Multifunctional molecules binding to TCR and uses thereof

Abstract

Provides herein are molecules or multifunctional molecules comprising an antigen binding domain that binds to a T cell receptor beta variable region (TCRβV) and a cytokine molecule, and methods of treating conditions or diseases in a subject using the same.

Description

WSGR Docket No.53676-777.601 MULTIFUNCTIONAL MOLECULES BINDING TO TCR AND USES THEREOF CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application 63 / 650,132, filed May21, 2024, which is incorporated herein by reference in its entirety. BACKGROUND

[0002] Currently available molecules designed to redirect T cells to promote tumor cell lysis for cancerimmunotherapy typically target the CD3 epsilon (CD3e) subunit of the T cell receptor (TCR). However, there are limitations to this approach. Previous studies have shown that, e.g., low doses of anti-CD3e monoclonal antibody (mAb) can cause T cell dysfunction and exert immunosuppressive effects. Thus, there is a need for improved T cell receptor-binding molecules that redirect T cells for cancer immunotherapy. Such improved T cell receptor-binding molecules can be used to enhance the therapeutic effects of existing anti-cancer therapies. SUMMARY

[0003] Provided herein, in some embodiment is, inter alia¸ a method of treating a disease or a conditionin a subject in need thereof comprising: (a) administering a therapeutically effective amount of a first agent comprising (i) a first domain that binds to a TCR β variable (TCRβV) region and (ii) a molecule that binds to a co-stimulatory receptor of a T cell; and (b) administering a therapeutically effective amount of a second agent comprising an antibody-drug conjugate.

[0004] Also provided herein, in some embodiment, is a combination therapy for treating a disease or acondition in a subject in need thereof, comprising: (a) a first agent comprising (i) a first domain that binds to a TCR β variable (TCRβV) region and (ii) a molecule that binds to a co-stimulatory receptor of a T cell; and (b)a second agent comprising an antibody-drug conjugate. Also provided herein, in some embodiment, is a composition for treating a disease or condition in a subject in need thereof comprising: (a) a first agent comprising (i) a first domain that binds to a TCR β variable (TCRβV) region and (ii) a molecule that binds to a co-stimulatory receptor of a T cell; and (b) a second agent comprising an antibody-drug conjugate. Also provided herein, in some embodiment, is a kit for treating a disease or condition in a subject in need thereof comprising: (a) a first agent comprising (i) a first domain that binds to a TCR β variable (TCRβV) region and (ii) a molecule that binds to a co-stimulatory receptor of a T cell; and (b) a second agent comprising an antibody-drug conjugate. Also provided herein, in some embodiment, is a method of treating a disease or a condition in a subject in need thereof comprising: (a) administering a therapeutically effective amount of a first agent comprising (i) a first domain that binds to a TCR β variable (TCRβV) region and (ii) a molecule that binds to a co-stimulatory receptor of a T cell; and (b) administering a therapeutically effective amount of a second agent comprising (i) a second domain that binds to a TCR β variable (TCRβV) region and (ii) a third domain that binds to trophoblast cell surface antigen 2 (TROP2). Also provided herein, in some embodiment, is a combination therapy for treating a disease or a condition in a subject in need thereof comprising: (a) a first agent comprising (i) aWSGR Docket. No.53676-777.601 first domain that binds to a TCR β variable (TCRβV) region and (ii) a molecule that binds to a co- stimulatory receptor of a T cell; and (b) a second agent comprising (i) a second domain that binds to a TCR β variable (TCRβV) region and (ii) a third domain that binds to trophoblast cell surface antigen 2 (TROP2). Also provided herein, in some embodiment, is a composition for treating a disease or condition in a subject in need thereof comprising: (a) a first agent comprising (i) a first domain that binds to a TCR β variable (TCRβV) region and (ii) a molecule that binds to a co-stimulatory receptor of a T cell; and (b) a second agent comprising (i) a second domain that binds to a TCR β variable (TCRβV) region and (ii) a third domain that binds to trophoblast cell surface antigen 2 (TROP2). Also provided herein, in some embodiment, is a kit for treating a disease or condition in a subject in need thereof comprising: (a) a first agent comprising (i) a first domain that binds to a TCR β variable (TCRβV) region and (ii) a molecule that binds to a co-stimulatory receptor of a T cell; and (b)a second agent comprising (i) a second domain that binds to a TCR β variable (TCRβV) region and (ii) a third domain that binds to trophoblast cell surface antigen 2 (TROP2).

[0005] In some embodiment, the TCRβV-binding moiety is covalently linked to the molecule that bindsto a co-stimulatory receptor of a T cell. In some embodiment, the molecule that binds to a co-stimulatory receptor of a T cell activates the co-stimulatory receptor when the molecule that binds to a co-stimulatory receptor of a T cell binds to the co-stimulatory receptor. In some embodiment, the molecule that binds to a co-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof. In some embodiment, the molecule that binds to a co-stimulatory receptor of a T cell comprises an antibody molecule, an antigen binding domain, a ligand, an extracellular domain of a receptor, or any combination thereof.

[0006] In some embodiment, the administration of the second agent to the subject is conducted beforethe administration of the first agent to the subject. In some embodiment, the administration of the first agent to the subject is conducted before the administration of the second agent to the subject. In some embodiment, the administration of the first agent improves therapeutic efficacy of the second agent to the subject. In some embodiment, the administration of the first agent and the second agent promotes an enhanced anti-tumor immune response in the subject.

[0007] In some embodiment, the first agent comprises (i) a first domain that binds to TCR β V6(TCRβV-6) subfamily or TCR β V10 (TCRβV-10) subfamily and (ii) an IL-2 cytokine molecule or a functional variant thereof.

[0008] In some embodiment, the first agent further comprises a tumor-associated antigen bindingmoiety. In some embodiment, the tumor-associated antigen binding moiety binds to a cancer antigen selected from the group consisting of trophoblast cell surface antigen 2 (TROP2), CD19, CD123, CD22, CD30, CD171, CS-1, C-type lectin-like molecule-1, CD33, epidermal growth factor receptor variant III (EGFRvIII), ganglioside G2 (GD2), ganglioside GD3, TNF receptor family member B cell maturation (BCMA), Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr)), prostate-specific membrane antigen (PSMA), Receptor tyrosine kinase-like orphan receptor 1 (ROR1), Fms-Like Tyrosine Kinase 3 (FLT3), Tumor- associated glycoprotein 72 (TAG72), CD38, CD44v6, Carcinoembryonic antigen (CEA), Epithelial cellWSGR Docket No.53676-777.601 adhesion molecule (EPCAM), B7H3 (CD276), KIT (CD117), Interleukin-13 receptor subunit alpha-2, mesothelin, Interleukin 11 receptor alpha (IL-11Ra), prostate stem cell antigen (PSCA), Protease Serine 21, vascular endothelial growth factor receptor 2 (VEGFR2), Lewis(Y) antigen, CD24, Platelet-derived growth factor receptor beta (PDGFR-beta), Stage-specific embryonic antigen-4 (SSEA-4), CD20, Folate receptor alpha, Receptor tyrosine-protein kinase ERBB2 (Her2 / neu), Mucin 1, cell surface associated (MUC1), epidermal growth factor receptor (EGFR), neural cell adhesion molecule (NCAM), Prostase, prostatic acid phosphatase (PAP), elongation factor 2 mutated (ELF2M), Ephrin B2, fibroblast activation protein alpha (FAP), insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX), Proteasome (Prosome, Macropain) Subunit, Beta Type, 9 (LMP2), glycoprotein 100 (gp100 / pmel17), oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr-abl), tyrosinase, ephrin type-A receptor 2 (EphA2), Fucosyl GM1, sialyl Lewis adhesion molecule (sLe), ganglioside GM3, transglutaminase 5 (TGS5), high molecular weight-melanoma-associated antigen (HMWMAA), o-acetyl-GD2 ganglioside (OAcGD2), Folate receptor beta, tumor endothelial marker 1 (TEM1 / CD248), tumor endothelial marker 7-related (TEM7R), claudin 6 (CLDN6), thyroid stimulating hormone receptor (TSHR), G protein- coupled receptor class C group 5, member D (GPRC5D), chromosome X open reading frame 61 (CXORF61), CD97, CD179a, anaplastic lymphoma kinase (ALK), Polysialic acid, placenta-specific 1 (PLAC1), hexasaccharide portion of globoH glycoceramide (GloboH), mammary gland differentiation antigen (NY-BR-1), uroplakin 2 (UPK2), Hepatitis A virus cellular receptor 1 (HAVCR1), adrenoceptor beta 3 (ADRB3), pannexin 3 (PANX3), G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex, locus K 9 (LY6K), Olfactory receptor 51E2 (OR51E2), TCR Gamma Alternate Reading Frame Protein (TARP), Wilms tumor protein (WT1), Cancer / testis antigen 1 (NY-ESO-1 / LAGE-1), Cancer / testis antigen 2 (LAGE-1a), Melanoma-associated antigen 1 (MAGE-A1), ETS translocation- variant gene 6, located on chromosome 12p (ETV6-AML), sperm protein 17 (SPA17), X Antigen Family, Member 1A (XAGE1), angiopoietin-binding cell surface receptor 2 (Tie 2), melanoma cancer testis antigen-1 (MAD-CT-1), melanoma cancer testis antigen-2 (MAD-CT-2), Fos-related antigen 1, tumor protein p53 (p53), p53 mutant, prostein, Survivin, telomerase, prostate carcinoma tumor antigen-1, melanoma antigen recognized by T cells 1, Rat sarcoma (Ras) mutant, human Telomerase reverse transcriptase (hTERT), sarcoma translocation breakpoints, melanoma inhibitor of apoptosis (ML-IAP), ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene), N-Acetyl glucosaminyl- transferase V (NA17), paired box protein Pax-3 (PAX3), Androgen receptor, Cyclin B1, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), Ras Homolog Family Member C (RhoC), Tyrosinase-related protein 2 (TRP-2), Cytochrome P4501B1 (CYP1B1), CCCTC- Binding Factor (Zinc Finger Protein)-Like, Squamous Cell Carcinoma Antigen Recognized By T Cells 3 (SART3), Paired box protein Pax-5 (PAX5), proacrosin binding protein sp32 (OY-TES1), lymphocyte- specific protein tyrosine kinase (LCK), A kinase anchor protein 4 (AKAP-4), synovial sarcoma, X breakpoint 2 (SSX2), Receptor for Advanced Glycation Endproducts (RAGE-1), renal ubiquitous 1 (RU1), renal ubiquitous 2 (RU2), legumain, human papilloma virus E6 (HPV E6), human papillomaWSGR Docket. No.53676-777.601 virus E7 (HPV E7), intestinal carboxyl esterase, heat shock protein 70-2 mutated (mut hsp70-2), CD79a, CD79b, CD72, Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), Fc fragment of IgA receptor (FCAR or CD89), Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2), CD300 molecule-like family member f (CD300LF), C-type lectin domain family 12 member A (CLEC12A), bone marrow stromal cell antigen 2 (BST2), EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2), lymphocyte antigen 75 (LY75), Glypican-3 (GPC3), Fc receptor-like 5 (FCRL5), FcRH5, PDL1, CD47, prostate specific membrane antigen (PMSA), prostate-specific antigen (PSA), Ron Kinase, c-Met, Immature laminin receptor, TAG-72, BING-4, Calcium-activated chloride channel 2, Cyclin-B1, 9D7, Ep-CAM, EphA3, SAP-1, PRAME, SSX-2, Melan-A / MART-1, TRP1 / gp75, MC1R, β-catenin, BRCA1 / 2, CDK4, CML66, Fibronectin, Ras, TGF-Β receptor, AFP, ETA, MAGE, CA-125, BAGE, GAGE, CDC27, α actinin-4, gangliosides, MART-2, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RU11, RU12, SAGE, TRG, TSTA, L1-CAM, gpA33, GM2, VEGFR, Intergrins, carbohydrates, TRAILR1, TRAILR2, RANKL, TGF-beta, hyaluronic acid, collagen, tenascin C, tenascin W, and immunoglobulin lambda-like polypeptide 1 (IGLL1). In some embodiment, the tumor-associated antigen binding moiety binds to a cancer antigen selected from the group consisting of CD20, MSLN, gp75 (Tryp1), and any combination thereof.

[0009] In some embodiment, the tumor-associated antigen binding moiety comprises a heavy chainvariable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1), a heavy chain complementarity determining region 2 (HC CDR2), and a heavy chain complementarity determining region 3 (HC CDR3) comprising the sequences of SEQ ID NO: 524, SEQ ID NO: 525, and SEQ ID NO: 526, respectively, or a VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 comprising the sequences of SEQ ID NO: 538, SEQ ID NO: 539, and SEQ ID NO: 540, respectively. In some embodiment, the tumor-associated antigen binding moiety comprises a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1), a light chain complementarity determining region 2 (LC CDR2) and a light chain complementarity determining region 3 (LC CDR3) comprising the sequences of SEQ ID NO: 1168, SEQ ID NO: 1295, and SEQ ID NO: 528, respectively, or a VL comprising a LC CDR1, a LC CDR2 and a LC CDR3 comprising the sequences of SEQ ID NO: 562, SEQ ID NO: 563, and SEQ ID NO: 564, respectively. In some embodiment, the tumor-associated antigen binding moiety comprises a VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 comprising the sequences of SEQ ID NO: 524, SEQ ID NO: 525, and SEQ ID NO: 526, respectively, and a VL comprising a LC CDR1, a LC CDR2 and a LC CDR3 comprising the sequences of SEQ ID NO: 1168, SEQ ID NO: 1295, and SEQ ID NO: 528, respectively. In some embodiment, the tumor-associated antigen binding moiety comprises a VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 comprising the sequences of SEQ ID NO: 538, SEQ ID NO: 539, and SEQ ID NO: 540, respectively, and a VL comprising a LC CDR1, a LC CDR2 and a LC CDR3 comprising the sequences of SEQ ID NO: 562, SEQ ID NO: 563, and SEQ ID NO: 564, respectively. In some embodiment, the tumor-associated antigen binding moiety comprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,WSGR Docket No.53676-777.601 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 523 or the sequence of SEQ ID NO: 537.

[0010] In some embodiment, the tumor-associated antigen binding moiety comprises a VL comprising asequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 527 or the sequence of SEQ ID NO: 561. In some embodiment, the tumor-associated antigen binding moiety comprises a VH comprising the sequence of SEQ ID NO: 523 or the sequence of SEQ ID NO: 537. In some embodiment, the tumor-associated antigen binding moiety comprises a VL comprising the sequence of SEQ ID NO: 527 or the sequence of SEQ ID NO: 561. In some embodiment, the tumor- associated antigen binding moiety comprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 523 and a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 527. In some embodiment, the tumor-associated antigen binding moiety comprises a VH comprising the sequence of SEQ ID NO: 523 and a VL comprising the sequence of SEQ ID NO: 527. In some embodiment, the tumor-associated antigen binding moiety comprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 537 and a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 561. In some embodiment, the tumor-associated antigen binding moiety comprises a VH comprising the sequence of SEQ ID NO: 537 and a VL comprising the sequence of SEQ ID NO: 561. In some embodiment, the tumor-associated antigen binding moiety comprises a VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 comprising the sequences of SEQ ID NO: 581, SEQ ID NO: 582, and SEQ ID NO: 583, respectively. In some embodiment, the tumor-associated antigen binding moiety comprises a VL comprising a LC CDR1, a LC CDR2 and a LC CDR3 comprising the sequences of SEQ ID NO: 586, SEQ ID NO: 587, and SEQ ID NO: 588, respectively. In some embodiment, the tumor-associated antigen binding moiety comprises a VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 comprising the sequences of SEQ ID NO: 581, SEQ ID NO: 582, and SEQ ID NO: 583, respectively, and a VL comprising a LC CDR1, a LC CDR2 and a LC CDR3 comprising the sequences of SEQ ID NO: 586, SEQ ID NO: 587, and SEQ ID NO: 588, respectively. In some embodiment, the tumor-associated antigen binding moiety comprises a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 580. In some embodiment, the tumor-associated antigen binding moiety comprises a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 585. In some embodiment, the tumor-associated antigen binding moiety comprises a VH comprising the sequence of SEQ ID NO: 580. In some embodiment, the tumor-WSGR Docket. No.53676-777.601 associated antigen binding moiety comprises a VL comprising the sequence of SEQ ID NO: 585. In some embodiment, the tumor-associated antigen binding moiety comprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 580 and a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 585. In some embodiment, the tumor-associated antigen binding moiety comprises a VH comprising the sequence of SEQ ID NO: 580 and a VL comprising the sequence of SEQ ID NO: 585.

[0011] In some embodiment, the antibody-drug conjugate comprises: (a) an antibody (Mab) comprisinga first domain that binds to trophoblast cell surface antigen 2 (TROP2), wherein the first domain comprises: (i) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) amino acid sequence of NYGMN (SEQ ID NO: 500), a heavy chain complementarity determining region 2 (HC CDR2) amino acid sequence of WINTYTGEPTYTDDFKG (SEQ ID NO: 501), and a heavy chain complementarity determining region 3 (HC CDR3) amino acid sequence of GGFGSSYWYFDV (SEQ ID NO: 502); and (ii) a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) amino acid sequence of KASQDVSIAVA (SEQ ID NO: 503), a light chain complementarity determining region 2 (LC CDR2) amino acid sequence of SASYRYT (SEQ ID NO: 504), and a light chain complementarity determining region 3 (LC CDR3) amino acid sequence of QQHYITPLT (SEQ ID NO: 505); and (b) a cytotoxic drug, wherein the cytotoxic drug is conjugated to the Mab.

[0012] In some embodiment, the third domain that binds to TROP2 or the first domain that binds toTROP2 comprises: (a) a VH comprising a HC CDR1 amino acid sequence of NYGMN (SEQ ID NO: 500), a HC CDR2 amino acid sequence of WINTYTGEPTYTDDFKG (SEQ ID NO: 501), and a HC CDR3 amino acid sequence of GGFGSSYWYFDV (SEQ ID NO: 502); and (b) a VL comprising a LC CDR1 amino acid sequence of KASQDVSIAVA (SEQ ID NO: 503), a LC CDR2 amino acid sequence of SASYRYT (SEQ ID NO: 504), and a LC CDR3 amino acid sequence of QQHYITPLT (SEQ ID NO: 505). In some embodiment, the first domain that binds to TROP2 or the third domain that binds to TROP2 comprises a VH sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 506. In some embodiment, the first domain that binds to TROP2 or the third domain that binds to TROP2 comprises a VH sequence comprising the sequence of SEQ ID NO: 506. In some embodiment, the first domain that binds to TROP2 or the third domain that binds to TROP2 comprises a VL sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 508. In some embodiment, the first domain that binds to TROP2 or the third domain that binds to TROP2 comprises a VL sequence comprising the sequence of SEQ ID NO: 508. In some embodiment, the first domain that binds to TROP2 or the third domain that binds to TROP2 comprises a VH comprising the sequence of SEQ ID NO: 506 and a VL comprising the sequence of SEQ ID NO: 508. InWSGR Docket No.53676-777.601 some embodiment, the first domain that binds to TROP2 or the third domain that binds to TROP2 is a Fab, F(ab')2, Fv, a single chain Fv (scFv), a diabody, a single domain antibody, a VHH, or a camelid antibody. In some embodiment, the first domain that binds to TROP2 or the third domain that binds to TROP2 comprises a dimerization module, comprising a first immunoglobulin chain constant region and a second immunoglobulin chain constant region. In some embodiment, the first immunoglobulin chain constant region comprises the first fragment crystallizable region (Fc region) and the second first immunoglobulin chain constant region comprises the second fragment crystallizable region (Fc region).5 In some embodiment, the first domain that binds to TROP2 or the third domain that binds to TROP2 comprises one or more heavy chain constant regions selected from IgG4 heavy chain constant region or fragment thereof and IgG1 heavy chain constant region or fragment thereof. In some embodiment, the first domain that binds to TROP2 or the third domain that binds to TROP2 further comprises a heavy chain constant domain 1 (CH1) linked to the VH. In some embodiment, the first domain that binds to TROP2 or the third domain that binds to TROP2 further comprises a light chain constant domain (CL) linked to the VL. In some embodiment, the first domain that binds to TROP2 or the third domain that binds to TROP2 comprises a first polypeptide comprising the VH and the CH1 linked to the VH. In some embodiment, the first domain that binds to TROP2 or the third domain that binds to TROP2 comprises a first polypeptide comprising the VL and the CL linked to the VL. In some embodiment, the first polypeptide comprises the sequence of SEQ ID NOs: 515 or 516. In some embodiment, the second polypeptide comprises the sequence of SEQ ID NOs: 509 or 512. In some embodiment, the first polypeptide and the second polypeptide chains are non-contiguous. In some embodiment, the cytotoxic drug is a topoisomerase I inhibitor.

[0013] In some embodiment, the antibody-drug conjugate has a formula selected from the groupconsisting of MAb-CL2A-SN-38, MAb-CL6-SN-38, MAb-CL7-SN-38, MAb-CLX-SN-38, and MAb- CLY-SN-38, with a structure represented by:MAb-CL6-SN-38WSGR Docket. No.53676-777.601MAb-CLX-SN-38, where R is hydrogen or C1 to C10 alkyl group and AA is selected from any one of the following L-amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine,where R and R’ can be independently hydrogen or methyl; and when R=R’=methyl, referred to as MAb- CL2E-SN-38.WSGR Docket No.53676-777.601

[0014] In some embodiment, the antibody-drug conjugate has a formula selected from the groupconsisting of MAb-CL2A-SN-38, MAb-CL6-SN-38, MAb-CL7-SN-38, and MAb-CLX-SN-38, with a structure represented by:where R is hydrogen or C1 to C10 alkyl group and AA is selected from any one of the following L-amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine, wherein the 10-hydroxy position of SN-38 in MAb-CL2A-SN-38 or MAb-CL6-SN-38 or MAb-CL7-SN-38 or MAb-CLX-SN-38 is a 10-O-ester or 10-O-carbonate derivative using a ‘COR’ moiety where the R group is a substituted alkyl residue “N(CH3)2—(CH2)n—”, where n is 2-10 and wherein the terminal amino group is optionally in the form of a quaternary salt for enhanced aqueous solubility, or an alkyl residue “CH3—(CH2)n—” where n is 0-10, or an alkoxy residue “CH3—WSGR Docket. No.53676-777.601 (CH2)n—O—” where n is 0-10, or “N(CH3)2—(CH2)n—O—” where n is 2-10, or “R1O—(CH2— CH2—O)n—CH2—CH2—O—” where R1 is ethyl or methyl and n is an integer with values of 0-10.

[0015] In some embodiment, the antibody-drug conjugate has a formula of MAb-CLY- SN-38, with astructure represented by:

[0016] MAb-CLY-SN-38.

[0017] In some embodiment, administering the first agent and the second agent induces an improvedtherapeutic effect in the subject, relative to a subject administered the second agent without the first agent. In some embodiment, administering the first agent and the second agent induces more activated and / or expanded T cells in a tumor in the subject, relative to a tumor in a subject administered the second agent without the first agent. In some embodiment, administering the first agent and the second agent induces less exhausted T cells in a tumor in the subject, relative to a tumor in a subject administered the second agent without the first agent. In some embodiment, administering the first agent and the second agent induces a higher anti-tumor efficacy level in the subject, relative to a subject administered the second agent without the first agent. In some embodiment, administering the first agent and the second agent induces a higher number of T cells that are cytotoxic against tumor cells or cancer cells in the subject, relative to a subject administered the second agent without the first agent. In some embodiment, administering the first agent and the second agent induces a higher level of cytotoxicity against tumor cells or cancer cells in the subject, relative to a subject administered the second agent without the first agent. In some embodiment, administering the first agent and the second agent expands or activates a higher number of T cells that are cytotoxic against tumor cells or cancer cells in the subject, relative to a subject administered the second agent without the first agent. In some embodiment, administering the first agent and the second agent induces a higher level of cytotoxic activity against tumor cells or cancer cells in the subject, relative to a subject administered the second agent without the first agent. In someWSGR Docket No.53676-777.601 embodiment, the subject exhibits an improved therapeutic effect after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent. In some embodiment, the subject produces a higher number of activated and / or expanded T cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent. In some embodiment, the subject comprises less exhausted T cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent. In some embodiment, the subject exhibits a higher level of anti-tumor efficacy after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent. In some embodiment, the subject produces a higher number of T cells that are more cytotoxic against tumor cells or cancer cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent. In some embodiment, the subject produces a higher number of T cells that are cytotoxic against tumor cells or cancer cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.In some embodiment, the subject exhibits a higher level of cytotoxic activity against tumor cells or cancer cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

[0018] In some embodiment, the T cells are TCRβV+. In some embodiment, the subject comprisestumors that are more immune infiltrated after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent. In some embodiment, the first agent and the second agent are not concomitantly administered to the subject. In some embodiment, the first agent and the second agent are concomitantly administered to the subject. In some embodiment, the method comprises administering the first agent to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at least 1, 2, 3, 4, 5, 6, or 7 days, at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years after the subject has been treated with a dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at least 1, 2, 3, 4, 5, 6, or 7 days, at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years after the subject has been treated with a first dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at least 1, 2, 3, 4, 5, 6, or 7 days, at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years after the subject has been treated with a last dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years after being treated with the second agent. In some embodiment, the method comprises administering the first agent to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years after being treated with a dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject atWSGR Docket. No.53676-777.601 most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years after being treated with a first dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years after being treated with a last dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject from 1 hour to 24 hours after being treated with a dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject from 1 day to 7 days after being treated with a dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject from 1 week to 4 weeks after being treated with a dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject from 1 month to 12 months after being treated with a dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject from 1 year to 3 years after being treated with a dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject from 1 hour to 24 hours after being treated with a first dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject from 1 day to 7 days after being treated with a first dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject from 1 week to 4 weeks after being treated with a first dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject from 1 month to 12 months after being treated with a first dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject from 1 year to 3 years after being treated with a first dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject from 1 hour to 24 hours after being treated with a last dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject from 1 week to 4 weeks after being treated with a last dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject from 1 month to 12 months after being treated with a last dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject from 1 year to 3 years after being treated with a last dose of the second agent. In some embodiment, the method comprises administering the first agent to the subject on the same day the subject had been previously treated with the second agent.

[0019] In some embodiment, the method is repeated twice or more. In some embodiment, theadministration of the first agent comprises one or more doses. In some embodiment, the administration of the first agent comprises two or more doses. In some embodiment, the administration of the first agent comprises one dose per week. In some embodiment, the administration of the first agent comprises two or more doses per week. In some embodiment, the first agent is administered to the subject once every two weeks. In some embodiment, the first agent is administered to the subject once every three weeks. In some embodiment, the first agent is administered to the subject once every week for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years. In someWSGR Docket No.53676-777.601 embodiment, the administration of the first agent comprises two or more doses per week for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years. In some embodiment, the first agent is administered to the subject once every two weeks for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years. In some embodiment, the first agent is administered to the subject once every three weeks for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.

[0020] In some embodiment, the administration of the second agent comprises one or more doses. Insome embodiment, the administration of the second agent comprises two or more doses. In some embodiment, the administration of the second agent comprises one dose per week. In some embodiment, the administration of the second agent comprises two or more doses per week. In some embodiment, the second agent is administered to the subject once every two weeks. In some embodiment, the second agent is administered to the subject once every three weeks. In some embodiment, the second agent is administered to the subject once every week for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years. In some embodiment, the administration of the second agent comprises two or more doses per week for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years. In some embodiment, the second agent is administered to the subject once every two weeks for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years. In some embodiment, the second agent is administered to the subject once every three weeks for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years. In some embodiment, the method comprises administering the first agent to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at least 1, 2, 3, 4, 5, 6, or 7 days, at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years prior to administering the second agent to the subject. In some embodiment, the method comprises administering the first agent to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years prior to administering the second agent to the subject.

[0021] In some embodiment, the method comprises administering the first agent to the subject from 1hour to 24 hours prior to administering the second agent to the subject. In some embodiment, the method comprises administering the first agent to the subject from 1 day to 7 days prior to administering the second agent to the subject. In some embodiment, the method comprises administering the first agent to the subject from 1 week to 4 weeks prior to administering the second agent to the subject. In some embodiment, the method comprises administering the first agent to the subject from 1 month to 12 months prior to administering the second agent to the subject. In some embodiment, the method comprises administering the first agent to the subject from 1 year to 3 years prior to administering the second agent to the subject. In some embodiment, the administration of the first agent comprises two or more doses, and each dose comprises a same amount of the first agent. In some embodiment, the administration of the first agent comprises two or more doses, and each dose comprises different amounts of the first agent. In some embodiment, the administration of the second agent comprises two or moreWSGR Docket. No.53676-777.601 doses, and each dose comprises a same amount of the second agent. In some embodiment, the administration of the second agent comprises two or more doses, and each dose comprises different amounts of the second agent.

[0022] In some embodiment, the first agent is administered to the subject at a dose of from about 0.001mg / kg to about 20 mg / kg. In some embodiment, the second agent is administered to the subject at a dose of from about 0.001 mg / kg to about 20 mg / kg.

[0023] In some embodiment, the method comprises administering the first agent and the second agent tothe subject simultaneously or on the same day.

[0024] In some embodiment, the disease or condition in the subject is treated to a higher extent relativeto a corresponding method in which the first agent is administered and the second agent is not administered. In some embodiment, the method is more effective to treat the disease or condition in the subject relative to a method in which the first agent is administered to the subject but not the second agent. In some embodiment, the method is more effective to treat the disease or condition in the subject relative to a method in which the second agent is administered to the subject but not the first agent.

[0025] In some embodiment, the TCRβV region is a human TCRβV region. In some embodiment, thehuman TCRβV region is selected from the group consisting of TCRβ V1 subfamily, TCRβ V2 subfamily, TCRβ V3 subfamily, TCRβ V4 subfamily, TCRβ V5 subfamily, TCRβ V6 subfamily, TCRβ V7 subfamily, TCRβ V8 subfamily, TCRβ V9 subfamily, TCRβ V10 subfamily, TCRβ V11 subfamily, TCRβ V12 subfamily, TCRβ V13 subfamily, TCRβ V14 subfamily, TCRβ V15 subfamily, TCRβ V16 subfamily, TCRβ V17 subfamily, TCRβ V18 subfamily, TCRβ V19, TCRβ V20 subfamily, TCRβ V21 subfamily, TCRβ V22 subfamily TCRβ V23 subfamily, TCRβ V24 subfamily, TCRβ V25 subfamily, TCRβ V26 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V29 subfamily, and TCRβ V30 subfamily. In some embodiment, the human TCRβV region is selected from the group consisting of: (i) TCRβ V1 subfamily comprising TCRβ V1*01; (ii) TCRβ V2 subfamily comprising one or more selected from TCRβ V2*01, TCRβ V2*02, and TCRβ V2*03; (iii) TCRβ V3 subfamily comprising one or more selected from TCRβ V3-1*01 and TCRβ V3-1*02; (iv) TCRβ V4 subfamily comprising one or more selected from TCRβ V4-1*01, TCRβ V4-1*02, TCRβ V4-2*01, TCRβ V4-2*02, TCRβ V4-3*01, TCRβ V4-3*02, TCRβ V4-3*03, and TCRβ V4-3*04;(v) TCRβ V5 subfamily comprising one or more selected from TCRβ V5-1*01, TCRβ V5-1*02, TCRβ V5-3*01, TCRβ V5-3*02, TCRβ V5-4*01, TCRβ V5-4*02, TCRβ V5-4*03, TCRβ V5-4*04, TCRβ V5-5*01, TCRβ V5-5*02, TCRβ V5-5*03, TCRβ V5- 6*01, TCRβ V5-7*01, TCRβ V5-8*01, and TCRβ V5-8*02; (vi) TCRβ V6 subfamily comprising one or more selected from TCRβ V6-1*01, TCRβ V6-2*01, TCRβ V6-3*01, TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-5*01, TCRβ V6-6*01, TCRβ V6-6*02, TCRβ V6-6*03, TCRβ V6-6*04, TCRβ V6-6*05, TCRβ V6-7*01, TCRβ V6-8*01, and TCRβ V6-9*01; (vii) TCRβ V7 subfamily comprising one or more selected from TCRβ V7-1*01, TCRβ V7-2*01, TCRβ V7-2*02, TCRβ V7-2*03, TCRβ V7-2*04, TCRβ V7-3*01, TCRβ V7-3*02, TCRβ V7-3*03, TCRβ V7-3*04, TCRβ V7-3*05, TCRβ V7-4*01, TCRβ V7- 4*02, TCRβ V7-6*01, TCRβ V7-6*02, TCRβ V7-7*01, TCRβ V7-7*02, TCRβ V7-8*01, TCRβ V7- 8*02, TCRβ V7-8*03, TCRβ V7-9*01, TCRβ V7-9*02, TCRβ V7-9*03, TCRβ V7-9*04, TCRβ V7-WSGR Docket No.53676-777.601 9*05, TCRβ V7-9*06, and TCRβ V7-9*07; (viii) TCRβ V8 subfamily comprising one or more selected from TCRβ V8-1*01, TCRβ V8-1*02, TCRβ V8-2*01, and TCRβ V8-2*02; (ix) TCRβ V9 subfamily comprising one or more selected from TCRβ V9-1*01, TCRβ V9-1*02, and TCRβ V9-1*03; (x) TCRβ V10 subfamily comprising one or more selected from TCRβ V10-1*01, TCRβ V10-1*02, TCRβ V10- 1*03, TCRβ V10-2*01, TCRβ V10-2*02, TCRβ V10-3*01, TCRβ V10-3*02, TCRβ V10-3*03, and TCRβ V10-3*04; (xi) TCRβ V11 subfamily comprising TCRβ V11-1*01, TCRβ V11-2*01, TCRβ V11- 2*02, TCRβ V11-2*03, TCRβ V11-3*01, TCRβ V11-3*02, TCRβ V11-3*03, and TCRβ V11-3*04; (xii) TCRβ V12 subfamily comprising one or more selected from TCRβ V12-3*01, TCRβ V12-4*01, TCRβ V12-4*02, and TCRβ V12-5*01; (xiii) TCRβ V13 subfamily comprising one or more selected from TCRβ V13*01 and TCRβ V13*02; (xiv) TCRβ V14 subfamily comprising one or more comprising from TCRβ V14*01 and TCRβ V14*02; (xv) TCRβ V15 subfamily comprising one or more selected from TCRβ V15*01, TCRβ V15*02, and TCRβ V15*03; (xvi) TCRβ V16 subfamily comprising one or more selected from TCRβ V16*01, TCRβ V16*02, and TCRβ V16*03; (xvii) TCRβ V17 subfamily comprising TCRβ V17*01; (xviii) TCRβ V18 subfamily comprising TCRβ V18*01; (xix) TCRβ V19 subfamily comprising one or more selected from TCRβ V19*01, TCRβ V19*02, and TCRβ V19*03; (xx) TCRβ V20 subfamily comprising one or more selected from TCRβ V20-1*01, TCRβ V20-1*02, TCRβ V20-1*03, TCRβ V20-1*04, TCRβ V20-1*05, TCRβ V20-1*06, and TCRβ V20-1*07; (xxi) TCRβ V21 subfamily comprising one or more selected from TCRβ V21-1*01 and TCRβ V21-1*02; (xxii) TCRβ V22 subfamily comprising TCRβ V22-1*01; (xxiii) TCRβ V23 subfamily comprising TCRβ V23-1*01; (xxiv) TCRβ V24 subfamily comprising TCRβ V24-1*01; (xxv) TCRβ V25 subfamily comprising TCRβ V25-1*01; (xxvi) TCRβ V26 subfamily comprising TCRβ V26-1*01; (xxvii) TCRβ V27 subfamily comprising TCRβ V27*01; (xxviii) TCRβ V28 subfamily comprising TCRβ V28*01; (xxix) TCRβ V29 subfamily comprising one or more selected from TCRβ V29-1*01, TCRβ V29-1*02, and TCRβ V29-1*03; and (xxx) TCRβ V30 subfamily comprising one or more selected from TCRβ V30*01, TCRβ V30*02, TCRβ V30*03, TCRβ V30*04, and TCRβ V30*05.

