some embodiments, the method further comprises determining that the subject suffers from psoriatic arthritis (PsA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily. In some embodiments, the method further comprises determining that the subject suffers from type I narcolepsy that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V4WSGR Docket No.: 53676-780.601 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V4 subfamily.

[0051] In some embodiments, the agent comprises an antibody molecule or antigen binding fragment thereof. In some embodiments, the antibody molecule comprises an Fc region. In some embodiments, the Fc region comprises a binding mutation. In some embodiments, the agent is functionally linked to a cytotoxic agent. In some embodiments, the cytotoxic agent comprises calicheamicin, monomethyl auristatin E, maytansine derivative, or exatecan derivative. In some embodiments, the Fc region comprises no mutation that affects binding of the Fc region to a Fc receptor. In some embodiments, the cytotoxic agent mediates killing of the autoreactive T cells in the subject. In some embodiments, the Fc region comprises an amino acid mutation that enhances an effector function. In some embodiments, the effector function comprises antibody dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement dependent cytotoxicity (CDC). In some embodiments, the effector function mediates killing of the autoreactive T cells in the subject.

[0052] In some embodiments, the agent comprises an another moiety. In some embodiments, the another moiety comprises aNK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In some embodiments, the another moiety comprises the NK cell engager, and wherein 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. In some embodiments, binding of the another moiety to NKp30 activates an NK cell and mediates killing of the autoreactive T cells in the subject. In some embodiments, the another moiety comprises the NK cell engager, and wherein the NK cell engager binds to a KIR receptor and / or CD94-NKG2A.In some embodiments, binding of the another moiety to the KIR receptor and / or CD94-NKG2A disinhibits an NK cell and mediates killing of the autoreactive T cells in the subject. In some embodiments, the another moiety comprises the T cell engager, and wherein the T cell engager binds to an antigen expressed on a CD8+ and / or CD4+ T cell. In some embodiments, the another moiety comprises the T cell engager, and wherein the T cell engager binds to a TCRaV or a TCRPV. In some embodiments, the TCRaV or the TCRPV that the T cell engager binds to is different from the TCR variable region that the moiety of the agent binds to.

[0053] In some embodiments, the another moiety that binds to the TCRaV or a TCRPV binds a TCRaV in a subfamily selected from the group consisting of: TCRa VI subfamily, TCRa V2 subfamily, TCRa V3 subfamily, TCRa V4, TCRa V5 subfamily, TCRa V6 subfamily, TCRa V7WSGR Docket No.: 53676-780.601 subfamily, TCRa V8 subfamily, TCRa V9 subfamily, TCRa V10 subfamily, TCRa V12 subfamily, TCRa V13 subfamily, TCRa V14 subfamily, TCRa V16 subfamily, TCRa V17 subfamily, TCRa VI 8 subfamily, TCRa VI 9 subfamily, TCRa V20 subfamily, TCRa V21 subfamily, TCRa V22 subfamily, TCRa V23 subfamily, TCRa V24 subfamily, TCRa V25 subfamily, TCRa V26 subfamily, TCRa V27 subfamily, TCRa V29 subfamily, TCRa V3O subfamily, TCRa V34 subfamily, TCRa V35 subfamily, TCRa V36 subfamily, TCRa V38 subfamily, TCRa V39 subfamily, TCRa V40 subfamily, and TCRa V41 subfamily, as well as family members of the subfamilies, and variants thereof. In some embodiments, the another moiety that binds to the TCRaV or the TCRPV binds to a TCRPV in a subfamily selected from the group consisting of: TCRP V2 subfamily, TCRP V3 subfamily, TCRP V4 subfamily, TCRP V5 subfamily, TCRP V6 subfamily, TCRP V9 subfamily, TCRP V10 subfamily, TCRP VI 1 subfamily, TCRP V12 subfamily, TCRP V13 subfamily, TCRP V16 subfamily, TCRP V19 subfamily, TCRP V21 subfamily, TCRP V23 subfamily, TCRP V27 subfamily, TCRP V28 subfamily, TCRP V29 subfamily, and TCRP V30 subfamily, as well as family members of the subfamilies, and variants thereof.

[0054] In some embodiments, the another moiety comprises the T cell engager, and wherein the T cell engager binds to CD3. In some embodiments, binding of the T cell engager to the CD8+ and / or CD4+ T cell mediates killing of the autoreactive T cells in the subject.

[0055] In some embodiments, the subject suffers from multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRaVl-1 or TCRaVl-2 family. In some embodiments, the subject suffers from type I diabetes, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRaV12- 3 family. In some embodiments, the subject suffers from Sjogren's syndrome, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRaV13-l or TCRaV13-2 family. In some embodiments, the subject suffers from celiac disease, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRaV26- 1 or TCRaV26-2 family. In some embodiments, the subject suffers from primary Sjogren’s syndrome, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRPV6-1, TCRPV6-2 / 3, or TCRPV6-5 family. In some embodiments, the subject suffers from amyotrophic lateral sclerosis, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRPV7-1 or TCRPV7-8 / 9 family. In some embodiments, the subject suffers from celiac disease, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRPV7-1 or TCRPV7-8 / 9 family. In some embodiments, the subject suffers from multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRPV7-1 or TCRPV7-8 / 9WSGR Docket No.: 53676-780.601 family. In some embodiments, the subject suffers from multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRpV10-3 family. In some embodiments, the subject suffers from COVID-induced multisystem inflammatory syndrome, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRPV11-2 family. In some embodiments, the subject is a child. In some embodiments, the subject suffers from type I diabetes, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRPV12-3 / 4 family. In some embodiments, the subject suffers from multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRPV20-1 family. In some embodiments, the subject suffers from multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRPV29-1 family.

[0056] In some aspects, the present disclosure provides a method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRpV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRa VI subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRa VI subfamily, the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP V7 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP V7 subfamily, the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP V6 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP V6 subfamily, the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP VI 0 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP V10 subfamily, the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCRWSGR Docket No.: 53676-780.601 variable region in a TCRP V20 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP V20 subfamily, or the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP V29 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP V29 subfamily, and wherein the moiety does not bind to a different TCRaV and / or TCRPV subfamily.

[0057] In some aspects, the present disclosure provides a method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRa VI subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRa VI subfamily, the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP V7 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP V7 subfamily, the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP V6 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP V6 subfamily, the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP VI 0 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP VI 0 subfamily, the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP V20 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP V20 subfamily, or the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP V29 subfamily, and wherein the moiety that binds to the TCR variable region binds toWSGR Docket No.: 53676-780.601 the TCR variable region in the TCRP V29 subfamily, and wherein the moiety does not bind to a different TCRaV and / or TCRPV subfamily.

[0058] In some aspects, the present disclosure provides a method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having amyotrophic lateral sclerosis or a symptom of amyotrophic lateral sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V7 subfamily, TCRP V13 subfamily, or TCRP V23 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V7 subfamily, TCRP VI 3 subfamily, or TCRP V23 subfamily, or the subject is identified as having amyotrophic lateral sclerosis or a symptom of amyotrophic lateral sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V7 subfamily, TCRP V13 subfamily, or TCRP V23 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V7 subfamily, TCRP VI 3 subfamily, or TCRP V23 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

[0059] In some aspects, the present disclosure provides a method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having amyotrophic lateral sclerosis or a symptom of amyotrophic lateral sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V7 subfamily, TCRP VI 3 subfamily, or TCRP V23 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V7 subfamily, TCRP V13 subfamily, or TCRP V23 subfamily, or the subject is identified as having amyotrophic lateral sclerosis or a symptom of amyotrophic lateral sclerosis that is associatedWSGR Docket No.: 53676-780.601 with a biased TCR clonotype that comprises the TCR variable region in TCRP V7 subfamily, TCRP VI 3 subfamily, or TCRP V23 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V7 subfamily, TCRP VI 3 subfamily, or TCRP V23 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

[0060] In some aspects, the present disclosure provides a method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having celiac disease or a symptom of celiac disease that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, or the subject is identified as having celiac disease or a symptom of celiac disease that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

[0061] In some aspects, the present disclosure provides a method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having celiac disease or a symptom of celiac disease that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V26 subfamily,WSGR Docket No.: 53676-780.601TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, or the subject is identified as having celiac disease or a symptom of celiac disease that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

[0062] In some aspects, the present disclosure provides a method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having ankylosing spondylitis or a symptom of ankylosing spondylitis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V21 subfamily or TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V21 subfamily or TCRP V9 subfamily, or the subject is identified as having ankylosing spondylitis or a symptom of ankylosing spondylitis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V21 subfamily or TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V21 subfamily or TCRP V9 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

[0063] In some aspects, the present disclosure provides a method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: theWSGR Docket No.: 53676-780.601 subject is identified as having ankylosing spondylitis or a symptom of ankylosing spondylitis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V21 subfamily or TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V21 subfamily or TCRP V9 subfamily, or the subject is identified as having ankylosing spondylitis or a symptom of ankylosing spondylitis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V21 subfamily or TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V21 subfamily or TCRP V9 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

[0064] In some aspects, the present disclosure provides a method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having COVID- induced multisystem inflammatory syndrome in children or a symptom of COVID-induced multisystem inflammatory syndrome in children that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP VI 1 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP VI 1 subfamily, or the subject is identified as having COVID-induced multisystem inflammatory syndrome in children or a symptom of COVID-induced multisystem inflammatory syndrome in children that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP VI 1 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP VI 1 subfamily , and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

[0065] In some aspects, the present disclosure provides a method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / orWSGR Docket No.: 53676-780.601TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having COVID-induced multisystem inflammatory syndrome in children or a symptom of COVID-induced multisystem inflammatory syndrome in children that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP VI 1 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP VI 1 subfamily, or the subject is identified as having COVID-induced multisystem inflammatory syndrome in children or a symptom of COVID-induced multisystem inflammatory syndrome in children that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP VI 1 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP VI 1 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

[0066] In some aspects, the present disclosure provides a method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having primary Sjogren’s syndrome or a symptom of primary Sjogren’s syndrome that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V6 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V6 subfamily, or the subject is identified as having primary Sjogren’s syndrome or a symptom of primary Sjogren’s syndrome that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V6 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V6 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

[0067] In some aspects, the present disclosure provides a method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / orWSGR Docket No.: 53676-780.601TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having primary Sjogren’s syndrome or a symptom of primary Sjogren’s syndrome that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V6 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V6 subfamily, or the subject is identified as having primary Sjogren’s syndrome or a symptom of primary Sjogren’s syndrome that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V6 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V6 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

[0068] In some aspects, the present disclosure provides a method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having Type I diabetes or a symptom Type I diabetes that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V12 subfamily or TCRa V12 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V12 subfamily or TCRa V12 subfamily, or the subject is identified as having Type I diabetes or a symptom Type I diabetes that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V12 subfamily or TCRa V12 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V12 subfamily or TCRa V12 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

[0069] In some aspects, the present disclosure provides a method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / orWSGR Docket No.: 53676-780.601TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having Type I diabetes or a symptom Type I diabetes that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V12 subfamily or TCRa V12 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V12 subfamily or TCRa V12 subfamily, or the subject is identified as having Type I diabetes or a symptom Type I diabetes that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V12 subfamily or TCRa V12 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V12 subfamily or TCRa V12 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

[0070] In some aspects, the present disclosure provides a method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having acute anterior uveitis (UAA) or a symptom of acute anterior uveitis (UAA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily or TCRa V21 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily or TCRa V21 subfamily, or the subject is identified as having acute anterior uveitis (UAA) or a symptom of acute anterior uveitis (UAA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily or TCRa V21 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily or TCRa V21 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

[0071] In some aspects, the present disclosure provides a method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / orWSGR Docket No.: 53676-780.601TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having acute anterior uveitis (UAA) or a symptom of acute anterior uveitis (UAA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily or TCRa V21 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily or TCRa V21 subfamily, or the subject is identified as having acute anterior uveitis (UAA) or a symptom of acute anterior uveitis (UAA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily or TCRa V21 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily or TCRa V21 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

[0072] In some aspects, the present disclosure provides a method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having psoriatic arthritis (PsA) or a symptom of psoriatic arthritis (PsA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily, or the subject is identified as having psoriatic arthritis (PsA) or a symptom of psoriatic arthritis (PsA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily, and wherein the moiety does not bind to any other different TCRPV subfamily.

[0073] In some aspects, the present disclosure provides a method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / orWSGR Docket No.: 53676-780.601TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having psoriatic arthritis (PsA) or a symptom of psoriatic arthritis (PsA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily, or the subject is identified as having psoriatic arthritis (PsA) or a symptom of psoriatic arthritis (PsA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily, and wherein the moiety does not bind to any other different TCRPV subfamily.

[0074] In some aspects, the present disclosure provides a method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having type I narcolepsy or a symptom of type I narcolepsy that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V4 subfamily, or the subject is identified as having type I narcolepsy or a symptom of type I narcolepsy that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V4 subfamily, and wherein the moiety does not bind to any other different TCRPV subfamily.

[0075] In some aspects, the present disclosure provides a method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein a concentration of the agent is at least about 0.001 mg / ml, and wherein: the subject is identified as having type I narcolepsy or a symptom of type I narcolepsy that isWSGR Docket No.: 53676-780.601 associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V4 subfamily, or the subject is identified as having type I narcolepsy or a symptom of type I narcolepsy that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V4 subfamily, and wherein the moiety does not bind to any other different TCRPV subfamily.

[0076] In some embodiments, the agent is present in the composition at a concentration of at least about 0.01 mg / ml. In some embodiments, the agent is present in the composition at a concentration of at least about 0.1 mg / ml. In some embodiments, the agent is present in the composition at a concentration of at least about 1.0 mg / ml.

[0077] In some aspects, the present disclosure provides an agent comprising a moiety that binds to a TCR variable region comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of WINAYTGTPTYADDFEG.

[0078] In some embodiments, the VH comprises a HC CDR3 comprising the amino acid sequence SWRRGIRGIGFDY. In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of GYTFTDYIVH. In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQHNEYPPT. In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of AGSTLQS. In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of KASKSINKYLA.

[0079] In some embodiments, the moiety comprises: a HC CDR2 comprising the amino acid sequence of WINAYTGTPTYADDFEG, a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY, a HC CDR1 comprising the amino acid sequence of GYTFTDYIVH, a LC CDR3 comprising the amino acid sequence of QQHNEYPPT, a LC CDR2 comprising the amino acid sequence of AGSTLQS, and a LC CDR1 comprising the amino acid sequence of KASKSINKYLA.

[0080] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWINAYTG TPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLQSGVPWSGR Docket No.: 53676-780.601DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK. In some embodiments, the VH comprises the amino acid sequence of QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWINAYTG TPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises the amino acid sequence ofDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK.

[0081] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINAYTGT PTYADDFEGQFTFSLDASISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK. In some embodiments, the VH comprises the amino acid sequence ofELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINAYTGT PTYADDFEGQFTFSLDASISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises the amino acid sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK.

[0082] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceQVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINAYTG TPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK. In some embodiments, the VH comprises the amino acid sequence ofQVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINAYTG TPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises the amino acid sequence ofDIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK.WSGR Docket No.: 53676-780.601

[0083] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINAYTGT PTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK. In some embodiments, the VH comprises the amino acid sequence of EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINAYTGT PTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK.

[0084] In some aspects, the present disclosure provides an agent comprising a moiety that binds to a TCR variable region comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VL comprises: a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of AGSTLQS.

[0085] In some embodiments, the VL comprises a LC CDR3 comprising the amino acid sequence of QQHNEYPPT. In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of KASKSINKYLA. In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SWRRGIRGIGFDY. In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence WINAYTGTPTYADDFEG. In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of GYTFTDYIVH.

[0086] In some embodiments, the moiety comprises: a HC CDR2 comprising the amino acid sequence of WINAYTGTPTYADDFEG, a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY, a HC CDR1 comprising the amino acid sequence of GYTFTDYIVH, a LC CDR3 comprising the amino acid sequence of QQHNEYPPT, a LC CDR2 comprising the amino acid sequence of AGSTLQS, and a LC CDR1 comprising the amino acid sequence of KASKSINKYLA.

[0087] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWINAYTG TPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQGWSGR Docket No.: 53676-780.601TMVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK. In some embodiments, the VH comprises the amino acid sequence ofQLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWINAYTG TPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises the amino acid sequence ofDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK.

[0088] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINAYTGT PTYADDFEGQFTFSLDASISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK. In some embodiments, the VH comprises the amino acid sequence ofELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINAYTGT PTYADDFEGQFTFSLDASISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises the amino acid sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK.

[0089] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceQVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINAYTG TPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK. In some embodiments, the VH comprises the amino acid sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINAYTGTPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQGWSGR Docket No.: 53676-780.601TMVTVSS. In some embodiments, the VL comprises the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK.

[0090] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINAYTGT PTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK. In some embodiments, the VH comprises the amino acid sequence of EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINAYTGT PTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS. In some embodiments, the VL comprises the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK.

[0091] In some aspects, the present disclosure provides an agent comprising a moiety that binds to a TCR variable region comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of YFDGYLDY.

[0092] In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of GFTFSSFGMH. In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of YISSGSSNIQYADTMKG. In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQWSSNPLT. In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of SVSSSVSYVH. In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of LTFNLAS.

[0093] In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of YFDGYLDY, a HC CDR2 comprising the amino acid sequence of YISSGSSNIQYADTMKG, a HC CDR1 comprising the amino acid sequence of GFTFSSFGMH, a LC CDR3 comprising the amino acid sequence of QQWSSNPLT, a LC CDR2 comprising the amino acid sequence of LTFNLAS, and a LC CDR1 comprising the amino acid sequence of SVSSSVSYVH.WSGR Docket No.: 53676-780.601

[0094] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVESGGGL VQPGGSRKLSC VVSGFTFS SFGMHWVRQAPEKGLEWVAYIS SGS SNIQ YADTMKGRFTISRDNPKNTLFLQMTSLRSEDTAMYYCARYFDGYLDYWGQGTTLTVSS . In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceQIVLTHSPTIMS ASPGEK VTMTC S VS S S VS YVHW YQQKPGS SPRLWIYLTFNL ASGVPGR FSGSGSGTSYSLSISSMEAEDAATYYCQQWSSNPLTFGAGTKLELK. In some embodiments, the VH comprises the amino acid sequence ofEVQLVESGGGL VQPGGSRKLSC VVSGFTFS SFGMHWVRQAPEKGLEWVAYIS SGS SNIQ YADTMKGRFTISRDNPKNTLFLQMTSLRSEDTAMYYCARYFDGYLDYWGQGTTLTVSS . In some embodiments, the VL comprises the amino acid sequence ofQIVLTHSPTIMS ASPGEK VTMTC S VS S S VS YVHW YQQKPGS SPRLWIYLTFNL ASGVPGR FSGSGSGTSYSLSISSMEAEDAATYYCQQWSSNPLTFGAGTKLELK.

[0095] In some aspects, the present disclosure provides an agent comprising a moiety that binds to a TCR variable region comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of YYRDDVNYAMDY.

[0096] In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of GFNIKDTHMH. In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of RTDPASGDIKYDPKFQG. In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQYNTYPYT. In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of KASQNVGSNVA. In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of SSSFRYS.

[0097] In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of YYRDDVNYAMDY, a HC CDR2 comprising the amino acid sequence of RTDPASGDIKYDPKFQG, a HC CDR1 comprising the amino acid sequence of GFNIKDTHMH, a LC CDR3 comprising the amino acid sequence of QQYNTYPYT, a LC CDR2 comprising the amino acid sequence of SSSFRYS, and a LC CDR1 comprising the amino acid sequence of KASQNVGSNVA.

[0098] In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLQQSGAELVKPGASVKLSCTASGFNIKDTHMHWVKQRPEQGLEWIGRTDPASGDI KYDPKFQGKATITADTSSNTAYLHLSSLTSEDTAVYYCAHYYRDDVNYAMDYWGQGTWSGR Docket No.: 53676-780.601SVTVSS. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSQKFLSTSVGDRVSVTCKASQNVGSNVAWYQQKPGQSPKSLIYSSSFRYSGVP DRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNTYPYTFGGGTELEIR. In some embodiments, the VH comprises the amino acid sequence of EVQLQQSGAELVKPGASVKLSCTASGFNIKDTHMHWVKQRPEQGLEWIGRTDPASGDI KYDPKFQGKATITADTSSNTAYLHLSSLTSEDTAVYYCAHYYRDDVNYAMDYWGQGT SVTVSS. In some embodiments, the VL comprises the amino acid sequence of DIVMTQSQKFLSTSVGDRVSVTCKASQNVGSNVAWYQQKPGQSPKSLIYSSSFRYSGVP DRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNTYPYTFGGGTELEIR.

[0099] In some embodiments, the moiety comprises an antibody molecule or antigen binding fragment thereof. In some embodiments, the antigen binding fragment thereof comprises a Fab, F(ab')2, Fv, a single chain Fv fragment, a single domain antibody, a diabody (dAb), a bivalent antibody, or bispecific antibody or fragment thereof, a single domain variant thereof, or a camelid antibody.

[0100] In some embodiments, the agent further comprises an Fc region. In some embodiments, the Fc region comprises one or more mutations. In some embodiments, the Fc region comprises an amino acid sequence with at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 or 42. In some embodiments, the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. In some embodiments, the Fc comprises one or more mutations comprising E233P, L234V, L235A, P329A, S267K, G237A, P238S, H268A, A330S, P331S, K322A, D265A, D265S, L235E, G236R, S239K, A327G, V273E, T299A, Y300S, or any combination thereof, where amino acid positioning is relative to SEQ ID NO: 42. In some embodiments, the Fc region comprises an Fc- silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function. In some embodiments, the Fc-silencing mutation comprises N297A of a sequence of SEQ ID NO: 42.

[0101] In some embodiments, the Fc region comprises no mutation.

[0102] In some embodiments, the agent is functionally linked to a cytotoxic agent. In some embodiments, the cytotoxic agent comprises calicheamicin, monomethyl auristatin E, maytansine derivative, or exatecan derivative. In some embodiments, the cytotoxic agent mediates killing of the autoreactive T cells in the subject. In some embodiments, the Fc region has enhanced effector function. In some embodiments, the enhanced effector function comprises antibody dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellularWSGR Docket No.: 53676-780.601 phagocytosis (ADCP) or complement dependent cytotoxicity (CDC). In some embodiments, the enhanced effector function mediates killing of the autoreactive T cells in a subject in need thereof.

[0103] In some embodiments, the agent comprises a second moiety. In some embodiments, the second moiety comprises aNK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In some embodiments, the second moiety comprises the NK cell engager, and wherein the NK cell engager binds to NKp30. In some embodiments, binding of the second moiety to NKp30 mediates killing of autoreactive T cells in a subject.

[0104] In some embodiments, the NK cell engager comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) the VH comprises a heavy chain complementarity determining region 1 (HC CDR1), HC CDR 2, and HC CDR 3 comprising: (i) an amino acid sequence of SEQ ID NOs: 6000, 6001, and 6003, respectively; (ii) an amino acid sequence of SEQ ID NOs: 6007, 6008, and 6009, respectively; (iii) an amino acid sequence of SEQ ID NOs: 7313, 6001, and 6002, respectively; (iv) an amino acid sequence of SEQ ID NOs: 7313, 6008, and 6009, respectively; (v) an amino acid sequence of SEQ ID NOs: 7313, 7385, and 7315, respectively; (vi) an amino acid sequence of SEQ ID NOs: 7313, 7318, and 6009, respectively; (vii) an amino acid sequence of SEQ ID NOs: 7313, 6001, and 7315, respectively; or (viii) an amino acid sequence of SEQ ID NOs: 7383, 7380, and 7352, respectively; and / or (b) the VL comprises a light chain complementarity determining region (LC CDR1), LC CDR2, and LC CDR3 comprising: (i) an amino acid sequence of SEQ ID NOs: 6063, 6064, and 67293, respectively; (ii) an amino acid sequence of SEQ ID NOs: 6070, 6071, and 6072, respectively; (iii) an amino acid sequence of SEQ ID NOs: 6070, 6064, and 7321, respectively; or (iv) an amino acid sequence of SEQ ID NOs: 7326, 7327, and 7329, respectively.

[0105] In some embodiments, the VH comprises a sequence with 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 6121-6134, 7295, 7297, 7298, 7300-7304, and 7384; and / or the VL comprises a sequence with 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 6136-6147, 7294, 7296, 7299, and 7305-7309. In some embodiments, the VH comprises an amino acid sequence of any one of SEQ ID NOs: 6121- 6134, 7295, 7297, 7298, 7300-7304, and 7384; and / or the VL comprises an amino acid sequence of any one of SEQ ID NOs: 6136-6147, 7294, 7296, 7299, and 7305-7309. In some embodiments, the NK cell engager that binds to NKp30 comprises an amino acid sequence as set forth in SEQ ID NO: 7310, 7311, 7400, 7401, 7402, 7403, 7404, 7405, 7406, 7407, or 7369.

[0106] In some embodiments, the second moiety comprises the T cell engager, and wherein said T cell engager binds to an antigen expressed on a CD8+ and / or CD4+ T cell. In some embodiments, the second moiety comprises the T cell engager, and wherein said T cell engagerWSGR Docket No.: 53676-780.601 binds to a TCRaV or a TCRPV. In some embodiments, the TCRaV or the TCRPV comprises a different TCRaV or a TCRPV from the TCR variable region that the moiety of the agent binds to. In some embodiments, the second moiety comprises the T cell engager, and wherein said T cell engager binds to CD3. In some embodiments, binding of the T cell engager to a CD8+ and / or CD4+ T cell mediates killing of autoreactive T cells in a subject.

[0107] In some embodiments, the agent binds to a NK cell with a KD of at most about 100 nM. In some embodiments, the agent binds to a NK cell with a KD of at most about 10 nM. In some embodiments, the agent comprising the NK cell engager binds to a NK cell with a KD of at least 0.5-fold lower than that of an otherwise identical agent that does not comprise the NK cell engager. In some embodiments, the agent binds to a T cell with a KD of at most about 100 nM. In some embodiments, the agent binds to a T cell with a KD of at most about 10 nM.

[0108] In some aspects, the present disclosure provides a multispecific molecule comprising: a first agent comprising a moiety that binds to a TCR variable region comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of WINAYTGTPTYADDFEG; and a second agent comprising a NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, a macrophage cell engager, or any combination thereof.

[0109] In some aspects, the present disclosure provides a multispecific molecule comprising: a first agent comprising a moiety that binds to a TCR variable region comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of YFDGYLDY or YYRDDVNYAMDY; and a second agent comprising a NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, a macrophage cell engager, or any combination thereof.

[0110] In some aspects, the present disclosure provides a multispecific molecule comprising: a first agent comprising a moiety that binds to a TCR variable region comprising a binding domain that binds to a TCRP or a TCRVa of a T cell with a KD of less than about 10 nM; and a second agent comprising a NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, a macrophage cell engager, or any combination thereof.[oni] In some embodiments, the multispecific molecule further comprises an Fc region comprising one or more Fc subunits. In some embodiments, the multispecific molecules comprises a first Fc subunit operably linked to the first agent and a second Fc subunit operably linked to the second agent. In some embodiments, the one or more Fc subunits comprise one or more mutations. In some embodiments, the Fc region comprises an amino acid sequence with atWSGR Docket No.: 53676-780.601 least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 41, 42, 3645, 4652, or 4655. In some embodiments, the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. In some embodiments, the Fc region comprises an Fc-silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function. In some embodiments, the Fc- silencing mutation comprises N297A of a sequence of SEQ ID NO: 42.

[0112] In some embodiments, the Fc region comprising no mutation.

[0113] In some embodiments, the multispecific molecule is functionally linked to a cytotoxic agent. In some embodiments, the cytotoxic agent comprises calicheamicin, monomethyl auristatin E, maytansine derivative, or exatecan derivative. In some embodiments, the cytotoxic agent mediates killing of the autoreactive T cells in the subject. In some embodiments, the Fc region has enhanced effector function. In some embodiments, the enhanced effector function comprises antibody dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement dependent cytotoxicity (CDC). In some embodiments, the enhanced effector function mediates killing of the autoreactive T cells in a subject in need thereof.

[0114] In some embodiments, the first Fc subunit comprises one or more mutations and the second Fc subunit comprises no mutation. In some embodiments, the first Fc subunit comprises no mutation and the second Fc subunit comprises one or more mutations.

[0115] In some embodiments, the multispecific molecule comprises the NK cell engager, and wherein the NK cell engager binds to NKp30. In some embodiments, the multispecific molecule binds to a NK cell with a KD of at least about 0.5-fold lower than that of an otherwise identical multispecific molecule that does not comprise the NK cell engager.

[0116] In some aspects, the present disclosure provides a polynucleotide encoding the agent described herein or the multispecific molecule described herein.

[0117] In some aspects, the present disclosure provides a polynucleotide encoding the heavy chain variable region (VH) and / or the light chain variable region (VL) of the agent described herein or the multispecific molecule described herein.

[0118] In some aspects, the present disclosure provides a vector comprising the polynucleotide described herein.

[0119] In some embodiments, the vector is a viral vector. In some embodiments, the viral vector is an adenoviral vector, lentiviral vector, retroviral vector, or adeno-associated viral vector.

[0120] In some aspects, the present disclosure provides a host cell comprising: the polynucleotide described herein; the vector described herein; a first polynucleotide encoding theWSGR Docket No.: 53676-780.601VH of the agent described herein or the multispecific molecule described herein, and a second polynucleotide encoding the VL of the agent described herein or the multispecific molecule described herein; or a first vector comprising a first polynucleotide encoding a VH of the agent described herein or the multispecific molecule described herein, and a second vector comprising a second polynucleotide encoding the VL of the agent described herein or the multispecific molecule described herein.

[0121] In some aspects, the present disclosure provides a pharmaceutical composition comprising the agent described herein or the multispecific molecule described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0122] In some aspects, the present disclosure provides a method of producing the agent described herein or the multispecific molecule described herein, the method comprising culturing the host cell described herein under suitable conditions to express the polynucleotide or the first polynucleotide and the second polynucleotide and to produce the agent or multispecific molecule.

[0123] In some aspects, the present disclosure provides a method of targeting a cell in a subject in need thereof, the method comprising administering to the subject the agent described herein, the multispecific molecule described herein, the polynucleotide described herein, the vector described herein, or the pharmaceutical composition described herein.

[0124] In some aspects, the present disclosure provides a composition for use in the manufacture of a medicament for treating a subject in need thereof, comprising the agent described herein, the multispecific molecule described herein, the polynucleotide described herein, or the vector described herein.

[0125] In some aspects, the present disclosure provides a method of treating a disease or condition or reducing a risk of developing the disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the agent described herein, the multispecific molecule described herein, the polynucleotide described herein, the vector described herein, or the pharmaceutical composition described herein.

[0126] In some embodiments, the subject has an autoimmune disease. In some embodiments, the autoimmune disease is selected from the group consisting of the autoimmune disease is selected from amyotrophic lateral sclerosis (ALS), coeliac disease (CD), ankylosing spondylitis (AS), Covid-induced multisystem inflammatory syndrome in children (MIS-C), type 1 narcolepsy, primary Sjogren’s syndrome (PSS), Churg-Strauss syndrome, sarcoidosis, systemic lupus erythematosus (SLE), type 1 diabetes, autoimmune hepatitis (e.g., type 1 or type 2), acute anterior uveitis (UAA), primary sclerosing cholangitis, primary biliary cirrhosis, multiple sclerosis, Guillain-Barre syndrome and the AMAN (axonal & neuronal neuropathy), chronicWSGR Docket No.: 53676-780.601 inflammatory demyelinating polyneuropathy (CIDP), psoriatic arthritis (PsA), transverse myelitis, Tolosa-Hunt syndrome (THS), Devic’s disease (neuromyelitis optica), paraneoplastic cerebellardegeneration (PCD), Lambert-Eaton syndrome, psoriasis, scleroderma, CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome, dermatitis herpetiformis, dermatomyositis, bullous pemphigoid, cicatricial pemphigoid / benign mucosal pemphigoid, pemphigoid gestationis, rheumatoid arthritis (RA), psoriatic arthritis, relapsing polychondritis, chronic recurrent multifocal osteomyelitis (CRMO), vasculitis, Kawasaki disease, granulomatosis with polyangiitis (GPA), Behcet’s disease (vasculitis), Takayasu’s arteritis, polyarteritis nodosa, microscopic polyangiitis (MPA), leukocytoclastic vasculitis, Cogan’s syndrome, uveitis, peripheral uveitis (Pars planitis), scleritis, autoimmune inner ear disease (AIED), Crohn’s, ulcerative colitis (UC), Dressier’s syndrome, Rheumatic fever, Evans syndrome, paroxysmal nocturnal hemoglobinuria (PNH), hemolytic anemia, thrombocytopenic purpura (TTP), polymyositis, juvenile myositis (JM), juvenile dermatomyositis (JDM), juvenile polymyositis (JPM), ocular cicatricial pemphigoid, and Hashimoto’s thyroiditis.

[0127] In some embodiments: the autoimmune disease is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRa VI subfamily; the autoimmune disease is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V2 subfamily; the autoimmune disease is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V4 subfamily; the autoimmune disease is Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCRa V12 subfamily; the autoimmune disease is Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily; the autoimmune disease is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V20 subfamily; the autoimmune disease is ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily; the autoimmune disease is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V22 subfamily; the autoimmune disease is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V26 subfamily; the autoimmune disease is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V40 subfamily; the autoimmune disease is joint implant failure, and the moiety that binds to the TCR variable region binds to a TCRa V41 subfamily; the autoimmune disease is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily; the autoimmune disease is primary Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily; the autoimmune disease is amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V7WSGR Docket No.: 53676-780.601 subfamily; the autoimmune disease is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily; the autoimmune disease is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily; the autoimmune disease is ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; the autoimmune disease is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP VI 0 subfamily; the autoimmune disease is COVID- induced multisystem inflammatory syndrome in children, and the moiety that binds to the TCR variable region binds to a TCRP VI 1 subfamily; the autoimmune disease is Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCRP V12 subfamily; the autoimmune disease is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP VI 0 subfamily; the autoimmune disease is amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V23 subfamily; the autoimmune disease is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V29 subfamily; the autoimmune disease is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily; the autoimmune disease is acute anterior uveitis (UAA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; the autoimmune disease is psoriatic arthritis (PsA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily; the autoimmune disease is type I narcolepsy, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily; the autoimmune disease is amyotrophic lateral sclerosis (ALS), and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily; or the autoimmune disease is UAA, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily.

[0128] In some embodiments, the method further comprises administering an additional therapeutic agent or therapy.

[0129] In some aspects, the present disclosure provides a method of identifying a subject with an autoimmune disease as a candidate for a therapeutic, the method comprising determining the subject has a biased TCRP and / or TCRVa clonotype, wherein the therapeutic comprises the agent described herein, the multispecific molecule described herein, the polynucleotide described herein, the vector described herein, or the pharmaceutical composition described herein.

[0130] In some embodiments, the biased TCRP and / or TCRVa clonotype is from a TCRa VI subfamily, a TCRa V2 subfamily, a TCRa V3 subfamily, a TCRa V4, a TCRa V5 subfamily, a TCRa V6 subfamily, a TCRa V7 subfamily, a TCRa V8 subfamily, a TCRa V9 subfamily, a TCRa V10 subfamily, a TCRa V12 subfamily, a TCRa V13 subfamily, a TCRa V14 subfamily, a TCRa VI 6 subfamily, a TCRa VI 7 subfamily, a TCRa VI 8 subfamily, a TCRa VI 9 subfamily, a TCRa V20 subfamily, a TCRa V21 subfamily, a TCRa V22 subfamily, a TCRaWSGR Docket No.: 53676-780.601V23 subfamily, a TCRa V24 subfamily, TCRa V25 subfamily, a TCRa V26 subfamily, a TCRa V27 subfamily, a TCRa V29 subfamily, a TCRa V30 subfamily, a TCRa V34 subfamily, a TCRa V35 subfamily, a TCRa V36 subfamily, a TCRa V38 subfamily, a TCRa V39 subfamily, a TCRa V40 subfamily, a TCRa V41 subfamily, a TCRP V6 subfamily, a TCRP VI 0 subfamily, a TCRP V12 subfamily, a TCRP V5 subfamily, a TCRP V7 subfamily, a TCRP VI 1 subfamily, a TCRP VI 4 subfamily, a TCRP VI 6 subfamily, a TCRP VI 8 subfamily, a TCRP V9 subfamily, a TCRP VI 3 subfamily, a TCRP V4 subfamily, a TCRP V3 subfamily, a TCRP V2 subfamily, a TCRP V15 subfamily, a TCRP V30 subfamily, a TCRP V19 subfamily, a TCRP V27 subfamily, a TCRP V28 subfamily, a TCRP V24 subfamily, a TCRP V20 subfamily, TCRP V25 subfamily, a TCRP V29 subfamily, a TCRP VI subfamily, a TCRP VI 7 subfamily, a TCRP V21 subfamily, a TCRP V23 subfamily, a TCRP V26 subfamily, or any variant thereof.

[0131] In some aspects, the present disclosure provides a method of treating an autoimmune disease or condition in a human subject in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of an agent comprising: (a) a moiety that binds to a TCR variable region, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor variable beta region (TCRPV); and (b) an NK cell engager that binds to a cell surface protein of an NK cell, wherein the NK cell engager activates the NK cell; and wherein the disease or condition is narcolepsy and the TCR variable region is TRAJ24, the disease or condition is Vitiligo and the TCR variable region is TRBV4, or the disease or condition is type 1 diabetes and the TCR variable region is TRBV5 or TRAV41.

[0132] In some embodiments, the disease or condition is narcolepsy and the TCR variable region is TRAJ24. In some embodiments, the disease or condition is Vitiligo and the TCR variable region is TRBV4. In some embodiments, the disease or condition is type 1 diabetes and the TCR variable region is TRBV5 or TRAV41.

[0133] In some aspects, the present disclosure provides a method of treating an autoimmune disease or condition in a human subject in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of an agent comprising: (a) a first moiety that binds to a first TCR variable region, wherein the first TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor variable beta region (TCRPV); (b) a second moiety that binds to a second TCR variable region, wherein the second TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor variable beta region (TCRPV); and (c) an NK cell engager that binds to a cell surface protein of an NK cell, wherein the NK cell engager activates the NK cell; and wherein the disease or condition is narcolepsy, the first TCR variable region is TRBV4-WSGR Docket No.: 53676-780.6012, and the second TCR variable region is TRAJ24, the disease or condition is multiple sclerosis, the first TCR variable region is TRBV6-5, and the second TCR variable region is TRBV5-1, or the disease or condition is type 1 diabetes, the first TCR variable region is TRBV5, and the second TCR variable region is TRAV41.

[0134] In some embodiments, the disease or condition is narcolepsy, the first TCR variable region is TRBV4-2, and the second TCR variable region is TRAJ24. In some embodiments, the disease or condition is multiple sclerosis, the first TCR variable region is TRBV6-5, and the second TCR variable region is TRBV5-1. In some embodiments, the disease or condition is type 1 diabetes, the first TCR variable region is TRBV5, and the second TCR variable region is TRAV41. In some embodiments, the cell surface protein comprises NKp30, NKp46, NKG2D, or CD 16. In some embodiments, binding of the NK cell engager activates an NK cell and mediates killing of an autoreactive T cells in the human subject. In some embodiments, the agent comprises an Fc region. In some embodiments, the Fc region has effector function or enhanced effector function. In some embodiments, the effector function or enhanced effector function comprises antibody dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement dependent cytotoxicity (CDC). In some embodiments, the effector function or enhanced effector function mediates killing of an autoreactive T cell in the human subj ect.

[0135] In some aspects, the present disclosure provides a method of treating an autoimmune disease or condition in a human subject in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, wherein the TCR variable region is TCRBV9, wherein the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH), wherein the VH comprises a heavy chain complementarity determining region 3 (HC CDR3) comprising an amino acid sequence as set forth in SWRRGIRGIGFDY (SEQ ID NO: 1250), wherein the autoimmune disease or condition is acute anterior uveitis (UAA), psoriatic arthritis (PsA), ankylosing spondylitis, Celiac disease, reactive arthritis, inflammatory bowel disease, sacroiliitis, Reiter's syndrome, juvenile rheumatoid arthritis, or any combination thereof.

