Claudin 18.2 T cell-antigen coupler and uses thereof

Abstract

Claudin 18.2 T cell antigen coupler (TAC) polypeptides are provided having (i) an antigen binding domain that binds to claudin 18.2, (ii) an antigen binding domain that binds to a protein associated with the TCR complex, and (iii) a signaling domain polypeptide of a T cell receptor. Nucleic acids encoding claudin 18 / 2 TACs are also provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 202,211, filed June 1, 2021; U.S. Provisional Patent Application No. 63 / 263,809, filed November 9, 2021; and U.S. Provisional Patent Application No. 63 / 362,594, filed April 6, 2022, the disclosures of each of which are incorporated by reference in their entirety for all purposes.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on May 31, 2022, is named TMV-006WO_SL.txt and is 87,860 bytes in size. Summary of the Invention

[0003] In certain embodiments, nucleic acids encoding claudin 18.2 T cell-antigen couplers (TACs) are disclosed herein. In some embodiments, the nucleic acid comprises: (a) a first polynucleotide encoding an antigen-binding domain that binds to claudin 18.2; (b) a second polynucleotide encoding an antigen-binding domain that binds to a protein associated with the TCR complex; and (c) a third polynucleotide encoding the cytosolic and transmembrane domains of a TCR coreceptor. In some embodiments, the nucleic acid comprises, in order (e.g., 5' to 3'): (a) a first polynucleotide encoding an antigen-binding domain that binds to claudin 18.2; (b) a second polynucleotide encoding an antigen-binding domain that binds to a protein associated with the TCR complex; and (c) a third polynucleotide encoding the cytosolic and transmembrane domains of a TCR coreceptor. In some embodiments, the antigen-binding domain that binds to claudin 18.2 is a designed ankyrin repeat (DARPin) polypeptide, a single-chain variable fragment (scFv), a single-domain antibody, a diabody, an affibody, an adnectin, an affilin, a phylomer, a finomar, an affimer, a peptide aptamer, a knottin, a sentinin, an anticalin, or a nanobody. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an antigen-binding domain derived from an antibody selected from IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, and aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of the antigen-binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of the antigen-binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182.In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of the antigen-binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or GC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of the antigen-binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of the antigen-binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of the antigen-binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of the antigen-binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of the antigen-binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the antigen binding domain that binds to claudin 18.2 comprises the amino acid sequence of the antigen binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182 (i.e., the antigen-binding domain that binds to claudin 18.2 comprises amino acid sequences including CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising an amino acid sequence that has at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 55 (claudin 18.2 nanobody 1). In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin18.2 Nanobody 1).In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin18.2 Nanobody 1). In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin18.2 Nanobody 1). In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin18.2 Nanobody 1). In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin18.2 Nanobody 1). In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin18.2 Nanobody 1). In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin18.2 Nanobody 1). In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 55 (Claudin18.2 Nanobody 1). In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 57 (Claudin18.2 Nanobody 1). In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising an amino acid sequence comprising CDR1 comprising SEQ ID NO: 60 (Claudin18.2 Nanobody 1 IMGT CDR1), CDR2 comprising SEQ ID NO: 61 (Claudin18.2 Nanobody 1 IMGT CDR2), and CDR3 comprising SEQ ID NO: 62 (Claudin18.2 Nanobody 1 IMGT CDR3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1 (i.e., the first polynucleotide encodes an antigen-binding domain comprising amino acid sequences comprising CDR1, CDR2, and CDR3, each of which has 100% identity to the corresponding CDRs of claudin 18.2 Nanobody 1). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 share 100% identity with the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 share at least 99% sequence identity with the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the first polynucleotide encodes the antigen-binding domain comprising an amino acid sequence that shares at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 56 (Claudin 18.2 Nanobody 2). In some embodiments, the first polynucleotide encodes the antigen-binding domain comprising an amino acid sequence that shares at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 56 (Claudin 18.2 Nanobody 2). In some embodiments, the first polynucleotide encodes the antigen-binding domain comprising an amino acid sequence that shares at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 56 (Claudin 18.2 Nanobody 2). In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 56 (Claudin18.2 Nanobody 2). In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 56 (Claudin18.2 Nanobody 2). In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 56 (Claudin18.2 Nanobody 2). In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 56 (Claudin18.2 Nanobody 2). In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 56 (Claudin18.2 Nanobody 2).In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 56 (Claudin18.2 Nanobody 2). In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising an amino acid sequence comprising a CDR1 comprising SEQ ID NO: 57 (Claudin18.2 Nanobody 2 Kabat CDR1), a CDR2 comprising SEQ ID NO: 63 (Claudin18.2 Nanobody 2 Kabat CDR2), and a CDR3 comprising SEQ ID NO: 59 (Claudin18.2 Nanobody 2 Kabat CDR3). In some embodiments, the first polynucleotide encodes an antigen-binding domain comprising an amino acid sequence comprising a CDR1 comprising SEQ ID NO: 64 (Claudin18.2 Nanobody 2 IMGT CDR1), a CDR2 comprising SEQ ID NO: 65 (Claudin18.2 Nanobody 2 IMGT CDR2), and a CDR3 comprising SEQ ID NO: 62 (Claudin18.2 Nanobody 2 IMGT CDR3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2 (i.e., the first polynucleotide encodes an antigen-binding domain comprising amino acid sequences comprising CDR1, CDR2, and CDR3, each of which has 100% identity to the corresponding CDRs of claudin 18.2 Nanobody 2). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% sequence identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the protein associated with the TCR complex is a CD3 protein, for example, a CD3 protein of the TCR complex of a T cell expressing TAC. In some embodiments, the CD3 protein is a CD3γ protein, a CD3δ protein, and / or a CD3ε protein. In some embodiments, the CD3 protein is a CD3ε protein. In some embodiments, binding of the CD3 protein induces T cell activation. In some embodiments, the antigen-binding domain that binds to the protein associated with the TCR complex is a designed ankyrin repeat (DARPin) polypeptide, a single-chain variable fragment (scFv), a single-domain antibody, a diabody, an affibody, an adnectin, an affilin, or a phylomer. , a finomar, an affimer, a peptide aptamer, a knottin, a sentinel, an anticalin, or a nanobody. In some embodiments, the antigen-binding domain that binds to a protein associated with the TCR complex is derived from an antibody selected from UCHT1, OKT3, F6A, and L2K. In some embodiments, the antigen-binding domain that binds to a protein associated with the TCR complex is a UCHT1 antigen-binding domain, e.g., a UCHT1-derived scFv. In some embodiments, the UCHT1 antigen-binding domain comprises a Y to T mutation at a position corresponding to amino acid 182 of SEQ ID NO: 8 (Y182T). In some embodiments, the UCHT1 antigen-binding domain is a humanized variant of UCHT1 (huUCHT1), e.g., a humanized variant of UCHT1 comprising a Y to T mutation at a position corresponding to amino acid 177 of SEQ ID NO: 34 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO:8 (UCHT1), SEQ ID NO:44 (UCHT1(Y182T)), SEQ ID NO:34 (huUCHT1), or SEQ ID NO:36 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:8 (UCHT1), SEQ ID NO:44 (UCHT1(Y182T)), SEQ ID NO:34 (huUCHT1), or SEQ ID NO:36 (huUCHT1(Y177T)). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)).In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO:8 (UCHT1), SEQ ID NO:44 (UCHT1(Y182T)), SEQ ID NO:34 (huUCHT1), or SEQ ID NO:36 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO:8 (UCHT1), SEQ ID NO:44 (UCHT1(Y182T)), SEQ ID NO:34 (huUCHT1), or SEQ ID NO:36 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO:8 (UCHT1), SEQ ID NO:44 (UCHT1(Y182T)), SEQ ID NO:34 (huUCHT1), or SEQ ID NO:36 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO:8 (UCHT1), SEQ ID NO:44 (UCHT1(Y182T)), SEQ ID NO:34 (huUCHT1), or SEQ ID NO:36 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises the amino acid sequence of SEQ ID NO:8 (UCHT1), SEQ ID NO:44 (UCHT1(Y182T)), SEQ ID NO:34 (huUCHT1), or SEQ ID NO:36 (huUCHT1(Y177T)).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)) (i.e., the antigen-binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence that includes CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T))). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)).In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex is an OKT3 antigen binding domain. In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence that has at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex comprises the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3) (i.e., the antigen-binding domain that binds to a protein associated with a TCR complex comprises amino acid sequences that include CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of the amino acid sequence of SEQ ID NO: 16 (OKT3)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3).In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex is an F6A antigen binding domain. In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen binding domain that binds to a protein associated with a TCR complex are 100% identical to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A) (i.e., the antigen binding domain that binds to a protein associated with a TCR complex comprises amino acid sequences comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of the amino acid sequence of SEQ ID NO: 18 (F6A)).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex is an L2K antigen-binding domain. In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence that has at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence that has at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 20 (L2K).In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO:20 (L2K). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO:20 (L2K). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 98 ... In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K) (i.e., the antigen binding domain that binds to a protein associated with a TCR complex comprises amino acid sequences comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of the amino acid sequence of SEQ ID NO: 20 (L2K)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K).In some embodiments, the cytosolic domain is a CD4 cytosolic domain and the transmembrane domain is a CD4 transmembrane domain. In some embodiments, the cytosolic domain is a CD8 cytosolic domain and the transmembrane domain is a CD8 transmembrane domain. In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 12 (CD4 transmembrane and cytosolic domain). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 12 (CD4 transmembrane and cytosolic domain). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 12 (CD4 transmembrane and cytosolic domain). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 12 (CD4 transmembrane and cytosolic domain). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise the amino acid sequence of SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the components encoded by the first, second and / or third polynucleotides are connected in any suitable order and / or in any suitable manner, such as with any suitable linker(s).In some embodiments, the component encoded by (a), the component encoded by (b), and the component encoded by (c) are fused directly to each other or joined by at least one linker. In some embodiments, the component encoded by (a) and the component encoded by (c) are fused to the component encoded by (b). In some embodiments, the component encoded by (b) and the component encoded by (c) are fused to the component encoded by (a). In some embodiments, at least one linker joins the component encoded by (a) to the component encoded by (b). In some embodiments, the at least one linker is a glycine- and / or serine-rich linker, a large protein domain, a long helix structure, or a short helix structure. In some embodiments, at least one linker comprises an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 85% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker).In some embodiments, at least one linker comprises an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 96% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 97% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker).In some embodiments, at least one linker comprises an amino acid sequence having at least 98% identity to the amino acid sequence of SEQ ID NO:6 ((G4S)4-based linker), SEQ ID NO:10 (G4S-based linker), SEQ ID NO:14 (CD4-based linker), SEQ ID NO:22 (short helix connector), SEQ ID NO:24 (long helix connector), SEQ ID NO:26 (large domain connector), SEQ ID NO:41 (flexible connector), SEQ ID NO:45 (G4S flexible linker), or SEQ ID NO:46 (G4S3 flexible linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 98% identity to the amino acid sequence of SEQ ID NO:6 ((G4S)4-based linker), SEQ ID NO:10 (G4S-based linker), SEQ ID NO:14 (CD4-based linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO:6 ((G4S)4-based linker), SEQ ID NO:10 (G4S-based linker), SEQ ID NO:14 (CD4-based linker), SEQ ID NO:22 (short helix connector), SEQ ID NO:24 (long helix connector), SEQ ID NO:26 (large domain connector), SEQ ID NO:41 (flexible connector), SEQ ID NO:45 (G4S flexible linker), or SEQ ID NO:46 (G4S3 flexible linker). In some embodiments, at least one linker comprises the amino acid sequence of SEQ ID NO:6 ((G4S)4-based linker), SEQ ID NO:10 (G4S-based linker), SEQ ID NO:14 (CD4-based linker), SEQ ID NO:22 (short helix connector), SEQ ID NO:24 (long helix connector), SEQ ID NO:26 (large domain connector), SEQ ID NO:41 (flexible connector), SEQ ID NO:45 (G4S flexible linker), or SEQ ID NO:46 (G4S3 flexible linker). In some embodiments, the nucleic acid sequence does not encode a costimulatory domain and / or an activation domain. In some embodiments, the nucleic acid sequence further encodes a leader sequence. In some embodiments, the leader sequence comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader).In some embodiments, the leader sequence comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the nucleic acid comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:70, or SEQ ID NO:72. In some embodiments, the claudin18.2-TAC polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:67, SEQ ID NO:69, SEQ ID NO:71, or SEQ ID NO:73.

[0004] In certain embodiments, disclosed herein is an expression vector comprising a nucleic acid disclosed herein (e.g., a nucleic acid encoding claudin18.2-TAC disclosed herein). In some embodiments, the expression vector comprises a promoter functional in mammalian cells. In some embodiments, the expression vector is a lentiviral vector, such as a VSV-G pseudotyped lentiviral vector. In some embodiments, the expression vector is a gamma retroviral vector, such as a GALV pseudotyped gamma retroviral vector.