[0026] In some embodiment, the first domain is a full antibody, an antigen binding domain thereof, or afunctional fragment or variant thereof, a bivalent antibody, a bispecific antibody, or a biparatopic antibody that binds to a TCRβV region. In some embodiment, the second domain is a full antibody, an antigen binding domain thereof, or a functional fragment or variant thereof, a bivalent antibody, a bispecific antibody, or a biparatopic antibody that binds to a TCRβV region. In some embodiment, the full antibody, an antigen binding domain thereof, or a functional fragment or variant thereof is a Fab, a Fab', a F(ab’)2, a F(ab)2, a variable fragment (Fv), a single domain antibody, a diabody, a nanobody, a camelid single domain antibody, a VHH or a single chain variable fragment (scFv).

[0027] In some embodiment, the first agent comprises one or more heavy chain constant regionsselected from the group consisting of IgG1 heavy chain constant region or fragment thereof, IgG2 heavy chain constant region or fragment thereof, IgG3 heavy chain constant region or fragment thereof, IgGA1 heavy chain constant region or fragment thereof, IgGA2 heavy chain constant region or fragment thereof, IgG4 heavy chain constant region or fragment thereof, IgJ heavy chain constant region or fragmentWSGR Docket. No.53676-777.601 thereof, IgM heavy chain constant region or fragment thereof, IgD heavy chain constant region or fragment thereof, and IgE heavy chain constant region or fragment thereof. In some embodiment, the first agent comprises a kappa light chain constant region or fragment thereof, a lambda light chain constant region or fragment thereof, or a combination thereof.

[0028] In some embodiment, the first agent is a multifunctional molecule. In some embodiment, the firstagent comprises at least two non-contiguous polypeptide chains; wherein a first polypeptide chain of the at least two non-contiguous polypeptide chains comprises a first Fc region, and a second polypeptide chain of the at least two non-contiguous polypeptide chains comprises a second Fc region. In some embodiment, the first Fc region and the second Fc region comprise an Fc interface with a knob-in-a hole. In some embodiment, the first Fc region, the second Fc region, or a combination thereof comprises an Asn297Ala mutation, a Leu234Ala / Leu235Ala mutation, or a combination thereof.

[0029] In some embodiment, the first agent is a multispecific molecule that further comprises one ormore of a second cytokine molecule, a stromal modifying moiety, or an immune cell engager. In some embodiment, the first agent is a multispecific molecule that further comprises a second cytokine molecule. In some embodiment, the first agent comprises a dimerization module, comprising a first immunoglobulin chain constant region and a second immunoglobulin chain constant region. In some embodiment, the first immunoglobulin chain constant region comprises the first fragment crystallizable region (Fc region) and the second first immunoglobulin chain constant region comprises the second fragment crystallizable region (Fc region). In some embodiment, dimerization of the first Fc region and the second Fc region is enhanced by providing an Fc interface of the first Fc region and the second Fc region with one or more of a paired cavity-protuberance, an electrostatic interaction, or a strand- exchange, such that a greater ratio of heteromultimer to homomultimer forms relative to a non- engineered interface.

[0030] In some embodiment, the immune cell engager is selected from the group consisting of a T cellengager, an NK cell engager, a B cell engager, a dendritic cell engager, a macrophage cell engager, and any combination thereof. In some embodiment, the at least one cytokine molecule is selected from the group consisting of interleukin-2 (IL-2) or functional variant thereof, interleukin-7 (IL-7) or functional variant thereof, interleukin-12 (IL-12) or functional variant thereof, interleukin-15 (IL-15) or functional variant thereof, interleukin-18 (IL-18) or functional variant thereof, interleukin-21 (IL-21) or functional variant thereof, interferon gamma or functional variant thereof, and any combination thereof. In some embodiment, the second cytokine molecule is selected from the group consisting of interleukin-2 (IL-2) or functional variant thereof, interleukin-7 (IL-7) or functional variant thereof, interleukin-12 (IL-12) or functional variant thereof, interleukin-15 (IL-15) or functional variant thereof, interleukin-18 (IL-18) or functional variant thereof, interleukin-21 (IL-21) or functional variant thereof, interferon gamma or functional variant thereof, and any combination thereof. In some embodiment, the cytokine molecule comprises interleukin-2 (IL-2) or functional variant thereof. In some embodiment, the interleukin-2 (IL- 2) or functional variant thereof comprises the sequence of SEQ ID NO: 2270 or SEQ ID NO: 2191.WSGR Docket No.53676-777.601

[0031] In some embodiment, the first agent is administered to the subject prior to, concurrently, or afteradministration of the second agent to the subject.

[0032] Also disclosed herein, in some embodiment, is a multifunctional molecule comprising: (a)atumor-associated antigen binding moiety, wherein the tumor-associated antigen binding moiety comprises a trophoblast cell surface antigen 2 (TROP2) binding moiety; (b) a molecule that binds to a co- stimulatory receptor of a T cell; and (c) a TCR β variable (TCRβV) region binding moiety.

[0033] In some embodiment, the TCRβV-binding moiety is covalently linked to the molecule that bindsto a co-stimulatory receptor of a T cell. In some embodiment, the molecule that binds to a co-stimulatory receptor of a T cell activates the co-stimulatory receptor when the molecule that binds to a co-stimulatory receptor of a T cell binds to the co-stimulatory receptor. In some embodiment, the molecule that binds to a co-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof. In some embodiment, the molecule that binds to a co-stimulatory receptor of a T cell comprises an antibody molecule, an antigen binding domain, a ligand, an extracellular domain of a receptor, or any combination thereof. In some embodiment, the TROP-2 binding moiety comprises an antibody domain or an antigen binding domain. In some embodiment, the antigen binding domain comprises any one selected from the group consisting of a Fab, a F(ab')2, an Fv, a single chain Fv (scFv), a single domain antibody, a diabody (dAb), a VHH, a camelid antibody, and any combination thereof.

[0034] In some embodiment, the TROP-2 binding moiety comprises: (a) a heavy chain variable region(VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) amino acid sequence of NYGMN (SEQ ID NO: 500), a heavy chain complementarity determining region 2 (HC CDR2) amino acid sequence of WINTYTGEPTYTDDFKG (SEQ ID NO: 501), and a heavy chain complementarity determining region 3 (HC CDR3) amino acid sequence of GGFGSSYWYFDV (SEQ ID NO: 502); and (b) a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) amino acid sequence of KASQDVSIAVA (SEQ ID NO: 503), a light chain complementarity determining region 2 (LC CDR2) amino acid sequence of SASYRYT (SEQ ID NO: 504), and a light chain complementarity determining region 3 (LC CDR3) amino acid sequence of QQHYITPLT (SEQ ID NO: 505). In some embodiment, the TROP-2 binding moiety comprises: (a) a VH comprising a HC CDR1 amino acid sequence of NYGMN (SEQ ID NO: 500), a HC CDR2 amino acid sequence of WINTYTGEPTYTDDFKG (SEQ ID NO: 501), and a HC CDR3 amino acid sequence of GGFGSSYWYFDV (SEQ ID NO: 502); and (b) a VL comprising a LC CDR1 amino acid sequence of KASQDVSIAVA (SEQ ID NO: 503), a LC CDR2 amino acid sequence of SASYRYT (SEQ ID NO: 504), and a LC CDR3 amino acid sequence of QQHYITPLT (SEQ ID NO: 505). In some embodiment, the TROP-2 binding moiety comprises a VH sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 506. In some embodiment, the TROP-2 binding moiety comprises a VH sequence comprising the sequence of SEQ ID NO: 506. In some embodiment, the first domain that binds to TROP2 or the third domain that binds to TROP2 comprises a VL sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 508. In some embodiment, the TROP-2 binding moiety comprises a VL sequence comprising the sequence of SEQ ID NO: 508. In some embodiment, theWSGR Docket. No.53676-777.601 TROP-2 binding moiety comprises a VH comprising the sequence of SEQ ID NO: 506 and a VL comprising the sequence of SEQ ID NO: 508. In some embodiment, the multifunctional molecule comprises a first polypeptide chain comprising a first portion of a dimerization module, and a second polypeptide chain comprising a second portion of the dimerization module; wherein the first polypeptide chain and the second polypeptide chain are non-contiguous, and wherein the tumor-associated antigen binding moiety is linked to the first portion of the dimerization module, and the TCRβV-binding moiety and / or the molecule that binds to a co-stimulatory receptor of a T cell are independently linked to the first portion of the dimerization module, the second portion of the dimerization module, or a combination thereof.

[0035] In some embodiment, (i) the tumor-associated antigen binding moiety is linked to the N-terminusof the first portion of the dimerization module, and the TCRβV-binding moiety is linked to the C- terminus of the first portion of the dimerization module, the N-terminus of the second portion of the dimerization module, the C-terminus of the second portion of the dimerization module, or any combination thereof; or (ii) the tumor-associated antigen binding moiety is linked to the C-terminus of the first portion of the dimerization module, and the molecule that binds to a co-stimulatory receptor of a T cell is linked to the N-terminus of the first portion of the dimerization module, the N-terminus of the second portion of the dimerization module, the C-terminus of the second portion of the dimerization module, or any combination thereof.

[0036] In some embodiment (i) the tumor-associated antigen binding moiety is linked to the N-terminusof the first portion of the dimerization module, and the molecule that binds to a co-stimulatory receptor of a T cell is linked to the C-terminus of the first portion of the dimerization module, the N-terminus of the second portion of the dimerization module, the C-terminus of the second portion of the dimerization module, or any combination thereof; or (ii) the tumor-associated antigen binding moiety is linked to the C-terminus of the first portion of the dimerization module, and the molecule that binds to a co- stimulatory receptor of a T cell is linked to the N-terminus of the first portion of the dimerization module, the N-terminus of the second portion of the dimerization module, the C-terminus of the second portion of the dimerization module, or any combination thereof.

[0037] In some embodiment, the TCRβV-binding moiety and the molecule that binds to a co-stimulatoryreceptor of a T cell is within a single contiguous polypeptide chain of the first polypeptide chain or the second polypeptide chain.

[0038] In some embodiment, the tumor-associated antigen binding moiety, the TCRβV-binding moiety,or a combination thereof comprises an antibody or antigen binding fragment thereof, or antigen binding domain, wherein the antigen binding fragment or antigen binding domain comprises any one selected from the group consisting of a Fab, a F(ab')2, an Fv, a single chain Fv (scFv), a single domain antibody, a diabody (dAb), a VHH, a camelid antibody, and any combination thereof.

[0039] In some embodiment, the TCRβV-binding moiety comprises a heavy chain variable domain(VH) and a light chain variable domain (VL), or a single domain antibody. In some embodiment, the TCRβV-binding moiety comprises a first portion of the TCRβV-binding moiety, and wherein theWSGR Docket No.53676-777.601 multifunctional molecule further comprises a third polypeptide chain comprising a second portion of the TCRβV-binding moiety, wherein the third polypeptide chain is non-contiguous with the first polypeptide chain and the second polypeptide chain. In some embodiment, the first portion of the TCRβV-binding moiety comprises a VH of the TCRβV-binding moiety and the second portion of the TCRβV-binding moiety comprises a VL of the TCRβV-binding moiety, or the first portion of the TCRβV-binding moiety comprises a VL of the TCRβV-binding moiety and the second portion of the TCRβV-binding moiety comprises a VH of the TCRβV-binding moiety. In some embodiment, the tumor-associated antigen binding moiety comprises a VH and a VL, or a single domain antibody. In some embodiment, the tumor- associated antigen binding moiety comprises a first portion of the tumor-associated antigen binding moiety, and wherein the multifunctional molecule further comprises a fourth polypeptide chain comprising a second portion of the tumor-associated antigen binding moiety, wherein the fourth polypeptide chain is non-contiguous with the first polypeptide chain, the second polypeptide chain, and the third polypeptide chain. In some embodiment, the first portion of the tumor-associated antigen binding moiety comprises a VH of the tumor-associated antigen binding moiety and the second portion of the tumor-associated antigen binding moiety comprises a VL of the tumor-associated antigen binding moiety, or the first portion of the tumor-associated antigen binding moiety comprises a VL of the tumor- associated antigen binding moiety and the second portion of the tumor-associated antigen binding moiety comprises a VH of the tumor-associated antigen binding moiety. In some embodiment, the first portion of the dimerization module and the second portion of the dimerization module are dimerized.

[0040] In some embodiment, (i) the tumor-associated antigen binding moiety further comprises a heavychain constant domain 1 (CH1) linked to the VH of the tumor-associated antigen binding moiety; (ii) the TCRβV-binding moiety further comprises a heavy chain constant domain 1 (CH1) linked to the VH of the TCRβV-binding moiety; or (iii) a combination thereof. In some embodiment, (i) the tumor- associated antigen binding moiety further comprises a light chain constant domain (CL) linked to the VL of the tumor-associated antigen binding moiety; (ii) the TCRβV-binding moiety further comprises a light chain constant domain (CL) linked to the VL of the TCRβV-binding moiety; or (iii) a combination thereof. In some embodiment, (i) the CL linked to the VL of the tumor-associated antigen binding moiety comprises a kappa chain constant domain or a lambda chain constant domain; (ii) the CL linked to the VL of the TCRβV-binding moiety comprises a kappa chain constant domain or a lambda chain constant domain; or (iii) a combination thereof. In some embodiment, the kappa chain constant domain or the lambda chain constant domain comprises any one of the light chain constant region sequences listed in Table 3, 21, or 22.

[0041] In some embodiment, the multifunctional molecule further comprises (i) a linker between thefirst portion of the dimerization module and the tumor-associated antigen binding moiety or the first portion of the tumor-associated antigen; (ii) a linker between the molecule that binds to a co-stimulatory receptor of a T cell and the first portion of the dimerization module, a linker between the molecule that binds to a co-stimulatory receptor of a T cell and the second portion of the dimerization module, or a combination thereof; (iii) a linker between the molecule that binds to a co-stimulatory receptor of a T cellWSGR Docket. No.53676-777.601 and the TCRβV-binding moiety or the first portion of the TCRβV-binding moiety; (iv) a linker between the VH and the VL of the tumor-associated antigen binding moiety; (v) a linker between the VH and the VL of the TCRβV-binding moiety; (vi) a linker between the CH1 and the VH of the tumor-associated antigen binding moiety;(vii) a linker between the CH1 and the VH of the TCRβV-binding moiety; (viii) a linker between the CL and the VL of the tumor-associated antigen binding moiety; (ix) a linker between the CL and the VL of the TCRβV-binding moiety; or(x) any combination thereof. In some embodiment, the linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non-helical linker. In some embodiment, the linker is the peptide linker, and wherein the linker comprises the sequence of SEQ ID NO: 3801, 3309, 3307, 3308, or 3643. In some embodiment, the multifunctional molecule is an isolated multifunctional molecule. In some embodiment, the tumor-associated antigen binding moiety, the TCRβV-binding moiety, or a combination thereof comprises a VHH, an Fab, or an scFv.

[0042] In some embodiment, the molecule that binds to a co-stimulatory receptor of a T cell comprisesat least one cytokine molecule or a functional fragment or functional variant thereof, and the at least one cytokine molecule or a functional fragment or functional variant thereof is selected from the group consisting of interleukin-2 (IL-2) or a functional fragment or functional variant thereof, interleukin-7 (IL- 7) or a functional fragment or functional variant thereof, interleukin-12 (IL-12) or a functional fragment or functional variant thereof, interleukin-15 (IL-15) or a functional fragment or functional variant thereof, interleukin-18 (IL-18) or a functional fragment or functional variant thereof, interleukin-21 (IL-21) or a functional fragment or functional variant thereof, or interferon gamma or a functional fragment or functional variant thereof, or any combination thereof. In some embodiment, the molecule that binds to a co-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof, and the at least one cytokine molecule or a functional fragment or functional variant thereof comprises interleukin-2 (IL-2) or a functional fragment or functional variant thereof. In some embodiment, the at least one cytokine molecule or a functional fragment or functional variant thereof is an IL-2 variant comprising a substitution mutation. In some embodiment, the at least one cytokine molecule or a functional fragment or functional variant thereof is an IL-2 variant comprising C125A mutation. In some embodiment, the at least one cytokine molecule or a functional fragment or functional variant thereof comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 2270 or the sequence of SEQ ID NO: 2191.

[0043] In some embodiment, the at least one cytokine molecule or a functional fragment or functionalvariant thereof comprises the sequence of SEQ ID NO: 2270 or the sequence of SEQ ID NO: 2191. In some embodiment, the molecule that binds to a co-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof, and the at least one cytokine molecule or a functional fragment or functional variant thereof comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to any one of the cytokine sequences as described herein orWSGR Docket No.53676-777.601 any one of the cytokine sequences as listed in Table 27. In some embodiment, the molecule that binds to a co-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof, and the at least one cytokine molecule or a functional fragment or functional variant thereof comprises any one of the cytokine sequences as described herein or any one of the cytokine sequences as listed in Table 27. In some embodiment, the molecule that binds to a co- stimulatory receptor of a T cell binds to CD2, 4-1BB, CD27, CD28, or any combination thereof.

[0044] In some embodiment, the first portion of the dimerization module comprises a firstimmunoglobulin constant regions (Fc regions) and the second portion of the dimerization module comprises a second Fc region. In some embodiment, the first Fc region, the second Fc region, or a combination thereof is selected from the group consisting of an IgG1 Fc region or a fragment thereof, an IgG2 Fc region or a fragment thereof, an IgG3 Fc region or a fragment thereof, an IgGA1 Fc region or a fragment thereof, an IgGA2 Fc region or a fragment thereof, an IgG4 Fc region or a fragment thereof, an IgJ Fc region or a fragment thereof, an IgM Fc region or a fragment thereof, an IgD Fc region or a fragment thereof, and an IgE Fc region or a fragment thereof. In some embodiment, the first Fc region, the second Fc region, or a combination thereof is selected from the group consisting of a human IgG1 Fc region or a fragment thereof, a human IgG2 Fc region or a fragment thereof, and a human IgG4 Fc region or a fragment thereof. In some embodiment, the first Fc region, the second Fc region, or a combination thereof comprises an Fc interface with one or more of: a paired cavity-protuberance, an electrostatic interaction, or a strand-exchange, wherein the dimerization of the first Fc region and the second Fc region is enhanced as indicated by a greater ratio of heteromultimer:homomultimer forms relative to a dimerization of Fc regions with a non-engineered interface.

[0045] In some embodiment, the first Fc region, the second Fc region, or a combination thereofcomprises an amino acid substitution listed in Table 4 or 14. In some embodiment, the first Fc region, the second Fc region, or a combination thereof comprises an Asn297Ala (N297A) mutation or a Leu234Ala / Leu235Ala (LALA) mutation. In some embodiment, the first Fc region, the second Fc region, or a combination thereof comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 40, 42, 3645, 3646, 3647, 3648, 3649, 3792, 3648, 3794, 3533, 1247, 1619, 1620, 571, 1669, 573, 1670, 1691, 1692, 1257, 550, 1080; 560, 1259, 1612, 1613, 579, 1678, 1700, 1704, 579, 1278, 1287, or 3794. In some embodiment, the first Fc region, the second Fc region, or a combination thereof comprises the sequence of SEQ ID NO: 40, 42, 3645, 3646, 3647, 3648, 3649, 3792, 3648, 3794, 3533, 1247, 1619, 1620, 571, 1669, 573, 1670, 1691, 1692, 1257, 550, 1080; 560, 1259, 1612, 1613, 579, 1678, 1700, 1704, 579, 1278, 1287, or 3794. In some embodiment, the first Fc region comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 3792, and the second Fc region comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 3648 orWSGR Docket. No.53676-777.601 SEQ ID NO: 3794, or the first Fc region comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 3794, and the second Fc region comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 3794. In some embodiment, the first Fc region comprises a sequence having the sequence of SEQ ID NO: 3649 or SEQ ID NO: 3792, and the second Fc region comprises the sequence of SEQ ID NO: 3648 or SEQ ID NO: 3794, or the first Fc region comprises the sequence of SEQ ID NO: 3648 or SEQ ID NO: 3794, and the second Fc region comprises the sequence of SEQ ID NO: 3648 or SEQ ID NO: 3794. In some embodiment, the first Fc region comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 3648, 3794, 3533, 1247, 1619, 1620, 571, 1669, 573, 1670, 1691, 1692, or 1257, and the second Fc region comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 550, 1080; 560, 1259, 1612, 1613, 579, 1678, 1700, 1704, 579, 1278, or 1287, or the first Fc region comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 550, 1080; 560, 1259, 1612, 1613, 579, 1678, 1700, 1704, 579, 1278, or 1287, and the second Fc region comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 3648, 3794, 3533, 1247, 1619, 1620, 571, 1669, 573, 1670, 1691, 1692, or 1257. In some embodiment, the first Fc region comprises a sequence having the sequence of SEQ ID NO: 3648, 3794, 3533, 1247, 1619, 1620, 571, 1669, 573, 1670, 1691, 1692, or 1257, and the second Fc region comprises the sequence of SEQ ID NO: 550, 1080; 560, 1259, 1612, 1613, 579, 1678, 1700, 1704, 579, 1278, or 1287, or the first Fc region comprises the sequence of SEQ ID NO: 550, 1080; 560, 1259, 1612, 1613, 579, 1678, 1700, 1704, 579, 1278, or 1287, and the second Fc region comprises the sequence of SEQ ID NO: 3648, 3794, 3533, 1247, 1619, 1620, 571, 1669, 573, 1670, 1691, 1692, or 1257.

[0046] In some embodiment, the TCRβV-binding moiety binds to one or more of a TCRβV subfamilyselected from the group consisting of TCRβ V2 subfamily, TCRβ V3 subfamily, TCRβ V4 subfamily, TCRβ V5 subfamily, TCRβ V6 subfamily, TCRβ V9 subfamily, TCRβ V10 subfamily, TCRβ V11 subfamily, TCRβ V12 subfamily, TCRβ V13 subfamily, TCRβ V16 subfamily, TCRβ V19, TCRβ V20 subfamily, TCRβ V21 subfamily, TCRβ V23 subfamily, TCRβ V27 subfamily, and TCRβ V28 subfamily. In some embodiment, the TCRβV-binding moiety binds to one or more of a TCRβV subfamily selected from the group consisting of: (i) TCRβ V2 subfamily comprising TCRβ V2*01; (ii) TCRβ V3 subfamily comprising TCRβ V3-1*01; (iii) TCRβ V4 subfamily comprising one or more selected from TCRβ V4-1, TCRβ V4-2, and TCRβ V4-3; (iv) TCRβ V5 subfamily comprising one orWSGR Docket No.53676-777.601 more selected from TCRβ V5-6*01, TCRβ V5-4*01, TCRβ V5-1*01, and TCRβ V5-8*01; (v) TCRβ V6 subfamily comprising one or more selected from TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01, and TCRβ V6-1*01; (vi) TCRβ V10 subfamily comprising one or more selected from TCRβ V10-1*01, TCRβ V10-1*02, TCRβ V10-3*01, and TCRβ V10-2*01; (vii) TCRβ V11 subfamily comprising TCRβ V11-2; (viii) TCRβ V12 subfamily comprising one or more selected from TCRβ V12-4*01, TCRβ V12- 3*01, and TCRβ V12-5*01; (ix) TCRβ V13 subfamily comprising TCRβ V13*01; (x) TCRβ V16 subfamily comprising TCRβ V16*01; (xi) TCRβ V19 subfamily comprising one or more selected from TCRβ V19*01 and TCRβ V19*02; or (xii) TCRβ V20 subfamily comprising TCRβ V20-1*01, or TCRβ V20-1*02. In some embodiment, the TCRβV-binding moiety binds to TCRβ V6 subfamily, TCRβV10 subfamily, TCRβV12 subfamily, or TCRβ V20 subfamily. In some embodiment, the TCRβV-binding moiety comprises: (i) a VH comprising a combination of a HC CDR1, a HC CDR2 and a HC CDR3 listed in Tables 1, 2, 10B, 10C, 11, 12, 13, 15- 21, 24, 29, or 30; (ii) a VL comprising a combination of a LC CDR1, a LC CDR2, and a LC CDR3 listed in Tables 1, 2, 10B, 10C, 11, 12, 13, 15- 21, 24, 29, or 30; or (iii) any combination thereof. In some embodiment, the TCRβV-binding moiety comprises: (i) a VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 of any one of the heavy chain variable domain amino acid sequences listed in Tables 1, 2, 10B, 10C, 11, 12, 13, 15- 21, 24, 29, or 30; (ii) a VL comprising a LC CDR1, a LC CDR2, and a LC CDR3 of any one of the light chain variable domain amino acid sequences listed in Tables 1, 2, 10B, 10C, 11, 12, 13, 15- 21, 24, 29, or 30; or (iii) any combination thereof. In some embodiment, the TCRβV-binding moiety comprises: (i) a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to any one of the heavy chain variable domain amino acid sequences listed in Tables 1, 2, 10B, 10C, 11, 12, 13, 15- 21, 24, 29, or 30; (ii) a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to any one of the light chain variable domain amino acid sequences listed in Tables 1, 2, 10B, 10C, 11, 12, 13, 15- 21, 24, 29, or 30; (iii) a combination thereof. In some embodiment, the TCRβV-binding moiety comprises: (i) a VH comprising any one of the heavy chain variable domain amino acid sequences listed in Tables 1, 2, 10B, 10C, 11, 12, 13, 15- 21, 24, 29, or 30; (ii) a VL comprising any one of the light chain variable domain amino acid sequences listed in Tables 1, 2, 10B, 10C, 11, 12, 13, 15- 21, 24, 29, or 30; (iii) a combination thereof. In some embodiment, the TCRβV-binding moiety comprises a heavy chain variable region (VH) comprising a heavy chain complementarity-determining region 1 (HC CDR1) sequence, a HC CDR2 sequence and a HC CDR3 sequence, wherein the HC CDR1, HC CDR2, HC CDR3 sequences have a sequence according to SEQ ID NOs: (a) 1232, 1233 and 544, respectively; (b) 1234, 543 and 544, respectively; (c) 1235, 1236 and 1237, respectively; or (d) 1238, 543 and 544, respectively. In some embodiment, the TCRβV-binding moiety comprises a light chain variable region (VL) comprising a light chain complementarity-determining region 1 (LC CDR1) sequence, a LC CDR2 sequence and a LC CDR3 sequence; wherein the LC CDR1, LC CDR2 and LC CDR3 sequences have aWSGR Docket. No.53676-777.601 sequence according to SEQ ID NOs: (a) 3655, 3653, and 8, respectively; (b) 1075, 1076, and 8, respectively; (c) 1218, 1219, and 8, respectively; (d) 1220, 1221, and 8, respectively; (e)545, 546, and 547, respectively; (f) 1239, 1240, and 547, respectively; (g) 3655, 1467, and 8, respectively; (h) 545, 546, and 1486, respectively; or (i) 1239, 1240, and 1486, respectively. In some embodiment, the TCRβV- binding moiety comprises a light chain variable region (VL) comprising a light chain complementarity- determining region 1 (LC CDR1) sequence, a LC CDR2 sequence and a LC CDR3 sequence; wherein the LC CDR1, LC CDR2 and LC CDR3 sequences have a sequence according to SEQ ID NOs: (a) 1218, 1219, and 8, respectively; (b) 1220, 1221, and 8, respectively; (c) 3655, 1467, and 8, respectively; (d) 545, 546, and 1486, respectively; or (e) 1239, 1240, and 1486, respectively. In some embodiment, the TCRβV-binding moiety comprises a heavy chain variable region (VH) comprising a heavy chain complementarity-determining region 1 (HC CDR1) sequence, a HC CDR2 sequence and a HC CDR3 sequence, wherein the HC CDR1, HC CDR2, HC CDR3 sequences have a sequence according to SEQ ID NOs: (a) 1069, 1070 and 5, respectively; (b) 1071, 3651 and 5, respectively; (c) 1072, 1073 and 1074, respectively; (d) 3650, 3651 and 5, respectively; (e) 1069, 1070 and 5, respectively; (f) 1071, 3651 and 5, respectively; (g) 1072, 1073 and 1074, respectively; (h) 3650, 3651 and 5, respectively; (i) 1232, 1233 and 544, respectively; (j) 1234, 543 and 544, respectively; (k) 1235, 1236 and 1237, respectively; (l) 1238, 543 and 544, respectively; (m) 1243, 1233 and 544, respectively; (n) 1244, 543 and 544, respectively; (o) 1245, 1236 and 1237, respectively; (p) 542, 543 and 544, respectively; (q) 1069, 1070 and 5, respectively; (r) 1071, 3651 and 5, respectively; (s) 3650, 3651 and 5, respectively; (t) 1232, 1233 and 544, respectively; (u) 1234, 543 and 544, respectively; (v) 1235, 1236 and 1237, respectively; or (w)1238, 543 and 544, respectively.

[0047] In some embodiment, the TCRβV-binding moiety comprises (A) a heavy chain variable region(VH) comprising a heavy chain complementarity-determining region 1 (HC CDR1) sequence, a HC CDR2 sequence and a HC CDR3 sequence, and (B) a light chain variable region (VL) comprising a light chain complementarity-determining region 1 (LC CDR1) sequence, a LC CDR2 sequence and a LC CDR3 sequence; wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 sequences have a sequence according to SEQ ID NOs: (a) 1069, 1070, 5, 3655, 3653, and 8, respectively; (b) 1071, 3651, 5, 3655, 3653, and 8, respectively; (c) 1072, 1073, 1074, 1075, 1076, and 8, respectively; (d) 3650, 3651, 5, 3655, 3653, and 8, respectively; (e) 1069, 1070, 5, 1218, 1219, and 8, respectively; (f) 1071, 3651, 5, 1218, 1219, and 8, respectively; (g) 1072, 1073, 1074, 1220, 1221, and 8, respectively; (h) 3650, 3651, 5, 1218, 1219, and 8, respectively; (i) 1232, 1233, 544, 545, 546, and 547, respectively; (j) 1234, 543, 544, 545, 546, and 547, respectively; (k) 1235, 1236, 1237, 1239, 1240, and 547, respectively; (l) 1238, 543, 544, 545, 546, and 547, respectively; (m) 1243, 1233, 544, 545, 546, and 547, respectively; (n) 1244, 543, 544, 545, 546, and 547, respectively; (o) 1245, 1236, 1237, 1239, 1240, and 547, respectively; (p) 542, 543, 544, 545, 546, and 547, respectively; (q) 1069, 1070, 5, 3655, 1467, and 8, respectively; (r) 1071, 3651, 5, 3655, 1467, and 8, respectively; (s) 1072, 1073, 1074, 1220, 1221, and 8, respectively; (t) 3650, 3651, 5, 3655, 1467, and 8, respectively; (u) 1232, 1233, 544, 545, 546, and 1486, respectively; (v) 1234, 543, 544, 545, 546, and 1486, respectively; (w) 1235, 1236, 1237, 1239,WSGR Docket No.53676-777.601 1240, and 1486, respectively; or (x) 1238, 543, 544, 545, 546, and 1486, respectively. In some embodiment, the TCRβV-binding moiety comprises (a) a VH having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1346 and a VL having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1349, (b) a VH having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO:1346 and a VL having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO:1217, (c) a VH having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1231 and a VL having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3527, (d) a VH having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 541 and a VL having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3527, (e) a VH having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1231 and a VL having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1485, or (f) a VH having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1346 and a VL having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1466.

[0048] In some embodiment, the TCRβV-binding moiety comprises (a) an scFv having at least 80%,81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1331, (b) an scFv having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1216, (c) an scFv having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1230, (d) an scFv having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1376, (e) an scFv having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1483, or (f) an scFv having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1701. In some embodiment, the second polypeptide chain comprises a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%WSGR Docket. No.53676-777.601 sequence identity to the sequence of SEQ ID NO: 1346, 541, or 1231, a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466, a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 2270, and a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 3648. In some embodiment, the second polypeptide chain comprises the sequence of SEQ ID NO: 1346, 541, or 1231, the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466, the sequence of SEQ ID NO: 2270, and the sequence of SEQ ID NO: 3648. In some embodiment, the second polypeptide chain further comprises the sequence of SEQ ID NO: 3801, the sequence of SEQ ID NO: 3309, the sequence of SEQ ID NO: 3308, or any combination thereof. In some embodiment, the second polypeptide chain comprises a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1346, 541, or 1231 operatively linked to a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466 operatively linked to a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 2270 operatively linked to a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 3648. In some embodiment, the sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1346, 541, or 1231 is operatively linked to the sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466 via the sequence of SEQ ID NO: 3801. In some embodiment, the sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466 is operatively linked to the sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 2270 via the sequence of SEQ ID NO: 3309. In some embodiment, the sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 2270 is operatively linked to the sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 3648 via the sequence of SEQ ID NO: 3308.WSGR Docket No.53676-777.601

[0049] In some embodiment, the second polypeptide chain comprises the sequence of SEQ ID NO:1346, 541, or 1231 operatively linked to the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466 operatively linked to the sequence of SEQ ID NO: 2270 operatively linked to the sequence of SEQ ID NO: 3648. In some embodiment, the sequence of SEQ ID NO: 1346, 541, or 1231 is operatively linked to the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466 via the sequence of SEQ ID NO: 3801. In some embodiment, the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466 is operatively linked to the sequence of SEQ ID NO: 2270 via the sequence of SEQ ID NO: 3309. In some embodiment, the sequence of SEQ ID NO: 2270 is operatively linked to the sequence of SEQ ID NO: 3648 via the sequence of SEQ ID NO: 3308. In some embodiment, the second polypeptide chain comprises a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 3800. In some embodiment, the second polypeptide chain comprises the sequence of SEQ ID NO: 3800. In some embodiment, the multifunctional molecule consists of a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises the tumor-associated antigen binding moiety linked to an Fc region, wherein the tumor-associated antigen binding moiety is an scFv that binds to a tumor-associated antigen, and the second polypeptide chain comprises the sequence of SEQ ID NO 3800. In some embodiment, the multifunctional molecule consists of a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises the tumor-associated antigen binding moiety linked to a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 3792, wherein the tumor-associated antigen binding moiety is an scFv that binds to a tumor-associated antigen, and the second polypeptide chain comprises the sequence of SEQ ID NO 3800. In some embodiment, the multifunctional molecule consists of a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises the tumor-associated antigen binding moiety linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 3792, wherein the tumor-associated antigen binding moiety is an scFv that binds to a tumor-associated antigen, and the second polypeptide chain comprises the sequence of SEQ ID NO 3800. In some embodiment, the multifunctional molecule consists of a first polypeptide chain, a second polypeptide chain, and a third polypeptide chain, wherein the first polypeptide chain comprises a first portion of the tumor-associated antigen binding moiety linked to an Fc region, wherein the tumor-associated antigen binding moiety is an Fab that binds to a tumor-associated antigen; the second polypeptide chain comprises the sequence of SEQ ID NO 3800; and the third polypeptide chain comprises a second portion of the tumor-associated antigen binding moiety.