[0136] In some embodiments, the autoimmune disease or condition UAA. In some embodiments, the autoimmune disease or condition is PsA. In some embodiments, the autoimmune disease or condition is ankylosing spondylitis. In some embodiments, the autoimmune disease or condition is Celiac disease. In some embodiments, the autoimmune disease or condition is reactive arthritis. In some embodiments, the autoimmune disease or condition is inflammatory bowel disease. In some embodiments, the autoimmune disease orWSGR Docket No.: 53676-780.601 condition is sacroiliitis. In some embodiments, the autoimmune disease or condition is Reiter's syndrome. In some embodiments, the autoimmune disease or condition is juvenile rheumatoid arthritis. In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of DYIVH (SEQ ID NO: 1248), GYTFTDY (SEQ ID NO: 1251), or GYTFTDYIVH (SEQ ID NO: 1253). In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of WINT YTGTPT YADDFEG (SEQ ID NO: 1249) or NTYTGT (SEQ ID NO: 1252). In some embodiments, the moiety comprises a light chain variable region (VL), wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of DGSTLQS (SEQ ID NO: 1255). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250), a HC CDR2 comprising the amino acid sequence ofWINT YTGTPT YADDFEG (SEQ ID NO: 1249) or NTYTGT (SEQ ID NO: 1252), a HC CDR1 comprising the amino acid sequence of DYIVH (SEQ ID NO: 1248), GYTFTDY (SEQ ID NO: 1251), or GYTFTDYIVH (SEQ ID NO: 1253), a LC CDR3 comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256), a LC CDR2 comprising the amino acid sequence of DGSTLQS (SEQ ID NO: 1255), and a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence QLQLVQSGPELREPGESVKISCKASGYTFTDYIVHWVKQAPGKGLKWMGWINTYTGTP TYADDFEGRFVFSLEASASTANLQISNLKNEDTATYFCARSWRRGIRGIGFDYWGQGVM VTVSS (SEQ ID NO: 7000). In some embodiments, the VH comprises a sequence of QLQLVQSGPELREPGESVKISCKASGYTFTDYIVHWVKQAPGKGLKWMGWINTYTGTP TYADDFEGRFVFSLEASASTANLQISNLKNEDTATYFCARSWRRGIRGIGFDYWGQGVM VTVSS (SEQ ID NO: 7000). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDVQMTQSPYNLAASPGESVSINCKASKSINKYLAWYQQKPGKPNKLLIYDGSTLQSGIPS RFSGSGSGTDFTLTIRGLEPEDFGLYYCQQHNEYPPTFGAGTKLELK (SEQ ID NO: 7001). In some embodiments, the VL comprises a sequence ofDVQMTQSPYNLAASPGESVSINCKASKSINKYLAWYQQKPGKPNKLLIYDGSTLQSGIPS RFSGSGSGTDFTLTIRGLEPEDFGLYYCQQHNEYPPTFGAGTKLELK (SEQ ID NO: 7001). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceWSGR Docket No.: 53676-780.601QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWINTYTGT PTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7002). In some embodiments, the VH comprises a sequence of QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWINTYTGT PTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7002). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003). In some embodiments, the VL comprises a sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceELQLVESGGGLVQPGRSLRLSCTASGYTFTDYIVHWVRQAPGKGLKWMGWINTYTGTP TYADDFEGRFTFSLDASKSIAYLQMNSLKTEDTAVYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7004). In some embodiments, the VH comprises a sequence of ELQLVESGGGLVQPGRSLRLSCTASGYTFTDYIVHWVRQAPGKGLKWMGWINTYTGTP TYADDFEGRFTFSLDASKSIAYLQMNSLKTEDTAVYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7004). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceEVVMTQSPPTLSLSPGERVTLSCKASKSINKYLAWYQQKPGQANKLLIYDGSTLQSGIPA RFSGSGSGTDFTLTISSLQPEDFAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7005). In some embodiments, the VL comprises a sequence of EVVMTQSPPTLSLSPGERVTLSCKASKSINKYLAWYQQKPGQANKLLIYDGSTLQSGIPA RFSGSGSGTDFTLTISSLQPEDFAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7005). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINTYTGTP TYADDFEGQFTFSLDASISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7006). In some embodiments, the VH comprises a sequence of ELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINTYTGTP TYADDFEGQFTFSLDASISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7006). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceWSGR Docket No.: 53676-780.601DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003). In some embodiments, the VL comprises a sequence ofDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceQLQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLKWMGWINTYTGT PTYADDFEGRFVFSLDASASTAYLQISSLKAEDMAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS (SEQ ID NO: 7008). In some embodiments, the VH comprises a sequence of QLQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLKWMGWINTYTGT PTYADDFEGRFVFSLDASASTAYLQISSLKAEDMAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS (SEQ ID NO: 7008). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDVQMTQSPSSLSASVGDRVTITCKASKSINKYLAWYQQKPGKANKLLIYDGSTLQSGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7007). In some embodiments, the VL comprises a sequence ofDVQMTQSPSSLSASVGDRVTITCKASKSINKYLAWYQQKPGKANKLLIYDGSTLQSGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7007). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceQLQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLKWMGWINTYTGT PTYADDFEGRFVFSLDASASTAYLQISSLKAEDMAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS (SEQ ID NO: 7008). In some embodiments, the VH comprises a sequence of QLQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLKWMGWINTYTGT PTYADDFEGRFVFSLDASASTAYLQISSLKAEDMAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS (SEQ ID NO: 7008). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003). In some embodiments, the VL comprises a sequence ofDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceWSGR Docket No.: 53676-780.601QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINTYTGT PTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7010). In some embodiments, the VH comprises a sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINTYTGT PTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7010). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009). In some embodiments, the VL comprises a sequence ofDIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINTYTGTP TYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7012). In some embodiments, the VH comprises a sequence of EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINTYTGTP TYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7012). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009). In some embodiments, the VL comprises a sequence ofDIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceQVQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLEWMGWINTYTGT PTYADDFEGRFVFSMDTSASTAYLQISSLKAEDMAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS (SEQ ID NO: 7014). In some embodiments, the VH comprises a sequence of QVQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLEWMGWINTYTGT PTYADDFEGRFVFSMDTSASTAYLQISSLKAEDMAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS (SEQ ID NO: 7014). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceWSGR Docket No.: 53676-780.601DIQMTQSPSSLSASVGDRVTITCKASKSINKYLAWYQQKPGKAPKLLIYDGSTLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7011). In some embodiments, the VL comprises a sequence ofDIQMTQSPSSLSASVGDRVTITCKASKSINKYLAWYQQKPGKAPKLLIYDGSTLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7011). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceQVQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLEWMGWINTYTGT PTYADDFEGRFVFSMDTSASTAYLQISSLKAEDMAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS (SEQ ID NO: 7014). In some embodiments, the VH comprises a sequence of QVQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLEWMGWINTYTGT PTYADDFEGRFVFSMDTSASTAYLQISSLKAEDMAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS (SEQ ID NO: 7014). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009). In some embodiments, the VL comprises a sequence ofDIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceQLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINTYTGT PTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYFCARSWRRGIRGIGFDYWGQGV MVTVSS (SEQ ID NO: 7015). In some embodiments, the VH comprises a sequence of QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINTYTGT PTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYFCARSWRRGIRGIGFDYWGQGV MVTVSS (SEQ ID NO: 7015). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGAGTKLELK (SEQ ID NO: 7013). In some embodiments, the VL comprises a sequence ofDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGAGTKLELK (SEQ ID NO: 7013). In some embodiments, the administering inhibits or prevents activation or expansion of autoreactive T cells in the human subject. In some embodiments, the autoreactive T cells targetWSGR Docket No.: 53676-780.601 an autologous cell in the human subject. In some embodiments, the autoreactive T cells express TCRaV and / or TCRPV. In some embodiments, the agent comprises an antibody molecule or antigen binding domain thereof. In some embodiments, the agent comprises an Fc region. In some embodiments, the Fc region comprises an amino acid sequence with at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 or 42. In some embodiments, the Fc region comprises one or more mutations. In some embodiments, the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. In some embodiments, the Fc comprises one or more mutations comprising E233P, L234V, L235A, P329A, S267K, G237A, P238S, H268A, A330S, P331S, K322A, D265A, D265S, L235E, G236R, S239K, A327G, V273E, T299A, Y300S, or any combination thereof, where amino acid positioning is relative to SEQ ID NO: 42. In some embodiments, the Fc region comprises an Fc-silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function. In some embodiments, the Fc region comprises no binding mutation. In some embodiments, the Fc region has effector function or enhanced effector function. In some embodiments, the effector function or enhanced effector function comprises antibody dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement dependent cytotoxicity (CDC). In some embodiments, the effector function or enhanced effector function mediates killing of the autoreactive T cells in the human subject. In some embodiments, the agent comprises an another moiety. In some embodiments, the another moiety comprises aNK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

[0137] In some aspects, the present disclosure provides a multispecific molecule comprising: (a) a first agent comprising a moiety that binds to a TCR variable region in a TCRP V9 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250); and (b) a second agent comprising a NK cell engager, comprising a second VH and a second VL, wherein the second VH comprises a HC CDR3 comprising the amino acid sequence of GDWHYFDY (SEQ ID NO: 7352).

[0138] In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of DYIVH (SEQ ID NO: 1248), GYTFTDY (SEQ ID NO: 1251), or GYTFTDYIVH (SEQ ID NO: 1253). In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of WINT YTGTPT YADDFEG (SEQ ID NO: 1249) or NTYTGT (SEQ ID NO: 1252). In some embodiments, the moiety comprises a light chain variable region (VL),WSGR Docket No.: 53676-780.601 wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of DGSTLQS (SEQ ID NO: 1255). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250), a HC CDR2 comprising the amino acid sequence of WINTYTGTPTYADDFEG (SEQ ID NO: 1249) or NTYTGT (SEQ ID NO: 1252), a HC CDR1 comprising the amino acid sequence of DYIVH (SEQ ID NO: 1248), GYTFTDY (SEQ ID NO: 1251), or GYTFTDYIVH (SEQ ID NO: 1253), a LC CDR3 comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256), a LC CDR2 comprising the amino acid sequence of DGSTLQS (SEQ ID NO: 1255), and a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence QLQLVQSGPELREPGESVKISCKASGYTFTDYIVHWVKQAPGKGLKWMGWINTYTGTP TYADDFEGRFVFSLEASASTANLQISNLKNEDTATYFCARSWRRGIRGIGFDYWGQGVM VTVSS (SEQ ID NO: 7000). In some embodiments, the VH comprises a sequence of QLQLVQSGPELREPGESVKISCKASGYTFTDYIVHWVKQAPGKGLKWMGWINTYTGTP TYADDFEGRFVFSLEASASTANLQISNLKNEDTATYFCARSWRRGIRGIGFDYWGQGVM VTVSS (SEQ ID NO: 7000). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDVQMTQSPYNLAASPGESVSINCKASKSINKYLAWYQQKPGKPNKLLIYDGSTLQSGIPS RFSGSGSGTDFTLTIRGLEPEDFGLYYCQQHNEYPPTFGAGTKLELK (SEQ ID NO: 7001). In some embodiments, the VL comprises a sequence of DVQMTQSPYNLAASPGESVSINCKASKSINKYLAWYQQKPGKPNKLLIYDGSTLQSGIPS RFSGSGSGTDFTLTIRGLEPEDFGLYYCQQHNEYPPTFGAGTKLELK (SEQ ID NO: 7001). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWINTYTGT PTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7002). In some embodiments, the VH comprises a sequence of QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWINTYTGT PTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7002). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceWSGR Docket No.: 53676-780.601DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003). In some embodiments, the VL comprises a sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceELQLVESGGGLVQPGRSLRLSCTASGYTFTDYIVHWVRQAPGKGLKWMGWINTYTGTP TYADDFEGRFTFSLDASKSIAYLQMNSLKTEDTAVYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7004). In some embodiments, the VH comprises a sequence of ELQLVESGGGLVQPGRSLRLSCTASGYTFTDYIVHWVRQAPGKGLKWMGWINTYTGTP TYADDFEGRFTFSLDASKSIAYLQMNSLKTEDTAVYYCARSWRRGIRGIGFDYWGQGTMVTVSS (SEQ ID NO: 7004). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence EVVMTQSPPTLSLSPGERVTLSCKASKSINKYLAWYQQKPGQANKLLIYDGSTLQSGIPA RFSGSGSGTDFTLTISSLQPEDFAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7005). In some embodiments, the VL comprises a sequence ofEVVMTQSPPTLSLSPGERVTLSCKASKSINKYLAWYQQKPGQANKLLIYDGSTLQSGIPA RFSGSGSGTDFTLTISSLQPEDFAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7005). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINTYTGTP TYADDFEGQFTFSLDASISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7006). In some embodiments, the VH comprises a sequence of ELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINTYTGTP TYADDFEGQFTFSLDASISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQGTMVTVSS (SEQ ID NO: 7006). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003). In some embodiments, the VL comprises a sequence ofDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceWSGR Docket No.: 53676-780.601QLQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLKWMGWINTYTGT PTYADDFEGRFVFSLDASASTAYLQISSLKAEDMAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS (SEQ ID NO: 7008). In some embodiments, the VH comprises a sequence of QLQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLKWMGWINTYTGT PTYADDFEGRFVFSLDASASTAYLQISSLKAEDMAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS (SEQ ID NO: 7008). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDVQMTQSPSSLSASVGDRVTITCKASKSINKYLAWYQQKPGKANKLLIYDGSTLQSGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7007). In some embodiments, the VL comprises a sequence ofDVQMTQSPSSLSASVGDRVTITCKASKSINKYLAWYQQKPGKANKLLIYDGSTLQSGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7007). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceQLQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLKWMGWINTYTGT PTYADDFEGRFVFSLDASASTAYLQISSLKAEDMAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS (SEQ ID NO: 7008). In some embodiments, the VH comprises a sequence of QLQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLKWMGWINTYTGT PTYADDFEGRFVFSLDASASTAYLQISSLKAEDMAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS (SEQ ID NO: 7008). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003). In some embodiments, the VL comprises a sequence ofDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceQVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINTYTGT PTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7010). In some embodiments, the VH comprises a sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINTYTGT PTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7010). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceWSGR Docket No.: 53676-780.601DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009). In some embodiments, the VL comprises a sequence ofDIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINTYTGTP TYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7012). In some embodiments, the VH comprises a sequence of EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINTYTGTP TYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGIGFDYWGQGT MVTVSS (SEQ ID NO: 7012). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009). In some embodiments, the VL comprises a sequence ofDIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceQVQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLEWMGWINTYTGT PTYADDFEGRFVFSMDTSASTAYLQISSLKAEDMAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS (SEQ ID NO: 7014). In some embodiments, the VH comprises a sequence of QVQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLEWMGWINTYTGT PTYADDFEGRFVFSMDTSASTAYLQISSLKAEDMAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS (SEQ ID NO: 7014). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDIQMTQSPSSLSASVGDRVTITCKASKSINKYLAWYQQKPGKAPKLLIYDGSTLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7011). In some embodiments, the VL comprises a sequence ofDIQMTQSPSSLSASVGDRVTITCKASKSINKYLAWYQQKPGKAPKLLIYDGSTLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7011). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceWSGR Docket No.: 53676-780.601QVQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLEWMGWINTYTGT PTYADDFEGRFVFSMDTSASTAYLQISSLKAEDMAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS (SEQ ID NO: 7014). In some embodiments, the VH comprises a sequence of QVQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLEWMGWINTYTGT PTYADDFEGRFVFSMDTSASTAYLQISSLKAEDMAMYYCARSWRRGIRGIGFDYWGQG TMVTVSS (SEQ ID NO: 7014). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009). In some embodiments, the VL comprises a sequence ofDIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQSGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceQLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINTYTGT PTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYFCARSWRRGIRGIGFDYWGQGV MVTVSS (SEQ ID NO: 7015). In some embodiments, the VH comprises a sequence of QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINTYTGT PTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYFCARSWRRGIRGIGFDYWGQGV MVTVSS (SEQ ID NO: 7015). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGAGTKLELK (SEQ ID NO: 7013). In some embodiments, the VL comprises a sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTLQSGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGAGTKLELK (SEQ ID NO: 7013). In some embodiments, the second VH comprises a HC CDR1 comprising the amino acid sequence of GFSIIRVGYHWN (SEQ ID NO: 7383). In some embodiments, the second VH comprises a HC CDR2 comprising the amino acid sequence of YIHRSGSTSYNPSLKS (SEQ ID NO: 7380). In some embodiments, the second VL comprises a LC CDR3 comprising the amino acid sequence of QFWDSTNSAV (SEQ ID NO: 7358). In some embodiments, the second VL comprises a LC CDR1 comprising the amino acid sequence of SGEKLSDKYVH (SEQ ID NO: 7356). In some embodiments, the second VL comprises a LC CDR2 comprising the amino acid sequence of ENDRRPS (SEQ ID NO: 7352). In some embodiments, the NK cell engager comprises: a HC CDR3 comprising the amino acid sequence of GDWHYFDY (SEQ ID NO:WSGR Docket No.: 53676-780.6017352), a HC CDR2 comprising the amino acid sequence of YIHRSGSTSYNPSLKS (SEQ ID NO: 7380, a HC CDR1 comprising the amino acid sequence of GFSIIRVGYHWN (SEQ ID NO: 7383), a LC CDR3 comprising the amino acid sequence of QFWDSTNSAV (SEQ ID NO: 7358), a LC CDR2 comprising the amino acid sequence of ENDRRPS (SEQ ID NO: 7352), and a LC CDR1 comprising the amino acid sequence of SGEKLSDKYVH (SEQ ID NO: 7356). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence EIQLLESGGGLVQPGGSLRLSCAVSGFSIIRVGYHWNWVRQAPGKGLEWVGYIHRSGST SYNPSLKSRFTISRDTSKNTFYLQMNSLRAEDTAVYYCARGDWHYFDYWGQGTMVTV SS (SEQ ID NO: 7384). In some embodiments, the VH comprises a sequence of EIQLLESGGGLVQPGGSLRLSCAVSGFSIIRVGYHWNWVRQAPGKGLEWVGYIHRSGST SYNPSLKSRFTISRDTSKNTFYLQMNSLRAEDTAVYYCARGDWHYFDYWGQGTMVTV SS (SEQ ID NO: 7384). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDSVTTQSPLSLPVTLGQPASISCSGEKLSDKYVHWYQQRPGQSPRMLIYENDRRPSGVPD RFSGSNSGNDATLKISRVEAEDVGVYFCQFWDSTNSAVFGGGTKVEIK (SEQ ID NO: 7309). In some embodiments, the VL comprises a sequence of DSVTTQSPLSLPVTLGQPASISCSGEKLSDKYVHWYQQRPGQSPRMLIYENDRRPSGVPD RFSGSNSGNDATLKISRVEAEDVGVYFCQFWDSTNSAVFGGGTKVEIK (SEQ ID NO: 7309). In some embodiments, the agent comprises an antibody molecule or antigen binding domain thereof. In some embodiments, the agent comprises an Fc region. In some embodiments, the Fc region comprises an amino acid sequence with at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 or 42. In some embodiments, the Fc region comprises one or more mutations. In some embodiments, the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. In some embodiments, the Fc comprises one or more mutations comprising E233P, L234V, L235A, P329A, S267K, G237A, P238S, H268A, A330S, P331S, K322A, D265A, D265S, L235E, G236R, S239K, A327G, V273E, T299A, Y300S, or any combination thereof, where amino acid positioning is relative to SEQ ID NO: 42. In some embodiments, the Fc region comprises an Fc- silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function. In some embodiments, the NK cell engager comprises an antibody molecule or antigen binding domain thereof. In some embodiments, the NK cell engager comprises a single chain variable fragment (scFv).WSGR Docket No.: 53676-780.601

[0139] In some aspects, the present disclosure provides a method of treating an autoimmune disease or condition in a human subject in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a first agent comprising a moiety that binds to a TCR variable region in a TCRP V9 subfamily and a second agent comprising a NK cell engager, wherein the autoimmune disease or condition is acute anterior uveitis (UAA), psoriatic arthritis (PsA), ankylosing spondylitis, Celiac disease, reactive arthritis, inflammatory bowel disease, sacroiliitis, Reiter's syndrome, juvenile rheumatoid arthritis, or any combination thereof.

[0140] In some embodiments, the autoimmune disease or condition UAA. In some embodiments, the autoimmune disease or condition is PsA. In some embodiments, the autoimmune disease or condition is ankylosing spondylitis. In some embodiments, the autoimmune disease or condition is Celiac disease. In some embodiments, the autoimmune disease or condition is reactive arthritis. In some embodiments, the autoimmune disease or condition is inflammatory bowel disease. In some embodiments, the autoimmune disease or condition is sacroiliitis. In some embodiments, the autoimmune disease or condition is Reiter's syndrome. In some embodiments, the autoimmune disease or condition is juvenile rheumatoid arthritis. In some embodiments, the moiety comprises a VH comprising a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250). In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of DYIVH (SEQ ID NO: 1248), GYTFTDY (SEQ ID NO: 1251), or GYTFTDYIVH (SEQ ID NO: 1253). In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of WINTYTGTPTYADDFEG (SEQ ID NO: 1249) or NTYTGT (SEQ ID NO: 1252). In some embodiments, the moiety comprises a light chain variable region (VL), wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of DGSTLQS (SEQ ID NO: 1255). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250), a HC CDR2 comprising the amino acid sequence of WINTYTGTPTYADDFEG (SEQ ID NO: 1249) or NTYTGT (SEQ ID NO: 1252), a HC CDR1 comprising the amino acid sequence of DYIVH (SEQ ID NO: 1248), GYTFTDY (SEQ ID NO: 1251), or GYTFTDYIVH (SEQ ID NO: 1253), a LC CDR3 comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256), a LC CDR2 comprising the amino acid sequence of DGSTLQS (SEQ ID NO: 1255), and a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254). In someWSGR Docket No.: 53676-780.601 embodiments, the NK cell engager comprises a second VH comprising a HC CDR3 comprising the amino acid sequence of GDWHYFDY (SEQ ID NO: 7352). In some embodiments, the second VH comprises a HC CDR1 comprising the amino acid sequence of GFSIIRVGYHWN (SEQ ID NO: 7383). In some embodiments, the second VH comprises a HC CDR2 comprising the amino acid sequence of YIHRSGSTSYNPSLKS (SEQ ID NO: 7380). In some embodiments, the second VL comprises a LC CDR3 comprising the amino acid sequence of QFWDSTNSAV (SEQ ID NO: 7358). In some embodiments, the second VL comprises a LC CDR1 comprising the amino acid sequence of SGEKLSDKYVH (SEQ ID NO: 7356). In some embodiments, the second VL comprises a LC CDR2 comprising the amino acid sequence of ENDRRPS (SEQ ID NO: 7352). In some embodiments, the NK cell engager comprises: a HC CDR3 comprising the amino acid sequence of GDWHYFDY (SEQ ID NO: 7352), a HC CDR2 comprising the amino acid sequence of YIHRSGSTSYNPSLKS (SEQ ID NO: 7380, a HC CDR1 comprising the amino acid sequence of GFSIIRVGYHWN (SEQ ID NO: 7383), a LC CDR3 comprising the amino acid sequence of QFWDSTNSAV (SEQ ID NO: 7358), a LC CDR2 comprising the amino acid sequence of ENDRRPS (SEQ ID NO: 7352), and a LC CDR1 comprising the amino acid sequence of SGEKLSDKYVH (SEQ ID NO: 7356). In some embodiments, the administering inhibits or prevents activation or expansion of autoreactive T cells in the human subject. In some embodiments, the autoreactive T cells target an autologous cell in the human subject. In some embodiments, the autoreactive T cells express TCRaV and / or TCRPV. In some embodiments, the first agent comprises an antibody molecule or antigen binding domain thereof. In some embodiments, the first agent comprises an Fc region. In some embodiments, the Fc region comprises an amino acid sequence with at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 or 42. In some embodiments, the Fc region comprises one or more mutations. In some embodiments, the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. In some embodiments, the Fc comprises one or more mutations comprising E233P, L234V, L235A, P329A, S267K, G237A, P238S, H268A, A330S, P331S, K322A, D265A, D265S, L235E, G236R, S239K, A327G, V273E, T299A, Y300S, or any combination thereof, where amino acid positioning is relative to SEQ ID NO: 42. In some embodiments, the Fc region comprises an Fc- silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function.

[0141] In some aspects, the present disclosure provides a method of treating an autoimmune disease or condition in a human subject in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeuticallyWSGR Docket No.: 53676-780.601 effective amount of an agent comprising a moiety that binds to a TCRP V20-1 region, wherein the autoimmune disease or condition is alopecia.

[0142] In some embodiments, the moiety comprises a heavy chain variable region (VH), wherein the VH comprises a heavy chain complementarity determining region 3 HC CDR3 comprising the amino acid sequence of SLNWDYGLDY (SEQ ID NO: 1104). In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of SAYMH (SEQ ID NO: 1102), GFNIKSA (SEQ ID NO: 1105), or GFNIKSAYMH (SEQ ID NO: 3640). In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of RIDPATGKTKYAPKFQA (SEQ ID NO: 1103) or DPATGK (SEQ ID NO: 1106). In some embodiments, the moiety comprises a light chain variable region (VL), wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQSIEDPWT (SEQ ID NO: 1109). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of RASKS VSILGTHLIH (SEQ ID NO: 1107). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 1108). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of SLNWDYGLDY (SEQ ID NO: 1104), a HC CDR2 comprising the amino acid sequence of RIDPATGKTKYAPKFQA (SEQ ID NO: 1103) or DPATGK (SEQ ID NO: 1106), a HC CDR1 comprising the amino acid sequence of SAYMH (SEQ ID NO: 1102), GFNIKSA (SEQ ID NO: 1105), or GFNIKSAYMH (SEQ ID NO: 3640), a LC CDR3 comprising the amino acid sequence of QQSIEDPWT (SEQ ID NO: 1109), a LC CDR2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 1108), and a LC CDR1 comprising the amino acid sequence of RASKS VSILGTHLIH (SEQ ID NO: 1107). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence QVQLVQSGAEVKKPGASVKVSCKASGFNIKSAYMHWVRQAPGQEPGCMGRIDPATGK TKYAPKFQARVTMTADTSINTAYTELSSLRSEDTATYYCARSLNWDYGLDYWGQGTLV TVSS (SEQ ID NO: 1114). In some embodiments, the VH comprises a sequence of QVQLVQSGAEVKKPGASVKVSCKASGFNIKSAYMHWVRQAPGQEPGCMGRIDPATGK TKYAPKFQARVTMTADTSINTAYTELSSLRSEDTATYYCARSLNWDYGLDYWGQGTLV TVSS (SEQ ID NO: 1114). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceEIVLTQSPATLSLSPGERATLSCRASKSVSILGTHLIHWYQQKPGLAPRLLIYAASNLESGI PDRFSGSGSETDFTLTISRLEPEDFAVYFCQQSIEDPWTFGGGTKVEIK (SEQ ID NO: 3700). In some embodiments, the VL comprises a sequence of EIVLTQSPATLSLSPGERATLSCRASKSVSILGTHLIHWYQQKPGLAPRLLIYAASNLESGI PDRFSGSGSETDFTLTISRLEPEDFAVYFCQQSIEDPWTFGGGTKVEIK (SEQ ID NO:WSGR Docket No.: 53676-780.6013700). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceQVQLVQSGAEVKKPGASVKVSCKASGFNIKSAYMHWVRQAPGQGLEWMGRIDPATGK TKYAPKFQARVTMTADTSTNTAYMELSSLRSEDTAVYYCARSLNWDYGLDYWGQGTL VTVSS (SEQ ID NO: 1113). In some embodiments, the VH comprises a sequence of QVQLVQSGAEVKKPGASVKVSCKASGFNIKSAYMHWVRQAPGQGLEWMGRIDPATGK TKYAPKFQARVTMTADTSTNTAYMELSSLRSEDTAVYYCARSLNWDYGLDYWGQGTL VTVSS (SEQ ID NO: 1113). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceEIVLTQSPGTLSLSPGERATLSCRASKSVSILGTHLIHWYQQKPGQAPRLLIYAASNLESGI PDRFSGSGSETDFTLTISRLEPEDFAVYFCQQSIEDPWTFGGGTKVEIK (SEQ ID NO: 7017). In some embodiments, the VL comprises a sequence of EIVLTQSPGTLSLSPGERATLSCRASKSVSILGTHLIHWYQQKPGQAPRLLIYAASNLESGI PDRFSGSGSETDFTLTISRLEPEDFAVYFCQQSIEDPWTFGGGTKVEIK (SEQ ID NO: 7017). In some embodiments, the administering inhibits or prevents activation or expansion of autoreactive T cells in the human subject. In some embodiments, the autoreactive T cells target an autologous cell in the human subject. In some embodiments, the autoreactive T cells express TCRaV and / or TCRPV. In some embodiments, the agent comprises an antibody molecule or antigen binding domain thereof. In some embodiments, the agent comprises an Fc region. In some embodiments, the Fc region comprises an amino acid sequence with at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 or 42. In some embodiments, the Fc region comprises one or more mutations. In some embodiments, the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. In some embodiments, the Fc comprises one or more mutations comprising E233P, L234V, L235A, P329A, S267K, G237A, P238S, H268A, A330S, P331S, K322A, D265A, D265S, L235E, G236R, S239K, A327G, V273E, T299A, Y300S, or any combination thereof, where amino acid positioning is relative to SEQ ID NO: 42. In some embodiments, the Fc region comprises an Fc-silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function. In some embodiments, the agent comprises a second moiety. In some embodiments, the second moiety comprises a IL-2R biased IL-2 mutein. In some embodiments, the second moiety comprises a cytokine. In some embodiments, the cytokine comprises IL-2. In some embodiments, the cytokine comprises a IL-2 variant. In some embodiments, the IL-2 variant comprises one or more amino acid substitutions comprising L18M, L19S, or C125A. In some embodiments, the cytokine comprises an aminoWSGR Docket No.: 53676-780.601 acid sequence with at least about 80% sequence identity to the sequence as set forth in SEQ ID NO: 2191. In some embodiments, the cytokine comprises one or more mutations comprising S4P, K8R, T10A, Q11R, Q13R, N26D, N30S, K35R, T37R, V69A, Q74P, N88D, I128T, T133A, I92T, based on an amino acid sequence as set forth in SEQ ID NO: 2191. In some embodiments, the second moiety comprises TGFp. In some embodiments, the cytokine comprises IL-7. In some embodiments, the second moiety comprises a IL-7 receptor (IL-7R) antagonist. In some embodiments, the IL-7R antagonist is configured to inhibit IL-7R heterodimerization. In some embodiments, the IL-7R antagonist comprises lusvertikimab or a binding fragment thereof.

[0143] In some aspects, the present disclosure provides a method of treating an autoimmune disease or condition in a human subject in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of an agent comprising a moiety that binds to a TCRP V5-1 region, wherein the autoimmune disease or condition is alopecia or multiple sclerosis. In some embodiments, the moiety comprises a heavy chain variable region (VH), wherein the VH comprises a heavy chain complementarity determining region 3 HC CDR3 comprising the amino acid sequence of WDGSSYFDY (SEQ ID NO: 1165).

[0144] In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of DYNIH (SEQ ID NO: 1163), GYTFTDY (SEQ ID NO: 7025), or GYTFTDYNIH (SEQ ID NO: 1166). In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of YINPYNGRTGYNQKFKA (SEQ ID NO: 1164) or NPYNGR (SEQ ID NO: 1167). In some embodiments, the moiety comprises a light chain variable region (VL), wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQWNYPLLT (SEQ ID NO: 1170). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of SASSSVSYMH (SEQ ID NO: 1168). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of EISKLAS (SEQ ID NO: 1169). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of WDGSSYFDY (SEQ ID NO: 1165), a HC CDR2 comprising the amino acid sequence of YINPYNGRTGYNQKFKA (SEQ ID NO: 1164) or NPYNGR (SEQ ID NO: 1167), a HC CDR1 comprising the amino acid sequence of DYNIH (SEQ ID NO: 1163), GYTFTDY (SEQ ID NO: 7025), or GYTFTDYNIH (SEQ ID NO: 1166), a LC CDR3 comprising the amino acid sequence of QQWNYPLLT (SEQ ID NO: 1170), a LC CDR2 comprising the amino acid sequence of EISKLAS (SEQ ID NO: 1169), and a LC CDR1 comprising the amino acid sequence of SASSSVSYMH (SEQ ID NO: 1168). In some embodiments, the VH comprises a sequence with at least 80% sequence identityWSGR Docket No.: 53676-780.601 to the sequence QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYNIHWVRQAPGQGLEWMGYINPYNGR TGYNQKFKARVTMTVDKSTSTAYMELSSLRSEDTAVYYCARWDGSSYFDYWGQGTLV TVSS (SEQ ID NO: 7018). In some embodiments, the VH comprises a sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYNIHWVRQAPGQGLEWMGYINPYNGR TGYNQKFKARVTMTVDKSTSTAYMELSSLRSEDTAVYYCARWDGSSYFDYWGQGTLV TVSS (SEQ ID NO: 7018). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence EIVLTQSPATLSVSPGERATLSCSASSSVSYMHWYQQKPGQAPRPLIYEISKLASGIPARF SGSGSGTEYTLTISSLQSEDFAVYYCQQWNYPLLTFGQGTKLEIK (SEQ ID NO: 7019). In some embodiments, the VL comprises a sequence of EIVLTQSPATLSVSPGERATLSCSASSSVSYMHWYQQKPGQAPRPLIYEISKLASGIPARF SGSGSGTEYTLTISSLQSEDFAVYYCQQWNYPLLTFGQGTKLEIK (SEQ ID NO: 7019). In some embodiments, the administering inhibits or prevents activation or expansion of autoreactive T cells in the human subject. In some embodiments, the autoreactive T cells target an autologous cell in the human subject. In some embodiments, the autoreactive T cells express TCRaV and / or TCRPV. In some embodiments, the agent comprises an antibody molecule or antigen binding domain thereof. In some embodiments, the agent comprises an Fc region. In some embodiments, the Fc region comprises an amino acid sequence with at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 or 42. In some embodiments, the Fc region comprises one or more mutations. In some embodiments, the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. In some embodiments, the Fc comprises one or more mutations comprising E233P, L234V, L235A, P329A, S267K, G237A, P238S, H268A, A330S, P331S, K322A, D265A, D265S, L235E, G236R, S239K, A327G, V273E, T299A, Y300S, or any combination thereof, where amino acid positioning is relative to SEQ ID NO: 42. In some embodiments, the Fc region comprises an Fc-silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function. In some embodiments, the agent comprises a second moiety. In some embodiments, the second moiety comprises a IL-2R biased IL-2 mutein. In some embodiments, the second moiety comprises a cytokine. In some embodiments, the cytokine comprises IL-2. In some embodiments, the cytokine comprises a IL-2 variant. In some embodiments, the IL-2 variant comprises one or more amino acid substitutions comprising L18M, L19S, or C125A. In some embodiments, the cytokine comprises an amino acid sequence with at least about 80% sequence identity to the sequence as set forth in SEQ IDWSGR Docket No.: 53676-780.601NO: 2191. In some embodiments, the cytokine comprises one or more mutations comprising S4P, K8R, T10A, Q11R, Q13R, N26D, N30S, K35R, T37R, V69A, Q74P, N88D, I128T, T133A, I92T, based on an amino acid sequence as set forth in SEQ ID NO: 2191. In some embodiments, the second moiety comprises TGFp. In some embodiments, the cytokine comprises IL-7. In some embodiments, the second moiety comprises a IL-7 receptor (IL-7R) antagonist. In some embodiments, the IL-7R antagonist is configured to inhibit IL-7R heterodimerization. In some embodiments, the IL-7R antagonist comprises lusvertikimab or a binding fragment thereof.

[0145] In some aspects, the present disclosure provides an agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of RDNYYGSHYRYFDV (SEQ ID NO: 9092).

[0146] In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of SYWMH (SEQ ID NO: 9090), GYTFTSY (SEQ ID NO: 9093), or GYTFTSYWMH (SEQ ID NO: 9095). In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of NIDPSDSETHYNQKFKD (SEQ ID NO: 9091) or DPSDSE (SEQ ID NO: 9094). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQGKTLMYT (SEQ ID NO: 9098). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of RASQDISNYLN (SEQ ID NO: 9096). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of YTSILHS (SEQ ID NO: 9097). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of RDNYYGSHYRYFDV (SEQ ID NO: 9092), a HC CDR2 comprising the amino acid sequence of NIDPSDSETHYNQKFKD (SEQ ID NO: 9091) or DPSDSE (SEQ ID NO: 9094), a HC CDR1 comprising the amino acid sequence of SYWMH (SEQ ID NO: 9090), GYTFTSY (SEQ ID NO: 9093), or GYTFTSYWMH (SEQ ID NO: 9095), a LC CDR3 comprising the amino acid sequence of QQGKTLMYT (SEQ ID NO: 9098), a LC CDR2 comprising the amino acid sequence of YTSILHS (SEQ ID NO: 9097), and a LC CDR1 comprising the amino acid sequence of RASQDISNYLN (SEQ ID NO: 9096). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence QVQLQQPGAELVRPGSSVKLSCKASGYTFTSYWMHWVKQRPIQGLEWIGNIDPSDSET HYNQKFKDK ATLTVDKS S STAYMQLS SLTSEDS AVYYC ARRDNYYGSHYRYFD VWGT GTTVTVSS (SEQ ID NO: 9078). In some embodiments, the VH comprises a sequence of QVQLQQPGAELVRPGSSVKLSCKASGYTFTSYWMHWVKQRPIQGLEWIGNIDPSDSETWSGR Docket No.: 53676-780.601HYNQKFKDK ATLTVDKS S STAYMQLS SLTSEDS AVYYC ARRDNYYGSHYRYFD VWGT GTTVTVSS (SEQ ID NO: 9078). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSILHSGVPSR FSGSGSGTDYSLTISNLEQEDIATYFCQQGKTLMYTFGGGTKLEIK (SEQ ID NO: 9084). In some embodiments, the VL comprises a sequence of DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSILHSGVPSR FSGSGSGTDYSLTISNLEQEDIATYFCQQGKTLMYTFGGGTKLEIK (SEQ ID NO: 9084). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQWSSNPPT (SEQ ID NO: 9103). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of SASSSVSYMH (SEQ ID NO: 9101). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of DTSKLAS (SEQ ID NO: 9102). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of RDNYYGSHYRYFDV (SEQ ID NO: 9092), a HC CDR2 comprising the amino acid sequence of NIDPSDSETHYNQKFKD (SEQ ID NO: 9091) or DPSDSE (SEQ ID NO: 9094), a HC CDR1 comprising the amino acid sequence of SYWMH (SEQ ID NO: 9090), GYTFTSY (SEQ ID NO: 9093), or GYTFTSYWMH (SEQ ID NO: 9095), a LC CDR3 comprising the amino acid sequence of SASSSVSYMH (SEQ ID NO: 9101), a LC CDR2 comprising the amino acid sequence of SASSSVSYMH (SEQ ID NO: 9101), and a LC CDR1 comprising the amino acid sequence of RDNYYGSHYRYFDV (SEQ ID NO: 9092). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPA RFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPPTFGGGTKLEIK (SEQ ID NO: 9085). In some embodiments, the VL comprises a sequence of QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPA RFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPPTFGGGTKLEIK (SEQ ID NO: 9085).

[0147] In some aspects, the present disclosure provides an agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of WVADY (SEQ ID NO: 9107).

[0148] In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of DYGMH (SEQ ID NO: 9105), GFTFSDY (SEQ ID NO: 9108), or GFTFSDYGMH (SEQ ID NO: 9110). In some embodiments, the VH comprises a HC CDR2 comprising theWSGR Docket No.: 53676-780.601 amino acid sequence of YISSGSSTIYYADTVKG (SEQ ID NO: 9106) or SSGSST (SEQ ID NO: 9109). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQGKTLMYT (SEQ ID NO: 9098). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of RASQDISNYLN (SEQ ID NO: 9096). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of YTSILHS (SEQ ID NO: 9097). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of WVADY (SEQ ID NO: 9107), a HC CDR2 comprising the amino acid sequence of YISSGSSTIYYADTVKG (SEQ ID NO: 9106) or SSGSST (SEQ ID NO: 9109), a HC CDR1 comprising the amino acid sequence of DYGMH (SEQ ID NO: 9105), GFTFSDY (SEQ ID NO: 9108), or GFTFSDYGMH (SEQ ID NO: 9110), a LC CDR3 comprising the amino acid sequence of QQGKTLMYT (SEQ ID NO: 9098), a LC CDR2 comprising the amino acid sequence of YTSILHS (SEQ ID NO: 9097), and a LC CDR1 comprising the amino acid sequence of RASQDISNYLN (SEQ ID NO: 9096). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVKPGGSLKLSCAASGFTFSDYGMHWVRQAPEKGLEWVAYISSGSSTIY YADTVKGRFTISRDNAKNTLFLQMTSLRSEDTAMYYCARWVADYWGQGTTLTVSS (SEQ ID NO: 9079). In some embodiments, the VH comprises a sequence ofEVQLVESGGGLVKPGGSLKLSCAASGFTFSDYGMHWVRQAPEKGLEWVAYISSGSSTIY YADTVKGRFTISRDNAKNTLFLQMTSLRSEDTAMYYCARWVADYWGQGTTLTVSS (SEQ ID NO: 9079). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSILHSGVPSR FSGSGSGTDYSLTISNLEQEDIATYFCQQGKTLMYTFGGGTKLEIK (SEQ ID NO: 9084). In some embodiments, the VL comprises a sequence ofDIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSILHSGVPSR FSGSGSGTDYSLTISNLEQEDIATYFCQQGKTLMYTFGGGTKLEIK (SEQ ID NO: 9084). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQWSSNPPT (SEQ ID NO: 9103). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of SASSSVSYMH (SEQ ID NO: 9101). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of DTSKLAS (SEQ ID NO: 9102). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of RDNYYGSHYRYFDV (SEQ ID NO: 9092), a HC CDR2 comprising the amino acid sequence of NIDPSDSETHYNQKFKD (SEQ ID NO: 9091) or DPSDSE (SEQ ID NO: 9094), a HCWSGR Docket No.: 53676-780.601CDR1 comprising the amino acid sequence of SYWMH (SEQ ID NO: 9090), GYTFTSY (SEQ ID NO: 9093), or GYTFTSYWMH (SEQ ID NO: 9095), a LC CDR3 comprising the amino acid sequence of SASSSVSYMH (SEQ ID NO: 9101), a LC CDR2 comprising the amino acid sequence of SASSSVSYMH (SEQ ID NO: 9101), and a LC CDR1 comprising the amino acid sequence of RDNYYGSHYRYFDV (SEQ ID NO: 9092). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPA RFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPPTFGGGTKLEIK (SEQ ID NO: 9085). In some embodiments, the VL comprises a sequence of QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPA RFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPPTFGGGTKLEIK (SEQ ID NO: 9085).

[0149] In some aspects, the present disclosure provides an agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of HKWDGWYFDV (SEQ ID NO: 9114).

[0150] In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of SYGVH (SEQ ID NO: 9112), GFSLISY (SEQ ID NO: 9115), or GFSLISYGVH (SEQ ID NO: 9117). In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of VIWSDGSTTYNSALKS (SEQ ID NO: 9113) or WSDGS (SEQ ID NO: 9116). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of HQGQSYPLT (SEQ ID NO: 9120). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of HASQNINVWLS (SEQ ID NO: 9118). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of KASNLHT (SEQ ID NO: 9119). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of HKWDGWYFDV (SEQ ID NO: 9114), a HC CDR2 comprising the amino acid sequence of VIWSDGSTTYNSALKS (SEQ ID NO: 9113) or WSDGS (SEQ ID NO: 9116), a HC CDR1 comprising the amino acid sequence of SYGVH (SEQ ID NO: 9112), GFSLISY (SEQ ID NO: 9115), or GFSLISYGVH (SEQ ID NO: 9117), a LC CDR3 comprising the amino acid sequence of HQGQSYPLT (SEQ ID NO: 9120), a LC CDR2 comprising the amino acid sequence of KASNLHT (SEQ ID NO: 9119), and a LC CDR1 comprising the amino acid sequence of HASQNINVWLS (SEQ ID NO: 9118). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence QVQLKESGPGLVAPSQSLSITCTVSGFSLISYGVHWVRQPPGKGLEWLVVIWSDGSTTYWSGR Docket No.: 53676-780.601NSALKSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCARHKWDGWYFDVWGTGTTVT VSS (SEQ ID NO: 9080). In some embodiments, the VH comprises a sequence of QVQLKESGPGLVAPSQSLSITCTVSGFSLISYGVHWVRQPPGKGLEWLVVIWSDGSTTY NSALKSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCARHKWDGWYFDVWGTGTTVT VSS (SEQ ID NO: 9080). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDIQMNQSPSSLSASLGDTITITCHASQNINVWLSWYQQKPGNIPKLLIYKASNLHTGVPSR FSGSGSGTGFTLTISSLRPEDIATYYCHQGQSYPLTFGAGTKLELK (SEQ ID NO: 9086). In some embodiments, the VL comprises a sequence ofDIQMNQSPSSLSASLGDTITITCHASQNINVWLSWYQQKPGNIPKLLIYKASNLHTGVPSR FSGSGSGTGFTLTISSLRPEDIATYYCHQGQSYPLTFGAGTKLELK (SEQ ID NO: 9086).

[0151] In some aspects, the present disclosure provides an agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of HGTAQAFFAMDY (SEQ ID NO: 9125).