[0005] In certain embodiments, claudin18.2 T cell-antigen couplers (TACs) are disclosed herein. In some embodiments, claudin18.2-TACs comprise (a) an antigen-binding domain that binds to claudin18.2; (b) an antigen-binding domain that binds to a protein associated with a TCR complex; and (c) a cytosolic domain and a transmembrane domain of a TCR co-receptor. In some embodiments, claudin18.2-TACs comprise, in order (e.g., from N-terminus to C-terminus): (a) an antigen-binding domain that binds to claudin18.2; (b) an antigen-binding domain that binds to a protein associated with a TCR complex; and (c) a cytosolic domain and a transmembrane domain of a TCR co-receptor. In some embodiments, the antigen-binding domain that binds to claudin 18.2 is a designed ankyrin repeat (DARPin) polypeptide, a single-chain variable fragment (scFv), a single-domain antibody, a diabody, an affibody, an adnectin, an affilin, a phylomer, a finomar, an affimer, a peptide aptamer, a knottin, a sentinin, an anticalin, or a nanobody. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an antigen-binding domain derived from an antibody selected from IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, and aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of the antigen-binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of the antigen-binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182.In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of the antigen-binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or GC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of the antigen-binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of the antigen-binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of the antigen-binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of the antigen-binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of the antigen-binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the antigen binding domain that binds to claudin 18.2 comprises the amino acid sequence of the antigen binding domain(s) of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182 (i.e., the antigen-binding domain that binds to claudin 18.2 comprises amino acid sequences including CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab), 43-14A, EPR19202, or aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence that has at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 55 (claudin 18.2 nanobody 1). In some embodiments, the antigen binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 55 (claudin 18.2 nanobody 1).In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin 18.2 Nanobody 1). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin 18.2 Nanobody 1). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin 18.2 Nanobody 1). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin 18.2 Nanobody 1). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin 18.2 Nanobody 1). In some embodiments, the antigen binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin 18.2 Nanobody 1). In some embodiments, the antigen binding domain that binds to claudin 18.2 comprises the amino acid sequence of SEQ ID NO: 55 (Claudin 18.2 Nanobody 1). In some embodiments, the antigen binding domain that binds to claudin 18.2 comprises a CDR1 comprising SEQ ID NO: 57 (Claudin 18.2 Nanobody 1 Kabat CDR1), a CDR2 comprising SEQ ID NO: 58 (Claudin 18.2 Nanobody 1 Kabat CDR2), and a CDR3 comprising SEQ ID NO: 59 (Claudin 18.2 Nanobody 1). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence comprising a CDR1 comprising SEQ ID NO: 60 (Claudin 18.2 Nanobody 1 IMGT CDR1), a CDR2 comprising SEQ ID NO: 61 (Claudin 18.2 Nanobody 1 IMGT CDR1), and a CDR3 comprising SEQ ID NO: 62 (Claudin 18.2 Nanobody 1 IMGT CDR3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 are 100% identical to the CDR sequences of claudin 18.2 Nanobody 1 (i.e., the antigen-binding domain that binds to claudin 18.2 comprises amino acid sequences comprising CDR1, CDR2, and CDR3 that each have 100% identity to the corresponding CDRs of claudin 18.2 Nanobody 1). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence that has at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 56 (claudin 18.2 Nanobody 2).In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 56 (claudin 18.2 nanobody 2). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 56 (claudin 18.2 nanobody 2). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 56 (claudin 18.2 nanobody 2). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 56 (claudin 18.2 nanobody 2). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 56 (claudin 18.2 nanobody 2). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 56 (claudin 18.2 nanobody 2). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 56 (claudin 18.2 nanobody 2). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises the amino acid sequence of SEQ ID NO: 56 (claudin 18.2 nanobody 2). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence comprising a CDR1 comprising SEQ ID NO: 57 (claudin 18.2 nanobody 2 Kabat CDR1), a CDR2 comprising SEQ ID NO: 63 (claudin 18.2 nanobody 2 Kabat CDR2), and a CDR3 comprising SEQ ID NO: 59 (claudin 18.2 nanobody 2 Kabat CDR3).In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence comprising CDR1 comprising SEQ ID NO: 64 (Claudin 18.2 Nanobody 2 IMGT CDR1), CDR2 comprising SEQ ID NO: 65 (Claudin 18.2 Nanobody 2 IMGT CDR1), and CDR3 comprising SEQ ID NO: 62 (Claudin 18.2 Nanobody 2 IMGT CDR3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 are 100% identical to the CDR sequences of claudin 18.2 Nanobody 2 (i.e., the antigen-binding domain that binds to claudin 18.2 comprises amino acid sequences comprising CDR1, CDR2, and CDR3 that each have 100% identity to the corresponding CDRs of claudin 18.2 Nanobody 2). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the protein associated with the TCR complex is a CD3 protein, for example, the CD3 protein of the TCR complex of a T cell expressing a TAC.In some embodiments, the CD3 protein is a CD3γ protein, a CD3δ protein, and / or a CD3ε protein. In some embodiments, the CD3 protein is a CD3ε protein. In some embodiments, binding of the CD3 protein induces T cell activation. In some embodiments, the antigen-binding domain that binds to a protein associated with the TCR complex is a designed ankyrin repeat (DARPin) polypeptide, a single-chain variable fragment (scFv), a single-domain antibody, a diabody, an affibody, an adnectin, an affilin, a filomer, a finomar, an affimer, a peptide aptamer, a knottin, a centrin, an anticalin, or a nanobody. In some embodiments, the antigen-binding domain that binds to a protein associated with the TCR complex is derived from an antibody selected from UCHT1, OKT3, F6A, and L2K. In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex is a UCHT1 antigen-binding domain, e.g., a UCHT1 single-chain antibody. In some embodiments, the UCHT1 antigen-binding domain comprises a Y to T mutation at a position corresponding to amino acid 182 of SEQ ID NO: 8 (Y182T). In some embodiments, the UCHT1 antigen-binding domain is a humanized variant of UCHT1 (huUCHT1), e.g., a humanized variant of UCHT1 comprising a Y to T mutation at a position corresponding to amino acid 177 of SEQ ID NO: 34 (huUCHT1(Y177T)). In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:8 (UCHT1), SEQ ID NO:44 (UCHT1(Y182T)), SEQ ID NO:34 (huUCHT1), or SEQ ID NO:36 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:8 (UCHT1), SEQ ID NO:44 (UCHT1(Y182T)), SEQ ID NO:34 (huUCHT1), or SEQ ID NO:36 (huUCHT1(Y177T)). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)).In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO:8 (UCHT1), SEQ ID NO:44 (UCHT1(Y182T)), SEQ ID NO:34 (huUCHT1), or SEQ ID NO:36 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO:8 (UCHT1), SEQ ID NO:44 (UCHT1(Y182T)), SEQ ID NO:34 (huUCHT1), or SEQ ID NO:36 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO:8 (UCHT1), SEQ ID NO:44 (UCHT1(Y182T)), SEQ ID NO:34 (huUCHT1), or SEQ ID NO:36 (huUCHT1(Y177T)). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)) (i.e., the antigen-binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence that includes CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T))).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), SEQ ID NO: 44 (UCHT1(Y182T)), SEQ ID NO: 34 (huUCHT1), or SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO:8 (UCHT1), SEQ ID NO:44 (UCHT1(Y182T)), SEQ ID NO:34 (huUCHT1), or SEQ ID NO:36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO:8 (UCHT1), SEQ ID NO:44 (UCHT1(Y182T)), SEQ ID NO:34 (huUCHT1), or SEQ ID NO:36 (huUCHT1(Y177T)). In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex is an OKT3 antigen-binding domain. In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence that has at least 85% sequence identity to the amino acid sequence of SEQ ID NO:16 (OKT3). In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3).In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 9 ... The antigen-binding domain that binds to a protein associated with a TCR complex comprises the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3) (i.e., the antigen-binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of the amino acid sequence of SEQ ID NO: 16 (OKT3)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3).In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex is an F6A antigen binding domain. In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen binding domain that binds to a protein associated with a TCR complex are 100% identical to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A) (i.e., the antigen binding domain that binds to a protein associated with a TCR complex comprises amino acid sequences comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of the amino acid sequence of SEQ ID NO: 18 (F6A)).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex is an L2K antigen-binding domain. In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence that has at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence that has at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 20 (L2K).In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO:20 (L2K). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO:20 (L2K). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO:20 (L2K). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO:20 (L2K). ) In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20(L2K) (i.e., the antigen-binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, which each have 100% identity to the corresponding CDRs of the amino acid sequence of SEQ ID NO: 20(L2K)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20(L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20(L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K).In some embodiments, the cytosolic domain is a CD4 cytosolic domain and the transmembrane domain is a CD4 transmembrane domain. In some embodiments, the cytosolic domain is a CD8 cytosolic domain and the transmembrane domain is a CD8 transmembrane domain. In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 96% sequence identity to SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 97% sequence identity to SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 98% sequence identity with SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 99% sequence identity with SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise the amino acid sequence of SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the components of claudin18.2-TAC are connected in any suitable order and / or in any suitable manner, such as with any suitable linker(s). In some embodiments, component (a), component (b), and component (c) are directly fused to each other or joined by at least one linker.In some embodiments, components (a) and (c) are fused to component (b). In some embodiments, components (b) and (c) are fused to component (a). In some embodiments, at least one linker joins component (a) to component (b). In some embodiments, at least one linker is a glycine and / or serine-rich linker, a large protein domain, a long helix structure, or a short helix structure. In some embodiments, at least one linker comprises an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO:6 ((G4S)4-based linker), SEQ ID NO:10 (G4S-based linker), SEQ ID NO:14 (CD4-based linker), SEQ ID NO:22 (short helix connector), SEQ ID NO:24 (long helix connector), SEQ ID NO:26 (large domain connector), SEQ ID NO:41 (flexible connector), SEQ ID NO:45 (G4S flexible linker), or SEQ ID NO:46 (G4S3 flexible linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 85% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker).In some embodiments, at least one linker comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 96% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 97% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 98% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker).In some embodiments, at least one linker comprises an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO:6 ((G4S)4-based linker), SEQ ID NO:10 (G4S-based linker), SEQ ID NO:14 (CD4-based linker), SEQ ID NO:22 (short helix connector), SEQ ID NO:24 (long helix connector), SEQ ID NO:26 (large domain connector), SEQ ID NO:41 (flexible connector), SEQ ID NO:45 (G4S flexible linker), or SEQ ID NO:46 (G4S3 flexible linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO:6 ((G4S)4-based linker), SEQ ID NO:10 (G4S-based linker), SEQ ID NO:14 (CD4-based linker), SEQ ID NO:22 (short helix connector), SEQ ID NO:24 (long helix connector), SEQ ID NO:26 (large domain connector). ), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker). In some embodiments, claudin18.2-TAC does not comprise a costimulatory domain and / or an activation domain. In some embodiments, claudin18.2-TAC further comprises a leader sequence. In some embodiments, the leader sequence comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 2 (muIgG leader), SEQ ID NO: 38 (huIgG leader), or SEQ ID NO: 40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 2 (muIgG leader), SEQ ID NO: 38 (huIgG leader), or SEQ ID NO: 40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 2 (muIgG leader), SEQ ID NO: 38 (huIgG leader), or SEQ ID NO: 40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader).In some embodiments, the leader sequence comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the claudin18.2-TAC polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:67. In some embodiments, the claudin18.2-TAC polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:69. In some embodiments, the claudin18.2-TAC polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 71. In some embodiments, the claudin18.2-TAC polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 73.

[0006] In certain embodiments, disclosed herein are T cells comprising a nucleic acid disclosed herein, an expression vector disclosed herein, or a claudin18.2-TAC disclosed herein. In some embodiments, the T cells are γδ T cells, such as δ2 T cells, δ1s T cells, or γ9δ2 T cells.

[0007] Disclosed herein, in certain embodiments, is a pharmaceutical composition comprising the T cells disclosed herein and a pharmaceutically acceptable excipient.

[0008] In certain embodiments, disclosed herein are methods of treating a cancer that expresses claudin 18.2 in an individual in need thereof, the method comprising administering to the individual a T cell or pharmaceutical composition disclosed herein. In some embodiments, the cancer is a solid cancer or a liquid cancer. In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic adenocarcinoma, gastric cancer (e.g., gastric adenocarcinoma), signet ring cell carcinoma, mucinous gastric cancer, gastroesophageal cancer (e.g., gastroesophageal junction (GEJ) adenocarcinoma), esophageal cancer, digestive system cancer, ovarian cancer, mucinous ovarian cancer cells, or lung cancer (e.g., non-small cell lung cancer).

[0009] In certain embodiments, disclosed herein is a conjugate comprising a T cell disclosed herein and a cancer cell expressing claudin 18.2. In some embodiments, the claudin 18.2-TAC polypeptide is present on the surface of the T cell, and the claudin 18.2 is present on the surface of the cancer cell. In some embodiments, the claudin 18.2-TAC polypeptide is bound to claudin 18.2. In some embodiments, the cancer cell is a solid cancer cell. In some embodiments, the cancer cell is a pancreatic cancer cell, a gastric cancer cell, a signet ring cell carcinoma cell, a digestive system cancer, a mucinous gastric cancer cell, a gastroesophageal cancer cell, an esophageal cancer cell, an ovarian cancer cell, a mucinous ovarian cancer cell, a non-small cell lung cancer cell, or a lung cancer cell. In some embodiments, the cancer cell is a gastric cancer cell or a gastroesophageal cancer cell. [Brief explanation of the drawings]

[0010] The present invention can be more fully understood with reference to the following drawings.