[0050] In some embodiment, the multifunctional molecule consists of a first polypeptide chain, a secondpolypeptide chain, and a third polypeptide chain, wherein the first polypeptide chain comprises a first portion of the tumor-associated antigen binding moiety linked to a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 3792, wherein theWSGR Docket. No.53676-777.601 tumor-associated antigen binding moiety is an Fab that binds to a tumor-associated antigen; the second polypeptide chain comprises the sequence of SEQ ID NO 3800; and the third polypeptide chain comprises a second portion of the tumor-associated antigen binding moiety. In some embodiment, the multifunctional molecule consists of a first polypeptide chain, a second polypeptide chain, and a third polypeptide chain, wherein the first polypeptide chain comprises a first portion of the tumor-associated antigen binding moiety linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 3792, wherein the tumor-associated antigen binding moiety is an Fab that binds to a tumor-associated antigen; the second polypeptide chain comprises the sequence of SEQ ID NO 3800; and the third polypeptide chain comprises a second portion of the tumor-associated antigen binding moiety. In some embodiment, the multifunctional molecule is a polypeptide molecule.

[0051] In some embodiment, the TCRβV-binding moiety comprises a VH comprising a sequence havingat least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1346, 541, or 1231. In some embodiment, the TCRβV-binding moiety comprises a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466. In some embodiment, the TCRβV-binding moiety comprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1346 and a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1349. In some embodiment, the TCRβV-binding moiety comprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 541 and a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity the sequence of SEQ ID NO: 3527. In some embodiment, the TCRβV-binding moiety comprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1346 and a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity the sequence of SEQ ID NO: 1217. In some embodiment, the TCRβV-binding moiety comprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1231 and a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity the sequence of SEQ ID NO: 3527. In some embodiment, the TCRβV-binding moiety comprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,WSGR Docket No.53676-777.601 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1231 and a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity the sequence of SEQ ID NO: 1485. In some embodiment, the TCRβV-binding moiety comprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1346 and a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity the sequence of SEQ ID NO: 1466. In some embodiment, the TCRβV-binding moiety comprises an scFv comprising the sequence of SEQ ID NO: 1346, 541, or 1231 operatively linked to the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466 via a linker comprising the sequence of SEQ ID NO: 3801. In some embodiment, the TCRβV- binding moiety comprises an scFv comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1331, 1216, 1230, 1376, 1483, or 1701. In some embodiment, the multifunctional molecule comprises a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1066, 1067, 1461, 1462, 1464, 1465, 1471, 1472, 1477, 1478, 1481, 1482, 1496, 1497, 1617, 1703, 1705, 1706, 615, or 1661. In some embodiment, the multifunctional molecule comprises a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1077 or 1078. In some embodiment, the multifunctional molecule comprises a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1081 or 508. In some embodiment, the multifunctional molecule comprises: (a) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1066 or 1067, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081; (b) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1461 or 1462, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081; (c) a first polypeptide chain having a sequence with at least 80%, 81%,WSGR Docket. No.53676-777.601 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1464 or 1465, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081; (d) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1471 or 1472, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081; (e) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1477 or 1478, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081; (f) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1481 or 1482, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081; (g) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1496 or 1497, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081; (h) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1617 or 1703, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%,WSGR Docket No.53676-777.601 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081; (i) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1705 or 1706, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081; or (j) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 615 or 1661, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081.

[0052] In some embodiment, the multifunctional molecule is a multispecific molecule.

[0053] Also described herein, in some embodiment, is a polynucleotide comprising a sequence encodingthe multifunctional molecule described herein. In some embodiment, the polynucleotide is an isolated nucleic acid molecule. Also described herein, in some embodiment, is a vector comprising one or more of the polynucleotide described herein. Also described herein, in some embodiment, is a cell comprising the polynucleotide described herein. Also described herein, in some embodiment, is a pharmaceutical composition comprising the multifunctional molecule, the polynucleotide, the vector, or the cell described herein, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0054] Also described herein, in some embodiment, is a method of treating a condition or disease in asubject in need thereof comprising administering to the subject a therapeutically effective amount of the multifunctional molecule, the polynucleotide, the vector, the cell, the pharmaceutical composition, or any combination thereof, wherein the administering is effective to treat the condition or disease in the subject. In some embodiment, the condition or disease is cancer. In some embodiment, the cancer is a solid tumor, a hematological cancer, a metastatic cancer, a soft tissue tumor, or any combination thereof. In some embodiment, the cancer is the solid tumor, and wherein the solid tumor is selected from the group consisting of breast cancer, colorectal cancer, lung cancer, prostate cancer, and a combination thereof. In some embodiment, the breast cancer is a Triple-Negative Breast Cancer (TNBC) or a metastatic Triple Negative Breast Cancer (mTNBC).283 In some embodiment, the cancer is the hematological cancer, and wherein the hematological cancer is selected from the group consisting of Hodgkin’s lymphoma, Non- Hodgkin’s lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia, myelodysplastic syndrome, multiple myeloma, T-cell lymphoma, acute lymphocytic leukemia, and a combination thereof. In some embodiment, the Non-Hodgkin’s lymphoma is selected from the group consisting of B cell lymphoma, diffuse large B cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocyticWSGR Docket. No.53676-777.601 leukemia (B-CLL), mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, and a combination thereof. In some embodiment, the T-cell lymphoma is peripheral T-cell lymphoma. In some embodiment, the cancer is characterized by a cancer antigen present on the cancer. In some embodiment, the cancer antigen is a tumor antigen, a stromal antigen, or a hematological antigen. In some embodiment, the cancer antigen is selected from the group consisting of CD19, CD123, CD22, CD30, CD171, CS-1, C-type lectin-like molecule-1, CD33, epidermal growth factor receptor variant III (EGFRvIII), ganglioside G2 (GD2), ganglioside GD3, TNF receptor family member B cell maturation (BCMA), Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr)), prostate-specific membrane antigen (PSMA), Receptor tyrosine kinase-like orphan receptor 1 (ROR1), Fms-Like Tyrosine Kinase 3 (FLT3), Tumor-associated glycoprotein 72 (TAG72), CD38, CD44v6, Carcinoembryonic antigen (CEA), Epithelial cell adhesion molecule (EPCAM), B7H3 (CD276), KIT (CD117), Interleukin-13 receptor subunit alpha-2, mesothelin, Interleukin 11 receptor alpha (IL-11Ra), prostate stem cell antigen (PSCA), Protease Serine 21, vascular endothelial growth factor receptor 2 (VEGFR2), Lewis(Y) antigen, CD24, Platelet-derived growth factor receptor beta (PDGFR-beta), Stage- specific embryonic antigen-4 (SSEA-4), CD20, Folate receptor alpha, Receptor tyrosine-protein kinase ERBB2 (Her2 / neu), Mucin 1, cell surface associated (MUC1), epidermal growth factor receptor (EGFR), neural cell adhesion molecule (NCAM), Prostase, prostatic acid phosphatase (PAP), elongation factor 2 mutated (ELF2M), Ephrin B2, fibroblast activation protein alpha (FAP), insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX), Proteasome (Prosome, Macropain) Subunit, Beta Type, 9 (LMP2), glycoprotein 100 (gp100 / pmel17), oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr-abl), tyrosinase, ephrin type-A receptor 2 (EphA2), Fucosyl GM1, sialyl Lewis adhesion molecule (sLe), ganglioside GM3, transglutaminase 5 (TGS5), high molecular weight-melanoma-associated antigen (HMWMAA), o-acetyl-GD2 ganglioside (OAcGD2), Folate receptor beta, tumor endothelial marker 1 (TEM1 / CD248), tumor endothelial marker 7-related (TEM7R), claudin 6 (CLDN6), thyroid stimulating hormone receptor (TSHR), G protein-coupled receptor class C group 5, member D (GPRC5D), chromosome X open reading frame 61 (CXORF61), CD97, CD179a, anaplastic lymphoma kinase (ALK), Polysialic acid, placenta-specific 1 (PLAC1), hexasaccharide portion of globoH glycoceramide (GloboH), mammary gland differentiation antigen (NY-BR-1), uroplakin 2 (UPK2), Hepatitis A virus cellular receptor 1 (HAVCR1), adrenoceptor beta 3 (ADRB3), pannexin 3 (PANX3), G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex, locus K 9 (LY6K), Olfactory receptor 51E2 (OR51E2), TCR Gamma Alternate Reading Frame Protein (TARP), Wilms tumor protein (WT1), Cancer / testis antigen 1 (NY-ESO-1 / LAGE-1), Cancer / testis antigen 2 (LAGE-1a), Melanoma-associated antigen 1 (MAGE-A1), ETS translocation-variant gene 6, located on chromosome 12p (ETV6-AML), sperm protein 17 (SPA17), X Antigen Family, Member 1A (XAGE1), angiopoietin-binding cell surface receptor 2 (Tie 2), melanoma cancer testis antigen-1 (MAD-CT-1), melanoma cancer testis antigen-2 (MAD-CT-2), Fos-related antigen 1, tumor protein p53 (p53), p53 mutant, prostein, Survivin, telomerase, prostate carcinoma tumor antigen-1, melanoma antigen recognized by T cells 1, Rat sarcoma (Ras)WSGR Docket No.53676-777.601 mutant, human Telomerase reverse transcriptase (hTERT), sarcoma translocation breakpoints, melanoma inhibitor of apoptosis (ML-IAP), ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene), N-Acetyl glucosaminyl-transferase V (NA17), paired box protein Pax-3 (PAX3), Androgen receptor, Cyclin B1, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), Ras Homolog Family Member C (RhoC), Tyrosinase-related protein 2 (TRP-2), Cytochrome P4501B1 (CYP1B1), CCCTC-Binding Factor (Zinc Finger Protein)-Like, Squamous Cell Carcinoma Antigen Recognized By T Cells 3 (SART3), Paired box protein Pax-5 (PAX5), proacrosin binding protein sp32 (OY-TES1), lymphocyte-specific protein tyrosine kinase (LCK), A kinase anchor protein 4 (AKAP-4), synovial sarcoma, X breakpoint 2 (SSX2), Receptor for Advanced Glycation Endproducts (RAGE-1), renal ubiquitous 1 (RU1), renal ubiquitous 2 (RU2), legumain, human papilloma virus E6 (HPV E6), human papilloma virus E7 (HPV E7), intestinal carboxyl esterase, heat shock protein 70-2 mutated (mut hsp70-2), CD79a, CD79b, CD72, Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), Fc fragment of IgA receptor (FCAR or CD89), Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2), CD300 molecule-like family member f (CD300LF), C-type lectin domain family 12 member A (CLEC12A), bone marrow stromal cell antigen 2 (BST2), EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2), lymphocyte antigen 75 (LY75), Glypican-3 (GPC3), Fc receptor-like 5 (FCRL5), FcRH5, PDL1, CD47, prostate specific membrane antigen (PMSA), prostate- specific antigen (PSA), Ron Kinase, c-Met, Immature laminin receptor, TAG-72, BING-4, Calcium- activated chloride channel 2, Cyclin-B1, 9D7, Ep-CAM, EphA3, SAP-1, PRAME, SSX-2, Melan- A / MART-1, TRP1 / gp75, MC1R, β-catenin, BRCA1 / 2, CDK4, CML66, Fibronectin, Ras, TGF-Β receptor, AFP, ETA, MAGE, CA-125, BAGE, GAGE, CDC27, α actinin-4, gangliosides, MART-2, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RU11, RU12, SAGE, TRG, TSTA, L1-CAM, gpA33, GM2, VEGFR, Integrins, carbohydrates, TRAILR1, TRAILR2, RANKL, TGF-beta, hyaluronic acid, collagen, tenascin C, tenascin W, and immunoglobulin lambda-like polypeptide 1 (IGLL1). In some embodiment, the cancer antigen is TROP-2. In some embodiment, the cancer is a TROP-2 associated cancer. In some embodiment, the cancer comprises breast cancer, colorectal cancer, lung cancer, prostate cancer, or any combination thereof. In some embodiment, the wherein the breast cancer is a Triple-Negative Breast Cancer (TNBC) or a metastatic Triple Negative Breast Cancer (mTNBC). In some embodiment, the method described herein further comprises administering a second therapeutic agent or therapy to the subject. In some embodiment, the second therapeutic agent or therapy comprises a chemotherapeutic agent, a biologic agent, a hormonal therapy, radiation, or surgery. In some embodiment, the second therapeutic agent or therapy is administered in combination with the multifunctional molecule, the polynucleotide, the vector, the cell, and / or the pharmaceutical composition, sequentially, simultaneously, or concurrently. In some embodiment, the multifunctional molecule, the polynucleotide, the vector, the cell, and / or the pharmaceutical composition induces T cell mediated cytotoxicity of tumor cells. In some embodiment, the multifunctional molecule, the polynucleotide, the vector, the cell, and / or the pharmaceutical composition induces T cell activation. In some embodiment,WSGR Docket. No.53676-777.601 the multifunctional molecule, the polynucleotide, the vector, the cell, and / or the pharmaceutical composition induces T cell proliferation. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] The novel features of the disclosure are set forth with particularity in the appended claims. Abetter understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0056] FIGS. 1-25 depict exemplary embodiments of multifunctional molecules as described herein.

[0057] FIGS. 1, 2, and 3 depict exemplary embodiments of multifunctional molecules containingmultiple, e.g., two, molecules of a cytokine molecule linked to one or more antibody molecule that binds to a T cell receptor beta variable region (TCRβV) (“anti-TCRβV antibody molecule”). FIG.1 shows a first cytokine molecule linked to C-terminus of a light chain of a first antibody molecule and a second cytokine molecule linked to C-terminus of a light chain of a second antibody molecule. FIG.2 shows a first cytokine molecule linked to N-terminus of a heavy chain of a first antibody molecule and a second cytokine molecule linked to N-terminus of a heavy chain of a second antibody molecule. FIG.3 shows a first cytokine molecule linked to N-terminus of a light chain of a first antibody molecule and a second cytokine molecule linked to N-terminus of a light chain of a second antibody molecule.

[0058] FIGS. 4, 5, and 6 depict exemplary embodiments of multifunctional molecules containing asingle molecule of a cytokine molecule linked to an anti-TCRβV antibody molecule. FIG.4 shows the cytokine molecule linked to C-terminus of the antibody molecule light chain. FIG.5 shows the cytokine molecule linked to N-terminus of the antibody molecule heavy chain. FIG.6 shows the cytokine molecule linked to N-terminus of the antibody molecule light chain.

[0059] FIGS. 7, 8, 9, and 10 depict exemplary embodiments of multifunctional molecules containing acytokine molecule linked to a first dimerization module, wherein the multifunctional molecule contains one or more anti-TCRβV antibody molecule. FIG.7 shows the cytokine molecule linked to N-terminus of the dimerization module. FIG.8 shows the cytokine molecule linked to C-terminus of the dimerization module. FIG.9 shows the cytokine molecule linked to C-terminus of the dimerization module. FIG.10 shows a first cytokine molecule linked to C-terminus of a first dimerization module and a second cytokine molecule linked to C-terminus of a second dimerization module.

[0060] FIGS. 11, 12, and 13 depict exemplary embodiments of multifunctional molecules containing anexemplary dimerization module, e.g., an Fc region comprising a N297A mutation, and multiple, e.g., two, molecules of a cytokine molecule linked to an anti-TCRβV antibody molecule. FIG.11 shows a first cytokine molecule linked to C-terminus of a light chain of a first antibody molecule and a second cytokine molecule linked to C-terminus of a light chain of a second antibody molecule. FIG.12 shows a first cytokine molecule linked to N-terminus of a heavy chain of a first antibody molecule and a second cytokine molecule linked to N-terminus of a heavy chain of a second antibody molecule. FIG.13 shows a first cytokine molecule linked to N-terminus of a light chain of a first antibody molecule and a second cytokine molecule linked to N-terminus of a light chain of a second antibody molecule.WSGR Docket No.53676-777.601

[0061] FIGS. 14, 15, and 16 depict exemplary embodiments of multifunctional molecules containing anexemplary dimerization module, e.g., an Fc region comprising a N297A mutation (Knob-in-hole), and a single molecule of a cytokine molecule linked to an anti-TCRβV antibody molecule. FIG.14 shows the cytokine molecule linked to C-terminus of the antibody molecule light chain. FIG.15 shows the cytokine molecule linked to N-terminus of the antibody molecule heavy chain. FIG.16 shows the cytokine molecule linked to N-terminus of the antibody molecule light chain.

[0062] FIGS. 17, 18, 19, and 20 depict exemplary embodiments of multifunctional moleculescontaining an exemplary dimerization module, e.g., an Fc region comprising a N297A mutation (Knob- in-hole), and a cytokine molecule linked to the exemplary dimerization module. FIG.17 shows the cytokine molecule linked to N-terminus of the dimerization module. FIG.18 shows the cytokine molecule linked to C-terminus of the dimerization module. FIG.19 shows the cytokine molecule linked to C-terminus of the dimerization module. FIG.20 shows a first cytokine molecule linked to C-terminus of a first dimerization module and a second cytokine molecule linked to C-terminus of a second dimerization module.

[0063] FIG. 21 shows an exemplary embodiment of multifunctional molecules comprising a TCRβV-binding moiety and a cytokine molecule (“cytokine”) as described herein.

[0064] FIGS. 22, 23, 24, and 25 show exemplary embodiments of multifunctional moleculescomprising a first TCRβV-binding moiety, a second TCRβV-binding moiety, and two cytokine molecules as described herein. FIG.22 shows a first cytokine molecule linked to C-terminus of a light chain of a first antibody molecule and a second cytokine molecule linked to C-terminus of a light chain of a second antibody molecule. FIG.23 shows a first cytokine molecule linked to N-terminus of a heavy chain of a first antibody molecule and a second cytokine molecule linked to N-terminus of a heavy chain of a second antibody molecule. FIG.24 shows a first cytokine molecule linked to C-terminus of a first dimerization module and a second cytokine molecule linked to C-terminus of a second dimerization module. FIG.25 shows a first cytokine molecule linked to C-terminus of a light chain of a first antibody molecule and a second cytokine molecule linked to C-terminus of a light chain of a second antibody molecule.

[0065] In some embodiments, the cytokine molecule comprises IL-2 or a functional fragment or variantthereof, IL2-C125A or a functional fragment or variant thereof, IL-15 or a functional fragment or variant thereof, IL-7 or a functional fragment or variant thereof, IL-12 or a functional fragment or variant thereof, or IL-21 or a functional fragment or variant thereof. In some embodiments, the cytokine molecule further comprises a cytokine receptor or a functional fragment or variant thereof. In some embodiments, the cytokine molecule comprises IL-15 or a functional fragment or variant thereof. In some embodiments, the cytokine molecule further comprises an IL15Ralpha dimerizing domain. In some embodiments, the cytokine molecule further comprises an IL15Ralpha dimerizing domain linked the IL- 15 or a functional fragment or variant thereof. In some embodiments, the cytokine molecule further comprises an IL15Ralpha dimerizing domain covalently linked the IL-15 or a functional fragment or variant thereof. In some embodiments, the cytokine molecule comprises IL-15 linked to an IL-15Ra. InWSGR Docket. No.53676-777.601 some embodiments, the cytokine molecule further comprises an IL15Ralpha dimerizing domain non- covalently linked the IL-15 or a functional fragment or variant thereof. In some embodiments, the IL15Ralpha dimerizing domain comprises an IL-15 receptor alpha sushi domain or a functional fragment or variant thereof. In some embodiments, the IL-15 or a functional fragment or variant thereof is covalently linked to the IL15Ralpha dimerizing domain via a linker. In some embodiments, the cytokine molecule comprises IL-15 linked to an IL-15Ra sushi domain. In some embodiments, the cytokine molecule comprises a cytokine dimer. In some embodiments, the cytokine molecule comprises an IL-12 beta subunit linked to an IL-12 alpha subunit.

[0066] FIGS. 26A and 26B shows the alignment of the Antibody A source mouse VH and VLframework 1, CDR 1, framework 2, CDR 2, framework 3, CDR3, and framework 4 regions with their respective humanized sequences. Kabat CDRs are shown in bold, Chothia CDRs are shown in italics, and combined CDRs are shown in boxes. The framework positions that were back mutated are double underlined. FIG.26A shows VH sequences for murine Antibody A (SEQ ID NO: 1) and humanized Antibody A-H (SEQ ID NO: 9). FIG.26B shows VL sequences for murine Antibody A (SEQ ID NO: 2) and humanized Anti-body A-H (SEQ ID NO: 10 and SEQ ID NO: 11).

[0067] FIGs. 27A, 27B and 27C show that anti-CD20 TriSTAR molecules, which are exemplaryembodiments of the multifunctional molecule as provided herein, induce highly potent Vβ -specific expansion, CD8+ T cell activation and killing of B cells in vitro. FIG.27A depicts in vitro murine Vβ T cell expansion, FIG.27B depicts in vitro murine CD8+ T cell activation and expansion, and FIG.27C depicts in vitro murine B cell depletion.

[0068] FIG. 28 shows that anti-CD20 TriSTAR T-cell engagers (TCEs), which are exemplaryembodiments of the multifunctional molecule as provided herein, also show potent B cell-depletion in vivo upon single IP dose of 3 mg / kg. In the same study anti-CD3 / CD20 bispecific was also tested and showed to have comparable potency in vivo.

[0069] FIGs. 29A and 29B show in vitro expansion with anti-MSLN TriSTAR (BLM0155), which is anexemplary embodiment of the multifunctional molecule as provided herein, and CD3 TCE (BMM0388). Both TriSTAR and CD3 engagers expanded in the presence of plate-bound MSLN. FIG.29A depicts %CD25+, and FIG.29B depicts EC50 and Emax (%).

[0070] FIGs. 30A and 30B show in vitro expansion with anti-MSLN Vb bispecific TCEs (BLM0158,1x1 format; BMM0274, 2x2 format), which are exemplary embodiments of the multifunctional molecule as provided herein, and CD3 TCE . Both Vb and CD3 engagers expanded in the presence of plate-bound MSLN. CD3 TCE expanded much more. FIG.30A depicts %CD25+, and FIG.30B depicts EC50 and Emax (%).

[0071] FIGs. 31A and 31B show in vitro cytotoxicity with anti-MSLN TriSTARs (BLM0155, 1x1x1TriSTAR ; BMM0462, 2x1x1 TriSTAR format), which are exemplary embodiments of the multifunctional molecule as provided herein, and CD3 TCE (BMM0388). FIG.31A depicts %cytotoxicity, and FIG.31B depicts EC50 and Emax (%).WSGR Docket No.53676-777.601

[0072] FIGs. 32A and 32B show in vitro cytotoxicity with anti-MSLN Vb bispecific TCEs (BLM0158,1x1 format; BMM0274, 2x2 format), which are exemplary embodiments of the multifunctional molecule as provided herein, and CD3 TCE . FIG.32A depicts %cytotoxicity, and FIG.32B depicts EC50 and Emax (%).

[0073] FIGs. 33A and 33B show in vitro expansion with anti-MSLN TriSTAR murine surrogates(BMM0449, 1x1x1 TriSTAR format; BMM0456, 2x1x1 TriSTAR format), which are exemplary embodiments of the multifunctional molecule as provided herein, and CD3 TCE (BMM0456, 1x1 CD3 TCE; BMM0469, 2x1 CD3 TCE). All the TCE constructs showed potent expansion in the presence of the plate-bound MSLN. FIG.33A depicts %CD25+, and FIG.33B depicts EC50 and Emax (%).

[0074] FIGs. 34A-34D show in vitro expansion with anti-MSLN Vb TCE murine surrogates(BMM0446, 1x1 format; BMM0439, 2x2 format), which is an exemplary embodiment of the multifunctional molecule as provided herein, and CD3 TCE (BMM0456). All the constructs demonstrated expansion in the presence of plate-bund MSLN. FIGs.34A and 34C depict %CD25+, and FIGs.34B and 34D depict EC50 and Emax (%).

[0075] FIG. 35 shows in vitro cytotoxicity of EMT6 cells with anti-MSLN TriSTAR murine surrogate(BMM0449) and CD3 TCE (BMM0456).

[0076] FIGs. 36A and 36B show in vitro cytotoxicity of EMT6 cells anti-MSLN Vb TCE murinesurrogates (BMM0446, 1x1 format; BMM0439, 2x2 format), which are exemplary embodiments of the multifunctional molecule as provided herein, and CD3 TCE .FIG.36A depicts %cytotoxicity, and FIG. 36B depicts EC50 and Emax (%).

[0077] FIGs. 37A and 37B show that anti-MSLN TriSTAR murine surrogate (BMM0449), which areexemplary embodiments of the multifunctional molecule as provided herein, show potent anti-tumor activity vs. αCD3 TCE (BMM0456) in EMT6 syngeneic mouse model. Tumor bearing mice received weekly doses of 3 mg / kg of the test articles for 4 weeks. FIG.37A depicts a scheme of the experimental design, and FIG.37B depicts mean tumor volume.

[0078] FIG. 38 shows PK data for anti-MSLN TriSTAR murine surrogate (BMM0449), which is anexemplary embodiment of the multifunctional molecule as provided herein.

[0079] FIG. 39 shows that anti-gp75 Vβ bispecific TCEs murine surrogates (BNM0104, 1x1 format andBNM0869, 2x2 format), which are exemplary embodiments of the multifunctional molecule as provided herein, showed limited activity in solid (B16F10) syngeneic tumors. Limited anti-tumor activity of 1x1 and 2x2 Vβ x gp75 TCEs, which are exemplary embodiments of the multifunctional molecule as provided herein, in B16F10 solid tumor model.

[0080] FIG. 40 shows that when combined with an exemplary multifunctional molecule comprising aanti-Vβ binder and IL-2 (BKM0307), anti-gp75 Vβ murine surrogate TCEs (BNM0104, 1x1 format and BNM0869, 2x2 format), which are exemplary embodiments of the multifunctional molecule as provided herein, are highly active.1x1 and 2x2 Vβ x gp75 T cell engagers are active in B16F10 tumor model when dosed with or following an exemplary multifunctional molecule comprising an anti-Vβ binder and IL-2.WSGR Docket. No.53676-777.601

[0081] FIG. 41 shows that anti-gp75 TriSTAR TCE murine surrogate (BNM0094), which is anexemplary embodiment of the multifunctional molecule as provided herein, promotes superior anti-tumor activity vs. anti-gp75 / αCD3 TCEs (BNM0092) in B16F10 model. Significant anti-tumor activity in refractory B16 mouse with TriSTAR TCE was observed.

[0082] FIGs. 42A-42C show pharmacokinetics of TriSTAR construct (BNM0094), which is anexemplary embodiment of the multifunctional molecule as provided herein. FIG.42A depicts the results of an exemplary embodiments of the multifunctional molecule as provided herein, BNM0094, and FIG. 42B depicts the results of a CD3 x gp75 bispecific molecule, BNM0092. FIG.42C depicts the experimental design.

[0083] FIGs. 43A-43C show that in B16F10 tumors, TriSTAR, which is an exemplary embodiment ofthe multifunctional molecule as provided herein, promotes greater expansion of cytotoxic CD8 T cells in the tumor microenvironment. FIG.43A depicts %CD8 of CD45 cells, FIG.43B depicts %CD8 CD25 cells, and FIG.43C depicts %CD8 granzyme B cells.

[0084] FIGs. 44A and 44B show Vβ13+ T cell expansion by Tri-STAR, which is an exemplaryembodiment of the multifunctional molecule as provided herein, in tumor microenvironment (TME). FIG.44A depicts CD8 Vb cells / mg tumor, and FIG.44B depicts %CD8 Vb subset frequency.

[0085] FIG. 45 shows dosing schedule and mean tumor volume upon treatment with BKM0307,BNM0094, BNM0092, BNM0104, BJM0869, or sequential treatment of BKM0307, followed by BNM0104, BJM0869, or BNM0092.

[0086] FIG. 46 shows dosing schedule and mean tumor volume upon treatment with BKM0307,BNM0094, BNM0092, BNM0104, BJM0869, or alternate dosing of BKM0307, followed by BNM0104, BJM0869, or BNM0092.

[0087] FIG. 47 shows dosing schedule and mean tumor volume upon treatment with BKM0307,BNM0094, BNM0092, BNM0104, or BNM0276, or co-dosing of BKM0307and BNM0092.

[0088] FIG. 48 shows dosing schedule and mean tumor volume upon treatment with BKM0307,BNM0094, BNM0092, BNM0104, or BNM0276, or alternate dosing of BKM0307, followed by BNM0104 or BNM0276. INCORPORATION BY REFERENCE

[0089] All publications, patents, and patent applications mentioned in this specification are hereinincorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION DEFINITION

[0090] Certain specific details of this description are set forth in order to provide a thoroughunderstanding of various embodiments. However, one skilled in the art will understand that the presentWSGR Docket No.53676-777.601 disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments.

[0091] Unless the context requires otherwise, throughout the specification and claims which follow, theword “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed disclosure.

[0092] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the”include plural referents unless the content clearly dictates otherwise. The use of the words “a” or “an” when used in conjunction with the term “comprising” herein may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0093] It should also be noted that the term “or” is generally employed in its sense including “and / or”unless the content clearly dictates otherwise.

[0094] Unless otherwise defined, all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below.

[0095] The term “about” when referring to a measurable value such as an amount, a temporal duration,and the like, is meant to encompass variations of ±20% or in some instances ±10%, or in some instances ±5%, or in some instances ±1%, or in some instances ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. As used herein, “about” and “approximately” generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given range of values.

[0096] The term “acquire” or “acquiring” as the terms are used herein, refer to obtaining possession of aphysical entity (e.g., a sample, a polypeptide, a nucleic acid, or a sequence), or a value, e.g., a numerical value, by “directly acquiring” or “indirectly acquiring” the physical entity or value. “Directly acquiring” means performing a process (e.g., performing a synthetic or analytical method) to obtain the physical entity or value. “Indirectly acquiring” refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value). Directly acquiring a physical entity includes performing a process that includes a physical change in a physical substance, e.g., a starting material. Directly acquiring a value includes performing a process that includes a physical change in a sample or another substance, e.g., performing an analytical process which includes a physical change in a substance, e.g., a sample.

[0097] “Antibody molecule” as used herein refers to a protein, e.g., an immunoglobulin chain orfragment thereof, comprising at least one immunoglobulin variable domain structure and / or sequence. An antibody molecule encompasses antibodies (e.g., full-length antibodies) and antibody fragments. In some embodiments, an antibody molecule comprises an antigen binding or functional fragment of a full length antibody, or a full length immunoglobulin chain. For example, a full-length antibody is anWSGR Docket. No.53676-777.601 immunoglobulin (Ig) molecule (e.g., an IgG antibody) that is naturally occurring or formed by normal immunoglobulin gene fragment recombinatorial processes). In embodiments, an antibody molecule refers to an immunologically active, antigen-binding portion of an immunoglobulin molecule, such as an antibody fragment. An antibody fragment, e.g., functional fragment, is a portion of an antibody, e.g., Fab, Fab′, F(ab′)2, F(ab)2, variable fragment (Fv), domain antibody (dAb), or single chain variable fragment (scFv). A functional antibody fragment binds to the same antigen as that recognized by the intact (e.g., full-length) antibody. The terms “antibody fragment” or “functional fragment” also include isolated fragments consisting of the variable regions, such as the “Fv” fragments consisting of the variable regions of the heavy and light chains or recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker (“scFv proteins”). In some embodiments, an antibody fragment does not include portions of antibodies without antigen binding activity, such as Fc fragments or single amino acid residues. Exemplary antibody molecules include full length antibodies and antibody fragments, e.g., dAb (domain antibody), single chain, Fab, Fab’, and F(ab’)2fragments, and single chain variable fragments (scFvs). In some embodiments, the antibody molecule is an antibody mimetic. In some embodiments, the antibody molecule is, or comprises, an antibody-like framework or scaffold, such as, fibronectins, ankyrin repeats (e.g., designed ankyrin repeat proteins (DARPins)), avimers, affibody affinity ligands, anticalins, or affilin molecules.

[0098] The term “human-like antibody molecule” as used herein refers to a humanized antibodymolecule, human antibody molecule or an antibody molecule having at least 95% sequence identity with a non-murine germline framework region, e.g., FR1, FR2, FR3 and / or FR4. In some embodiments, the human-like antibody molecule comprises a framework region having at least 95% sequence identity to a human germline framework region, e.g., a FR1, FR2, FR3 and / or FR4 of a human germline framework region. In some embodiments, the human-like antibody molecule is a recombinant antibody. In some embodiments, the human-like antibody molecule is a humanized antibody molecule. In some embodiments, the human-like antibody molecule is human antibody molecule. In some embodiments, the human-like antibody molecule is a phage display or a yeast display antibody molecule. In some embodiments, the human-like antibody molecule is a chimeric antibody molecule. In some embodiments, the human-like antibody molecule is a CDR grafted antibody molecule.

[0099] As used herein, an “immunoglobulin variable domain sequence” refers to an amino acidsequence which can form the structure of an immunoglobulin variable domain. For example, the sequence may include all or part of the amino acid sequence of a naturally-occurring variable domain. For example, the sequence may or may not include one, two, or more N- or C-terminal amino acids, or may include other alterations that are compatible with formation of the protein structure.

[0100] In embodiments, an antibody molecule is monospecific, e.g., it comprises binding specificity fora single epitope. In some embodiments, an antibody molecule is multispecific, e.g., it comprises a plurality of immunoglobulin variable domain sequences, where a first immunoglobulin variable domain sequence has binding specificity for a first epitope and a second immunoglobulin variable domain sequence has binding specificity for a second epitope. In some embodiments, an antibody molecule is aWSGR Docket No.53676-777.601 bispecific antibody molecule. “Bispecific antibody molecule” as used herein refers to an antibody molecule that has specificity for more than one (e.g., two, three, four, or more) epitope and / or antigen.

[0101] “Antigen” (Ag) as used herein refers to a molecule that can provoke an immune response, e.g.,involving activation of certain immune cells and / or antibody generation. Any macromolecule, including almost all proteins or peptides, can be an antigen. Antigens can also be derived from genomic recombinant or DNA. For example, any DNA comprising a nucleotide sequence or a partial nucleotide sequence that encodes a protein capable of eliciting an immune response encodes an “antigen.” In embodiments, an antigen does not need to be encoded solely by a full length nucleotide sequence of a gene, nor does an antigen need to be encoded by a gene at all. In embodiments, an antigen can be synthesized or can be derived from a biological sample, e.g., a tissue sample, a tumor sample, a cell, or a fluid with other biological components. As used, herein a “tumor antigen” or interchangeably, a “cancer antigen” includes any molecule present on, or associated with, a cancer, e.g., a cancer cell or a tumor microenvironment that can provoke an immune response. As used, herein an “immune cell antigen” includes any molecule present on, or associated with, an immune cell that can provoke an immune response.

[0102] The “antigen-binding site,” or “binding portion” of an antibody molecule refers to the part of anantibody molecule, e.g., an immunoglobulin (Ig) molecule, that participates in antigen binding. In embodiments, the antigen binding site is formed by amino acid residues of the variable (V) regions of the heavy (H) and light (L) chains. Three highly divergent stretches within the variable regions of the heavy and light chains, referred to as hypervariable regions, are disposed between more conserved flanking stretches called “framework regions,” (FRs). FRs are amino acid sequences that are naturally found between, and adjacent to, hypervariable regions in immunoglobulins. In embodiments, in an antibody molecule, the three hypervariable regions of a light chain and the three hypervariable regions of a heavy chain are disposed relative to each other in three dimensional space to form an antigen-binding surface, which is complementary to the three-dimensional surface of a bound antigen. The three hypervariable regions of each of the heavy and light chains are referred to as “complementarity-determining regions,” or “CDRs.” The framework region and CDRs have been defined and described, e.g., in Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242, and Chothia, C. et al. (1987) J. Mol. Biol.196:901-917. Each variable chain (e.g., variable heavy chain and variable light chain) is typically made up of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the amino acid order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0103] As used herein, an “immune cell” refers to any of various cells that function in the immunesystem, e.g., to protect against agents of infection and foreign matter. In embodiments, this term includes leukocytes, e.g., neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Innate leukocytes include phagocytes (e.g., macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells. Innate leukocytes identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms, and are mediators inWSGR Docket. No.53676-777.601 the activation of an adaptive immune response. The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are important types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response. The term “immune cell” includes immune effector cells.