[0152] In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of NSGVH (SEQ ID NO: 9123), GFSLTNS (SEQ ID NO: 9126), or GFSLTNSGVH (SEQ ID NO: 9128). In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of VIWSDGDTTYNSALKS (SEQ ID NO: 9124) or WSDGD (SEQ ID NO: 9127). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQGQSYPLT (SEQ ID NO: 9131). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of HASQNINVWLS (SEQ ID NO: 9129). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of KASNLHT (SEQ ID NO: 9130). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of HGTAQAFFAMDY (SEQ ID NO: 9125), a HC CDR2 comprising the amino acid sequence of VIWSDGDTTYNSALKS (SEQ ID NO: 9124) or WSDGD (SEQ ID NO: 9127), a HC CDR1 comprising the amino acid sequence of NSGVH (SEQ ID NO: 9123), GFSLTNS (SEQ ID NO: 9126), or GFSLTNSGVH (SEQ ID NO: 9128), a LC CDR3 comprising the amino acid sequence of QQGQSYPLT (SEQ ID NO: 9131), a LC CDR2 comprising the amino acid sequence of KASNLHT (SEQ ID NO: 9130), and a LC CDR1 comprising the amino acid sequence of HASQNINVWLS (SEQ ID NO: 9129). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequenceQVQLKESGPGLVAPSQSLSITCTVSGFSLTNSGVHWVRQPPGKGLEWLWIWSDGDTTYWSGR Docket No.: 53676-780.601NSALKSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCARHGTAQAFFAMDYWGQGTSV TVSS (SEQ ID NO: 9081). In some embodiments, the VH comprises a sequence of QVQLKESGPGLVAPSQSLSITCTVSGFSLTNSGVHWVRQPPGKGLEWLWIWSDGDTTY NSALKSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCARHGTAQAFFAMDYWGQGTSV TVSS (SEQ ID NO: 9081). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDIQMNQSPSSLSASLGDTITITCHASQNINVWLSWYQQKPGNIPKLLIYKASNLHTGVPSR FSGSGSGTGFTLTISSLQPEDIATYYCQQGQSYPLTFGGGTKLEIK (SEQ ID NO: 9087). In some embodiments, the VL comprises a sequence of DIQMNQSPSSLSASLGDTITITCHASQNINVWLSWYQQKPGNIPKLLIYKASNLHTGVPSR FSGSGSGTGFTLTISSLQPEDIATYYCQQGQSYPLTFGGGTKLEIK (SEQ ID NO: 9087). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of LQSDNLPYT (SEQ ID NO: 9136). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 9134). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of EGNTLRP (SEQ ID NO: 9135). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of HGTAQAFFAMDY (SEQ ID NO: 9125), a HC CDR2 comprising the amino acid sequence of VIWSDGDTTYNSALKS (SEQ ID NO: 9124) or WSDGD (SEQ ID NO: 9127), a HC CDR1 comprising the amino acid sequence of NSGVH (SEQ ID NO: 9123), GFSLTNS (SEQ ID NO: 9126), or GFSLTNSGVH (SEQ ID NO: 9128), a LC CDR3 comprising the amino acid sequence of LQSDNLPYT (SEQ ID NO: 9136), a LC CDR2 comprising the amino acid sequence of EGNTLRP (SEQ ID NO: 9135), and a LC CDR1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 9134). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceETTVTQSPASLSMAIGEKVTIRCITSTDIDDDMNWYQQKPGEPPKLLISEGNTLRPGVPSR FSSSGYGTDFVFTIENMLSEDVADYYCLQSDNLPYTFGGGTKLEIK (SEQ ID NO: 9088). In some embodiments, the VL comprises a sequence of ETTVTQSPASLSMAIGEKVTIRCITSTDIDDDMNWYQQKPGEPPKLLISEGNTLRPGVPSR FSSSGYGTDFVFTIENMLSEDVADYYCLQSDNLPYTFGGGTKLEIK (SEQ ID NO: 9088).

[0153] In some aspects, the present disclosure provides an agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of GDFYYDYDASFAY (SEQ ID NO: 9140).WSGR Docket No.: 53676-780.601

[0154] In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of SGYYWN (SEQ ID NO: 9138), GYSITSGY (SEQ ID NO: 9141), or GYSITSGYYWN (SEQ ID NO: 9143). In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of YISYDGSNNYNPSLKN (SEQ ID NO: 9139) or SYDGS (SEQ ID NO: 9142). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQGQSYPLT (SEQ ID NO: 9131). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of HASQNINVWLS (SEQ ID NO: 9129). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of KASNLHT (SEQ ID NO: 9130). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of GDFYYDYDASFAY (SEQ ID NO: 9140), a HC CDR2 comprising the amino acid sequence of YISYDGSNNYNPSLKN (SEQ ID NO: 9139) or SYDGS (SEQ ID NO: 9142), a HC CDR1 comprising the amino acid sequence of SGYYWN (SEQ ID NO: 9138), GYSITSGY (SEQ ID NO: 9141), or GYSITSGYYWN (SEQ ID NO: 9143), a LC CDR3 comprising the amino acid sequence of QQGQSYPLT (SEQ ID NO: 9131), a LC CDR2 comprising the amino acid sequence of KASNLHT (SEQ ID NO: 9130), and a LC CDR1 comprising the amino acid sequence of HASQNINVWLS (SEQ ID NO: 9129). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence DVQLQESGPGLVKPSQSLSLTCSVTGYSITSGYYWNWIRQFPGNKLEWMGYISYDGSNN YNPSLKNRISITRDTSKNQFFLKLNSVTTEDTATYYCARGDFYYDYDASFAYWGQGTLV TVSA (SEQ ID NO: 9082). In some embodiments, the VH comprises a sequence of DVQLQESGPGLVKPSQSLSLTCSVTGYSITSGYYWNWIRQFPGNKLEWMGYISYDGSNN YNPSLKNRISITRDTSKNQFFLKLNSVTTEDTATYYCARGDFYYDYDASFAYWGQGTLV TVSA (SEQ ID NO: 9082). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequenceDIQMNQSPSSLSASLGDTITITCHASQNINVWLSWYQQKPGNIPKLLIYKASNLHTGVPSR FSGSGSGTGFTLTISSLQPEDIATYYCQQGQSYPLTFGGGTKLEIK (SEQ ID NO: 9087). In some embodiments, the VL comprises a sequence of DIQMNQSPSSLSASLGDTITITCHASQNINVWLSWYQQKPGNIPKLLIYKASNLHTGVPSR FSGSGSGTGFTLTISSLQPEDIATYYCQQGQSYPLTFGGGTKLEIK (SEQ ID NO: 9087). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of LQSDNLPYT (SEQ ID NO: 9136). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 9134). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of EGNTLRP (SEQ ID NO: 9135). In some embodiments,WSGR Docket No.: 53676-780.601 the moiety comprises: a HC CDR3 comprising the amino acid sequence of GDFYYDYDASFAY (SEQ ID NO: 9140), a HC CDR2 comprising the amino acid sequence of YISYDGSNNYNPSLKN (SEQ ID NO: 9139) or SYDGS (SEQ ID NO: 9142), a HC CDR1 comprising the amino acid sequence of SGYYWN (SEQ ID NO: 9138), GYSITSGY (SEQ ID NO: 9141), or GYSITSGYYWN (SEQ ID NO: 9143), a LC CDR3 comprising the amino acid sequence of LQSDNLPYT (SEQ ID NO: 9136), a LC CDR2 comprising the amino acid sequence of EGNTLRP (SEQ ID NO: 9135), and a LC CDR1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 9134). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence ETTVTQSPASLSMAIGEKVTIRCITSTDIDDDMNWYQQKPGEPPKLLISEGNTLRPGVPSR FSSSGYGTDFVFTIENMLSEDVADYYCLQSDNLPYTFGGGTKLEIK (SEQ ID NO: 9088). In some embodiments, the VL comprises a sequence ofETTVTQSPASLSMAIGEKVTIRCITSTDIDDDMNWYQQKPGEPPKLLISEGNTLRPGVPSR FSSSGYGTDFVFTIENMLSEDVADYYCLQSDNLPYTFGGGTKLEIK (SEQ ID NO: 9088).

[0155] In some aspects, the present disclosure provides an agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of NRGYRYDVGAMDY (SEQ ID NO: 9147).

[0156] In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of TFGVH (SEQ ID NO: 9145), GFSLTTF (SEQ ID NO: 9148), or GFSLTTFGVH (SEQ ID NO: 9150). In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of VIWSDGSTTYNSALKS (SEQ ID NO: 9146) or WSDGS (SEQ ID NO: 9149). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QNDHSFPLT (SEQ ID NO: 9153). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of KSSQSLLNSGNQKNYLA (SEQ ID NO: 9151). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of GASTRES (SEQ ID NO: 9152). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of NRGYRYDVGAMDY (SEQ ID NO: 9147), a HC CDR2 comprising the amino acid sequence of VIWSDGSTTYNSALKS (SEQ ID NO: 9146) or WSDGS (SEQ ID NO: 9149), a HC CDR1 comprising the amino acid sequence of TFGVH (SEQ ID NO: 9145), GFSLTTF (SEQ ID NO: 9148), or GFSLTTFGVH (SEQ ID NO: 9150), a LC CDR3 comprising the amino acid sequence of QNDHSFPLT (SEQ ID NO: 9153), a LC CDR2 comprising the amino acid sequence of GASTRES (SEQ ID NO: 9152), and a LC CDR1 comprising the amino acid sequence ofWSGR Docket No.: 53676-780.601KSSQSLLNSGNQKNYLA (SEQ ID NO: 9151). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence QVQLKESGPGLVAPSQSLSITCTVSGFSLTTFGVHWVRQPPGKGLEWLVVIWSDGSTTY NSALKSRLSISKDNSKSQVFLEMNSLQTDDTAMYYCARNRGYRYDVGAMDYWGRGTS VTVSS (SEQ ID NO: 9083). In some embodiments, the VH comprises a sequence of QVQLKESGPGLVAPSQSLSITCTVSGFSLTTFGVHWVRQPPGKGLEWLVVIWSDGSTTY NSALKSRLSISKDNSKSQVFLEMNSLQTDDTAMYYCARNRGYRYDVGAMDYWGRGTS VTVSS (SEQ ID NO: 9083). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPSSLSVSAGEKVTMSCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYGAST RESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDHSFPLTFGAGTKLELK (SEQ ID NO: 9089). In some embodiments, the VL comprises a sequence of DIVMTQSPSSLSVSAGEKVTMSCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYGAST RESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDHSFPLTFGAGTKLELK (SEQ ID NO: 9089).

[0157] In some aspects, the present disclosure provides an agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of MRDSNYGGFAY (SEQ ID NO: 9178).

[0158] In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of TLGMGVN (SEQ ID NO: 9176), GFSLSTLGM (SEQ ID NO: 9179), or GFSLSTLGMGVN (SEQ ID NO: 9181). In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of HIWWDDDKYYNPALKS (SEQ ID NO: 9177) or WWDDD (SEQ ID NO: 9180). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQYWSTPYT (SEQ ID NO: 9184). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of KASEDIYNRLA (SEQ ID NO: 9182). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of GAASLET (SEQ ID NO: 9183). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of MRDSNYGGFAY (SEQ ID NO: 9178), a HC CDR2 comprising the amino acid sequence of HIWWDDDKYYNPALKS (SEQ ID NO: 9177) or WWDDD (SEQ ID NO: 9180), a HC CDR1 comprising the amino acid sequence of TLGMGVN (SEQ ID NO: 9176), GFSLSTLGM (SEQ ID NO: 9179), or GFSLSTLGMGVN (SEQ ID NO: 9181), a LC CDR3 comprising the amino acid sequence of QQYWSTPYT (SEQ ID NO: 9184), a LC CDR2WSGR Docket No.: 53676-780.601 comprising the amino acid sequence of GAASLET (SEQ ID NO: 9183), and a LC CDR1 comprising the amino acid sequence of KASEDIYNRLA (SEQ ID NO: 9182). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence QVTLKESGPGILQPSQTLSLTCSFSGFSLSTLGMGVNWIRQPSGKGLEWLAHIWWDDDK YYNPALKSRLTISKDTSKNQVFLKIANVDTADTATFYCARMRDSNYGGFAYWGQGTLV TVSA (SEQ ID NO: 9168). In some embodiments, the VH comprises a sequence of QVTLKESGPGILQPSQTLSLTCSFSGFSLSTLGMGVNWIRQPSGKGLEWLAHIWWDDDK YYNPALKSRLTISKDTSKNQVFLKIANVDTADTATFYCARMRDSNYGGFAYWGQGTLV TVSA (SEQ ID NO: 9168). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSSSSFSVSLGDRVPITCKASEDIYNRLAWYQQKPGNAPRLLISGAASLETGVPS RFSGSGSGKDYTLSITSLQTEDVATYYCQQYWSTPYTFGGGTKLEIK (SEQ ID NO: 9172). In some embodiments, the VL comprises a sequence of DIQMTQSSSSFSVSLGDRVPITCKASEDIYNRLAWYQQKPGNAPRLLISGAASLETGVPS RFSGSGSGKDYTLSITSLQTEDVATYYCQQYWSTPYTFGGGTKLEIK (SEQ ID NO: 9172).

[0159] In some aspects, the present disclosure provides an agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of GNYDYEGWFAY (SEQ ID NO: 9189).

[0160] In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of SYGIS (SEQ ID NO: 9187), GYNFTSY (SEQ ID NO: 9190), or GYNFTSYGIS (SEQ ID NO: 9193). In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of EFYPRSGNTYYNEKFRG (SEQ ID NO: 9188) or YPRSGN (SEQ ID NO: 9191). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of HQYLSSLT (SEQ ID NO: 9196). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of KSSQSVLYSSNQKNYLA (SEQ ID NO: 9194). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 9195). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of GNYDYEGWFAY (SEQ ID NO: 9189), a HC CDR2 comprising the amino acid sequence of EFYPRSGNTYYNEKFRG (SEQ ID NO: 9188) or YPRSGN (SEQ ID NO: 9191), a HC CDR1 comprising the amino acid sequence of SYGIS (SEQ ID NO: 9187), GYNFTSY (SEQ ID NO: 9190), or GYNFTSYGIS (SEQ ID NO: 9193), a LC CDR3 comprising the amino acid sequenceWSGR Docket No.: 53676-780.601 of HQYLSSLT (SEQ ID NO: 9196), a LC CDR2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 9195), and a LC CDR1 comprising the amino acid sequence of KSSQSVLYSSNQKNYLA (SEQ ID NO: 9194). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence QVQLQQSGAELARPGASVKLSCKASGYNFTSYGISWVKQRTGQGLEWIGEFYPRSGNT YYNEKFRGKATLTADKSSTTAYMELRSLTSEDSAVYFCATGNYDYEGWFAYWGQGTL VTVSA (SEQ ID NO: 9169). In some embodiments, the VH comprises a sequence of QVQLQQSGAELARPGASVKLSCKASGYNFTSYGISWVKQRTGQGLEWIGEFYPRSGNT YYNEKFRGKATLTADKSSTTAYMELRSLTSEDSAVYFCATGNYDYEGWFAYWGQGTL VTVSA (SEQ ID NO: 9169). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence NIMMTQSPSSLAVSAGEKVTMNCKSSQSVLYSSNQKNYLAWYQQKPGQSPKLLIYWAS TRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCHQYLSSLTFGAGTKLELK (SEQ ID NO: 9173). In some embodiments, the VL comprises a sequence ofNIMMTQSPSSLAVSAGEKVTMNCKSSQSVLYSSNQKNYLAWYQQKPGQSPKLLIYWAS TRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCHQYLSSLTFGAGTKLELK (SEQ ID NO: 9173).

[0161] In some aspects, the present disclosure provides an agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of RGLDYAMDY (SEQ ID NO: 9201).

[0162] In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of NYGMN (SEQ ID NO: 9199), GYTFTNY (SEQ ID NO: 9202), or GYTFTNYGMN (SEQ ID NO: 9204). In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of WINTYTGEPTYADDFKG (SEQ ID NO: 9200) or NTYTGE (SEQ ID NO: 9203). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QHSRELPLT (SEQ ID NO: 9207). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of RASKSVSTSGYSYMH (SEQ ID NO: 9205). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of LASNLES (SEQ ID NO: 9206). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of RGLDYAMDY (SEQ ID NO: 9201), a HC CDR2 comprising the amino acid sequence of WINTYTGEPTYADDFKG (SEQ ID NO: 9200) or NTYTGE (SEQ ID NO: 9203), a HC CDR1 comprising the amino acid sequence of NYGMN (SEQ ID NO: 9199),WSGR Docket No.: 53676-780.601GYTFTNY (SEQ ID NO: 9202), or GYTFTNYGMN (SEQ ID NO: 9204), a LC CDR3 comprising the amino acid sequence of QHSRELPLT (SEQ ID NO: 9207), a LC CDR2 comprising the amino acid sequence of LASNLES (SEQ ID NO: 9206), and a LC CDR1 comprising the amino acid sequence of RASKSVSTSGYSYMH (SEQ ID NO: 9205). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence QIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGWINTYTGE PTYADDFKGRFAFSLETSASTAYLQINNLKNEDTATYFCARRGLDYAMDYWGQGTSVT VSS (SEQ ID NO: 9170). In some embodiments, the VH comprises a sequence of QIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGWINTYTGE PTYADDFKGRFAFSLETSASTAYLQINNLKNEDTATYFCARRGLDYAMDYWGQGTSVT VSS (SEQ ID NO: 9170). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence DIVLTQSPASLAVSLGQRATISCRASKSVSTSGYSYMHWYQQKPGQPPKLLIYLASNLES GVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQHSRELPLTFGAGTKLELK (SEQ ID NO: 9174). In some embodiments, the VL comprises a sequence of DIVLTQSPASLAVSLGQRATISCRASKSVSTSGYSYMHWYQQKPGQPPKLLIYLASNLES GVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQHSRELPLTFGAGTKLELK (SEQ ID NO: 9174).

[0163] In some aspects, the present disclosure provides an agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of RGLDYAMDY (SEQ ID NO: 9212).

[0164] In some embodiments, the VH comprises a HC CDR1 comprising the amino acid sequence of TAGMQ (SEQ ID NO: 9210), GYTFTTA (SEQ ID NO: 9213), or GYTFTTAGMQ (SEQ ID NO: 9315). In some embodiments, the VH comprises a HC CDR2 comprising the amino acid sequence of WINTHSGEPKYAEDFKG (SEQ ID NO: 9211) or NTHSGE (SEQ ID NO: 9214). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QHSRELPLT (SEQ ID NO: 9218). In some embodiments, the VL comprises a LC CDR1 comprising the amino acid sequence of RASKSVSTSGYSYMH (SEQ ID NO: 9216). In some embodiments, the VL comprises a LC CDR2 comprising the amino acid sequence of LASNLDS (SEQ ID NO: 9217). In some embodiments, the moiety comprises: a HC CDR3 comprising the amino acid sequence of RGLDYAMDY (SEQ ID NO: 9212), a HC CDR2 comprising the amino acid sequence of WINTHSGEPKYAEDFKG (SEQ ID NO: 9211) or NTHSGE (SEQ ID NO: 9214), a HC CDR1WSGR Docket No.: 53676-780.601 comprising the amino acid sequence of TAGMQ (SEQ ID NO: 9210), GYTFTTA (SEQ ID NO: 9213), or GYTFTTAGMQ (SEQ ID NO: 9315), a LC CDR3 comprising the amino acid sequence of QHSRELPLT (SEQ ID NO: 9218), a LC CDR2 comprising the amino acid sequence of LASNLDS (SEQ ID NO: 9217), and a LC CDR1 comprising the amino acid sequence of RASKS VSTSGYSYMH (SEQ ID NO: 9216). In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence QIQLVQSGPELKKPGETVKISCKASGYTFTTAGMQWVQKMPGKGFKWIGWINTHSGEP KYAEDFKGRFAFSLETSASTAYLQISNLKNEDTATYFCARRGLDYAMDYWGQGTSVTV SS (SEQ ID NO: 9171). In some embodiments, the VH comprises a sequence of QIQLVQSGPELKKPGETVKISCKASGYTFTTAGMQWVQKMPGKGFKWIGWINTHSGEP KYAEDFKGRFAFSLETSASTAYLQISNLKNEDTATYFCARRGLDYAMDYWGQGTSVTV SS (SEQ ID NO: 9171). In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence DIVLTQSPASLAVSLGQRATISCRASKSVSTSGYSYMHWYQQIPGQPPKLLIYLASNLDS GVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQHSRELPLTFGAGTKLELK (SEQ ID NO: 9175). In some embodiments, the VL comprises a sequence of DIVLTQSPASLAVSLGQRATISCRASKSVSTSGYSYMHWYQQIPGQPPKLLIYLASNLDS GVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQHSRELPLTFGAGTKLELK (SEQ ID NO: 9175). In some embodiments, the agent comprises an antibody molecule or antigen binding domain thereof. In some embodiments, the agent comprises an Fc region. In some embodiments, the Fc region comprises no binding mutation. In some embodiments, the Fc region has effector function or enhanced effector function. In some embodiments, the effector function or enhanced effector function comprises antibody dependent cell-mediated cytotoxicity (ADCC), antibodydependent cellular phagocytosis (ADCP) or complement dependent cytotoxicity (CDC). In some embodiments, the effector function or enhanced effector function mediates killing of the autoreactive T cells in the human subject. In some embodiments, the agent comprises an another moiety. In some embodiments, the another moiety binds to a TCR variable region, wherein the TCR variable region is TCRBV9, wherein the another moiety that binds to the TCR variable region comprises a second VH, wherein the second VH comprises a heavy chain complementarity determining region 3 (HC CDR3) comprising an amino acid sequence as set forth in SWRRGIRGIGFDY (SEQ ID NO: 1250). In some embodiments, the second VH comprises a HC CDR1 comprising the amino acid sequence of DYIVH (SEQ ID NO: 1248), GYTFTDY (SEQ ID NO: 1251), or GYTFTDYIVH (SEQ ID NO: 1253). In some embodiments, the second VH comprises a HC CDR2 comprising the amino acid sequence of WINTYTGTPTYADDFEG (SEQ ID NO: 1249) or NTYTGT (SEQ ID NO: 1252). In someWSGR Docket No.: 53676-780.601 embodiments, the another moiety comprises a second VL, wherein the second VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256). In some embodiments, the second VL comprises a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO:1254). In some embodiments, the second VL comprises a LC CDR2 comprising the amino acid sequence of DGSTLQS (SEQ ID NO: 1255). In some embodiments, the another moiety comprises: a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250), a HC CDR2 comprising the amino acid sequence of WINTYTGTPTYADDFEG (SEQ ID NO: 1249) or NTYTGT (SEQ ID NO: 1252), a HC CDR1 comprising the amino acid sequence of DYIVH (SEQ ID NO: 1248), GYTFTDY (SEQ ID NO: 1251), or GYTFTDYIVH (SEQ ID NO: 1253), a LC CDR3 comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256), a LC CDR2 comprising the amino acid sequence of DGSTLQS (SEQ ID NO:1255), and a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254). In some embodiments, the another moiety comprises a NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In some embodiments, the NK cell engager comprises a second VH and a second VL, wherein the second VH comprises a HC CDR3 comprising the amino acid sequence of GDWHYFDY (SEQ ID NO: 7352). In some embodiments, the second VH comprises a HC CDR1 comprising the amino acid sequence of GFSFIRVGYHWN (SEQ ID NO: 7383). In some embodiments, the second VH comprises a HC CDR2 comprising the amino acid sequence of YIHRSGSTSYNPSLKS (SEQ ID NO: 7380). In some embodiments, the second VL comprises a LC CDR3 comprising the amino acid sequence of QFWDSTNSAV (SEQ ID NO: 7358). In some embodiments, the second VL comprises a LC CDR1 comprising the amino acid sequence of SGEKLSDKYVH (SEQ ID NO: 7356). In some embodiments, the second VL comprises a LC CDR2 comprising the amino acid sequence of ENDRRPS (SEQ ID NO: 7352). In some embodiments, the NK cell engager comprises: a HC CDR3 comprising the amino acid sequence of GDWHYFDY (SEQ ID NO: 7352), a HC CDR2 comprising the amino acid sequence of YIHRSGSTSYNPSLKS (SEQ ID NO: 7380, a HC CDR1 comprising the amino acid sequence of GFSFIRVGYHWN (SEQ ID NO: 7383), a LC CDR3 comprising the amino acid sequence of QFWDSTNSAV (SEQ ID NO: 7358), a LC CDR2 comprising the amino acid sequence of ENDRRPS (SEQ ID NO: 7352), and a LC CDR1 comprising the amino acid sequence of SGEKLSDKYVH (SEQ ID NO: 7356). In some embodiments, the agent comprises an Fc region. In some embodiments, the Fc region comprises an amino acid sequence with at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 or 42. In some embodiments, the Fc region comprises one or more mutations. In some embodiments, the Fc region comprises one or more amino acid substitutionsWSGR Docket No.: 53676-780.601 relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. In some embodiments, the Fc comprises one or more mutations comprising E233P, L234V, L235A, P329A, S267K, G237A, P238S, H268A, A330S, P331S, K322A, D265A, D265S, L235E, G236R, S239K, A327G, V273E, T299A, Y300S, or any combination thereof, where amino acid positioning is relative to SEQ ID NO: 42. In some embodiments, the Fc region comprises an Fc-silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function.

[0165] In some aspects, the present disclosure provides a method of treating a disease or condition or reducing a risk of developing the disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the agent described herein.

[0166] In some embodiments, the subject has an autoimmune disease. In some embodiments, the autoimmune disease is selected from the group consisting of the autoimmune disease is selected from amyotrophic lateral sclerosis (ALS), coeliac disease (CD), ankylosing spondylitis (AS), Covid-induced multisystem inflammatory syndrome in children (MIS-C), type 1 narcolepsy, primary Sjogren’s syndrome (PSS), Churg-Strauss syndrome, sarcoidosis, systemic lupus erythematosus (SLE), type 1 diabetes, autoimmune hepatitis (e.g., type 1 or type 2), acute anterior uveitis (UAA), primary sclerosing cholangitis, primary biliary cirrhosis, multiple sclerosis, Guillain-Barre syndrome and the AMAN (axonal & neuronal neuropathy), chronic inflammatory demyelinating polyneuropathy (CIDP), psoriatic arthritis (PsA), transverse myelitis, Tolosa-Hunt syndrome (THS), Devic’s disease (neuromyelitis optica), paraneoplastic cerebellardegeneration (PCD), Lambert-Eaton syndrome, psoriasis, scleroderma, CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome, dermatitis herpetiformis, dermatomyositis, bullous pemphigoid, cicatricial pemphigoid / benign mucosal pemphigoid, pemphigoid gestationis, rheumatoid arthritis (RA), psoriatic arthritis, relapsing polychondritis, chronic recurrent multifocal osteomyelitis (CRMO), vasculitis, Kawasaki disease, granulomatosis with polyangiitis (GPA), Behcet’s disease (vasculitis), Takayasu’s arteritis, polyarteritis nodosa, microscopic polyangiitis (MPA), leukocytoclastic vasculitis, Cogan’s syndrome, uveitis, peripheral uveitis (Pars planitis), scleritis, autoimmune inner ear disease (AIED), Crohn’s, ulcerative colitis (UC), Dressier’s syndrome, Rheumatic fever, Evans syndrome, paroxysmal nocturnal hemoglobinuria (PNH), hemolytic anemia, thrombocytopenic purpura (TTP), polymyositis, juvenile myositis (JM), juvenile dermatomyositis (JDM), juvenile polymyositis (JPM), ocular cicatricial pemphigoid, and Hashimoto’s thyroiditis. In some embodiments, the autoimmune disease or condition isWSGR Docket No.: 53676-780.601 ankylosing spondylitis. In some embodiments, the autoimmune disease or condition is Celiac disease. In some embodiments, the autoimmune disease or condition is reactive arthritis. In some embodiments, the autoimmune disease or condition is inflammatory bowel disease. In some embodiments, the autoimmune disease or condition is sacroiliitis. In some embodiments, the autoimmune disease or condition is Reiter's syndrome. In some embodiments, the autoimmune disease or condition is juvenile rheumatoid arthritis.INCORPORATION BY REFERENCE

[0167] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.BRIEF DESCRIPTION OF THE DRAWINGS

[0168] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0169] FIGs. 1A-1B show results of a NK cell binding assay. Percent of bound NK cells was measured over increasing concentration of tested constructs. FIG. 1A shows the binding curve for each construct. FIG. IB shows a table with binding dissociation constant (KD) values.

[0170] FIGs. 2A-2F show flow cytometry plots depicting the NK-cell binding panel of FIGs. 1A-1B. Target-fluorophore pairings included: viability -zombie NIR, CD3-BV510, CD4-Spark NIR 685, CD8-BUV805, CD56-RY610, and TCR-AlexaFluor® 647. FIG. 2A shows unfiltered results. FIG. 2B shows PBMC results. FIG. 2C shows singlets results. FIG. 2D shows viable results. FIG. 2E shows CD3- results. FIG. 2F shows NK cell results.

[0171] FIG. 3 shows results of hPBMC cell binding plate.

[0172] FIGs. 4A-4D show NK binding curves of constructs described herein. FIG. 4A shows binding of BOM0344 (anti-TCRpV 6 / 10) and BOM0347 (anti-TCRpV 6 / 10 x NKp30 binder). FIG. 4B binding of shows BOM0315 (anti-TCRpV 9), BOM0350 (anti-TCRpV 9 x NKp30), BOM0366 (humanized anti-TCRpV 9 vl), BOM0367 (humanized anti-TCRpV 9 v2), BOM0368 (humanized anti-TCRpV 9 v3), and BOM0369 (humanized anti-TCRpV 9 v4). FIG. 4C showsWSGR Docket No.: 53676-780.601 binding of BOM0345 (anti-TCRpV 7-2) and BOM0348 (anti-TCRpV 7-2 x NKp30). FIG. 4D shows binding of BOM0346 (anti-TCRaV 1-2) and BOM0349 (anti-TCRaV 1-2 x NKp30).

[0173] FIGs. 5A-5B show results of a T cell binding assay. Percent of bound T cells was measured over increasing concentration of tested constructs. FIG. 5A shows the binding curve for each construct. FIG. 5B shows a table with binding dissociation constant (KD) values.

[0174] FIGs. 6A-6D shows T cell binding curves of constructs described herein. FIG. 6A shows binding of BOM0344 (anti-TCRpV 6 / 10) and BOM0347 (anti-TCRpV 6 / 10 x NKp30 binder). FIG. 6B binding of shows BOM0315 (anti-TCRpV 9), BOM0350 (anti-TCRpV 9 x NKp30), BOM0366 (humanized anti-TCRpV 9 vl), BOM0367 (humanized anti-TCRpV 9 v2), BOM0368 (humanized anti-TCRpV 9 v3), and BOM0369 (humanized anti-TCRpV 9 v4). FIG. 6C shows binding of BOM0345 (anti-TCRpV 7-2) and BOM0348 (anti-TCRpV 7-2 x NKp30). FIG. 6D shows binding of BOM0346 (anti-TCRaV 1-2) and BOM0349 (anti-TCRaV 1-2 x NKp30).

[0175] FIGs. 7A-7E show flow cytometry plots displaying the gating scheme for the antibody dependent cell-mediated cytotoxicity (ADCC) assay. Cells were stained for surface markers CD3, CD4, CD8 and CD56 in addition to the TCR target of interest (TCRvP 6 / 10, TCRvP 7-2, TCRvP 9 or TCRva 1-2). FIG. 7A shows percentage stained of PBMCs. FIG. 7B shows singlets. FIG. 7C shows viable singlets. FIG. 7D shows CD3-positive cells. FIG. 7E shows CD3 -positive cells positive for the target construct.

[0176] FIGs. 8A-8D show depletion curves for the tested construct described herein. FIG. 8A shows percentage TCRPV 6 / 10-positive of CD3+cells. Construct BKM0259 had an anti-TCRpV 6 / 10 with a N297A Fc mutation. FIG. 8B shows percentage TCRaV 1-2-positive of CD3+cells. Construct BKM0075 had an anti-TCRaV 1-2 with a N297A Fc mutation. FIG. 8C shows percentage TCRPV 7-2 -positive of CD3+cells. Construct BKM0045 had an anti-TCRpV 7-2 with a N297A Fc mutation. FIG. 8D shows percentage TCRPV 9-positive of CD3+cells. Parental murine anti-TCRpV 9 construct was compared to humanized anti-TCRpV 9 constructs.

[0177] FIGs. 9A-9C shows schematic representations of constructs described herein. FIG. 9A shows an exemplary construct with a TCRva binder with an Fc region comprising a N297A mutation. FIG. 9B shows an exemplary construct with a TCRva binder with a wild-type Fc region. FIG. 9C shows an exemplary with a TCRva binder and a NK cell engager (e.g., NKp30 binder).

[0178] FIGs. 10A-10G shows schematic representations of agents (e.g., multispecific molecules) described herein. FIG. 10A shows an exemplary bispecific construct. FIG. 10B shows an exemplary monospecific construct. FIG. 10C shows an exemplary bispecific construct with a costimulatory molecule (denoted by the circular element). FIG. 10D shows an exemplary construct with an antigen-binding fragment and costimulatory molecule (denoted by the circularWSGR Docket No.: 53676-780.601 element). FIG. 10E shows an exemplary construct with two antigen-binding fragments and a costimulatory molecule (denoted by the circular element). FIG. 10F shows an exemplary construct with two antigen-binding fragments and a third binding region. FIG. 10G shows an exemplary construct with four antigen-binding fragments.

[0179] FIGs. 11A-11B show representations of the mechanisms described herein for targeting autoreactive T cells (e.g., disease-associated Va / p T cell subsets). FIG. 11A shows an exemplary agent described herein binding to a target autoreactive T cell and depleting the disease-associated cell with FC-enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). FIG. 11B shows an exemplary agent described herein binding to a target autoreactive T cell and a NK cell. The disease-associated cell is depleted by activating the nearby NK cell.

[0180] FIGs. 12A-12E show tables depicting exemplary molecules with cellular targets and indications. FIG. 12A shows molecules used to activate CD8 T cells, CD4 T cells, NK cells, or regulatory T cells (Tregs). FIG. 12B shows tri-specific molecules with binding targets and examples of costimulatory molecules. FIG. 12C shows multispecific molecules that bind to TCR beta variable regions. FIG. 12D shows exemplary molecules that bind to one or more TCR variable regions (e.g., TCR beta variable regions and / or TCR alpha variable regions). FIG. 12E shows multispecific molecules that activate NK cells using an NK cell engager.DETAILED DESCRIPTION

[0181] Disclosed herein, in some aspects, are methods of treating autoimmune diseases or conditions using TCR targeting molecules or cells expressing TCR targeting molecules. TCR targeting molecules can comprise a moiety that binds to a TCR variable beta chain (TCRBV) or a TCR variable alpha chain (TCRAV). TCR targeting molecules can further comprise one, two or all of: (ii) an immune cell engager; (iii) a cytokine inhibitor molecule; (iv) a cytotoxic agent; and / or (v) a death receptor signal enhancer.

[0182] Without wishing to be bound by theory, a TCR bias may exist in autoimmune diseases. This bias may be associated with dominant autoreactive TCR clones responsible for disease or associated with symptoms. Re-balancing the TCR repertoire, e.g., by eliminating or depleting T cells comprising an autoreactive clonotype, may treat the associated autoimmune disease and / or reduce symptoms of the autoimmune disease. Accordingly, the multispecific or multifunctional molecules disclosed herein are expected to target (e.g., localize, bridge and / or activate) an immune cell (e.g., an immune effector cell chosen from an NK cell, a T cell, a B cell, a dendritic cell or a macrophage), at a target cell (e.g., a T cell comprising a biased TCRAV or TCRBV clonotype or comprising a TCRAV or TCRBV antigen corresponding to a biased TCRAV or TCRBV clonotype). Increasing the proximity and / or activity of the immune cell using theWSGR Docket No.: 53676-780.601 multispecific molecules described herein is expected to enhance an immune response against the target cell (e.g., the T cell comprising a TCRAV or TCRBV, e.g., a TCRAV or TCRBV antigen corresponding to a biased TCRAV or TCRBV clonotype), thereby providing a more effective therapy (e.g., a more effective autoimmune disease therapy). Without being bound by theory, a targeted, localized immune response against the target cell (e.g., a T cell comprising a biased TCRAV or TCRBV clonotype is believed to reduce the effects of systemic toxicity of the multispecific molecules described herein. A targeted immune response against the autoreactive T cell population that targets non-autoreactive T cells to a lesser degree (e.g., does not target non- autoreactive T cells) is believed to have fewer deleterious effects than systemic ablation of all T cells.

[0183] Accordingly, provided herein are, inter alia, TCR targeting molecules (e.g., multispecific or multifunctional antibody molecules) that include the aforesaid moieties, nucleic acids encoding the same, methods of producing the aforesaid molecules, and methods of treating autoimmune disease using the aforesaid molecules. Also provided herein are anti-TCRaV or anti-TCRpV antibody molecules, nucleic acids encoding the same, methods of producing the aforesaid molecules, and methods of treating autoimmune disease using the anti-TCRaV or anti- TCRPV antibody molecules.

[0184] Further provided are methods for depletion (e.g., in vivo depletion) of biased TCRBV clonotypes, e.g., in the context of autoimmune disease with a multispecific molecule or an anti- TCRaV or anti-TCRpV antibody molecule. In some embodiments, the method involves identifying in a patient a clonal bias in TCRAV or TCRBV usage, e.g., associated with the autoreactive subpopulation, and responsive to this analysis administering a multifunctional molecule targeted to the TCRAV or TCRBV antigen corresponding to the biased TCRAV or TCRBV clonotype to decrease, e.g., eliminate, the clonal bias and promote, e.g., establish, a normal TCRBV distribution.

[0185] Accordingly, in one aspect, the disclosure features a multifunctional molecule, comprising: (i) a first antigen binding domain that binds to, e.g., selectively binds to, T cell receptor variable alpha (TCRAV), e.g., a TCRAV antigen, and (ii) one, two, or all of (a) an immune cell engager chosen from an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager; (b) a cytokine molecule or cytokine inhibitor molecule; and (c) a death receptor signal engager.

[0186] In another aspect, the disclosure features a multifunctional molecule, comprising: (i) a first antigen binding domain that binds to, e.g., selectively binds to, T cell receptor variable beta (TCRBV), e.g., a TCRBV antigen, and (ii) one, two, or all of: (a) an immune cell engager chosen from an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or aWSGR Docket No.: 53676-780.601 macrophage cell engager; (b) a cytokine molecule or cytokine inhibitor molecule; and (c) a death receptor signal engager.

[0187] In some embodiments, first antigen binding domain comprises an anti-TCRaV antibody molecule, e.g., as described herein.

[0188] In some embodiments, first antigen binding domain comprises an anti-TCRpV antibody molecule, e.g., as described herein.

[0189] In another aspect, the disclosure features a nucleic acid molecule encoding a multifunctional molecule disclosed herein.

[0190] In another aspect, the disclosure features a vector, e.g., an expression vector, comprising the nucleic acid molecules disclosed herein.

[0191] In another aspect, the disclosure features a host cell comprising a nucleic acid molecule or vector disclosed herein.

[0192] In another aspect, the disclosure features a method of making, e.g., producing, a multifunctional molecule disclosed herein, comprising culturing a host cell disclosed herein under suitable conditions, e.g., conditions suitable for gene expression and / or homo- or heterodimerization.

[0193] In another aspect, the disclosure features a pharmaceutical composition comprising a multifunctional molecule disclosed herein.

[0194] In another aspect, the disclosure features a method of treating a TCR bias, comprising administering to a subject in need thereof a multifunctional molecule disclosed herein, wherein the multifunctional molecule is administered in an amount effective to treat the TCR bias.

[0195] In another aspect, the disclosure features a method of treating an autoimmune disease (e.g., an autoimmune disease associated with a TCR bias), comprising administering to a subject in need thereof a multifunctional molecule disclosed herein, wherein the multifunctional molecule is administered in an amount effective to treat the autoimmune disease.

[0196] In another aspect, the disclosure features a method of identifying a subject in need of treatment for TCR bias or an autoimmune disease (e.g., associated with a TCR bias) using a multifunctional molecule disclosed herein, comprising determining (e.g., directly determining or indirectly determining, e.g., obtaining information regarding) whether a subject has a TCR bias (e.g., a biased TCRAV or TCRBV clonotype) and / or an autoimmune disease associated with said bias, wherein: responsive to determining that the subject has a TCR bias (e.g., a biased TCRAV or TCRBV clonotype) and / or an autoimmune disease associated with said bias, identifying the subject as a candidate for treatment using a multifunctional molecule comprising an antigen binding domain that binds to the TCRAV or TCRBV antigen.WSGR Docket No.: 53676-780.601

[0197] In another aspect, the disclosure features a method of evaluating a subject in need of treatment for a TCR bias (e.g., a biased TCRAV or TCRBV clonotype) and / or an autoimmune disease associated with said bias, comprising determining (e.g., directly determining or indirectly determining, e.g., obtaining information regarding) whether a subject has a TCR bias (e.g., a biased TCRAV or TCRBV clonotype).

[0198] In yet another aspect, disclosed herein is a method of treating an autoimmune disease (e.g., an autoimmune disease associated with a TCR bias), in a subject in need thereof, comprising administering to said subject an effective amount, e.g., a therapeutically effective amount, of an antibody molecule which binds (e.g., specifically binds) to a T cell receptor alpha variable region (TCRaV) (“anti-TCRaV antibody molecule”) or a T cell receptor beta variable region (TCRPV) (“anti-TCRpV antibody molecule”), thereby treating the disorder.

[0199] In another aspect, the disclosure provides a method of depleting a population of T cells in a subject having an autoimmune disorder (e.g., an autoimmune disease associated with a TCR bias), comprising, contacting the T cell population with an effective amount of an antibody molecule which binds (e.g., specifically binds) to a T cell receptor alpha variable region (TCRaV) (“anti-TCRaV antibody molecule”) or a T cell receptor beta variable region (TCRPV) (“anti-TCRpV antibody molecule”).

[0200] In another aspect, the disclosure features a nucleic acid molecule encoding an anti- TCRaV or anti-TCRpV antibody molecule disclosed herein.

[0201] In another aspect, the disclosure features a vector, e.g., an expression vector, comprising the nucleic acid molecules disclosed herein.

[0202] In another aspect, the disclosure features a host cell comprising a nucleic acid molecule or vector disclosed herein.

[0203] In another aspect, the disclosure features a method of making, e.g., producing, an anti- TCRaV or anti-TCRpV antibody molecule disclosed herein, comprising culturing a host cell disclosed herein under suitable conditions, e.g., conditions suitable for gene expression and / or homo- or heterodimerization.

[0204] In another aspect, the disclosure features a pharmaceutical composition comprising an anti-TCRpV antibody molecule disclosed herein.

[0205] Disclosed herein, in some aspects, are TCR targeting molecules that comprise an antigen binding domain that binds to, e.g., selectively binds to, T cell receptor variable beta (TCRBV), e.g., a TCRBV antigen. In some cases, the TCR targeting molecules comprise a Fc region that comprises one or more binding mutations that enhance effector function of the Fc region, such as antibody dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellularWSGR Docket No.: 53676-780.601 phagocytosis (ADCP) or complement dependent cytotoxicity (CDC). In some cases, the TCR targeting molecules comprise a Fc region that does not comprise a binding mutation.

[0206] Disclosed herein, in some aspects, are TCR targeting molecules that include a plurality of (e.g., two or more) functionalities (or binding specificities) (also referred to herein as multifunctional molecules or multispecific molecules), comprising (i) an antigen binding domain that binds to, e.g., selectively binds to, T cell receptor variable beta (TCRBV), e.g., a TCRBV antigen, and (ii) one, two, or all of: (a) an immune cell engager chosen from a T cell engager, an NK cell engager (e.g., a molecule that binds to NKp30, NKp46, NKG2D, or CD 16), a B cell engager, a dendritic cell engager, or a macrophage cell engager; (b) a cytokine inhibitor molecule; (c) a cytotoxic agent; (d) a death receptor signal engager.

[0207] In an embodiment, the TCR targeting molecule is a bispecific (or bifunctional) molecule, a trispecific (or trifunctional) molecule, or a tetraspecific (or tetrafunctional) molecule.