[0011] [Figure 1]Cell surface expression of the indicated TAC and mStrawberry red fluorescent protein transduction markers in T cells is shown. NTD: non-transduced control cells. [Figure 2]

[0023] Figure 2 shows evaluation of claudin 18.2-TAC T cell production. Figure 2A shows total cell counts over time for T cells engineered to express the indicated claudin 18.2-TAC. Figure 2B shows cell number doublings over time for T cells engineered to express the indicated claudin 18.2-TAC. Figure 2C shows percent viability over time for T cells engineered to express the indicated claudin 18.2-TAC. [Figure 3] Shown is a histogram of the expression of the indicated claudin18.2-TAC in T cells from the indicated donors as measured by flow cytometry. [Figure 4] Relative expression of the indicated claudin18.2-TAC in T cells as measured by flow cytometry is shown. [Figure 5A] Figure 1 shows binding of GFP-tagged claudin18.2 nanobody 2 to the indicated cells engineered to express claudin18.2 or a control. [Figure 5B] Figure 1 shows binding of GFP-claudin18.2 nanobody 2 fusion protein to a library of known membrane-anchored human proteins. [Figure 6A] Assays demonstrating activation of claudin 18.2-TAC T cells after co-culture with target cells expressing claudin 18.2 (top panel) or claudin 18.1 (bottom panel) are shown. Confirmation of claudin 18.2-TAC expression, as measured by flow cytometry, is shown. [Figure 6B] Assays demonstrating activation of claudin 18.2-TAC T cells after co-culture with target cells expressing claudin 18.2 (upper panel) or claudin 18.1 (lower panel) are shown. Scatter plots of CD69 (vertical axis) staining versus TAC expression (horizontal axis) are shown in engineered T cells exposed to cells expressing the indicated antigens. [Figure 6C]Assays demonstrating activation of claudin 18.2-TAC T cells after co-culture with target cells expressing claudin 18.2 (top panel) or claudin 18.1 (bottom panel) are shown. Normalized % CD69 positivity is shown for T cells expressing the indicated TAC and exposed to target cells expressing the indicated antigen. [Figure 7] Figure 1 shows the cytotoxicity induced by T cells expressing claudin18.2-TAC of SEQ ID NO: 69 or 73 after co-culture with KATO III cells engineered to express enhanced luciferase (KATO IIIeLuc). NTD: non-transduced control cells. The effector cell:target cell (E:T) ratio (IC50) that induced 50 percent killing of target cells was calculated, and the E:T ratio required to achieve half of the maximum cytotoxicity is shown. [Figure 8] FIG. 1 is a schematic diagram of the in vitro cytotoxicity assay described in Example 3. [Figure 9] Representative images of co-cultures of the indicated effector cells (TAC T cells) and target cells (NALM6CLDN18.2 / eGFP or NALM6eGFP cells) at different E:T ratios after 5 days of co-culture are shown. [Figure 10] Quantitative analysis of tumor cell proliferation, measured by eGFP area, is shown for cocultures of the indicated effector cells (TAC T cells) and target cells (NALM6CLDN18.2 / eGFP or NALM6eGFP cells) at different E:T ratios. NTD: non-transduced control cells. [Figure 11] 11 shows an area under the curve (AUC) analysis of the cytotoxicity results shown in FIG. [Figure 12] Figure 1 shows the production of IFNg, TNFa, and IL2 measured by flow cytometry after coculture of the indicated effector cells (TAC T cells) and target cells (NALM6CLDN18.2 or NALM6eGFP cells). Cytokine production by the indicated effector cells (TAC T cells) in the absence of any target cells is shown as a control. [Figure 13]Markers that allow assessment of T cell activation, exhaustion and memory phenotype are presented. [Figure 14] Figure 1 shows the results of a 16-parameter UMAP analysis highlighting CD8 and CD69 expression after co-culture of claudin18.2-TAC T cells or non-transduced (NTD) control cells with NALM6eGFP or NALM6CLDN18.2 / eGFP cells. Color indicates the relative abundance of the indicated markers. [Figure 15] Flow cytometry plots of CD69 staining (vertical axis) and claudin18.2-TAC transduction (horizontal axis) of CLDN18.9-TAC T cells cocultured with the indicated claudin18.2-expressing cell lines are shown. [Figure 16] Figure 16 shows an in vitro assay demonstrating target cell cytotoxicity by T cells expressing the indicated claudin18.2-TACs. Figure 16A shows normalized cytotoxicity at the indicated effector:target (E:T) ratios. Figure 16B shows the measured IC50 values ​​of T cells expressing the indicated TACs. [Figure 17A] 1 shows an assessment of proliferation of T cells expressing claudin18.2-TAC, as measured by flow cytometry-based detection of a cell tracking dye. [Figure 17B] Figure 1 shows the assessment of proliferation of T cells expressing claudin18.2-TAC. The measured mitotic index (DI) of T cells expressing the indicated TAC is shown. [Figure 18A] Figure 1 shows an assessment of activation of T cells expressing the indicated claudin18.2-TAC. Scatter plots of CD69 (vertical axis) staining versus TAC expression (horizontal axis) are shown in engineered T cells exposed to the indicated cell lines. [Figure 18B] Figure 1 shows an assessment of activation of T cells expressing the indicated claudin18.2-TACs. Normalized % CD69 positivity is shown in T cells expressing the indicated TACs and exposed to the indicated target cells. [Figure 19A] 1 shows an assay testing repeated stimulation of TAC-expressing T cells. Schematic of the assay is shown. [Figure 19B] 1 shows an assay testing repeated stimulation of T cells expressing a TAC. 2 shows a graph depicting the viability of the indicated target cells after incubation with T cells expressing the indicated TAC. [Figure 20] Schematic of the in vivo murine experiment described in Example 9 (top) and the total flux (photons / sec) obtained as the sum of the dorsal and ventral leads for the indicated treatment groups (bottom). [Figure 21] The relative changes in luminescence (total flux), overall survival, and body weight are shown for the indicated treatment groups. Figure 21A shows NT: untreated animals (squares); NTD: mice administered untransduced control T cells (circles). Figure 2B shows NT: untreated animals (squares); NTD: mice administered untransduced control T cells (circles). Figure 21C shows NT: untreated animals (squares); NTD: mice administered untransduced control T cells (circles). [Figure 22] Schematic of an in vivo murine model of the anti-tumor activity of claudin18.2-TAC T cells, showing tumor volume over time in response to the indicated doses. [Figure 23] Schematic of an in vivo murine model of the antitumor activity of claudin18.2-TAC T cells (top panel), luminescence (total flux; middle left panel), overall survival (bottom left panel), and whole-body scans (right panel) of mice in the indicated treatment groups over the course of treatment are shown. [Figure 24] Schematic of an in vivo murine model of the antitumor activity of claudin18.2-TAC T cells (top panel), showing tumor volume over time in response to the indicated dose (middle panel) and overall survival (bottom panel). [Figure 25A] Figure 1 shows the anti-tumor activity of claudin18.2-TAC T cells and different dosage levels in an in vivo murine model. A schematic diagram of the model is shown. [Figure 25B]Figure 1 shows the anti-tumor activity of claudin18.2-TAC T cells and different dose levels in an in vivo murine model. Measurements of tumor volume over the course of the experiment are shown after treatment with T cells expressing the indicated TAC at the indicated dose levels. [Figure 26A] Figure 1 shows the anti-tumor activity of claudin18.2-TAC T cells and different dosage levels in an in vivo murine model. A schematic diagram of the model is shown. [Figure 26B] Figure 1 shows the anti-tumor activity of claudin18.2-TAC T cells and different dose levels in an in vivo murine model. Measurements of tumor volume over the course of the experiment are shown after treatment with T cells expressing the indicated TAC at the indicated dose levels. [Figure 27A] Figure 1 shows the anti-tumor activity of claudin18.2-TAC T cells and different dosage levels in an in vivo murine model. A schematic diagram of the model is shown. [Figure 27B] Figure 1 shows the antitumor activity of claudin18.2-TAC T cells and different dose levels in an in vivo murine model. Measurement of tumor flux over the course of the experiment after treatment with T cells expressing the indicated TACs at the indicated dose levels is shown. [Figure 28A] Figure 1 shows an in vivo murine re-challenge model of the anti-tumor activity of claudin18.2-TAC T cells in MHC knockout mice. A schematic diagram of the model is shown. [Figure 28B] 1 shows an in vivo murine re-challenge model of the anti-tumor activity of claudin18.2-TAC T cells in MHC knockout mice. Measurements of tumor volume over the course of the experiment are shown following treatment with T cells expressing the indicated TACs over the course of the experiment, with the indicated re-challenge time points. DETAILED DESCRIPTION OF THE INVENTION

[0012] Cancer is a major health challenge. According to the American Cancer Society, more than one million people are diagnosed with cancer each year in the United States. While patients with early-stage disease can be effectively treated with conventional therapies (surgery, radiation, chemotherapy), few options are available for patients with advanced disease, and those options are usually palliative in nature.

[0013] Active immunotherapy utilizes the patient's immune system to attempt to clear tumors, providing an option for patients who have failed conventional therapies. Generally, this treatment involves injecting large numbers of tumor-specific T cells into patients. This approach has proven successful in early-stage clinical trials for several diseases, including melanoma, myeloma, leukemia, lymphoma, and synovial sarcoma. Specifically, several clinical studies have demonstrated that T cell-based immunotherapy is curative in patients with advanced melanoma, confirming the utility of this approach. Additionally, patients with chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL) have also been effectively treated and cured with T cell immunotherapy.

[0014] In this regard, most engineered T cell therapies involve genetic modification of T cells to (i) force expression of a T cell receptor (TCR); or (ii) generate chimeric antigen receptors (CARs) specific for tumor antigen targets. To date, chimeric antigen receptors used to engineer T cells consist of (i) a targeting domain, usually a single-chain fragment variable (scFv); (ii) a transmembrane domain; and (iii) a cytosolic domain containing signaling elements derived from the T cell receptor and related proteins. Such chimeric antigen receptors have also been referred to as "T bodies" or "chimeric immune receptors" (CIRs), although most researchers currently use the term "CAR." One advantage of the CAR approach is that it allows any patient's immune cells to be targeted to any desired target in a major histocompatibility complex (MHC)-independent manner. This is attractive because MHC presentation is often defective in tumor cells.

[0015] CARs are thought of in modular terms, and scientists have spent considerable time investigating the influence of different cytoplasmic signaling domains on CAR function. Conventional CARs generally share two major components: (i) a CD3 zeta cytoplasmic domain containing immunotyrosine-based activation motifs (ITAMs) important for T cell activation; and (ii) a costimulatory receptor component that triggers important survival pathways, such as the Akt pathway.

[0016] First-generation CARs used a single signaling domain derived from either CD3ζ or FcεRIγ. Second-generation CARs combined the signaling domain of CD3ζ with the cytoplasmic domain of a costimulatory receptor from either the CD28 or TNFR family of receptors. Most CAR-engineered T cells currently being tested in clinical trials use second-generation CARs in which CD3ζ is coupled to the cytoplasmic domain of either CD28 or CD137. These second-generation CARs have demonstrated antitumor activity in CD19-positive tumors. Third-generation CARs combined multiple costimulatory domains, but there are concerns that third-generation CARs may lose antigen specificity.

[0017] While CAR-engineered T cells have shown considerable promise in clinical applications, they rely on synthetic methods to replace the native activation signals provided by the T cell receptor (TCR). Because these synthetic receptors do not deliver all signaling components associated with the TCR (e.g., ITAMs of CD3γ, CD3δ, and CD3ε), it remains unclear whether T cells are optimally activated by CARs or how CAR activation affects T cell differentiation (e.g., progression to memory). Furthermore, because the CAR signaling domain is decoupled from its native regulatory partners by the very nature of the CAR structure, there is an inherent risk that CARs may result in low-level constitutive activation and potentially off-target toxicity. Thus, the synthetic nature of prototype CARs may subvert canonical mechanisms that limit TCR activation, potentially contributing to the severe toxicity often associated with therapeutic doses of conventional CAR T cells.

[0018] Given these limitations, it is preferable to redirect T cells to attack tumors via their native TCR. Alternative chimeric receptors, called T cell antigen coupler (TAC or TAC) receptors, have been developed, which use a different biology to direct T cells to attack tumors. While CARs are fully synthetic receptors that assemble together components of the T cell receptor (TCR) signaling complex, TAC receptors redirect TCRs to tumor targets, recapitulating the native TCR signaling structure. For example, in some embodiments, the TACs disclosed herein activate native major histocompatibility complex (MHC) signaling through the T cell receptor (TCR) while retaining MHC-unrestricted targeting. Furthermore, the TACs disclosed herein recruit T cell receptors (TCRs) in combination with co-receptor stimulation. Moreover, in some embodiments, the TACs disclosed herein exhibit enhanced activity and safety.

[0019] TACs differ from conventional CAR technology in that they contain a second extracellular ligand that binds to a protein associated with the TCR complex. Furthermore, TACs contain the cytosolic domain of a TCR coreceptor, as opposed to the TCR signaling domain used in CARs. The TCR coreceptor domain can promote T cell activation through endogenous TCR signaling, in contrast to CARs, which function independently of the endogenous TCR. Instead, CARs typically function through their own synthetic activation domain (e.g., CD3z). This tonic signaling induced by CARs can lead to effector cell exhaustion. The structural differences between TACs and CARs result in molecules with different structural features and functionalities. For example, an antigen-binding domain that is not functional in CARs may be satisfactorily manufacturable or functional in the context of a TAC.

[0020] Claudin 18.1 and 18.2 (CLDN18.1 and CLDN18.2) are highly conserved multi-transmembrane proteins found in tight junctions. The extracellular domains of claudin 18.1 and 18.2 contain two prominent loops. Claudin 18.1 and 18.2 show significant differences in the first extracellular loop but are otherwise identical. Claudin 18.1 is widely expressed in lung tissue, while claudin 18.2 is primarily expressed in gastric tissue and is therefore a target for treating gastric cancer.

[0021] Specific Terms The term "antigen-binding domain" refers to any substance or molecule that directly or indirectly binds to a target (e.g., claudin 18.2). Antigen-binding domains include antibodies or fragments thereof, peptides, peptidomimetics, proteins, glycoproteins, proteoglycans, carbohydrates, lipids, nucleic acids, or small molecules that bind to a target.