[0104] “Immune effector cell,” as that term is used herein, refers to a cell that is involved in an immuneresponse, e.g., in the promotion of an immune effector response. Examples of immune effector cells include, but are not limited to, T cells, e.g., alpha / beta T cells and gamma / delta T cells, B cells, natural killer (NK) cells, natural killer T (NK T) cells, and mast cells.

[0105] The term “effector function” or “effector response” refers to a specialized function of a cell.Effector function of a T cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines.

[0106] The terms “polypeptide”, “peptide” and “protein” (if single chain) are used interchangeablyherein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. The polypeptide can be isolated from natural sources, can be a produced by recombinant techniques from a eukaryotic or prokaryotic host, or can be a product of synthetic procedures.

[0107] The terms “nucleic acid,” “nucleic acid sequence,” “nucleotide sequence,” or “polynucleotidesequence,” and “polynucleotide” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. The polynucleotide may be either single-stranded or double-stranded, and if single-stranded may be the coding strand or non- coding (antisense) strand. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. The nucleic acid may be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semisynthetic, or synthetic origin which either does not occur in nature or is linked to another polynucleotide in a non-natural arrangement.

[0108] The term “isolated,” as used herein, refers to material that is removed from its original or nativeenvironment (e.g., the natural environment if it is naturally occurring). For example, a naturally- occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide, separated by human intervention from some or all of the co-existing materials in the natural system, is isolated. Such polynucleotides could be part of a vector and / or such polynucleotides or polypeptides could be part of a composition, and still be isolated in that such vector or composition is not part of the environment in which it is found in nature. An isolated polynucleotide (ribonucleic acid (RNA), deoxyribonucleic acid (DNA)), or polypeptide is free of the genes / nucleic acids or sequences / amino acids that flank it in its naturally-occurring state.WSGR Docket No.53676-777.601

[0109] The compositions and methods of the present invention encompass polypeptides and nucleicacids having the sequences specified, or sequences substantially identical or similar thereto, e.g., sequences at least 80%, 85%, 90%, 95% identical or higher to the sequence specified. In the context of an amino acid sequence, the term “substantially identical” is used herein to refer to a first amino acid that contains a sufficient or minimum number of amino acid residues that are i) identical to, or ii) conservative substitutions of aligned amino acid residues in a second amino acid sequence such that the first and second amino acid sequences can have a common structural domain and / or common functional activity. For example, amino acid sequences that contain a common structural domain having at least about 80%, 85%, 90%.91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99%, 99.5%, 99.9%, or 100% sequence identity to a reference sequence, e.g., a sequence provided herein. In the context of nucleotide sequence, the term “substantially identical” is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimum number of nucleotides that are identical to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide having common functional activity, or encode a common structural polypeptide domain or a common functional polypeptide activity. For example, nucleotide sequences having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99%, 99.5%, 99.9%, or 100% sequence identity to a reference sequence, e.g., a sequence provided herein.

[0110] The term “variant” refers to a polypeptide that has a substantially identical amino acid sequenceto a reference amino acid sequence, or is encoded by a substantially identical nucleotide sequence. In some embodiments, the variant is a functional variant. In some embodiments, a TCRβV variant can bind to TCRα and form a TCR α:β complex.

[0111] The term “functional variant” refers to a polypeptide that has a substantially identical amino acidsequence to a reference amino acid sequence, or is encoded by a substantially identical nucleotide sequence, and is capable of having one or more activities of the reference amino acid sequence.

[0112] The term “functional fragment” refers to a polypeptide that has a partial amino acid sequence of areference amino acid sequence, and is capable of having one or more activities of the reference amino acid sequence. In some embodiments, the functional fragment comprises at least about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99%, 99.5%, or 99.9% amino acid sequence of a reference amino acid sequence. In some embodiments, the functional fragment comprises an amino acid sequence that has at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 amino acid deletion from the reference amino acid sequence. In some embodiments, the functional fragment comprises an amino acid sequence that has at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, 400, 450, or 500 amino acids of the reference amino acid sequence.WSGR Docket. No.53676-777.601

[0113] Calculations of homology or sequence identity between sequences (the terms are usedinterchangeably herein) are performed as follows. To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”).

[0114] The percent identity between the two sequences is a function of the number of identical positionsshared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol.48:444-453 ) algorithm which has been incorporated into the GAP program in the GCG software package (available at http: / / www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at http: / / www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and the one that should be used unless otherwise specified) are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.

[0115] The percent identity between two amino acid or nucleotide sequences can be determined usingthe algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The nucleic acid and protein sequences described herein can be used as a “query sequence” to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol.215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to a nucleic acid molecule of the invention. BLAST protein searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res.25:3389-3402. When utilizing BLAST andWSGR Docket No.53676-777.601 Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[0116] It is understood that the molecules of the present invention may have additional conservative ornon-essential amino acid substitutions, which do not have a substantial effect on their functions.

[0117] The term “amino acid” is intended to embrace all molecules, whether natural or synthetic, whichinclude both an amino functionality and an acid functionality and capable of being included in a polymer of naturally-occurring amino acids. Exemplary amino acids include naturally-occurring amino acids; analogs, derivatives and congeners thereof; amino acid analogs having variant side chains; and all stereoisomers of any of any of the foregoing. As used herein the term “amino acid” includes both the D- or L- optical isomers and peptidomimetics.

[0118] A “conservative amino acid substitution” is one in which the amino acid residue is replaced withan amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0119] As used herein, the term “molecule” as used in, e.g., antibody molecule, cytokine molecule,receptor molecule, includes full-length, naturally-occurring molecules, as well as variants, e.g., functional variants (e.g., truncations, fragments, mutated (e.g., substantially similar sequences) or derivatized form thereof), so long as at least one function and / or activity of the unmodified (e.g., naturally-occurring) molecule remains.

[0120] As used herein, the term “mutation” refers to an alteration in the nucleotide sequence of thegenome of an organism, virus, or extrachromosomal DNA. In some embodiments, the mutation may be a large-scale mutation, such as amplifications (or gene duplications) or repetitions of a chromosomal segment, deletions of large chromosomal regions, chromosomal rearrangements (e.g., chromosomal translocations, chromosomal inversions, non-homologous chromosomal crossover, and interstitial deletions), and loss of heterozygosity. In some embodiments, the mutation may be a small-scale mutation, such as insertions, deletions, and substitution mutations. As used herein, the term “substitution mutation” refers to the transition that exchange a single nucleotide for another.

[0121] “Interleukin-2” also known as IL2, IL-2, IL 2, TCGF, lymphokine, and interleukin 2, as referredto herein, includes any of the recombinant or naturally-occurring forms of IL-2 or variants or homologs thereof that have or maintain IL-2 activity (e.g., at least 40% 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity). In some aspects, the variants or homologs have at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring IL-2. In some embodiments, IL-2 isWSGR Docket. No.53676-777.601 substantially identical to the protein identified by the UniProt reference number P60568 or a variant or homolog having substantial identity thereto.

[0122] In some embodiments, the terms TCRvB, TCRBV, TCRβV, and TCRVβ are interchangeablyused.

[0123] In some embodiments, the terms antibody-drug conjugate, antibody drug conjugate, and ADC areinterchangeably used. Anti-TCRβV antibodies Human T cell receptor (TCR) complex

[0124] TCR is a disulfide-linked membrane-anchored heterodimeric protein normally consisting of thehighly variable alpha (α) and beta (β) chains expressed as part of a complex with the invariant CD3 chain molecules. TCR on αβ T cells is formed by a heterodimer of one alpha chain and one beta chain. Each alpha or beta chain consists of a constant domain and a highly variable domain classified as the Immunoglobulin superfamily (IgSF) fold. The TCRβV chains can be further classified into 30 subfamilies (TRBV1-30). Despite their high structural and functional homology, the amino acid sequence homology in the TRBV genes is very low. Only 4 amino acids out of approximately 95 are identical while 10 additional amino acids are conserved among all subfamilies. Nevertheless, TCRs formed between alpha and beta chains of highly diverse sequences show a remarkable structural homology and elicit a similar function, e.g., activation of T cells.

[0125] T cell receptors (TCR) can be found on the surface of T cells. TCRs recognize antigens, e.g.,peptides, presented on, e.g., bound to, major histocompatibility complex (MHC) molecules on the surface of cells, e.g., antigen-presenting cells. TCRs are heterodimeric molecules and can comprise an alpha chain, a beta chain, a gamma chain or a delta chain. TCRs comprising an alpha chain and a beta chain are also referred to as TCRαβ. The TCR beta chain consists of the following regions (also known as segments): variable (V), diversity (D), joining (J) and constant (C) (see Mayer G. and Nyland J. (2010) Chapter 10: Major Histocompatibility Complex and T-cell Receptors-Role in Immune Responses. In: Microbiology and Immunology on-line, University of South Carolina School of Medicine). The TCR alpha chain consists of V, J and C regions. The rearrangement of the T-cell receptor (TCR) through somatic recombination of V (variable), D (diversity), J (joining), and C (constant) regions is a defining event in the development and maturation of a T cell. TCR gene rearrangement takes place in the thymus.

[0126] TCRs can comprise a receptor complex, known as the TCR complex, which comprises a TCRheterodimer comprising of an alpha chain and a beta chain, and dimeric signaling molecules, e.g., CD3 co-receptors, e.g., CD3δ / ε, and / or CD3γ / ε.

[0127] As used herein, the term “T cell receptor beta variable chain” or “TCRβV,” refers to anextracellular region of the T cell receptor beta chain which comprises the antigen recognition domain of the T cell receptor. The term TCRβV includes isoforms, mammalian, e.g., human TCRβV, species homologs of human and analogs comprising at least one common epitope with TCRβV. Human TCRβV comprises a gene family comprising subfamilies including, but not limited to: a TCRβ V6 subfamily, aWSGR Docket No.53676-777.601 TCRβ V10 subfamily, a TCRβ V12 subfamily, a TCRβ V5 subfamily, a TCRβ V7 subfamily, a TCRβ V11 subfamily, a TCRβ V14 subfamily, a TCRβ V16 subfamily, a TCRβ V18 subfamily, a TCRβ V9 subfamily, a TCRβ V13 subfamily, a TCRβ V4 subfamily, a TCRβ V3 subfamily, a TCRβ V2 subfamily, a TCRβ V15 subfamily, a TCRβ V30 subfamily, a TCRβ V19 subfamily, a TCRβ V27 subfamily, a TCRβ V28 subfamily, a TCRβ V24 subfamily, a TCRβ V20 subfamily, TCRβ V25 subfamily, a TCRβ V29 subfamily, a TCRβ V1 subfamily, a TCRβ V17 subfamily, a TCRβ V21 subfamily, a TCRβ V23 subfamily, or a TCRβ V26 subfamily, as well as family members of said subfamilies, and variants thereof (e.g., a structural or functional variant thereof). In some embodiments, the TCRβ V6 subfamily comprises: TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01 or TCRβ V6-1*01. In some embodiments, TCRβV comprises TCRβ V6-5*01, or a variant thereof, e.g., a variant having 85%, 90%, 95%, 99% or more identity the naturally-occurring sequence. TCRβ V6-5*01 is also known as TRBV65; TCRBV6S5; TCRBV13S1, or TCRβ V13.1. The amino acid sequence of TCRβ V6-5*01, e.g., human TCRβ V6-5*01, is known in that art, e.g., as provided by IMGT ID L36092. In some embodiments, TCRβ V6-5*01 is encoded by the nucleic acid sequence of SEQ ID NO: 43, or a sequence having 85%, 90%, 95%, 99% or more identity thereof. In some embodiments, TCRβ V6-5*01 comprises the amino acid sequence of SEQ ID NO: 44, or a sequence having 85%, 90%, 95%, 99% or more identity thereof.

[0128] SEQ ID NO: 43ATGAGCATCGGCCTCCTGTGCTGTGCAGCCTTGTCTCTCCTGTGGGCAGGTCCAGTGAATGC TGGTGTCACTCAGACCCCAAAATTCCAGGTCCTGAAGACAGGACAGAGCATGACACTGCAG TGTGCCCAGGATATGAACCATGAATACATGTCCTGGTATCGACAAGACCCAGGCATGGGGC TGAGGCTGATTCATTACTCAGTTGGTGCTGGTATCACTGACCAAGGAGAAGTCCCCAATGGC TACAATGTCTCCAGATCAACCACAGAGGATTTCCCGCTCAGGCTGCTGTCGGCTGCTCCCTC CCAGACATCTGTGTACTTCTGTGCCAGCAGTTACTC

[0129] SEQ ID NO: 44MSIGLLCCAALSLLWAGPVNAGVTQTPKFQVLKTGQSMTLQCAQDMNHEYMSWYRQDPGMG LRLIHY-SVGAGITDQGEVPNGYNVSRSTTEDFPLRLLSAAPSQTSVYFCASSY TCR beta V (TCRβV)

[0130] Diversity in the immune system enables protection against a huge array of pathogens. Since thegermline genome is limited in size, diversity is achieved not only by the process of V(D)J recombination but also by junctional (junctions between V-D and D-J segments) deletion of nucleotides and addition of pseudo-random, non-templated nucleotides. The TCR beta gene undergoes gene arrangement to generate diversity.

[0131] The TCR V beta repertoire varies between individuals and populations because of, e.g., 7frequently occurring inactivating polymorphisms in functional gene segments and a large insertion / deletion-related polymorphism encompassing 2 V beta gene segments.WSGR Docket. No.53676-777.601

[0132] Provided herein are, inter alia, antibody molecules and fragments thereof, that bind, e.g.,specifically bind, to a human TCR beta V chain (TCRβV), e.g., a TCRβV gene family (also referred to as a group), e.g., a TCRβV subfamily (also referred to as a subgroup), e.g., as described herein. TCR beta V families and subfamilies are known in the art, e.g., as described in Yassai et al., (2009) Immunogenetics61(7)pp:493-502; Wei S. and Concannon P. (1994) Human Immunology 41(3) pp: 201-206. Theantibodies described herein can be recombinant antibodies, e.g., recombinant non-murine antibodies, e.g., recombinant human or humanized antibodies.

[0133] The terms TCRBV, TCRVB, TRBV, TCRβV, TCRVβ or TRβV are used interchangeably hereinand refer to a TCR beta V chain, e.g., as described herein.

[0134] In some embodiments, provided herein is an anti-TCRβV antibody molecule that binds to humanTCRβV, e.g., a TCRβV family, e.g., gene family or a variant thereof. In some embodiments a TCRBV gene family comprises one or more subfamilies, e.g., as described herein Table 8A or Table 8B. In some embodiments, the TCRβV gene family comprises: a TCRβ V6 subfamily, a TCRβ V10 subfamily, a TCRβ V12 subfamily, a TCRβ V5 subfamily, a TCRβ V7 subfamily, a TCRβ V11 subfamily, a TCRβ V14 subfamily, a TCRβ V16 subfamily, a TCRβ V18 subfamily, a TCRβ V9 subfamily, a TCRβ V13 subfamily, a TCRβ V4 subfamily, a TCRβ V3 subfamily, a TCRβ V2 subfamily, a TCRβ V15 subfamily, a TCRβ V30 subfamily, a TCRβ V19 subfamily, a TCRβ V27 subfamily, a TCRβ V28 subfamily, a TCRβ V24 subfamily, a TCRβ V20 subfamily, TCRβ V25 subfamily, a TCRβ V29 subfamily, a TCRβ V1 subfamily, a TCRβ V17 subfamily, a TCRβ V21 subfamily, a TCRβ V23 subfamily, or a TCRβ V26 subfamily.

[0135] In some embodiments, TCRβ V6 subfamily is also known as TCRβ V13.1. In someembodiments, the TCRβ V6 subfamily comprises: TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01 or TCRβ V6-1*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-4*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-4*02, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-9*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-8*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-5*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-6*02, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-6*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-2*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-3*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-1*01, or a variant thereof.

[0136] In some embodiments, TCRβ V6 comprises TCRβ V6-5*01, or a variant thereof. In someembodiments, TCRβ V6, e.g., TCRβ V6-5*01, is recognized, e.g., bound, by SEQ ID NO: 1 and / or SEQ ID NO: 2. In some embodiments, TCRβ V6, e.g., TCRβ V6-5*01, is recognized, e.g., bound, by SEQ ID NO: 9 and / or SEQ ID NO: 10. In some embodiments, TCRβ V6 is recognized, e.g., bound, by SEQ ID NO: 9 and / or SEQ ID NO: 11.WSGR Docket No.53676-777.601

[0137] In some embodiments, TCRβ V10 subfamily is also known as TCRβ V12. In some embodiments,the TCRβ V10 subfamily comprises: TCRβ V10-1*01, TCRβ V10-1*02, TCRβ V10-3*01 or TCRβ V10-2*01, or a variant thereof.

[0138] In some embodiments, TCRβ V12 subfamily is also known as TCRβ V8.1. In someembodiments, the TCRβ V12 subfamily comprises: TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12- 5*01, or a variant thereof. In some embodiments, TCRβ V12 is recognized, e.g., bound, by SEQ ID NO: 15 and / or SEQ ID NO: 16. In some embodiments, TCRβ V12 is recognized, e.g., bound, by any one of SEQ ID NOs 23-25, and / or any one of SEQ ID NO: 26-30:

[0139] In some embodiments, the TCRβ V5 subfamily is chosen from: TCRβ V5-5*01, TCRβ V5-6*01,TCRβ V5-4*01, TCRβ V5-8*01, TCRβ V5-1*01, or a variant thereof.

[0140] In some embodiments, the TCRβ V7 subfamily comprises TCRβ V7-7*01, TCRβ V7-6*01,TCRβ V7 -8*02, TCRβ V7 -4*01, TCRβ V7-2*02, TCRβ V7-2*03, TCRβ V7-2*01, TCRβ V7-3*01, TCRβ V7-9*03, or TCRβ V7-9*01, or a variant thereof.

[0141] In some embodiments, the TCRβ V11 subfamily comprises: TCRβ V11-1*01, TCRβ V11-2*01or TCRβ V11-3*01, or a variant thereof. In some embodiments, the TCRβ V14 subfamily comprises TCRβ V14*01, or a variant thereof. In some embodiments, the TCRβ V16 subfamily comprises TCRβ V16*01, or a variant thereof. In some embodiments, the TCRβ V18 subfamily comprises TCRβ V18*01, or a variant thereof. In some embodiments, the TCRβ V9 subfamily comprises TCRβ V9*01 or TCRβ V9*02, or a variant thereof. In some embodiments, the TCRβ V13 subfamily comprises TCRβ V13*01, or a variant thereof. In some embodiments, the TCRβ V4 subfamily comprises TCRβ V4-2*01, TCRβ V4-3*01, or TCRβ V4-1*01, or a variant thereof. In some embodiments, the TCRβ V3 subfamily comprises TCRβ V3-1*01, or a variant thereof. In some embodiments, the TCRβ V2 subfamily comprises TCRβ V2*01, or a variant thereof. In some embodiments, the TCRβ V15 subfamily comprises TCRβ V15*01, or a variant thereof. In some embodiments, the TCRβ V30 subfamily comprises TCRβ V30*01, or TCRβ V30*02, or a variant thereof. In some embodiments, the TCRβ V19 subfamily comprises TCRβ V19*01, or TCRβ V19*02, or a variant thereof. In some embodiments, the TCRβ V27 subfamily comprises TCRβ V27*01, or a variant thereof. In some embodiments, the TCRβ V28 subfamily comprises TCRβ V28*01, or a variant thereof. In some embodiments, the TCRβ V24 subfamily comprises TCRβ V24-1*01, or a variant thereof. In some embodiments, the TCRβ V20 subfamily comprises TCRβ V20-1*01, or TCRβ V20-1*02, or a variant thereof. In some embodiments, the TCRβ V25 subfamily comprises TCRβ V25-1*01, or a variant thereof. In some embodiments, the TCRβ V29 subfamily comprises TCRβ V29-1*01, or a variant thereof.

[0142] Exemplary amino acid sequences for TCRβV subfamily members can be found on theImMunoGeneTics Information System website: http: / / www.imgt.org / , or in a similar resource.

[0143] Anti-TCRβV antibodies

[0144] Current bispecific constructs designed to redirect T cells to promote tumor cell lysis for cancerimmunotherapy typically utilize antibody fragments (Fab, scFv, VH, single domain antibody, etc.) thatWSGR Docket. No.53676-777.601 are derived from monoclonal antibodies (mAb) directed against the CD3e subunit of the T cell receptor (TCR). However, there are limitations to this approach which may prevent the full realization of the therapeutic potential for such bispecific constructs. Previous studies have shown that even low “activating” doses of anti-CD3e mAb can cause long-term T cell dysfunction and exert immunosuppressive effects. In addition, anti-CD3e mAbs have been associated with side effects that result from massive T cell activation. The large number of activated T cells secrete substantial amounts of cytokines, the most important of which is Interferon gamma (IFNγ). This excess amount of IFNγ in turn activates macrophages which then overproduce proinflammatory cytokines such as IL-1beta, IL-6, IL-10 and TNF-alpha, causing a “cytokine storm” known as the cytokine release syndrome (CRS) (Shimabukuro-Vornhagen et al., J Immunother Cancer.2018 Jun 15;6(1):56, herein incorporated by reference in its entirety). Thus, the need exists for developing antibodies that are capable of binding and activating only a subset of effector T cells, e.g., to re-duce the CRS and / or neurotoxicity (NT).

[0145] Described herein are molecules targeting the TCRβV chain of TCR and methods thereof.Without wishing to be bound by theory, such molecules are capable of binding, activating, and / or expanding only a subset of T cells, avoiding or reducing CRS and / or NT and minimizing potential immunosuppressive effects of anti-CD3 mAbs.

[0146] Described herein is a class of antibodies, i.e., anti-TCRβV antibody molecules as describedherein, which despite having low sequence similarity (e.g., low sequence identity among the different antibody molecules that recognize different TCRβV subfamilies), recognize a structurally conserved, yet sequence-wise variable, region, e.g., domain, on the TCRβV protein and have a similar function (e.g., activation of T cells and a similar cytokine profile as described herein). Thus, the anti-TCRβV antibody molecules as described herein share a structure-function relationship.

[0147] Without wishing to be bound by theory, in some embodiments, the anti-TCRβV antibodymolecules as described herein bind to an outward facing epitope of a TCRβV protein when it is in a complex with a TCRalpha protein. In some embodiments, the anti-TCRβV antibody molecules as described herein recognize (e.g., bind to), a domain (e.g., an epitope) on the TCRβV protein that is: (1) structurally conserved among different TCRβV subfamilies; and (2) has minimal sequence identity among the different TCRβV subfamilies. TCRβV proteins from the different TCRBV subfamilies share minimal sequence similarity. However, TCRβV proteins which have minimal sequence similarity, share a similar 3D conformation and structure. In particular, the TRBV sequences from different subfamilies are considerably different from each other.

[0148] In some embodiments, the anti-TCRβV antibody molecules as described herein do not recognize,e.g., bind to, an interface of a TCRβV:TCRalpha complex. In some embodiments, the anti-TCRβV antibody molecules as described herein do not recognize, e.g., bind to, a constant region of a TCRβV protein. An exemplary antibody that binds to a constant region of a TCRBV region is JOVI.1 as described in Viney et al., (Hybridoma.1992 Dec;11(6):701-13). In some embodiments, the anti-TCRβV antibody molecules as described herein do not recognize, e.g., bind to, one or more (e.g., all) of a complementarity determining region (e.g., CDR1, CDR2 and / or CDR3) of a TCRβV protein.WSGR Docket No.53676-777.601

[0149] Provided herein are, inter alia, antibody molecules directed to the variable chain of the betasubunit of TCR (TCRβV) which bind and, e.g., activate a subset of T cells. The anti-TCRβV antibody molecules as described herein result in lesser or no production of cytokines associated with CRS, e.g., IL- 6, IL-1beta, IL-10 and TNF alpha; and enhanced and / or delayed production of IL-2 and IFNγ. In some embodiments, the anti-TCRβV antibodies as described herein have a cytokine profile, e.g., as described herein, which differs from a cytokine profile of a T cell engager that binds to a receptor or molecule other than a TCRβV region (“a non-TCRβV-binding T cell engager”). In some embodiments, the non-TCRβV- binding T cell engager comprises an antibody that binds to a CD3 molecule (e.g., CD3 epsilon (CD3e) molecule); or a TCR alpha (TCRα) molecule. In some embodiments, the non-TCRβV-binding T cell engager is an OKT3 antibody or an SP34-2 antibody.

[0150] In some embodiments, the anti-TCRβV antibodies as described herein result in expansion ofTCRβV+ T cells, e.g., a subset of memory effector T cells known as TEMRA. Without wishing to be bound by theory, it is believed that in some embodiments, TEMRA cells can promote tumor cell lysis but not CRS. Accordingly, provided herein are methods of making said anti-TCRβV antibody molecules and uses thereof. Also described herein are multispecific molecules, e.g., bispecific molecules comprising said anti-TCRβV antibody molecules. In some embodiments, compositions comprising anti-TCRβV antibody molecules of the present disclosure, can be used, e.g., to: (1) activate and redirect T cells to promote tumor cell lysis for cancer immuno-therapy; and / or (2) expand TCRβV+ T cells. In some embodiments, compositions comprising anti-TCRβV antibody molecules as described herein limit the harmful side-effects of CRS and / or NT, e.g., CRS and / or NT associated with anti-CD3e targeting.

[0151] In some embodiments, the anti-TCRβV antibody molecule binds to one or more of TRBV2,TRBV3-1, TRBV4-1, TRBV4-2, TRBV4-3, TRBV5-1, TRBV5-4, TRBV5-5, TRBV5-6, TRBV5-8, TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8, TRBV6-9, TRBV7-2, TRBV7-3, TRBV7-4, TRBV7-6, TRBV7-7, TRBV7-8, TRBV7-9, TRBV9, TRBV10-1, TRBV10-2, TRBV10-3, TRBV11-1, TRBV11-2, TRBV11-3, TRBV12-3, TRBV12-4, TRBV12-5, TRBV13, TRBV14, TRBV15, TRBV16, TRBV18, TRBV19, TRBV20-1, TRBV24-1, TRBV25-1, TRBV27, TRBV28, TRBV29-1 and TRBV30. In some embodiments, the anti-TCRβV antibody molecule binds to one or more of TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8 and TRBV6-9. In some embodiments, the anti-TCRβV antibody molecule is an anti-TRBV2, anti-TRBV3-1, anti-TRBV4-1, anti-TRBV4-2, anti-TRBV4-3, anti-TRBV5-1, anti-TRBV5-4, anti-TRBV5-5, anti- TRBV5-6, anti-TRBV5-8, anti-TRBV6-1, anti-TRBV6-2, anti-TRBV6-3, anti-TRBV6-4, anti-TRBV6-5, anti-TRBV6-6, anti-TRBV6-8, anti-TRBV6-9, anti-TRBV7-2, anti-TRBV7-3, anti-TRBV7-4, anti- TRBV7-6, anti-TRBV7-7, anti-TRBV7-8, anti-TRBV7-9, anti-TRBV9, anti-TRBV10-1, anti-TRBV10- 2, anti-TRBV10-3, anti-TRBV11-1, anti-TRBV11-2, anti-TRBV11-3, anti-TRBV12-3, anti-TRBV12-4, anti-TRBV12-5, anti-TRBV13, anti-TRBV14, anti-TRBV15, anti-TRBV16, anti-TRBV18, anti- TRBV19, anti-TRBV20-1, anti-TRBV24-1, anti-TRBV25-1, anti-TRBV27, anti-TRBV28, anti- TRBV29-1, or anti-TRBV30. Exemplary anti-TCRβV antibody molecules and the corresponding TCRβV subfamilies recognized by said anti-TCRβV antibody molecules are disclosed in Table 10A.WSGR Docket. No.53676-777.601

[0152] In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV2,TRBV3-1, TRBV4-1, TRBV4-2, TRBV4-3, TRBV5-1, TRBV5-4, TRBV5-5, TRBV5-6, TRBV5-8, TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8, TRBV6-9, TRBV7-2, TRBV7-3, TRBV7-4, TRBV7-6, TRBV7-7, TRBV7-8, TRBV7-9, TRBV9, TRBV10-1, TRBV10-2, TRBV10-3, TRBV11-1, TRBV11-2, TRBV11-3, TRBV12-3, TRBV12-4, TRBV12-5, TRBV13, TRBV14, TRBV15, TRBV16, TRBV18, TRBV19, TRBV20-1, TRBV24-1, TRBV25-1, TRBV27, TRBV28, TRBV29-1 or TRBV30. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-1. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-2. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-3. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-4. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-5. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-6. In some embodiments, the anti- TCRβV antibody molecule binds specifically to TRBV6-8. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-9.

[0153] In some embodiments, the anti-TCRβV antibody molecule does not bind to TCRβ V12, or bindsto TCRβ V12 with an affinity and / or binding specificity that is less than (e.g., less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof as de-scribed in US Patent 5,861,155.

[0154] In some embodiments, the anti-TCRβV antibody molecule binds to TCRβ V12 with an affinityand / or binding specificity that is greater than (e.g., greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof as described in US Patent 5,861,155.

[0155] In some embodiments, the anti-TCRβV antibody molecule binds to a TCRβV region other thanTCRβ V12 (e.g., TCRβV region as described herein, e.g., TCRβ V6 subfamily (e.g., TCRβ V6-5*01) with an affinity and / or binding specificity that is greater than (e.g., greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof as de-scribed in US Patent 5,861,155.

[0156] In some embodiments, the anti-TCRβV antibody molecule does not comprise the CDRs of theAntibody B murine antibody.

[0157] In some embodiments, the anti-TCRβV antibody molecule does not bind to TCRβ V5-5*01 orTCRβ V5-1*01, or binds to TCRβ V5-5*01 or TCRβ V5-1*01 with an affinity and / or binding specificity that is less than (e.g., less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the TM23 murine antibody or a humanized version thereof as described in US Patent 5,861,155.

[0158] In some embodiments, the anti-TCRβV antibody molecule binds to TCRβ V5-5*01 or TCRβ V5-1*01with an affinity and / or binding specificity that is greater than (e.g., greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the TM23 murine antibody or a humanized version thereof as de-scribed in US Patent 5,861,155.WSGR Docket No.53676-777.601

[0159] In some embodiments, the anti-TCRβV antibody molecule binds to a TCRβV region other thanTCRβ V5-5*01 or TCRβ V5-1*01 (e.g., TCRβV region as described herein, e.g., TCRβ V6 subfamily (e.g., TCRβ V6-5*01) with an affinity and / or binding specificity that is greater than (e.g., greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the TM23 murine antibody or a humanized version thereof as described in US Patent 5,861,155.

[0160] In some embodiments, the anti-TCRβV antibody molecule does not comprise the CDRs of theTM23 murine antibody.

[0161] In some embodiments, the light or the heavy chain variable framework (e.g., the regionencompassing at least FR1, FR2, FR3, and optionally FR4) of the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule can be chosen from: (a) a light or heavy chain variable framework including at least 80%, 85%, 87% 90%, 92%, 93%, 95%, 97%, 98%, or 100% of the amino acid residues from a human light or heavy chain variable framework, e.g., a light or heavy chain variable framework residue from a human mature antibody, a human germline sequence, or a human consensus sequence; (b) a light or heavy chain variable framework including from 20% to 80%, 40% to 60%, 60% to 90%, or 70% to 95% of the amino acid residues from a human light or heavy chain variable framework, e.g., a light or heavy chain variable framework residue from a human mature antibody, a human germline sequence, or a human consensus sequence; (c) a non-human framework (e.g., a rodent framework); or (d) a non-human framework that has been modified, e.g., to remove antigenic or cytotoxic determinants, e.g., deimmunized, or partially humanized. In some embodiments, the light or heavy chain variable framework region (particularly FR1, FR2 and / or FR3) includes a light or heavy chain variable framework sequence at least 70, 75, 80, 85, 87, 88, 90, 92, 94, 95, 96, 97, 98, 99% identical or identical to the frameworks of a VL or VH segment of a human germline gene.

[0162] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises a heavy chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more changes, e.g., amino acid substitutions or deletions, from an amino acid sequence of any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, e.g., the amino acid sequence of the FR region in the entire variable region, e.g., in SEQ ID NO: 9.

[0163] Alternatively, or in combination with the heavy chain substitutions described herein, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more amino acid changes, e.g., amino acid substitutions or deletions, from an amino acid sequence of any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, e.g., the amino acid sequence of the FR region in the entire variable region, e.g., SEQ ID NO: 10 or SEQ ID NO: 11.

[0164] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, includes one, two, three, or four heavy chain framework regions or a sequence substantially identical thereto.WSGR Docket. No.53676-777.601

[0165] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, includes one, two, three, or four light chain framework regions or a sequence substantially identical thereto.

[0166] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises the light chain framework region 1 of A-H.1 or A-H.2.

[0167] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises the light chain framework region 2 of A-H.1 or A-H.2.

[0168] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises the light chain framework region 3 of A-H.1 or A-H.2.

[0169] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises the light chain framework region 4 of A-H.1 or A-H.2.

[0170] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises a light chain variable domain comprising a framework region, e.g., framework region 1 (FR1), comprising a change, e.g., a substitution (e.g., a conservative substitution) at position 10 according to Kabat numbering. In some embodiments, the FR1 comprises a Phenylalanine at position 10, e.g., a Serine to Phenylalanine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0171] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises a light chain variable domain comprising a framework region, e.g., framework region 2 (FR2), comprising a change, e.g., a substitution (e.g., a conservative substitution) at a position as described herein according to Kabat numbering. In some embodiments, FR2 comprises a Histidine at position 36, e.g., a substitution at position 36 according to Kabat numbering, e.g., a Tyrosine to Histidine substitution. In some embodiments, FR2 comprises an Alanine at position 46, e.g., a substitution at position 46 according to Kabat numbering, e.g., an Arginine to Alanine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0172] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises a light chain variable domain comprising a framework region, e.g., framework region 3 (FR3), comprising a change, e.g., a substitution (e.g., a conservative substitution) at a position as described herein according to Kabat numbering. In some embodiments, FR3 comprises a Phenylalanine at position 87, e.g., a substitution at position 87 according to Kabat numbering, e.g., a Tyrosine to Phenylalanine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0173] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises a light chain variable domain comprising: (a) a framework region 1 (FR1) comprising a Phenylalanine at position 10, e.g., a substitution at position 10 according to Kabat numbering, e.g., a Serine to Phenylalanine substitution; (b) a framework region 2 (FR2) comprising a Histidine at position 36, e.g., a substitution at position 36 according to Kabat numbering,WSGR Docket No.53676-777.601 e.g., a Tyrosine to Histidine substitution, and a Alanine at position 46, e.g., a substitution at position 46 according to Kabat numbering, e.g., a Arginine to Alanine substitution; and (c) a framework region 3 (FR3) comprising a Phenylalanine at position 87, e.g., a substitution at position 87 according to Kabat numbering, e.g., a Tyrosine to Phenylalanine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 10. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0174] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises a light chain variable domain comprising: (a) a framework region 2 (FR2) comprising a Histidine at position 36, e.g., a substitution at position 36 according to Kabat numbering, e.g., a Tyrosine to Histidine substitution, and a Alanine at position 46, e.g., a substitution at position 46 according to Kabat numbering, e.g., a Arginine to Alanine substitution; and (b) a framework region 3 (FR3) comprising a Phenylalanine at position 87, e.g., a substitution at position 87 according to Kabat numbering, e.g., a Tyrosine to Phenylalanine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 11. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0175] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises a light chain variable domain comprising: (a) a framework region 1 (FR1) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all) positions as described herein according to Kabat numbering, ; (b) a framework region 2 (FR2) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all) position as described herein according to Kabat numbering and (c) a framework region 3 (FR3) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all) position as described herein according to Kabat numbering. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0176] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises the heavy chain framework region 1 of A-H.1 or A-H.2. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the heavy chain framework region 2 of A-H.1 or A-H.2. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the heavy chain framework region 3 of A-H.1 or A-H.2. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the heavy chain framework region 4 of A-H.1 or A-H.2.