[0208] In some embodiments, the TCR targeting molecule comprises an antigen binding domain that binds a TCRAV or TCRBV antigen on the surface of a lymphocyte, e.g., T cell. In some embodiments, the TCRAV or TCRBV antigen corresponds to a biased TCRAV or TCRBV clonotype, e.g., TCRs comprising the TCRAV or TCRBV antigen may be over-represented in the TCR repertoire or lymphocyte (e.g., T cell) pool of a subject (e.g., subjects with autoimmune disease associated with TCR bias), or expressed at a level that is higher than the level in other subjects (e.g., non-autoimmune disease subjects).

[0209] Without being bound by theory, the TCR targeting molecules disclosed herein are expected to localize (e.g., bridge) and / or activate an immune cell (e.g., an immune effector cell chosen from a T cell, an NK cell, a B cell, a dendritic cell or a macrophage), in the presence of a cell (e.g., a lymphocyte, e.g., T cell) expressing the TCRAV or TCRBV antigen (e.g., a TCRAV or TCRBV antigen corresponding to a biased TCRAV or TCRBV clonotype), e.g., on the cell surface. Increasing the proximity and / or activity of the immune cell, in the presence of the cell (e.g., a lymphocyte, e.g., T cell) expressing the TCRAV or TCRBV antigen (e.g., a TCRAV or TCRBV antigen corresponding to a biased TCRAV or TCRBV clonotype) using the TCR targeting molecules described herein is expected to enhance an immune response against the target cell, thereby providing a more effective therapy (e.g., by decreasing the level of the biased TCR and / or T cell expressing the biased TCR). In another embodiment, targeting a cell (e.g., a lymphocyte, e.g., T cell) expressing the TCRAV or TCRBV antigen (e.g., a TCRAV or TCRBV antigen corresponding to a biased TCRAV or TCRBV clonotype) with a TCR targeting molecule also comprising a cell death inducing moiety (e.g., a death receptor signal engager) is thought to promote the death of the target cell (e.g., by decreasing the level of the biased TCR and / or T cell expressing the biased TCR).WSGR Docket No.: 53676-780.601

[0210] Without being bound by theory, by utilizing, in some embodiments, a TCR targeting molecule specific for a particular TCRAV or TCRBV antigen (e.g., a TCRAV or TCRBV antigen corresponding to a biased TCRAV or TCRBV clonotype), but not with specificity for other or all types of T cell receptors, it is expected that the deleterious effects of increasing the proximity or activity of immune cells toward T cells generally or promoting cell death in T cells generally may be mitigated. In this way, it is thought that use of the TCR targeting molecules disclosed herein may increase the proximity or activity of immune cells toward cells comprising TCRAV or TCRBV antigen corresponding to a biased TCRAV or TCRBV clonotype without necessarily increasing proximity or activity of immune cells toward T cells generally, or promote cell death in cells comprising TCRAV or TCRBV antigen corresponding to a biased TCRBV clonotype without necessarily increasing cell death in T cells generally.

[0211] Accordingly, provided herein are, inter alia, TCR targeting molecules (e.g., multifunctional antibody molecules) that include the aforesaid moieties, nucleic acids encoding the same, methods of producing the aforesaid molecules, and methods of treating a disease or disorder, e.g., an autoimmune disease or a TCR bias, using the aforesaid molecules.Certain Terminology

[0212] Certain specific details of this description are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the present disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments.

[0213] Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed disclosure.

[0214] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. The use of the words “a” or “an” when used in conjunction with the term “comprising” herein may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0215] It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0216] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can beWSGR Docket No.: 53676-780.601 used in the practice or testing of the present disclosure, suitable methods and materials are described below.

[0217] The term “about” when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or in some instances ±10%, or in some instances ±5%, or in some instances ±1%, or in some instances ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. As used herein, “about” and “approximately” generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given range of values.

[0218] The term “acquire” or “acquiring” as the terms are used herein, refer to obtaining possession of a physical entity (e.g., a sample, a polypeptide, a nucleic acid, or a sequence), or a value, e.g., a numerical value, by “directly acquiring” or “indirectly acquiring” the physical entity or value. “Directly acquiring” means performing a process (e.g., performing a synthetic or analytical method) to obtain the physical entity or value. “Indirectly acquiring” refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value). Directly acquiring a physical entity includes performing a process that includes a physical change in a physical substance, e.g., a starting material. Directly acquiring a value includes performing a process that includes a physical change in a sample or another substance, e.g., performing an analytical process which includes a physical change in a substance, e.g., a sample.

[0219] “Antibody molecule” as used herein refers to a protein, e.g., an immunoglobulin chain or fragment thereof, comprising at least one immunoglobulin variable domain structure and / or sequence. An antibody molecule encompasses antibodies (e.g., full-length antibodies) and antibody fragments. In some embodiments, an antibody molecule comprises an antigen binding or functional fragment of a full length antibody, or 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 normal immunoglobulin gene fragment recombinatorial processes). In embodiments, an antibody molecule refers to an immunologically active, antigenbinding portion of an immunoglobulin molecule, such as an antibody fragment. An antibody fragment, e.g., functional fragment, is a portion of an antibody, e.g., Fab, Fab', F(ab')2, F(ab)2, variable fragment (Fv), domain antibody (dAb), or single chain variable fragment (scFv). A functional antibody fragment binds to the same antigen as that recognized by the intact (e.g., full-length) antibody. The terms “antibody fragment” or “functional fragment” also include isolated fragments consisting of the variable regions, such as the “Fv” fragments consisting ofWSGR Docket No.: 53676-780.601 the variable regions of the heavy and light chains or recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker (“scFv proteins”). In some embodiments, an antibody fragment does not include portions of antibodies without antigen binding activity, such as Fc fragments or single amino acid residues. Exemplary antibody molecules include full length antibodies and antibody fragments, e.g., dAb (domain antibody), single chain, Fab, Fab’, and F(ab’)2 fragments, and single chain variable fragments (scFvs). In some embodiments, the antibody molecule is an antibody mimetic. In some embodiments, the antibody molecule is, or comprises, an antibody-like framework or scaffold, such as, fibronectins, ankyrin repeats (e.g., designed ankyrin repeat proteins (DARPins)), avimers, affibody affinity ligands, anticalins, or affilin molecules.

[0220] The term “human-like antibody molecule” as used herein refers to a humanized antibody molecule, human antibody molecule or an antibody molecule having at least 95% sequence identity with a non-murine germline framework region, e.g., FR1, FR2, FR3 and / or FR4. In some embodiments, the human-like antibody molecule comprises a framework region having at least 95% sequence identity to a human germline framework region, e.g., a 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 human antibody molecule. In some embodiments, the human-like antibody molecule is a phage display 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 grafted antibody molecule.

[0221] As used herein, an “immunoglobulin variable domain sequence” refers to an amino acid sequence which can form the structure of an immunoglobulin variable domain. For example, the sequence may include all or part of the amino acid sequence of a naturally-occurring variable domain. For example, the sequence may or may not include one, two, or more N- or C-terminal amino acids, or may include other alterations that are compatible with formation of the protein structure.

[0222] In embodiments, an antibody molecule is monospecific, e.g., it comprises binding specificity for a single epitope. In some embodiments, an antibody molecule is multispecific, e.g., it comprises a plurality of immunoglobulin variable domain sequences, where a first immunoglobulin variable domain sequence has binding specificity for a first epitope and a second immunoglobulin variable domain sequence has binding specificity for a second epitope. In some embodiments, an antibody molecule is a bispecific antibody molecule. “Bispecific antibody molecule” as used herein refers to an antibody molecule that has specificity for moreWSGR Docket No.: 53676-780.601 than one (e.g., two, three, four, or more) epitope and / or antigen. The terms “agent” and “construct” may be used interchangeably herein.

[0223] “Antigen” (Ag) as used herein refers to a molecule that can provoke an immune response, e.g., involving activation of certain immune cells and / or antibody generation. Any macromolecule, including almost all proteins or peptides, can be an antigen. Antigens can also be derived from genomic recombinant or DNA. For example, any DNA comprising a nucleotide sequence or a partial nucleotide sequence that encodes a protein capable of eliciting an immune response encodes an “antigen.” In embodiments, an antigen does not need to be encoded solely by a full length nucleotide sequence of a gene, nor does an antigen need to be encoded by a gene at all. As used, herein an “immune cell antigen” includes any molecule present on, or associated with, an immune cell that can provoke an immune response.

[0224] The “antigen-binding site,” or “binding portion” of an antibody molecule refers to the part of an antibody molecule, e.g., an immunoglobulin (Ig) molecule, that participates in antigen binding. In embodiments, the antigen binding site is formed by amino acid residues of the variable (V) regions of the heavy (H) and light (L) chains. Three highly divergent stretches within the variable regions of the heavy and light chains, referred to as hypervariable regions, are disposed between more conserved flanking stretches called “framework regions,” (FRs). FRs are amino acid sequences that are naturally found between, and adjacent to, hypervariable regions in immunoglobulins. In embodiments, in an antibody molecule, the three hypervariable regions of a light chain and the three hypervariable regions of a heavy chain are disposed relative to each other in three dimensional space to form an antigen-binding surface, which is complementary to the three-dimensional surface of a bound antigen. The three hypervariable regions of each of the heavy and light chains are referred to as “complementarity-determining regions,” or “CDRs.” The framework region and CDRs have been defined and described, e.g., in Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NTH 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) is typically made up of three CDRs and four FRs, arranged from amino-terminus to carboxyterminus in the amino acid order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0225] As used herein, an “immune cell” refers to any of various cells that function in the immune system, e.g., to protect against agents of infection and foreign matter. In embodiments, this term includes leukocytes, e.g., neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Innate leukocytes include phagocytes (e.g., macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells. Innate leukocytes identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing andWSGR Docket No.: 53676-780.601 then killing microorganisms, and are mediators in the activation of an adaptive immune response. The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are important types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response. The term “immune cell” includes immune effector cells.

[0226] “Immune effector cell,” as that term is used herein, refers to a cell that is involved in an immune response, e.g., in the promotion of an immune effector response. Examples of immune effector cells include, but are not limited to, T cells, e.g., alpha / beta T cells and gamma / delta T cells, B cells, natural killer (NK) cells, natural killer T (NK T) cells, and mast cells.

[0227] The term “effector function” or “effector response” refers to a specialized function of a cell. Effector function of a T cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines.

[0228] The terms “polypeptide”, “peptide” and “protein” (if single chain) are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by nonamino acids. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. The polypeptide can be isolated from natural sources, can be a produced by recombinant techniques from a eukaryotic or prokaryotic host, or can be a product of synthetic procedures.

[0229] The terms “nucleic acid,” “nucleic acid sequence,” “nucleotide sequence,” or “polynucleotide sequence,” and “polynucleotide” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. The polynucleotide may be either single-stranded or double-stranded, and if single-stranded may be the coding strand or non-coding (antisense) strand. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. The nucleic acid may be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semisynthetic, or synthetic origin which either does not occur in nature or is linked to another polynucleotide in a non-natural arrangement.

[0230] The term “isolated,” as used herein, refers to material that is removed from its original or native environment (e.g., the natural environment if it is naturally occurring). For example, a naturally-occurring polynucleotide or polypeptide present in a living animal is not isolated, butWSGR Docket No.: 53676-780.601 the same polynucleotide or polypeptide, separated by human intervention from some or all of the co-existing materials in the natural system, is isolated. Such polynucleotides could be part of a vector and / or such polynucleotides or polypeptides could be part of a composition, and still be isolated in that such vector or composition is not part of the environment in which it is found in nature. An isolated polynucleotide (ribonucleic acid (RNA), deoxyribonucleic acid (DNA)), or polypeptide is free of the genes / nucleic acids or sequences / amino acids that flank it in its naturally-occurring state.

[0231] The compositions and methods of the present invention encompass polypeptides and nucleic acids having the sequences specified, or sequences substantially identical or similar thereto, e.g., sequences at least 80%, 85%, 90%, 95% identical or higher to the sequence specified. In the context of an amino acid sequence, the term “substantially identical” is used herein to refer to a first amino acid that contains a sufficient or minimum number of amino acid residues that are i) identical to, or ii) conservative substitutions of aligned amino acid residues in a second amino acid sequence such that the first and second amino acid sequences can have a common structural domain and / or common functional activity. For example, amino acid sequences that contain a common structural domain having at least about 80%, 85%, 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99%, 99.5%, 99.9%, or 100% sequence identity to a reference sequence, e.g., a sequence provided herein. In the context of nucleotide sequence, the term “substantially identical” is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimum number of nucleotides that are identical to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide having common functional activity, or encode a common structural polypeptide domain or a common functional polypeptide activity. For example, nucleotide sequences having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99%, 99.5%, 99.9%, or 100% sequence identity to a reference sequence, e.g., a sequence provided herein.

[0232] The term “variant” refers to a polypeptide that has a substantially identical amino acid sequence to a reference amino acid sequence, or is encoded by a substantially identical nucleotide sequence. In some embodiments, the variant is a functional variant. In some embodiments, a TCRPV variant can bind to TCRa and form a TCR a:P complex.

[0233] The term “functional variant” refers to a polypeptide that has a substantially identical amino acid sequence to a reference amino acid sequence, or is encoded by a substantially identical nucleotide sequence, and is capable of having one or more activities of the reference amino acid sequence.

[0234] Calculations of homology or sequence identity between sequences (the terms are used interchangeably herein) are performed as follows. To determine the percent identity of twoWSGR Docket No.: 53676-780.601 amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, the length of a 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%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”).

[0235] The percent identity between the 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, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453 ) algorithm which has been incorporated into the GAP program in the GCG software package (available at http: / / www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at http: / / www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and the one that should be used unless otherwise specified) are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.

[0236] The percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CAB IOS, 4: 11-17) which has been incorporated into the ALIGN program (version 2.0), using a 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 a “query sequence” to perform a search against public databases to, for example, identify 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. BLAST nucleotide searches can be performed with the NBLAST program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to a nucleic acid molecule ofWSGR Docket No.: 53676-780.601 the invention. BLAST protein searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[0237] It is understood that the molecules of the present invention may have additional conservative or non-essential amino acid substitutions, which do not have a substantial effect on their functions.

[0238] The term “amino acid” is intended to embrace all molecules, whether natural or synthetic, which include both an amino functionality and an acid functionality and capable of being included in a polymer of naturally-occurring amino acids. Exemplary amino acids include naturally-occurring amino acids; analogs, derivatives and congeners thereof; amino acid analogs having variant side chains; and all stereoisomers of any of any of the foregoing. As used herein the term “amino acid” includes both the D- or L- optical isomers and peptidomimetics.

[0239] A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0240] As used herein, the term “molecule” as used in, e.g., antibody molecule, cytokine molecule, receptor molecule, includes full-length, naturally-occurring molecules, as well as variants, e.g., functional variants (e.g., truncations, fragments, mutated (e.g., substantially similar sequences) or derivatized form thereof), so long as at least one function and / or activity of the unmodified (e.g., naturally-occurring) molecule remains.

[0241] As used herein, the term “mutation” refers to an alteration in the nucleotide sequence of the genome of an organism, virus, or extrachromosomal DNA. In some embodiments, the mutation may be a large-scale mutation, such as amplifications (or gene duplications) or repetitions of a chromosomal segment, deletions of large chromosomal regions, chromosomal rearrangements (e.g., chromosomal translocations, chromosomal inversions, non-homologous chromosomal crossover, and interstitial deletions), and loss of heterozygosity. In some embodiments, the mutation may be a small-scale mutation, such as insertions, deletions, andWSGR Docket No.: 53676-780.601 substitution mutations. As used herein, the term “substitution mutation” refers to the transition that exchange a single nucleotide for another.

[0242] In some embodiments, the agent is the TCR targeting molecule as provided herein.Human T cell receptor (TCR) complex

[0243] TCR is a disulfide-linked membrane-anchored heterodimeric protein normally consisting of the highly variable alpha (a) and beta (P) chains expressed as part of a complex with the invariant CD3 chain molecules. TCR on aP 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 classified as the Immunoglobulin superfamily (IgSF) fold. The TCRPV chains can be further classified into 30 subfamilies (TRBV1-30). Despite their high structural and functional homology, the amino acid sequence homology in the TRBV genes is very low. Only 4 amino acids out of approximately 95 are identical while 10 additional amino acids are conserved among all subfamilies (see, an alignment of TCRBV amino acid sequences in Table 8). Nevertheless, TCRs formed between alpha and beta chains of highly diverse sequences show a remarkable structural homology and elicit a similar function, e.g., activation of T cells.

[0244] T cell receptors (TCR) can be found on the surface of T cells. TCRs recognize antigens, e.g., peptides, presented on, e.g., bound to, major histocompatibility complex (MHC) molecules on the surface of cells, e.g., antigen-presenting cells. TCRs are heterodimeric molecules and can comprise an alpha chain, a beta chain, a gamma chain or a delta chain. TCRs comprising an alpha chain and a beta chain are also referred to as TCRap. The TCR beta chain consists of the following regions (also known as segments): variable (V), diversity (D), joining (J) and constant (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 on-line, University of South Carolina School of Medicine). The TCR alpha chain consists of V, J and C regions. The rearrangement of the T-cell receptor (TCR) through somatic recombination of V (variable), D (diversity), J (joining), and C (constant) regions is a defining event in the development and maturation of a T cell. TCR gene rearrangement takes place in the thymus.

[0245] TCRs can comprise a receptor complex, known as the TCR complex, which comprises a TCR heterodimer comprising of an alpha chain and a beta chain, and dimeric signaling molecules, e.g., CD3 co-receptors, e.g., CD35 / s, and / or CD3y / s.

[0246] As used herein, the term “T cell receptor alpha variable chain” or “TCRaV,” or “TRAV,” refers to an extracellular region of the T cell receptor alpha chain which can comprise a portion of the antigen recognition domain of the T cell receptor. The term TCRaV includes isoforms, mammalian, e.g., human TCRaV, species homologs of human and analogs comprising at least one common epitope with TCRaV. Human TCRaV comprises a gene family comprisingWSGR Docket No.: 53676-780.601 subfamilies including, but not limited to: a TCRa VI subfamily, a TCRa V2 subfamily, a TCRa V3 subfamily, a TCRa V4, a TCRa V5 subfamily, a TCRa V6 subfamily, a TCRa V7 subfamily, a TCRa V8 subfamily, a TCRa V9 subfamily, a TCRa V10 subfamily, a TCRa V12 subfamily, a TCRa V13 subfamily, a TCRa V14 subfamily, a TCRa V16 subfamily, a TCRa VI 7 subfamily, a TCRa VI 8 subfamily, a TCRa VI 9 subfamily, a TCRa V20 subfamily, a TCRa V21 subfamily, a TCRa V22 subfamily, a TCRa V23 subfamily, a TCRa V24 subfamily, TCRa V25 subfamily, a TCRa V26 subfamily, a TCRa V27 subfamily, a TCRa V29 subfamily, a TCRa V30 subfamily, a TCRa V34 subfamily, a TCRa V35 subfamily, a TCRa V36 subfamily, a TCRa V38 subfamily, a TCRa V39 subfamily, a TCRa V40 subfamily, or a TCRa V41 subfamily, as well as family members of said subfamilies, and variants thereof (e.g., a structural or functional variant thereof).

[0247] In some embodiments, the TCRa VI subfamily comprises: TCRaVl-1 or TCRaVl-2, or a variant thereof.

[0248] In some embodiments, the TCRa V8 subfamily comprises: TCRaV8-l, TCRaV8-2, TCRaV8-3, TCRaV8-4, or TCRaV8-6, or a variant thereof.

[0249] In some embodiments, the TCRa V9 subfamily comprises: TCRaV9-l or TCRaV9-2, or a variant thereof.

[0250] In some embodiments, the TCRa V12 subfamily comprises: TCRaV12-l, TCRaV12-2, or TCRaV12-3, or a variant thereof.

[0251] In some embodiments, the TCRa V13 subfamily comprises: TCRaV13-l or TCRaV13-2, or a variant thereof.

[0252] In some embodiments, the TCRa V14 subfamily comprises: TCRaV14 / DV4, or a variant thereof.

[0253] In some embodiments, the TCRa V23 subfamily comprises: TCRaV23 / DV6, or a variant thereof.

[0254] In some embodiments, the TCRa V26 subfamily comprises: TCRaV26-l or TCRaV26-2, or a variant thereof.

[0255] In some embodiments, the TCRa V29 subfamily comprises: TCRaV29 / DV5, or a variant thereof.

[0256] In some embodiments, the TCRa V36 subfamily comprises: TCRaV236 / DV7, or a variant thereof.

[0257] In some embodiments, the TCRa V38 subfamily comprises: TCRaV38-l or TCRaV38- 2 / DV8, or a variant thereof.

[0258] As used herein, the term “T cell receptor beta variable chain” or “TCRPV,” refers to an extracellular region of the T cell receptor beta chain which comprises the antigen recognitionWSGR Docket No.: 53676-780.601 domain of the T cell receptor. The term TCRPV includes isoforms, mammalian, e.g., human TCRPV, species homologs of human and analogs comprising at least one common epitope with TCRPV. Human TCRPV comprises a gene family comprising subfamilies including, but not limited to: a TCRP V6 subfamily, a TCRP V10 subfamily, a TCRP V12 subfamily, a TCRP V5 subfamily, a TCRP V7 subfamily, a TCRP VI 1 subfamily, a TCRP V14 subfamily, a TCRP V16 subfamily, a TCRP VI 8 subfamily, a TCRP V9 subfamily, a TCRP VI 3 subfamily, a TCRP V4 subfamily, a TCRP V3 subfamily, a TCRP V2 subfamily, a TCRP V15 subfamily, a TCRP V30 subfamily, a TCRP VI 9 subfamily, a TCRP V27 subfamily, a TCRP V28 subfamily, a TCRP V24 subfamily, a TCRP V20 subfamily, TCRP V25 subfamily, a TCRP V29 subfamily, a TCRP VI subfamily, a TCRP VI 7 subfamily, a TCRP V21 subfamily, a TCRP V23 subfamily, or a TCRP V26 subfamily, as well as family members of said subfamilies, and variants thereof (e.g., a structural or functional variant thereof). In some embodiments, the TCRP V6 subfamily comprises: TCRP V6-4*01, TCRP V6-4*02, TCRP V6-9*01, TCRP V6-8*01, TCRP V6-5*01, TCRP V6-6*02, TCRP V6-6*01, TCRP V6-2*01, TCRP V6-3*01 or TCRP V6-l*01. In some embodiments, TCRPV comprises TCRP V6-5*01, or a variant thereof, e.g., a variant having 85%, 90%, 95%, 99% or more identity the naturally-occurring sequence. TCRP V6-5*01 is also known as TRBV65; TCRBV6S5; TCRBV13S1, or TCRP V13.1. The amino acid sequence of TCRP V6-5*01, e.g., human TCRP V6-5*01, is known in that art, e.g., as provided by IMGT ID L36092. In some embodiments, TCRP 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 thereof. In some embodiments, TCRP V6-5*01 comprises the amino acid sequence of SEQ ID NO: 44, or a sequence having 85%, 90%, 95%, 99% or more identity thereof.

[0259] SEQ ID NO: 43ATGAGCATCGGCCTCCTGTGCTGTGCAGCCTTGTCTCTCCTGTGGGCAGGTCCAGTG AATGCTGGTGTCACTCAGACCCCAAAATTCCAGGTCCTGAAGACAGGACAGAGCAT GACACTGCAGTGTGCCCAGGATATGAACCATGAATACATGTCCTGGTATCGACAAG ACCCAGGCATGGGGCTGAGGCTGATTCATTACTCAGTTGGTGCTGGTATCACTGACC AAGGAGAAGTCCCCAATGGCTACAATGTCTCCAGATCAACCACAGAGGATTTCCCG CTCAGGCTGCTGTCGGCTGCTCCCTCCCAGACATCTGTGTACTTCTGTGCCAGCAGTT ACTC

[0260] SEQ ID NO: 44MSIGLLCCAALSLLWAGPVNAGVTQTPKFQVLKTGQSMTLQCAQDMNHEYMSWYRQ DPGMGLRLIHYSVGAGITDQGEVPNGYNVSRSTTEDFPLRLLSAAPSQTSVYFCASSYWSGR Docket No.: 53676-780.601TCR alpha V (TCRaV)

[0261] Diversity in the immune system enables protection against a huge array of pathogens. Since the germline genome is limited in size, diversity is achieved not only by the process of V(D)J recombination but also by junctional (junctions between V-D and D-J segments) deletion of nucleotides and addition of pseudo-random, non-templated nucleotides. The TCR alpha gene undergoes gene arrangement to generate diversity.

[0262] The TCR V alpha repertoire varies between individuals and populations because of, e.g., 7 frequently occurring inactivating polymorphisms in functional gene segments and a large insertion / deletion-related polymorphism encompassing 2 V alpha gene segments.

[0263] Provided herein are, inter alia, antibody molecules and fragments thereof, that bind, e.g., specifically bind, to a human TCR alpha V chain (TCRaV), e.g., a TCRaV gene family (also referred to as a group), e.g., a TCRaV subfamily (also referred to as a subgroup), e.g., as described herein. TCR alpha V families and subfamilies are known in the art, e.g., as described in 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 can be recombinant antibodies, e.g., recombinant non-murine antibodies, e.g., recombinant human or humanized antibodies.

[0264] The terms TCRAV, TCRVA, TRAV, TCRaV, TCRVa or TRaV are used interchangeably herein and refer to a TCR alpha V chain, e.g., as described herein.

[0265] In some embodiments, provided herein is an anti-TCRaV antibody molecule that binds to human TCRaV, e.g., a TCRaV family, e.g., gene family or a variant thereof.

[0266] Exemplary amino acid sequences for TCRaV subfamily members can be found on the ImMunoGeneTics Information System website: www.imgt.org, or in a similar resource.TCR beta V (TCRpV)

[0267] Diversity in the immune system enables protection against a huge array of pathogens. Since the germline genome is limited in size, diversity is achieved not only by the process of V(D)J recombination but also by junctional (junctions between V-D and D-J segments) deletion of nucleotides and addition of pseudo-random, non-templated nucleotides. The TCR beta gene undergoes gene arrangement to generate diversity.

[0268] The TCR V beta repertoire varies between individuals and populations because of, e.g., 7 frequently occurring inactivating polymorphisms in functional gene segments and a large insertion / deletion-related polymorphism encompassing 2 V beta gene segments.

[0269] Provided herein are, inter alia, antibody molecules and fragments thereof, that bind, e.g., specifically bind, to a human TCR beta V chain (TCRPV), e.g., a TCRPV gene family (also referred to as a group), e.g, a TCRPV subfamily (also referred to as a subgroup), e.g, asWSGR Docket No.: 53676-780.601 described herein. TCR beta V families and subfamilies are known in the art, e.g., as described in 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 can be recombinant antibodies, e.g, recombinant non-murine antibodies, e.g, recombinant human or humanized antibodies.

[0270] The terms TCRB V, TCRVB, TRBV, TCRpV, TCRVP or TRpV are used interchangeably herein and refer to a TCR beta V chain, e.g., as described herein.

[0271] In some embodiments, provided herein is an anti-TCRpV antibody molecule that binds to human TCRPV, e.g., a TCRPV family, e.g., gene family or a variant thereof. In some embodiments a TCRBV gene family comprises one or more subfamilies, e.g., as described herein, e.g., in Table 6 or Table 7. In some embodiments, the TCRPV gene family comprises: a TCRP V6 subfamily, a TCRP V10 subfamily, a TCRP V12 subfamily, a TCRP V5 subfamily, a TCRP V7 subfamily, a TCRP VI 1 subfamily, a TCRP V14 subfamily, a TCRP V16 subfamily, a TCRP VI 8 subfamily, a TCRP V9 subfamily, a TCRP VI 3 subfamily, a TCRP V4 subfamily, a TCRP V3 subfamily, a TCRP V2 subfamily, a TCRP VI 5 subfamily, a TCRP V30 subfamily, a TCRP VI 9 subfamily, a TCRP V27 subfamily, a TCRP V28 subfamily, a TCRP V24 subfamily, a TCRP V20 subfamily, TCRP V25 subfamily, a TCRP V29 subfamily, a TCRP VI subfamily, a TCRP VI 7 subfamily, a TCRP V21 subfamily, a TCRP V23 subfamily, or a TCRP V26 subfamily.

[0272] In some embodiments, TCRP V6 subfamily is also known as TCRP VI 3.1. In some embodiments, the TCRP V6 subfamily comprises: TCRP V6-4*01, TCRP V6-4*02, TCRP V6- 9*01, TCRP V6-8*01, TCRP V6-5*01, TCRP V6-6*02, TCRP V6-6*01, TCRP V6-2*01, TCRP V6-3*01 or TCRP V6-l*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-4*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6- 4*02, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-9*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-8*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-5*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-6*02, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-6*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-2*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-3*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6- 1*01, or a variant thereof.

[0273] In some embodiments, TCRP V6 comprises TCRP V6-5*01, or a variant thereof. In some embodiments, TCRP V6, e.g., TCRP V6-5*01, is recognized, e.g., bound, by SEQ ID NO: 1 and / or SEQ ID NO: 2. In some embodiments, TCRP V6, e.g., TCRP V6-5*01, is recognized,WSGR Docket No.: 53676-780.601 e.g., bound, by SEQ ID NO: 9 and / or SEQ ID NO: 10. In some embodiments, TCRP V6 is recognized, e.g., bound, by SEQ ID NO: 9 and / or SEQ ID NO: 11.

[0274] In some embodiments, TCRP V10 subfamily is also known as TCRP V12. In some embodiments, the TCRP V10 subfamily comprises: TCRP V10-l*01, TCRP V10-l*02, TCRP VI 0-3 *01 or TCRP VI 0-2*01, or a variant thereof.

[0275] In some embodiments, TCRP V12 subfamily is also known as TCRP V8.1. In some embodiments, the TCRP V12 subfamily comprises: TCRP V12-4*01, TCRP V12-3*01, or TCRP V12-5*01, or a variant thereof. In some embodiments, TCRP V12 is recognized, e.g., bound, by SEQ ID NO: 15 and / or SEQ ID NO: 16. In some embodiments, TCRP V12 is recognized, e.g., bound, by any one of SEQ ID NOs 23-25, and / or any one of SEQ ID NO: 26-30:

[0276] In some embodiments, the TCRP V5 subfamily is chosen from: TCRP V5-5*01, TCRP V5-6*01, TCRP V5-4*01, TCRP V5-8*01, TCRP V5-l*01, or a variant thereof.

[0277] In some embodiments, the TCRP V7 subfamily comprises TCRP V7-7*01, TCRP V7- 6*01, TCRP V7 -8*02, TCRP V7 -4*01, TCRP V7-2*02, TCRP V7-2*03, TCRP V7-2*01, TCRP V7-3*01, TCRP V7-9*03, or TCRP V7-9*01, or a variant thereof.

[0278] In some embodiments, the TCRP VI 1 subfamily comprises: TCRP VI 1-1*01, TCRP VI 1-2*01 or TCRP VI 1-3*01, or a variant thereof. In some embodiments, the TCRP V14 subfamily comprises TCRP V14*01, or a variant thereof. In some embodiments, the TCRP V16 subfamily comprises TCRP V16*01, or a variant thereof. In some embodiments, the TCRP V18 subfamily comprises TCRP V18*01, or a variant thereof. In some embodiments, the TCRP V9 subfamily comprises TCRP V9*01 or TCRP V9*02, or a variant thereof. In some embodiments, the TCRP VI 3 subfamily comprises TCRP VI 3 *01, or a variant thereof. In some embodiments, the TCRP V4 subfamily comprises TCRP V4-2*01, TCRP V4-3*01, or TCRP V4-l*01, or a variant thereof. In some embodiments, the TCRP V3 subfamily comprises TCRP V3-l*01, or a variant thereof. In some embodiments, the TCRP V2 subfamily comprises TCRP V2*01, or a variant thereof. In some embodiments, the TCRP VI 5 subfamily comprises TCRP VI 5 *01, or a variant thereof. In some embodiments, the TCRP V30 subfamily comprises TCRP V30*01, or TCRP V30*02, or a variant thereof. In some embodiments, the TCRP V19 subfamily comprises TCRP VI 9*01, or TCRP VI 9*02, or a variant thereof. In some embodiments, the TCRP V27 subfamily comprises TCRP V27*01, or a variant thereof. In some embodiments, the TCRP V28 subfamily comprises TCRP V28*01, or a variant thereof. In some embodiments, the TCRP V24 subfamily comprises TCRP V24-l*01, or a variant thereof. In some embodiments, the TCRP V20 subfamily comprises TCRP V20-l*01, or TCRP V20-l*02, or a variant thereof. In some embodiments, the TCRP V25 subfamily comprises TCRP V25-l*01, or a variant thereof. In some embodiments, the TCRP V29 subfamily comprises TCRP V29-l*01, or a variant thereof.WSGR Docket No.: 53676-780.601

[0279] Exemplary amino acid sequences for TCRPV subfamily members can be found on the ImMunoGeneTics Information System website: www.imgt.org, or in a similar resource. Treatment of Subjects

[0280] Any of the compositions provided herein may be administered to an individual. “Individual” may be used interchangeably with “subject” or “patient.” An individual may be a mammal, for example a human or animal such as a non-human primate, a rodent, a rabbit, a rat, a mouse, a horse, a donkey, a goat, a cat, a dog, a cow, a pig, or a sheep. In some embodiments, the individual is a human. In some embodiments, the individual is a fetus, an embryo, or a child. In other embodiments, the individual may be another eukaryotic organism, such as a plant. In some embodiments, the compositions provided herein are administered to a cell ex vivo.

[0281] In some embodiments, the compositions provided herein are administered to an individual as a method of treating a disease or disorder. In some embodiments, the individual has a genetic disease, such as any of the diseases described herein. In some embodiments, the individual is at risk of having a disease, such as any of the diseases described herein. In some embodiments, the individual is at increased risk of having a disease or disorder caused by insufficient amount of a protein or ins...

Claims

1. WSGR Docket No.: 53676-780.601CLAIMSWhat is claimed is:

1. A method of treating a disease or condition or reducing a risk of developing the disease or condition in a subject in need thereof, comprising administering to the subject a composition, wherein the composition comprises an agent comprising a moiety that binds to a TCR variable region, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor variable beta region (TCRPV), and wherein:(a) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily;(b) the disease or condition is acute anterior uveitis (UAA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(c) the disease or condition is psoriatic arthritis (PsA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(d) the disease or condition is type I narcolepsy, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily;(e) the disease or condition is amyotrophic lateral sclerosis (ALS), and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily;(f) the disease or condition is UAA, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily;(g) the disease or condition is PsA, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily;(h) the disease or condition is Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCRa V41 subfamily;(i) the disease or condition is alopecia, and the moiety that binds to the TCR variable region binds to a TCRP VI 5 subfamily; or(j) the disease or condition is alopecia, and the moiety that binds to the TCR variable region binds to a TCRP V2 subfamily.

2. A method of treating a disease or condition or reducing a risk of developing the disease or condition in a subject in need thereof, comprising administering to the subject a composition, wherein the composition comprises an agent comprising a moiety that binds to a TCR variable region,WSGR Docket No.: 53676-780.601 wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the agent is present in the composition at a concentration of at least about 0.001 mg / ml, and wherein:(a) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRa VI subfamily;(b) the disease or condition is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V2 subfamily;(c) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V4 subfamily;(d) the disease or condition is Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCRa V12 subfamily;(e) the disease or condition is Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily;(f) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V20 subfamily;(g) the disease or condition is ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily;(h) the disease or condition is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V22 subfamily;(i) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V26 subfamily;(j) the disease or condition is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V40 subfamily;(k) the disease or condition is joint implant failure, and the moiety that binds to the TCR variable region binds to a TCRa V41 subfamily;(l) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily;(m) the disease or condition is primary Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily;(n) the disease or condition is amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily;(o) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily;WSGR Docket No.: 53676-780.601(p) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily;(q) the disease or condition is ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(r) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP VI 0 subfamily;(s) the disease or condition is COVID-induced multisystem inflammatory syndrome in children, and the moiety that binds to the TCR variable region binds to a TCRP VI 1 subfamily;(t) the disease or condition is Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCRP V12 subfamily;(u) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP VI 0 subfamily;(v) the disease or condition is Amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V23 subfamily;(w) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V29 subfamily;(x) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily;(y) the disease or condition is acute anterior uveitis (UAA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(z) the disease or condition is psoriatic arthritis (PsA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(aa) the disease or condition is type I narcolepsy, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily;(bb) the disease or condition is amyotrophic lateral sclerosis (ALS), and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily; or(cc) the disease or condition is UAA, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily.

3. The method of claim 2, wherein the agent is present in the composition at a concentration of at least about 0.01 mg / ml.

4. The method of claim 2, wherein the agent is present in the composition at a concentration of at least about 0.1 mg / ml.

5. The method of claim 2, wherein the agent is present in the composition at a concentration of at least about 1.0 mg / ml.WSGR Docket No.: 53676-780.6016. A method of treating a disease or condition or reducing a risk of developing the disease or condition in a subject in need thereof, comprising administering to the subject a composition, wherein the composition comprises an agent comprising a moiety that binds to a TCR variable region, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the moiety binds to the TCR variable region with a KD of at most about 500 nM, and wherein:(a) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRa VI subfamily;(b) the disease or condition is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V2 subfamily;(c) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V4 subfamily;(d) the disease or condition is Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCRa V12 subfamily;(e) the disease or condition is Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily;(f) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V20 subfamily;(g) the disease or condition is ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily;(h) the disease or condition is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V22 subfamily;(i) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V26 subfamily;(j) the disease or condition is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V40 subfamily;(k) the disease or condition is joint implant failure, and the moiety that binds to the TCR variable region binds to a TCRa V41 subfamily;(l) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily;(m) the disease or condition is amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily;WSGR Docket No.: 53676-780.601(n) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily;(o) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily;(p) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP VI 0 subfamily;(q) the disease or condition is COVID-induced multisystem inflammatory syndrome in children, and the moiety that binds to the TCR variable region binds to a TCRP VI 1 subfamily;(r) the disease or condition is Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCRP V12 subfamily;(s) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP VI 0 subfamily;(t) the disease or condition is Amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V23 subfamily;(u) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V29 subfamily;(v) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily;(w) the disease or condition is acute anterior uveitis (UAA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(x) the disease or condition is psoriatic arthritis (PsA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(y) the disease or condition is type I narcolepsy, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily;(z) the disease or condition is amyotrophic lateral sclerosis (ALS), and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily; or(aa) the disease or condition is UAA, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily.

7. The method of claim 6, wherein the moiety binds to the TCR variable region with a KD of at most about 100 nM.

8. The method of claim 6, wherein the moiety binds to the TCR variable region with a KD of at most about 10 nM.

9. The method of claim 6, wherein the moiety binds to the TCR variable region with a KD of at most about 1 nM.WSGR Docket No.: 53676-780.60110. The method of any one of claims 1-9, wherein the administration of the composition inhibits or prevents activation or expansion of autoreactive T cells in the subject.

11. The method of claim 10, wherein the autoreactive T cells target an autologous cell in the subject.

12. The method of claim 10 or 11, wherein the autoreactive T cells express TCRaV and / orTCRPV.

13. The method of any one of claims 1-12, wherein the agent comprises an antibody molecule or antigen binding domain thereof.

14. The method of claim 13, wherein the antibody molecule comprises an Fc region.

15. The method of claim 14, wherein the Fc region comprises a binding mutation.

16. The method of any one of claims 1-15, wherein the agent is functionally linked to a cytotoxic agent.

17. The method of claim 16, wherein the cytotoxic agent comprises calicheamicin, monomethyl auristatin E, maytansine derivative, or exatecan derivative.

18. The method of claim 14, wherein the Fc region comprises no binding mutation.

19. The method of any one of claims 16-18, wherein the cytotoxic agent mediates killing of the autoreactive T cells in the subject.

20. The method of claim 14, wherein the Fc region has effector function or enhanced effector function.

21. The method of claim 20, wherein the effector function or enhanced effector function comprises antibody dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement dependent cytotoxicity (CDC).

22. The method of claim 20 or 21, wherein the effector function or enhanced effector function mediates killing of the autoreactive T cells in the subject.

23. The method of any one of claims 1-12, wherein the agent comprises an another moiety.

24. The method of claim 23, wherein the another moiety comprises aNK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

25. The method of claim 24, wherein the another moiety comprises the NK cell engager, and wherein said NK cell engager binds to NKp30.

26. The method of claim 25, wherein binding of the another moiety to NKp30 mediates killing of the autoreactive T cells in the subject.

27. The method of claim 25 or 26, wherein the NK cell engager comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) the VH comprises a heavy chain complementarity determining region 1 (HC CDR1), HC CDR 2, and HC CDR 3 comprising: (i) an amino acid sequence of SEQ ID NOs: 6000, 6001, and 6003,WSGR Docket No.: 53676-780.601 respectively; (ii) an amino acid sequence of SEQ ID NOs: 6007, 6008, and 6009, respectively; (iii) an amino acid sequence of SEQ ID NOs: 7313, 6001, and 6002, respectively; (iv) an amino acid sequence of SEQ ID NOs: 7313, 6008, and 6009, respectively; (v) an amino acid sequence of SEQ ID NOs: 7313, 7385, and 7315, respectively; (vi) an amino acid sequence of SEQ ID NOs: 7313, 7318, and 6009, respectively; (vii) an amino acid sequence of SEQ ID NOs: 7313, 6001, and 7315, respectively; or (viii) an amino acid sequence of SEQ ID NOs: 7383, 7380, and 7352, respectively; and / or (b) the VL comprises a light chain complementarity determining region (LC CDR1), LC CDR2, and LC CDR3 comprising: (i) an amino acid sequence of SEQ ID NOs: 6063, 6064, and 67293, respectively; (ii) an amino acid sequence of SEQ ID NOs: 6070, 6071, and 6072, respectively; (iii) an amino acid sequence of SEQ ID NOs: 6070, 6064, and 7321, respectively; or (iv) an amino acid sequence of SEQ ID NOs: 7326, 7327, and 7329, respectively.

28. The method of claim 27, wherein the VH comprises a sequence with 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 6121-6134, 7295, 7297, 7298, 7300-7304, and 7384; and / or the VL comprises a sequence with 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 6136-6147, 7294, 7296, 7299, and 7305-7309.

29. The method of claim 27 or 28, wherein the VH comprises an amino acid sequence of any one of SEQ ID NOs: 6121-6134, 7295, 7297, 7298, 7300-7304, and 7384; and / or the VL comprises an amino acid sequence of any one of SEQ ID NOs: 6136-6147, 7294, 7296, 7299, and 7305-7309.

30. The method of any one of claims 25-29, wherein the NK cell engager that binds to NKp30 comprises an amino acid sequence as set forth in SEQ ID NO: 7310, 7311, 7400, 7401, 7402, 7403, 7404, 7405, 7406, 7407, or 7369.

31. The method of claim 24, wherein the another moiety comprises the T cell engager, and wherein said T cell engager binds to an antigen expressed on a CD8+ and / or CD4+ T cell.

32. The method of claim 31, wherein the another moiety comprises the T cell engager, and wherein said T cell engager binds to a TCRaV or a TCRPV.

33. The method of claim 31, wherein the TCRaV or a TCRPV comprises a different TCRaV or aTCRPV from the TCR variable region that the moiety of the agent binds to.

34. The method of claim 24, wherein the another moiety comprises the T cell engager, and wherein said T cell engager binds to CD3.

35. The method of any one of claims 31-34, wherein binding of the T cell engager to a CD8+ and / or CD4+ T cell mediates killing of the autoreactive T cells in the subject.WSGR Docket No.: 53676-780.60136. The method of any one of claims 31-35, wherein the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRaVl-1 or TCRaVl-2.