[0022] As used herein, unless otherwise specified, the term "antibody" is understood to mean an intact antibody (e.g., an intact monoclonal antibody), or a fragment thereof, such as an Fc fragment of an antibody (e.g., an Fc fragment of a monoclonal antibody), or a modified, engineered, or chemically conjugated intact antibody, antigen-binding fragment, or antigen-binding fragment of an antibody (e.g., an antigen-binding fragment of a monoclonal antibody) comprising an Fc fragment. Generally, an antibody is a multimeric protein comprising four polypeptide chains. Two of the polypeptide chains are called immunoglobulin heavy chains (H chains), and two of the polypeptide chains are called immunoglobulin light chains (L chains). The heavy and light chains of an immunoglobulin are connected by an interchain disulfide bond. The immunoglobulin heavy chains are connected by an interchain disulfide bond. The light chain consists of one variable region (VL) and one constant region (CL). The heavy chain consists of one variable region (VH) and at least three constant regions (CH1, CH2, and CH3). The variable regions determine the binding specificity of the antibody. Each variable region contains three hypervariable regions known as complementarity-determining regions (CDRs), flanked by four relatively conserved regions known as framework regions (FRs). The extent of the FRs and CDRs has been defined (Kabat, E. A. et al. (1991) Sequences of Proteins of Immunological Interest, 5th ed., USDapartment of Health and Human Services, NIH Publication No. 91-3242; and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917). The three CDRs, designated CDR1, CDR2, and CDR3, contribute to the binding specificity of the antibody. Naturally occurring antibodies have been used as starting materials for engineered antibodies, such as chimeric and humanized antibodies. Examples of antibody-based antigen-binding fragments include Fab, Fab', (Fab')2, Fv, single chain antibodies (eg, scFv), minibodies, and diabodies.Examples of modified or engineered antibodies include chimeric antibodies, humanized antibodies, and multispecific antibodies (e.g., bispecific antibodies). An example of a chemically conjugated antibody is an antibody conjugated to a toxin moiety.

[0023] As used herein, the term "T cell" refers to a type of lymphocyte that plays a central role in cell-mediated immunity. T cells, also called T lymphocytes, are distinguished from other lymphocytes, such as B cells and natural killer cells, by the presence of a T cell receptor (TCR) on the cell surface. There are several subsets of T cells with different functions, including, but not limited to, T helper cells, cytotoxic T cells, memory T cells, regulatory T cells, and natural killer T cells.

[0024] As used herein, the term "γδ T cell" or "gamma delta T cell" or "gd T cell" refers to any lymphocyte that has a γδ T cell receptor (TCR) on its surface, which contains one γ chain and one δ chain.

[0025] The term "T cell antigen coupler" or TAC is used interchangeably with "trifunctional T cell antigen coupler" or Tri-TAC and refers to an engineered nucleic acid construct or polypeptide that includes (a) an antigen-binding domain that binds to a target, (b) an antigen-binding domain that binds to a protein associated with the T cell receptor (TCR) complex, and (c) a T cell receptor signaling domain.

[0026] As used herein, the terms "polynucleotide" and / or "nucleic acid sequence" and / or "nucleic acid" refer to a sequence of nucleoside or nucleotide monomers, consisting of bases, sugars, and intersugar (backbone) linkages. The term also includes modified or substituted sequences, including non-naturally occurring monomers or portions thereof. The nucleic acid sequences of the present application may be deoxyribonucleic acid sequences (DNA) or ribonucleic acid sequences (RNA) and may contain naturally occurring bases, including adenine, guanine, cytosine, thymidine, and uracil. The sequences may also contain modified bases. Examples of such modified bases include aza- and deaza-adenine, guanine, cytosine, thymidine, and uracil; and xanthine and hypoxanthine. The nucleic acids of the present disclosure may be isolated from biological organisms, formed by recombinant genetic laboratory methods, or obtained by chemical synthesis or other known protocols for producing nucleic acids.

[0027] As used herein, the term "isolated polynucleotide" or "isolated nucleic acid sequence" refers to a nucleic acid that is substantially free of cellular material or culture medium when produced by recombinant DNA techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. An isolated nucleic acid is also substantially free of sequences that naturally flank the nucleic acid from which it is derived (i.e., sequences located at the 5' and 3' ends of the nucleic acid). The term "nucleic acid" is intended to include DNA and RNA, and can be either double-stranded or single-stranded, and refer to either the sense or antisense strand. Furthermore, the term "nucleic acid" includes complementary nucleic acid sequences.

[0028] As used herein, the term "recombinant nucleic acid" or "engineered nucleic acid" refers to a nucleic acid or polynucleotide that is not found in a biological organism. For example, a recombinant nucleic acid can be formed by laboratory methods of genetic recombination (such as molecular cloning) to create a sequence that would not otherwise be found in nature. Recombinant nucleic acids may also be produced by chemical synthesis or other known protocols for producing nucleic acids.

[0029] As used herein, the terms "peptide," "polypeptide," or "protein" refer to a chain of amino acids. As used herein, the term protein further refers to a larger molecule comprising one or more chains of amino acids, and in some embodiments, a protein fragment or domain or a full-length protein. Furthermore, as used herein, the term protein refers to either a linear chain of amino acids or a chain of amino acids that has been processed and folded into a functional protein. Protein structure is divided into four different levels: (1) primary structure—refers to the sequence of amino acids in the polypeptide chain; (2) secondary structure—refers to the regular, local substructures on the polypeptide backbone chain, such as α-helices and β-sheets; (3) tertiary structure—refers to the three-dimensional structure in the case of monomeric and multimeric protein molecules; and (4) quaternary structure—refers to the three-dimensional structure comprising the aggregation of two or more individual polypeptide chains that operate as a single functional unit. The use of peptide or polypeptide herein does not imply that the chain of amino acids is not a protein (i.e., a chain of amino acids with secondary, tertiary, or quaternary structure).

[0030] The term "isolated polypeptide" refers to a polypeptide that is substantially free of cellular material or culture medium when produced by recombinant DNA techniques, or that is substantially free of chemical precursors or other chemicals when chemically synthesized.

[0031] As used herein, the term "vector" refers to a polynucleotide used to deliver a nucleic acid into a cell. In some embodiments, the vector is an expression vector that includes an expression control sequence (e.g., a promoter) operably linked to the nucleic acid to be expressed in the cell. Vectors known in the art include, but are not limited to, plasmids, phages, cosmids, and viruses.

[0032] As used herein, the term "tumor antigen" or "tumor-associated antigen" refers to an antigenic substance (e.g., presented by an MHC complex) produced by a tumor cell that elicits an immune response in a host. In some embodiments, the tumor antigen is on the surface of a tumor cell.

[0033] As used herein, the term "transmembrane and cytosolic domains" refers to polypeptides comprising the transmembrane and cytosolic domains of proteins associated with the T cell receptor (TCR) complex. In some embodiments, such transmembrane and cytosolic domains may include, but are not limited to, protein domains that (a) associate with lipid rafts and / or (b) bind to Lck.

[0034] As used herein, "TCR co-receptor" refers to a molecule that helps the T cell receptor (TCR) communicate with an antigen-presenting cell and can be considered part of the first signal that leads to TCR activation. Examples of TCR co-receptors include, but are not limited to, CD4, LAG3, and CD8.

[0035] As used herein, "TCR costimulator" or "costimulatory domain" refers to a molecule that enhances the response of T cells to antigens and can be considered a second signal that leads to TCR activation. Examples of TCR costimulators include, but are not limited to, ICOS, CD27, CD28, 4-1BB (CD137), OX40 (CD134), CD30, CD40, lymphocyte fiction-associated antigen 1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and ligands that specifically bind to CD83.

[0036] The terms "recipient," "individual," "subject," "host," and "patient" are used interchangeably herein and, in some embodiments, refer to any mammalian subject, particularly humans, for whom diagnosis, treatment, or therapy is desired. "Mammal" for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and laboratory, zoo, sport, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys, etc. In some embodiments, the mammal is a human. None of these terms require the supervision of a medical professional.

[0037] As used herein, the terms "treatment," "treating," and the like, in some embodiments, refer to administering an agent or performing a procedure for the purpose of obtaining an effect. The effect can be preventative, in that it completely or partially prevents a disease or its symptoms, and / or therapeutic, in that it affects a partial or complete cure of the disease and / or the symptoms of the disease. "Treatment," as used herein, can include the treatment of a disease or disorder (e.g., cancer) in a mammal, particularly a human, and includes (a) preventing the occurrence of a disease or disease symptoms in a subject who may be predisposed to the disease but has not yet been diagnosed with the disease (including, for example, diseases that may be associated with or caused by a primary disease); (b) inhibiting the disease, i.e., halting its development; and (c) palliating the disease, i.e., causing regression of the disease. Treating can refer to any indication of success in treating, improving, or preventing cancer, including any objective or subjective parameter, such as relief; remission; reducing symptoms; or making disease symptoms more tolerable to patients; slowing the rate of deterioration or decline; or making the end point of deterioration less debilitating. Treating or improving symptoms is based on one or more objective or subjective parameters, including the results of a physician's examination. Thus, the term "treating" includes administering a compound or agent of the present invention to prevent, delay, alleviate, stop, or inhibit the onset of symptoms or symptoms associated with a disease (e.g., cancer). The term "therapeutic effect" refers to the reduction, elimination, or prevention of a disease, a symptom of a disease, or a side effect of a disease in a subject.

[0038] As used herein, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an antibody" includes a plurality of antibodies, reference to "an antibody" in some embodiments includes multiple antibodies, etc.

[0039] As used herein, all numerical values ​​or ranges include whole integers within or encompassing such ranges, and fractions of values ​​or integers within or encompassing ranges, unless the context clearly dictates otherwise. Thus, for example, a reference to a range of 90-100% includes 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc. In another example, a reference to a range of 1 to 5,000 times includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5 times, etc., 2.1, 2.2, 2.3, 2.4, 2.5 times, etc.

[0040] As used herein, "about" a number refers to a range that is inclusive of the number, ranging from 10% below to 10% above that number. Ranges preceded by "about" refer to ranges that extend from 10% below the lower limit of the range to 10% above the upper limit of the range.

[0041] "Percent identity (%)" refers to the degree to which two sequences (nucleotides or amino acids) have the same residues at the same positions in the alignment. For example, "an amino acid sequence is X% identical to SEQ ID NO: Y" refers to the % identity of an amino acid sequence to SEQ ID NO: Y, and states that X% of the residues in the amino acid sequence are identical to the residues in the sequence disclosed in SEQ ID NO: Y. Generally, a computer program is used for such calculations. Exemplary programs for comparing and aligning pairs of sequences include ALIGN (Myers and Miller, 1988), FASTA (Pearson and Lipman, 1988; Pearson, 1990), and Gapped BLAST (Altschul et al., 1997), BLASTP, BLASTN, or GCG (Devereux et al., 1984).

[0042] As used herein, the term "selective binding" refers to the higher affinity with which a molecule (e.g., a protein such as the target antigen-binding domain of TAC) binds to its target molecule (e.g., a target antigen such as claudin 18.2) than to other molecules. Unless otherwise indicated, the terms "selective binding" and "specific binding" are used interchangeably herein.

[0043] T cell-antigen coupler (TAC) In certain embodiments, nucleic acids encoding claudin18.2 T cell-antigen coupler (TAC) polypeptides are disclosed herein. In some embodiments, the nucleic acid encoding claudin18.2-TAC comprises (a) a first polynucleotide encoding an antigen-binding domain that binds to claudin18.2; (b) a second polynucleotide encoding an antigen-binding domain that binds to a TCR complex; and (c) a third polynucleotide encoding a transmembrane domain and a cytosolic domain. In some embodiments, the nucleic acid comprises, in order (e.g., 5' to 3'), (a) a first polynucleotide; (b) a second polynucleotide; and (c) a third polynucleotide encoding a cytosolic domain and a transmembrane domain of a TCR co-receptor. In some embodiments, the nucleic acid encoding claudin18.2-TAC does not encode a costimulatory domain. In some embodiments, the nucleic acid encoding claudin18.2-TAC does not encode a co-activation domain.

[0044] In certain embodiments, claudin18.2 T cell-antigen coupler (TAC) polypeptides are further disclosed herein. In some embodiments, the claudin18.2-TAC polypeptide comprises (a) an antigen-binding domain that binds to claudin18.2; (b) an antigen-binding domain that binds to the TCR complex; and (c) a transmembrane domain and a cytosolic domain. In some embodiments, the claudin18.2-TAC polypeptide comprises, in order (e.g., from the N-terminus to the C-terminus), (a) an antigen-binding domain that binds to claudin18.2; (b) an antigen-binding domain that binds to the TCR complex; and (c) a transmembrane domain and a cytosolic domain. In some embodiments, the claudin18.2-TAC polypeptide does not comprise a costimulatory domain. In some embodiments, the claudin18.2-TAC polypeptide does not comprise a co-activation domain.

[0045] Further disclosed herein, in certain embodiments, is an expression vector comprising a nucleic acid encoding a claudin18.2-TAC polypeptide described herein.

[0046] Further disclosed herein, in certain embodiments, are T cells comprising a nucleic acid encoding a claudin18.2-TAC polypeptide described herein, a T cell comprising an expression vector encoding a claudin18.2-TAC polypeptide described herein, or a T cell comprising a claudin18.2-TAC polypeptide described herein.

[0047] Further disclosed herein, in certain embodiments, are methods of treating cancer in an individual in need thereof, the method comprising administering to the individual T cells comprising a claudin18.2 T-cell-antigen coupler (TAC) polypeptide described herein.

[0048] Claudin 18.2 antigen-binding domain In certain embodiments, the claudin 18.2-TAC polypeptide comprises a claudin 18.2 antigen-binding domain. In some embodiments, the claudin 18.2 antigen-binding domain selectively binds to claudin 18.2. In some embodiments, the claudin 18.2 antigen-binding domain binds to claudin 18.2 on a target cell. In some embodiments, the target cell is a cell associated with a disease state, including, but not limited to, cancer. In some embodiments, the target cell is a tumor cell.