[0177] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises a heavy chain variable domain comprising a framework region, e.g., framework region 3 (FR3), comprising a change, e.g., a substitution (e.g., a conservative substitution) at a position as described herein according to Kabat numbering. In some embodiments, FR3 comprises a Threonine at position 73, e.g., a substitution at position 73 according to Kabat numbering, e.g., a Glutamic Acid to Threonine substitution. In some embodiments, FR3 comprises a Glycine atWSGR Docket. No.53676-777.601 position 94, e.g., a substitution at position 94 according to Kabat numbering, e.g., an Arginine to Glycine substitution. In some embodiments, the substitution is relative to a human germline heavy chain framework region sequence.

[0178] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises a heavy chain variable domain comprising a framework region 3 (FR3) comprising a Threonine at position 73, e.g., a substitution at position 73 according to Kabat numbering, e.g., a Glutamic Acid to Threonine substitution, and a Glycine at position 94, e.g., a substitution at position 94 according to Kabat numbering, e.g., a Arginine to Glycine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 10.

[0179] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises the heavy chain framework regions 1-4 of A-H.1 or A-H.2, e.g., SEQ ID NO: 9. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the light chain framework regions 1-4 of A-H.1, e.g., SEQ ID NO: 10. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the light chain framework regions 1-4 of A-H.2, e.g., SEQ ID NO: 11. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the heavy chain framework regions 1-4 of A-H.1, e.g., SEQ ID NO: 9; and the light chain framework regions 1-4 of A-H.1, e.g., SEQ ID NO: 10. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the heavy chain framework regions 1-4 of A-H.2, e.g., SEQ ID NO: 9; and the light chain framework regions 1-4 of A-H.2, e.g., SEQ ID NO: 11.

[0180] In some embodiments, the heavy or light chain variable domain, or both, of the anti-TCRβVantibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes an amino acid sequence, which is substantially identical to an amino acid as described herein, e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical to a variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or as described in Table 1, or encoded by the nucleotide sequence in Table 1; or which differs at least 1 or 5 residues, but less than 40, 30, 20, or 10 residues, from a variable region of an antibody described herein.

[0181] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises at least one, two, three, or four antigen-binding regions, e.g., variable regions, having an amino acid sequence as set forth in Table 1, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the sequences shown in Table 1. In another embodiment, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes a VH and / or VL domain encoded by a nucleic acid having a nucleotide sequence as set forth in Table 1, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Table 1.WSGR Docket No.53676-777.601

[0182] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 9, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 9, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 9; and / or a VL domain comprising the amino acid sequence of SEQ ID NO: 10, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 10.

[0183] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 9, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 9, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 9; and / or a VL domain comprising the amino acid sequence of SEQ ID NO: 11, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 11, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 11.

[0184] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule is a full antibody or fragment thereof (e.g., a Fab, F(ab')2, Fv, single domain antibody, or a single chain Fv fragment (scFv)). In embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule is a monoclonal antibody or an antibody with single specificity. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti- TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, can also be a humanized, chimeric, camelid, shark, or an in vitro-generated antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a humanized antibody molecule. The heavy and light chains of the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, can be full-length (e.g., an antibody can include at least one, and preferably two, complete heavy chains, and at least one, and preferably two, complete light chains) or can include an antigen-binding fragment (e.g., a Fab, F(ab')2, Fv, a single chain Fv fragment, a single domain antibody, a diabody (dAb), a bivalent antibody, or bispecific antibody or fragment thereof, a single domain variant thereof, or a camelid antibody).

[0185] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, is in the form of a multispecific molecule, e.g., a bispecific molecule, e.g., as described herein.

[0186] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, has a heavy chain constant region (Fc) chosen from, e.g., the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE. In some embodiments, the Fc region is chosen from the heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4. In some embodiments, the Fc region is chosen from the heavy chain constant region of IgG1 or IgG2 (e.g., humanWSGR Docket. No.53676-777.601 IgG1, or IgG2). In some embodiments, the heavy chain constant region is human IgG1. In some embodiments, the Fc region comprises a Fc region variant, e.g., as described herein.

[0187] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, has a light chain constant region chosen from, e.g., the light chain constant regions of kappa or lambda, preferably kappa (e.g., human kappa). In some embodiments, the constant region is altered, e.g., mutated, to modify the properties of the anti-TCRβV antibody molecule, e.g., anti- TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function). For example, the constant region is mutated at positions 296 (M to Y), 298 (S to T), 300 (T to E), 477 (H to K) and 478 (N to F) to alter Fc receptor binding (e.g., the mutated positions correspond to positions 132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K) and 314 (N to F) of SEQ ID NOs: 212 or 214; or positions 135 (M to Y), 137 (S to T), 139 (T to E), 316 (H to K) and 317 (N to F) of SEQ ID NOs: 215, 216, 217 or 218), e.g., relative to human IgG1.

[0188] Antibody A-H.1 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:3278 and a light chain comprising the amino acid sequence of SEQ ID NO: 72. Antibody A-H.2 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 3278 and a light chain comprising the amino acid sequence of SEQ ID NO: 3279. Antibody A-H.68 comprises the amino acid sequence of SEQ ID NO: 1337, or a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity thereto. Antibody A-H.69 comprises the amino acid sequence of SEQ ID NO: 1500, or a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity thereto.

[0189] Additional exemplary humanized anti-TCRB V6 antibodies are provided in Table 1. In someembodiments, the anti-TCRβ V6 is antibody A, e.g., humanized antibody A (antibody A-H), as provided in Table 1. In some embodiments, the anti-TCRβV antibody comprises one or more (e.g., all three) of a LC CDR1, LC CDR2, and LC CDR3 provided in Table 1; and / or one or more (e.g., all three) of a HC CDR1, HC CDR2, and HC CDR3 provided in Table 1, or a sequence with at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity thereto. In some embodiments, antibody A comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 1, or a sequence with at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity thereto.

[0190] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule comprises a VH of A-H.1, A-H.2, A-H.3, A-H.4, A-H.5, A-H.6, A-H.7, A- H.8, A-H.9, A-H.10, A-H.11, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16, A-H.17, A-H.18, A-H.19, A- H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A- H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.1, A-H.42, A-H.43, A- H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A- H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A- H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A-WSGR Docket No.53676-777.601 H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0191] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule comprises a VL of A-H.1, A-H.2, A-H.3, A-H.4, A-H.5, A-H.6, A-H.7, A- H.8, A-H.9, A-H.10, A-H.11, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16, A-H.17, A-H.18, A-H.19, A- H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A- H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.1, A-H.42, A-H.43, A- H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A- H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A- H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A- H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0192] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule comprises a VH of A-H.1, A-H.2, A-H.3, A-H.4, A-H.5, A-H.6, A-H.7, A- H.8, A-H.9, A-H.10, A-H.11, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16, A-H.17, A-H.18, A-H.19, A- H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A- H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.1, A-H.42, A-H.43, A- H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A- H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A- H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A- H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto; and a VL of A-H.1, A-H.2, A-H.3, A-H.4, A-H.5, A-H.6, A-H.7, A-H.8, A-H.9, A-H.10, A-H.11, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16, A-H.17, A-H.18, A- H.19, A-H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A- H.31, A-H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.1, A-H.42, A- H.43, A-H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A- H.55, A-H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A- H.67, A-H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A- H.79, A-H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0193] Exemplary anti-TCRβV antibody molecules and the corresponding TCRβV subfamiliesrecognized by said anti-TCRβV antibody molecules are disclosed in Table 10A.

[0194] The various TCRβV subfamilies and / or subfamily members can be expressed at different levelsin individuals, e.g., healthy individuals, as disclosed in Kitaura K. et al (2016), BMC Immunology vol 17: 38, the entire contents of which are hereby incorporated by reference. For example, TCRβ V6-5 is represented in approximately 3-6% healthy donors.

[0195] The representation of various TCRBV subfamilies and / or subfamily members can also bedifferent in cancer cells. For example, TCRβV is present in about 3-6% of tumor infiltrating T cellsWSGR Docket. No.53676-777.601 irrespective of tumor type (see Li B. et al., Nature Genetics, 2016, vol:48(7):725-32 the entire contents of which are hereby incorporated by references). Li et al., also disclose that TCRβ V6-5 is present at a high frequency in tumor cells. Anti-TCRβ V6 antibodies

[0196] In one aspect, provided herein is an anti-TCRβV antibody molecule that binds to human TCRβV6, e.g., a TCRβ V6 subfamily comprising: TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01 or TCRβ V6-1*01. In some embodiments the TCRβ V6 subfamily comprises TCRβ V6-5*01 or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-4*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-4*02, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-9*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-8*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-5*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-6*02, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-6*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-2*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-3*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-1*01, or a variant thereof.

[0197] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, is a non-murine antibody molecule, e.g., a human or humanized antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti- TCRβ V6-5*01) antibody molecule is a human antibody molecule. In some embodiments, the anti- TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule is a humanized antibody molecule.

[0198] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, is isolated or recombinant.

[0199] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises at least one antigen-binding region, e.g., a variable region or an antigen-binding fragment thereof, from an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, or encoded by a nucleotide sequence in Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0200] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises at least one, two, three or four variable regions from an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A- H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.WSGR Docket No.53676-777.601

[0201] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises at least one or two heavy chain variable regions from an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody molecule described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0202] In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain variableregion (VH) having a consensus sequence of SEQ ID NO: 231 or 3290.

[0203] SEQ ID NO: 231 - Consensus VHQVQLVQSGAEVKKPGSSVKVSCKASGH / T / G / YD / T / SFH / R / D / K / TL / D / K / T / NW / F / T / I / Y / GYIHWV RQAPGQGLEWMGR / WV / I / FF / S / YA / PGSGN / ST / V / Y / IK / RYNEKFKGRVTITADTSTSTAYMELSS LRSEDTAVYYCAG / VSY / IYSY / AD / GVLDYWGQGTTVTVSS

[0204] SEQ ID NO: 3290 - Consensus VHQVQLVQSGAEVKKPGSSVKVSCKASGX1X2FX3X4X5YIHWVRQAPGQGLEWMGX6X7X8X9GSGX10X11X12YNEKFKGRVTITADTSTSTAYMELSSLRSEDTAVYYCAX13SX14YSX15X16VLDYWGQGT TVTVSS, where-in: X1 is H or T or G or Y; X2 is D or T or S; X3 is H or R or D or K or T; X4 is L or D or K or T or N; X5 is W or F or T or I or Y or G; X6 is R or W; X7 is V or I or F; X8 is F or S or Y; X9 is A or P; X10 is N or S; X11 is T or V or Y or I; X12 is K or R; X13 is G or V; X14 is Y or I; X15 is Y or A; and X16 is D or G.

[0205] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises at least one or two light chain variable regions from an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A- H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0206] In some embodiments, the anti-TCRβV antibody molecule comprises a light chain variableregion (VL) having a consensus sequence of SEQ ID NO: 230 or 3289.

[0207] SEQ ID NO: 230 - Consensus VLDIQMTQSPSFLSASVGDRVTITCKASQNVG / E / A / DN / DR / KVAWY / HQQKPGKAPKALIYSSSHRY K / SGVPSRFSGSGSGTEFTLTISSLQPEDFATYFCQQFKSYPLTFGQGTKLEIK

[0208] SEQ ID NO: 3289 - Consensus VLDIQMTQSPSFLSASVGDRVTITCKASQNVX1X2X3VAWX4QQKPGKAPKALIYSSSHRYX5GVPSRF SGSGSGTEFTLTISSLQPEDFATYFCQQFKSYPLTFGQGTKLEIK, wherein X1 is G, E, A or D; X2 is N or D; X3 is R or K; X4 is Y or H; and X5 is K or S

[0209] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises a heavy chain constant region for an IgG4, e.g., a human IgG4. In still another embodiment, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes a heavy chain constant region for an IgG1, e.g., a human IgG1. InWSGR Docket. No.53676-777.601 some embodiments, the heavy chain constant region comprises an amino sequence set forth in Table 3, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto.

[0210] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, includes a kappa light chain constant region, e.g., a human kappa light chain constant region. In some embodiments, the light chain constant region comprises an amino sequence set forth in Table 3, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto.

[0211] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, includes at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region (VH) of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0212] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, includes at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23.

[0213] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, includes at least one, two, or three complementarity determining regions (CDRs) from a light chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0214] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, includes at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23.WSGR Docket No.53676-777.601

[0215] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23.

[0216] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, molecule includes all six CDRs from an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23, or closely related CDRs, e.g., CDRs which are identical or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions). In some embodiments, the anti-TCRβV antibody molecule, e.g., anti- TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, may include any CDR described herein.

[0217] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule includes at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Table 1, Table 16, or Table 23) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Kabat et al. shown in Table 1, Table 16, or Table 23.

[0218] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule includes at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Table 1, Table 16, or Table 23) from a light chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Kabat et al. shown in Table 1, Table 16, or Table 23.

[0219] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, includes at least one, two, three, four, five, or six CDRs according to KabatWSGR Docket. No.53676-777.601 et al. (e.g., at least one, two, three, four, five, or six CDRs according to the Kabat definition as set out in Table 1, Table 16, or Table 23) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, three, four, five, or six CDRs according to Kabat et al. shown in Table 1, Table 16, or Table 23.

[0220] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, includes all six CDRs according to Kabat et al. (e.g., all six CDRs according to the Kabat definition as set out in Table 1, Table 16, or Table 23) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to all six CDRs according to Kabat et al. shown in Table 1, Table 16, or Table 23. In some embodiments, the anti- TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, may include any CDR described herein.

[0221] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, includes at least one, two, or three hypervariable loops that have the same canonical structures as the corresponding hypervariable loop of an antibody described herein, e.g., an antibody chosen from chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, e.g., the same canonical structures as at least loop 1 and / or loop 2 of the heavy and / or light chain variable domains of an antibody described herein. See, e.g., Chothia et al., (1992) J. Mol. Biol.227:799-817; Tomlinson et al., (1992) J. Mol. Biol.227:776-798 for descriptions of hypervariable loop canonical structures. These structures can be determined by inspection of the tables described in these references.

[0222] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule includes at least one, two, or three CDRs according to Chothia et al. (e.g., at least one, two, or three CDRs according to the Chothia definition as set out in Table 1, Table 16, or Table 23) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or as described in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g.,WSGR Docket No.53676-777.601 conservative substitutions) relative to one, two, or three CDRs according to Chothia et al. shown in Table 1, Table 16, or Table 23.

[0223] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule includes at least one, two, or three CDRs according to Chothia et al. (e.g., at least one, two, or three CDRs according to the Chothia definition as set out in Table 1, Table 16, or Table 23) from a light chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Chothia et al. shown in Table 1, Table 16, or Table 23.

[0224] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, includes at least one, two, three, four, five, or six CDRs according to Chothia et al. (e.g., at least one, two, three, four, five, or six CDRs according to the Chothia definition as set out in Table 1, Table 16, or Table 23) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A- H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by the nucleotide sequence in Table 1, Table 16, or Table 23; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, three, four, five, or six CDRs according to Chothia et al. shown in Table 1, Table 16, or Table 23.

[0225] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, includes all six CDRs according to Chothia et al. (e.g., all six CDRs according to the Chothia definition as set out in Table 1, Table 16, or Table 23) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to all six CDRs according to Chothia et al. shown in Table 1, Table 16, or Table 23. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, may include any CDR described herein.

[0226] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, molecule includes a combination of CDRs or hypervariable loops definedWSGR Docket. No.53676-777.601 according to Kabat et al., Chothia et al., or by ImMunoGeneTics (IMGT) numbering system, or as described in Table 1, Table 16, or Table 23.

[0227] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, can contain any combination of CDRs or hypervariable loops according to the Kabat and Chothia definitions, ImMunoGeneTics (IMGT) numbering system.

[0228] In some embodiments, a combined CDR as set out in Table 1, Table 16, or Table 23 is a CDRthat comprises a Kabat CDR and a Chothia CDR, or by ImMunoGeneTics (IMGT) numbering system.

[0229] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, molecule includes a combination of CDRs or hypervariable loops identified as combined CDRs in Table 1, Table 16, or Table 23. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, can contain any combination of CDRs or hypervariable loops according the “combined” CDRs are described in Table 1, Table 16, or Table 23.

[0230] In some embodiments, e.g., an embodiment comprising a variable region, a CDR (e.g., acombined CDR, Chothia CDR or Kabat CDR, or by ImMunoGeneTics (IMGT) numbering system), or other sequence referred to herein, e.g., in Table 1, Table 16, or Table 23, the antibody molecule is a monospecific antibody molecule, a bispecific antibody molecule, a bivalent antibody molecule, a biparatopic antibody molecule, or an antibody molecule that comprises an antigen binding fragment of an antibody, e.g., a half antibody or antigen binding fragment of a half antibody. In certain embodiments the antibody molecule comprises a multispecific molecule, e.g., a bispecific molecule, e.g., as described herein.

[0231] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule comprises a VH and / or a VL of an antibody described in Table 1, Table 16, or Table 23, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0232] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule comprises a VH and a VL of an antibody described in Table 1, Table 16, or Table 23, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0233] In some embodiments, an anti-TCRVb antibody as described herein has an antigen bindingdomain having a VL having a consensus sequence of SEQ ID NO: 230, wherein position 30 is G, E, A or D; position 31 is N or D; position 32 is R or K; position 36 is Y or H; and / or position 56 is K or S.

[0234] In some embodiments, an anti-TCRVb antibody as described herein has an antigen bindingdomain having a VH having a consensus sequence of SEQ ID NO: 231, wherein: position 27 is H or T or G or Y; position 28 is D or T or S; position 30 is H or R or D or K or T; position 31 is L or D or K or T or N; position 32 is W or F or T or I or Y or G; position 49 is R or W; position 50 is V or I or F; position 51 is F or S or Y; position 52 is A or P; position 56 is N or S; position 57 is T or V or Y or I; position 58WSGR Docket No.53676-777.601 is K or R; position 97 is G or V; position 99 is Y or I; position 102 is Y or A; and / or position 103 is D or G. Anti-TCRβ V5 antibodies

[0235] In one aspect, provided herein is an anti-TCRβV antibody molecule that binds to human TCRβV5. In some embodiments, the TCRβ V5 subfamily comprises TCRβ V5-5*01, TCRβ V5-6*01, TCRβ V5-4*01, TCRβ V5-8*01, TCRβ V5-1*01, or a variant thereof.

[0236] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V5 (e.g., anti-TCRβV5-1*01) antibody molecule, is a non-murine antibody molecule, e.g., a human or humanized antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V5 (e.g., anti- TCRβ V-1*01) antibody molecule is a human antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V5 (e.g., anti-TCRβ V5-1*01) antibody molecule is a humanized antibody molecule.

[0237] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V5 (e.g., anti-TCRβV5-1*01) antibody molecule, is isolated or recombinant.

[0238] Exemplary anti-TCRβ V5 antibodies are provided in Table 10B. In some embodiments, the anti-TCRβ V5 is an antibody C, e.g., humanized antibody C (antibody C-H), as provided in Table 10B. In some embodiments, the anti-TCRβV antibody comprises one or more (e.g., all three) of a LC CDR1, LC CDR2, and LC CDR3 provided in Table 10B; and / or one or more (e.g., all three) of a HC CDR1, HC CDR2, and HC CDR3 provided in Table 10B, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody C comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 10B, or a sequence with at least 95% sequence identity thereto.

[0239] Exemplary anti-TCRβ V5 antibodies are provided in Table 10C. In some embodiments, the anti-TCRβ V5 is antibody N, as provided in Table 10C. In some embodiments, the anti-TCRβV antibody comprises one or more (e.g., all three) of a LC CDR1, LC CDR2, and LC CDR3 provided in Table 10C; and / or one or more (e.g., all three) of a HC CDR1, HC CDR2, and HC CDR3 provided in Table 10C, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 10C, or a sequence with at least 95% sequence identity thereto.

[0240] Exemplary anti-TCRβ V5 antibodies are provided in Table 11. In some embodiments, the anti-TCRβ V5 is antibody E, e.g., humanized antibody E (antibody E-H), as provided in Table 11. In some embodiments, the anti-TCRβV antibody comprises one or more (e.g., all three) of a LC CDR1, LC CDR2, and LC CDR3 provided in Table 11; and / or one or more (e.g., all three) of a HC CDR1, HC CDR2, and HC CDR3 provided in Table 11, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody E comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 11, or a sequence with at least 95% sequence identity thereto.WSGR Docket. No.53676-777.601

[0241] In some embodiments, antibody E comprises a heavy chain comprising the amino acid sequenceof SEQ ID NO: 3284 and / or a light chain comprising the amino acid sequence of SEQ ID NO: 3285, or a sequence with at least 95% sequence identity thereto.

[0242] In some embodiments, the anti-TCRβ V5 antibody molecule comprises a VH and / or a VL of anantibody described in Table 10B, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0243] In some embodiments, the anti-TCRβ V5 antibody molecule comprises a VH and a VL of anantibody described in Table 10B, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0244] In some embodiments, the anti-TCRβ V5 antibody molecule comprises a VH and / or a VL of anantibody described in Table 10C, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0245] In some embodiments, the anti-TCRβ V5 antibody molecule comprises a VH and a VL of anantibody described in Table 10C, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0246] In some embodiments, the anti-TCRβ V5 antibody molecule comprises a VH and / or a VL of anantibody described in Table 11, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0247] In some embodiments, the anti-TCRβ V5 antibody molecule comprises a VH and a VL of anantibody described in Table 11, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto. Anti-TCRβ V12 antibodies

[0248] In one aspect, provided herein is an anti-TCRβV antibody molecule that binds to human TCRβV12, e.g., a TCRβ V12 subfamily comprising: TCRβ V12-4*01, TCRβ V12-3*01 or TCRβ V12-5*01. In some embodiments the TCRβ V12 subfamily comprises TCRβ V12-4*01. In some embodiments the TCRβ V12 subfamily comprises TCRβ V12-3*01.

[0249] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule, is a non-murine antibody molecule, e.g., a human or humanized antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule is a human antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule is a humanized antibody molecule.

[0250] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule, is isolated or recombinant.

[0251] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule, comprises at least one antigen-binding region, e.g., a variable region or an antigen-binding fragment thereof, from an antibody described herein, e.g., an antibody described in Table 2, or encodedWSGR Docket No.53676-777.601 by a nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0252] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule, comprises at least one, two, three or four variable regions from an antibody described herein, e.g., an antibody as described in Table 2, or encoded by a nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0253] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule, comprises at least one or two heavy chain variable regions from an antibody described herein, e.g., an antibody as described in Table 2, or encoded by a nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0254] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule, comprises at least one or two light chain variable regions from an antibody described herein, e.g., an antibody as described in Table 2, or encoded by a nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0255] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule, comprises a heavy chain constant region for an IgG4, e.g., a human IgG4. In still another embodiment, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule, includes a heavy chain constant region for an IgG1, e.g., a human IgG1. In some embodiments, the heavy chain constant region comprises an amino sequence set forth in Table 3, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto.

[0256] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule, includes a kappa light chain constant region, e.g., a human kappa light chain constant region. In some embodiments, the light chain constant region comprises an amino sequence set forth in Table 3, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto.

[0257] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule, includes at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0258] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule, includes at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Table 2, or encoded by a nucleotide sequence shown in Table 2. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions,WSGR Docket. No.53676-777.601 relative to the amino acid sequence shown in Table 2, or encoded by a nucleotide sequence shown in Table 2.

[0259] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule, includes at least one, two, or three complementarity determining regions (CDRs) from a light chain variable region of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0260] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule, includes at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Table 2, or encoded by a nucleotide sequence shown in Table 2. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 2, or encoded by a nucleotide sequence shown in Table 2.

[0261] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule, includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 2, or encoded by a nucleotide sequence shown in Table 2. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 2, or encoded by a nucleotide sequence shown in Table 2.

[0262] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule, molecule includes all six CDRs from an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2, or closely related CDRs, e.g., CDRs which are identical or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions). In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule, may include any CDR described herein.

[0263] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule includes at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Table 2) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen as described in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Kabat et al. shown in Table 2.

[0264] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule includes at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, orWSGR Docket No.53676-777.601 three CDRs according to the Kabat definition as set out in Table 2) from a light chain variable region of an antibody described herein, e.g., an antibody as described in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Kabat et al. shown in Table 2.

[0265] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule includes at least one, two, three, four, five, or six CDRs according to Kabat et al. (e.g., at least one, two, three, four, five, or six CDRs according to the Kabat definition as set out in Table 2) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, three, four, five, or six CDRs according to Kabat et al. shown in Table 2.

[0266] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule includes all six CDRs according to Kabat et al. (e.g., all six CDRs according to the Kabat definition as set out in Table 2) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2; or encoded by the nucleotide sequence in Table 2; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to all six CDRs according to Kabat et al. shown in Table 2. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti- TCRβ V12 antibody molecule may include any CDR described herein.

[0267] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule includes at least one, two, or three hypervariable loops that have the same canonical structures as the corresponding hypervariable loop of an antibody described herein, e.g., an antibody described in Table 2, e.g., the same canonical structures as at least loop 1 and / or loop 2 of the heavy and / or light chain variable domains of an antibody described herein. See, e.g., Chothia et al., (1992) J. Mol. Biol.227:799- 817; Tomlinson et al., (1992) J. Mol. Biol.227:776-798 for descriptions of hypervariable loop canonical structures. These structures can be determined by inspection of the tables described in these references.

[0268] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule includes at least one, two, or three CDRs according to Chothia et al. (e.g., at least one, two, or three CDRs according to the Chothia definition as set out in Table 2) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen as described in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two,WSGR Docket. No.53676-777.601 three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Chothia et al. shown in Table 2.

[0269] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule includes at least one, two, or three CDRs according to Chothia et al. (e.g., at least one, two, or three CDRs according to the Chothia definition as set out in Table 2) from a light chain variable region of an antibody described herein, e.g., an antibody as described in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Chothia et al. shown in Table 2.

[0270] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule includes at least one, two, three, four, five, or six CDRs according to Chothia et al. (e.g., at least one, two, three, four, five, or six CDRs according to the Chothia definition as set out in Table 2) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, three, four, five, or six CDRs according to Chothia et al. shown in Table 2.

[0271] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule includes all six CDRs according to Chothia et al. (e.g., all six CDRs according to the Chothia definition as set out in Table 2) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2; or encoded by the nucleotide sequence in Table 2; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to all six CDRs according to Chothia et al. shown in Table 2. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti- TCRβ V12 antibody molecule may include any CDR described herein.

[0272] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule includes at least one, two, or three CDRs according to a combined CDR (e.g., at least one, two, or three CDRs according to the combined CDR definition as set out in Table 2) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen as described in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to combined CDR shown in Table 2.WSGR Docket No.53676-777.601

[0273] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule includes at least one, two, or three CDRs according to a combined CDR (e.g., at least one, two, or three CDRs according to the combined CDR definition as set out in Table 2) from a light chain variable region of an antibody described herein, e.g., an antibody as described in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to a combined CDR shown in Table 2.

[0274] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule includes at least one, two, three, four, five, or six CDRs according to a combined CDR. (e.g., at least one, two, three, four, five, or six CDRs according to the combined CDR definition as set out in Table 2) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, three, four, five, or six CDRs according to a combined CDR shown in Table 2.

[0275] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule includes all six CDRs according to a combined CDR (e.g., all six CDRs according to the combined CDR definition as set out in Table 2) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2; or encoded by the nucleotide sequence in Table 2; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to all six CDRs according to a combined CDR shown in Table 2. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule may include any CDR described herein.

[0276] In some embodiments, a combined CDR as set out in Table 1 is a CDR that comprises a KabatCDR and a Chothia CDR.

[0277] In some embodiments, the anti-TCRβV antibody molecule, e e.g., anti-TCRβ V12 antibodymolecule, molecule includes a combination of CDRs or hypervariable loops identified as combined CDRs in Table 1. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule, can contain any combination of CDRs or hypervariable loops according the “combined” CDRs are described in Table 1.

[0278] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule includes a combination of CDRs or hypervariable loops defined according to the Kabat et al. and Chothia et al., or as described in Table 1.WSGR Docket. No.53676-777.601

[0279] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule can contain any combination of CDRs or hypervariable loops according to the Kabat and Chothia definitions, or by ImMunoGeneTics (IMGT) numbering system.

[0280] In some embodiments, e.g., an embodiment comprising a variable region, a CDR (e.g., acombined CDR, Chothia CDR or Kabat CDR, or by ImMunoGeneTics (IMGT) numbering system), or other sequence referred to herein, e.g., in Table 2, the antibody molecule is a monospecific antibody molecule, a bispecific antibody molecule, a bivalent antibody molecule, a biparatopic antibody molecule, or an antibody molecule that comprises an antigen binding fragment of an antibody, e.g., a half antibody or antigen binding fragment of a half antibody. In certain embodiments the antibody molecule comprises a multispecific molecule, e.g., a bispecific molecule, e.g., as described herein.

[0281] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule includes: (i) one, two or all of a light chain complementarity determining region 1 (LC CDR1), a light chain complementarity determining region 2 (LC CDR2), and a light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO: 16, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29 or SEQ ID NO: 30, and / or (ii) one, two or all of a heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 15, SEQ ID NO: 23, SEQ ID NO: 24 or SEQ ID NO: 25.

[0282] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 20, a LC CDR2 amino acid sequence of SEQ ID NO: 21, or a LC CDR3 amino acid sequence of SEQ ID NO: 22; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 17, a HC CDR2 amino acid sequence of SEQ ID NO: 18, or a HC CDR3 amino acid sequence of SEQ ID NO: 19.

[0283] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1 amino acid sequence of SEQ ID NO: 20, a LC CDR2 amino acid sequence of SEQ ID NO: 21, and a LC CDR3 amino acid sequence of SEQ ID NO: 2; and / or (ii) a heavy chain variable region (VH) comprising a HC CDR1 amino acid sequence of SEQ ID NO: 17, a HC CDR2 amino acid sequence of SEQ ID NO: 18, and a HC CDR3 amino acid sequence of SEQ ID NO: 19.

[0284] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 63, a LC CDR2 amino acid sequence of SEQ ID NO: 64, or a LC CDR3 amino acid sequence of SEQ ID NO: 65; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 57, a HC CDR2 amino acid sequence of SEQ ID NO: 58, or a HC CDR3 amino acid sequence of SEQ ID NO: 59.

[0285] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1 amino acid sequence of SEQ ID NO: 63, a LC CDR2 amino acid sequence of SEQ ID NO: 64, or a LC CDR3 amino acid sequence of SEQ ID NO: 65; and / or (ii) a heavy chain variable region (VH) comprising a HC CDR1WSGR Docket No.53676-777.601 amino acid sequence of SEQ ID NO: 57, a HC CDR2 amino acid sequence of SEQ ID NO: 58, or a HC CDR3 amino acid sequence of SEQ ID NO: 59.

[0286] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 66, a LC CDR2 amino acid sequence of SEQ ID NO: 67, or a LC CDR3 amino acid sequence of SEQ ID NO: 68; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 60, a HC CDR2 amino acid sequence of SEQ ID NO: 61, or a HC CDR3 amino acid sequence of SEQ ID NO: 62.

[0287] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1 amino acid sequence of SEQ ID NO: 63, a LC CDR2 amino acid sequence of SEQ ID NO: 64, or a LC CDR3 amino acid sequence of SEQ ID NO: 65; and / or (ii) a heavy chain variable region (VH) comprising a HC CDR1 amino acid sequence of SEQ ID NO: 57, a HC CDR2 amino acid sequence of SEQ ID NO: 58, or a HC CDR3 amino acid sequence of SEQ ID NO: 59.

[0288] In some embodiments, the light or the heavy chain variable framework (e.g., the regionencompassing at least FR1, FR2, FR3, and optionally FR4) of the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule can be chosen from: (a) a light or heavy chain variable framework including at least 80%, 85%, 87% 90%, 92%, 93%, 95%, 97%, 98%, or 100% of the amino acid residues from a human light or heavy chain variable framework, e.g., a light or heavy chain variable framework residue from a human mature antibody, a human germline sequence, or a human consensus sequence; (b) a light or heavy chain variable framework including from 20% to 80%, 40% to 60%, 60% to 90%, or 70% to 95% of the amino acid residues from a human light or heavy chain variable framework, e.g., a light or heavy chain variable framework residue from a human mature antibody, a human germline sequence, or a human consensus sequence; (c) a non-human framework (e.g., a rodent framework); or (d) a non-human framework that has been modified, e.g., to remove antigenic or cytotoxic determinants, e.g., deimmunized, or partially humanized. In some embodiments, the light or heavy chain variable framework region (particularly FR1, FR2 and / or FR3) includes a light or heavy chain variable framework sequence at least 70, 75, 80, 85, 87, 88, 90, 92, 94, 95, 96, 97, 98, 99% identical or identical to the frameworks of a VL or VH segment of a human germline gene.

[0289] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule, comprises a heavy chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more changes, e.g., amino acid substitutions or deletions, from an amino acid sequence described in Table 2.e.g., the amino acid sequence of the FR region in the entire variable region, e.g., SEQ ID NOs: 23-25.

[0290] Alternatively, or in combination with the heavy chain substitutions described herein the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises a light chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more amino acid changes, e.g., amino acid substitutions or deletions, from an amino acid sequence of an antibodyWSGR Docket. No.53676-777.601 described herein e.g., the amino acid sequence of the FR region in the entire variable region, e.g., SEQ ID NOs: 26-30.

[0291] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule includes one, two, three, or four heavy chain framework regions a sequence substantially identical thereto.

[0292] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule includes one, two, three, or four light chain framework regions or a sequence substantially identical thereto. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises the light chain framework region 1. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises the light chain framework region 2. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises the light chain framework region 3. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises the light chain framework region 4.

[0293] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises a light chain comprising a framework region, e.g., framework region 1 (FR1), comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more, e.g., all, position as described herein according to Kabat numbering. In some embodiments, FR1 comprises an Aspartic Acid at position 1, e.g., a substitution at position 1 according to Kabat numbering, e.g., an Alanine to Aspartic Acid substitution. In some embodiments, FR1 comprises an Asparagine at position 2, e.g., a substitution at position 2 according to Kabat numbering, e.g., an Isoleucine to Asparagine substitution, Serine to Asparagine substitution or Tyrosine to Asparagine substitution. In some embodiments, FR1 comprises a Leucine at position 4, e.g., a substitution at position 4 according to Kabat numbering, e.g., a Methionine to Leucine substitution.