37. The method of any one of claims 31-35, wherein the disease or condition is type I diabetes, and wherein the moiety that binds to the TCR variable region binds to TCRaV12-3.

38. The method of any one of claims 31-35, wherein the disease or condition is Sjogren's syndrome, and wherein the moiety that binds to the TCR variable region binds to TCRaV13-l or TCRaV13-2.

39. The method of any one of claims 31-35, wherein the disease or condition is celiac disease, and wherein the moiety that binds to the TCR variable region binds to TCRaV26-l or TCRaV26-2.

40. The method of any one of claims 31-35, wherein the disease or condition is primarySjogren’s syndrome, and wherein the moiety that binds to the TCR variable region binds to TCR V6-1, TCRPV6-2 / 3, or TCRPV6-5.

41. The method of any one of claims 31-35, wherein the disease or condition is amyotrophic lateral sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV7-1 or TCRPV7-8 / 9.

42. The method of any one of claims 31-35, wherein the disease or condition is celiac disease, and wherein the moiety that binds to the TCR variable region binds to TCRPV7-1 or TCRPV7-8 / 9.

43. The method of any one of claims 31-35, wherein the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV7-1 or TCRPV7-8 / 9.

44. The method of any one of claims 31-35, wherein the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV10- 3.

45. The method of any one of claims 31-35, wherein the disease or condition is COVID-induced multisystem inflammatory syndrome, and wherein the moiety that binds to the TCR variable region binds to TCRPV11-2.

46. The method of claim 45, wherein the subject is a child.

47. The method of any one of claims 31-35, wherein the disease or condition is type I diabetes, and wherein the moiety that binds to the TCR variable region binds to TCRPV12-3 / 4.

48. The method of any one of claims 31-35, wherein the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV20- 1.WSGR Docket No.: 53676-780.60149. The method of any one of claims 31-35, wherein the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV29- 1.

50. The method of any one of claims 1-49, wherein the agent comprising the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of WINAYTGTPTYADDFEG (SEQ ID NO: 4626).

51. The method of claim 50, wherein the VH comprises a HC CDR3 comprising the amino acid sequence SWRRGIRGIGFDY (SEQ ID NO: 1250).

52. The method of claim 50 or 51, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of GYTFTDYIVH (SEQ ID NO: 1253).

53. The method of any one of claims 50-52, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256).

54. The method of claim 53, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of AGSTLQS (SEQ ID NO: 4628).

55. The method of claim 53 or 54, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254).

56. The method of any one of claims 50-55, wherein the moiety comprises: a HC CDR2 comprising the amino acid sequence of WINAYTGTPTYADDFEG (SEQ ID NO: 4626), a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250), a HC CDR1 comprising the amino acid sequence of GYTFTDYIVH (SEQ ID NO:1253), a LC CDR3 comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256), a LC CDR2 comprising the amino acid sequence of AGSTLQS (SEQ ID NO: 4628), and a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO:1254).

57. The method of any one of claims 50-56, wherein the VH comprises a sequence with at least80% sequence identity to the sequence QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWIN AYTGTPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4629).WSGR Docket No.: 53676-780.60158. The method of any one of claims 50-57, wherein the VL comprises a sequence with at least80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4630).

59. The method of any one of claims 50-58, wherein the VH comprises the amino acid sequence of QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWIN AYTGTPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4629).

60. The method of any one of claims 50-59, wherein the VL comprises the amino acid sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4630).

61. The method of any one of claims 50-56, wherein the VH comprises a sequence with at least80% sequence identity to the sequence ELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINA YTGTPT YADDFEGQFTF SLD ASISTAYLQWS SLKASDTAMYYC ARSWRRGIRGIG FDYWGQGTMVTVSS (SEQ ID NO: 4633).

62. The method of any one of claims 50-56 and 61, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4634).

63. The method of any one of claims 50-56, 61, and 62, wherein the VH comprises the amino acid sequence of ELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINA YTGTPT YADDFEGQFTF SLD ASISTAYLQWS SLKASDTAMYYC ARSWRRGIRGIG FDYWGQGTMVTVSS (SEQ ID NO: 4633).

64. The method of any one of claims 50-56 and 61-63, wherein the VL comprises the amino acid sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4634).WSGR Docket No.: 53676-780.60165. The method of any one of claims 50-56, wherein the VH comprises a sequence with at least80% sequence identity to the sequence QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWIN AYTGTPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4637).

66. The method of any one of claims 50-56 and 65, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4638).

67. The method of any one of claims 50-56, 65, and 66, wherein the VH comprises the amino acid sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWIN AYTGTPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4637).

68. The method of any one of claims 50-56 and 65-67, wherein the VL comprises the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4638).

69. The method of any one of claims 50-56, wherein the VH comprises a sequence with at least80% sequence identity to the sequence EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINA YTGTPTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4641).

70. The method of any one of claims 50-56 and 69, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4642).

71. The method of any one of claims 50-56, 69, and 70, wherein the VH comprises the amino acid sequence of EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINA YTGTPTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4641).WSGR Docket No.: 53676-780.60172. The method of any one of claims 50-56 and 69-71, wherein the VL comprises the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4642).

73. The method of any one of claims 1-49, wherein the agent comprising the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VL comprises: a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of AGSTLQS (SEQ ID NO: 4628).

74. The method of claim 73, wherein the VL comprises a LC CDR3 comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256).

75. The method of claim 73 or 74, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254).

76. The method of any one of claims 73-75, wherein the VH comprises a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250).

77. The method of any one of claims 73-76, wherein the VH comprises a HC CDR2 comprising the amino acid sequence WINAYTGTPTYADDFEG (SEQ ID NO: 4626).

78. The method of any one of claims 73-77, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of GYTFTDYIVH (SEQ ID NO: 1253).

79. The method of any one of claims 73-78, wherein the moiety comprises: a HC CDR2 comprising the amino acid sequence of WINAYTGTPTYADDFEG (SEQ ID NO: 4626), a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250), a HC CDR1 comprising the amino acid sequence of GYTFTDYIVH (SEQ ID NO:1253), a LC CDR3 comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256), a LC CDR2 comprising the amino acid sequence of AGSTLQS (SEQ ID NO: 4628), and a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO:1254).

80. The method of any one of claims 73-79, wherein the VH comprises a sequence with at least80% sequence identity to the sequence QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWINWSGR Docket No.: 53676-780.601AYTGTPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4629).

81. The method of any one of claims 73-80, wherein the VL comprises a sequence with at least80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4630).

82. The method of any one of claims 73-81, wherein the VH comprises the amino acid sequence of QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWIN AYTGTPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4629).

83. The method of any one of claims 73-82, wherein the VL comprises the amino acid sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4630).

84. The method of any one of claims 73-79, wherein the VH comprises a sequence with at least80% sequence identity to the sequence ELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINA YTGTPT YADDFEGQFTF SLD ASISTAYLQWS SLKASDTAMYYC ARSWRRGIRGIG FDYWGQGTMVTVSS (SEQ ID NO: 4633).

85. The method of any one of claims 73-79 and 84, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4634).

86. The method of any one of claims 73-79, 84, and 85, wherein the VH comprises the amino acid sequence of ELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINA YTGTPT YADDFEGQFTF SLD ASISTAYLQWS SLKASDTAMYYC ARSWRRGIRGIG FDYWGQGTMVTVSS (SEQ ID NO: 4633).

87. The method of any one of claims 73-79 and 84-86, wherein the VL comprises the amino acid sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLWSGR Docket No.: 53676-780.601QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4634).

88. The method of any one of claims 73-79, wherein the VH comprises a sequence with at least80% sequence identity to the sequence QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWIN AYTGTPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4637).

89. The method of any one of claims 73-79 and 88, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4638).

90. The method of any one of claims 73-79, 88, and 89, wherein the VH comprises the amino acid sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWIN AYTGTPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4637).

91. The method of any one of claims 73-79 and 88-90, wherein the VL comprises the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4638).

92. The method of any one of claims 73-79, wherein the VH comprises a sequence with at least80% sequence identity to the sequence EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINA YTGTPTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4641).

93. The method of any one of claims 73-79 and 92, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4642).

94. The method of any one of claims 73-79, 92, and 93, wherein the VH comprises the amino acid sequence of EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINAWSGR Docket No.: 53676-780.601YTGTPTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4641).

95. The method of any one of claims 73-79 and 92-94, wherein the VL comprises the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4642).

96. The method of any one of claims 1-49, wherein the agent comprising the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of YFDGYLDY (SEQ ID NO: 4602).

97. The method of claim 96, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of GFTFSSFGMH (SEQ ID NO: 4605).

98. The method of claim 96 or 97, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of YISSGSSNIQYADTMKG (SEQ ID NO: 4601).

99. The method of any one of claims 96-98, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQWSSNPLT (SEQ ID NO: 4608).

100. The method of any one of claims 96-99, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of SVSSSVSYVH (SEQ ID NO: 4606).

101. The method of any one of claims 96-100, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of LTFNLAS (SEQ ID NO: 4607).

102. The method of any one of claims 96-101, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of YFDGYLDY (SEQ ID NO: 4602), a HC CDR2 comprising the amino acid sequence of YISSGSSNIQYADTMKG (SEQ ID NO: 4601), a HC CDR1 comprising the amino acid sequence of GFTFSSFGMH (SEQ ID NO: 4605), a LC CDR3 comprising the amino acid sequence of QQWSSNPLT (SEQ ID NO: 4608), a LC CDR2 comprising the amino acid sequence of LTFNLAS (SEQ ID NO: 4607), and a LC CDR1 comprising the amino acid sequence of SVSSSVSYVH (SEQ ID NO: 4606).

103. The method of any one of claims 96-102, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSRKLSCVVSGFTFSSFGMHWVRQAPEKGLEWVAYISSGWSGR Docket No.: 53676-780.601SSNIQYADTMKGRFTISRDNPKNTLFLQMTSLRSEDTAMYYCARYFDGYLDYW GQGTTLTVSS (SEQ ID NO: 4609).

104. The method of any one of claims 96-103, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence QIVLTHSPTIMS ASPGEK VTMTC S VS S S VS YVHW YQQKPGS SPRLWIYLTFNL AS GVPGRFSGSGSGTSYSLSISSMEAEDAATYYCQQWSSNPLTFGAGTKLELK (SEQ ID NO: 4610).

105. The method of any one of claims 96-104, wherein the VH comprises the amino acid sequence of EVQLVESGGGLVQPGGSRKLSCVVSGFTFSSFGMHWVRQAPEKGLEWVAYISSG SSNIQYADTMKGRFTISRDNPKNTLFLQMTSLRSEDTAMYYCARYFDGYLDYW GQGTTLTVSS (SEQ ID NO: 4609).

106. The method of any one of claims 96-105, wherein the VL comprises the amino acid sequence of QIVLTHSPTIMS ASPGEK VTMTC S VS S S VS YVHW YQQKPGS SPRLWIYLTFNL AS GVPGRFSGSGSGTSYSLSISSMEAEDAATYYCQQWSSNPLTFGAGTKLELK (SEQ ID NO: 4610).

107. The method of any one of claims 1-49, wherein the agent comprising the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of YYRDDVNYAMDY (SEQ ID NO: 4615).

108. The method of claim 107, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of GFNIKDTHMH (SEQ ID NO: 4618).

109. The method of claim 107 or 108, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of RTDPASGDIKYDPKFQG (SEQ ID NO: 4614).

110. The method of any one of claims 107-109, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQYNTYPYT (SEQ ID NO: 4621).

111. The method of any one of claims 107-110, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of KASQNVGSNVA (SEQ ID NO: 4619).

112. The method of any one of claims 107-111, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of SSSFRYS (SEQ ID NO: 4620).

113. The method of any one of claims 107-112, wherein the moiety comprises:WSGR Docket No.: 53676-780.601 a HC CDR3 comprising the amino acid sequence of YYRDDVNYAMDY (SEQ ID NO: 4615), a HC CDR2 comprising the amino acid sequence of RTDPASGDIKYDPKFQG (SEQ ID NO: 4614), a HC CDR1 comprising the amino acid sequence of GFNIKDTHMH (SEQ ID NO:4618), a LC CDR3 comprising the amino acid sequence of QQYNTYPYT (SEQ ID NO: 4621), a LC CDR2 comprising the amino acid sequence of SSSFRYS (SEQ ID NO: 4620), and a LC CDR1 comprising the amino acid sequence of KASQNVGSNVA (SEQ ID NO:4619).

114. The method of any one of claims 107-113, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLQQSGAELVKPGASVKLSCTASGFNIKDTHMHWVKQRPEQGLEWIGRTDP ASGDIKYDPKFQGKATITADTSSNTAYLHLSSLTSEDTAVYYCAHYYRDDVNYA MDYWGQGTSVTVSS (SEQ ID NO: 4622).

115. The method of any one of claims 107-114, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSQKFLSTSVGDRVSVTCKASQNVGSNVAWYQQKPGQSPKSLIYSSSFR YSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNTYPYTFGGGTELEIR (SEQ ID NO: 4623).

116. The method of any one of claims 107-115, wherein the VH comprises the amino acid sequence of EVQLQQSGAELVKPGASVKLSCTASGFNIKDTHMHWVKQRPEQGLEWIGRTDP ASGDIKYDPKFQGKATITADTSSNTAYLHLSSLTSEDTAVYYCAHYYRDDVNYA MDYWGQGTSVTVSS (SEQ ID NO: 4622).

117. The method of any one of claims 107-116, wherein the VL comprises the amino acid sequence of DIVMTQSQKFLSTSVGDRVSVTCKASQNVGSNVAWYQQKPGQSPKSLIYSSSFR YSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNTYPYTFGGGTELEIR (SEQ ID NO: 4623).

118. A composition comprising a recombinant T cell receptor or a chimeric antigen receptor(CAR) comprising a moiety that binds to a TCR variable region, wherein the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH), wherein the VH comprises a heavy chain complementarity determining region 3 (HC CDR3) comprising an amino acid sequence as set forth in SEQ ID NOs: 4602 or 4615.WSGR Docket No.: 53676-780.601119. A composition comprising a recombinant T cell receptor or a chimeric antigen receptor(CAR) comprising a moiety that binds to a TCR variable region, wherein the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH), wherein the VH comprises a heavy chain complementarity determining region 2 (HC CDR2) comprising an amino acid sequence as set forth in SEQ ID NOs: 4601, 4614, or 4626.

120. A composition comprising a T cell comprising a recombinant T cell receptor or a chimeric antigen receptor (CAR), wherein the recombinant T cell receptor or the CAR comprises a moiety that binds to a TCR variable region, wherein the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH), wherein the VH comprises a heavy chain complementarity determining region 3 (HC CDR3) comprising an amino acid sequence as set forth in SEQ ID NOs: 4602 or 4615.

121. A composition comprising a T cell comprising a recombinant T cell receptor or a chimeric antigen receptor (CAR), wherein the recombinant T cell receptor or the CAR comprises a moiety that binds to a TCR variable region, wherein the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH), wherein the VH comprises a heavy chain complementarity determining region 2 (HC CDR2) comprising an amino acid sequence as set forth in SEQ ID NOs: 4601, 4614, or 4626.

122. The composition of any one of claims 118-121, wherein the recombinant T cell receptor or the CAR comprises(a) an extracellular domain comprising the moiety that binds to the TCR variable region,(b) a transmembrane domain; and(c) an intracellular domain comprising an intracellular signaling domain.

123. The composition of claim 122, wherein the extracellular domain comprises a CD8 or CD28 extracellular domain.

124. The composition of claim 122 or 123, wherein the transmembrane domain comprises a CD8 or CD28 transmembrane domain.

125. The composition of any one of claims 122-124, wherein the intracellular domain comprises a CD3 zeta intracellular signaling domain.

126. The composition of any one of claims 122-125, wherein the moiety that binds to the TCR variable region binds a TCRaV subfamily selected from the group consisting of: a TCRa VI subfamily, a TCRa V2 subfamily, a TCRa V3 subfamily, a TCRa V4, a TCRa V5 subfamily, a TCRa V6 subfamily, a TCRa V7 subfamily, a TCRa V8 subfamily, a TCRa V9 subfamily, a TCRa V10 subfamily, a TCRa V12 subfamily, a TCRa V13 subfamily, a TCRa V14 subfamily, a TCRa V16 subfamily, a TCRa V17 subfamily, a TCRa V18 subfamily, a TCRa VI 9 subfamily, a TCRa V20 subfamily, a TCRa V21 subfamily, aWSGR Docket No.: 53676-780.601TCRa V22 subfamily, a TCRa V23 subfamily, a TCRa V24 subfamily, TCRa V25 subfamily, a TCRa V26 subfamily, a TCRa V27 subfamily, a TCRa V29 subfamily, a TCRa V30 subfamily, a TCRa V34 subfamily, a TCRa V35 subfamily, a TCRa V36 subfamily, a TCRa V38 subfamily, a TCRa V39 subfamily, a TCRa V40 subfamily, a TCRa V41 subfamily, a TCRP V2 subfamily, a TCRP V3 subfamily, a TCRP V4 subfamily, a TCRP V5 subfamily, a TCRP V6 subfamily, a TCRP V9 subfamily, a TCRP V10 subfamily, a TCRP VI 1 subfamily, a TCRP V12 subfamily, a TCRP V13 subfamily, a TCRP VI 6 subfamily, a TCRP VI 9 subfamily, a TCRP V21 subfamily, a TCRP V23 subfamily, a TCRP V27 subfamily, a TCRP V28 subfamily, TCRP V29 subfamily, and TCRP V3O subfamily, as well as family members of said subfamilies, and variants thereof.

127. A pharmaceutical composition comprising the composition of any one of claims 118-126, and a pharmaceutically acceptable diluent, carrier, excipient, or stabilizer.

128. A method of treating a disease or condition, or reducing a risk of developing the disease or condition in a subject in need thereof comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 127 to the subject.

129. The method of claim 128, wherein the disease or condition is an autoimmune disease.

130. The method of claim 129, wherein the autoimmune disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), coeliac disease (CD), ankylosing spondylitis (AS), Covid-induced multisystem inflammatory syndrome in children (MIS- C), primary Sjogren’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 cirrhosis, multiple sclerosis, Guillain- Barre syndrome and the AMAN (axonal & neuronal neuropathy), chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis, Tolosa-Hunt syndrome (THS), Devic’s disease (neuromyelitis optica), paraneoplastic cerebellardegeneration (PCD), Lambert-Eaton syndrome, psoriasis, scleroderma, CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome, dermatitis herpetiformis, dermatomyositis, bullous pemphigoid, cicatricial pemphigoid / benign mucosal pemphigoid, pemphigoid gestationis, rheumatoid arthritis (RA), psoriatic arthritis, relapsing polychondritis, chronic recurrent multifocal osteomyelitis (CRMO), vasculitis, Kawasaki disease, granulomatosis with polyangiitis (GPA), Behcet’s disease (vasculitis), Takayasu’s arteritis, polyarteritis nodosa, microscopic polyangiitis (MPA), leukocytoclasticvasculitis, Cogan’s syndrome, uveitis, peripheral uveitis (Pars planitis), scleritis, autoimmune inner ear disease (AIED),WSGR Docket No.: 53676-780.601Crohn’s, ulcerative colitis (UC), Dressier’s syndrome, Rheumatic fever, Evans syndrome, paroxysmal nocturnal hemoglobinuria (PNH), hemolytic anemia, thrombocytopenic purpura (TTP), polymyositis, juvenile myositis (JM), including JuvenileDermatomyositis (JDM) and Juvenile Polymyositis (JPM), ocular cicatricial pemphigoid, or Hashimoto’s thyroiditis.

131. The method of claim 128, wherein:(a) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRa VI subfamily;(b) the disease or condition is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V2 subfamily;(c) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V4 subfamily;(d) the disease or condition is Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCRa V12 subfamily;(e) the disease or condition is Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily;(f) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V20 subfamily;(g) the disease or condition is ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily;(h) the disease or condition is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V22 subfamily;(i) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V26 subfamily;(j) the disease or condition is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V40 subfamily;(k) the disease or condition is joint implant failure, and the moiety that binds to the TCR variable region binds to a TCRa V41 subfamily;(l) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily;(m)the disease or condition is primary Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily;(n) the disease or condition is amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily;WSGR Docket No.: 53676-780.601(o) the disease or condition is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily;(p) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily;(q) the disease or condition is ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(r) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V10 subfamily;(s) the disease or condition is COVID-induced multisystem inflammatory syndrome in children, and the moiety that binds to the TCR variable region binds to a TCRP VI 1 subfamily;(t) the disease or condition is Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCRP V12 subfamily;(u) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V10 subfamily;(v) the disease or condition is Amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V23 subfamily; or(w)the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V29 subfamily.

132. The method of any one of claims 128-131, wherein the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRaVl-1 or TCRaVl-2.

133. The method of any one of claims 128-131, wherein the disease or condition is type I diabetes, and wherein the moiety that binds to the TCR variable region binds to TCRaV12-3.

134. The method of any one of claims 128-131, wherein the disease or condition is Sjogren's syndrome, and wherein the moiety that binds to the TCR variable region binds to TCRaV13-l or TCRaV13-2.

135. The method of any one of claims 128-131, wherein the disease or condition is celiac disease, and wherein the moiety that binds to the TCR variable region binds to TCRaV26-l or TCRaV26-2.

136. The method of any one of claims 128-131, wherein the disease or condition is primarySjogren’s syndrome, and wherein the moiety that binds to the TCR variable region binds to TCRPV6-1, TCRPV6-2 / 3, or TCRPV6-5.WSGR Docket No.: 53676-780.601137. The method of any one of claims 128-131, wherein the disease or condition is amyotrophic lateral sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV7-1 or TCRPV7-8 / 9.

138. The method of any one of claims 128-131, wherein the disease or condition is celiac disease, and wherein the moiety that binds to the TCR variable region binds to TCRPV7- 1 or TCRPV7-8 / 9.

139. The method of any one of claims 128-131, wherein the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV7-1 or TCRPV7-8 / 9.

140. The method of any one of claims 128-131, wherein the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV10-3.

141. The method of any one of claims 128-131, wherein the disease or condition is COVID- induced multisystem inflammatory syndrome, and wherein the moiety that binds to the TCR variable region binds to TCRPV11-2.

142. The method of claim 141, wherein the subject is a child.

143. The method of any one of claims 128-131, wherein the disease or condition is type I diabetes, and wherein the moiety that binds to the TCR variable region binds to TCRPV12-3 / 4.

144. The method of any one of claims 128-131, wherein the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV20-1.

145. The method of any one of claims 128-131, wherein the disease or condition is multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to TCRPV29-1.

146. The method of any one of claims 1-49 or 128-131, further comprising administering a second therapeutic agent or therapy to the subject.

147. The method of claim 146, wherein the second therapeutic agent or therapy comprises a chemotherapeutic agent, a biologic agent, an immunosuppressive agent, or radiation.

148. The method of claim 146 or 147, wherein the second therapeutic agent or therapy is administered in combination with the agent of any one of claims 1-49, the composition of any one of claims 118-126 or the pharmaceutical composition of claim 127, sequentially, simultaneously, or concurrently.

149. A method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject aWSGR Docket No.: 53676-780.601 composition, wherein the composition comprises an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of at least about 0.001 mg / ml, and wherein:(a) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI subfamily;(b) the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V2 subfamily;(c) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V4 subfamily;(d) the subject suffers from Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V12 subfamily;(e) the subject suffers from Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI 3 subfamily;(f) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V20 subfamily;(g) the subject suffers from ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V21 subfamily;(h) the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V22 subfamily;(i) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V26 subfamily;(j) the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V40 subfamily;(k) the subject suffers from joint implant failure, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V41 subfamily;(l) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V4 subfamily;WSGR Docket No.: 53676-780.601(m) the subject suffers from primary Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V6 subfamily;(n) the subject suffers from amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily;(o) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily;(p) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily;(q) the subject suffers from ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V9 subfamily;(r) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V10 subfamily;(s) the subject suffers from COVID-induced multisystem inflammatory syndrome in children, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP VI 1 subfamily;(t) the subject suffers from Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V12 subfamily;(u) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V10 subfamily;(v) the subject suffers from Amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V23 subfamily;(w) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V29 subfamily;(x) the disease or condition is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily;(y) the disease or condition is acute anterior uveitis (UAA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(z) the disease or condition is psoriatic arthritis (PsA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(aa) the disease or condition is type I narcolepsy, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily;(bb) the disease or condition is amyotrophic lateral sclerosis (ALS), and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily; orWSGR Docket No.: 53676-780.601(cc) the disease or condition is UAA, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily.

150. A method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a composition, wherein the composition comprises an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of at least about 0.001 mg / ml, and wherein:(a) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI subfamily;(b) the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V2 subfamily;(c) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V4 subfamily;(d) the subject suffers from Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V12 subfamily;(e) the subject suffers from Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI 3 subfamily;(f) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V20 subfamily;(g) the subject suffers from ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V21 subfamily;(h) the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V22 subfamily;(i) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V26 subfamily;(j) the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V40 subfamily;WSGR Docket No.: 53676-780.601(k) the subject suffers from joint implant failure, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V41 subfamily;(l) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V4 subfamily;(m) the subject suffers from primary Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V6 subfamily;(n) the subject suffers from amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily;(o) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily;(p) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily;(q) the subject suffers from ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V9 subfamily;(r) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V10 subfamily;(s) the subject suffers from COVID-induced multisystem inflammatory syndrome in children, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP VI 1 subfamily;(t) the subject suffers from Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V12 subfamily;(u) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V10 subfamily;(v) the subject suffers from Amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V23 subfamily;(w) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V29 subfamily;(x) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily;(y) the subject suffers from acute anterior uveitis (UAA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(z) the subject suffers from psoriatic arthritis (PsA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;WSGR Docket No.: 53676-780.601(aa) the subject suffers from type I narcolepsy, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily;(bb) the subject suffers from amyotrophic lateral sclerosis (ALS), and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily; or(cc) the subject suffers from UAA, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily.

151. The method of claim 149 or 150, wherein the agent is present in the composition at a concentration of at least about 0.01 mg / ml.

152. The method of claim 149 or 150, wherein the agent is present in the composition at a concentration of at least about 0.1 mg / ml.

153. The method of claim 149 or 150, wherein the agent is present in the composition at a concentration of at least about 1.0 mg / ml.

154. A method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a composition, wherein the composition comprises an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the moiety binds to the TCR variable region with a KD of at most about 500 nM, and wherein:(a) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI subfamily;(b) the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V2 subfamily;(c) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V4 subfamily;(d) the subject suffers from Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V12 subfamily;(e) the subject suffers from Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI 3 subfamily;WSGR Docket No.: 53676-780.601(f) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V20 subfamily;(g) the subject suffers from ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V21 subfamily;(h) the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V22 subfamily;(i) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V26 subfamily;(j) the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V40 subfamily;(k) the subject suffers from joint implant failure, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V41 subfamily;(l) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V4 subfamily;(m) the subject suffers from primary Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V6 subfamily;(n) the subject suffers from amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily;(o) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily;(p) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily;(q) the subject suffers from ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V9 subfamily;(r) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V10 subfamily;(s) the subject suffers from COVID-induced multisystem inflammatory syndrome in children, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP VI 1 subfamily;(t) the subject suffers from Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V12 subfamily;(u) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V10 subfamily;WSGR Docket No.: 53676-780.601(v) the subject suffers from Amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V23 subfamily;(w) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V29 subfamily;(x) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily;(y) the subject suffers from acute anterior uveitis (UAA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(z) the subject suffers from psoriatic arthritis (PsA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(aa) the subject suffers from type I narcolepsy, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily;(bb) the subject suffers from amyotrophic lateral sclerosis (ALS), and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily; or(cc) the subject suffers from UAA, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily.

155. A method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a composition, wherein the composition comprises an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the moiety binds to the TCR variable region with a KD of at most about 500 nM, and wherein:(a) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI subfamily;(b) the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V2 subfamily;(c) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V4 subfamily;WSGR Docket No.: 53676-780.601(d) the subject suffers from Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V12 subfamily;(e) the subject suffers from Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa VI 3 subfamily;(f) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V20 subfamily;(g) the subject suffers from ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V21 subfamily;(h) the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V22 subfamily;(i) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V26 subfamily;(j) the subject suffers from Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V40 subfamily;(k) the subject suffers from joint implant failure, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRa V41 subfamily;(l) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V4 subfamily;(m) the subject suffers from primary Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V6 subfamily;(n) the subject suffers from amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily;(o) the subject suffers from celiac disease, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily;(p) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V7 subfamily;(q) the subject suffers from ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V9 subfamily;(r) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V10 subfamily;(s) the subject suffers from COVID-induced multisystem inflammatory syndrome in children, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP VI 1 subfamily;WSGR Docket No.: 53676-780.601(t) the subject suffers from Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V12 subfamily;(u) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V10 subfamily;(v) the subject suffers from Amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V23 subfamily;(w) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCR variable region in TCRP V29 subfamily;(x) the subject suffers from multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily;(y) the subject suffers from acute anterior uveitis (UAA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(z) the subject suffers from psoriatic arthritis (PsA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(aa) the subject suffers from type I narcolepsy, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily;(bb) the subject suffers from amyotrophic lateral sclerosis (ALS), and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily; or(cc) the subject suffers from UAA, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily.

156. The method of claim 154 or 155, wherein the moiety binds to the TCR variable region with a KD of at most about 100 nM.

157. The method of claim 154 or 155, wherein the moiety binds to the TCR variable region with a KD of at most about 10 nM.

158. The method of claim 154 or 155, wherein the moiety binds to the TCR variable region with a KD of at most about 1 nM.

159. The method of any one of claims 149-158, wherein the method further comprises determining that the subject suffers from multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa VI subfamily, TCRP V7 subfamily, TCRP VI 0 subfamily, TCRP V20 subfamily or TCRP V29 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa VI subfamily, TCRP V7 subfamily, TCRP VI 0 subfamily, TCRP V20 subfamily or TCRP V29 subfamily.WSGR Docket No.: 53676-780.601160. The method of any one of claims 149-158, wherein the method further comprises determining that the subject suffers from amyotrophic lateral sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V7 subfamily, TCRa VI 3 subfamily, or TCRP V23 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V7 subfamily, TCRa VI 3 subfamily, or TCRP V23 subfamily.

161. The method of any one of claims 149-158, wherein the method further comprises determining that the subject suffers from celiac disease that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily.

162. The method of any one of claims 149-158, wherein the method further comprises determining that the subject suffers from ankylosing spondylitis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V21 subfamily or TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V21 subfamily or TCRP V9 subfamily.

163. The method of any one of claims 149-158, wherein the method further comprises determining that the subject suffers from COVID-induced multisystem inflammatory syndrome in children that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP VI 1 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP VI 1 subfamily.

164. The method of any one of claims 149-158, wherein the method further comprises determining that the subject suffers from primary Sjogren’s syndrome that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V6 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V6 subfamily.

165. The method of any one of claims 149-158, wherein the method further comprises determining that the subject suffers from Type I diabetes that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V12 subfamily or TCRP V12 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V12 subfamily or TCRP V12 subfamily.

166. The method of any one of claims 149-158, wherein the method further comprises determining that the subject suffers from acute anterior uveitis (UAA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9WSGR Docket No.: 53676-780.601 subfamily or TCRa V21 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily or TCRa V21 subfamily.

167. The method of any one of claims 149-158, wherein the method further comprises determining that the subject suffers from psoriatic arthritis (PsA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily.

168. The method of any one of claims 149-158, wherein the method further comprises determining that the subject suffers from type I narcolepsy that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V4 subfamily.

169. The method of any one of claims 149-165, wherein the agent comprises an antibody molecule or antigen binding fragment thereof.

170. The method of claim 169, wherein the antibody molecule comprises an Fc region.

171. The method of claim 170, wherein the Fc region comprises a binding mutation.

172. The method of any one of claims 149-171, wherein the agent is functionally linked to a cytotoxic agent.

173. The method of claim 172, wherein the cytotoxic agent comprises calicheamicin, monomethyl auristatin E, maytansine derivative, or exatecan derivative.

174. The method of claim 169, wherein the Fc region comprises no mutation that affects binding of the Fc region to a Fc receptor.

175. The method of claim 172 or 173, wherein the cytotoxic agent mediates killing of the autoreactive T cells in the subject.

176. The method of claim 170 or 171, wherein the Fc region comprises an amino acid mutation that enhances an effector function.

177. The method of claim 176, wherein the effector function comprises antibody dependent cell- mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement dependent cytotoxicity (CDC).

178. The method of claim 176 or 177, wherein the effector function mediates killing of the autoreactive T cells in the subject.

179. The method of any one of claim 149-178, wherein the agent comprises an another moiety.

180. The method of claim 179, wherein the another moiety comprises aNK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.WSGR Docket No.: 53676-780.601181. The method of claim 180, wherein the another moiety comprises the NK cell engager, and wherein 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 CD 160.

182. The method of claim 181, wherein binding of the another moiety to NKp30 activates an NK cell and mediates killing of the autoreactive T cells in the subject.

183. The method of claim 182, wherein the another moiety comprises the NK cell engager, and wherein the NK cell engager binds to a KIR receptor and / or CD94-NKG2A.

184. The method of claim 183, wherein binding of the another moiety to the KIR receptor and / orCD94-NKG2A disinhibits an NK cell and mediates killing of the autoreactive T cells in the subj ect.

185. The method of claim 182, wherein the another moiety comprises the T cell engager, and wherein the T cell engager binds to an antigen expressed on a CD8+ and / or CD4+ T cell.

186. The method of claim 185, wherein the another moiety comprises the T cell engager, and wherein the T cell engager binds to a TCRaV or a TCRPV.

187. The method of claim 186, wherein the TCRaV or the TCRPV that the T cell engager binds to is different from the TCR variable region that the moiety of the agent binds to.

188. The method of claim 186 or 187, wherein the another moiety that binds to the TCRaV or aTCRPV binds a TCRaV in a subfamily selected from the group consisting of: TCRa VI subfamily, TCRa V2 subfamily, TCRa V3 subfamily, TCRa V4, TCRa V5 subfamily, TCRa V6 subfamily, TCRa V7 subfamily, TCRa V8 subfamily, TCRa V9 subfamily, TCRa V10 subfamily, TCRa V12 subfamily, TCRa V13 subfamily, TCRa V14 subfamily, TCRa V16 subfamily, TCRa V17 subfamily, TCRa V18 subfamily, TCRa VI 9 subfamily, TCRa V20 subfamily, TCRa V21 subfamily, TCRa V22 subfamily, TCRa V23 subfamily, TCRa V24 subfamily, TCRa V25 subfamily, TCRa V26 subfamily, TCRa V27 subfamily, TCRa V29 subfamily, TCRa V30 subfamily, TCRa V34 subfamily, TCRa V35 subfamily, TCRa V36 subfamily, TCRa V38 subfamily, TCRa V39 subfamily, TCRa V40 subfamily, and TCRa V41 subfamily, as well as family members of the subfamilies, and variants thereof.

189. The method of claim 186 or 187, wherein the another moiety that binds to the TCRaV or the TCRPV binds to a TCRPV in a subfamily selected from the group consisting of: TCRP V2 subfamily, TCRP V3 subfamily, TCRP V4 subfamily, TCRP V5 subfamily, TCRP V6 subfamily, TCRP V9 subfamily, TCRP V10 subfamily, TCRP VI 1 subfamily,WSGR Docket No.: 53676-780.601TCRp V12 subfamily, TCRp V13 subfamily, TCRp V16 subfamily, TCRp V19 subfamily, TCRP V21 subfamily, TCRP V23 subfamily, TCRP V27 subfamily, TCRP V28 subfamily, TCRP V29 subfamily, and TCRP V30 subfamily, as well as family members of the subfamilies, and variants thereof.

190. The method of claim 182, wherein the another moiety comprises the T cell engager, and wherein the T cell engager binds to CD3.

191. The method of any one of claims 185-190, wherein binding of the T cell engager to theCD8+ and / or CD4+ T cell mediates killing of the autoreactive T cells in the subject.

192. The method of any one of claims 186-191, wherein the subject suffers from multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRaVl-1 or TCRaVl-2 family.

193. The method of any one of claims 186-191, wherein the subject suffers from type I diabetes, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRaV12-3 family.

194. The method of any one of claims 186-191, wherein the subject suffers from Sjogren's syndrome, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRaV13-l or TCRaV13-2 family.

195. The method of any one of claims 186-191, wherein the subject suffers from celiac disease, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRaV26-l or TCRaV26-2 family.

196. The method of any one of claims 186-191, wherein the subject suffers from primarySjogren’s syndrome, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRPV6-1, TCRPV6-2 / 3, or TCRPV6-5 family.

197. The method of any one of claims 186-191, wherein the subject suffers from amyotrophic lateral sclerosis, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRPV7-1 or TCRPV7-8 / 9 family.

198. The method of any one of claims 186-191, wherein the subject suffers from celiac disease, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRPV7-1 or TCRPV7-8 / 9 family.

199. The method of any one of claims 186-191, wherein the subject suffers from multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRPV7-1 or TCRPV7-8 / 9 family.

200. The method of any one of claims 186-191, wherein the subject suffers from multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRPV10-3 family.WSGR Docket No.: 53676-780.601201. The method of any one of claims 186-191, wherein the subject suffers from COVID- induced multisystem inflammatory syndrome, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRPV11-2 family.

202. The method of claim 109, wherein the subject is a child.

203. The method of any one of claims 186-191, wherein the subject suffers from type I diabetes, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRPV12-3 / 4 family.

204. The method of any one of claims 186-191, wherein the subject suffers from multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRPV20-1 family.

205. The method of any one of claims 186-191, wherein the subject suffers from multiple sclerosis, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in TCRPV29-1 family.

206. A method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRa VI subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRa VI subfamily,(b) the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP V7 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP V7 subfamily,(c) the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable regionWSGR Docket No.: 53676-780.601 in a TCRP V6 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP V6 subfamily,(d) the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP VI 0 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP VI 0 subfamily,(e) the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP V20 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP V20 subfamily, or(f) the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP V29 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP V29 subfamily, and wherein the moiety does not bind to a different TCRaV and / or TCRPV subfamily.

207. A method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRa VI subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRa VI subfamily,(b) the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP V7 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP V7 subfamily,WSGR Docket No.: 53676-780.601(c) the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP V6 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP V6 subfamily,(d) the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP VI 0 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP VI 0 subfamily,(e) the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP V20 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP V20 subfamily, or(f) the subject is identified as having multiple sclerosis or a symptom of multiple sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in a TCRP V29 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable region in the TCRP V29 subfamily, and wherein the moiety does not bind to a different TCRaV and / or TCRPV subfamily.

208. A method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having amyotrophic lateral sclerosis or a symptom of amyotrophic lateral sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V7 subfamily, TCRP VI 3 subfamily, or TCRP V23 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V7 subfamily, TCRP VI 3 subfamily, or TCRP V23 subfamily, orWSGR Docket No.: 53676-780.601(b) the subject is identified as having amyotrophic lateral sclerosis or a symptom of amyotrophic lateral sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V7 subfamily, TCRP VI 3 subfamily, or TCRP V23 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V7 subfamily, TCRP VI 3 subfamily, or TCRP V23 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

209. A method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having amyotrophic lateral sclerosis or a symptom of amyotrophic lateral sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V7 subfamily, TCRP VI 3 subfamily, or TCRP V23 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V7 subfamily, TCRP VI 3 subfamily, or TCRP V23 subfamily, or(b) the subject is identified as having amyotrophic lateral sclerosis or a symptom of amyotrophic lateral sclerosis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V7 subfamily, TCRP VI 3 subfamily, or TCRP V23 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V7 subfamily, TCRP VI 3 subfamily, or TCRP V23 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

210. A method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCRWSGR Docket No.: 53676-780.601 variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having celiac disease or a symptom of celiac disease that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, or(b) the subject is identified as having celiac disease or a symptom of celiac disease that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

211. A method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having celiac disease or a symptom of celiac disease that is associated with a biased TCR clonotype that comprises the TCR variable region inWSGR Docket No.: 53676-780.601TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, or(b) the subject is identified as having celiac disease or a symptom of celiac disease that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V26 subfamily, TCRa V4 subfamily, TCRP V7 subfamily, or TCRP V4 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

212. A method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having ankylosing spondylitis or a symptom of ankylosing spondylitis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V21 subfamily or TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V21 subfamily or TCRP V9 subfamily, or(b) the subject is identified as having ankylosing spondylitis or a symptom of ankylosing spondylitis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V21 subfamily or TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V21 subfamily or TCRP V9 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.WSGR Docket No.: 53676-780.601213. A method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having ankylosing spondylitis or a symptom of ankylosing spondylitis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V21 subfamily or TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V21 subfamily or TCRP V9 subfamily, or(b) the subject is identified as having ankylosing spondylitis or a symptom of ankylosing spondylitis that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRa V21 subfamily or TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRa V21 subfamily or TCRP V9 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

214. A method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of is at least about 0.001 mg / ml, and wherein:WSGR Docket No.: 53676-780.601(a) the subject is identified as having COVID-induced multisystem inflammatory syndrome in children or a symptom of COVID-induced multisystem inflammatory syndrome in children that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP VI 1 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP VI 1 subfamily, or(b) the subject is identified as having COVID-induced multisystem inflammatory syndrome in children or a symptom of COVID-induced multisystem inflammatory syndrome in children that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP VI 1 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP VI 1 subfamily , and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

215. A method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of is at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having COVID-induced multisystem inflammatory syndrome in children or a symptom of COVID-induced multisystem inflammatory syndrome in children that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP VI 1 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP VI 1 subfamily, or(b) the subject is identified as having COVID-induced multisystem inflammatory syndrome in children or a symptom of COVID-induced multisystem inflammatory syndrome in children that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP VI 1 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP VI 1 subfamily , and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.WSGR Docket No.: 53676-780.601216. A method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of is at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having primary Sjogrens syndrome or a symptom of primary Sjogrens syndrome that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V6 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V6 subfamily, or(b) the subject is identified as having primary Sjogrens syndrome or a symptom of primary Sjogrens syndrome that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V6 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V6 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

217. A method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of is at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having primary Sjogrens syndrome or a symptom of primary Sjogrens syndrome that is associated with a biased TCR clonotype that comprises theWSGR Docket No.: 53676-780.601TCR variable region in TCRP V6 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V6 subfamily, or(b) the subject is identified as having primary Sjogrens syndrome or a symptom of primary Sjogrens syndrome that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V6 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V6 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

218. A method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of is at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having Type I diabetes or a symptom Type I diabetes that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V12 subfamily or TCRa V12 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V12 subfamily or TCRa VI 2 subfamily, or(b) the subject is identified as having Type I diabetes or a symptom Type I diabetes that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V12 subfamily or TCRa V12 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V12 subfamily or TCRa VI 2 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

219. A method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of autoreactive T cells in the subject,WSGR Docket No.: 53676-780.601 wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of is at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having Type I diabetes or a symptom Type I diabetes that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V12 subfamily or TCRa V12 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V12 subfamily or TCRa VI 2 subfamily, or(b) the subject is identified as having Type I diabetes or a symptom Type I diabetes that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V12 subfamily or TCRa V12 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V12 subfamily or TCRa VI 2 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

220. A method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of is at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having acute anterior uveitis (UAA) or a symptom of acute anterior uveitis (UAA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily or TCRa V21 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily or TCRa V21 subfamily, orWSGR Docket No.: 53676-780.601(b) the subject is identified as having acute anterior uveitis (UAA) or a symptom of acute anterior uveitis (UAA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily or TCRa V21 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily or TCRa V21 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

221. A method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of is at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having acute anterior uveitis (UAA) or a symptom of acute anterior uveitis (UAA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily or TCRa V21 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily or TCRa V21 subfamily, or(b) the subject is identified as having acute anterior uveitis (UAA) or a symptom of acute anterior uveitis (UAA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily or TCRa V21 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily or TCRa V21 subfamily, and wherein the moiety does not bind to any other different TCRaV and / or TCRPV subfamily.