[0049] In some embodiments, the claudin 18.2 antigen-binding domain is an antibody or a fragment thereof. In some embodiments, the claudin 18.2 antigen-binding domain is selected from a single-chain antibody (e.g., a single-chain fragment variable antibody (scFv)), a single-domain antibody (e.g., a heavy chain-only antibody (VHH), a shark heavy chain-only antibody (VNAR)), a nanobody, a diabody, a minibody, a Fab fragment, a Fab' fragment, a F(ab')2 fragment, or an Fv fragment that binds to claudin 18.2.

[0050] In some embodiments, the claudin 18.2 antigen-binding domain is selected from an ankyrin repeat protein (DARPin), an affibody, an adnectin, an affilin, a phylomer, a finomar, an affimer, a peptide aptamer, a lectin, a knottin, a centilin, an anticalin, a peptide, a peptidomimetic, a protein, a glycoprotein, or a proteoglycan that binds to claudin 18.2, or a naturally occurring ligand of claudin 18.2. In some embodiments, the claudin 18.2 antigen-binding domain is a non-protein compound (including, but not limited to, a carbohydrate, a lipid, a nucleic acid, or a small molecule) that binds to claudin 18.2.

[0051] In some embodiments, the claudin 18.2 antigen-binding domain is a designed ankyrin repeat (DARPin) targeted to claudin 18.2. In some embodiments, the claudin 18.2 antigen-binding domain is a single-chain variable fragment (ScFv) targeted to claudin 18.2. In some embodiments, the claudin 18.2 antigen-binding domain is a nanobody targeted to claudin 18.2.

[0052] In some embodiments, the claudin18.2 antigen-binding domain is that of the Nanobody referred to herein as Claudin18.2 Nanobody 1 (having the amino acid sequence set forth in SEQ ID NO: 55). In some embodiments, the antigen-binding domain that binds to claudin18.2 comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin18.2 Nanobody 1). In some embodiments, the antigen-binding domain that binds to claudin18.2 comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin18.2 Nanobody 1). In some embodiments, the antigen-binding domain that binds to claudin18.2 comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin18.2 Nanobody 1). In some embodiments, the antigen-binding domain that binds to claudin18.2 comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin18.2 Nanobody 1). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin 18.2 Nanobody 1). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin 18.2 Nanobody 1). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin 18.2 Nanobody 1). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 55 (Claudin 18.2 Nanobody 1). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises the amino acid sequence of SEQ ID NO: 55 (Claudin 18.2 Nanobody 1).In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence comprising a CDR1 comprising SEQ ID NO: 57 (Claudin 18.2 Nanobody 1 Kabat CDR1), a CDR2 comprising SEQ ID NO: 58 (Claudin 18.2 Nanobody 1 Kabat CDR2), and a CDR3 comprising SEQ ID NO: 59 (Claudin 18.2 Nanobody 1 Kabat CDR3). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence comprising a CDR1 comprising SEQ ID NO: 60 (Claudin 18.2 Nanobody 1 IMGT CDR1), a CDR2 comprising SEQ ID NO: 61 (Claudin 18.2 Nanobody 1 IMGT CDR2), and a CDR3 comprising SEQ ID NO: 62 (Claudin 18.2 Nanobody 1 IMGT CDR3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1 (i.e., the antigen-binding domain that binds to claudin 18.2 comprises amino acid sequences comprising CDR1, CDR2, and CDR3, each of which has 100% identity to the corresponding CDRs of claudin 18.2 Nanobody 1). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 1, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 1.

[0053] In some embodiments, the claudin18.2 antigen-binding domain is that of the Nanobody referred to herein as Claudin18.2 Nanobody 2 (having the amino acid sequence set forth in SEQ ID NO: 56). In some embodiments, the antigen-binding domain that binds to claudin18.2 comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 56 (Claudin18.2 Nanobody 2). In some embodiments, the antigen-binding domain that binds to claudin18.2 comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 56 (Claudin18.2 Nanobody 2). In some embodiments, the antigen-binding domain that binds to claudin18.2 comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 56 (Claudin18.2 Nanobody 2). In some embodiments, the antigen-binding domain that binds to claudin18.2 comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 56 (Claudin18.2 Nanobody 2). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 56 (claudin 18.2 nanobody 2). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 56 (claudin 18.2 nanobody 2). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 56 (claudin 18.2 nanobody 2). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 56 (claudin 18.2 nanobody 2). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises the amino acid sequence of SEQ ID NO: 56 (claudin 18.2 nanobody 2).In some embodiments, an antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence comprising a CDR1 comprising SEQ ID NO: 57 (Claudin 18.2 Nanobody 2 Kabat CDR1), a CDR2 comprising SEQ ID NO: 63 (Claudin 18.2 Nanobody 2 Kabat CDR2), and a CDR3 comprising SEQ ID NO: 59 (Claudin 18.2 Nanobody 2 Kabat CDR3). In some embodiments, an antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence comprising a CDR1 comprising SEQ ID NO: 64 (Claudin 18.2 Nanobody 2 IMGT CDR1), a CDR2 comprising SEQ ID NO: 65 (Claudin 18.2 Nanobody 2 IMGT CDR2), and a CDR3 comprising SEQ ID NO: 62 (Claudin 18.2 Nanobody 2 IMGT CDR3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2 (i.e., the antigen-binding domain that binds to claudin 18.2 comprises amino acid sequences comprising CDR1, CDR2, and CDR3, each of which has 100% identity to the corresponding CDRs of claudin 18.2 Nanobody 2). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of claudin 18.2 Nanobody 2, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of claudin 18.2 Nanobody 2.

[0054] In some embodiments, the claudin 18.2 antigen-binding domain is that of an antibody selected from IMAB362 (also known as claudiximab and zolbetuximab; having a heavy chain variable region set forth in SEQ ID NO: 48 and a light chain variable region set forth in SEQ ID NO: 49), 43-14A (available from Creative Biolabs, catalog number HPAB-0120-YJ), EPR19202 (available from Abcam, catalog number ab222512), and aGC182. In some embodiments, the claudin 18.2 antigen-binding domain comprises a humanized antigen-binding domain of an antibody selected from 43-14A and EPR19202.

[0055] In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an antigen-binding domain derived from IMAB362 (claudiximab, zolbetuximab). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 48 (the heavy chain variable region of IMAB362) and an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 49 (the light chain variable region of IMAB362). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 48 (the heavy chain variable region of IMAB362) and an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 49 (the light chain variable region of IMAB362). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 48 (heavy chain variable region of IMAB362) and an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 49 (light chain variable region of IMAB362). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 48 (heavy chain variable region of IMAB362) and an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 49 (light chain variable region of IMAB362). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 48 (heavy chain variable region of IMAB362) and an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 49 (light chain variable region of IMAB362). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 48 (the heavy chain variable region of IMAB362) and an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 49 (the light chain variable region of IMAB362).In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 48 (heavy chain variable region of IMAB362) and an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 49 (light chain variable region of IMAB362). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 48 (heavy chain variable region of IMAB362) and an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 49 (light chain variable region of IMAB362). In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises the amino acid sequence of SEQ ID NO: 48 (heavy chain variable region of IMAB362) and the amino acid sequence of SEQ ID NO: 49 (light chain variable region of IMAB362). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab) (i.e., the antigen-binding domain that binds to claudin 18.2 comprises amino acid sequences including CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of IMAB362 (claudiximab, zolbetuximab)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab).In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity with the CDR sequences of IMAB362 (claudiximab, zolbetuximab), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 85% sequence identity with the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity with the CDR sequences of IMAB362 (claudiximab, zolbetuximab), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 90% sequence identity with the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity with the CDR sequences of IMAB362 (claudiximab, zolbetuximab), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 95% sequence identity with the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity with the CDR sequences of IMAB362 (claudiximab, zolbetuximab), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 96% sequence identity with the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of IMAB362 (claudiximab, zolbetuximab), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab).In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity with the CDR sequences of IMAB362 (claudiximab, zolbetuximab), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 98% sequence identity with the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity with the CDR sequences of IMAB362 (claudiximab, zolbetuximab), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 99% sequence identity with the non-CDR (e.g., framework) sequences of IMAB362 (claudiximab, zolbetuximab).

[0056] In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an antigen-binding domain derived from the mouse anti-claudin 18.2 recombinant antibody clone 43-14A. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of the antigen-binding domain(s) of 43-14A. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of the antigen-binding domain(s) of 43-14A. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of the antigen-binding domain(s) of 43-14A. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of the antigen-binding domain(s) of 43-14A. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of the antigen-binding domain(s) of 43-14A. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of the antigen-binding domain(s) of 43-14A. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of the antigen-binding domain(s) of 43-14A. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of the antigen-binding domain(s) of 43-14A. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises the amino acid sequence of the antigen-binding domain(s) of 43-14A.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 share 100% identity with the CDR sequences of 43-14A (i.e., the antigen-binding domain that binds to claudin 18.2 comprises amino acid sequences including CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which shares 100% identity with the corresponding CDRs of 43-14A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 share 100% identity with the CDR sequences of 43-14A, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 share at least 80% sequence identity with the non-CDR (e.g., framework) sequences of 43-14A. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 share 100% identity with the CDR sequences of 43-14A, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 share at least 85% sequence identity with the non-CDR (e.g., framework) sequences of 43-14A. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 share 100% identity with the CDR sequences of 43-14A, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 share at least 90% sequence identity with the non-CDR (e.g., framework) sequences of 43-14A. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 are 100% identical to the CDR sequences of 43-14A, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 are at least 95% identical to the non-CDR (e.g., framework) sequences of 43-14A. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 are 100% identical to the CDR sequences of 43-14A, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 are at least 96% identical to the non-CDR (e.g., framework) sequences of 43-14A.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 are 100% identical to the CDR sequences of 43-14A, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 are at least 97% identical to the non-CDR (e.g., framework) sequences of 43-14A. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 are 100% identical to the CDR sequences of 43-14A, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 are at least 98% identical to the non-CDR (e.g., framework) sequences of 43-14A. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of 43-14A, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of 43-14A.

[0057] In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an antigen-binding domain derived from a rabbit monoclonal antibody against claudin 18.2 EPR19202. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of the antigen-binding domain(s) of EPR19202. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of the antigen-binding domain(s) of EPR19202. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of the antigen-binding domain(s) of EPR19202. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of the antigen-binding domain(s) of EPR19202. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of the antigen-binding domain(s) of EPR19202. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of the antigen-binding domain(s) of EPR19202. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of the antigen-binding domain(s) of EPR19202. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of the antigen-binding domain(s) of EPR19202. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises the amino acid sequence of the antigen-binding domain(s) of EPR19202.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of EPR19202 (i.e., the antigen-binding domain that binds to claudin 18.2 comprises amino acid sequences including CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of EPR19202). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of EPR19202, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of EPR19202. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of EPR19202, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of EPR19202. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of EPR19202, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of EPR19202. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity with the CDR sequences of EPR19202, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 95% sequence identity with the non-CDR (e.g., framework) sequences of EPR19202.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of EPR19202, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of EPR19202. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of EPR19202, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of EPR19202. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of EPR19202, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of EPR19202. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of EPR19202, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of EPR19202.

[0058] In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an antigen-binding domain derived from the monoclonal mouse anti-claudin 18.2 antibody aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of the antigen-binding domain(s) of aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of the antigen-binding domain(s) of aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of the antigen-binding domain(s) of aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of the antigen-binding domain(s) of aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of the antigen-binding domain(s) of aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of the antigen-binding domain(s) of aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of the antigen-binding domain(s) of aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of the antigen-binding domain(s) of aGC182. In some embodiments, the antigen-binding domain that binds to claudin 18.2 comprises the amino acid sequence of the antigen-binding domain(s) of aGC182.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 share 100% identity with the CDR sequences of aGC182 (i.e., the antigen-binding domain that binds to claudin 18.2 comprises amino acid sequences including CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which shares 100% identity with the corresponding CDRs of aGC182). In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 share 100% identity with the CDR sequences of aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 share at least 80% sequence identity with the non-CDR (e.g., framework) sequences of aGC182. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity with the CDR sequences of aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 85% sequence identity with the non-CDR (e.g., framework) sequences of aGC182. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity with the CDR sequences of aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 90% sequence identity with the non-CDR (e.g., framework) sequences of aGC182. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of aGC182. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of aGC182.In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of aGC182. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity to the CDR sequences of aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of aGC182. In some embodiments, the CDR sequences of the antigen-binding domain that binds to claudin 18.2 have 100% identity with the CDR sequences of aGC182, and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to claudin 18.2 have at least 99% sequence identity with the non-CDR (e.g., framework) sequences of aGC182.

[0059] The amino acid sequences of exemplary antigen-binding domains that bind to claudin 18.2 are provided in Table 1.

[0060] [Table 1]

[0061] TCR complex protein antigen-binding domain In certain embodiments, claudin 18.2-TAC comprises an antigen-binding domain that binds to a protein associated with the TCR complex. A "TCR complex protein antigen-binding domain," also referred to as a "TCR complex antigen-binding domain," an "antigen-binding domain that binds to a TCR complex," or an "antigen-binding domain that binds to a protein associated with the TCR complex," refers to any substance or molecule that directly or indirectly binds to a protein associated with the TCR complex. In some embodiments, an antigen-binding domain that binds to a protein associated with the TCR complex selectively binds to a TCR protein. In some embodiments, an antigen-binding domain that binds to a protein associated with the TCR complex comprises a substance that specifically binds to a TCR protein.