[0294] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises a light chain comprising a framework region, e.g., framework region 1 (FR1), comprising a substitution at position 1 according to Kabat numbering, e.g., an Alanine to Aspartic Acid substitution, a substitution at position 2 according to Kabat numbering, e.g., an Isoleucine to Asparagine substitution, Serine to Asparagine substitution or Tyrosine to Asparagine substitution, and a substitution at position 4 according to Kabat numbering, e.g., a Methionine to Leucine substitution. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 1 (FR1), comprising a substitution at position 1 according to Kabat numbering, e.g., an Alanine to Aspartic Acid substitution, and a substitution at position 2 according to Kabat numbering, e.g., an Isoleucine to Asparagine substitution, Serine to Asparagine substitution or Tyrosine to Asparagine substitution. In some embodiments, the anti- TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 1 (FR1), comprising a substitution at position 1 according to Kabat numbering, e.g., an Alanine to Aspartic Acid substitution, and a substitution at position 4 according to Kabat numbering, e.g., a Methionine to Leucine substitution. In some embodiments, theWSGR Docket No.53676-777.601 anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 1 (FR1), comprising a substitution at position 2 according to Kabat numbering, e.g., an Isoleucine to Asparagine substitution, Serine to Asparagine substitution or Tyrosine to Asparagine substitution, and a substitution at position 4 according to Kabat numbering, e.g., a Methionine to Leucine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0295] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises a light chain comprising a framework region, e.g., framework region 3 (FR3), comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more, e.g., all, position as described herein according to Kabat numbering. In some embodiments, FR3 comprises a Glycine at position 66, e.g., a substitution at position 66 according to Kabat numbering, e.g., a Lysine to Glycine substitution, or a Serine to Glycine substitution. In some embodiments, FR3 comprises an Asparagine at position 69, e.g., a substitution at position 69 according to Kabat numbering, e.g., a Tyrosine to Asparagine substitution. In some embodiments, FR3 comprises a Tyrosine at position 71, e.g., a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, or an Alanine to Tyrosine substitution.

[0296] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises a light chain comprising a framework region, e.g., framework region 3 (FR3), comprising a substitution at position 66 according to Kabat numbering, e.g., a Lysine to Glycine substitution, or a Serine to Glycine substitution, and a substitution at position 69 according to Kabat numbering, e.g., a Tyrosine to Asparagine substitution.. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 3 (FR3), comprising a substitution at position 66 according to Kabat numbering, e.g., Lysine to Glycine substitution, or a Serine to Glycine substitution, and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, or an Alanine to Tyrosine substitution. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 3 (FR3), comprising a substitution at position 69 according to Kabat numbering, e.g., a Tyrosine to Asparagine substitution and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, or an Alanine to Tyrosine substitution. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 3 (FR3), comprising a substitution at position 66 according to Kabat numbering, e.g., a Lysine to Glycine substitution, or a Serine to Glycine substitution, a substitution at position 69 according to Kabat numbering, e.g., a Tyrosine to Asparagine substitution and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, or an Alanine to Tyrosine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.WSGR Docket. No.53676-777.601

[0297] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises a light chain comprising: a framework region 1 (FR1) comprising a substitution at position 2 according to Kabat numbering, e.g., a Isoleucine to Asparagine substitution; and a framework region 3 (FR3), comprising a substitution at position 69 according to Kabat numbering, e.g., a Threonine to Asparagine substitution and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 26. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0298] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises a light chain comprising: (a) a framework region 1 (FR1) comprising a substitution at position 1 according to Kabat numbering, e.g., a Alanine to Aspartic Acid substitution, and a substitution at position 2 according to Kabat numbering, e.g., a Isoleucine to Asparagine substitution; and (b) a framework region 3 (FR3), comprising a substitution at position 69 according to Kabat numbering, e.g., a Threonine to Asparagine substitution and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 27 In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0299] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises a light chain comprising: (a) a framework region 1 (FR1) comprising a substitution at position 2 according to Kabat numbering, e.g., a Serine to Asparagine substitution; and a substitution at position 4 according to Kabat numbering, e.g., a Methionine to Leucine substitution; and (b) a framework region 3 (FR3), comprising a substitution at position 69 according to Kabat numbering, e.g., a Threonine to Asparagine substitution and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 28 In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0300] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises a light chain comprising: (a) a framework region 1 (FR1) comprising a substitution at position 2 according to Kabat numbering, e.g., a Serine to Asparagine substitution; and (b) a framework region 3 (FR3) comprising a substitution at position 66 according to Kabat numbering, e.g., a Lysine to Glycine substitution; a substitution at position 69 according to Kabat numbering, e.g., a Threonine to Asparagine substitution; and a substitution at position 71 according to Kabat numbering, e.g., a Alanine to Tyrosine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 29. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0301] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises a light chain comprising: (a) a framework region 1 (FR1) comprising a substitution at position 2 according to Kabat numbering, e.g., a Tyrosine to Asparagine substitution; and (b) aWSGR Docket No.53676-777.601 framework region 3 (FR3) comprising a substitution at position 66 according to Kabat numbering, e.g., a Serine to Glycine substitution; a substitution at position 69 according to Kabat numbering, e.g., a Threonine to Asparagine substitution; and a substitution at position 71 according to Kabat numbering, e.g., a Alanine to Tyrosine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 29. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0302] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises a light chain variable domain comprising: (a) a framework region 1 (FR1) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all) positions as described herein according to Kabat numbering, and (b) a framework region 3 (FR3) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all) position as described herein according to Kabat numbering. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0303] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises the heavy chain framework region 1. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises the heavy chain framework region 2. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises the heavy chain framework region 3. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises the heavy chain framework region 4. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises the heavy chain framework regions 1-4, e.g., SEQ ID NOS: 20-23. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises the light chain framework regions 1-4, e.g., SEQ ID NOs: 26-30.

[0304] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises the heavy chain framework regions 1-4, e.g., SEQ ID NOs: 23-25; and the light chain framework regions 1-4, e.g., SEQ ID NOs: 26-30.

[0305] In some embodiments, the heavy or light chain variable domain, or both, of, the anti-TCRβVantibody molecule, e.g., anti-TCRβ V12 antibody molecule includes an amino acid sequence, which is substantially identical to an amino acid as described herein, e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical to a variable region of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2; or which differs at least 1 or 5 residues, but less than 40, 30, 20, or 10 residues, from a variable region of an antibody described herein.

[0306] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises at least one, two, three, or four antigen-binding regions, e.g., variable regions, having an amino acid sequence as set forth in Table 2, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the sequences shown in Table 2. In another embodiment,, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule includes a VH and / or VLWSGR Docket. No.53676-777.601 domain encoded by a nucleic acid having a nucleotide sequence as set forth in Table 2, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Table 2.

[0307] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: a VH domain comprising an amino acid sequence chosen from the amino acid sequence of SEQ ID NO: 23, SEQ ID NO:24 or SEQ ID NO:25, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, SEQ ID NO:24 or SEQ ID NO:25, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 23, SEQ ID NO:24 or SEQ ID NO:25; and / or a VL domain comprising an amino acid sequence chosen from the amino acid sequence of SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29 or SEQ ID NO: 30, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29 or SEQ ID NO: 30, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29 or SEQ ID NO: 30. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 26, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 26, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 26.

[0308] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 27, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 27, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 27.

[0309] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 28, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to theWSGR Docket No.53676-777.601 amino acid sequence SEQ ID NO: 28, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 28.

[0310] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 29, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 29, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 29.

[0311] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 30, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 30, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 30.

[0312] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 24 or 25, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 24 or 25, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 24 or 25; and a VL domain comprising the amino acid sequence of SEQ ID NO: 26, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 26, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 26.

[0313] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 24 or 25, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 24 or 25, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 24 or 25; and a VL domain comprising the amino acid sequence of SEQ ID NO: 27, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 27, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 27.

[0314] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 24 or 25, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 24 or 25, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 aminoWSGR Docket. No.53676-777.601 acid residues from the amino acid sequence of SEQ ID NO: 24 or 25; and a VL domain comprising the amino acid sequence of SEQ ID NO: 28, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 28, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 28.

[0315] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 24 or 25, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 24 or 25, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 24 or 25; and a VL domain comprising the amino acid sequence of SEQ ID NO: 29, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 29, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 29.

[0316] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 24 or 25, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 24 or 25, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 24 or 25; and a VL domain comprising the amino acid sequence of SEQ ID NO: 30, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 30, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 30.

[0317] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 25 or 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 25 or 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 25 or 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 26, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 26, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 26.

[0318] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 25 or 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 25 or 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 25 or 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 27, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 27, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 27.

[0319] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 25 or 23, anWSGR Docket No.53676-777.601 amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 25 or 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 25 or 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 28, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 28, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 28.

[0320] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 25 or 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 25 or 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 25 or 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 29, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 29, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 29.

[0321] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 25 or 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 25 or 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 25 or 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 30, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 30, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 30.

[0322] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule is a full antibody or fragment thereof (e.g., a Fab, F(ab')2, Fv, or a single chain Fv fragment (scFv)). In embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6- 5*01) antibody molecule is a monoclonal antibody or an antibody with single specificity. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule, can also be a humanized, chimeric, camelid, shark, or an in vitro-generated antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule is a humanized antibody molecule. The heavy and light chains of the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule can be full-length (e.g., an antibody can include at least one, and preferably two, complete heavy chains, and at least one, and preferably two, complete light chains) or can include an antigen-binding fragment (e.g., a Fab, F(ab')2, Fv, a single chain Fv fragment, a single domain antibody, a diabody (dAb), a bivalent antibody, or bispecific antibody or fragment thereof, a single domain variant thereof, or a camelid antibody).

[0323] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule is in the form of a multispecific molecule, e.g., a bispecific molecule, e.g., as described herein.WSGR Docket. No.53676-777.601

[0324] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule has a heavy chain constant region (Fc) chosen from, e.g., the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE. In some embodiments, the Fc region is chosen from the heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4. In some embodiments, the Fc region is chosen from the heavy chain constant region of IgG1 or IgG2 (e.g., human IgG1, or IgG2). In some embodiments, the heavy chain constant region is human IgG1.

[0325] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule has a light chain constant region chosen from, e.g., the light chain constant regions of kappa or lambda, preferably kappa (e.g., human kappa). In some embodiments, the constant region is altered, e.g., mutated, to modify the properties of the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function). For example, the constant region is mutated at positions 296 (M to Y), 298 (S to T), 300 (T to E), 477 (H to K) and 478 (N to F) to alter Fc receptor binding (e.g., the mutated positions correspond to positions 132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K) and 314 (N to F) of SEQ ID NOs: 212 or 214; or positions 135 (M to Y), 137 (S to T), 139 (T to E), 316 (H to K) and 317 (N to F) of SEQ ID NOs: 215, 216, 217 or 218).

[0326] Antibody B-H.1 comprises a first chain comprising the amino acid sequence of SEQ ID NO:3280 and a second chain comprising the amino acid sequence of SEQ ID NO: 3281.

[0327] Additional exemplary anti-TCRβ V12 antibodies are provided in Table 2. In some embodiments,the anti-TCRβ V12 is antibody B, e.g., humanized antibody B (antibody B-H), as provided in Table 2. In some embodiments, the anti-TCRβV antibody comprises one or more (e.g., all three) of a LC CDR1, LC CDR2, and LC CDR3 provided in Table 2; and / or one or more (e.g., all three) of a HC CDR1, HC CDR2, and HC CDR3 provided in Table 2, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody B comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 2, or a sequence with at least 95% sequence identity thereto.

[0328] In some embodiments, the anti-TCRVB 12 antibody molecule (e.g., anti-TCRVB 12-3 or anti-TCRVB 12-4 antibody molecule) comprises a VH of B-H.1A, B-H.1B, B-H.1C, B-H.1D, B-H.1E, B- H.1F, B-H.1G, B-H.1H, B-H.1, B-H.2, B-H.3, B-H.4, B-H.5, or B-H.6, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0329] In some embodiments, the anti-TCRVB 12 antibody molecule (e.g., anti-TCRVB 12-3 or anti-TCRVB 12-4 antibody molecule) comprises a VL of B-H.1A, B-H.1B, B-H.1C, B-H.1D, B-H.1E, B- H.1F, B-H.1G, B-H.1H, B-H.1, B-H.2, B-H.3, B-H.4, B-H.5, or B-H.6, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0330] In some embodiments, the anti-TCRVB 12 antibody molecule (e.g., anti-TCRVB 12-3 or anti-TCRVB 12-4 antibody molecule) comprises a VH of B-H.1A, B-H.1B, B-H.1C, B-H.1D, B-H.1E, B- H.1F, B-H.1G, B-H.1H, B-H.1, B-H.2, B-H.3, B-H.4, B-H.5, or B-H.6, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto; and a VL of B-H.1A, B-H.1B, B-H.1C,WSGR Docket No.53676-777.601 B-H.1D, B-H.1E, B-H.1F, B-H.1G, B-H.1H, B-H.1, B-H.2, B-H.3, B-H.4, B-H.5, or B-H.6, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto. Anti-TCRβ V10 antibodies

[0331] In one aspect, provided herein is an anti-TCRβV antibody molecule that binds to a human TCRβV10 subfamily member. In some embodiments, TCRβ V10 subfamily is also known as TCRβ V12. In some embodiments, the TCRβ V10 subfamily comprises: TCRβ V10-1*01, TCRβ V10-1*02, TCRβ V10-3*01 or TCRβ V10-2*01, or a variant thereof.

[0332] Exemplary anti-TCRβ V10 antibodies are provided in Table 12. In some embodiments, the anti-TCRβ V10 is antibody D, e.g., humanized antibody D (antibody D-H), as provided in Table 12. In some embodiments, antibody D comprises one or more (e.g., three) light chain CDRs and / or one or more (e.g., three) heavy chain CDRs provided in Table 12, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody D comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 12, or a sequence with at least 95% sequence identity thereto.

[0333] In some embodiments, the anti-TCRβ V10 antibody molecule comprises a VH and / or a VL of anantibody described in Table 12, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0334] In some embodiments, the anti-TCRβ V10 antibody molecule comprises a VH and a VL of anantibody described in Table 12, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto. Anti-TCRβ V19 antibodies

[0335] In one aspect, provided herein is an anti-TCRβV antibody molecule that binds to a human TCRβV19 subfamily member. In some embodiments, the TCRβ V19 subfamily comprises: TCRβ V19-1*01, TCRβ V19-1*02, or TCRβ V19-1*03, or a variant thereof.

[0336] Exemplary anti-TCRβ V19 antibodies are provided in Table 18. In some embodiments, the anti-TCRβ V19 is antibody Q, as provided in Table 18. In some embodiments, antibody Q comprises one or more (e.g., three) light chain CDRs and / or one or more (e.g., three) heavy chain CDRs provided in Table 18, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody Q comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 18, or a sequence with at least 95% sequence identity thereto.

[0337] In some embodiments, the anti-TCRβ V19 antibody molecule comprises a VH and / or a VL of anantibody described in Table 18, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0338] In some embodiments, the anti-TCRβ V19 antibody molecule comprises a VH and a VL of anantibody described in Table 18, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.WSGR Docket. No.53676-777.601 Anti-TCRβ V20 antibodies

[0339] In one aspect, provided herein is an anti-TCRβV antibody molecule that binds to a human TCRβV20 subfamily member. In some embodiments, the TCRβ V20 subfamily comprises: TCRβ V20-1*01, TCRβ V20-1*02, TCRβ V20-1*03, TCRβ V20-1*04, TCRβ V20-1*05, TCRβ V20-1*06, or TCRβ V20- 1*07, or a variant thereof.

[0340] Exemplary anti-TCRβ V20 antibodies are provided in Table 15. In some embodiments, the anti-TCRβ V20 is antibody L, as provided in Table 15. In some embodiments, antibody L comprises one or more (e.g., three) light chain CDRs and / or one or more (e.g., three) heavy chain CDRs provided in Table 15, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody L comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 15, or a sequence with at least 95% sequence identity thereto.

[0341] In some embodiments, the anti-TCRβ V20 is antibody M, as provided in Table 15. In someembodiments, antibody M comprises one or more (e.g., three) light chain CDRs and / or one or more (e.g., three) heavy chain CDRs provided in Table 15, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody M comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 15, or a sequence with at least 95% sequence identity thereto.

[0342] In some embodiments, the anti-TCRβ V20 antibody molecule comprises a VH and / or a VL of anantibody described in Table 15, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0343] In some embodiments, the anti-TCRβ V20 antibody molecule comprises a VH and a VL of anantibody described in Table 15, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto. Anti-TCRβ V28 antibodies

[0344] In one aspect, provided herein is an anti-TCRβV antibody molecule that binds to a human TCRβV28 subfamily member. In some embodiments, the TCRβ V28 subfamily comprises: TCRβ V28-1*01, or a variant thereof.

[0345] Exemplary anti-TCRβ V28 antibodies are provided in Table 17. In some embodiments, the anti-TCRβ V28 is antibody P, as provided in Table 17. In some embodiments, antibody P comprises one or more (e.g., three) light chain CDRs and / or one or more (e.g., three) heavy chain CDRs provided in Table 17, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody P comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 17, or a sequence with at least 95% sequence identity thereto.

[0346] In some embodiments, the anti-TCRβ V28 antibody molecule comprises a VH and / or a VL of anantibody described in Table 17, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0347] In some embodiments, the anti-TCRβ V28 antibody molecule comprises a VH and a VL of anantibody described in Table 17, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.WSGR Docket No.53676-777.601 Anti-TCRβ V15 antibodies

[0348] In one aspect, provided herein is an anti-TCRβV antibody molecule that binds to a human TCRβV15 subfamily member. In some embodiments, the TCRβ V15 subfamily comprises: TCRβ V15*01, TCRβ V15*02, or TCRβ V15*03, or a variant thereof. Anti-TCRβ V7 antibodies

[0349] In one aspect, provided herein is an anti-TCRβV antibody molecule that binds to a human TCRβV7 subfamily member. In some embodiments, the TCRβ V7 subfamily comprises: TCRβ V7-1*01, TCRβ V7-2*01, TCRβ V7-2*02, TCRβ V2-1*03, TCRβ V7-2*04, TCRβ V7-3*01, TCRβ V7-3*02, TCRβ V7-3*03, TCRβ V7-3*04, TCRβ V7-3*05, TCRβ V7-4*01, TCRβ V7-4*02, TCRβ V7-5*01, TCRβ V7-5*02, TCRβ V7-6*01, TCRβ V7-6*02, TCRβ V7-7*01, TCRβ V7-7*02, TCRβ V7-8*01, TCRβ V7-8*02, TCRβ V7-8*03, TCRβ V7-9*01, TCRβ V7-9*02, TCRβ V7-9*03, TCRβ V7-9*04, TCRβ V7-9*05, TCRβ V7-9*06, or TCRβ V7-9*07, or a variant thereof. Antibody-like Frameworks or Scaffolds

[0350] A wide variety of antibody / immunoglobulin frameworks or scaffolds can be employed in theanti-TCRvb antibody molecules as described herein or multifunctional formats thereof so long as the resulting polypeptide includes at least one binding region which specifically binds to the target antigen, e.g., a TCRvb, a tumor antigen, among others. Such frameworks or scaffolds include the 5 main idiotypes of human immunoglobulins, or fragments thereof, and include immunoglobulins of other animal species, preferably having humanized aspects. Novel frameworks, scaffolds and fragments continue to be discovered and developed by those skilled in the art.

[0351] In some embodiments, the anti-TCRvb antibody molecules as described herein or multifunctionalformats thereof include non-immunoglobulin based antibodies using non- immunoglobulin scaffolds onto which CDRs can be grafted. Any non-immunoglobulin frameworks and scaffolds may be employed, as long as they comprise a binding region specific for the target antigen (e.g., TCRvb or a tumor antigen). Exemplary non-immunoglobulin frameworks or scaffolds include, but are not limited to, fibronectin (Compound Therapeutics, Inc., Waltham, MA), ankyrin (Molecular Partners AG, Zurich, Switzerland), domain antibodies (Domantis, Ltd., Cambridge, MA, and Ablynx nv, Zwijnaarde, Belgium), lipocalin (Pieris Proteolab AG, Freising, Germany), small modular immuno-pharmaceuticals (Trubion Pharmaceuticals Inc., Seattle, WA), maxybodies (Avidia, Inc., Mountain View, CA), Protein A (Affibody AG, Sweden), and affilin (gamma-crystallin or ubiquitin) (Scil Proteins GmbH, Halle, Germany).

[0352] Fibronectin scaffolds are typically based on fibronectin type III domain (e.g., the tenth module ofthe fibronectin type III (10 Fn3 domain)). The fibronectin type III domain has 7 or 8 beta strands which are distributed between two beta sheets, which themselves pack against each other to form the core of the protein, and further containing loops (analogous to CDRs) which connect the beta strands to each other and are solvent exposed. There are at least three such loops at each edge of the beta sheet sandwich, where the edge is the boundary of the protein perpendicular to the direction of the beta strands (see US 6,818,418). Because of this structure, the non-immunoglobulin antibody mimics antigen bindingWSGR Docket. No.53676-777.601 properties that are similar in nature and affinity to those of antibodies. These scaffolds can be used in a loop randomization and shuffling strategy in vitro that is similar to the process of affinity maturation of antibodies in vivo. These fibronectin-based molecules can be used as scaffolds where the loop regions of the molecule can be replaced with CDRs of the invention using standard cloning techniques.

[0353] The ankyrin technology is based on using proteins with ankyrin derived repeat modules asscaffolds for bearing variable regions which can be used for binding to different targets. The ankyrin repeat module typically is a about 33 amino acid polypeptide consisting of two anti-parallel α-helices and a β-turn. Binding of the variable regions can be optimized by using ribosome display.

[0354] Avimers are used by nature for protein-protein interactions and in human over 250 proteins arestructurally based on A-domains. Avimers consist of a number of different “A-domain” monomers (2-10) linked via amino acid linkers. Avimers can be created that can bind to the target antigen using the methodology described in, for example, U.S. Patent Application Publication Nos.20040175756; 20050053973; 20050048512; and 20060008844.

[0355] Affibody affinity ligands are small, simple proteins composed of a three-helix bundle based onthe scaffold of one of the IgG-binding domains of Protein A. Protein A is a surface protein from the bacterium Staphylococcus aureus. This scaffold domain consists of 58 amino acids, 13 of which are randomized to generate affibody libraries with a large number of ligand variants (See e.g., US 5,831,012). Affibody molecules mimic antibodies, they have a molecular weight of 6 kDa, compared to the molecular weight of antibodies, which is 150 kDa. In spite of its small size, the binding site of affibody molecules is similar to that of an antibody.

[0356] Anticalins are known commercially, e.g., Pieris ProteoLab AG. They are derived from lipocalins,a widespread group of small and robust proteins that are usually involved in the physiological transport or storage of chemically sensitive or insoluble compounds. Several natural lipocalins occur in human tissues or body liquids. The protein architecture is reminiscent of immunoglobulins, with hypervariable loops on top of a rigid framework. However, in contrast with antibodies or their recombinant frag...

Claims

WSGR Docket No.53676-777.601 CLAIMS WHAT IS CLAIMED IS:

1. A method of treating a disease or a condition in a subject in need thereof comprising:(a) administering a therapeutically effective amount of a first agent comprising (i) a first domainthat binds to a TCR β variable (TCRβV) region and (ii) a molecule that binds to a co- stimulatory receptor of a T cell; and (b) administering a therapeutically effective amount of a second agent comprising an antibody-drugconjugate.

2. A combination therapy for treating a disease or a condition in a subject in need thereof, comprising:(a) a first agent comprising (i) a first domain that binds to a TCR β variable (TCRβV) region and(ii) a molecule that binds to a co-stimulatory receptor of a T cell; and (b) a second agent comprising an antibody-drug conjugate.

3. A composition for treating a disease or condition in a subject in need thereof comprising:(a) a first agent comprising (i) a first domain that binds to a TCR β variable (TCRβV) region and(ii) a molecule that binds to a co-stimulatory receptor of a T cell; and (b) a second agent comprising an antibody-drug conjugate.

4. A kit for treating a disease or condition in a subject in need thereof comprising:(a) A first agent comprising (i) a first domain that binds to a TCR β variable (TCRβV) region and(ii) a molecule that binds to a co-stimulatory receptor of a T cell; and (b) a second agent comprising an antibody-drug conjugate.

5. A method of treating a disease or a condition in a subject in need thereof comprising:(a) administering a therapeutically effective amount of a first agent comprising (i) a first domainthat binds to a TCR β variable (TCRβV) region and (ii) a molecule that binds to a co- stimulatory receptor of a T cell; and (b) administering a therapeutically effective amount of a second agent comprising (i) a seconddomain that binds to a TCR β variable (TCRβV) region and (ii) a third domain that binds to trophoblast cell surface antigen 2 (TROP2).

6. A combination therapy for treating a disease or a condition in a subject in need thereof comprising:(a) a first agent comprising (i) a first domain that binds to a TCR β variable (TCRβV) region and(ii) a molecule that binds to a co-stimulatory receptor of a T cell; and (b) a second agent comprising (i) a second domain that binds to a TCR β variable (TCRβV) regionand (ii) a third domain that binds to trophoblast cell surface antigen 2 (TROP2).

7. A composition for treating a disease or condition in a subject in need thereof comprising:(a) a first agent comprising (i) a first domain that binds to a TCR β variable (TCRβV) region and(ii) a molecule that binds to a co-stimulatory receptor of a T cell; and (b) a second agent comprising (i) a second domain that binds to a TCR β variable (TCRβV) regionand (ii) a third domain that binds to trophoblast cell surface antigen 2 (TROP2).

8. A kit for treating a disease or condition in a subject in need thereof comprising:WSGR Docket. No.53676-777.601 (a) a first agent comprising (i) a first domain that binds to a TCR β variable (TCRβV) region and(ii) a molecule that binds to a co-stimulatory receptor of a T cell; and (b) a second agent comprising (i) a second domain that binds to a TCR β variable (TCRβV) regionand (ii) a third domain that binds to trophoblast cell surface antigen 2 (TROP2).

9. The method of claim 1 or 5, the combination therapy of claim 2 or 6, the composition of claim 3 or 7,or the kit of claim 4 or 8, wherein the TCRβV-binding moiety is covalently linked to the molecule that binds to a co-stimulatory receptor of a T cell.

10. The method of claim 1, 5 or 9, the combination therapy of claim 2, 6, or 9, the composition of claim3, 7, or 9, or the kit of claim 4, 8, or 9, wherein the molecule that binds to a co-stimulatory receptor of a T cell activates the co-stimulatory receptor when the molecule that binds to a co-stimulatory receptor of a T cell binds to the co-stimulatory receptor.

11. The method of any one of claims 1, 5, 9, and 10, the combination therapy of any one of claims 2, 6, 9,and 10, the composition of any one of claims 3, 7, 9, and 10, or the kit of any one of claims 4, 8, 9, and 10, wherein the molecule that binds to a co-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof.

12. The method of any one of claims 1, 5, and 9-11, the combination therapy of any one of claims 2, 6,and 9-11, the composition of any one of claims 3, 7, and 9-11, or the kit of any one of claims 4, 8, and 9-11, wherein the molecule that binds to a co-stimulatory receptor of a T cell comprises an antibody molecule, an antigen binding domain, a ligand, an extracellular domain of a receptor, or any combination thereof.

13. The method of claim 1 or 5, wherein the administration of the second agent to the subject isconducted before the administration of the first agent to the subject.

14. The method of claim 1 or 5, wherein the administration of the first agent to the subject is conductedbefore the administration of the second agent to the subject.

15. The method of any one of claims 1, 5, and 9-14, wherein the administration of the first agentimproves therapeutic efficacy of the second agent to the subject.

16. The method of any one of claims 1, 5, and 9-15, wherein the administration of the first agent and thesecond agent promotes an enhanced anti-tumor immune response in the subject.

17. The method, the combination therapy, the composition, or the kit of any one of claims 9-16, whereinthe first agent comprises (i) a first domain that binds to TCR β V6 (TCRβV-6) subfamily or TCR β V10 (TCRβV-10) subfamily and (ii) an IL-2 cytokine molecule or a functional variant thereof.

18. The method, the combination therapy, the composition, or the kit of any one of claims 1-17, whereinthe first agent further comprises a tumor-associated antigen binding moiety.

19. The method, the combination therapy, the composition, or the kit of claim 18, wherein the tumor-associated antigen binding moiety binds to a cancer antigen selected from the group consisting of trophoblast cell surface antigen 2 (TROP2), CD19, CD123, CD22, CD30, CD171, CS-1, C-type lectin-like molecule-1, CD33, epidermal growth factor receptor variant III (EGFRvIII), ganglioside G2 (GD2), ganglioside GD3, TNF receptor family member B cell maturation (BCMA), Tn antigenWSGR Docket No.53676-777.601 ((Tn Ag) or (GalNAcα-Ser / Thr)), prostate-specific membrane antigen (PSMA), Receptor tyrosine kinase-like orphan receptor 1 (ROR1), Fms-Like Tyrosine Kinase 3 (FLT3), Tumor-associated glycoprotein 72 (TAG72), CD38, CD44v6, Carcinoembryonic antigen (CEA), Epithelial cell adhesion molecule (EPCAM), B7H3 (CD276), KIT (CD117), Interleukin-13 receptor subunit alpha- 2, mesothelin, Interleukin 11 receptor alpha (IL-11Ra), prostate stem cell antigen (PSCA), Protease Serine 21, vascular endothelial growth factor receptor 2 (VEGFR2), Lewis(Y) antigen, CD24, Platelet-derived growth factor receptor beta (PDGFR-beta), Stage-specific embryonic antigen-4 (SSEA-4), CD20, Folate receptor alpha, Receptor tyrosine-protein kinase ERBB2 (Her2 / neu), Mucin 1, cell surface associated (MUC1), epidermal growth factor receptor (EGFR), neural cell adhesion molecule (NCAM), Prostase, prostatic acid phosphatase (PAP), elongation factor 2 mutated (ELF2M), Ephrin B2, fibroblast activation protein alpha (FAP), insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX), Proteasome (Prosome, Macropain) Subunit, Beta Type, 9 (LMP2), glycoprotein 100 (gp100 / pmel17), oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr-abl), tyrosinase, ephrin type-A receptor 2 (EphA2), Fucosyl GM1, sialyl Lewis adhesion molecule (sLe), ganglioside GM3, transglutaminase 5 (TGS5), high molecular weight-melanoma-associated antigen (HMWMAA), o-acetyl-GD2 ganglioside (OAcGD2), Folate receptor beta, tumor endothelial marker 1 (TEM1 / CD248), tumor endothelial marker 7-related (TEM7R), claudin 6 (CLDN6), thyroid stimulating hormone receptor (TSHR), G protein-coupled receptor class C group 5, member D (GPRC5D), chromosome X open reading frame 61 (CXORF61), CD97, CD179a, anaplastic lymphoma kinase (ALK), Polysialic acid, placenta-specific 1 (PLAC1), hexasaccharide portion of globoH glycoceramide (GloboH), mammary gland differentiation antigen (NY-BR-1), uroplakin 2 (UPK2), Hepatitis A virus cellular receptor 1 (HAVCR1), adrenoceptor beta 3 (ADRB3), pannexin 3 (PANX3), G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex, locus K 9 (LY6K), Olfactory receptor 51E2 (OR51E2), TCR Gamma Alternate Reading Frame Protein (TARP), Wilms tumor protein (WT1), Cancer / testis antigen 1 (NY-ESO-1 / LAGE-1), Cancer / testis antigen 2 (LAGE-1a), Melanoma-associated antigen 1 (MAGE-A1), ETS translocation-variant gene 6, located on chromosome 12p (ETV6-AML), sperm protein 17 (SPA17), X Antigen Family, Member 1A (XAGE1), angiopoietin-binding cell surface receptor 2 (Tie 2), melanoma cancer testis antigen-1 (MAD-CT-1), melanoma cancer testis antigen-2 (MAD-CT-2), Fos-related antigen 1, tumor protein p53 (p53), p53 mutant, prostein, Survivin, telomerase, prostate carcinoma tumor antigen-1, melanoma antigen recognized by T cells 1, Rat sarcoma (Ras) mutant, human Telomerase reverse transcriptase (hTERT), sarcoma translocation breakpoints, melanoma inhibitor of apoptosis (ML-IAP), ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene), N-Acetyl glucosaminyl-transferase V (NA17), paired box protein Pax-3 (PAX3), Androgen receptor, Cyclin B1, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), Ras Homolog Family Member C (RhoC), Tyrosinase-related protein 2 (TRP-2), Cytochrome P4501B1 (CYP1B1), CCCTC-Binding Factor (Zinc Finger Protein)-Like, Squamous Cell Carcinoma AntigenWSGR Docket. No.53676-777.601 Recognized By T Cells 3 (SART3), Paired box protein Pax-5 (PAX5), proacrosin binding protein sp32 (OY-TES1), lymphocyte-specific protein tyrosine kinase (LCK), A kinase anchor protein 4 (AKAP-4), synovial sarcoma, X breakpoint 2 (SSX2), Receptor for Advanced Glycation Endproducts (RAGE-1), renal ubiquitous 1 (RU1), renal ubiquitous 2 (RU2), legumain, human papilloma virus E6 (HPV E6), human papilloma virus E7 (HPV E7), intestinal carboxyl esterase, heat shock protein 70-2 mutated (mut hsp70-2), CD79a, CD79b, CD72, Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), Fc fragment of IgA receptor (FCAR or CD89), Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2), CD300 molecule-like family member f (CD300LF), C-type lectin domain family 12 member A (CLEC12A), bone marrow stromal cell antigen 2 (BST2), EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2), lymphocyte antigen 75 (LY75), Glypican-3 (GPC3), Fc receptor-like 5 (FCRL5), FcRH5, PDL1, CD47, prostate specific membrane antigen (PMSA), prostate-specific antigen (PSA), Ron Kinase, c- Met, Immature laminin receptor, TAG-72, BING-4, Calcium-activated chloride channel 2, Cyclin- B1, 9D7, Ep-CAM, EphA3, SAP-1, PRAME, SSX-2, Melan-A / MART-1, TRP1 / gp75, MC1R, β- catenin, BRCA1 / 2, CDK4, CML66, Fibronectin, Ras, TGF-Β receptor, AFP, ETA, MAGE, CA-125, BAGE, GAGE, CDC27, α actinin-4, gangliosides, MART-2, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RU11, RU12, SAGE, TRG, TSTA, L1-CAM, gpA33, GM2, VEGFR, Intergrins, carbohydrates, TRAILR1, TRAILR2, RANKL, TGF-beta, hyaluronic acid, collagen, tenascin C, tenascin W, and immunoglobulin lambda-like polypeptide 1 (IGLL1).

20. The method, the combination therapy, the composition, or the kit of claim 18 or 19, wherein thetumor-associated antigen binding moiety binds to a cancer antigen selected from the group consisting of CD20, MSLN, gp75 (Tryp1), and any combination thereof.

21. The method, the combination therapy, the composition, or the kit of any one of claims 18-20, whereinthe tumor-associated antigen binding moiety comprises a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1), a heavy chain complementarity determining region 2 (HC CDR2), and a heavy chain complementarity determining region 3 (HC CDR3) comprising the sequences of SEQ ID NO: 524, SEQ ID NO: 525, and SEQ ID NO: 526, respectively, or a VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 comprising the sequences of SEQ ID NO: 538, SEQ ID NO: 539, and SEQ ID NO: 540, respectively.

22. The method, the combination therapy, the composition, or the kit of any one of claims 18-21, whereinthe tumor-associated antigen binding moiety comprises a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1), a light chain complementarity determining region 2 (LC CDR2) and a light chain complementarity determining region 3 (LC CDR3) comprising the sequences of SEQ ID NO: 1168, SEQ ID NO: 1295, and SEQ ID NO: 528, respectively, or a VL comprising a LC CDR1, a LC CDR2 and a LC CDR3 comprising the sequences of SEQ ID NO: 562, SEQ ID NO: 563, and SEQ ID NO: 564, respectively.WSGR Docket No.53676-777.60123. The method, the combination therapy, the composition, or the kit of any one of claims 18-22, whereinthe tumor-associated antigen binding moiety comprises a VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 comprising the sequences of SEQ ID NO: 524, SEQ ID NO: 525, and SEQ ID NO: 526, respectively, and a VL comprising a LC CDR1, a LC CDR2 and a LC CDR3 comprising the sequences of SEQ ID NO: 1168, SEQ ID NO: 1295, and SEQ ID NO: 528, respectively.