222. A method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject,WSGR Docket No.: 53676-780.601 wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of is at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having psoriatic arthritis (PsA) or a symptom of psoriatic arthritis (PsA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily, or(b) the subject is identified as having psoriatic arthritis (PsA) or a symptom of psoriatic arthritis (PsA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily, and wherein the moiety does not bind to any other different TCRPV subfamily.

223. A method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of is at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having psoriatic arthritis (PsA) or a symptom of psoriatic arthritis (PsA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily, or(b) the subject is identified as having psoriatic arthritis (PsA) or a symptom of psoriatic arthritis (PsA) that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V9 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V9 subfamily, andWSGR Docket No.: 53676-780.601 wherein the moiety does not bind to any other different TCRPV subfamily.

224. A method of inhibiting or preventing activation and / or expansion of autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, thereby inhibiting or preventing the activation and / or expansion of the autoreactive T cells in the subject, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor beta variable region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having type I narcolepsy or a symptom of type I narcolepsy that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V4 subfamily, or(b) the subject is identified as having type I narcolepsy or a symptom of type I narcolepsy that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V4 subfamily, and wherein the moiety does not bind to any other different TCRPV subfamily.

225. A method of reducing or depleting autoreactive T cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising a moiety 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 (TCRaV) or a T cell receptor variable beta region (TCRPV), wherein the autoreactive T cells target an autologous cell in the subject, wherein the autoreactive T cells express TCRaV and / or TCRPV, wherein the agent is present in the composition at a concentration of at least about 0.001 mg / ml, and wherein:(a) the subject is identified as having type I narcolepsy or a symptom of type I narcolepsy that is associated with a biased TCR clonotype that comprises the TCR variable regionWSGR Docket No.: 53676-780.601 in TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V4 subfamily, or(b) the subject is identified as having type I narcolepsy or a symptom of type I narcolepsy that is associated with a biased TCR clonotype that comprises the TCR variable region in TCRP V4 subfamily, and wherein the moiety that binds to the TCR variable region binds to the TCR variable domain in TCRP V4 subfamily, and wherein the moiety does not bind to any other different TCRPV subfamily.

226. The method of any one of claims 206-225, wherein the agent is present in the composition at a concentration of at least about 0.01 mg / ml.

227. The method of any one of claims 206-225, wherein the agent is present in the composition at a concentration of at least about 0.1 mg / ml.

228. The method of any one of claims 206-225, wherein the agent is present in the composition at a concentration of at least about 1.0 mg / ml.

229. An agent comprising a moiety that binds to a TCR variable region comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of WINAYTGTPTYADDFEG (SEQ ID NO: 4626).

230. The agent of claim 229, wherein the VH comprises a HC CDR3 comprising the amino acid sequence SWRRGIRGIGFDY (SEQ ID NO: 1250).

231. The agent of claim 229 or 230, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of GYTFTDYIVH (SEQ ID NO: 1253).

232. The agent of any one of claims 229-231, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256).

233. The agent of claim 232, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of AGSTLQS (SEQ ID NO: 4628).

234. The agent of claim 232 or 233, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254).

235. The agent of any one of claims 229-234, wherein the moiety comprises: a HC CDR2 comprising the amino acid sequence of WINAYTGTPTYADDFEG (SEQ ID NO: 4626), a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250), a HC CDR1 comprising the amino acid sequence of GYTFTDYIVH (SEQ ID NO: 1253),WSGR Docket No.: 53676-780.601 a LC CDR3 comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256), a LC CDR2 comprising the amino acid sequence of AGSTLQS (SEQ ID NO: 4628), and a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254).

236. The agent of any one of claims 229-235, wherein the VH comprises a sequence with at least80% sequence identity to the sequence QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWIN AYTGTPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4629).

237. The agent of any one of claims 229-236, wherein the VL comprises a sequence with at least80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4630).

238. The agent of any one of claims 229-237, wherein the VH comprises the amino acid sequence of QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWIN AYTGTPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4629).

239. The agent of any one of claims 229-238, wherein the VL comprises the amino acid sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4630).

240. The agent of any one of claims 229-235, wherein the VH comprises a sequence with at least80% sequence identity to the sequence ELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINA YTGTPT YADDFEGQFTF SLD ASISTAYLQWS SLKASDTAMYYC ARSWRRGIRGIG FDYWGQGTMVTVSS (SEQ ID NO: 4633).

241. The agent of any one of claims 229-235 and 240, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4634).WSGR Docket No.: 53676-780.601242. The agent of any one of claims 229-235, 240, and 241, wherein the VH comprises the amino acid sequence of ELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINA YTGTPT YADDFEGQFTF SLD ASISTAYLQWS SLKASDTAMYYC ARSWRRGIRGIG FDYWGQGTMVTVSS (SEQ ID NO: 4633).

243. The agent of any one of claims 229-235 and 240-242, wherein the VL comprises the amino acid sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4634).

244. The agent of any one of claims 229-235, wherein the VH comprises a sequence with at least80% sequence identity to the sequence QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWIN AYTGTPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4637).

245. The agent of any one of claims 229-235 and 244, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4638).

246. The agent of any one of claims 229-235, 244, and 245, wherein the VH comprises the amino acid sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWIN AYTGTPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4637).

247. The agent of any one of claims 229-235 and 244-246, wherein the VL comprises the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4638).

248. The agent of any one of claims 229-235, wherein the VH comprises a sequence with at least80% sequence identity to the sequence EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINA YTGTPTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4641).WSGR Docket No.: 53676-780.601249. The agent of any one of claims 229-235 and 248, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4642).

250. The agent of any one of claims 229-235, 248, and 249, wherein the VH comprises the amino acid sequence of EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINA YTGTPTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4641).

251. The agent of any one of claims 229-235 and 248-250, wherein the VL comprises the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4642).

252. An agent comprising a moiety that binds to a TCR variable region comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VL comprises: a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of AGSTLQS (SEQ ID NO: 4628).

253. The agent of claim 252, wherein the VL comprises a LC CDR3 comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256).

254. The agent of claim 252 or 253, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254).

255. The agent of any one of claims 252-254, wherein the VH comprises a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250).

256. The agent of any one of claims 252-255, wherein the VH comprises a HC CDR2 comprising the amino acid sequence WINAYTGTPTYADDFEG (SEQ ID NO: 4626).

257. The agent of any one of claims 252-256, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of GYTFTDYIVH (SEQ ID NO: 1253).

258. The agent of any one of claims 252-257, wherein the moiety comprises: a HC CDR2 comprising the amino acid sequence of WINAYTGTPTYADDFEG (SEQ ID NO: 4626), a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250),WSGR Docket No.: 53676-780.601 a HC CDR1 comprising the amino acid sequence of GYTFTDYIVH (SEQ ID NO:1253), a LC CDR3 comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256), a LC CDR2 comprising the amino acid sequence of AGSTLQS (SEQ ID NO: 4628), and a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO:1254).

259. The agent of any one of claims 252-258, wherein the VH comprises a sequence with at least80% sequence identity to the sequence QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWIN AYTGTPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4629).

260. The agent of any one of claims 252-259, wherein the VL comprises a sequence with at least80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4630).

261. The agent of any one of claims 252-260, wherein the VH comprises the amino acid sequence of QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWIN AYTGTPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4629).

262. The agent of any one of claims 252-261, wherein the VL comprises the amino acid sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4630).

263. The agent of any one of claims 252-258, wherein the VH comprises a sequence with at least80% sequence identity to the sequence ELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINA YTGTPT YADDFEGQFTF SLD ASISTAYLQWS SLKASDTAMYYC ARSWRRGIRGIG FDYWGQGTMVTVSS (SEQ ID NO: 4633).

264. The agent of any one of claims 252-258 and 263, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTLWSGR Docket No.: 53676-780.601QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4634).

265. The agent of any one of claims 252-258, 263, and 264, wherein the VH comprises the amino acid sequence of ELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINA YTGTPT YADDFEGQFTF SLD ASISTAYLQWS SLKASDTAMYYC ARSWRRGIRGIG FDYWGQGTMVTVSS (SEQ ID NO: 4633).

266. The agent of any one of claims 252-258 and 263-265, wherein the VL comprises the amino acid sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYAGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4634).

267. The agent of any one of claims 252-258, wherein the VH comprises a sequence with at least80% sequence identity to the sequence QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWIN AYTGTPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4637).

268. The agent of any one of claims 252-258 and 267, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4638).

269. The agent of any one of claims 252-258, 267, and 268, wherein the VH comprises the amino acid sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWIN AYTGTPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4637).

270. The agent of any one of claims 252-258 and 267-269, wherein the VL comprises the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4638).

271. The agent of any one of claims 252-258, wherein the VH comprises a sequence with at least80% sequence identity to the sequence EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINAWSGR Docket No.: 53676-780.601YTGTPTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4641).

272. The agent of any one of claims 252-258 and 271, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4642).

273. The agent of any one of claims 252-258, 271, and 272, wherein the VH comprises the amino acid sequence of EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINA YTGTPTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 4641).

274. The agent of any one of claims 252-258 and 271-273, wherein the VL comprises the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYAGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 4642).

275. An agent comprising a moiety that binds to a TCR variable region comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of YFDGYLDY (SEQ ID NO: 4602).

276. The agent of claim 275, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of GFTFSSFGMH (SEQ ID NO: 4605).

277. The agent of claim 275 or 276, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of YISSGSSNIQYADTMKG (SEQ ID NO: 4601).

278. The agent of any one of claims 275-277, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQWSSNPLT (SEQ ID NO: 4608).

279. The agent of any one of claims 275-278, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of SVSSSVSYVH (SEQ ID NO: 4606).

280. The agent of any one of claims 275-279, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of LTFNLAS (SEQ ID NO: 4607).

281. The agent of any one of claims 275-280, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of YFDGYLDY (SEQ ID NO: 4602),WSGR Docket No.: 53676-780.601 a HC CDR2 comprising the amino acid sequence of YISSGSSNIQYADTMKG (SEQ ID NO: 4601), a HC CDR1 comprising the amino acid sequence of GFTFSSFGMH (SEQ ID NO: 4605), a LC CDR3 comprising the amino acid sequence of QQWSSNPLT (SEQ ID NO: 4608), a LC CDR2 comprising the amino acid sequence of LTFNLAS (SEQ ID NO: 4607), and a LC CDR1 comprising the amino acid sequence of SVSSSVSYVH (SEQ ID NO: 4606).

282. The agent of any one of claims 275-281, wherein the VH comprises a sequence with at least80% sequence identity to the sequence EVQLVESGGGLVQPGGSRKLSCVVSGFTFSSFGMHWVRQAPEKGLEWVAYISSG SSNIQYADTMKGRFTISRDNPKNTLFLQMTSLRSEDTAMYYCARYFDGYLDYW GQGTTLTVSS (SEQ ID NO: 4609).

283. The agent of any one of claims 275-282, wherein the VL comprises a sequence with at least80% sequence identity to the sequence QIVLTHSPTIMS ASPGEK VTMTC S VS S S VS YVHW YQQKPGS SPRLWIYLTFNL AS GVPGRFSGSGSGTSYSLSISSMEAEDAATYYCQQWSSNPLTFGAGTKLELK (SEQ ID NO: 4610).

284. The agent of any one of claims 275-283, wherein the VH comprises the amino acid sequence of EVQLVESGGGLVQPGGSRKLSCVVSGFTFSSFGMHWVRQAPEKGLEWVAYISSG SSNIQYADTMKGRFTISRDNPKNTLFLQMTSLRSEDTAMYYCARYFDGYLDYW GQGTTLTVSS (SEQ ID NO: 4609).

285. The agent of any one of claims 275-284, wherein the VL comprises the amino acid sequence of QIVLTHSPTIMS ASPGEK VTMTC S VS S S VS YVHW YQQKPGS SPRLWIYLTFNL AS GVPGRFSGSGSGTSYSLSISSMEAEDAATYYCQQWSSNPLTFGAGTKLELK (SEQ ID NO: 4610).

286. An agent comprising a moiety that binds to a TCR variable region comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of YYRDDVNYAMDY (SEQ ID NO: 4615).

287. The agent of claim 286, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of GFNIKDTHMH (SEQ ID NO: 4618).

288. The agent of claim 286 or 287, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of RTDPASGDIKYDPKFQG (SEQ ID NO: 4614).WSGR Docket No.: 53676-780.601289. The agent of any one of claims 286-288, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQYNTYPYT (SEQ ID NO: 4621).

290. The agent of any one of claims 286-289, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of KASQNVGSNVA (SEQ ID NO: 4619).

291. The agent of any one of claims 286-290, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of SSSFRYS (SEQ ID NO: 4620).

292. The agent of any one of claims 286-291, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of YYRDDVNYAMDY (SEQ ID NO: 4615), a HC CDR2 comprising the amino acid sequence of RTDPASGDIKYDPKFQG (SEQ ID NO: 4614), a HC CDR1 comprising the amino acid sequence of GFNIKDTHMH (SEQ ID NO:4618), a LC CDR3 comprising the amino acid sequence of QQYNTYPYT (SEQ ID NO: 4621), a LC CDR2 comprising the amino acid sequence of SSSFRYS (SEQ ID NO: 4620), and a LC CDR1 comprising the amino acid sequence of KASQNVGSNVA (SEQ ID NO:4619).

293. The agent of any one of claims 286-292, wherein the VH comprises a sequence with at least80% sequence identity to the sequence EVQLQQSGAELVKPGASVKLSCTASGFNIKDTHMHWVKQRPEQGLEWIGRTDP ASGDIKYDPKFQGKATITADTSSNTAYLHLSSLTSEDTAVYYCAHYYRDDVNYA MDYWGQGTSVTVSS (SEQ ID NO: 4622).

294. The agent of any one of claims 286-293, wherein the VL comprises a sequence with at least80% sequence identity to the sequence DIVMTQSQKFLSTSVGDRVSVTCKASQNVGSNVAWYQQKPGQSPKSLIYSSSFR YSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNTYPYTFGGGTELEIR (SEQ ID NO: 4623).

295. The agent of any one of claims 286-294, wherein the VH comprises the amino acid sequence of EVQLQQSGAELVKPGASVKLSCTASGFNIKDTHMHWVKQRPEQGLEWIGRTDP ASGDIKYDPKFQGKATITADTSSNTAYLHLSSLTSEDTAVYYCAHYYRDDVNYA MDYWGQGTSVTVSS (SEQ ID NO: 4622).

296. The agent of any one of claims 286-295, wherein the VL comprises the amino acid sequence ofWSGR Docket No.: 53676-780.601DIVMTQSQKFLSTSVGDRVSVTCKASQNVGSNVAWYQQKPGQSPKSLIYSSSFR YSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNTYPYTFGGGTELEIR (SEQ ID NO: 4623).

297. The agent of any one of claims 229-296, wherein the moiety comprises an antibody molecule or antigen binding fragment thereof.

298. The agent of claim 297, wherein the antigen binding fragment thereof comprises a Fab,F(ab')2, Fv, a single chain Fv fragment, a single domain antibody, a diabody (dAb), a bivalent antibody, or bispecific antibody or fragment thereof, a single domain variant thereof, or a camelid antibody.

299. The agent of any one of claims 229-298, wherein the agent further comprises an Fc region.

300. The agent of claim 299, wherein the Fc region comprises one or more mutations.

301. The agent of claim 299 or 300, wherein the Fc region comprises an amino acid sequence with at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 or 42.

302. The agent of any one of claims 299-301, wherein the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

303. The agent of any one of claims 300-302, wherein the Fc comprises one or more mutations comprising E233P, L234V, L235A, P329A, S267K, G237A, P238S, H268A, A330S, P331S, K322A, D265A, D265S, L235E, G236R, S239K, A327G, V273E, T299A, Y300S, or any combination thereof, where amino acid positioning is relative to SEQ ID NO: 42.

304. The agent of any one of claims 299-302, wherein the Fc region comprises an Fc-silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function.

305. The agent of claim 304, wherein the Fc-silencing mutation comprises N297A of a sequence of SEQ ID NO: 42.

306. The agent of claim 299, wherein the Fc region comprises no mutation.

307. The agent of any one of claims 229-306, wherein the agent is functionally linked to a cytotoxic agent.

308. The agent of claim 307, wherein the cytotoxic agent comprises calicheamicin, monomethyl auristatin E, maytansine derivative, or exatecan derivative.

309. The agent of claim 307 or 308, wherein the cytotoxic agent mediates killing of the autoreactive T cells in the subject.WSGR Docket No.: 53676-780.601310. The agent of any one of claims 299-302, wherein the Fc region has effector function or enhanced effector function.

311. The agent of claim 310, wherein the effector function or enhanced effector function comprises antibody dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement dependent cytotoxicity (CDC).

312. The agent of claim 310 or 311, wherein the effector function or enhanced effector function mediates killing of the autoreactive T cells in a subject in need thereof.

313. The agent of any one of claims 229-312, wherein the agent comprises a second moiety.

314. The agent of claim 313, wherein the second moiety comprises a NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

315. The agent of claim 314, wherein the second moiety comprises the NK cell engager, and wherein the NK cell engager binds to NKp30.

316. The agent of claim 315, wherein binding of the second moiety to NKp30 mediates killing of autoreactive T cells in a subject.

317. The agent of claim 315 or 316, wherein the NK cell engager comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) the VH comprises a heavy chain complementarity determining region 1 (HC CDR1), HC CDR 2, and HC CDR 3 comprising: (i) an amino acid sequence of SEQ ID NOs: 6000, 6001, and 6003, respectively; (ii) an amino acid sequence of SEQ ID NOs: 6007, 6008, and 6009, respectively; (iii) an amino acid sequence of SEQ ID NOs: 7313, 6001, and 6002, respectively; (iv) an amino acid sequence of SEQ ID NOs: 7313, 6008, and 6009, respectively; (v) an amino acid sequence of SEQ ID NOs: 7313, 7385, and 7315, respectively; (vi) an amino acid sequence of SEQ ID NOs: 7313, 7318, and 6009, respectively; (vii) an amino acid sequence of SEQ ID NOs: 7313, 6001, and 7315, respectively; or (viii) an amino acid sequence of SEQ ID NOs: 7383, 7380, and 7352, respectively; and / or (b) the VL comprises a light chain complementarity determining region (LC CDR1), LC CDR2, and LC CDR3 comprising: (i) an amino acid sequence of SEQ ID NOs: 6063, 6064, and 67293, respectively; (ii) an amino acid sequence of SEQ ID NOs: 6070, 6071, and 6072, respectively; (iii) an amino acid sequence of SEQ ID NOs: 6070, 6064, and 7321, respectively; or (iv) an amino acid sequence of SEQ ID NOs: 7326, 7327, and 7329, respectively.

318. The agent of claim 317, wherein the VH comprises a sequence with 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 6121-6134, 7295, 7297, 7298, 7300-7304, and 7384; and / or the VL comprises a sequence with 90% sequence identity toWSGR Docket No.: 53676-780.601 the amino acid sequence of any one of SEQ ID NOs: 6136-6147, 7294, 7296, 7299, and 7305-7309.

319. The agent of claim 317 or 318, wherein the VH comprises an amino acid sequence of any one of SEQ ID NOs: 6121-6134, 7295, 7297, 7298, 7300-7304, and 7384; and / or the VL comprises an amino acid sequence of any one of SEQ ID NOs: 6136-6147, 7294, 7296, 7299, and 7305-7309.

320. The agent of any one of claims 314-319, wherein the NK cell engager that binds to NKp30 comprises an amino acid sequence as set forth in SEQ ID NO: 7310, 7311, 7400, 7401, 7402, 7403, 7404, 7405, 7406, 7407, or 7369.

321. The agent of claim 314, wherein the second moiety comprises the T cell engager, and wherein said T cell engager binds to an antigen expressed on a CD8+ and / or CD4+ T cell.

322. The agent of claim 314, wherein the second moiety comprises the T cell engager, and wherein said T cell engager binds to a TCRaV or a TCRPV.

323. The agent of claim 322, wherein the TCRaV or the TCRPV comprises a different TCRaV or a TCRPV from the TCR variable region that the moiety of the agent binds to.

324. The agent of claim 314, wherein the second moiety comprises the T cell engager, and wherein said T cell engager binds to CD3.

325. The agent of any one of claims 314-323, wherein binding of the T cell engager to a CD8+ and / or CD4+ T cell mediates killing of autoreactive T cells in a subject.

326. The agent of any one of claims 229-325, wherein the agent binds to a NK cell with a KD of at most about 100 nM.

327. The agent of any one of claims 229-325, wherein the agent binds to a NK cell with a KD of at most about 10 nM.

328. The agent of any one of claims 314-316, wherein the agent comprising the NK cell engager binds to a NK cell with a KD of at least 0.5-fold lower than that of an otherwise identical agent that does not comprise the NK cell engager.

329. The agent of any one of claims 229-328, wherein the agent binds to a T cell with a KD of at most about 100 nM.

330. The agent of any one of claims 229-328, wherein the agent binds to a T cell with a KD of at most about 10 nM.

331. A multispecific molecule comprising:(a) a first agent comprising a moiety that binds to a TCR variable region comprising a heavy chain variable region (VH) and a light chain variable region (VL), whereinWSGR Docket No.: 53676-780.601 the VH comprises: a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of WINAYTGTPTYADDFEG; and(b) a second agent comprising a NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, a macrophage cell engager, or any combination thereof.

332. A multispecific molecule comprising:(a) a first agent comprising a moiety that binds to a TCR variable region comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of YFDGYLDY or YYRDDVNYAMDY; and(b) a second agent comprising a NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, a macrophage cell engager, or any combination thereof.

333. A multispecific molecule comprising:(a) a first agent comprising a moiety that binds to a TCR variable region comprising a binding domain that binds to a TCRP or a TCRVa of a T cell with a KD of less than about 10 nM; and(b) a second agent comprising a NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, a macrophage cell engager, or any combination thereof.

334. The multispecific molecule of any one of claims 331-333, further comprising an Fc region comprising one or more Fc subunits.

335. The multispecific molecule of claim 334, wherein the multispecific molecules comprises a first Fc subunit operably linked to the first agent and a second Fc subunit operably linked to the second agent.

336. The multispecific molecule of claim 334 or 335, wherein the one or more Fc subunits comprise one or more mutations.

337. The multispecific molecule of any one of claims 334-336, wherein the Fc region comprises an amino acid sequence with at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 41, 42, 4652, or 4655.

338. The multispecific agent of any one of claims 334-337, wherein the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

339. The multispecific molecule of any one of claims 334-338, wherein the Fc region comprises an Fc-silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function.WSGR Docket No.: 53676-780.601340. The multispecific molecule of claim 339, wherein the Fc-silencing mutation comprisesN297A of a sequence of SEQ ID NO: 42.

341. The multispecific molecule of claim 334 or 335, wherein the Fc region comprising no mutation.

342. The multispecific molecule of any one of claims 331-341, wherein the multispecific molecule is functionally linked to a cytotoxic agent.

343. The multispecific molecule of claim 342, wherein the cytotoxic agent comprises calicheamicin, monomethyl auristatin E, maytansine derivative, or exatecan derivative.

344. The multispecific molecule of claim 342 or 343, wherein the cytotoxic agent mediates killing of the autoreactive T cells in the subject.

345. The multispecific molecule of claim 334-338, wherein the Fc region has effector function or enhanced effector function.

346. The multispecific molecule of claim 345, wherein the effector function or enhanced effector function comprises antibody dependent cell-mediated cytotoxicity (ADCC), antibodydependent cellular phagocytosis (ADCP) or complement dependent cytotoxicity (CDC).

347. The multispecific molecule of claim 345 or 346, wherein the effector function or enhanced effector function mediates killing of the autoreactive T cells in a subject in need thereof.

348. The multispecific molecule of claim 335, wherein the first Fc subunit comprises one or more mutations and the second Fc subunit comprises no mutation.

349. The multispecific molecule of claim 335, wherein the first Fc subunit comprises no mutation and the second Fc subunit comprises one or more mutations.

350. The multispecific molecule of any one of claims 331-349, wherein the multispecific molecule comprises the NK cell engager, and wherein the NK cell engager binds to NKp30.

351. The multispecific molecule of claim 350, wherein the multispecific molecule binds to a NK cell with a KD of at least about 0.5-fold lower than that of an otherwise identical multispecific molecule that does not comprise the NK cell engager.

352. A polynucleotide encoding the agent of any one of claims 229-330 or the multispecific molecule of any one of claims 331-351.

353. A polynucleotide encoding the heavy chain variable region (VH) and / or the light chain variable region (VL) of the agent of any one of claims 229-330 or the multispecific molecule of any one of claims 331-351.

354. A vector comprising the polynucleotide of claim 352 or 353.

355. The vector of claim 354, wherein the vector is a viral vector.WSGR Docket No.: 53676-780.601356. The vector of claim 355, wherein the viral vector is an adenoviral vector, lentiviral vector, retroviral vector, or adeno-associated viral vector.

357. A host cell comprising: the polynucleotide of claim 352 or 353; the vector of any one of claims 354-356; a first polynucleotide encoding the VH of the agent of any one of claims 229-330 or the multispecific molecule of any one of claims 331-351, and a second polynucleotide encoding the VL of the agent of any one of claims 229-330 or the multispecific molecule of any one of claims 331-351; or a first vector comprising a first polynucleotide encoding a VH of the agent of any one of claims 229-330 or the multispecific molecule of any one of claims 331-351, and a second vector comprising a second polynucleotide encoding the VL of the agent of any one of claims 229-330 or the multispecific molecule of any one of claims 331-351.

358. A pharmaceutical composition comprising the agent of any one of claims 229-330 or the multispecific molecule of any one of claims 331-351, and a pharmaceutically acceptable carrier, diluent, or excipient.

359. A method of producing the agent of any one of claims 229-330 or the multispecific molecule of any one of claims 331-351, the method comprising culturing the host cell of claim 357 under suitable conditions to express the polynucleotide or the first polynucleotide and the second polynucleotide and to produce the agent or multispecific molecule.

360. A method of targeting a cell in a subject in need thereof, the method comprising administering to the subject the agent of any one of claims 229-330, the multispecific molecule of any one of claims 331-351, the polynucleotide of claim 352 or 353, the vector of any one of claims 354-356, or the pharmaceutical composition of claim 358.

361. A composition for use in the manufacture of a medicament for treating a subject in need thereof, comprising the agent of any one of claims 229-330, the multispecific molecule of any one of claims 331-351, the polynucleotide of claim 352 or 353, or the vector of any one of claims 354-356.

362. A method of treating a disease or condition or reducing a risk of developing the disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the agent of any one of claims 229-330, the multispecific molecule of any one of claims 331-351, the polynucleotide of claim 352 or 353, the vector of any one of claims 354-356, or the pharmaceutical composition of claim 358.

363. The method of claim 362, wherein the subject has an autoimmune disease.WSGR Docket No.: 53676-780.601364. The method of claim 363, wherein the autoimmune disease is selected from the group consisting of the autoimmune disease is selected from amyotrophic lateral sclerosis (ALS), coeliac disease (CD), ankylosing spondylitis (AS), Covid-induced multisystem inflammatory syndrome in children (MIS-C), type 1 narcolepsy, primary Sjogren’s syndrome (PSS), Churg-Strauss syndrome, sarcoidosis, systemic lupus erythematosus (SLE), type 1 diabetes, autoimmune hepatitis (e.g., type 1 or type 2), acute anterior uveitis (UAA), primary sclerosing cholangitis, primary biliary cirrhosis, multiple sclerosis, Guillain-Barre syndrome and the AMAN (axonal & neuronal neuropathy), chronic inflammatory demyelinating polyneuropathy (CIDP), psoriatic arthritis (PsA), transverse myelitis, Tolosa-Hunt syndrome (THS), Devic’s disease (neuromyelitis optica), paraneoplastic cerebellardegeneration (PCD), Lambert-Eaton syndrome, psoriasis, scleroderma, CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome, dermatitis herpetiformis, dermatomyositis, bullous pemphigoid, cicatricial pemphigoid / benign mucosal pemphigoid, pemphigoid gestationis, rheumatoid arthritis (RA), psoriatic arthritis, relapsing polychondritis, chronic recurrent multifocal osteomyelitis (CRMO), vasculitis, Kawasaki disease, granulomatosis with polyangiitis (GPA), Behcet’s disease (vasculitis), Takayasu’s arteritis, polyarteritis nodosa, microscopic polyangiitis (MPA), leukocytoclasticvasculitis, Cogan’s syndrome, uveitis, peripheral uveitis (Pars planitis), scleritis, autoimmune inner ear disease (AIED), Crohn’s, ulcerative colitis (UC), Dressier’s syndrome, Rheumatic fever, Evans syndrome, paroxysmal nocturnal hemoglobinuria (PNH), hemolytic anemia, thrombocytopenic purpura (TTP), polymyositis, juvenile myositis (JM), juvenile dermatomyositis (JDM), juvenile polymyositis (JPM), ocular cicatricial pemphigoid, and Hashimoto’s thyroiditis.

365. The method of claim 362 or 363, wherein:(a) the autoimmune disease is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRa VI subfamily;(b) the autoimmune disease is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V2 subfamily;(c) the autoimmune disease is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V4 subfamily;(d) the autoimmune disease is Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCRa V12 subfamily;(e) the autoimmune disease is Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily;WSGR Docket No.: 53676-780.601(f) the autoimmune disease is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V20 subfamily;(g) the autoimmune disease is ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily;(h) the autoimmune disease is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V22 subfamily;(i) the autoimmune disease is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRa V26 subfamily;(j) the autoimmune disease is Crohn’s disease, and the moiety that binds to the TCR variable region binds to a TCRa V40 subfamily;(k) the autoimmune disease is joint implant failure, and the moiety that binds to the TCR variable region binds to a TCRa V41 subfamily;(l) the autoimmune disease is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily;(m) the autoimmune disease is primary Sjogren’s syndrome, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily;(n) the autoimmune disease is amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily;(o) the autoimmune disease is celiac disease, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily;(p) the autoimmune disease is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V7 subfamily;(q) the autoimmune disease is ankylosing spondylitis, and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(r) the autoimmune disease is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V10 subfamily;(s) the autoimmune disease is COVID-induced multisystem inflammatory syndrome in children, and the moiety that binds to the TCR variable region binds to a TCRP VI 1 subfamily;(t) the autoimmune disease is Type I diabetes, and the moiety that binds to the TCR variable region binds to a TCRP V12 subfamily;(u) the autoimmune disease is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP VI 0 subfamily;(v) the autoimmune disease is amyotrophic lateral sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V23 subfamily;WSGR Docket No.: 53676-780.601(w) the autoimmune disease is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V29 subfamily;(x) the autoimmune disease is multiple sclerosis, and the moiety that binds to the TCR variable region binds to a TCRP V6 subfamily;(y) the autoimmune disease is acute anterior uveitis (UAA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(z) the autoimmune disease is psoriatic arthritis (PsA), and the moiety that binds to the TCR variable region binds to a TCRP V9 subfamily;(aa) the autoimmune disease is type I narcolepsy, and the moiety that binds to the TCR variable region binds to a TCRP V4 subfamily;(bb) the autoimmune disease is amyotrophic lateral sclerosis (ALS), and the moiety that binds to the TCR variable region binds to a TCRa VI 3 subfamily; or(cc) the autoimmune disease is UAA, and the moiety that binds to the TCR variable region binds to a TCRa V21 subfamily.

366. The method of any one of claims 362-365, further comprising administering an additional therapeutic agent or therapy.

367. A method of identifying a subject with an autoimmune disease as a candidate for a therapeutic, the method comprising determining the subject has a biased TCRP and / or TCRVa clonotype, wherein the therapeutic comprises the agent of any one of claims 229- 330, the multispecific molecule of any one of claims 331-351, the polynucleotide of claim 352 or 353, the vector of any one of claims 354-356, or the pharmaceutical composition of claim 358.

368. The method of claim 367, wherein the biased TCRP and / or TCRVa clonotype is from aTCRa VI subfamily, a TCRa V2 subfamily, a TCRa V3 subfamily, a TCRa V4, a TCRa V5 subfamily, a TCRa V6 subfamily, a TCRa V7 subfamily, a TCRa V8 subfamily, a TCRa V9 subfamily, a TCRa V10 subfamily, a TCRa V12 subfamily, a TCRa V13 subfamily, a TCRa V14 subfamily, a TCRa V16 subfamily, a TCRa V17 subfamily, a TCRa VI 8 subfamily, a TCRa VI 9 subfamily, a TCRa V20 subfamily, a TCRa V21 subfamily, a TCRa V22 subfamily, a TCRa V23 subfamily, a TCRa V24 subfamily, TCRa V25 subfamily, a TCRa V26 subfamily, a TCRa V27 subfamily, a TCRa V29 subfamily, a TCRa V30 subfamily, a TCRa V34 subfamily, a TCRa V35 subfamily, a TCRa V36 subfamily, a TCRa V38 subfamily, a TCRa V39 subfamily, a TCRa V40 subfamily, a TCRa V41 subfamily, a TCRP V6 subfamily, a TCRP V10 subfamily, a TCRP V12 subfamily, a TCRP V5 subfamily, a TCRP V7 subfamily, a TCRP VI 1 subfamily, a TCRP VI 4 subfamily, a TCRP VI 6 subfamily, a TCRP VI 8 subfamily, aWSGR Docket No.: 53676-780.601TCRP V9 subfamily, a TCRP VI 3 subfamily, a TCRP V4 subfamily, a TCRP V3 subfamily, a TCRP V2 subfamily, a TCRP VI 5 subfamily, a TCRP V30 subfamily, a TCRP VI 9 subfamily, a TCRP V27 subfamily, a TCRP V28 subfamily, a TCRP V24 subfamily, a TCRP V20 subfamily, TCRP V25 subfamily, a TCRP V29 subfamily, a TCRP VI subfamily, a TCRP VI 7 subfamily, a TCRP V21 subfamily, a TCRP V23 subfamily, a TCRP V26 subfamily, or any variant thereof.

369. A method of treating an autoimmune disease or condition in a human subject in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of an agent comprising(a) a moiety that binds to a TCR variable region, wherein the TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor variable beta region (TCRPV); and(b) an NK cell engager that binds to a cell surface protein of an NK cell, wherein the NK cell engager activates the NK cell; and wherein the disease or condition is narcolepsy and the TCR variable region is TRAJ24, the disease or condition is Vitiligo and the TCR variable region is TRBV4, or the disease or condition is type 1 diabetes and the TCR variable region is TRBV5 or TRAV41.

370. The method of claim 369, wherein the disease or condition is narcolepsy and the TCR variable region is TRAJ24.

371. The method of claim 369, wherein the disease or condition is Vitiligo and the TCR variable region is TRBV4.

372. The method of claim 369, wherein the disease or condition is type 1 diabetes and the TCR variable region is TRBV5 or TRAV41.

373. A method of treating an autoimmune disease or condition in a human subject in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of an agent comprising(a) a first moiety that binds to a first TCR variable region, wherein the first TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor variable beta region (TCRPV);(b) a second moiety that binds to a second TCR variable region, wherein the second TCR variable region is a T cell receptor alpha variable region (TCRaV) or a T cell receptor variable beta region (TCRPV); andWSGR Docket No.: 53676-780.601(c) an NK cell engager that binds to a cell surface protein of an NK cell, wherein the NK cell engager activates the NK cell; and wherein the disease or condition is narcolepsy, the first TCR variable region is TRBV4-2, and the second TCR variable region is TRAJ24, the disease or condition is multiple sclerosis, the first TCR variable region is TRBV6- 5, and the second TCR variable region is TRBV5-1, or the disease or condition is type 1 diabetes, the first TCR variable region is TRBV5, and the second TCR variable region is TRAV41.

374. The method of claim 373, wherein the disease or condition is narcolepsy, the first TCR variable region is TRBV4-2, and the second TCR variable region is TRAJ24.

375. The method of claim 373, wherein the disease or condition is multiple sclerosis, the firstTCR variable region is TRBV6-5, and the second TCR variable region is TRBV5-1.

376. The method of claim 373, wherein the disease or condition is type 1 diabetes, the first TCR variable region is TRBV5, and the second TCR variable region is TRAV41.

377. The method of any one of claims 369-376, wherein the cell surface protein comprisesNKp30, NKp46, NKG2D, or CD16.

378. The method of any one of claims 369-377, wherein binding of the NK cell engager activates an NK cell and mediates killing of an autoreactive T cell in the human subject.

379. The method of any one of claims 369-378, wherein the agent comprises an Fc region.

380. The method of claim 379, wherein the Fc region has effector function or enhanced effector function.

381. The method of claim 380, wherein the effector function or enhanced effector function comprises antibody dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement dependent cytotoxicity (CDC).

382. The method of claim 380 or 381, wherein the effector function or enhanced effector function mediates killing of an autoreactive T cell in the human subject.

383. A method of treating an autoimmune disease or condition in a human subject in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of an agent comprising a moiety that binds to a TCR variable region, wherein the TCR variable region is TCRBV9, wherein the moiety that binds to the TCR variable region comprises a heavy chain variable region (VH), wherein the VH comprises a heavy chain complementarity determining region 3 (HC CDR3) comprising an amino acid sequence as set forth in SWRRGIRGIGFDY (SEQ ID NO: 1250),WSGR Docket No.: 53676-780.601 wherein the autoimmune disease or condition is acute anterior uveitis (UAA), psoriatic arthritis (PsA), ankylosing spondylitis, Celiac disease, reactive arthritis, inflammatory bowel disease, sacroiliitis, Reiter's syndrome, juvenile rheumatoid arthritis, or any combination thereof.

384. The method of claim 383, wherein the autoimmune disease or condition UAA.

385. The method of claim 383, wherein the autoimmune disease or condition is PsA.

386. The method of claim 383, wherein the autoimmune disease or condition is ankylosing spondylitis.

387. The method of claim 383, wherein the autoimmune disease or condition is Celiac disease.

388. The method of claim 383, wherein the autoimmune disease or condition is reactive arthritis.

389. The method of claim 383, wherein the autoimmune disease or condition is inflammatory bowel disease.

390. The method of claim 383, wherein the autoimmune disease or condition is sacroiliitis.

391. The method of claim 383, wherein the autoimmune disease or condition is Reiter's syndrome.

392. The method of claim 383, wherein the autoimmune disease or condition is juvenile rheumatoid arthritis.

393. The method of any one of claims 383-392, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of DYIVH (SEQ ID NO: 1248), GYTFTDY (SEQ ID NO: 1251), or GYTFTDYIVH (SEQ ID NO: 1253).

394. The method of any one of claims 383-393, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of WINTYTGTPTYADDFEG (SEQ ID NO: 1249) or NTYTGT (SEQ ID NO: 1252).

395. The method of any one of claims 383-394, wherein the moiety comprises a light chain variable region (VL), wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256).

396. The method of any one of claims 383-395, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254).

397. The method of any one of claims 383-396, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of DGSTLQS (SEQ ID NO: 1255).

398. The method of any one of claims 383-397, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250),WSGR Docket No.: 53676-780.601 a HC CDR2 comprising the amino acid sequence of WINTYTGTPTYADDFEG (SEQ ID NO: 1249) or NTYTGT (SEQ ID NO: 1252), a HC CDR1 comprising the amino acid sequence of DYIVH (SEQ ID NO: 1248), GYTFTDY (SEQ ID NO: 1251), or GYTFTDYIVH (SEQ ID NO: 1253), a LC CDR3 comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256), a LC CDR2 comprising the amino acid sequence of DGSTLQS (SEQ ID NO: 1255), and a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254).

399. The method of any one of claims 383-398, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QLQLVQSGPELREPGESVKISCKASGYTFTDYIVHWVKQAPGKGLKWMGWINT YTGTPTYADDFEGRFVFSLEASASTANLQISNLKNEDTATYFCARSWRRGIRGIG FDYWGQGVMVTVSS (SEQ ID NO: 7000).

400. The method of any one of claims 383-399, wherein the VH comprises a sequence ofQLQLVQSGPELREPGESVKISCKASGYTFTDYIVHWVKQAPGKGLKWMGWINT YTGTPTYADDFEGRFVFSLEASASTANLQISNLKNEDTATYFCARSWRRGIRGIG FDYWGQGVMVTVSS (SEQ ID NO: 7000).

401. The method of any one of claims 383-400, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DVQMTQSPYNLAASPGESVSINCKASKSINKYLAWYQQKPGKPNKLLIYDGSTL QSGIPSRFSGSGSGTDFTLTIRGLEPEDFGLYYCQQHNEYPPTFGAGTKLELK (SEQ ID NO: 7001).

402. The method of any one of claims 383-401, wherein the VL comprises a sequence ofDVQMTQSPYNLAASPGESVSINCKASKSINKYLAWYQQKPGKPNKLLIYDGSTL QSGIPSRFSGSGSGTDFTLTIRGLEPEDFGLYYCQQHNEYPPTFGAGTKLELK (SEQ ID NO: 7001).

403. The method of any one of claims 383-398, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWIN TYTGTPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 7002).

404. The method of any one of claims 383-398 and 403, wherein the VH comprises a sequence of QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWINWSGR Docket No.: 53676-780.601TYTGTPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 7002).

405. The method of any one of claims 383-398, 403, and 404, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003).

406. The method of any one of claims 383-398 and 403-405, wherein the VL comprises a sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003).

407. The method of any one of claims 383-398, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence ELQLVESGGGLVQPGRSLRLSCTASGYTFTDYIVHWVRQAPGKGLKWMGWINT YTGTPTYADDFEGRFTFSLDASKSIAYLQMNSLKTEDTAVYYCARSWRRGIRGIG FDYWGQGTMVTVSS (SEQ ID NO: 7004).

408. The method of any one of claims 383-398 and 407, wherein the VH comprises a sequence of ELQLVESGGGLVQPGRSLRLSCTASGYTFTDYIVHWVRQAPGKGLKWMGWINT YTGTPTYADDFEGRFTFSLDASKSIAYLQMNSLKTEDTAVYYCARSWRRGIRGIG FDYWGQGTMVTVSS (SEQ ID NO: 7004).

409. The method of any one of claims 383-398, 407, and 408, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence EVVMTQSPPTLSLSPGERVTLSCKASKSINKYLAWYQQKPGQANKLLIYDGSTLQ SGIPARFSGSGSGTDFTLTISSLQPEDFAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7005).

410. The method of any one of claims 383-398 and 407-409, wherein the VL comprises a sequence of EVVMTQSPPTLSLSPGERVTLSCKASKSINKYLAWYQQKPGQANKLLIYDGSTLQ SGIPARFSGSGSGTDFTLTISSLQPEDFAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7005).

411. The method of any one of claims 383-398, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence ELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINTWSGR Docket No.: 53676-780.601YTGTPT YADDFEGQFTF SLD ASISTAYLQWS SLKASDTAMYYC ARSWRRGIRGIG FDYWGQGTMVTVSS (SEQ ID NO: 7006).

412. The method of any one of claims 383-398 and 411, wherein the VH comprises a sequence of ELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINT YTGTPT YADDFEGQFTF SLD ASISTAYLQWS SLKASDTAMYYC ARSWRRGIRGIG FDYWGQGTMVTVSS (SEQ ID NO: 7006).