[0062] In some embodiments, the TCR complex protein antigen-binding domain is selected from an antibody or fragment thereof, such as a single-chain antibody (e.g., a single-chain fragment variable antibody (scFv)), a single-domain antibody (e.g., a heavy-chain-only antibody (VHH), a shark heavy-chain-only antibody (VNAR)), a nanobody, a diabody, a minibody, a Fab fragment, a Fab' fragment, a F(ab')2 fragment, or an Fv fragment, that binds to a TCR protein. In some embodiments, the TCR complex protein antigen-binding domain is selected from an ankyrin repeat protein (DARPin), an affibody, an adnectin, an affilin, a filomer, a finomar, an affimer, a peptide aptamer, a lectin, a knottin, a centilin, an anticalin, a peptide, a peptidomimetic, a protein, a glycoprotein, or a proteoglycan, or a naturally occurring ligand for a TCR protein. In some embodiments, the TCR complex protein antigen-binding domain is a non-protein compound that binds to the TCR protein, including but not limited to a carbohydrate, lipid, nucleic acid, or small molecule. In some embodiments, the TCR complex protein antigen-binding domain is a designed ankyrin repeat (DARPin) targeted to the TCR protein. In some embodiments, the TCR complex protein antigen-binding domain is a single-chain variable fragment (ScFv) targeted to the TCR protein. In some embodiments, the TCR complex protein antigen-binding domain is a nanobody targeted to the TCR protein.

[0063] TCR-associated proteins include, but are not limited to, TCR alpha (α) chain, TCR beta (β) chain, TCR gamma (γ) chain, TCR delta (δ) chain, CD3γ chain, CD3δ chain, and CD3ε chain. In some embodiments, the antigen-binding domain that binds to a protein associated with the TCR complex is an antibody against the TCR alpha (α) chain, TCR beta (β) chain, TCR gamma (γ) chain, TCR delta (δ) chain, CD3γ chain, CD3δ chain, and / or CD3ε chain. In some embodiments, the protein associated with the TCR complex is CD3. In some embodiments, the protein associated with the TCR complex is CD3ε. In some embodiments, the antigen-binding domain that binds to CD3 is an antibody, e.g., a single-chain antibody, e.g., a single-chain variable fragment (scFv). Examples of CD3 antibodies include, but are not limited to, UCHT1, OKT3, F6A, L2K, muromonab, otelixizumab, teplizumab, visilizumab, CD3-12, MEM-57, 4D10A6, CD3D, or TR66.

[0064] In some embodiments, the antigen binding domain that binds to the TCR complex is UCHT1, or a variant thereof. In some embodiments, the UCHT1 antigen binding domain is encoded by SEQ ID NO:7. In some embodiments, the UCHT1 antigen binding domain comprises SEQ ID NO:8. In some embodiments, the UCHT1 antigen binding domain is mutated. In some embodiments, the UCHT1 antigen binding domain comprises a Y to T mutation (Y182T) at a position corresponding to amino acid 182 of SEQ ID NO:8. In some embodiments, the UCHT1(Y182T) antigen binding domain is encoded by SEQ ID NO:43. In some embodiments, the UCHT1(Y182T) antigen binding domain comprises SEQ ID NO:44. In some embodiments, the antigen binding domain that binds to the TCR complex is humanized UCHT1 (huUCHT1). In some embodiments, the huUCHT1 antigen binding domain is encoded by SEQ ID NO:33. In some embodiments, the huUCHT1 antigen binding domain comprises SEQ ID NO:34. In some embodiments, the huUCHT1 has a Y to T mutation (Y177T) at a position corresponding to amino acid 177 of SEQ ID NO:34. In some embodiments, the huUCHT1(Y177T) antigen binding domain is encoded by SEQ ID NO: 35. In some embodiments, the huUCHT1 antigen binding domain comprises SEQ ID NO: 36.

[0065] In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 70% sequence identity to the nucleotide sequence of SEQ ID NO:7(UCHT1). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 75% sequence identity to the nucleotide sequence of SEQ ID NO:7(UCHT1). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 80% sequence identity to the nucleotide sequence of SEQ ID NO:7(UCHT1). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 85% sequence identity to the nucleotide sequence of SEQ ID NO:7(UCHT1). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence of SEQ ID NO:7(UCHT1). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 95% sequence identity to the nucleotide sequence of SEQ ID NO:7(UCHT1). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 96% sequence identity to the nucleotide sequence of SEQ ID NO:7 (UCHT1). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 97% sequence identity to the nucleotide sequence of SEQ ID NO:7 (UCHT1). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 98% sequence identity to the nucleotide sequence of SEQ ID NO:7 (UCHT1).In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 99% sequence identity to the nucleotide sequence of SEQ ID NO:7 (UCHT1). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises the nucleotide sequence of SEQ ID NO:7 (UCHT1).

[0066] In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:8 (UCHT1). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 75% sequence identity to the amino acid sequence of SEQ ID NO:8 (UCHT1). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:8 (UCHT1). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO:8 (UCHT1). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:8 (UCHT1). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:8 (UCHT1). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 8 (UCHT1). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 8 (UCHT1). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 8 (UCHT1). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 8 (UCHT1). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises the amino acid sequence of SEQ ID NO: 8 (UCHT1).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1) (i.e., the antigen-binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence that includes CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of the amino acid sequence of SEQ ID NO: 8 (UCHT1)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 8 (UCHT1).

[0067] In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 70% sequence identity to the nucleotide sequence of SEQ ID NO: 43 (UCHT1(Y182T)). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 75% sequence identity to the nucleotide sequence of SEQ ID NO: 43 (UCHT1(Y182T)). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 80% sequence identity to the nucleotide sequence of SEQ ID NO: 43 (UCHT1(Y182T)). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 85% sequence identity to the nucleotide sequence of SEQ ID NO: 43 (UCHT1(Y182T)). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence of SEQ ID NO: 43 (UCHT1(Y182T)). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 95% sequence identity to the nucleotide sequence of SEQ ID NO: 43 (UCHT1(Y182T)). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 96% sequence identity to the nucleotide sequence of SEQ ID NO: 43 (UCHT1(Y182T)). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 97% sequence identity to the nucleotide sequence of SEQ ID NO: 43 (UCHT1(Y182T)).In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 98% sequence identity to the nucleotide sequence of SEQ ID NO: 43 (UCHT1(Y182T)). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 99% sequence identity to the nucleotide sequence of SEQ ID NO: 43 (UCHT1(Y182T)). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises the nucleotide sequence of SEQ ID NO: 43 (UCHT1(Y182T)).

[0068] In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 75% sequence identity to the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)).In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex comprises the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)) (i.e., the antigen-binding domain that binds to a protein associated with a TCR complex comprises amino acid sequences that include CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T))). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 44 (UCHT1(Y182T)).

[0069] In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 70% sequence identity to the nucleotide sequence of SEQ ID NO: 33 (huUCHT1). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 75% sequence identity to the nucleotide sequence of SEQ ID NO: 33 (huUCHT1). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 80% sequence identity to the nucleotide sequence of SEQ ID NO: 33 (huUCHT1). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 85% sequence identity to the nucleotide sequence of SEQ ID NO: 33 (huUCHT1). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence of SEQ ID NO: 33 (huUCHT1). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 95% sequence identity to the nucleotide sequence of SEQ ID NO: 33 (huUCHT1). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 96% sequence identity to the nucleotide sequence of SEQ ID NO: 33 (huUCHT1). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 97% sequence identity to the nucleotide sequence of SEQ ID NO: 33 (huUCHT1).In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 98% sequence identity to the nucleotide sequence of SEQ ID NO: 33 (huUCHT1). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 99% sequence identity to the nucleotide sequence of SEQ ID NO: 33 (huUCHT1). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises the nucleotide sequence of SEQ ID NO: 33 (huUCHT1).

[0070] In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 34 (huUCHT1). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 75% sequence identity to the amino acid sequence of SEQ ID NO: 34 (huUCHT1). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 34 (huUCHT1). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 34 (huUCHT1). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 34 (huUCHT1). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 34 (huUCHT1). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 34 (huUCHT1). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 34 (huUCHT1). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 34 (huUCHT1). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 34 (huUCHT1).In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex comprises the amino acid sequence of SEQ ID NO: 34 (huUCHT1). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 34 (huUCHT1) (i.e., the antigen-binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of the amino acid sequence of SEQ ID NO: 34 (huUCHT1)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 34 (huUCHT1), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 34 (huUCHT1). In some embodiments, the CDR sequences of the antigen binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 34 (huUCHT1), and the non-CDR (e.g., framework) sequences of the antigen binding domain that binds to a protein associated with a TCR complex have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 34 (huUCHT1). In some embodiments, the CDR sequences of the antigen binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 34 (huUCHT1), and the non-CDR (e.g., framework) sequences of the antigen binding domain that binds to a protein associated with a TCR complex have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 34 (huUCHT1).In some embodiments, the CDR sequences of the antigen binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 34 (huUCHT1), and the non-CDR (e.g., framework) sequences of the antigen binding domain that binds to a protein associated with a TCR complex have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 34 (huUCHT1). In some embodiments, the CDR sequences of the antigen binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 34 (huUCHT1), and the non-CDR (e.g., framework) sequences of the antigen binding domain that binds to a protein associated with a TCR complex have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 34 (huUCHT1). In some embodiments, the CDR sequences of the antigen binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 34 (huUCHT1), and the non-CDR (e.g., framework) sequences of the antigen binding domain that binds to a protein associated with a TCR complex have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 34 (huUCHT1). In some embodiments, the CDR sequences of the antigen binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 34 (huUCHT1), and the non-CDR (e.g., framework) sequences of the antigen binding domain that binds to a protein associated with a TCR complex have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 34 (huUCHT1).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 34 (huUCHT1), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 34 (huUCHT1).

[0071] In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 70% sequence identity to the nucleotide sequence of SEQ ID NO: 35 (huUCHT1(Y177T)). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 75% sequence identity to the nucleotide sequence of SEQ ID NO: 35 (huUCHT1(Y177T)). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 80% sequence identity to the nucleotide sequence of SEQ ID NO: 35 (huUCHT1(Y177T)). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 85% sequence identity to the nucleotide sequence of SEQ ID NO: 35 (huUCHT1(Y177T)). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence of SEQ ID NO: 35 (huUCHT1(Y177T)). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 95% sequence identity to the nucleotide sequence of SEQ ID NO: 35 (huUCHT1(Y177T)). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 96% sequence identity to the nucleotide sequence of SEQ ID NO: 35 (huUCHT1(Y177T)). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 97% sequence identity to the nucleotide sequence of SEQ ID NO: 35 (huUCHT1(Y177T)).In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 98% sequence identity to the nucleotide sequence of SEQ ID NO: 35 (huUCHT1(Y177T)). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 99% sequence identity to the nucleotide sequence of SEQ ID NO: 35 (huUCHT1(Y177T)). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises the nucleotide sequence of SEQ ID NO: 35 (huUCHT1(Y177T)).

[0072] In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 75% sequence identity to the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)).In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the CDR sequences of the antigen binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)) (i.e., the antigen binding domain that binds to a protein associated with a TCR complex comprises amino acid sequences comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T))). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 36 (huUCHT1(Y177T)).

[0073] In some embodiments, the antigen-binding domain that binds to a protein associated with the TCR complex is OKT3. In some embodiments, the murine OKT3 antigen-binding domain is encoded by SEQ ID NO: 15. In some embodiments, the OKT3 antigen-binding domain comprises SEQ ID NO: 16.

[0074] In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 70% sequence identity to the nucleotide sequence of SEQ ID NO: 15 (OKT3). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 75% sequence identity to the nucleotide sequence of SEQ ID NO: 15 (OKT3). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 80% sequence identity to the nucleotide sequence of SEQ ID NO: 15 (OKT3). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 85% sequence identity to the nucleotide sequence of SEQ ID NO: 15 (OKT3). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence of SEQ ID NO: 15 (OKT3). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 95% sequence identity to the nucleotide sequence of SEQ ID NO: 15 (OKT3). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 96% sequence identity to the nucleotide sequence of SEQ ID NO: 15 (OKT3). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 97% sequence identity to the nucleotide sequence of SEQ ID NO: 15 (OKT3). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 98% sequence identity to the nucleotide sequence of SEQ ID NO: 15 (OKT3).In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 99% sequence identity to the nucleotide sequence of SEQ ID NO: 15 (OKT3). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises the nucleotide sequence of SEQ ID NO: 15 (OKT3).

[0075] In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 75% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises the amino acid sequence of SEQ ID NO: 16 (OKT3).In some embodiments, the CDR sequences of the antigen binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3) (i.e., the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen binding domain that binds to a protein associated with a TCR complex have at least 80% identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 90% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 16 (OKT3).

[0076] In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex is F6A. In some embodiments, the murine F6A antigen-binding domain is encoded by SEQ ID NO: 17. In some embodiments, the F6A antigen-binding domain comprises SEQ ID NO: 18.

[0077] In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 70% sequence identity to the nucleotide sequence of SEQ ID NO: 17(F6A). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 75% sequence identity to the nucleotide sequence of SEQ ID NO: 17(F6A). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 80% sequence identity to the nucleotide sequence of SEQ ID NO: 17(F6A). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 85% sequence identity to the nucleotide sequence of SEQ ID NO: 17(F6A). In some embodiments, the polynucleotide encoding an antigen binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence of SEQ ID NO: 17(F6A). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 95% sequence identity to the nucleotide sequence of SEQ ID NO: 17(F6A). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 96% sequence identity to the nucleotide sequence of SEQ ID NO: 17(F6A). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 97% sequence identity to the nucleotide sequence of SEQ ID NO: 17(F6A). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 98% sequence identity to the nucleotide sequence of SEQ ID NO: 17(F6A).In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 99% sequence identity to the nucleotide sequence of SEQ ID NO: 17(F6A). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises the nucleotide sequence of SEQ ID NO: 17(F6A).