24. The method, the combination therapy, the composition, or the kit of any one of claims 18-23, whereinthe tumor-associated antigen binding moiety comprises a VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 comprising the sequences of SEQ ID NO: 538, SEQ ID NO: 539, and SEQ ID NO: 540, respectively, and a VL comprising a LC CDR1, a LC CDR2 and a LC CDR3 comprising the sequences of SEQ ID NO: 562, SEQ ID NO: 563, and SEQ ID NO: 564, respectively.

25. The method, the combination therapy, the composition, or the kit of any one of claims 18-24, whereinthe tumor-associated antigen binding moiety comprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 523 or the sequence of SEQ ID NO: 537.

26. The method, the combination therapy, the composition, or the kit of any one of claims 18-25, whereinthe tumor-associated antigen binding moiety comprises a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 527 or the sequence of SEQ ID NO: 561.

27. The method, the combination therapy, the composition, or the kit of any one of claims 18-26, whereinthe tumor-associated antigen binding moiety comprises a VH comprising the sequence of SEQ ID NO: 523 or the sequence of SEQ ID NO: 537.

28. The method, the combination therapy, the composition, or the kit of any one of claims 18-27, whereinthe tumor-associated antigen binding moiety comprises a VL comprising the sequence of SEQ ID NO: 527 or the sequence of SEQ ID NO: 561.

29. The method, the combination therapy, the composition, or the kit of any one of claims 18-28, whereinthe tumor-associated antigen binding moiety comprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 523 and a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 527.

30. The method, the combination therapy, the composition, or the kit of any one of claims 18-29, whereinthe tumor-associated antigen binding moiety comprises a VH comprising the sequence of SEQ ID NO: 523 and a VL comprising the sequence of SEQ ID NO: 527.WSGR Docket. No.53676-777.60131. The method, the combination therapy, the composition, or the kit of any one of claims 18-28, whereinthe tumor-associated antigen binding moiety comprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 537 and a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 561.

32. The method, the combination therapy, the composition, or the kit of any one of claims 18-28 and 31,wherein the tumor-associated antigen binding moiety comprises a VH comprising the sequence of SEQ ID NO: 537 and a VL comprising the sequence of SEQ ID NO: 561.

33. The method, the combination therapy, the composition, or the kit of any one of claims 18-23, whereinthe tumor-associated antigen binding moiety comprises a VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 comprising the sequences of SEQ ID NO: 581, SEQ ID NO: 582, and SEQ ID NO: 583, respectively.

34. The method, the combination therapy, the composition, or the kit of any one of claims 18-23 and 33,wherein the tumor-associated antigen binding moiety comprises a VL comprising a LC CDR1, a LC CDR2 and a LC CDR3 comprising the sequences of SEQ ID NO: 586, SEQ ID NO: 587, and SEQ ID NO: 588, respectively.

35. The method, the combination therapy, the composition, or the kit of any one of claims 18-23, 33, and34, wherein the tumor-associated antigen binding moiety comprises a VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 comprising the sequences of SEQ ID NO: 581, SEQ ID NO: 582, and SEQ ID NO: 583, respectively, and a VL comprising a LC CDR1, a LC CDR2 and a LC CDR3 comprising the sequences of SEQ ID NO: 586, SEQ ID NO: 587, and SEQ ID NO: 588, respectively.

36. The method, the combination therapy, the composition, or the kit of any one of claims 18-23 and 33-35, wherein the tumor-associated antigen binding moiety comprises a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 580.

37. The method, the combination therapy, the composition, or the kit of any one of claims 18-23 and 33-36, wherein the tumor-associated antigen binding moiety comprises a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 585.

38. The method, the combination therapy, the composition, or the kit of any one of claims 18-23 and 33-37, wherein the tumor-associated antigen binding moiety comprises a VH comprising the sequence of SEQ ID NO: 580.

39. The method, the combination therapy, the composition, or the kit of any one of claims 18-23 and 33-38, wherein the tumor-associated antigen binding moiety comprises a VL comprising the sequence of SEQ ID NO: 585.WSGR Docket No.53676-777.60140. The method, the combination therapy, the composition, or the kit of any one of claims 18-23 and 33-39, wherein the tumor-associated antigen binding moiety comprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 580 and a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 585.

41. The method, the combination therapy, the composition, or the kit of any one of claims 18-23 and 33-40, wherein the tumor-associated antigen binding moiety comprises a VH comprising the sequence of SEQ ID NO: 580 and a VL comprising the sequence of SEQ ID NO: 585.

42. The method, combination therapy, composition, or kit of any one of claims 1-4 and 9-41, wherein theantibody-drug conjugate comprises: (a) an antibody (Mab) comprising a first domain that binds to trophoblast cell surface antigen 2(TROP2), wherein the first domain comprises: (i) a heavy chain variable region (VH) comprising a heavy chain complementaritydetermining region 1 (HC CDR1) amino acid sequence of NYGMN (SEQ ID NO: 500), a heavy chain complementarity determining region 2 (HC CDR2) amino acid sequence of WINTYTGEPTYTDDFKG (SEQ ID NO: 501), and a heavy chain complementarity determining region 3 (HC CDR3) amino acid sequence of GGFGSSYWYFDV (SEQ ID NO: 502); and (ii) a light chain variable region (VL) comprising a light chain complementarity determiningregion 1 (LC CDR1) amino acid sequence of KASQDVSIAVA (SEQ ID NO: 503), a light chain complementarity determining region 2 (LC CDR2) amino acid sequence of SASYRYT (SEQ ID NO: 504), and a light chain complementarity determining region 3 (LC CDR3) amino acid sequence of QQHYITPLT (SEQ ID NO: 505); and (b) a cytotoxic drug, wherein the cytotoxic drug is conjugated to the Mab.

43. The method of claim 5, the combination therapy of claim 6, the composition of claim 7, or the kit ofclaim 8, wherein the third domain that binds to TROP2 or the first domain that binds to TROP2 comprises: (a) a VH comprising a HC CDR1 amino acid sequence of NYGMN (SEQ ID NO: 500), a HCCDR2 amino acid sequence of WINTYTGEPTYTDDFKG (SEQ ID NO: 501), and a HC CDR3 amino acid sequence of GGFGSSYWYFDV (SEQ ID NO: 502); and (b) a VL comprising a LC CDR1 amino acid sequence of KASQDVSIAVA (SEQ ID NO: 503), aLC CDR2 amino acid sequence of SASYRYT (SEQ ID NO: 504), and a LC CDR3 amino acid sequence of QQHYITPLT (SEQ ID NO: 505).

44. The method, the combination therapy, the composition, or the kit of claim 42 or 43, wherein the firstdomain that binds to TROP2 or the third domain that binds to TROP2 comprises a VH sequenceWSGR Docket. No.53676-777.601 having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 506.

45. The method, the combination therapy, the composition, or the kit of any one of claims 42-44, whereinthe first domain that binds to TROP2 or the third domain that binds to TROP2 comprises a VH sequence comprising the sequence of SEQ ID NO: 506.

46. The method, the combination therapy, the composition, or the kit of any one of claims 42-45, whereinthe first domain that binds to TROP2 or the third domain that binds to TROP2 comprises a VL sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to the sequence of SEQ ID NO: 508.

47. The method, the combination therapy, the composition, or the kit of claim 46, wherein the firstdomain that binds to TROP2 or the third domain that binds to TROP2 comprises a VL sequence comprising the sequence of SEQ ID NO: 508.

48. The method, the combination therapy, the composition, or the kit of any one of claims 42-47, whereinthe first domain that binds to TROP2 or the third domain that binds to TROP2 comprises a VH comprising the sequence of SEQ ID NO: 506 and a VL comprising the sequence of SEQ ID NO: 508.

49. The method, the combination therapy, the composition, or the kit of any one of claims 42-48, whereinthe first domain that binds to TROP2 or the third domain that binds to TROP2 is a Fab, F(ab')2, Fv, a single chain Fv (scFv), a diabody, a single domain antibody, a VHH, or a camelid antibody.

50. The method, the combination therapy, the composition, or the kit of any one of claims 42-49, whereinthe first domain that binds to TROP2 or the third domain that binds to TROP2 comprises a dimerization module, comprising a first immunoglobulin chain constant region and a second immunoglobulin chain constant region.

51. The method, the combination therapy, the composition, or the kit of claim 50, wherein the firstimmunoglobulin chain constant region comprises the first fragment crystallizable region (Fc region) and the second first immunoglobulin chain constant region comprises the second fragment crystallizable region (Fc region).

52. The method, the combination therapy, the composition, or the kit of any one of claims 42-51, whereinthe first domain that binds to TROP2 or the third domain that binds to TROP2 comprises one or more heavy chain constant regions selected from IgG4 heavy chain constant region or fragment thereof and IgG1 heavy chain constant region or fragment thereof.

53. The method, the combination therapy, the composition, or the kit of any one of claims 42-52, whereinthe first domain that binds to TROP2 or the third domain that binds to TROP2 further comprises a heavy chain constant domain 1 (CH1) linked to the VH.

54. The method, the combination therapy, the composition, or the kit of any one of claims 42-53, whereinthe first domain that binds to TROP2 or the third domain that binds to TROP2 further comprises a light chain constant domain (CL) linked to the VL.WSGR Docket No.53676-777.60155. The method, the combination therapy, the composition, or the kit of claim 53 or 54, wherein the firstdomain that binds to TROP2 or the third domain that binds to TROP2 comprises a first polypeptide comprising the VH and the CH1 linked to the VH.

56. The method, the combination therapy, the composition, or the kit of claim 54-55, wherein the firstdomain that binds to TROP2 or the third domain that binds to TROP2 comprises a first polypeptide comprising the VL and the CL linked to the VL.

57. The method, the combination therapy, the composition, or the kit of claim 55 or 56, wherein the firstpolypeptide comprises the sequence of SEQ ID NOs: 515 or 516.

58. The method, the combination therapy, the composition, or the kit of claims 55-57, wherein the secondpolypeptide comprises the sequence of SEQ ID NOs: 509 or 512.

59. The method, the combination therapy, the composition, or the kit of any one of claims 55-58, whereinthe first polypeptide and the second polypeptide chains are non-contiguous.

60. The method, the combination therapy, the composition, or the kit of any one of claims 42-59, whereinthe cytotoxic drug is a topoisomerase I inhibitor.

61. The method, the combination therapy, the composition, or the kit of any one of claims 1-4 and 9-60,wherein the antibody-drug conjugate has a formula selected from the group consisting of MAb- CL2A-SN-38, MAb-CL6-SN-38, MAb-CL7-SN-38, MAb-CLX-SN-38, and MAb-CLY-SN-38, with a structure represented by:MAb-CL6-SN-38WSGR Docket. No.53676-777.601MAb-CLX-SN-38 where R is hydrogen or C1 to C10 alkyl group and AA is selected from any one of the following L- amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine,where R and R’ can be independently hydrogen or methyl; and when R=R’=methyl, referred to as MAb-CL2E-SN-38.

62. The method, the combination therapy, the composition, or the kit of any one of claims 1-4 and 9-61,wherein the antibody-drug conjugate has a formula selected from the group consisting of MAb- CL2A-SN-38, MAb-CL6-SN-38, MAb-CL7-SN-38, and MAb-CLX-SN-38, with a structure represented by:WSGR Docket No.53676-777.601where R is hydrogen or C1 to C10 alkyl group and AA is selected from any one of the following L- amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine, wherein the 10-hydroxy position of SN-38 in MAb-CL2A-SN-38 or MAb-CL6-SN-38 or MAb-CL7- SN-38 or MAb-CLX-SN-38 is a 10-O-ester or 10-O-carbonate derivative using a ‘COR’ moiety where the R group is a substituted alkyl residue “N(CH3)2—(CH2)n—”, where n is 2-10 and wherein the terminal amino group is optionally in the form of a quaternary salt for enhanced aqueous solubility, or an alkyl residue “CH3—(CH2)n—” where n is 0-10, or an alkoxy residue “CH3— (CH2)n—O—” where n is 0-10, or “N(CH3)2—(CH2)n—O—” where n is 2-10, or “R1O—(CH2— CH2—O)n—CH2—CH2—O—” where R1 is ethyl or methyl and n is an integer with values of 0-10.WSGR Docket. No.53676-777.60163. The method, the combination therapy, the composition, or the kit of any one of claims 1-4 and 9-62,wherein the antibody-drug conjugate has a formula of MAb-CLY- SN-38, with a structure represented by:MAb-CLY-SN-38.

64. The method, the combination therapy, the composition, or the kit of any one of claims 1-63, whereinadministering the first agent and the second agent induces an improved therapeutic effect in the subject, relative to a subject administered the second agent without the first agent.

65. The method, the combination therapy, the composition, or the kit of any one of claims 1-64, whereinadministering the first agent and the second agent induces more activated and / or expanded T cells in a tumor in the subject, relative to a tumor in a subject administered the second agent without the first agent.

66. The method, the combination therapy, the composition, or the kit of any one of claims 1-65, whereinadministering the first agent and the second agent induces less exhausted T cells in a tumor in the subject, relative to a tumor in a subject administered the second agent without the first agent.

67. The method, the combination therapy, the composition, or the kit of any one of claims 1-66, whereinadministering the first agent and the second agent induces a higher anti-tumor efficacy level in the subject, relative to a subject administered the second agent without the first agent.

68. The method, the combination therapy, the composition, or the kit of any one of claims 1-67, whereinadministering the first agent and the second agent induces a higher number of T cells that are cytotoxic against tumor cells or cancer cells in the subject, relative to a subject administered the second agent without the first agent.

69. The method, the combination therapy, the composition, or the kit of any one of claims 1-68, whereinadministering the first agent and the second agent induces a higher level of cytotoxicity against tumorWSGR Docket No.53676-777.601 cells or cancer cells in the subject, relative to a subject administered the second agent without the first agent.

70. The method, the combination therapy, the composition, or the kit of any one of claims 1-69, whereinadministering the first agent and the second agent expands or activates a higher number of T cells that are cytotoxic against tumor cells or cancer cells in the subject, relative to a subject administered the second agent without the first agent.

71. The method, the combination therapy, the composition, or the kit of any one of claims 1-70, whereinadministering the first agent and the second agent induces a higher level of cytotoxic activity against tumor cells or cancer cells in the subject, relative to a subject administered the second agent without the first agent.

72. The method, the combination therapy, the composition, or the kit of any one of claims 1-71, whereinthe subject exhibits an improved therapeutic effect after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

73. The method, the combination therapy, the composition, or the kit of any one of claims 1-72, whereinthe subject produces a higher number of activated and / or expanded T cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

74. The method, the combination therapy, the composition, or the kit of any one of claims 1-73, whereinthe subject comprises less exhausted T cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

75. The method, the combination therapy, the composition, or the kit of any one of claims 1-74, whereinthe subject exhibits a higher level of anti-tumor efficacy after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

76. The method, the combination therapy, the composition, or the kit of any one of claims 1-75, whereinthe subject produces a higher number of T cells that are more cytotoxic against tumor cells or cancer cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

77. The method, the combination therapy, the composition, or the kit of any one of claims 1-76, whereinthe subject produces a higher number of T cells that are cytotoxic against tumor cells or cancer cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

78. The method, the combination therapy, the composition, or the kit of any one of claims 1-77, whereinthe subject exhibits a higher level of cytotoxic activity against tumor cells or cancer cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

79. The method, the combination therapy, the composition, or the kit of claims 65, 66, 68, 70, 73, 74, 76,and 77, wherein the T cells are TCRβV+.WSGR Docket. No.53676-777.60180. The method, the combination therapy, the composition, or the kit of any one of claims 1-79, whereinthe subject comprises tumors that are more immune infiltrated after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

81. The method, the combination therapy, the composition, or the kit of any one of claims 1-80, whereinthe first agent and the second agent are not concomitantly administered to the subject.

82. The method, the combination therapy, the composition, or the kit of any one of claims 1-80, whereinthe first agent and the second agent are concomitantly administered to the subject.

83. The method of any one of claims 1, 5, and 9-82, wherein the method comprises administering thefirst agent to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at least 1, 2, 3, 4, 5, 6, or 7 days, at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years after the subject has been treated with a dose of the second agent.

84. The method of any one of claims 1, 5, and 9-82, wherein the method comprises administering thefirst agent to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at least 1, 2, 3, 4, 5, 6, or 7 days, at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years after the subject has been treated with a first dose of the second agent.

85. The method of any one of claims 1, 5, and 9-82, wherein the method comprises administering thefirst agent to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at least 1, 2, 3, 4, 5, 6, or 7 days, at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years after the subject has been treated with a last dose of the second agent.

86. The method of any one of claims 1, 5, and 9-82, wherein the method comprises administering thefirst agent to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years after being treated with the second agent.

87. The method of any one of claims 1, 5, and 9-82, wherein the method comprises administering thefirst agent to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years after being treated with a dose of the second agent.

88. The method of any one of claims 1, 5, and 9-82, wherein the method comprises administering thefirst agent to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years after being treated with a first dose of the second agent.

89. The method of any one of claims 1, 5, and 9-82, wherein the method comprises administering thefirst agent to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years after being treated with a last dose of the second agent.

90. The method of any one of claims 1, 5, and 9-89, wherein the method comprises administering thefirst agent to the subject from 1 hour to 24 hours after being treated with a dose of the second agent.WSGR Docket No.53676-777.60191. The method of any one of claims 1, 5, and 9-89, wherein the method comprises administering thefirst agent to the subject from 1 day to 7 days after being treated with a dose of the second agent.

92. The method of any one of claims 1, 5, and 9-89, wherein the method comprises administering thefirst agent to the subject from 1 week to 4 weeks after being treated with a dose of the second agent.

93. The method of any one of claims 1, 5, and 9-89, wherein the method comprises administering thefirst agent to the subject from 1 month to 12 months after being treated with a dose of the second agent.

94. The method of any one of claims 1, 5, and 9-89, wherein the method comprises administering thefirst agent to the subject from 1 year to 3 years after being treated with a dose of the second agent.

95. The method of any one of claims 1, 5, and 9-89, wherein the method comprises administering thefirst agent to the subject from 1 hour to 24 hours after being treated with a first dose of the second agent.

96. The method of any one of claims 1, 5, and 9-89, wherein the method comprises administering thefirst agent to the subject from 1 day to 7 days after being treated with a first dose of the second agent.

97. The method of any one of claims 1, 5, and 9-89, wherein the method comprises administering thefirst agent to the subject from 1 week to 4 weeks after being treated with a first dose of the second agent.

98. The method of any one of claims 1, 5, and 9-89, wherein the method comprises administering thefirst agent to the subject from 1 month to 12 months after being treated with a first dose of the second agent.

99. The method of any one of claims 1, 5, and 9-89, wherein the method comprises administering thefirst agent to the subject from 1 year to 3 years after being treated with a first dose of the second agent.

100. The method of any one of claims 1, 5, and 9-89, wherein the method comprises administering thefirst agent to the subject from 1 hour to 24 hours after being treated with a last dose of the second agent.

101. The method of any one of claims 1, 5, and 9-89, wherein the method comprises administering thefirst agent to the subject from 1 week to 4 weeks after being treated with a last dose of the second agent.

102. The method of any one of claims 1, 5, and 9-89, wherein the method comprises administering thefirst agent to the subject from 1 month to 12 months after being treated with a last dose of the second agent.

103. The method of any one of claims 1, 5, and 9-89, wherein the method comprises administering thefirst agent to the subject from 1 year to 3 years after being treated with a last dose of the second agent.

104. The method of any one of claims 1, 5, and 9-89, wherein the method comprises administering thefirst agent to the subject on the same day the subject had been previously treated with the second agent.WSGR Docket. No.53676-777.601105. The method of any one of claims 1, 5, and 9-104, wherein the method is repeated twice or more.

106. The method of any one of claims 1, 5, and 9-105, wherein the administration of the first agentcomprises one or more doses.

107. The method of any one of claims 1, 5, and 9-106, wherein the administration of the first agentcomprises two or more doses.

108. The method of any one of claims 1, 5, and 9-107, wherein the administration of the first agentcomprises one dose per week.

109. The method of any one of claims 1, 5, and 9-107, wherein the administration of the first agentcomprises two or more doses per week.

110. The method of any one of claims 1, 5, and 9-107, wherein the first agent is administered to thesubject once every two weeks.

111. The method of any one of claims 1, 5, and 9-107, wherein the first agent is administered to thesubject once every three weeks.

112. The method of any one of claims 1, 5, and 9-111, wherein the first agent is administered to thesubject once every week for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.

113. The method of any one of claims 1, 5, and 9-112, wherein the administration of the first agentcomprises two or more doses per week for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.

114. The method of any one of claims 1, 5, and 9-113, wherein the first agent is administered to thesubject once every two weeks for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.

115. The method of any one of claims 1, 5, and 9-113, wherein the first agent is administered to thesubject once every three weeks for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.

116. The method of any one of claims 1, 5, and 9-115, wherein the administration of the second agentcomprises one or more doses.

117. The method of any one of claims 1, 5, and 9-116, wherein the administration of the second agentcomprises two or more doses.

118. The method of any one of claims 1, 5, and 9-117, wherein the administration of the second agentcomprises one dose per week.

119. The method of any one of claims 1, 5, and 9-117, wherein the administration of the second agentcomprises two or more doses per week.

120. The method of any one of claims 1, 5, and 9-117, wherein the second agent is administered to thesubject once every two weeks.

121. The method of any one of claims 1, 5, and 9-117, wherein the second agent is administered to thesubject once every three weeks.WSGR Docket No.53676-777.601122. The method of any one of claims 1, 5, and 9-118, wherein the second agent is administered to thesubject once every week for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.

123. The method of any one of claims 1, 5, and 9-119, wherein the administration of the second agentcomprises two or more doses per week for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.

124. The method of any one of claims 1, 5, and 9-120, wherein the second agent is administered to thesubject once every two weeks for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.

125. The method of any one of claims 1, 5, and 9-121, wherein the second agent is administered to thesubject once every three weeks for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.

126. The method of any one of claims 1, 5, and 9-125, wherein the method comprises administering thefirst agent to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at least 1, 2, 3, 4, 5, 6, or 7 days, at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years prior to administering the second agent to the subject.

127. The method of any one of claims 1, 5, and 9-126, wherein the method comprises administering thefirst agent to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years prior to administering the second agent to the subject.

128. The method of any one of claims 1, 5, and 9-127, wherein the method comprises administering thefirst agent to the subject from 1 hour to 24 hours prior to administering the second agent to the subject.

129. The method of any one of claims 1, 5, and 9-127, wherein the method comprises administering thefirst agent to the subject from 1 day to 7 days prior to administering the second agent to the subject.

130. The method of any one of claims 1, 5, and 9-127, wherein the method comprises administering thefirst agent to the subject from 1 week to 4 weeks prior to administering the second agent to the subject.

131. The method of any one of claims 1, 5, and 9-127, wherein the method comprises administering thefirst agent to the subject from 1 month to 12 months prior to administering the second agent to the subject.

132. The method of any one of claims 1, 5, and 9-127, wherein the method comprises administering thefirst agent to the subject from 1 year to 3 years prior to administering the second agent to the subject.

133. The method of any one of claims 1, 5, and 9-132, wherein the administration of the first agentcomprises two or more doses, and each dose comprises a same amount of the first agent.

134. The method of any one of claims 1, 5, and 9-132, wherein the administration of the first agentcomprises two or more doses, and each dose comprises different amounts of the first agent.WSGR Docket. No.53676-777.601135. The method of any one of claims 1, 5, and 9-134, wherein the administration of the second agentcomprises two or more doses, and each dose comprises a same amount of the second agent.

136. The method of any one of claims 1, 5, and 9-135, wherein the administration of the second agentcomprises two or more doses, and each dose comprises different amounts of the second agent.

137. The method of any one of claims 1, 5, and 9-136, wherein the first agent is administered to thesubject at a dose of from about 0.001 mg / kg to about 20 mg / kg.

138. The method of any one of claims 1, 5, and 9-137, wherein the second agent is administered to thesubject at a dose of from about 0.001 mg / kg to about 20 mg / kg.

139. The method of any one of claims 1, 5, and 9-138, wherein the method comprises administering thefirst agent and the second agent to the subject simultaneously or on the same day.

140. The method of any one of claims 1, 5, and 9-139, wherein the disease or condition in the subject istreated to a higher extent relative to a corresponding method in which the first agent is administered and the second agent is not administered.

141. The method of any one of claims 1, 5, and 9-140, wherein the method is more effective to treat thedisease or condition in the subject relative to a method in which the first agent is administered to the subject but not the second agent.

142. The method of any one of claims 1, 5, and 9-141, wherein the method is more effective to treat thedisease or condition in the subject relative to a method in which the second agent is administered to the subject but not the first agent.

143. The method, the combination therapy, the composition, or the kit of any one of claims 1-142,wherein the TCRβV region is a human TCRβV region.

144. The method, the combination therapy, the composition, or the kit of claim 143, wherein the humanTCRβV region is selected from the group consisting of TCRβ V1 subfamily, TCRβ V2 subfamily, TCRβ V3 subfamily, TCRβ V4 subfamily, TCRβ V5 subfamily, TCRβ V6 subfamily, TCRβ V7 subfamily, TCRβ V8 subfamily, TCRβ V9 subfamily, TCRβ V10 subfamily, TCRβ V11 subfamily, TCRβ V12 subfamily, TCRβ V13 subfamily, TCRβ V14 subfamily, TCRβ V15 subfamily, TCRβ V16 subfamily, TCRβ V17 subfamily, TCRβ V18 subfamily, TCRβ V19, TCRβ V20 subfamily, TCRβ V21 subfamily, TCRβ V22 subfamily TCRβ V23 subfamily, TCRβ V24 subfamily, TCRβ V25 subfamily, TCRβ V26 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V29 subfamily, and TCRβ V30 subfamily.

145. The method, the combination therapy, the composition, or the kit of claim 144, wherein the humanTCRβV region is selected from the group consisting of: (i) TCRβ V1 subfamily comprising TCRβ V1*01; (ii) TCRβ V2 subfamily comprising one or more selected from TCRβ V2*01, TCRβ V2*02, and TCRβ V2*03; (iii) TCRβ V3 subfamily comprising one or more selected from TCRβ V3-1*01 and TCRβ V3- 1*02;WSGR Docket No.53676-777.601 (iv) TCRβ V4 subfamily comprising one or more selected from TCRβ V4-1*01, TCRβ V4-1*02, TCRβ V4-2*01, TCRβ V4-2*02, TCRβ V4-3*01, TCRβ V4-3*02, TCRβ V4-3*03, and TCRβ V4-3*04; (v) TCRβ V5 subfamily comprising one or more selected from TCRβ V5-1*01, TCRβ V5-1*02, TCRβ V5-3*01, TCRβ V5-3*02, TCRβ V5-4*01, TCRβ V5-4*02, TCRβ V5-4*03, TCRβ V5- 4*04, TCRβ V5-5*01, TCRβ V5-5*02, TCRβ V5-5*03, TCRβ V5-6*01, TCRβ V5-7*01, TCRβ V5-8*01, and TCRβ V5-8*02; (vi) TCRβ V6 subfamily comprising one or more selected from TCRβ V6-1*01, TCRβ V6-2*01, TCRβ V6-3*01, TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-5*01, TCRβ V6-6*01, TCRβ V6- 6*02, TCRβ V6-6*03, TCRβ V6-6*04, TCRβ V6-6*05, TCRβ V6-7*01, TCRβ V6-8*01, and TCRβ V6-9*01; (vii) TCRβ V7 subfamily comprising one or more selected from TCRβ V7-1*01, TCRβ V7- 2*01, TCRβ V7-2*02, TCRβ V7-2*03, TCRβ V7-2*04, TCRβ V7-3*01, TCRβ V7-3*02, TCRβ V7-3*03, TCRβ V7-3*04, TCRβ V7-3*05, TCRβ V7-4*01, TCRβ V7-4*02, TCRβ V7-6*01, TCRβ V7-6*02, TCRβ V7-7*01, TCRβ V7-7*02, TCRβ V7-8*01, TCRβ V7-8*02, TCRβ V7- 8*03, TCRβ V7-9*01, TCRβ V7-9*02, TCRβ V7-9*03, TCRβ V7-9*04, TCRβ V7-9*05, TCRβ V7-9*06, and TCRβ V7-9*07; (viii) TCRβ V8 subfamily comprising one or more selected from TCRβ V8-1*01, TCRβ V8- 1*02, TCRβ V8-2*01, and TCRβ V8-2*02; (ix) TCRβ V9 subfamily comprising one or more selected from TCRβ V9-1*01, TCRβ V9-1*02, and TCRβ V9-1*03; (x) TCRβ V10 subfamily comprising one or more selected from TCRβ V10-1*01, TCRβ V10- 1*02, TCRβ V10-1*03, TCRβ V10-2*01, TCRβ V10-2*02, TCRβ V10-3*01, TCRβ V10-3*02, TCRβ V10-3*03, and TCRβ V10-3*04; (xi) TCRβ V11 subfamily comprising TCRβ V11-1*01, TCRβ V11-2*01, TCRβ V11-2*02, TCRβ V11-2*03, TCRβ V11-3*01, TCRβ V11-3*02, TCRβ V11-3*03, and TCRβ V11-3*04; (xii) TCRβ V12 subfamily comprising one or more selected from TCRβ V12-3*01, TCRβ V12- 4*01, TCRβ V12-4*02, and TCRβ V12-5*01; (xiii) TCRβ V13 subfamily comprising one or more selected from TCRβ V13*01 and TCRβ V13*02; (xiv) TCRβ V14 subfamily comprising one or more comprising from TCRβ V14*01 and TCRβ V14*02; (xv) TCRβ V15 subfamily comprising one or more selected from TCRβ V15*01, TCRβ V15*02, and TCRβ V15*03; (xvi) TCRβ V16 subfamily comprising one or more selected from TCRβ V16*01, TCRβ V16*02, and TCRβ V16*03; (xvii) TCRβ V17 subfamily comprising TCRβ V17*01; (xviii) TCRβ V18 subfamily comprising TCRβ V18*01;WSGR Docket. No.53676-777.601 (xix) TCRβ V19 subfamily comprising one or more selected from TCRβ V19*01, TCRβ V19*02, and TCRβ V19*03; (xx) TCRβ V20 subfamily comprising one or more selected from TCRβ V20-1*01, TCRβ V20- 1*02, TCRβ V20-1*03, TCRβ V20-1*04, TCRβ V20-1*05, TCRβ V20-1*06, and TCRβ V20- 1*07; (xxi) TCRβ V21 subfamily comprising one or more selected from TCRβ V21-1*01 and TCRβ V21-1*02; (xxii) TCRβ V22 subfamily comprising TCRβ V22-1*01; (xxiii) TCRβ V23 subfamily comprising TCRβ V23-1*01; (xxiv) TCRβ V24 subfamily comprising TCRβ V24-1*01; (xxv) TCRβ V25 subfamily comprising TCRβ V25-1*01; (xxvi) TCRβ V26 subfamily comprising TCRβ V26-1*01; (xxvii) TCRβ V27 subfamily comprising TCRβ V27*01; (xxviii) TCRβ V28 subfamily comprising TCRβ V28*01; (xxix) TCRβ V29 subfamily comprising one or more selected from TCRβ V29-1*01, TCRβ V29-1*02, and TCRβ V29-1*03; and (xxx) TCRβ V30 subfamily comprising one or more selected from TCRβ V30*01, TCRβ V30*02, TCRβ V30*03, TCRβ V30*04, and TCRβ V30*05.

146. The method, the combination therapy, the composition, or the kit of any one of claims 143-145,wherein the first domain is a full antibody, an antigen binding domain thereof, or a functional fragment or variant thereof, a bivalent antibody, a bispecific antibody, or a biparatopic antibody that binds to a TCRβV region.

147. The multispecific molecule of any one of claims 143-145, wherein the second domain is a fullantibody, an antigen binding domain thereof, or a functional fragment or variant thereof, a bivalent antibody, a bispecific antibody, or a biparatopic antibody that binds to a TCRβV region.

148. The method, the combination therapy, the composition, or the kit of claim 146 or 147, wherein thefull antibody, an antigen binding domain thereof, or a functional fragment or variant thereof is a Fab, a Fab', a F(ab’)2, a F(ab)2, a variable fragment (Fv), a single domain antibody, a diabody, a nanobody, a camelid single domain antibody, a VHH or a single chain variable fragment (scFv).

149. The method, the combination therapy, the composition, or the kit of any one of claims 1-148,wherein the first agent comprises one or more heavy chain constant regions selected from the group consisting of IgG1 heavy chain constant region or fragment thereof, IgG2 heavy chain constant region or fragment thereof, IgG3 heavy chain constant region or fragment thereof, IgGA1 heavy chain constant region or fragment thereof, IgGA2 heavy chain constant region or fragment thereof, IgG4 heavy chain constant region or fragment thereof, IgJ heavy chain constant region or fragment thereof, IgM heavy chain constant region or fragment thereof, IgD heavy chain constant region or fragment thereof, and IgE heavy chain constant region or fragment thereof.WSGR Docket No.53676-777.601150. The method, the combination therapy, the composition, or the kit of any one of claims 1-149,wherein the first agent comprises a kappa light chain constant region or fragment thereof, a lambda light chain constant region or fragment thereof, or a combination thereof.

151. The method, the combination therapy, the composition, or the kit of any one of claims 1-150,wherein the first agent is a multifunctional molecule.

152. The method, the combination therapy, the composition, or the kit of any one of claims 1-151,wherein the first agent comprises at least two non-contiguous polypeptide chains; wherein a first polypeptide chain of the at least two non-contiguous polypeptide chains comprises a first Fc region, and a second polypeptide chain of the at least two non-contiguous polypeptide chains comprises a second Fc region.

153. The method, the combination therapy, the composition, or the kit of claim 152, wherein the first Fcregion and the second Fc region comprise an Fc interface with a knob-in-a hole.

154. The method or the combination therapy of claim 152 or 153, wherein the first Fc region, the secondFc region, or a combination thereof comprises an Asn297Ala mutation, a Leu234Ala / Leu235Ala mutation, or a combination thereof.

155. The method, the combination therapy, the composition, or the kit of any one of claims 1-154,wherein the first agent is a multispecific molecule that further comprises one or more of a second cytokine molecule, a stromal modifying moiety, or an immune cell engager.

156. The method, the combination therapy, the composition, or the kit of any one of claims 1-155,wherein the first agent is a multispecific molecule that further comprises a second cytokine molecule.

157. The method, the combination therapy, the composition, or the kit of any one of claims 1-156,wherein the first agent comprises a dimerization module, comprising a first immunoglobulin chain constant region and a second immunoglobulin chain constant region.

158. The method, the combination therapy, the composition, or the kit of claim 157, wherein the firstimmunoglobulin chain constant region comprises the first fragment crystallizable region (Fc region) and the second first immunoglobulin chain constant region comprises the second fragment crystallizable region (Fc region).

159. The method, the combination therapy, the composition, or the kit of claim 158, whereindimerization of the first Fc region and the second Fc region is enhanced by providing an Fc interface of the first Fc region and the second Fc region with one or more of a paired cavity-protuberance, an electrostatic interaction, or a strand-exchange, such that a greater ratio of heteromultimer to homomultimer forms relative to a non-engineered interface.

160. The method, the combination therapy, the composition, or the kit of any one of claims 155-159,wherein the immune cell engager is selected from the group consisting of a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, a macrophage cell engager, and any combination thereof.

161. The method, the combination therapy, the composition, or the kit of any one of claims 11-160,wherein the at least one cytokine molecule is selected from the group consisting of interleukin-2 (IL-WSGR Docket. No.53676-777.601 2) or functional variant thereof, interleukin-7 (IL-7) or functional variant thereof, interleukin-12 (IL- 12) or functional variant thereof, interleukin-15 (IL-15) or functional variant thereof, interleukin-18 (IL-18) or functional variant thereof, interleukin-21 (IL-21) or functional variant thereof, interferon gamma or functional variant thereof, and any combination thereof.