413. The method of any one of claims 383-398, 411, and 412, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003).

414. The method of any one of claims 383-398 and 411-413, wherein the VL comprises a sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003).

415. The method of any one of claims 383-398, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QLQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLKWMGWIN TYTGTPTYADDFEGRFVF SLD AS ASTAYLQIS SLKAEDMAMYYC ARSWRRGIRG IGFDYWGQGTMVTVSS (SEQ ID NO: 7008).

416. The method of any one of claims 383-398 and 415, wherein the VH comprises a sequence of QLQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLKWMGWIN TYTGTPTYADDFEGRFVF SLD AS ASTAYLQIS SLKAEDMAMYYC ARSWRRGIRG IGFDYWGQGTMVTVSS (SEQ ID NO: 7008).

417. The method of any one of claims 383-398, 415, and 416, wherein the VL comprises a sequence with at least 80% sequence identity to the sequenceDVQMTQ SP S SLS AS VGDRVTITCKASKSINKYLAWYQQKPGKANKLLIYDGSTL QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7007).

418. The method of any one of claims 383-398 and 415-417, wherein the VL comprises a sequence ofDVQMTQ SP S SLS AS VGDRVTITCKASKSINKYLAWYQQKPGKANKLLIYDGSTLWSGR Docket No.: 53676-780.601QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7007).

419. The method of any one of claims 383-398, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QLQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLKWMGWIN TYTGTPTYADDFEGRFVF SLD AS ASTAYLQIS SLKAEDMAMYYC ARSWRRGIRG IGFDYWGQGTMVTVSS (SEQ ID NO: 7008).

420. The method of any one of claims 383-398 and 419, wherein the VH comprises a sequence of QLQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLKWMGWIN TYTGTPTYADDFEGRFVF SLD AS ASTAYLQIS SLKAEDMAMYYC ARSWRRGIRG IGFDYWGQGTMVTVSS (SEQ ID NO: 7008).

421. The method of any one of claims 383-398, 419, and 420, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003).

422. The method of any one of claims 383-398 and 419-421, wherein the VL comprises a sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003).

423. The method of any one of claims 383-398, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWIN TYTGTPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 7010).

424. The method of any one of claims 383-398 and 423, wherein the VH comprises a sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWIN TYTGTPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 7010).

425. The method of any one of claims 383-398, 423, and 424, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQWSGR Docket No.: 53676-780.601SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009).

426. The method of any one of claims 383-398 and 423-425, wherein the VL comprises a sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009).

427. The method of any one of claims 383-398, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINT YTGTPTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 7012).

428. The method of any one of claims 383-398 and 427, wherein the VH comprises a sequence of EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINT YTGTPTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 7012).

429. The method of any one of claims 383-398, 427, and 428, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009).

430. The method of any one of claims 383-398 and 427-429, wherein the VL comprises a sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009).

431. The method of any one of claims 383-398, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QVQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLEWMGWIN TYTGTPTYADDFEGRFVFSMDTSASTAYLQISSLKAEDMAMYYCARSWRRGIRG IGFDYWGQGTMVTVSS (SEQ ID NO: 7014).

432. The method of any one of claims 383-398 and 431, wherein the VH comprises a sequence of QVQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLEWMGWINWSGR Docket No.: 53676-780.601TYTGTPTYADDFEGRFVFSMDTSASTAYLQISSLKAEDMAMYYCARSWRRGIRG IGFDYWGQGTMVTVSS (SEQ ID NO: 7014).

433. The method of any one of claims 383-398, 431, and 432, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCKASKSINKYLAWYQQKPGKAPKLLIYDGSTLQ SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7011).

434. The method of any one of claims 383-398 and 431-433, wherein the VL comprises a sequence of DIQMTQSPSSLSASVGDRVTITCKASKSINKYLAWYQQKPGKAPKLLIYDGSTLQ SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7011).

435. The method of any one of claims 383-398, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QVQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLEWMGWIN TYTGTPTYADDFEGRFVFSMDTSASTAYLQISSLKAEDMAMYYCARSWRRGIRG IGFDYWGQGTMVTVSS (SEQ ID NO: 7014).

436. The method of any one of claims 383-398 and 435, wherein the VH comprises a sequence of QVQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLEWMGWIN TYTGTPTYADDFEGRFVFSMDTSASTAYLQISSLKAEDMAMYYCARSWRRGIRG IGFDYWGQGTMVTVSS (SEQ ID NO: 7014).

437. The method of any one of claims 383-398, 435, and 436, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009).

438. The method of any one of claims 383-398 and 435-437, wherein the VL comprises a sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009).

439. The method of any one of claims 383-398, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINWSGR Docket No.: 53676-780.601TYTGTPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYFCARSWRRGIRGI GFDYWGQGVMVTVSS (SEQ ID NO: 7015).

440. The method of any one of claims 383-398 and 439, wherein the VH comprises a sequence of QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWIN TYTGTPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYFCARSWRRGIRGI GFDYWGQGVMVTVSS (SEQ ID NO: 7015).

441. The method of any one of claims 383-398, 439, and 440, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGAGTKLELK (SEQ ID NO: 7013).

442. The method of any one of claims 383-398 and 439-441, wherein the VL comprises a sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGAGTKLELK (SEQ ID NO: 7013).

443. The method of any one of claims 383-442, wherein the administering inhibits or prevents activation or expansion of autoreactive T cells in the human subject.

444. The method of claim 443, wherein the autoreactive T cells target an autologous cell in the human subj ect.

445. The method of claim 443 or 444, wherein the autoreactive T cells express TCRaV and / orTCRPV.

446. The method of any one of claims 383-445, wherein the agent comprises an antibody molecule or antigen binding domain thereof.

447. The method of any one of claims 383-445, wherein the agent comprises an Fc region.

448. The method of claim 447, wherein the Fc region comprises an amino acid sequence with at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 or 42.

449. The method of claim 447 or 448, wherein the Fc region comprises one or more mutations.

450. The method of claim 449, wherein the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

451. The method of any one of claims 448-450, wherein the Fc comprises one or more mutations comprising E233P, L234V, L235A, P329A, S267K, G237A, P238S, H268A, A330S,WSGR Docket No.: 53676-780.601P331S, K322A, D265A, D265S, L235E, G236R, S239K, A327G, V273E, T299A, Y300S, or any combination thereof, where amino acid positioning is relative to SEQ ID NO: 42.

452. The method of any one of claims 448-451, wherein the Fc region comprises an Fc-silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function.

453. The method of claim 447, wherein the Fc region comprises no binding mutation.

454. The method of claim 453, wherein the Fc region has effector function or enhanced effector function.

455. The method of claim 454, wherein the effector function or enhanced effector function comprises antibody dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement dependent cytotoxicity (CDC).

456. The method of claim 454 or 455, wherein the effector function or enhanced effector function mediates killing of the autoreactive T cells in the human subject.

457. The method of any one of claims 383-456, wherein the agent comprises an another moiety.

458. The method of claim 457, wherein the another moiety comprises aNK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

459. A multispecific molecule comprising:(a) a first agent comprising a moiety that binds to a TCR variable region in a TCRP V9 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250); and(b) a second agent comprising a NK cell engager, comprising a second VH and a second VL, wherein the second VH comprises a HC CDR3 comprising the amino acid sequence of GDWHYFDY (SEQ ID NO: 7352).

460. The multispecific molecule of claim 459, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of DYIVH (SEQ ID NO: 1248), GYTFTDY (SEQ ID NO: 1251), or GYTFTDYIVH (SEQ ID NO: 1253).

461. The multispecific molecule of claim 459 or 460, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of WINTYTGTPTYADDFEG (SEQ ID NO: 1249) or NTYTGT (SEQ ID NO: 1252).

462. The multispecific molecule of any one of claims 459-461, wherein the moiety comprises a light chain variable region (VL), wherein the VL comprises a light chainWSGR Docket No.: 53676-780.601 complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256).

463. The multispecific molecule of any one of claims 459-462, wherein the VL comprises a LCCDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254).

464. The multispecific molecule of any one of claims 459-463, wherein the VL comprises a LCCDR2 comprising the amino acid sequence of DGSTLQS (SEQ ID NO: 1255).

465. The multispecific molecule of any one of claims 459-464, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250), a HC CDR2 comprising the amino acid sequence of WINTYTGTPTYADDFEG (SEQ ID NO: 1249) or NTYTGT (SEQ ID NO: 1252), a HC CDR1 comprising the amino acid sequence of DYIVH (SEQ ID NO: 1248), GYTFTDY (SEQ ID NO: 1251), or GYTFTDYIVH (SEQ ID NO: 1253), a LC CDR3 comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256), a LC CDR2 comprising the amino acid sequence of DGSTLQS (SEQ ID NO: 1255), and a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254).

466. The multispecific molecule of any one of claims 459-465, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QLQLVQSGPELREPGESVKISCKASGYTFTDYIVHWVKQAPGKGLKWMGWINT YTGTPTYADDFEGRFVFSLEASASTANLQISNLKNEDTATYFCARSWRRGIRGIG FDYWGQGVMVTVSS (SEQ ID NO: 7000).

467. The multispecific molecule of any one of claims 459-466, wherein the VH comprises a sequence of QLQLVQSGPELREPGESVKISCKASGYTFTDYIVHWVKQAPGKGLKWMGWINT YTGTPTYADDFEGRFVFSLEASASTANLQISNLKNEDTATYFCARSWRRGIRGIG FDYWGQGVMVTVSS (SEQ ID NO: 7000).

468. The multispecific molecule of any one of claims 459-467, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DVQMTQSPYNLAASPGESVSINCKASKSINKYLAWYQQKPGKPNKLLIYDGSTL QSGIPSRFSGSGSGTDFTLTIRGLEPEDFGLYYCQQHNEYPPTFGAGTKLELK (SEQ ID NO: 7001).

469. The multispecific molecule of any one of claims 459-468, wherein the VL comprises a sequence of DVQMTQSPYNLAASPGESVSINCKASKSINKYLAWYQQKPGKPNKLLIYDGSTLWSGR Docket No.: 53676-780.601QSGIPSRFSGSGSGTDFTLTIRGLEPEDFGLYYCQQHNEYPPTFGAGTKLELK (SEQ ID NO: 7001).

470. The multispecific molecule of any one of claims 459-465, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWIN TYTGTPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 7002).

471. The multispecific molecule of any one of claims 459-465 and 470, wherein the VH comprises a sequence of QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLKWMGWIN TYTGTPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 7002).

472. The multispecific molecule of any one of claims 459-465, 470, and 471, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003).

473. The multispecific molecule of any one of claims 459-465 and 470-472, wherein the VL comprises a sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003).

474. The multispecific molecule of any one of claims 459-465, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence ELQLVESGGGLVQPGRSLRLSCTASGYTFTDYIVHWVRQAPGKGLKWMGWINT YTGTPTYADDFEGRFTFSLDASKSIAYLQMNSLKTEDTAVYYCARSWRRGIRGIG FDYWGQGTMVTVSS (SEQ ID NO: 7004).

475. The multispecific molecule of any one of claims 459-465 and 474, wherein the VH comprises a sequence of ELQLVESGGGLVQPGRSLRLSCTASGYTFTDYIVHWVRQAPGKGLKWMGWINT YTGTPTYADDFEGRFTFSLDASKSIAYLQMNSLKTEDTAVYYCARSWRRGIRGIG FDYWGQGTMVTVSS (SEQ ID NO: 7004).

476. The multispecific molecule of any one of claims 459-465, 474, and 475, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence EVVMTQSPPTLSLSPGERVTLSCKASKSINKYLAWYQQKPGQANKLLIYDGSTLQWSGR Docket No.: 53676-780.601SGIPARFSGSGSGTDFTLTISSLQPEDFAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7005).

477. The multispecific molecule of any one of claims 459-465 and 474-476, wherein the VL comprises a sequence of EVVMTQSPPTLSLSPGERVTLSCKASKSINKYLAWYQQKPGQANKLLIYDGSTLQ SGIPARFSGSGSGTDFTLTISSLQPEDFAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7005).

478. The multispecific molecule of any one of claims 459-465, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence ELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINT YTGTPT YADDFEGQFTF SLD ASISTAYLQWS SLKASDTAMYYC ARSWRRGIRGIG FDYWGQGTMVTVSS (SEQ ID NO: 7006).

479. The multispecific molecule of any one of claims 459-465 and 478, wherein the VH comprises a sequence of ELQLVQSGAEVKKPGESLKISCKASGYTFTDYIVHWVRQMPGKGLKWMGWINT YTGTPT YADDFEGQFTF SLD ASISTAYLQWS SLKASDTAMYYC ARSWRRGIRGIG FDYWGQGTMVTVSS (SEQ ID NO: 7006).

480. The multispecific molecule of any one of claims 459-465, 478, and 479, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003).

481. The multispecific molecule of any one of claims 459-465 and 478-480, wherein the VL comprises a sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003).

482. The multispecific molecule of any one of claims 459-465, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QLQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLKWMGWIN TYTGTPTYADDFEGRFVF SLD AS ASTAYLQIS SLKAEDMAMYYC ARSWRRGIRG IGFDYWGQGTMVTVSS (SEQ ID NO: 7008).

483. The multispecific molecule of any one of claims 459-465 and 482, wherein the VH comprises a sequence of QLQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLKWMGWINWSGR Docket No.: 53676-780.601TYTGTPTYADDFEGRFVF SLD AS ASTAYLQIS SLKAEDMAMYYC ARSWRRGIRG IGFDYWGQGTMVTVSS (SEQ ID NO: 7008).

484. The multispecific molecule of any one of claims 459-465, 482, and 483, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DVQMTQ SP S SLS AS VGDRVTITCKASKSINKYLAWYQQKPGKANKLLIYDGSTL QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7007).

485. The multispecific molecule of any one of claims 459-465 and 482-484, wherein the VL comprises a sequence ofDVQMTQ SP S SLS AS VGDRVTITCKASKSINKYLAWYQQKPGKANKLLIYDGSTL QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7007).

486. The multispecific molecule of any one of claims 459-465, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QLQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLKWMGWIN TYTGTPTYADDFEGRFVF SLD AS ASTAYLQIS SLKAEDMAMYYC ARSWRRGIRG IGFDYWGQGTMVTVSS (SEQ ID NO: 7008).

487. The multispecific molecule of any one of claims 459-465 and 486, wherein the VH comprises a sequence of QLQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLKWMGWIN TYTGTPTYADDFEGRFVF SLD AS ASTAYLQIS SLKAEDMAMYYC ARSWRRGIRG IGFDYWGQGTMVTVSS (SEQ ID NO: 7008).

488. The multispecific molecule of any one of claims 459-465, 486, and 487, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003).

489. The multispecific molecule of any one of claims 459-465 and 486-488, wherein the VL comprises a sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7003).

490. The multispecific molecule of any one of claims 459-465, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWINWSGR Docket No.: 53676-780.601TYTGTPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 7010).

491. The multispecific molecule of any one of claims 459-465 and 490, wherein the VH comprises a sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWIN TYTGTPTYADDFEGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 7010).

492. The multispecific molecule of any one of claims 459-465, 490, and 491, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009).

493. The multispecific molecule of any one of claims 459-465 and 490-492, wherein the VL comprises a sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009).

494. The multispecific molecule of any one of claims 459-465, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINT YTGTPTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 7012).

495. The multispecific molecule of any one of claims 459-465 and 494, wherein the VH comprises a sequence of EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYIVHWVRQMPGKGLEWMGWINT YTGTPTYADDFEGQVTISADKSISTAYLQWSSLKASDTAMYYCARSWRRGIRGI GFDYWGQGTMVTVSS (SEQ ID NO: 7012).

496. The multispecific molecule of any one of claims 459-465, 494, and 495, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009).

497. The multispecific molecule of any one of claims 459-465 and 494-496, wherein the VL comprises a sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQWSGR Docket No.: 53676-780.601SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009).

498. The multispecific molecule of any one of claims 459-465, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QVQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLEWMGWIN TYTGTPTYADDFEGRFVFSMDTSASTAYLQISSLKAEDMAMYYCARSWRRGIRG IGFDYWGQGTMVTVSS (SEQ ID NO: 7014).

499. The multispecific molecule of any one of claims 459-465 and 498, wherein the VH comprises a sequence of QVQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLEWMGWIN TYTGTPTYADDFEGRFVFSMDTSASTAYLQISSLKAEDMAMYYCARSWRRGIRG IGFDYWGQGTMVTVSS (SEQ ID NO: 7014).

500. The multispecific molecule of any one of claims 459-465, 498, and 499, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCKASKSINKYLAWYQQKPGKAPKLLIYDGSTLQ SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7011).

501. The multispecific molecule of any one of claims 459-465 and 498-500, wherein the VL comprises a sequence of DIQMTQSPSSLSASVGDRVTITCKASKSINKYLAWYQQKPGKAPKLLIYDGSTLQ SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7011).

502. The multispecific molecule of any one of claims 459-465, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QVQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLEWMGWIN TYTGTPTYADDFEGRFVFSMDTSASTAYLQISSLKAEDMAMYYCARSWRRGIRG IGFDYWGQGTMVTVSS (SEQ ID NO: 7014).

503. The multispecific molecule of any one of claims 459-465 and 502, wherein the VH comprises a sequence of QVQLVQSGHEVKQPGASVKVSCKASGYTFTDYIVHWVPQAPGQGLEWMGWIN TYTGTPTYADDFEGRFVFSMDTSASTAYLQISSLKAEDMAMYYCARSWRRGIRG IGFDYWGQGTMVTVSS (SEQ ID NO: 7014).

504. The multispecific molecule of any one of claims 459-465, 502, and 503, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQWSGR Docket No.: 53676-780.601SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009).

505. The multispecific molecule of any one of claims 459-465 and 502-504, wherein the VL comprises a sequence of DIVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPPKLLIYDGSTLQ SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGQGTKLEIK (SEQ ID NO: 7009).

506. The multispecific molecule of any one of claims 459-465, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWIN TYTGTPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYFCARSWRRGIRGI GFDYWGQGVMVTVSS (SEQ ID NO: 7015).

507. The multispecific molecule of any one of claims 459-465 and 506, wherein the VH comprises a sequence of QLQLVQSGAEVKKPGASVKVSCKASGYTFTDYIVHWVRQAPGQRLEWMGWIN TYTGTPTYADDFEGRFTFTLDASASTAYMELSSLRSEDTAVYFCARSWRRGIRGI GFDYWGQGVMVTVSS (SEQ ID NO: 7015).

508. The multispecific molecule of any one of claims 459-465, 506, and 507, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGAGTKLELK (SEQ ID NO: 7013).

509. The multispecific molecule of any one of claims 459-465 and 506-508, wherein the VL comprises a sequence of DVVMTQSPDSLAVSLGERATINCKASKSINKYLAWYQQKPGQPNKLLIYDGSTL QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHNEYPPTFGAGTKLELK (SEQ ID NO: 7013).

510. The multispecific molecule of any one of claims 459-509, wherein the second VH comprises a HC CDR1 comprising the amino acid sequence of GFSIIRVGYHWN (SEQ ID NO: 7383).

511. The multispecific molecule of any one of claims 459-510, wherein the second VH comprises a HC CDR2 comprising the amino acid sequence of YIHRSGSTSYNPSLKS (SEQ ID NO: 7380).WSGR Docket No.: 53676-780.601512. The multispecific molecule of any one of claims 459-511, wherein the second VL comprises a LC CDR3 comprising the amino acid sequence of QFWDSTNSAV (SEQ ID NO: 7358).

513. The multispecific molecule of any one of claims 459-512, wherein the second VL comprises a LC CDR1 comprising the amino acid sequence of SGEKLSDKYVH (SEQ ID NO: 7356).

514. The multispecific molecule of any one of claims 459-513, wherein the second VL comprises a LC CDR2 comprising the amino acid sequence of ENDRRPS (SEQ ID NO: 7352).

515. The multispecific molecule of any one of claims 459-514, wherein the NK cell engager comprises: a HC CDR3 comprising the amino acid sequence of GDWHYFDY (SEQ ID NO: 7352), a HC CDR2 comprising the amino acid sequence of YH4RSGSTSYNPSLKS (SEQ ID NO: 7380, a HC CDR1 comprising the amino acid sequence of GFSIIRVGYHWN (SEQ ID NO: 7383), a LC CDR3 comprising the amino acid sequence of QFWDSTNSAV (SEQ ID NO: 7358), a LC CDR2 comprising the amino acid sequence of ENDRRPS (SEQ ID NO: 7352), and a LC CDR1 comprising the amino acid sequence of SGEKLSDKYVH (SEQ ID NO: 7356).

516. The multispecific molecule of any one of claims 459-515, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EIQLLESGGGLVQPGGSLRLSCAVSGFSIIRVGYHWNWVRQAPGKGLEWVGYIH RSGSTSYNPSLKSRFTISRDTSKNTFYLQMNSLRAEDTAVYYCARGDWHYFDYW GQGTMVTVSS (SEQ ID NO: 7384).

517. The multispecific molecule of any one of claims 459-516, wherein the VH comprises a sequence of EIQLLESGGGLVQPGGSLRLSCAVSGFSIIRVGYHWNWVRQAPGKGLEWVGYIH RSGSTSYNPSLKSRFTISRDTSKNTFYLQMNSLRAEDTAVYYCARGDWHYFDYW GQGTMVTVSS (SEQ ID NO: 7384).

518. The multispecific molecule of any one of claims 459-517, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DSVTTQSPLSLPVTLGQPASISCSGEKLSDKYVHWYQQRPGQSPRMLIYENDRRPWSGR Docket No.: 53676-780.601SGVPDRFSGSNSGNDATLKISRVEAEDVGVYFCQFWDSTNSAVFGGGTKVEIK (SEQ ID NO: 7309).

519. The multispecific molecule of any one of claims 459-518, wherein the VL comprises a sequence of DSVTTQSPLSLPVTLGQPASISCSGEKLSDKYVHWYQQRPGQSPRMLIYENDRRP SGVPDRFSGSNSGNDATLKISRVEAEDVGVYFCQFWDSTNSAVFGGGTKVEIK (SEQ ID NO: 7309).

520. The multispecific molecule of any one of claims 383-519, wherein the agent comprises an antibody molecule or antigen binding domain thereof.

521. The multispecific molecule of any one of claims 383-520, wherein the agent comprises anFc region.

522. The multispecific molecule of claim 521, wherein the Fc region comprises an amino acid sequence with at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 or 42.

523. The multispecific molecule of claim 521 or 522, wherein the Fc region comprises one or more mutations.

524. The multispecific molecule of claim 523, wherein the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

525. The multispecific molecule of any one of claims 521-524, wherein the Fc comprises one or more mutations comprising E233P, L234V, L235A, P329A, S267K, G237A, P238S, H268A, A330S, P331S, K322A, D265A, D265S, L235E, G236R, S239K, A327G, V273E, T299A, Y300S, or any combination thereof, where amino acid positioning is relative to SEQ ID NO: 42.

526. The multispecific molecule of any one of claims 521-525, wherein the Fc region comprises an Fc-silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function.

527. The multispecific molecule of any one of claims 383-526, wherein the NK cell engager comprises an antibody molecule or antigen binding domain thereof.

528. The multispecific molecule of claim 527, wherein the NK cell engager comprises a single chain variable fragment (scFv).

529. A method of treating an autoimmune disease or condition in a human subject in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a firstWSGR Docket No.: 53676-780.601 agent comprising a moiety that binds to a TCR variable region in a TCRP V9 subfamily and a second agent comprising a NK cell engager, wherein the autoimmune disease or condition is acute anterior uveitis (UAA), psoriatic arthritis (PsA), ankylosing spondylitis, Celiac disease, reactive arthritis, inflammatory bowel disease, sacroiliitis, Reiter's syndrome, juvenile rheumatoid arthritis, or any combination thereof.

530. The method of claim 529, wherein the autoimmune disease or condition UAA.

531. The method of claim 529, wherein the autoimmune disease or condition is PsA.

532. The method of claim 529, wherein the autoimmune disease or condition is ankylosing spondylitis.

533. The method of claim 529, wherein the autoimmune disease or condition is Celiac disease.

534. The method of claim 529, wherein the autoimmune disease or condition is reactive arthritis.

535. The method of claim 529, wherein the autoimmune disease or condition is inflammatory bowel disease.

536. The method of claim 529, wherein the autoimmune disease or condition is sacroiliitis.

537. The method of claim 529, wherein the autoimmune disease or condition is Reiter's syndrome.

538. The method of claim 529, wherein the autoimmune disease or condition is juvenile rheumatoid arthritis.

539. The method of any one of claims 529-538, wherein the moiety comprises a VH comprising a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250).

540. The method of claim 539, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of DYIVH (SEQ ID NO: 1248), GYTFTDY (SEQ ID NO: 1251), or GYTFTDYIVH (SEQ ID NO: 1253).

541. The method of claim 539 or 540, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of WINTYTGTPTYADDFEG (SEQ ID NO: 1249) or NTYTGT (SEQ ID NO: 1252).

542. The method of any one of claims 539-541, wherein the moiety comprises a light chain variable region (VL), wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256).

543. The method of any one of claims 539-542, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254).WSGR Docket No.: 53676-780.601544. The method of any one of claims 539-543, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of DGSTLQS (SEQ ID NO: 1255).

545. The method of any one of claims 539-544, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250), a HC CDR2 comprising the amino acid sequence of WINTYTGTPTYADDFEG (SEQ ID NO: 1249) or NTYTGT (SEQ ID NO: 1252), a HC CDR1 comprising the amino acid sequence of DYIVH (SEQ ID NO: 1248), GYTFTDY (SEQ ID NO: 1251), or GYTFTDYIVH (SEQ ID NO: 1253), a LC CDR3 comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256), a LC CDR2 comprising the amino acid sequence of DGSTLQS (SEQ ID NO: 1255), and a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254).

546. The method of any one of claims 529-545, wherein the NK cell engager comprises a secondVH comprising a HC CDR3 comprising the amino acid sequence of GDWHYFDY (SEQ ID NO: 7352).

547. The method of claim 546, wherein the second VH comprises a HC CDR1 comprising the amino acid sequence of GFSIIRVGYHWN (SEQ ID NO: 7383).

548. The method of claim 546 or 547, wherein the second VH comprises a HC CDR2 comprising the amino acid sequence of YIHRSGSTSYNPSLKS (SEQ ID NO: 7380).

549. The method of any one of claims 546-548, wherein the second VL comprises a LC CDR3 comprising the amino acid sequence of QFWDSTNSAV (SEQ ID NO: 7358).

550. The method of any one of claims 546-549, wherein the second VL comprises a LC CDR1 comprising the amino acid sequence of SGEKLSDKYVH (SEQ ID NO: 7356).

551. The method of any one of claims 546-550, wherein the second VL comprises a LC CDR2 comprising the amino acid sequence of ENDRRPS (SEQ ID NO: 7352).

552. The method of any one of claims 546-551, wherein the NK cell engager comprises: a HC CDR3 comprising the amino acid sequence of GDWHYFDY (SEQ ID NO: 7352), a HC CDR2 comprising the amino acid sequence of YIHRSGSTSYNPSLKS (SEQ ID NO: 7380, a HC CDR1 comprising the amino acid sequence of GFSIIRVGYHWN (SEQ ID NO: 7383), a LC CDR3 comprising the amino acid sequence of QFWDSTNSAV (SEQ ID NO: 7358), a LC CDR2 comprising the amino acid sequence of ENDRRPS (SEQ ID NO: 7352), andWSGR Docket No.: 53676-780.601 a LC CDR1 comprising the amino acid sequence of SGEKLSDKYVH (SEQ ID NO: 7356).

553. The method of any one of claims 529-552, wherein the administering inhibits or prevents activation or expansion of autoreactive T cells in the human subject.

554. The method of claim 553, wherein the autoreactive T cells target an autologous cell in the human subj ect.

555. The method of claim 553 or 554, wherein the autoreactive T cells express TCRaV and / orTCRPV.

556. The method of any one of claims 529-555, wherein the first agent comprises an antibody molecule or antigen binding domain thereof.

557. The method of any one of claims 529-556, wherein the first agent comprises an Fc region.

558. The method of claim 557, wherein the Fc region comprises an amino acid sequence with at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 or 42.

559. The method of claim 557 or 558, wherein the Fc region comprises one or more mutations.

560. The method of claim 559, wherein the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

561. The method of any one of claims 558-560, wherein the Fc comprises one or more mutations comprising E233P, L234V, L235A, P329A, S267K, G237A, P238S, H268A, A330S, P331S, K322A, D265A, D265S, L235E, G236R, S239K, A327G, V273E, T299A, Y300S, or any combination thereof, where amino acid positioning is relative to SEQ ID NO: 42.

562. The method of any one of claims 557-561, wherein the Fc region comprises an Fc-silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function.

563. A method of treating an autoimmune disease or condition in a human subject in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of an agent comprising a moiety that binds to a TCRP V20-1 region, wherein the autoimmune disease or condition is alopecia.

564. The method of claim 563, wherein the moiety comprises a heavy chain variable region(VH), wherein the VH comprises a heavy chain complementarity determining region 3 HC CDR3 comprising the amino acid sequence of SLNWDYGLDY (SEQ ID NO: 1104).WSGR Docket No.: 53676-780.601565. The method of claim 563 or 564, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of SAYMH (SEQ ID NO: 1102), GFNIKSA (SEQ ID NO: 1105), or GFNIKSAYMH (SEQ ID NO: 3640).

566. The method of any one of claims 563-565, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of RIDPATGKTKYAPKFQA (SEQ ID NO: 1103) or DPATGK (SEQ ID NO: 1106).

567. The method of any one of claims 563-566, wherein the moiety comprises a light chain variable region (VL), wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQSIEDPWT (SEQ ID NO: 1109).

568. The method of any one of claims 563-567, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of RASKS VSILGTHLIH (SEQ ID NO: 1107).

569. The method of any one of claims 563-568, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 1108).

570. The method of any one of claims 563-569, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of SLNWDYGLDY (SEQ ID NO: H04), a HC CDR2 comprising the amino acid sequence of RIDPATGKTKYAPKFQA (SEQ ID NO: 1103) or DPATGK (SEQ ID NO: 1106), a HC CDR1 comprising the amino acid sequence of SAYMH (SEQ ID NO: 1102), GFNIKSA (SEQ ID NO: 1105), or GFNIKSAYMH (SEQ ID NO: 3640), a LC CDR3 comprising the amino acid sequence of QQSIEDPWT (SEQ ID NO: 1109), a LC CDR2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 1108), and a LC CDR1 comprising the amino acid sequence of RASKS VSILGTHLIH (SEQ ID NO: 1107).

571. The method of any one of claims 563-570, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QVQLVQSGAEVKKPGASVKVSCKASGFNIKSAYMHWVRQAPGQEPGCMGRIDP ATGKTKYAPKFQARVTMTADTSINTAYTELSSLRSEDTATYYCARSLNWDYGLD YWGQGTLVTVSS (SEQ ID NO: 1114).

572. The method of any one of claims 563-571, wherein the VH comprises a sequence ofQVQLVQSGAEVKKPGASVKVSCKASGFNIKSAYMHWVRQAPGQEPGCMGRIDP ATGKTKYAPKFQARVTMTADTSINTAYTELSSLRSEDTATYYCARSLNWDYGLD YWGQGTLVTVSS (SEQ ID NO: 1114).WSGR Docket No.: 53676-780.601573. The method of any one of claims 563-572, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence EIVLTQSPATLSLSPGERATLSCRASKSVSILGTHLIHWYQQKPGLAPRLLIYAASN LESGIPDRFSGSGSETDFTLTISRLEPEDFAVYFCQQSIEDPWTFGGGTKVEIK (SEQ ID NO: 3700).

574. The method of any one of claims 563-573, wherein the VL comprises a sequence ofEIVLTQSPATLSLSPGERATLSCRASKSVSILGTHLIHWYQQKPGLAPRLLIYAASN LESGIPDRFSGSGSETDFTLTISRLEPEDFAVYFCQQSIEDPWTFGGGTKVEIK (SEQ ID NO: 3700).

575. The method of any one of claims 563-570, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QVQLVQSGAEVKKPGASVKVSCKASGFNIKSAYMHWVRQAPGQGLEWMGRID PATGKTKYAPKFQARVTMTADTSTNTAYMELSSLRSEDTAVYYCARSLNWDYG LDYWGQGTLVTVSS (SEQ ID NO: 1113).

576. The method of any one of claims 563-570 and 575, wherein the VH comprises a sequence of QVQLVQSGAEVKKPGASVKVSCKASGFNIKSAYMHWVRQAPGQGLEWMGRID PATGKTKYAPKFQARVTMTADTSTNTAYMELSSLRSEDTAVYYCARSLNWDYG LDYWGQGTLVTVSS (SEQ ID NO: 1113).

577. The method of any one of claims 563-570, 575, and 576, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence EIVLTQSPGTLSLSPGERATLSCRASKSVSILGTHLIHWYQQKPGQAPRLLIYAAS NLESGIPDRFSGSGSETDFTLTISRLEPEDFAVYFCQQSIEDPWTFGGGTKVEIK (SEQ ID NO: 7017).

578. The method of any one of claims 563-570 and 575-577, wherein the VL comprises a sequence of EIVLTQSPGTLSLSPGERATLSCRASKSVSILGTHLIHWYQQKPGQAPRLLIYAAS NLESGIPDRFSGSGSETDFTLTISRLEPEDFAVYFCQQSIEDPWTFGGGTKVEIK (SEQ ID NO: 7017).

579. The method of any one of claims 563-578, wherein the administering inhibits or prevents activation or expansion of autoreactive T cells in the human subject.

580. The method of claim 579, wherein the autoreactive T cells target an autologous cell in the human subj ect.

581. The method of claim 579 or 580, wherein the autoreactive T cells express TCRaV and / orTCRPV.WSGR Docket No.: 53676-780.601582. The method of any one of claims 563-581, wherein the agent comprises an antibody molecule or antigen binding domain thereof.

583. The method of any one of claims 563-582, wherein the agent comprises an Fc region.

584. The method of claim 583, wherein the Fc region comprises an amino acid sequence with at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 or 42585. The method of claim 583 or 584, wherein the Fc region comprises one or more mutations.

586. The method of claim 585, wherein the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

587. The method of any one of claims 584-586, wherein the Fc comprises one or more mutations comprising E233P, L234V, L235A, P329A, S267K, G237A, P238S, H268A, A330S, P331S, K322A, D265A, D265S, L235E, G236R, S239K, A327G, V273E, T299A, Y300S, or any combination thereof, where amino acid positioning is relative to SEQ ID NO: 42.

588. The method of any one of claims 583-587, wherein the Fc region comprises an Fc-silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function.

589. The method of any one of claims 563-588, wherein the agent comprises a second moiety.

590. The method of claim 589, wherein the second moiety comprises a IL-2R biased IL-2 mutein.

591. The method of claim 589, wherein the second moiety comprises a cytokine.

592. The method of claim 591, wherein the cytokine comprises IL-2.

593. The method of claim 591, wherein the cytokine comprises a IL-2 variant.

594. The method of claim 593, wherein the IL-2 variant comprises one or more amino acid substitutions comprising L18M, L19S, or C125A.

595. The method of claim 593, wherein the cytokine comprises an amino acid sequence with at least about 80% sequence identity to the sequence as set forth in SEQ ID NO: 2191.

596. The method of claim 595, wherein the cytokine comprises one or more mutations comprising S4P, K8R, T10A, Q11R, Q13R, N26D, N30S, K35R, T37R, V69A, Q74P, N88D, I128T, T133A, I92T, based on an amino acid sequence as set forth in SEQ ID NO: 2191.

597. The method of claim 589, wherein the second moiety comprises TGFp.

598. The method of claim 591, wherein the cytokine comprises IL-7.WSGR Docket No.: 53676-780.601599. The method of claim 589, wherein the second moiety comprises a IL-7 receptor (IL-7R) antagonist.

600. The method of claim 599, wherein the IL-7R antagonist is configured to inhibit IL-7R heterodimerization.

601. The method of claim 599 or 600, wherein the IL-7R antagonist comprises lusvertikimab or a binding fragment thereof.

602. A method of treating an autoimmune disease or condition in a human subject in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of an agent comprising a moiety that binds to a TCRP V5-1 region, wherein the autoimmune disease or condition is alopecia or multiple sclerosis.

603. The method of claim 602, wherein the moiety comprises a heavy chain variable region(VH), wherein the VH comprises a heavy chain complementarity determining region 3 HC CDR3 comprising the amino acid sequence of WDGSSYFDY (SEQ ID NO: 1165).

604. The method of claim 603, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of DYNIH (SEQ ID NO: 1163), GYTFTDY (SEQ ID NO: 7025), or GYTFTDYNIH (SEQ ID NO: 1166).

605. The method of claim 603 or 604, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of YINPYNGRTGYNQKFKA (SEQ ID NO: 1164) or NPYNGR (SEQ ID NO: 1167).

606. The method of any one of claims 603-605, wherein the moiety comprises a light chain variable region (VL), wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQWNYPLLT (SEQ ID NO: 1170).

607. The method of any one of claims 603-606, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of SASSSVSYMH (SEQ ID NO: 1168).

608. The method of any one of claims 603-607, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of EISKLAS (SEQ ID NO: 1169).

609. The method of any one of claims 603-608, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of WDGSSYFDY (SEQ ID NO: 1165), a HC CDR2 comprising the amino acid sequence of YINPYNGRTGYNQKFKA (SEQ ID NO: 1164) or NPYNGR (SEQ ID NO: 1167), a HC CDR1 comprising the amino acid sequence of DYNIH (SEQ ID NO: 1163), GYTFTDY (SEQ ID NO: 7025), or GYTFTDYNIH (SEQ ID NO: 1166), a LC CDR3 comprising the amino acid sequence of QQWNYPLLT (SEQ ID NO: 1170),WSGR Docket No.: 53676-780.601 a LC CDR2 comprising the amino acid sequence of EISKLAS (SEQ ID NO: 1169), and a LC CDR1 comprising the amino acid sequence of SASSSVSYMH (SEQ ID NO: 1168).

610. The method of any one of claims 603-609, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYNIHWVRQAPGQGLEWMGYIN PYNGRTGYNQKFKARVTMTVDKSTSTAYMELSSLRSEDTAVYYCARWDGSSYF DYWGQGTLVTVSS (SEQ ID NO: 7018).

611. The method of any one of claims 603-610, wherein the VH comprises a sequence ofQVQLVQSGAEVKKPGASVKVSCKASGYTFTDYNIHWVRQAPGQGLEWMGYIN PYNGRTGYNQKFKARVTMTVDKSTSTAYMELSSLRSEDTAVYYCARWDGSSYF DYWGQGTLVTVSS (SEQ ID NO: 7018).

612. The method of any one of claims 603-611, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence EIVLTQSPATLSVSPGERATLSCSASSSVSYMHWYQQKPGQAPRPLIYEISKLASGI PARFSGSGSGTEYTLTISSLQSEDFAVYYCQQWNYPLLTFGQGTKLEIK (SEQ ID NO: 7019).

613. The method of any one of claims 603-612, wherein the VL comprises a sequence ofEIVLTQSPATLSVSPGERATLSCSASSSVSYMHWYQQKPGQAPRPLIYEISKLASGI PARFSGSGSGTEYTLTISSLQSEDFAVYYCQQWNYPLLTFGQGTKLEIK (SEQ ID NO: 7019).

614. The method of any one of claims 603-613, wherein the administering inhibits or prevents activation or expansion of autoreactive T cells in the human subject.

615. The method of claim 614, wherein the autoreactive T cells target an autologous cell in the human subj ect.

616. The method of claim 614 or 615, wherein the autoreactive T cells express TCRaV and / orTCRPV.

617. The method of any one of claims 603-616, wherein the agent comprises an antibody molecule or antigen binding domain thereof.

618. The method of any one of claims 603-617, wherein the agent comprises an Fc region.

619. The method of claim 618, wherein the Fc region comprises an amino acid sequence with at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 or 42.

620. The method of claim 618 or 619, wherein the Fc region comprises one or more mutations.WSGR Docket No.: 53676-780.601621. The method of claim 620, wherein the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

622. The method of any one of claims 619-621, wherein the Fc comprises one or more mutations comprising E233P, L234V, L235A, P329A, S267K, G237A, P238S, H268A, A330S, P331S, K322A, D265A, D265S, L235E, G236R, S239K, A327G, V273E, T299A, Y300S, or any combination thereof, where amino acid positioning is relative to SEQ ID NO: 42.

623. The method of any one of claims 618-622, wherein the Fc region comprises an Fc-silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function.

624. The method of any one of claims 603-623, wherein the agent comprises a second moiety.

625. The method of claim 624, wherein the second moiety comprises a IL-2R biased IL-2 mutein.

626. The method of claim 624, wherein the second moiety comprises a cytokine.

627. The method of claim 626, wherein the cytokine comprises IL-2.

628. The method of claim 626, wherein the cytokine comprises a IL-2 variant.

629. The method of claim 628, wherein the IL-2 variant comprises one or more amino acid substitutions comprising L18M, L19S, or C125A.

630. The method of claim 626, wherein the cytokine comprises an amino acid sequence with at least about 80% sequence identity to the sequence as set forth in SEQ ID NO: 2191.

631. The method of claim 626, wherein the cytokine comprises one or more mutations comprising S4P, K8R, T10A, Q11R, Q13R, N26D, N30S, K35R, T37R, V69A, Q74P, N88D, I128T, T133A, I92T, based on an amino acid sequence as set forth in SEQ ID NO: 2191.

632. The method of claim 624, wherein the second moiety comprises TGFp.

633. The method of claim 626, wherein the cytokine comprises IL-7.

634. The method of claim 624, wherein the second moiety comprises a IL-7 receptor (IL-7R) antagonist.

635. The method of claim 634, wherein the IL-7R antagonist is configured to inhibit IL-7R heterodimerization.

636. The method of claim 634 or 635, wherein the IL-7R antagonist comprises lusvertikimab or a binding fragment thereof.

637. An agent comprising:WSGR Docket No.: 53676-780.601 a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of RDNYYGSHYRYFDV (SEQ ID NO: 9092).

638. The agent of claim 637, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of SYWMH (SEQ ID NO: 9090), GYTFTSY (SEQ ID NO: 9093), or GYTFTSYWMH (SEQ ID NO: 9095).

639. The agent of claim 637 or 638, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of NIDPSDSETHYNQKFKD (SEQ ID NO: 9091) or DPSDSE (SEQ ID NO: 9094).

640. The agent of any one of claims 637-639, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQGKTLMYT (SEQ ID NO: 9098).

641. The agent of any one of claims 637-640, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of RASQDISNYLN (SEQ ID NO: 9096).

642. The agent of any one of claims 637-641, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of YTSILHS (SEQ ID NO: 9097).

643. The agent of any one of claims 637-642, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of RDNYYGSHYRYFDV (SEQ ID NO: 9092), a HC CDR2 comprising the amino acid sequence of NIDPSDSETHYNQKFKD (SEQ ID NO: 9091) or DPSDSE (SEQ ID NO: 9094), a HC CDR1 comprising the amino acid sequence of SYWMH (SEQ ID NO: 9090), GYTFTSY (SEQ ID NO: 9093), or GYTFTSYWMH (SEQ ID NO: 9095), a LC CDR3 comprising the amino acid sequence of QQGKTLMYT (SEQ ID NO: 9098), a LC CDR2 comprising the amino acid sequence of YTSILHS (SEQ ID NO: 9097), and a LC CDR1 comprising the amino acid sequence of RASQDISNYLN (SEQ ID NO: 9096).