[0078] In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 75% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises the amino acid sequence of SEQ ID NO: 18 (F6A).In some embodiments, the CDR sequences of the antigen binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A) (i.e., the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of the amino acid sequence of SEQ ID NO: 18 (F6A). The CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 85% sequence identity to the CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 18 (F6A), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 18 (F6A).

[0079] In some embodiments, the antigen-binding domain that binds to a protein associated with a TCR complex is L2K. In some embodiments, the murine L2K antigen-binding domain is encoded by SEQ ID NO: 19. In some embodiments, the L2K antigen-binding domain comprises SEQ ID NO: 20.

[0080] In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 70% sequence identity to the nucleotide sequence of SEQ ID NO: 19 (L2K). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 75% sequence identity to the nucleotide sequence of SEQ ID NO: 19 (L2K). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 80% sequence identity to the nucleotide sequence of SEQ ID NO: 19 (L2K). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 85% sequence identity to the nucleotide sequence of SEQ ID NO: 19 (L2K). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence of SEQ ID NO: 19 (L2K). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 95% sequence identity to the nucleotide sequence of SEQ ID NO: 19 (L2K). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 96% sequence identity to the nucleotide sequence of SEQ ID NO: 19 (L2K). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 97% sequence identity to the nucleotide sequence of SEQ ID NO: 19 (L2K). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 98% sequence identity to the nucleotide sequence of SEQ ID NO: 19 (L2K).In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises a nucleotide sequence having at least 99% sequence identity to the nucleotide sequence of SEQ ID NO: 19(L2K). In some embodiments, the polynucleotide encoding an antigen-binding domain that binds to a protein associated with a TCR complex comprises the nucleotide sequence of SEQ ID NO: 19(L2K).

[0081] In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:20 (L2K). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 75% sequence identity to the amino acid sequence of SEQ ID NO:20 (L2K). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:20 (L2K). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO:20 (L2K). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:20 (L2K). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:20 (L2K). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO:20 (L2K). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO:20 (L2K). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO:20 (L2K). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO:20 (L2K). In some embodiments, an antigen binding domain that binds to a protein associated with a TCR complex comprises the amino acid sequence of SEQ ID NO:20 (L2K).In some embodiments, the CDR sequences of the antigen binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K) (i.e., the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the antigen binding domain that binds to a protein associated with a TCR complex comprises an amino acid sequence comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, each of which has 100% identity to the corresponding CDRs of the amino acid sequence of SEQ ID NO: 20 (L2K). The CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 80% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 85% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 85% sequence identity to the CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 95% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K).In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 96% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 97% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 98% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K). In some embodiments, the CDR sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have 100% identity to the CDR sequences of the amino acid sequence of SEQ ID NO: 20 (L2K), and the non-CDR (e.g., framework) sequences of the antigen-binding domain that binds to a protein associated with a TCR complex have at least 99% sequence identity to the non-CDR (e.g., framework) sequences of the amino acid sequence of SEQ ID NO: 20 (L2K).

[0082] The amino acid and nucleotide sequences of exemplary antigen-binding domains that bind to proteins associated with the TCR complex are provided in Table 2.

[0083] [Table 2]

[0084] Transmembrane and cytosolic domains In some embodiments, the claudin 18.2 T cell antigen coupler polypeptide comprises a T cell receptor signaling domain polypeptide. In some embodiments, the claudin 18.2 T cell antigen coupler polypeptide comprises a transmembrane domain of a TCR signaling domain. In some embodiments, the claudin 18.2 T cell antigen coupler polypeptide comprises a cytosolic domain of a TCR signaling domain polypeptide. In some embodiments, the claudin 18.2 T cell antigen coupler polypeptide comprises a transmembrane domain and a cytosolic domain of a TCR signaling domain polypeptide.

[0085] In some embodiments, the T cell receptor signaling domain polypeptide comprises a TCR co-receptor domain. In some embodiments, the TCR signaling domain polypeptide comprises a transmembrane domain and / or a cytosolic domain of a TCR co-receptor polypeptide. In some embodiments, the TCR co-receptor is CD4, CD8, LAG3, or a chimeric variation thereof.

[0086] In some embodiments, the TCR co-receptor is CD4. In some embodiments, claudin 18.2-TAC comprises the transmembrane and cytosolic domains of the CD4 co-receptor. In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 70% sequence identity to the nucleotide sequence of SEQ ID NO: 11 (CD4 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 75% sequence identity to the nucleotide sequence of SEQ ID NO: 11 (CD4 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 80% sequence identity to the nucleotide sequence of SEQ ID NO: 11 (CD4 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 85% sequence identity to the nucleotide sequence of SEQ ID NO: 11 (CD4 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence of SEQ ID NO:11 (CD4 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 95% sequence identity to the nucleotide sequence of SEQ ID NO:11 (CD4 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 96% sequence identity to the nucleotide sequence of SEQ ID NO:11 (CD4 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 97% sequence identity to the nucleotide sequence of SEQ ID NO:11 (CD4 transmembrane and cytosolic domains).In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 98% sequence identity to the nucleotide sequence of SEQ ID NO:11 (CD4 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 99% sequence identity to the nucleotide sequence of SEQ ID NO:11 (CD4 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises the nucleotide sequence of SEQ ID NO:11 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 75% sequence identity to the amino acid sequence of SEQ ID NO:12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains).In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise the amino acid sequence of SEQ ID NO: 12 (CD4 transmembrane and cytosolic domains).

[0087] In some embodiments, the TCR co-receptor is CD8. In some embodiments, the TCR co-receptor is CD8α. In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 70% sequence identity to the nucleotide sequence of SEQ ID NO:27 (CD8 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 75% sequence identity to the nucleotide sequence of SEQ ID NO:27 (CD8 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 80% sequence identity to the nucleotide sequence of SEQ ID NO:27 (CD8 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 85% sequence identity to the nucleotide sequence of SEQ ID NO:27 (CD8 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence of SEQ ID NO:27 (CD8 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 95% sequence identity to the nucleotide sequence of SEQ ID NO:27 (CD8 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 96% sequence identity to the nucleotide sequence of SEQ ID NO:27 (CD8 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 97% sequence identity to the nucleotide sequence of SEQ ID NO:27 (CD8 transmembrane and cytosolic domains).In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 98% sequence identity to the nucleotide sequence of SEQ ID NO:27 (CD8 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 99% sequence identity to the nucleotide sequence of SEQ ID NO:27 (CD8 transmembrane and cytosolic domains). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises the nucleotide sequence of SEQ ID NO:27 (CD8 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:28 (CD8 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 75% sequence identity to the amino acid sequence of SEQ ID NO:28 (CD8 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:28 (CD8 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO:28 (CD8 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:28 (CD8 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:28 (CD8 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO:28 (CD8 transmembrane and cytosolic domains).In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO:28 (CD8 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO:28 (CD8 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO:28 (CD8 transmembrane and cytosolic domains). In some embodiments, the cytosolic and transmembrane domains comprise the amino acid sequence of SEQ ID NO:28 (CD8 transmembrane and cytosolic domains).

[0088] In some embodiments, the TCR signaling domain polypeptide comprises a chimera of sequences or domains from co-receptors. In some embodiments, the TCR signaling domain polypeptide comprises a chimera of CD8α and CD8β, in which the CD8α arginine-rich region is replaced with the CD8β arginine-rich region (CD8α+R(β) chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domain comprises a nucleotide sequence having at least 70% sequence identity to the nucleotide sequence of SEQ ID NO:29 (CD8α+R(β) chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domain comprises a nucleotide sequence having at least 75% sequence identity to the nucleotide sequence of SEQ ID NO:29 (CD8α+R(β) chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domain comprises a nucleotide sequence having at least 80% sequence identity to the nucleotide sequence of SEQ ID NO:29 (CD8α+R(β) chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 85% sequence identity to the nucleotide sequence of SEQ ID NO:29 (CD8α+R(β) chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence of SEQ ID NO:29 (CD8α+R(β) chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 95% sequence identity to the nucleotide sequence of SEQ ID NO:29 (CD8α+R(β) chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 96% sequence identity to the nucleotide sequence of SEQ ID NO:29 (CD8α+R(β) chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 97% sequence identity to the nucleotide sequence of SEQ ID NO:29 (CD8α+R(β) chimera).In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 98% sequence identity to the nucleotide sequence of SEQ ID NO:29 (CD8α+R(β) chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 99% sequence identity to the nucleotide sequence of SEQ ID NO:29 (CD8α+R(β) chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises the nucleotide sequence of SEQ ID NO:29 (CD8α+R(β) chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:30 (CD8α+R(β) chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 75% sequence identity to the amino acid sequence of SEQ ID NO:30 (CD8α+R(β) chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 30 (CD8α+R(β) chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 30 (CD8α+R(β) chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 30 (CD8α+R(β) chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 30 (CD8α+R(β) chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 30 (CD8α+R(β) chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 30 (CD8α+R(β) chimera).In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 30 (CD8α+R(β) chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 30 (CD8α+R(β) chimera). In some embodiments, the cytosolic and transmembrane domains comprise the amino acid sequence of SEQ ID NO: 30 (CD8α+R(β) chimera).

[0089] In some embodiments, the TCR signaling domain polypeptide comprises a chimera of CD8α and CD8β, wherein a CD8α CXCP domain containing an Lck-binding motif is appended to the C-terminus of the CD8β cytosolic domain (CD8β+Lck chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domain comprises a nucleotide sequence having at least 70% sequence identity to the nucleotide sequence of SEQ ID NO: 31 (CD8β+Lck chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domain comprises a nucleotide sequence having at least 75% sequence identity to the nucleotide sequence of SEQ ID NO: 31 (CD8β+Lck chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domain comprises a nucleotide sequence having at least 80% sequence identity to the nucleotide sequence of SEQ ID NO: 31 (CD8β+Lck chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domain comprises a nucleotide sequence having at least 85% sequence identity to the nucleotide sequence of SEQ ID NO: 31 (CD8β+Lck chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence of SEQ ID NO: 31 (CD8β+Lck chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 95% sequence identity to the nucleotide sequence of SEQ ID NO: 31 (CD8β+Lck chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 96% sequence identity to the nucleotide sequence of SEQ ID NO: 31 (CD8β+Lck chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 97% sequence identity to the nucleotide sequence of SEQ ID NO: 31 (CD8β+Lck chimera).In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 98% sequence identity to the nucleotide sequence of SEQ ID NO: 31 (CD8β+Lck chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises a nucleotide sequence having at least 99% sequence identity to the nucleotide sequence of SEQ ID NO: 31 (CD8β+Lck chimera). In some embodiments, the polynucleotide encoding the cytosolic and transmembrane domains comprises the nucleotide sequence of SEQ ID NO: 31 (CD8β+Lck chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 32 (CD8β+Lck chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 75% sequence identity to the amino acid sequence of SEQ ID NO: 32 (CD8β+Lck chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 32 (CD8β+Lck chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 32 (CD8β+Lck chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 32 (CD8β+Lck chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 32 (CD8β+Lck chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 32 (CD8β+Lck chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 32 (CD8β+Lck chimera).In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 32 (CD8β+Lck chimera). In some embodiments, the cytosolic and transmembrane domains comprise an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 32 (CD8β+Lck chimera). In some embodiments, the cytosolic and transmembrane domains comprise the amino acid sequence of SEQ ID NO: 32 (CD8β+Lck chimera).

[0090] In some embodiments, the TCR signaling domain polypeptide comprises both the cytosolic and transmembrane domains of a TCR coreceptor protein, in some embodiments, the cytosolic and transmembrane domains are from the same coreceptor or from different coreceptors.

[0091] The amino acid and nucleotide sequences of exemplary transmembrane and cytosolic domains are provided in Table 3.

[0092] [Table 3]

[0093] Configuration, Linkers, and Connectors In some embodiments, the nucleic acids disclosed herein are arranged in the following order from 5' to 3': (1) a first polynucleotide encoding an antigen-binding domain that binds to claudin 18.2; (2) a second polynucleotide encoding an antigen-binding domain that binds to the TCR complex; and (3) a third polynucleotide encoding a transmembrane domain and a cytosolic domain. In some embodiments, the nucleic acids disclosed herein are arranged in the following order from 5' to 3': (1) a first polynucleotide encoding an antigen-binding domain that binds to claudin 18.2; (2) a second polynucleotide encoding an antigen-binding domain that binds to the TCR complex; and (3) a third polynucleotide encoding a transmembrane domain and a cytosolic domain. In some embodiments, the nucleic acids disclosed herein are arranged in the following order from 3' to 5': (1) a first polynucleotide encoding an antigen-binding domain that binds to claudin 18.2; (2) a second polynucleotide encoding an antigen-binding domain that binds to the TCR complex; and (3) a third polynucleotide encoding a transmembrane domain and a cytosolic domain. In some embodiments, the nucleic acids described herein are arranged in the following order from 5' to 3': (1) a first polynucleotide encoding an antigen-binding domain that binds to the TCR complex; (2) a second polynucleotide encoding an antigen-binding domain that binds to claudin 18.2; and (3) a third polynucleotide encoding a transmembrane domain and a cytosolic domain. In some embodiments, the nucleic acids described herein are arranged in the following order from 5' to 3': (1) a first polynucleotide encoding an antigen-binding domain that binds to the TCR complex; (2) a second polynucleotide encoding an antigen-binding domain that binds to claudin 18.2; and (3) a third polynucleotide encoding a transmembrane domain and a cytosolic domain. In some embodiments, the nucleic acids described herein are arranged in the following order from 3' to 5': (1) a first polynucleotide encoding an antigen-binding domain that binds to the TCR complex; (2) a second polynucleotide encoding an antigen-binding domain that binds to claudin 18.2; and (3) a third polynucleotide encoding a transmembrane domain and a cytosolic domain.