644. The agent of any one of claims 637-643, wherein the VH comprises a sequence with at least80% sequence identity to the sequenceQVQLQQPGAELVRPGSSVKLSCKASGYTFTSYWMHWVKQRPIQGLEWIGNIDPS DSETHYNQKFKDK ATLTVDKS S STAYMQLS SLTSEDS AVYYCARRDNYYGSHY RYFDVWGTGTTVTVSS (SEQ ID NO: 9078).

645. The agent of any one of claims 637-644, wherein the VH comprises a sequence ofQVQLQQPGAELVRPGSSVKLSCKASGYTFTSYWMHWVKQRPIQGLEWIGNIDPSWSGR Docket No.: 53676-780.601DSETHYNQKFKDK ATLTVDKS S STAYMQLS SLTSEDS AVYYCARRDNYYGSHY RYFDVWGTGTTVTVSS (SEQ ID NO: 9078).

646. The agent of any one of claims 637-645, wherein the VL comprises a sequence with at least80% sequence identity to the sequence DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSILHS GVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGKTLMYTFGGGTKLEIK (SEQ ID NO: 9084).

647. The agent of any one of claims 637-646, wherein the VL comprises a sequence ofDIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSILHS GVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGKTLMYTFGGGTKLEIK (SEQ ID NO: 9084).

648. The agent of any one of claims 637-639, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQWSSNPPT (SEQ ID NO: 9103).

649. The agent of any one of claims 637-639 and 648, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of SASSSVSYMH (SEQ ID NO: 9101).

650. The agent of any one of claims 637-639, 648, and 649, wherein the VL comprises a LCCDR2 comprising the amino acid sequence of DTSKLAS (SEQ ID NO: 9102).

651. The agent of any one of claims 637-639 and 648-650, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of RDNYYGSHYRYFDV (SEQ ID NO: 9092), a HC CDR2 comprising the amino acid sequence of NIDPSDSETHYNQKFKD (SEQ ID NO: 9091) or DPSDSE (SEQ ID NO: 9094), a HC CDR1 comprising the amino acid sequence of SYWMH (SEQ ID NO: 9090), GYTFTSY (SEQ ID NO: 9093), or GYTFTSYWMH (SEQ ID NO: 9095), a LC CDR3 comprising the amino acid sequence of SASSSVSYMH (SEQ ID NO: 9101), a LC CDR2 comprising the amino acid sequence of SASSSVSYMH (SEQ ID NO: 9101), and a LC CDR1 comprising the amino acid sequence of RDNYYGSHYRYFDV (SEQ ID NO: 9092).

652. The agent of any one of claims 637-639 and 648-651, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLAWSGR Docket No.: 53676-780.601SGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPPTFGGGTKLEIK (SEQ ID NO: 9085).

653. The agent of any one of claims 637-639 and 648-652, wherein the VL comprises a sequence ofQIVLTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLA SGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPPTFGGGTKLEIK (SEQ ID NO: 9085).

654. An agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of WVADY (SEQ ID NO: 9107).

655. The agent of claim 654, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of DYGMH (SEQ ID NO: 9105), GFTFSDY (SEQ ID NO: 9108), or GFTFSDYGMH (SEQ ID NO: 9110).

656. The agent of claim 654 or 655, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of YISSGSSTIYYADTVKG (SEQ ID NO: 9106) or SSGSST (SEQ ID NO: 9109).

657. The agent of any one of claims 654-656, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQGKTLMYT (SEQ ID NO: 9098).

658. The agent of any one of claims 654-657, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of RASQDISNYLN (SEQ ID NO: 9096).

659. The agent of any one of claims 654-658, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of YTSILHS (SEQ ID NO: 9097).

660. The agent of any one of claims 654-659, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of WVADY (SEQ ID NO: 9107), a HC CDR2 comprising the amino acid sequence of YISSGSSTIYYADTVKG (SEQ ID NO: 9106) or SSGSST (SEQ ID NO: 9109), a HC CDR1 comprising the amino acid sequence of DYGMH (SEQ ID NO: 9105), GFTFSDY (SEQ ID NO: 9108), or GFTFSDYGMH (SEQ ID NO: 9110), a LC CDR3 comprising the amino acid sequence of QQGKTLMYT (SEQ ID NO: 9098), a LC CDR2 comprising the amino acid sequence of YTSILHS (SEQ ID NO: 9097), and a LC CDR1 comprising the amino acid sequence of RASQDISNYLN (SEQ ID NO: 9096).WSGR Docket No.: 53676-780.601661. The agent of any one of claims 654-660, wherein the VH comprises a sequence with at least80% sequence identity to the sequence EVQLVESGGGLVKPGGSLKLSCAASGFTFSDYGMHWVRQAPEKGLEWVAYISS GSSTIYYADTVKGRFTISRDNAKNTLFLQMTSLRSEDTAMYYCARWVADYWGQ GTTLTVSS (SEQ ID NO: 9079).

662. The agent of any one of claims 654-661, wherein the VH comprises a sequence ofEVQLVESGGGLVKPGGSLKLSCAASGFTFSDYGMHWVRQAPEKGLEWVAYISS GSSTIYYADTVKGRFTISRDNAKNTLFLQMTSLRSEDTAMYYCARWVADYWGQ GTTLTVSS (SEQ ID NO: 9079).

663. The agent of any one of claims 654-662, wherein the VL comprises a sequence with at least80% sequence identity to the sequence DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSILHS GVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGKTLMYTFGGGTKLEIK (SEQ ID NO: 9084).

664. The agent of any one of claims 654-663, wherein the VL comprises a sequence ofDIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSILHS GVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGKTLMYTFGGGTKLEIK (SEQ ID NO: 9084).

665. The agent of any one of claims 654-656, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQWSSNPPT (SEQ ID NO: 9103).

666. The agent of any one of claims 654-656 and 665, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of SASSSVSYMH (SEQ ID NO: 9101).

667. The agent of any one of claims 654-656, 665, and 666, wherein the VL comprises a LCCDR2 comprising the amino acid sequence of DTSKLAS (SEQ ID NO: 9102).

668. The agent of any one of claims 654-656 and 665-667, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of RDNYYGSHYRYFDV (SEQ ID NO: 9092), a HC CDR2 comprising the amino acid sequence of NIDPSDSETHYNQKFKD (SEQ ID NO: 9091) or DPSDSE (SEQ ID NO: 9094), a HC CDR1 comprising the amino acid sequence of SYWMH (SEQ ID NO: 9090), GYTFTSY (SEQ ID NO: 9093), or GYTFTSYWMH (SEQ ID NO: 9095), a LC CDR3 comprising the amino acid sequence of SASSSVSYMH (SEQ ID NO: 9101),WSGR Docket No.: 53676-780.601 a LC CDR2 comprising the amino acid sequence of SASSSVSYMH (SEQ ID NO: 9101), and a LC CDR1 comprising the amino acid sequence of RDNYYGSHYRYFDV (SEQ ID NO: 9092).

669. The agent of any one of claims 654-656 and 665-668, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLA SGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPPTFGGGTKLEIK (SEQ ID NO: 9085).

670. The agent of any one of claims 654-656 and 665-669, wherein the VL comprises a sequence of QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLA SGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPPTFGGGTKLEIK (SEQ ID NO: 9085).

671. An agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of HKWDGWYFDV (SEQ ID NO: 9114).

672. The agent of claim 671, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of SYGVH (SEQ ID NO: 9112), GFSLISY (SEQ ID NO: 9115), or GFSLISYGVH (SEQ ID NO: 9117).

673. The agent of claim 671 or 672, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of VIWSDGSTTYNSALKS (SEQ ID NO: 9113) or WSDGS (SEQ ID NO: 9116).

674. The agent of any one of claims 671-673, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of HQGQSYPLT (SEQ ID NO: 9120).

675. The agent of any one of claims 671-674, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of HASQNINVWLS (SEQ ID NO: 9118).

676. The agent of any one of claims 671-675, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of KASNLHT (SEQ ID NO: 9119).

677. The agent of any one of claims 671-676, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of HKWDGWYFDV (SEQ ID NO: 9H4),WSGR Docket No.: 53676-780.601 a HC CDR2 comprising the amino acid sequence of VIWSDGSTTYNSALKS (SEQ ID NO: 9113) or WSDGS (SEQ ID NO: 9116), a HC CDR1 comprising the amino acid sequence of SYGVH (SEQ ID NO: 9112), GFSLISY (SEQ ID NO: 9115), or GFSLISYGVH (SEQ ID NO: 9117), a LC CDR3 comprising the amino acid sequence of HQGQSYPLT (SEQ ID NO: 9120), a LC CDR2 comprising the amino acid sequence of KASNLHT (SEQ ID NO: 9119), and a LC CDR1 comprising the amino acid sequence of HASQNINVWLS (SEQ ID NO: 9118).

678. The agent of any one of claims 671-677, wherein the VH comprises a sequence with at least80% sequence identity to the sequence QVQLKESGPGLVAPSQSLSITCTVSGFSLISYGVHWVRQPPGKGLEWLVVIWSDG STTYNSALKSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCARHKWDGWYFDV WGTGTTVTVSS (SEQ ID NO: 9080).

679. The agent of any one of claims 671-678, wherein the VH comprises a sequence ofQVQLKESGPGLVAPSQSLSITCTVSGFSLISYGVHWVRQPPGKGLEWLVVIWSDG STTYNSALKSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCARHKWDGWYFDV WGTGTTVTVSS (SEQ ID NO: 9080).

680. The agent of any one of claims 671-679, wherein the VL comprises a sequence with at least80% sequence identity to the sequence DIQMNQSPSSLSASLGDTITITCHASQNINVWLSWYQQKPGNIPKLLIYKASNLHT GVPSRFSGSGSGTGFTLTISSLRPEDIATYYCHQGQSYPLTFGAGTKLELK (SEQ ID NO: 9086).

681. The agent of any one of claims 671-680, wherein the VL comprises a sequence ofDIQMNQSPSSLSASLGDTITITCHASQNINVWLSWYQQKPGNIPKLLIYKASNLHT GVPSRFSGSGSGTGFTLTISSLRPEDIATYYCHQGQSYPLTFGAGTKLELK (SEQ ID NO: 9086).

682. An agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of HGTAQAFFAMDY (SEQ ID NO: 9125).

683. The agent of claim 682, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of NSGVH (SEQ ID NO: 9123), GFSLTNS (SEQ ID NO: 9126), or GFSLTNSGVH (SEQ ID NO: 9128).WSGR Docket No.: 53676-780.601684. The agent of claim 682 or 683, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of VIWSDGDTTYNSALKS (SEQ ID NO: 9124) or WSDGD (SEQ ID NO: 9127).

685. The agent of any one of claims 682-684, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQGQSYPLT (SEQ ID NO: 9131).

686. The agent of any one of claims 682-685, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of HASQNINVWLS (SEQ ID NO: 9129).

687. The agent of any one of claims 682-686, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of KASNLHT (SEQ ID NO: 9130).

688. The agent of any one of claims 682-687, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of HGTAQAFFAMDY (SEQ ID NO: 9125), a HC CDR2 comprising the amino acid sequence of VIWSDGDTTYNSALKS (SEQ ID NO: 9124) or WSDGD (SEQ ID NO: 9127), a HC CDR1 comprising the amino acid sequence of NSGVH (SEQ ID NO: 9123), GFSLTNS (SEQ ID NO: 9126), or GFSLTNSGVH (SEQ ID NO: 9128), a LC CDR3 comprising the amino acid sequence of QQGQSYPLT (SEQ ID NO: 9131), a LC CDR2 comprising the amino acid sequence of KASNLHT (SEQ ID NO: 9130), and a LC CDR1 comprising the amino acid sequence of HASQNINVWLS (SEQ ID NO: 9129).

689. The agent of any one of claims 682-688, wherein the VH comprises a sequence with at least80% sequence identity to the sequence QVQLKESGPGLVAPSQSLSITCTVSGFSLTNSGVHWVRQPPGKGLEWLVVIWSD GDTTYNSALKSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCARHGTAQAFFAM DYWGQGTSVTVSS (SEQ ID NO: 9081).

690. The agent of any one of claims 682-689, wherein the VH comprises a sequence ofQVQLKESGPGLVAPSQSLSITCTVSGFSLTNSGVHWVRQPPGKGLEWLVVIWSD GDTTYNSALKSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCARHGTAQAFFAM DYWGQGTSVTVSS (SEQ ID NO: 9081).

691. The agent of any one of claims 682-690, wherein the VL comprises a sequence with at least80% sequence identity to the sequence DIQMNQSPSSLSASLGDTITITCHASQNINVWLSWYQQKPGNIPKLLIYKASNLHT GVPSRFSGSGSGTGFTLTISSLQPEDIATYYCQQGQSYPLTFGGGTKLEIK (SEQ ID NO: 9087).WSGR Docket No.: 53676-780.601692. The agent of any one of claims 682-691, wherein the VL comprises a sequence ofDIQMNQSPSSLSASLGDTITITCHASQNINVWLSWYQQKPGNIPKLLIYKASNLHT GVPSRFSGSGSGTGFTLTISSLQPEDIATYYCQQGQSYPLTFGGGTKLEIK (SEQ ID NO: 9087).

693. The agent of any one of claims 682-684, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of LQSDNLPYT (SEQ ID NO: 9136).

694. The agent of any one of claims 682-684 and 693, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 9134).

695. The agent of any one of claims 682-684, 693, and 694, wherein the VL comprises a LCCDR2 comprising the amino acid sequence of EGNTLRP (SEQ ID NO: 9135).

696. The agent of any one of claims 682-684 and 693-695, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of HGTAQAFFAMDY (SEQ ID NO: 9125), a HC CDR2 comprising the amino acid sequence of VIWSDGDTTYNSALKS (SEQ ID NO: 9124) or WSDGD (SEQ ID NO: 9127), a HC CDR1 comprising the amino acid sequence of NSGVH (SEQ ID NO: 9123), GFSLTNS (SEQ ID NO: 9126), or GFSLTNSGVH (SEQ ID NO: 9128), a LC CDR3 comprising the amino acid sequence of LQSDNLPYT (SEQ ID NO: 9136), a LC CDR2 comprising the amino acid sequence of EGNTLRP (SEQ ID NO: 9135), and a LC CDR1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 9134).

697. The agent of any one of claims 682-684 and 693-696, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence ETTVTQSPASLSMAIGEKVTIRCITSTDIDDDMNWYQQKPGEPPKLLISEGNTLRP GVPSRFSSSGYGTDFVFTIENMLSEDVADYYCLQSDNLPYTFGGGTKLEIK (SEQ ID NO: 9088).

698. The agent of any one of claims 682-684 and 693-697, wherein the VL comprises a sequence of ETTVTQSPASLSMAIGEKVTIRCITSTDIDDDMNWYQQKPGEPPKLLISEGNTLRP GVPSRFSSSGYGTDFVFTIENMLSEDVADYYCLQSDNLPYTFGGGTKLEIK (SEQ ID NO: 9088).

699. An agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VHWSGR Docket No.: 53676-780.601 comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of GDF YYDYD ASF AY (SEQ ID NO: 9140).

700. The agent of claim 699, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of SGYYWN (SEQ ID NO: 9138), GYSITSGY (SEQ ID NO: 9141), or GYSITSGYYWN (SEQ ID NO: 9143).

701. The agent of claim 699 or 700, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of YISYDGSNNYNPSLKN (SEQ ID NO: 9139) or SYDGS (SEQ ID NO: 9142).

702. The agent of any one of claims 699-701, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQGQSYPLT (SEQ ID NO: 9131).

703. The agent of any one of claims 699-702, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of HASQNINVWLS (SEQ ID NO: 9129).

704. The agent of any one of claims 699-703, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of KASNLHT (SEQ ID NO: 9130).

705. The agent of any one of claims 699-704, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of GDFYYDYDASFAY (SEQ ID NO: 9140), a HC CDR2 comprising the amino acid sequence of YISYDGSNNYNPSLKN (SEQ ID NO: 9139) or SYDGS (SEQ ID NO: 9142), a HC CDR1 comprising the amino acid sequence of SGYYWN (SEQ ID NO: 9138), GYSITSGY (SEQ ID NO: 9141), or GYSITSGYYWN (SEQ ID NO: 9143), a LC CDR3 comprising the amino acid sequence of QQGQSYPLT (SEQ ID NO: 9131), a LC CDR2 comprising the amino acid sequence of KASNLHT (SEQ ID NO: 9130), and a LC CDR1 comprising the amino acid sequence of HASQNINVWLS (SEQ ID NO: 9129).

706. The agent of any one of claims 699-705, wherein the VH comprises a sequence with at least80% sequence identity to the sequence DVQLQESGPGLVKPSQSLSLTCSVTGYSITSGYYWNWIRQFPGNKLEWMGYISY DGSNNYNPSLKNRISITRDTSKNQFFLKLNSVTTEDTATYYCARGDFYYDYDASF AYWGQGTLVTVSA (SEQ ID NO: 9082).

707. The agent of any one of claims 699-706, wherein the VH comprises a sequence ofDVQLQESGPGLVKPSQSLSLTCSVTGYSITSGYYWNWIRQFPGNKLEWMGYISY DGSNNYNPSLKNRISITRDTSKNQFFLKLNSVTTEDTATYYCARGDFYYDYDASF AYWGQGTLVTVSA (SEQ ID NO: 9082).WSGR Docket No.: 53676-780.601708. The agent of any one of claims 699-707, wherein the VL comprises a sequence with at least80% sequence identity to the sequence DIQMNQSPSSLSASLGDTITITCHASQNINVWLSWYQQKPGNIPKLLIYKASNLHT GVPSRFSGSGSGTGFTLTISSLQPEDIATYYCQQGQSYPLTFGGGTKLEIK (SEQ ID NO: 9087).

709. The agent of any one of claims 699-708, wherein the VL comprises a sequence ofDIQMNQSPSSLSASLGDTITITCHASQNINVWLSWYQQKPGNIPKLLIYKASNLHT GVPSRFSGSGSGTGFTLTISSLQPEDIATYYCQQGQSYPLTFGGGTKLEIK (SEQ ID NO: 9087).

710. The agent of any one of claims 699-701, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of LQSDNLPYT (SEQ ID NO: 9136).

711. The agent of any one of claims 699-701 and 710, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 9134).

712. The agent of any one of claims 699-701, 710, and 711, wherein the VL comprises a LCCDR2 comprising the amino acid sequence of EGNTLRP (SEQ ID NO: 9135).

713. The agent of any one of claims 699-701 and 710-712, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of GDFYYDYDASFAY (SEQ ID NO: 9140), a HC CDR2 comprising the amino acid sequence of YISYDGSNNYNPSLKN (SEQ ID NO: 9139) or SYDGS (SEQ ID NO: 9142), a HC CDR1 comprising the amino acid sequence of SGYYWN (SEQ ID NO: 9138), GYSITSGY (SEQ ID NO: 9141), or GYSITSGYYWN (SEQ ID NO: 9143), a LC CDR3 comprising the amino acid sequence of LQSDNLPYT (SEQ ID NO: 9136), a LC CDR2 comprising the amino acid sequence of EGNTLRP (SEQ ID NO: 9135), and a LC CDR1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 9134).

714. The agent of any one of claims 699-701 and 710-713, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence ETTVTQSPASLSMAIGEKVTIRCITSTDIDDDMNWYQQKPGEPPKLLISEGNTLRP GVPSRFSSSGYGTDFVFTIENMLSEDVADYYCLQSDNLPYTFGGGTKLEIK (SEQ ID NO: 9088).

715. The agent of any one of claims 699-701 and 710-714, wherein the VL comprises a sequence of ETTVTQSPASLSMAIGEKVTIRCITSTDIDDDMNWYQQKPGEPPKLLISEGNTLRPWSGR Docket No.: 53676-780.601GVPSRFSSSGYGTDFVFTIENMLSEDVADYYCLQSDNLPYTFGGGTKLEIK (SEQ ID NO: 9088).

716. An agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of NRGYRYDVGAMDY (SEQ ID NO: 9147).

717. The agent of claim 716, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of TFGVH (SEQ ID NO: 9145), GFSLTTF (SEQ ID NO: 9148), or GFSLTTFGVH (SEQ ID NO: 9150).

718. The agent of claim 716 or 717, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of VIWSDGSTTYNSALKS (SEQ ID NO: 9146) or WSDGS (SEQ ID NO: 9149).

719. The agent of any one of claims 716-718, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QNDHSFPLT (SEQ ID NO: 9153).

720. The agent of any one of claims 716-719, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of KSSQSLLNSGNQKNYLA (SEQ ID NO: 9151).

721. The agent of any one of claims 716-720, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of GASTRES (SEQ ID NO: 9152).

722. The agent of any one of claims 716-721, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of NRGYRYDVGAMDY (SEQ ID NO: 9147), a HC CDR2 comprising the amino acid sequence of VIWSDGSTTYNSALKS (SEQ ID NO: 9146) or WSDGS (SEQ ID NO: 9149), a HC CDR1 comprising the amino acid sequence of TFGVH (SEQ ID NO: 9145), GFSLTTF (SEQ ID NO: 9148), or GFSLTTFGVH (SEQ ID NO: 9150), a LC CDR3 comprising the amino acid sequence of QNDHSFPLT (SEQ ID NO: 9153), a LC CDR2 comprising the amino acid sequence of GASTRES (SEQ ID NO: 9152), and a LC CDR1 comprising the amino acid sequence of KSSQSLLNSGNQKNYLA (SEQ ID NO: 9151).

723. The agent of any one of claims 716-722, wherein the VH comprises a sequence with at least80% sequence identity to the sequenceQVQLKESGPGLVAPSQSLSITCTVSGFSLTTFGVHWVRQPPGKGLEWLVVIWSDWSGR Docket No.: 53676-780.601GSTTYNSALKSRLSISKDNSKSQVFLEMNSLQTDDTAMYYCARNRGYRYDVGA MDYWGRGTSVTVSS (SEQ ID NO: 9083).

724. The agent of any one of claims 716-723, wherein the VH comprises a sequence ofQVQLKESGPGLVAPSQSLSITCTVSGFSLTTFGVHWVRQPPGKGLEWLVVIWSD GSTTYNSALKSRLSISKDNSKSQVFLEMNSLQTDDTAMYYCARNRGYRYDVGA MDYWGRGTSVTVSS (SEQ ID NO: 9083).

725. The agent of any one of claims 716-724, wherein the VL comprises a sequence with at least80% sequence identity to the sequence DIVMTQSPSSLSVSAGEKVTMSCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLI YGASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDHSFPLTFGAGTK LELK (SEQ ID NO: 9089).

726. The agent of any one of claims 716-725, wherein the VL comprises a sequence ofDIVMTQSPSSLSVSAGEKVTMSCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLI YGASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDHSFPLTFGAGTK LELK (SEQ ID NO: 9089).

727. An agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of MRDSNYGGFAY (SEQ ID NO: 9178).

728. The agent of claim 727, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of TLGMGVN (SEQ ID NO: 9176), GFSLSTLGM (SEQ ID NO: 9179), or GFSLSTLGMGVN (SEQ ID NO: 9181).

729. The agent of claim 727 or 728, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of HIWWDDDKYYNPALKS (SEQ ID NO: 9177) or WWDDD (SEQ ID NO: 9180).

730. The agent of any one of claims 727-729, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQYWSTPYT (SEQ ID NO: 9184).

731. The agent of any one of claims 727-730, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of KASEDIYNRLA (SEQ ID NO: 9182).

732. The agent of any one of claims 727-731, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of GAASLET (SEQ ID NO: 9183).

733. The agent of any one of claims 727-732, wherein the moiety comprises:WSGR Docket No.: 53676-780.601 a HC CDR3 comprising the amino acid sequence of MRDSNYGGFAY (SEQ ID NO: 9178), a HC CDR2 comprising the amino acid sequence of HIWWDDDKYYNPALKS (SEQ ID NO: 9177) or WWDDD (SEQ ID NO: 9180), a HC CDR1 comprising the amino acid sequence of TLGMGVN (SEQ ID NO: 9176), GFSLSTLGM (SEQ ID NO: 9179), or GFSLSTLGMGVN (SEQ ID NO: 9181), a LC CDR3 comprising the amino acid sequence of QQYWSTPYT (SEQ ID NO: 9184), a LC CDR2 comprising the amino acid sequence of GAASLET (SEQ ID NO: 9183), and a LC CDR1 comprising the amino acid sequence of KASEDIYNRLA (SEQ ID NO: 9182).

734. The agent of any one of claims 727-733, wherein the VH comprises a sequence with at least80% sequence identity to the sequence QVTLKESGPGILQPSQTLSLTCSFSGFSLSTLGMGVNWIRQPSGKGLEWLAHIWW DDDKYYNPALKSRLTISKDTSKNQVFLKIANVDTADTATFYCARMRDSNYGGFA YWGQGTLVTVSA (SEQ ID NO: 9168).

735. The agent of any one of claims 727-734, wherein the VH comprises a sequence ofQVTLKESGPGILQPSQTLSLTCSFSGFSLSTLGMGVNWIRQPSGKGLEWLAHIWW DDDKYYNPALKSRLTISKDTSKNQVFLKIANVDTADTATFYCARMRDSNYGGFA YWGQGTLVTVSA (SEQ ID NO: 9168).

736. The agent of any one of claims 727-735, wherein the VL comprises a sequence with at least80% sequence identity to the sequence DIQMTQSSSSFSVSLGDRVPITCKASEDIYNRLAWYQQKPGNAPRLLISGAASLET GVPSRFSGSGSGKDYTLSITSLQTEDVATYYCQQYWSTPYTFGGGTKLEIK (SEQ ID NO: 9172).

737. The agent of any one of claims 727-736, wherein the VL comprises a sequence ofDIQMTQSSSSFSVSLGDRVPITCKASEDIYNRLAWYQQKPGNAPRLLISGAASLET GVPSRFSGSGSGKDYTLSITSLQTEDVATYYCQQYWSTPYTFGGGTKLEIK (SEQ ID NO: 9172).

738. An agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of GNYDYEGWF AY (SEQ ID NO: 9189).WSGR Docket No.: 53676-780.601739. The agent of claim 738, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of SYGIS (SEQ ID NO: 9187), GYNFTSY (SEQ ID NO: 9190), or GYNFTSYGIS (SEQ ID NO: 9193).

740. The agent of claim 738 or 739, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of EFYPRSGNTYYNEKFRG (SEQ ID NO: 9188) or YPRSGN (SEQ ID NO: 9191).

741. The agent of any one of claims 738-740, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of HQYLSSLT (SEQ ID NO: 9196).

742. The agent of any one of claims 738-741, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of KSSQSVLYSSNQKNYLA (SEQ ID NO: 9194).

743. The agent of any one of claims 738-742, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 9195).

744. The agent of any one of claims 738-743, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of GNYDYEGWFAY (SEQ ID NO: 9189), a HC CDR2 comprising the amino acid sequence of EFYPRSGNTYYNEKFRG (SEQ ID NO: 9188) or YPRSGN (SEQ ID NO: 9191), a HC CDR1 comprising the amino acid sequence of SYGIS (SEQ ID NO: 9187), GYNFTSY (SEQ ID NO: 9190), or GYNFTSYGIS (SEQ ID NO: 9193), a LC CDR3 comprising the amino acid sequence of HQYLSSLT (SEQ ID NO: 9196), a LC CDR2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 9195), and a LC CDR1 comprising the amino acid sequence of KSSQSVLYSSNQKNYLA (SEQ ID NO: 9194).

745. The agent of any one of claims 738-744, wherein the VH comprises a sequence with at least80% sequence identity to the sequence QVQLQQSGAELARPGASVKLSCKASGYNFTSYGISWVKQRTGQGLEWIGEFYPR SGNTYYNEKFRGKATLTADKSSTTAYMELRSLTSEDSAVYFCATGNYDYEGWF AYWGQGTLVTVSA (SEQ ID NO: 9169).

746. The agent of any one of claims 738-745, wherein the VH comprises a sequence ofQVQLQQSGAELARPGASVKLSCKASGYNFTSYGISWVKQRTGQGLEWIGEFYPR SGNTYYNEKFRGKATLTADKSSTTAYMELRSLTSEDSAVYFCATGNYDYEGWF AYWGQGTLVTVSA (SEQ ID NO: 9169).

747. The agent of any one of claims 738-746, wherein the VL comprises a sequence with at least80% sequence identity to the sequenceWSGR Docket No.: 53676-780.601NIMMTQSPSSLAVSAGEKVTMNCKSSQSVLYSSNQKNYLAWYQQKPGQSPKLLI YWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCHQYLSSLTFGAGTKL ELK (SEQ ID NO: 9173).

748. The agent of any one of claims 738-747, wherein the VL comprises a sequence ofNIMMTQSPSSLAVSAGEKVTMNCKSSQSVLYSSNQKNYLAWYQQKPGQSPKLLI YWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCHQYLSSLTFGAGTKL ELK (SEQ ID NO: 9173).

749. An agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of RGLDYAMDY (SEQ ID NO: 9201).

750. The agent of claim 749, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of NYGMN (SEQ ID NO: 9199), GYTFTNY (SEQ ID NO: 9202), or GYTFTNYGMN (SEQ ID NO: 9204).

751. The agent of claim 749 or 750, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of WINTYTGEPTYADDFKG (SEQ ID NO: 9200) or NTYTGE (SEQ ID NO: 9203).

752. The agent of any one of claims 749-751, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QHSRELPLT (SEQ ID NO: 9207).

753. The agent of any one of claims 749-752, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of RASKS VSTSGYSYMH (SEQ ID NO: 9205).

754. The agent of any one of claims 749-753, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of LASNLES (SEQ ID NO: 9206).

755. The agent of any one of claims 749-754, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of RGLDYAMDY (SEQ ID NO: 9201), a HC CDR2 comprising the amino acid sequence of WINTYTGEPTYADDFKG (SEQ ID NO: 9200) or NTYTGE (SEQ ID NO: 9203), a HC CDR1 comprising the amino acid sequence of NYGMN (SEQ ID NO: 9199), GYTFTNY (SEQ ID NO: 9202), or GYTFTNYGMN (SEQ ID NO: 9204), a LC CDR3 comprising the amino acid sequence of QHSRELPLT (SEQ ID NO: 9207), a LC CDR2 comprising the amino acid sequence of LASNLES (SEQ ID NO: 9206), andWSGR Docket No.: 53676-780.601 a LC CDR1 comprising the amino acid sequence of RASKS VSTSGYSYMH (SEQ ID NO: 9205).

756. The agent of any one of claims 749-755, wherein the VH comprises a sequence with at least80% sequence identity to the sequenceQIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGWINT YTGEPTYADDFKGRFAFSLETSASTAYLQINNLKNEDTATYFCARRGLDYAMDY WGQGTSVTVSS (SEQ ID NO: 9170).

757. The agent of any one of claims 749-756, wherein the VH comprises a sequence ofQIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGWINT YTGEPTYADDFKGRFAFSLETSASTAYLQINNLKNEDTATYFCARRGLDYAMDY WGQGTSVTVSS (SEQ ID NO: 9170).

758. The agent of any one of claims 749-757, wherein the VL comprises a sequence with at least80% sequence identity to the sequence DIVLTQSPASLAVSLGQRATISCRASKSVSTSGYSYMHWYQQKPGQPPKLLIYLA SNLESGVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQHSRELPLTFGAGTKLEL K (SEQ ID NO: 9174).

759. The agent of any one of claims 749-758, wherein the VL comprises a sequence ofDIVLTQSPASLAVSLGQRATISCRASKSVSTSGYSYMHWYQQKPGQPPKLLIYLA SNLESGVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQHSRELPLTFGAGTKLEL K (SEQ ID NO: 9174).

760. An agent comprising: a moiety that binds to a TCR variable region in a TCRa V21 subfamily comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of RGLDYAMDY (SEQ ID NO: 9212).

761. The agent of claim 760, wherein the VH comprises a HC CDR1 comprising the amino acid sequence of TAGMQ (SEQ ID NO: 9210), GYTFTTA (SEQ ID NO: 9213), or GYTFTTAGMQ (SEQ ID NO: 9315).

762. The agent of claim 760 or 761, wherein the VH comprises a HC CDR2 comprising the amino acid sequence of WINTHSGEPKYAEDFKG (SEQ ID NO: 9211) or NTHSGE (SEQ ID NO: 9214).

763. The agent of any one of claims 760-762, wherein the VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QHSRELPLT (SEQ ID NO: 9218).WSGR Docket No.: 53676-780.601764. The agent of any one of claims 760-763, wherein the VL comprises a LC CDR1 comprising the amino acid sequence of RASKS VSTSGYSYMH (SEQ ID NO: 9216).

765. The agent of any one of claims 760-764, wherein the VL comprises a LC CDR2 comprising the amino acid sequence of LASNLDS (SEQ ID NO: 9217).

766. The agent of any one of claims 760-765, wherein the moiety comprises: a HC CDR3 comprising the amino acid sequence of RGLDYAMDY (SEQ ID NO: 9212), a HC CDR2 comprising the amino acid sequence of WINTHSGEPKYAEDFKG (SEQ ID NO: 9211) or NTHSGE (SEQ ID NO: 9214), a HC CDR1 comprising the amino acid sequence of TAGMQ (SEQ ID NO: 9210), GYTFTTA (SEQ ID NO: 9213), or GYTFTTAGMQ (SEQ ID NO: 9315), a LC CDR3 comprising the amino acid sequence of QHSRELPLT (SEQ ID NO: 9218), a LC CDR2 comprising the amino acid sequence of LASNLDS (SEQ ID NO: 9217), and a LC CDR1 comprising the amino acid sequence of RASKS VSTSGYSYMH (SEQ ID NO: 9216).

767. The agent of any one of claims 760-766, wherein the VH comprises a sequence with at least80% sequence identity to the sequence QIQLVQSGPELKKPGETVKISCKASGYTFTTAGMQWVQKMPGKGFKWIGWINT HSGEPKYAEDFKGRFAFSLETSASTAYLQISNLKNEDTATYFCARRGLDYAMDY WGQGTSVTVSS (SEQ ID NO: 9171).

768. The agent of any one of claims 760-767, wherein the VH comprises a sequence ofQIQLVQSGPELKKPGETVKISCKASGYTFTTAGMQWVQKMPGKGFKWIGWINT HSGEPKYAEDFKGRFAFSLETSASTAYLQISNLKNEDTATYFCARRGLDYAMDY WGQGTSVTVSS (SEQ ID NO: 9171).

769. The agent of any one of claims 760-768, wherein the VL comprises a sequence with at least80% sequence identity to the sequence DIVLTQSPASLAVSLGQRATISCRASKSVSTSGYSYMHWYQQIPGQPPKLLIYLAS NLDSGVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQHSRELPLTFGAGTKLELK (SEQ ID NO: 9175).

770. The agent of any one of claims 760-769, wherein the VL comprises a sequence ofDIVLTQSPASLAVSLGQRATISCRASKSVSTSGYSYMHWYQQIPGQPPKLLIYLAS NLDSGVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQHSRELPLTFGAGTKLELK (SEQ ID NO: 9175).

771. The agent of any one of claims 637-770, wherein the agent comprises an antibody molecule or antigen binding domain thereof.WSGR Docket No.: 53676-780.601772. The agent of any one of claims 637-771, wherein the agent comprises an Fc region.

773. The agent of claim 772, wherein the Fc region comprises no binding mutation.

774. The agent of claim 773, wherein the Fc region has effector function or enhanced effector function.

775. The agent of claim 774, wherein the effector function or enhanced effector function comprises antibody dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement dependent cytotoxicity (CDC).

776. The agent of claim 774 or 775, wherein the effector function or enhanced effector function mediates killing of the autoreactive T cells in the human subject.

777. The agent of any one of claims 637-776, wherein the agent comprises an another moiety.

778. The agent of claim 777, wherein the another moiety binds to a TCR variable region, wherein the TCR variable region is TCRBV9, wherein the another moiety that binds to the TCR variable region comprises a second VH, wherein the second VH comprises a heavy chain complementarity determining region 3 (HC CDR3) comprising an amino acid sequence as set forth in SWRRGIRGIGFDY (SEQ ID NO: 1250).

779. The agent of claim 778, wherein the second VH comprises a HC CDR1 comprising the amino acid sequence of DYIVH (SEQ ID NO: 1248), GYTFTDY (SEQ ID NO: 1251), or GYTFTDYIVH (SEQ ID NO: 1253).

780. The agent of any one of claims 778 or 779, wherein the second VH comprises a HC CDR2 comprising the amino acid sequence of WINTYTGTPTYADDFEG (SEQ ID NO: 1249) or NTYTGT (SEQ ID NO: 1252).

781. The agent of any one of claims 778-780, wherein the another moiety comprises a secondVL, wherein the second VL comprises a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256).

782. The agent of any one of claims 778-781, wherein the second VL comprises a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254).

783. The agent of any one of claims 778-782, wherein the second VL comprises a LC CDR2 comprising the amino acid sequence of DGSTLQS (SEQ ID NO: 1255).

784. The agent of any one of claims 778-783, wherein the another moiety comprises: a HC CDR3 comprising the amino acid sequence of SWRRGIRGIGFDY (SEQ ID NO: 1250), a HC CDR2 comprising the amino acid sequence of WINTYTGTPTYADDFEG (SEQ ID NO: 1249) or NTYTGT (SEQ ID NO: 1252),WSGR Docket No.: 53676-780.601 a HC CDR1 comprising the amino acid sequence of DYIVH (SEQ ID NO: 1248), GYTFTDY (SEQ ID NO: 1251), or GYTFTDYIVH (SEQ ID NO: 1253), a LC CDR3 comprising the amino acid sequence of QQHNEYPPT (SEQ ID NO: 1256), a LC CDR2 comprising the amino acid sequence of DGSTLQS (SEQ ID NO: 1255), and a LC CDR1 comprising the amino acid sequence of KASKSINKYLA (SEQ ID NO: 1254).

785. The agent of claim 777, wherein the another moiety comprises a NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

786. The agent of claim 785, wherein the NK cell engager comprises a second VH and a secondVL, wherein the second VH comprises a HC CDR3 comprising the amino acid sequence of GDWHYFDY (SEQ ID NO: 7352).

787. The agent of any one of claims 786, wherein the second VH comprises a HC CDR1 comprising the amino acid sequence of GFSIIRVGYHWN (SEQ ID NO: 7383).

788. The agent of any one of claims 786 or 787, wherein the second VH comprises a HC CDR2 comprising the amino acid sequence of YIHRSGSTSYNPSLKS (SEQ ID NO: 7380).

789. The agent of any one of claims 786-788, wherein the second VL comprises a LC CDR3 comprising the amino acid sequence of QFWDSTNSAV (SEQ ID NO: 7358).

790. The agent of any one of claims 786-789, wherein the second VL comprises a LC CDR1 comprising the amino acid sequence of SGEKLSDKYVH (SEQ ID NO: 7356).

791. The agent of any one of claims 786-790, wherein the second VL comprises a LC CDR2 comprising the amino acid sequence of ENDRRPS (SEQ ID NO: 7352).

792. The agent of any one of claims 786-791, wherein the NK cell engager comprises: a HC CDR3 comprising the amino acid sequence of GDWHYFDY (SEQ ID NO: 7352), a HC CDR2 comprising the amino acid sequence of YIHRSGSTSYNPSLKS (SEQ ID NO: 7380, a HC CDR1 comprising the amino acid sequence of GFSIIRVGYHWN (SEQ ID NO: 7383), a LC CDR3 comprising the amino acid sequence of QFWDSTNSAV (SEQ ID NO: 7358), a LC CDR2 comprising the amino acid sequence of ENDRRPS (SEQ ID NO: 7352), and a LC CDR1 comprising the amino acid sequence of SGEKLSDKYVH (SEQ ID NO: 7356).

793. The agent of any one of claims 786-792, wherein the agent comprises an Fc region.WSGR Docket No.: 53676-780.601794. The agent of claim 793, wherein the Fc region comprises an amino acid sequence with at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 or 42.

795. The agent of claim 793 or 794, wherein the Fc region comprises one or more mutations.

796. The agent of claim 795, wherein the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

797. The agent of any one of claims 794-796, wherein the Fc comprises one or more mutations comprising E233P, L234V, L235A, P329A, S267K, G237A, P238S, H268A, A330S, P331S, K322A, D265A, D265S, L235E, G236R, S239K, A327G, V273E, T299A, Y300S, or any combination thereof, where amino acid positioning is relative to SEQ ID NO: 42.

798. The agent of any one of claims 793-797, wherein the Fc region comprises an Fc-silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function.

799. A method of treating a disease or condition or reducing a risk of developing the disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the agent of any one of claims 637-798.

800. The method of claim 799, wherein the subject has an autoimmune disease or condition.

801. The method of claim 800, wherein the autoimmune disease or condition is selected from the group consisting of the autoimmune disease is selected from amyotrophic lateral sclerosis (ALS), coeliac disease (CD), ankylosing spondylitis (AS), Covid-induced multisystem inflammatory syndrome in children (MIS-C), type 1 narcolepsy, primary Sjogren’s syndrome (PSS), Churg-Strauss syndrome, sarcoidosis, systemic lupus erythematosus (SLE), type 1 diabetes, autoimmune hepatitis (e.g., type 1 or type 2), acute anterior uveitis (UAA), primary sclerosing cholangitis, primary biliary cirrhosis, multiple sclerosis, Guillain-Barre syndrome and the AMAN (axonal & neuronal neuropathy), chronic inflammatory demyelinating polyneuropathy (CIDP), psoriatic arthritis (PsA), transverse myelitis, Tolosa-Hunt syndrome (THS), Devic’s disease (neuromyelitis optica), paraneoplastic cerebellardegeneration (PCD), Lambert-Eaton syndrome, psoriasis, scleroderma, CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome, dermatitis herpetiformis, dermatomyositis, bullous pemphigoid, cicatricial pemphigoid / benign mucosal pemphigoid, pemphigoid gestationis, rheumatoid arthritis (RA), psoriatic arthritis, relapsing polychondritis, chronic recurrent multifocal osteomyelitis (CRMO), vasculitis,WSGR Docket No.: 53676-780.601Kawasaki disease, granulomatosis with polyangiitis (GPA), Behcet’s disease (vasculitis), Takayasu’s arteritis, polyarteritis nodosa, microscopic polyangiitis (MPA), leukocytoclastic vasculitis, Cogan’s syndrome, uveitis, peripheral uveitis (Pars planitis), scleritis, autoimmune inner ear disease (AIED), Crohn’s, ulcerative colitis (UC), Dressier’s syndrome, Rheumatic fever, Evans syndrome, paroxysmal nocturnal hemoglobinuria (PNH), hemolytic anemia, thrombocytopenic purpura (TTP), polymyositis, juvenile myositis (JM), juvenile dermatomyositis (JDM), juvenile polymyositis (JPM), ocular cicatricial pemphigoid, and Hashimoto’s thyroiditis.

802. The method of claim 800, wherein the autoimmune disease or condition is ankylosing spondylitis.

803. The method of claim 800, wherein the autoimmune disease or condition is Celiac disease.

804. The method of claim 800, wherein the autoimmune disease or condition is reactive arthritis.

805. The method of claim 800, wherein the autoimmune disease or condition is inflammatory bowel disease.

806. The method of claim 800, wherein the autoimmune disease or condition is sacroiliitis.

807. The method of claim 800, wherein the autoimmune disease or condition is Reiter's syndrome.

808. The method of claim 800, wherein the autoimmune disease or condition is juvenile rheumatoid arthritis.

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