[0094] In some embodiments, the claudin18.2-TAC polypeptide disclosed herein has (1) an antigen-binding domain that binds to claudin18.2; (2) an antigen-binding domain that binds to the TCR complex; and (3) a transmembrane domain and a cytosolic domain, in the order of N-terminus to C-terminus. In some embodiments, the claudin18.2-TAC polypeptide disclosed herein has (1) an antigen-binding domain that binds to claudin18.2; (2) an antigen-binding domain that binds to the TCR complex; and (3) a transmembrane domain and a cytosolic domain, in the order of C-terminus to N-terminus. In some embodiments, the claudin18.2-TAC polypeptide described herein has (1) an antigen-binding domain that binds to the TCR complex; (2) an antigen-binding domain that binds to claudin18.2; and (3) a transmembrane domain and a cytosolic domain, in the order of N-terminus to C-terminus. In some embodiments, the claudin18.2-TAC polypeptide described herein has the following order from C-terminus to N-terminus: (1) an antigen-binding domain that binds to the TCR complex; (2) an antigen-binding domain that binds to claudin18.2; and (3) a transmembrane domain and a cytosolic domain.

[0095] In some embodiments, the antigen-binding domain that binds to claudin 18.2, the antigen-binding domain that binds to the TCR complex, and / or the transmembrane and cytosolic domains are directly fused. For example, the antigen-binding domain that binds to claudin 18.2 and the transmembrane and cytosolic domains are both fused to the antigen-binding domain that binds to the TCR complex. In some embodiments, the antigen-binding domain that binds to claudin 18.2, the antigen-binding domain that binds to the TCR complex, and / or the transmembrane and cytosolic domains are joined by at least one linker. In some embodiments, the antigen-binding domain that binds to claudin 18.2 and the antigen-binding domain that binds to the TCR complex are directly fused and joined to the transmembrane and cytosolic domains by a linker. In some embodiments, the antigen-binding domain that binds to the TCR complex and the transmembrane and cytosolic domains are directly fused and joined to the antigen-binding domain that binds to claudin 18.2 by a linker.

[0096] In some embodiments, the linker is a peptide linker. In some embodiments, the peptide linker comprises 1 to 40 amino acids. In some embodiments, the peptide linker comprises 1 to 30 amino acids. In some embodiments, the peptide linker comprises 1 to 15 amino acids. In some embodiments, the peptide linker comprises 1 to 10 amino acids. In some embodiments, the peptide linker comprises 1 to 6 amino acids. In some embodiments, the peptide linker comprises 30 to 40 amino acids. In some embodiments, the peptide linker comprises 32 to 36 amino acids. In some embodiments, the peptide linker comprises 5 to 30 amino acids. In some embodiments, the peptide linker comprises 5 amino acids. In some embodiments, the peptide linker comprises 10 amino acids. In some embodiments, the peptide linker comprises 15 amino acids. In some embodiments, the peptide linker comprises 20 amino acids. In some embodiments, the peptide linker comprises 25 amino acids. In some embodiments, the peptide linker comprises 30 amino acids. In some embodiments, the peptide linker comprises a glycine and / or serine rich linker.

[0097] In some embodiments, at least one linker comprises an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 85% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker).In some embodiments, at least one linker comprises an amino acid sequence having at least 96% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 97% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 98% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker). In some embodiments, at least one linker comprises an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker).In some embodiments, at least one linker comprises the amino acid sequence of SEQ ID NO: 6 ((G4S)4-based linker), SEQ ID NO: 10 (G4S-based linker), SEQ ID NO: 14 (CD4-based linker), SEQ ID NO: 22 (short helix connector), SEQ ID NO: 24 (long helix connector), SEQ ID NO: 26 (large domain connector), SEQ ID NO: 41 (flexible connector), SEQ ID NO: 45 (G4S flexible linker), or SEQ ID NO: 46 (G4S3 flexible linker).

[0098] In some embodiments, the peptide linker joining the antigen-binding domain that binds to claudin 18.2 to the antigen-binding domain that binds to the TCR complex (e.g., UCHT1) is known as a connector to distinguish this protein domain from other linkers within the TAC. The connector can be of any size. In some embodiments, the connector between the antigen-binding domain that binds to the TCR complex and the antigen-binding domain that binds to claudin 18.2 is a short helix comprising SEQ ID NO: 22. In some embodiments, the connector between the antigen-binding domain that binds to the TCR complex and the antigen-binding domain that binds to claudin 18.2 is a short helix encoded by SEQ ID NO: 21. In some embodiments, the connector between the antigen-binding domain that binds to the TCR complex and the antigen-binding domain that binds to claudin 18.2 is a long helix comprising SEQ ID NO: 24. In some embodiments, the connector between the antigen-binding domain that binds to the TCR complex and the antigen-binding domain that binds to claudin 18.2 is a long helix encoded by SEQ ID NO: 23. In some embodiments, the connector between the antigen-binding domain that binds to the TCR complex and the antigen-binding domain that binds to claudin 18.2 is a large domain comprising SEQ ID NO: 26. In some embodiments, the connector between the antigen binding domain that binds to the TCR complex and the antigen binding domain that binds to claudin 18.2 is the large domain encoded by SEQ ID NO:25.

[0099] In some embodiments, a nucleic acid or TAC disclosed herein comprises a leader sequence. In some embodiments, the leader sequence is encoded by a nucleotide sequence having at least 80% sequence identity to the nucleotide sequence of SEQ ID NO:1 (muIgG leader), SEQ ID NO:37 (huIgG leader), or SEQ ID NO:39 (huCD8a leader). In some embodiments, the leader sequence is encoded by a nucleotide sequence having at least 85% sequence identity to the nucleotide sequence of SEQ ID NO:1 (muIgG leader), SEQ ID NO:37 (huIgG leader), or SEQ ID NO:39 (huCD8a leader). In some embodiments, the leader sequence is encoded by a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence of SEQ ID NO:1 (muIgG leader), SEQ ID NO:37 (huIgG leader), or SEQ ID NO:39 (huCD8a leader). In some embodiments, the leader sequence is encoded by a nucleotide sequence having at least 95% sequence identity to the nucleotide sequence of SEQ ID NO:1 (muIgG leader), SEQ ID NO:37 (huIgG leader), or SEQ ID NO:39 (huCD8a leader). In some embodiments, the leader sequence is encoded by a nucleotide sequence having at least 96% sequence identity to the nucleotide sequence of SEQ ID NO:1 (muIgG leader), SEQ ID NO:37 (huIgG leader), or SEQ ID NO:39 (huCD8a leader). In some embodiments, the leader sequence is encoded by a nucleotide sequence having at least 97% sequence identity to the nucleotide sequence of SEQ ID NO:1 (muIgG leader), SEQ ID NO:37 (huIgG leader), or SEQ ID NO:39 (huCD8a leader). In some embodiments, the leader sequence is encoded by a nucleotide sequence having at least 98% sequence identity to the nucleotide sequence of SEQ ID NO:1 (muIgG leader), SEQ ID NO:37 (huIgG leader), or SEQ ID NO:39 (huCD8a leader).In some embodiments, the leader sequence is encoded by a nucleotide sequence having at least 99% sequence identity to the nucleotide sequence of SEQ ID NO: 1 (muIgG leader), SEQ ID NO: 37 (huIgG leader), or SEQ ID NO: 39 (huCD8a leader). In some embodiments, the leader sequence comprises the nucleotide sequence of SEQ ID NO: 1 (muIgG leader), SEQ ID NO: 37 (huIgG leader), or SEQ ID NO: 39 (huCD8a leader).

[0100] In some embodiments, a nucleic acid or TAC disclosed herein comprises a leader sequence. In some embodiments, the leader sequence comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader). In some embodiments, the leader sequence comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO:2 (muIgG leader), SEQ ID NO:38 (huIgG leader), or SEQ ID NO:40 (huCD8a leader).In some embodiments, the leader sequence comprises the amino acid sequence of SEQ ID NO: 2 (muIgG leader), SEQ ID NO: 38 (huIgG leader), or SEQ ID NO: 40 (huCD8a leader).

[0101] The amino acid and nucleotide sequences of exemplary linker, connector, and leader sequences are provided in Table 4.

[0102] [Table 4]

[0103] Specific TAC Disclosed herein is a claudin 18.2-TAC polypeptide comprising (a) an antigen-binding domain that binds to claudin 18.2, (b) a single-chain antibody (scFv) that binds to CD3ε, and (c) the transmembrane and cytosolic domains of the CD4 co-receptor. In some embodiments, the claudin 18.2-TAC polypeptide comprises (a) an antigen-binding domain that binds to claudin 18.2, (b) UCHT1, and (c) the transmembrane and cytosolic domains of the CD4 co-receptor. In some embodiments, the claudin 18.2-TAC polypeptide comprises (a) an antigen-binding domain that binds to claudin 18.2, (b) UCHT1(Y182T), and (c) the transmembrane and cytosolic domains of the CD4 co-receptor. In some embodiments, the claudin 18.2-TAC polypeptide comprises (a) an antigen-binding domain that binds to claudin 18.2, (b) huUCHT1, and (c) the transmembrane and cytosolic domains of the CD4 co-receptor. In some embodiments, the claudin 18.2-TAC polypeptide comprises (a) an antigen-binding domain that binds to claudin 18.2, (b) huUCHT1(Y177T), and (c) the transmembrane and cytosolic domains of the CD4 coreceptor. In some embodiments, the claudin 18.2-TAC polypeptide comprises...

Claims

**Claim 1** A Claudin 18.2 T cell-antigen coupler (TAC) polypeptide comprising: (a) a Claudin 18.2 antigen-binding domain, (b) a CD3 antigen-binding domain, and (c) a TCR coreceptor domain polypeptide comprising a CD4 cytosolic domain and a CD4 transmembrane domain, wherein components (a), (b), and (c) are either directly fused to each other or joined by at least one linker. **Claim 2** The Claudin 18.2-TAC polypeptide according to claim 1, wherein the Claudin 18.2 antigen-binding domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 57 (Claudin 18.2 nanobody 2 Kabat CDR1), a CDR2 comprising the amino acid sequence of SEQ ID NO: 63 (Claudin 18.2 nanobody 2 Kabat CDR2), and a CDR3 comprising the amino acid sequence of SEQ ID NO: 59 (Claudin 18.2 nanobody 2 Kabat CDR3). **Claim 3** The Claudin 18.2-TAC polypeptide according to claim 1, wherein: (a) the Claudin 18.2 antigen-binding domain comprises a CDR1 having the amino acid sequence of SEQ ID NO: 57, a CDR2 having the amino acid sequence of SEQ ID NO: 63, and a CDR3 having the amino acid sequence of SEQ ID NO: 59; (b) the CD3 antigen-binding domain comprises an amino acid sequence having at least 100% sequence identity to SEQ ID NO: 36; and (c) the TCR coreceptor domain polypeptide comprises an amino acid sequence having at least 100% sequence identity to SEQ ID NO:

12. **Claim 4** The Claudin 18.2-TAC polypeptide according to claim 1, wherein the Claudin 18.2 antigen-binding domain comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO:

56. **Claim 5** The Claudin 18.2-TAC polypeptide according to claim 1, wherein the Claudin 18.2 antigen-binding domain comprises the amino acid sequence of SEQ ID NO:

56. ​ ​ **Claim 6**: The Claudin 18.2-TAC polypeptide according to any one of claims 1 to 5, wherein component (a) and component (c) are fused to component (b), or component (b) and component (c) are fused to component (a). **Claim 7**: The Claudin 18.2-TAC polypeptide according to any one of claims 1 to 5, wherein the Claudin 18.2-TAC polypeptide does not contain a co-stimulatory domain or an activation domain. **Claim 8**: The Claudin 18.2-TAC polypeptide according to any one of claims 1 to 5, comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

73. **Claim 9**: The Claudin 18.2-TAC polypeptide according to any one of claims 1 to 5, comprising an amino acid sequence having the amino acid sequence of SEQ ID NO:

73. **Claim 10**: A nucleic acid encoding the Claudin 18.2-TAC polypeptide according to any one of claims 1 to 5. **Claim 11**: The nucleic acid according to claim 10, comprising a sequence having at least 80% sequence identity with the nucleic acid sequence of SEQ ID NO:

72. **Claim 12**: An expression vector comprising the nucleic acid according to claim 11. **Claim 13**: An engineered T cell comprising the expression vector according to claim 12, wherein the Claudin 18.2-TAC polypeptide is expressed by the engineered T cell. **Claim 14**: The T cell according to claim 13, which is a γδ T cell. **Claim 15**: A pharmaceutical composition comprising the T cell according to claim 13 and a pharmaceutically acceptable excipient. **Claim 16**: A pharmaceutical composition comprising the T cell according to claim 14 and a pharmaceutically acceptable excipient. **Claim 17**: Use of the pharmaceutical composition according to claim 15 in the manufacture of a medicament for treating cancer that expresses Claudin 18.2 in an individual in need of treatment for cancer that expresses Claudin 18.

2. **Claim 18**: The use according to claim 17, wherein the cancer is a solid cancer. **Claim 19**: The use according to claim 17, wherein the cancer is pancreatic cancer, gastric cancer, signet ring cell carcinoma, mucinous gastric cancer, gastroesophageal cancer, esophageal cancer, digestive system cancer, ovarian cancer, mucinous ovarian cancer, non-small cell lung cancer, or lung cancer. The use according to claim 18, wherein the cancer is pancreatic cancer, gastric cancer, signet ring cell carcinoma, mucinous gastric cancer, gastroesophageal cancer, esophageal cancer, digestive system cancer, ovarian cancer, mucinous ovarian cancer, non-small cell lung cancer, or lung cancer. The pharmaceutical composition according to claim 15, for use as a medicament.

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