162. The method, the combination therapy, the composition, or the kit of any one of claims 155-160,wherein the second cytokine molecule is selected from the group consisting of interleukin-2 (IL-2) or functional variant thereof, interleukin-7 (IL-7) or functional variant thereof, interleukin-12 (IL-12) or functional variant thereof, interleukin-15 (IL-15) or functional variant thereof, interleukin-18 (IL-18) or functional variant thereof, interleukin-21 (IL-21) or functional variant thereof, interferon gamma or functional variant thereof, and any combination thereof.

163. The method, the combination therapy, the composition, or the kit of claim 161 or 162, wherein thecytokine molecule comprises interleukin-2 (IL-2) or functional variant thereof.

164. The method, the combination therapy, the composition, or the kit of claim 163, wherein theinterleukin-2 (IL-2) or functional variant thereof comprises the sequence of SEQ ID NO: 2270 or SEQ ID NO: 2191.

165. The method of claim 1, 5, and 9-164, or the combination therapy of any one of claims 2, 6, and 9-164, wherein the first agent is administered to the subject prior to, concurrently, or after administration of the second agent to the subject.

166. A multifunctional molecule comprising:(a) a tumor-associated antigen binding moiety, wherein the tumor-associated antigen bindingmoiety comprises a trophoblast cell surface antigen 2 (TROP2) binding moiety; (b) a molecule that binds to a co-stimulatory receptor of a T cell; and(c) a TCR β variable (TCRβV) region binding moiety.

167. The multifunctional molecule of claim 166, wherein the TCRβV-binding moiety is covalently linkedto the molecule that binds to a co-stimulatory receptor of a T cell.

168. The multifunctional molecule of claim 166 or 167, wherein the molecule that binds to a co-stimulatory receptor of a T cell activates the co-stimulatory receptor when the molecule that binds to a co-stimulatory receptor of a T cell binds to the co-stimulatory receptor.

169. The multifunctional molecule of any one of claims 166-168, wherein the molecule that binds to aco-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof.

170. The multifunctional molecule of any one of claims 166-169, wherein the molecule that binds to aco-stimulatory receptor of a T cell comprises an antibody molecule, an antigen binding domain, a ligand, an extracellular domain of a receptor, or any combination thereof.

171. The multifunctional molecule of any one of claims 166-170, wherein the TROP-2 binding moietycomprises an antibody domain or an antigen binding domain.

172. The multifunctional molecule of any one of claims 166-171, wherein the antigen binding domaincomprises any one selected from the group consisting of a Fab, a F(ab')2, an Fv, a single chain FvWSGR Docket No.53676-777.601 (scFv), a single domain antibody, a diabody (dAb), a VHH, a camelid antibody, and any combination thereof.

173. The multifunctional molecule of any one of claims 166-172, wherein the TROP-2 binding moietycomprises: (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determiningregion 1 (HC CDR1) amino acid sequence of NYGMN (SEQ ID NO: 500), a heavy chain complementarity determining region 2 (HC CDR2) amino acid sequence of WINTYTGEPTYTDDFKG (SEQ ID NO: 501), and a heavy chain complementarity determining region 3 (HC CDR3) amino acid sequence of GGFGSSYWYFDV (SEQ ID NO: 502); and (b) a light chain variable region (VL) comprising a light chain complementarity determining region1 (LC CDR1) amino acid sequence of KASQDVSIAVA (SEQ ID NO: 503), a light chain complementarity determining region 2 (LC CDR2) amino acid sequence of SASYRYT (SEQ ID NO: 504), and a light chain complementarity determining region 3 (LC CDR3) amino acid sequence of QQHYITPLT (SEQ ID NO: 505).

174. The multifunctional molecule of 173, wherein the TROP-2 binding moiety comprises:(a) a VH comprising a HC CDR1 amino acid sequence of NYGMN (SEQ ID NO: 500), a HCCDR2 amino acid sequence of WINTYTGEPTYTDDFKG (SEQ ID NO: 501), and a HC CDR3 amino acid sequence of GGFGSSYWYFDV (SEQ ID NO: 502); and (b) a VL comprising a LC CDR1 amino acid sequence of KASQDVSIAVA (SEQ ID NO: 503), aLC CDR2 amino acid sequence of SASYRYT (SEQ ID NO: 504), and a LC CDR3 amino acid sequence of QQHYITPLT (SEQ ID NO: 505).

175. The multifunctional molecule of claim 173 or 174, wherein the TROP-2 binding moiety comprises aVH sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 506.

176. The multifunctional molecule of any one of claims 173-175, wherein the TROP-2 binding moietycomprises a VH sequence comprising the sequence of SEQ ID NO: 506.

177. The multifunctional molecule of any one of claims 173-176, wherein the first domain that binds toTROP2 or the third domain that binds to TROP2 comprises a VL sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 508.

178. The multifunctional molecule of claim 177, wherein the TROP-2 binding moiety comprises a VLsequence comprising the sequence of SEQ ID NO: 508.

179. The multifunctional molecule of any one of claims 173-178, wherein the TROP-2 binding moietycomprises a VH comprising the sequence of SEQ ID NO: 506 and a VL comprising the sequence of SEQ ID NO: 508.

180. The multifunctional molecule of any one of claims 166-179, wherein the multifunctional moleculecomprises a first polypeptide chain comprising a first portion of a dimerization module, and a second polypeptide chain comprising a second portion of the dimerization module; wherein the first polypeptide chain and the second polypeptide chain are non-contiguous, andWSGR Docket. No.53676-777.601 wherein the tumor-associated antigen binding moiety is linked to the first portion of the dimerization module, and the TCRβV-binding moiety and / or the molecule that binds to a co- stimulatory receptor of a T cell are independently linked to the first portion of the dimerization module, the second portion of the dimerization module, or a combination thereof.

181. The multifunctional molecule of claim 180, wherein:(i) the tumor-associated antigen binding moiety is linked to the N-terminus of the first portion of the dimerization module, and the TCRβV-binding moiety is linked to the C-terminus of the first portion of the dimerization module, the N-terminus of the second portion of the dimerization module, the C-terminus of the second portion of the dimerization module, or any combination thereof; or (ii) the tumor-associated antigen binding moiety is linked to the C-terminus of the first portion of the dimerization module, and the molecule that binds to a co-stimulatory receptor of a T cell is linked to the N-terminus of the first portion of the dimerization module, the N-terminus of the second portion of the dimerization module, the C-terminus of the second portion of the dimerization module, or any combination thereof.

182. The multifunctional molecule of claim 180 or 181, wherein:(i) the tumor-associated antigen binding moiety is linked to the N-terminus of the first portion of the dimerization module, and the molecule that binds to a co-stimulatory receptor of a T cell is linked to the C-terminus of the first portion of the dimerization module, the N-terminus of the second portion of the dimerization module, the C-terminus of the second portion of the dimerization module, or any combination thereof; or (ii) the tumor-associated antigen binding moiety is linked to the C-terminus of the first portion of the dimerization module, and the molecule that binds to a co-stimulatory receptor of a T cell is linked to the N-terminus of the first portion of the dimerization module, the N-terminus of the second portion of the dimerization module, the C-terminus of the second portion of the dimerization module, or any combination thereof.

183. The multifunctional molecule of any one of claims 180-182, wherein the TCRβV-binding moietyand the molecule that binds to a co-stimulatory receptor of a T cell is within a single contiguous polypeptide chain of the first polypeptide chain or the second polypeptide chain.

184. The multifunctional molecule of any one of claims 166-183, wherein the tumor-associated antigenbinding moiety, the TCRβV-binding moiety, or a combination thereof comprises an antibody or antigen binding fragment thereof, or antigen binding domain, wherein the antigen binding fragment or antigen binding domain comprises any one selected from the group consisting of a Fab, a F(ab')2, an Fv, a single chain Fv (scFv), a single domain antibody, a diabody (dAb), a VHH, a camelid antibody, and any combination thereof.

185. The multifunctional molecule of any one of claims 166-184, wherein the TCRβV-binding moietycomprises a heavy chain variable domain (VH) and a light chain variable domain (VL), or a single domain antibody.WSGR Docket No.53676-777.601186. The multifunctional molecule of any one of claims 180-184, wherein the TCRβV-binding moietycomprises a first portion of the TCRβV-binding moiety, and wherein the multifunctional molecule further comprises a third polypeptide chain comprising a second portion of the TCRβV-binding moiety, wherein the third polypeptide chain is non- contiguous with the first polypeptide chain and the second polypeptide chain.

187. The multifunctional molecule of claim 186, wherein the first portion of the TCRβV-binding moietycomprises a VH of the TCRβV-binding moiety and the second portion of the TCRβV-binding moiety comprises a VL of the TCRβV-binding moiety, or the first portion of the TCRβV-binding moiety comprises a VL of the TCRβV-binding moiety and the second portion of the TCRβV-binding moiety comprises a VH of the TCRβV-binding moiety.

188. The multifunctional molecule of any one of claims 166-187, wherein the tumor-associated antigenbinding moiety comprises a VH and a VL, or a single domain antibody.

189. The multifunctional molecule of any one of claims 180-187, wherein the tumor-associated antigenbinding moiety comprises a first portion of the tumor-associated antigen binding moiety, and wherein the multifunctional molecule further comprises a fourth polypeptide chain comprising a second portion of the tumor-associated antigen binding moiety, wherein the fourth polypeptide chain is non-contiguous with the first polypeptide chain, the second polypeptide chain, and the third polypeptide chain.

190. The multifunctional molecule of claim 189, wherein the first portion of the tumor-associated antigenbinding moiety comprises a VH of the tumor-associated antigen binding moiety and the second portion of the tumor-associated antigen binding moiety comprises a VL of the tumor-associated antigen binding moiety, or the first portion of the tumor-associated antigen binding moiety comprises a VL of the tumor-associated antigen binding moiety and the second portion of the tumor-associated antigen binding moiety comprises a VH of the tumor-associated antigen binding moiety.

191. The multifunctional molecule of any one of claims 166-190, wherein the first portion of thedimerization module and the second portion of the dimerization module are dimerized.

192. The multifunctional molecule of any one of claims 166-191, wherein:(i) the tumor-associated antigen binding moiety further comprises a heavy chain constant domain 1 (CH1) linked to the VH of the tumor-associated antigen binding moiety; (ii) the TCRβV-binding moiety further comprises a heavy chain constant domain 1 (CH1) linked to the VH of the TCRβV-binding moiety; or (iii) a combination thereof.

193. The multifunctional molecule of any one of claims 166-192, wherein:(i) the tumor-associated antigen binding moiety further comprises a light chain constant domain (CL) linked to the VL of the tumor-associated antigen binding moiety; (ii) the TCRβV-binding moiety further comprises a light chain constant domain (CL) linked to the VL of the TCRβV-binding moiety; or (iii) a combination thereof.WSGR Docket. No.53676-777.601194. The multifunctional molecule of claim 193, wherein:(i) the CL linked to the VL of the tumor-associated antigen binding moiety comprises a kappa chain constant domain or a lambda chain constant domain; (ii) the CL linked to the VL of the TCRβV-binding moiety comprises a kappa chain constant domain or a lambda chain constant domain; or (iii) a combination thereof.

195. The multifunctional molecule of claim 194, wherein the kappa chain constant domain or the lambdachain constant domain comprises any one of the light chain constant region sequences listed in Table 3, 21, or 22.

196. The multifunctional molecule of any one of claims 166-195, further comprising:(i) a linker between the first portion of the dimerization module and the tumor-associated antigen binding moiety or the first portion of the tumor-associated antigen; (ii) a linker between the molecule that binds to a co-stimulatory receptor of a T cell and the first portion of the dimerization module, a linker between the molecule that binds to a co-stimulatory receptor of a T cell and the second portion of the dimerization module, or a combination thereof; (iii) a linker between the molecule that binds to a co-stimulatory receptor of a T cell and the TCRβV-binding moiety or the first portion of the TCRβV-binding moiety; (iv) a linker between the VH and the VL of the tumor-associated antigen binding moiety; (v) a linker between the VH and the VL of the TCRβV-binding moiety; (vi) a linker between the CH1 and the VH of the tumor-associated antigen binding moiety; (vii) a linker between the CH1 and the VH of the TCRβV-binding moiety; (viii) a linker between the CL and the VL of the tumor-associated antigen binding moiety; (ix) a linker between the CL and the VL of the TCRβV-binding moiety; or (x) any combination thereof.

197. The multifunctional molecule of claim 196, wherein the linker is selected from the group consistingof a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non-helical linker.

198. The multifunctional molecule of claim 197, wherein the linker is the peptide linker, and wherein thelinker comprises the sequence of SEQ ID NO: 3801, 3309, 3307, 3308, or 3643.

199. The multifunctional molecule of any one of claims 166-198, wherein the multifunctional moleculeis an isolated multifunctional molecule .

200. The multifunctional molecule of any one of claims 166-199, wherein the tumor-associated antigenbinding moiety, the TCRβV-binding moiety, or a combination thereof comprises a VHH, an Fab, or an scFv.

201. The multifunctional molecule of any one of claims 166-200, wherein the molecule that binds to aco-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof, and the at least one cytokine molecule or a functional fragment orWSGR Docket No.53676-777.601 functional variant thereof is selected from the group consisting of interleukin-2 (IL-2) or a functional fragment or functional variant thereof, interleukin-7 (IL-7) or a functional fragment or functional variant thereof, interleukin-12 (IL-12) or a functional fragment or functional variant thereof, interleukin-15 (IL-15) or a functional fragment or functional variant thereof, interleukin-18 (IL-18) or a functional fragment or functional variant thereof, interleukin-21 (IL-21) or a functional fragment or functional variant thereof, or interferon gamma or a functional fragment or functional variant thereof, or any combination thereof.

202. The multifunctional molecule of any one of claims 166-201, wherein the molecule that binds to aco-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof, and the at least one cytokine molecule or a functional fragment or functional variant thereof comprises interleukin-2 (IL-2) or a functional fragment or functional variant thereof.

203. The multifunctional molecule of claim 202, wherein the at least one cytokine molecule or afunctional fragment or functional variant thereof is an IL-2 variant comprising a substitution mutation.

204. The multifunctional molecule of claim 203, wherein the at least one cytokine molecule or afunctional fragment or functional variant thereof is an IL-2 variant comprising C125A mutation.

205. The multifunctional molecule of any one of claims 202-204, wherein the at least one cytokinemolecule or a functional fragment or functional variant thereof comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 2270 or the sequence of SEQ ID NO: 2191.

206. The multifunctional molecule of any one of claims 202-205, wherein the at least one cytokinemolecule or a functional fragment or functional variant thereof comprises the sequence of SEQ ID NO: 2270 or the sequence of SEQ ID NO: 2191.

207. The multifunctional molecule of any one of claims 166-206, wherein the molecule that binds to aco-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof, and the at least one cytokine molecule or a functional fragment or functional variant thereof comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to any one of the cytokine sequences as described herein or any one of the cytokine sequences as listed in Table 27.

208. The multifunctional molecule of any one of claims 166-207, wherein the molecule that binds to aco-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof, and the at least one cytokine molecule or a functional fragment or functional variant thereof comprises any one of the cytokine sequences as described herein or any one of the cytokine sequences as listed in Table 27.WSGR Docket. No.53676-777.601209. The multifunctional molecule of any one of claims 166-200, wherein the molecule that binds to aco-stimulatory receptor of a T cell binds to CD2, 4-1BB, CD27, CD28, or any combination thereof.

210. The multifunctional molecule of any one of claims 166-209, wherein the first portion of thedimerization module comprises a first immunoglobulin constant regions (Fc regions) and the second portion of the dimerization module comprises a second Fc region.

211. The multifunctional molecule of claim 210, wherein the first Fc region, the second Fc region, or acombination thereof is selected from the group consisting of an IgG1 Fc region or a fragment thereof, an IgG2 Fc region or a fragment thereof, an IgG3 Fc region or a fragment thereof, an IgGA1 Fc region or a fragment thereof, an IgGA2 Fc region or a fragment thereof, an IgG4 Fc region or a fragment thereof, an IgJ Fc region or a fragment thereof, an IgM Fc region or a fragment thereof, an IgD Fc region or a fragment thereof, and an IgE Fc region or a fragment thereof.

212. The multifunctional molecule of claim 211, wherein the first Fc region, the second Fc region, or acombination thereof is selected from the group consisting of a human IgG1 Fc region or a fragment thereof, a human IgG2 Fc region or a fragment thereof, and a human IgG4 Fc region or a fragment thereof.

213. The multifunctional molecule of any one of claims 210-212, wherein the first Fc region, the secondFc region, or a combination thereof comprises an Fc interface with one or more of: a paired cavity- protuberance, an electrostatic interaction, or a strand-exchange, wherein the dimerization of the first Fc region and the second Fc region is enhanced as indicated by a greater ratio of heteromultimer:homomultimer forms relative to a dimerization of Fc regions with a non-engineered interface.

214. The multifunctional molecule of claim 213, wherein the first Fc region, the second Fc region, or acombination thereof comprises an amino acid substitution listed in Table 4 or 14.

215. The multifunctional molecule of claim 214, wherein the first Fc region, the second Fc region, or acombination thereof comprises an Asn297Ala (N297A) mutation or a Leu234Ala / Leu235Ala (LALA) mutation.

216. The multifunctional molecule of claim 213, wherein the first Fc region, the second Fc region, or acombination thereof comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 40, 42, 3645, 3646, 3647, 3648, 3649, 3792, 3648, 3794, 3533, 1247, 1619, 1620, 571, 1669, 573, 1670, 1691, 1692, 1257, 550, 1080; 560, 1259, 1612, 1613, 579, 1678, 1700, 1704, 579, 1278, 1287, or 3794.

217. The multifunctional molecule of claim 213, wherein the first Fc region, the second Fc region, or acombination thereof comprises the sequence of SEQ ID NO: 40, 42, 3645, 3646, 3647, 3648, 3649, 3792, 3648, 3794, 3533, 1247, 1619, 1620, 571, 1669, 573, 1670, 1691, 1692, 1257, 550, 1080; 560, 1259, 1612, 1613, 579, 1678, 1700, 1704, 579, 1278, 1287, or 3794.

218. The multifunctional molecule of claim 213, wherein the first Fc region comprises a sequence havingat least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,WSGR Docket No.53676-777.601 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 3792, and the second Fc region comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 3794, or the first Fc region comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 3794, and the second Fc region comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 3794.

219. The multifunctional molecule of claim 213, wherein the first Fc region comprises a sequence havingthe sequence of SEQ ID NO: 3649 or SEQ ID NO: 3792, and the second Fc region comprises the sequence of SEQ ID NO: 3648 or SEQ ID NO: 3794, or the first Fc region comprises the sequence of SEQ ID NO: 3648 or SEQ ID NO: 3794, and the second Fc region comprises the sequence of SEQ ID NO: 3648 or SEQ ID NO: 3794.

220. The multifunctional molecule of claim 213, wherein the first Fc region comprises a sequence havingat least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 3648, 3794, 3533, 1247, 1619, 1620, 571, 1669, 573, 1670, 1691, 1692, or 1257, and the second Fc region comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 550, 1080; 560, 1259, 1612, 1613, 579, 1678, 1700, 1704, 579, 1278, or 1287, or the first Fc region comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 550, 1080; 560, 1259, 1612, 1613, 579, 1678, 1700, 1704, 579, 1278, or 1287, and the second Fc region comprises a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 3648, 3794, 3533, 1247, 1619, 1620, 571, 1669, 573, 1670, 1691, 1692, or 1257.

221. The multifunctional molecule of claim 213, wherein the first Fc region comprises a sequence havingthe sequence of SEQ ID NO: 3648, 3794, 3533, 1247, 1619, 1620, 571, 1669, 573, 1670, 1691, 1692, or 1257, and the second Fc region comprises the sequence of SEQ ID NO: 550, 1080; 560, 1259, 1612, 1613, 579, 1678, 1700, 1704, 579, 1278, or 1287, or the first Fc region comprises the sequence of SEQ ID NO: 550, 1080; 560, 1259, 1612, 1613, 579, 1678, 1700, 1704, 579, 1278, or 1287, and the second Fc region comprises the sequence of SEQ ID NO: 3648, 3794, 3533, 1247, 1619, 1620, 571, 1669, 573, 1670, 1691, 1692, or 1257.

222. The multifunctional molecule of any one of claims 166-221, wherein the TCRβV-binding moietybinds to one or more of a TCRβV subfamily selected from the group consisting of TCRβ V2WSGR Docket. No.53676-777.601 subfamily, TCRβ V3 subfamily, TCRβ V4 subfamily, TCRβ V5 subfamily, TCRβ V6 subfamily, TCRβ V9 subfamily, TCRβ V10 subfamily, TCRβ V11 subfamily, TCRβ V12 subfamily, TCRβ V13 subfamily, TCRβ V16 subfamily, TCRβ V19, TCRβ V20 subfamily, TCRβ V21 subfamily, TCRβ V23 subfamily, TCRβ V27 subfamily, and TCRβ V28 subfamily.

223. The multifunctional molecule of any one of claims 166-222, wherein the TCRβV-binding moietybinds to one or more of a TCRβV subfamily selected from the group consisting of: (i) TCRβ V2 subfamily comprising TCRβ V2*01; (ii) TCRβ V3 subfamily comprising TCRβ V3-1*01; (iii) TCRβ V4 subfamily comprising one or more selected from TCRβ V4-1, TCRβ V4-2, and TCRβ V4-3; (iv) TCRβ V5 subfamily comprising one or more selected from TCRβ V5-6*01, TCRβ V5-4*01, TCRβ V5-1*01, and TCRβ V5-8*01; (v) TCRβ V6 subfamily comprising one or more selected from TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6- 2*01, TCRβ V6-3*01, and TCRβ V6-1*01; (vi) TCRβ V10 subfamily comprising one or more selected from TCRβ V10-1*01, TCRβ V10- 1*02, TCRβ V10-3*01, and TCRβ V10-2*01; (vii) TCRβ V11 subfamily comprising TCRβ V11-2; (viii) TCRβ V12 subfamily comprising one or more selected from TCRβ V12-4*01, TCRβ V12- 3*01, and TCRβ V12-5*01; (ix) TCRβ V13 subfamily comprising TCRβ V13*01; (x) TCRβ V16 subfamily comprising TCRβ V16*01; (xi) TCRβ V19 subfamily comprising one or more selected from TCRβ V19*01 and TCRβ V19*02; or (xii) TCRβ V20 subfamily comprising TCRβ V20-1*01, or TCRβ V20-1*02.

224. The method, the combination therapy, the composition, or the kit of any one of claims 1-165 and themultifunctional molecule of any one of claims 166-223, wherein the TCRβV-binding moiety binds to TCRβ V6 subfamily, TCRβV10 subfamily, TCRβV12 subfamily, or TCRβ V20 subfamily.

225. The method, the combination therapy, the composition, or the kit of any one of claims 1-165 and224, or the multifunctional molecule of any one of claims 166-224, wherein the TCRβV-binding moiety comprises: (i) a VH comprising a combination of a HC CDR1, a HC CDR2 and a HC CDR3 listed in Tables 1, 2, 10B, 10C, 11, 12, 13, 15- 21, 24, 29, or 30; (ii) a VL comprising a combination of a LC CDR1, a LC CDR2, and a LC CDR3 listed in Tables 1, 2, 10B, 10C, 11, 12, 13, 15- 21, 24, 29, or 30; or (iii) any combination thereof.WSGR Docket No.53676-777.601226. The method, the combination therapy, the composition, or the kit of any one of claims 1-165, 224,and 225, or the multifunctional molecule of any one of claims 166-225, wherein the TCRβV-binding moiety comprises: (i) a VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 of any one of the heavy chain variable domain amino acid sequences listed in Tables 1, 2, 10B, 10C, 11, 12, 13, 15- 21, 24, 29, or 30; (ii) a VL comprising a LC CDR1, a LC CDR2, and a LC CDR3 of any one of the light chain variable domain amino acid sequences listed in Tables 1, 2, 10B, 10C, 11, 12, 13, 15- 21, 24, 29, or 30; or (iii) any combination thereof.

227. The method, the combination therapy, the composition, or the kit of any one of claims 1-165 and224-226, or the multifunctional molecule of any one of claims 166-226, wherein the TCRβV-binding moiety comprises: (i) a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to any one of the heavy chain variable domain amino acid sequences listed in Tables 1, 2, 10B, 10C, 11, 12, 13, 15- 21, 24, 29, or 30; (ii) a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to any one of the light chain variable domain amino acid sequences listed in Tables 1, 2, 10B, 10C, 11, 12, 13, 15- 21, 24, 29, or 30; (iii) a combination thereof.

228. The method, the combination therapy, the composition, or the kit of any one of claims 1-165 and224-227, or the multifunctional molecule of any one of claims 166-227, wherein the TCRβV-binding moiety comprises: (i) a VH comprising any one of the heavy chain variable domain amino acid sequences listed in Tables 1, 2, 10B, 10C, 11, 12, 13, 15- 21, 24, 29, or 30; (ii) a VL comprising any one of the light chain variable domain amino acid sequences listed in Tables 1, 2, 10B, 10C, 11, 12, 13, 15- 21, 24, 29, or 30; (iii) a combination thereof.

229. The method, the combination therapy, the composition, or the kit of any one of claims 1-165 and224, or the multifunctional molecule of any one of claims 166-224, wherein the TCRβV-binding moiety comprises a heavy chain variable region (VH) comprising a heavy chain complementarity- determining region 1 (HC CDR1) sequence, a HC CDR2 sequence and a HC CDR3 sequence, wherein the HC CDR1, HC CDR2, HC CDR3 sequences have a sequence according to SEQ ID NOs: (a) 1232, 1233 and 544, respectively;(b) 1234, 543 and 544, respectively;(c) 1235, 1236 and 1237, respectively; orWSGR Docket. No.53676-777.601 (d) 1238, 543 and 544, respectively.

230. The method, the combination therapy, the composition, or the kit of any one of claims 1-165, 224,and 229, or the multifunctional molecule of any one of claims 166-224 and 229, wherein the TCRβV-binding moiety comprises a light chain variable region (VL) comprising a light chain complementarity-determining region 1 (LC CDR1) sequence, a LC CDR2 sequence and a LC CDR3 sequence; wherein the LC CDR1, LC CDR2 and LC CDR3 sequences have a sequence according to SEQ ID NOs: (a) 3655, 3653, and 8, respectively;(b) 1075, 1076, and 8, respectively;(c) 1218, 1219, and 8, respectively;(d) 1220, 1221, and 8, respectively;(e) 545, 546, and 547, respectively;(f) 1239, 1240, and 547, respectively;(g) 3655, 1467, and 8, respectively;(h) 545, 546, and 1486, respectively; or(i) 1239, 1240, and 1486, respectively.

231. The method, the combination therapy, the composition, or the kit of any one of claims 1-165, 224,229, and 230, or the multifunctional molecule of any one of claims 166-224, 229, and 230, wherein the TCRβV-binding moiety comprises a light chain variable region (VL) comprising a light chain complementarity-determining region 1 (LC CDR1) sequence, a LC CDR2 sequence and a LC CDR3 sequence; wherein the LC CDR1, LC CDR2 and LC CDR3 sequences have a sequence according to SEQ ID NOs: (a) 1218, 1219, and 8, respectively;(b) 1220, 1221, and 8, respectively;(c) 3655, 1467, and 8, respectively;(d) 545, 546, and 1486, respectively; or(e) 1239, 1240, and 1486, respectively.

232. The method, the combination therapy, the composition, or the kit of any one of claims 1-165, 224,and 229-231, or the multifunctional molecule of any one of claims 166-224, and 229-231, wherein the TCRβV-binding moiety comprises a heavy chain variable region (VH) comprising a heavy chain complementarity-determining region 1 (HC CDR1) sequence, a HC CDR2 sequence and a HC CDR3 sequence, wherein the HC CDR1, HC CDR2, HC CDR3 sequences have a sequence according to SEQ ID NOs: (a) 1069, 1070 and 5, respectively;(b) 1071, 3651 and 5, respectively;(c) 1072, 1073 and 1074, respectively;(d) 3650, 3651 and 5, respectively;(e) 1069, 1070 and 5, respectively;WSGR Docket No.53676-777.601 (f) 1071, 3651 and 5, respectively;(g) 1072, 1073 and 1074, respectively;(h) 3650, 3651 and 5, respectively;(i) 1232, 1233 and 544, respectively;(j) 1234, 543 and 544, respectively;(k) 1235, 1236 and 1237, respectively;(l) 1238, 543 and 544, respectively;(m) 1243, 1233 and 544, respectively;(n) 1244, 543 and 544, respectively;(o) 1245, 1236 and 1237, respectively;(p) 542, 543 and 544, respectively;(q) 1069, 1070 and 5, respectively;(r) 1071, 3651 and 5, respectively;(s) 3650, 3651 and 5, respectively;(t) 1232, 1233 and 544, respectively;(u) 1234, 543 and 544, respectively;(v) 1235, 1236 and 1237, respectively; or(w) 1238, 543 and 544, respectively.

233. The method, the combination therapy, the composition, or the kit of any one of claims 1-165, 224,and 229-232, or the multifunctional molecule of any one of claims 166-224, and 229-232, wherein the TCRβV-binding moiety comprises (A) a heavy chain variable region (VH) comprising a heavy chain complementarity-determining region 1 (HC CDR1) sequence, a HC CDR2 sequence and a HC CDR3 sequence, and (B) a light chain variable region (VL) comprising a light chain complementarity-determining region 1 (LC CDR1) sequence, a LC CDR2 sequence and a LC CDR3 sequence; wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 sequences have a sequence according to SEQ ID NOs: (a) 1069, 1070, 5, 3655, 3653, and 8, respectively;(b) 1071, 3651, 5, 3655, 3653, and 8, respectively;(c) 1072, 1073, 1074, 1075, 1076, and 8, respectively;(d) 3650, 3651, 5, 3655, 3653, and 8, respectively;(e) 1069, 1070, 5, 1218, 1219, and 8, respectively;(f) 1071, 3651, 5, 1218, 1219, and 8, respectively;(g) 1072, 1073, 1074, 1220, 1221, and 8, respectively;(h) 3650, 3651, 5, 1218, 1219, and 8, respectively;(i) 1232, 1233, 544, 545, 546, and 547, respectively;(j) 1234, 543, 544, 545, 546, and 547, respectively;(k) 1235, 1236, 1237, 1239, 1240, and 547, respectively;(l) 1238, 543, 544, 545, 546, and 547, respectively;WSGR Docket. No.53676-777.601 (m) 1243, 1233, 544, 545, 546, and 547, respectively;(n) 1244, 543, 544, 545, 546, and 547, respectively;(o) 1245, 1236, 1237, 1239, 1240, and 547, respectively;(p) 542, 543, 544, 545, 546, and 547, respectively;(q) 1069, 1070, 5, 3655, 1467, and 8, respectively;(r) 1071, 3651, 5, 3655, 1467, and 8, respectively;(s) 1072, 1073, 1074, 1220, 1221, and 8, respectively;(t) 3650, 3651, 5, 3655, 1467, and 8, respectively;(u) 1232, 1233, 544, 545, 546, and 1486, respectively;(v) 1234, 543, 544, 545, 546, and 1486, respectively;(w) 1235, 1236, 1237, 1239, 1240, and 1486, respectively; or(x) 1238, 543, 544, 545, 546, and 1486, respectively.

234. The method, the combination therapy, the composition, or the kit of any one of claims 1-165, 224,and 229-233, or the multifunctional molecule of any one of claims 166-224, and 229-233, wherein the TCRβV-binding moiety comprises (a) a VH having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1346 and a VL having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1349, (b) a VH having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO:1346 and a VL having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO:1217, (c) a VH having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1231 and a VL having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3527, (d) a VH having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 541 and a VL having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3527, (e) a VH having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1231 and a VL having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1485, or (f) a VH having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1346 and aWSGR Docket No.53676-777.601 VL having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1466.

235. The method, the combination therapy, the composition, or the kit of any one of claims 1-165 and224-229, or the multifunctional molecule of any one of claims 166-229, wherein the TCRβV-binding moiety comprises (a) an scFv having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1331, (b) an scFv having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1216, (c) an scFv having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1230, (d) an scFv having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1376, (e) an scFv having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1483, or (f) an scFv having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1701.

236. The multifunctional molecule of any one of claims 180-235, wherein the second polypeptide chaincomprises a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1346, 541, or 1231, a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466, a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 2270, and a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 3648.

237. The multifunctional molecule of any one of claims 180-236, wherein the second polypeptide chaincomprises the sequence of SEQ ID NO: 1346, 541, or 1231, the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466, the sequence of SEQ ID NO: 2270, and the sequence of SEQ ID NO: 3648.

238. The multifunctional molecule of claim 235 or 237, wherein the second polypeptide chain furthercomprises the sequence of SEQ ID NO: 3801, the sequence of SEQ ID NO: 3309, the sequence of SEQ ID NO: 3308, or any combination thereof.

239. The multifunctional molecule of any one of claims 180-235, wherein the second polypeptide chaincomprises a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence ofWSGR Docket. No.53676-777.601 SEQ ID NO: 1346, 541, or 1231 operatively linked to a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466 operatively linked to a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 2270 operatively linked to a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 3648.

240. The multifunctional molecule of claim 239, wherein the sequence having at least 80%, 81%, 82%,83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1346, 541, or 1231 is operatively linked to the sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466 via the sequence of SEQ ID NO: 3801.

241. The multifunctional molecule of claim 239 or 240, wherein the sequence having at least 80%, 81%,82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466 is operatively linked to the sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 2270 via the sequence of SEQ ID NO: 3309.

242. The multifunctional molecule of any one of claims 239-241, wherein the sequence having at least80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 2270 is operatively linked to the sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 3648 via the sequence of SEQ ID NO: 3308.

243. The multifunctional molecule of any one of claims 180-242, wherein the second polypeptide chaincomprises the sequence of SEQ ID NO: 1346, 541, or 1231 operatively linked to the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466 operatively linked to the sequence of SEQ ID NO: 2270 operatively linked to the sequence of SEQ ID NO: 3648.

244. The multifunctional molecule of claim 243, wherein the sequence of SEQ ID NO: 1346, 541, or1231 is operatively linked to the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466 via the sequence of SEQ ID NO: 3801.

245. The multifunctional molecule of claim 243 or 244, wherein the sequence of SEQ ID NO: 1349,1217, 3527, 1485, or 1466 is operatively linked to the sequence of SEQ ID NO: 2270 via the sequence of SEQ ID NO: 3309.WSGR Docket No.53676-777.601246. The multifunctional molecule of any one of claims 243-245, wherein the sequence of SEQ ID NO:2270 is operatively linked to the sequence of SEQ ID NO: 3648 via the sequence of SEQ ID NO: 3308.

247. The multifunctional molecule of any one of claims 180-246, wherein the second polypeptide chaincomprises a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 3800.

248. The multifunctional molecule of any one of claims 180-247, wherein the second polypeptide chaincomprises the sequence of SEQ ID NO: 3800.

249. The multifunctional molecule of any one of claims 166-248, wherein the multifunctional moleculeconsists of a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises the tumor-associated antigen binding moiety linked to an Fc region, wherein the tumor-associated antigen binding moiety is an scFv that binds to a tumor-associated antigen, and the second polypeptide chain comprises the sequence of SEQ ID NO 3800.

250. The multifunctional molecule of any one of claims 166-249, wherein the multifunctional moleculeconsists of a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises the tumor-associated antigen binding moiety linked to a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 3792, wherein the tumor-associated antigen binding moiety is an scFv that binds to a tumor- associated antigen, and the second polypeptide chain comprises the sequence of SEQ ID NO 3800.

251. The multifunctional molecule of any one of claims 166-250, wherein the multifunctional moleculeconsists of a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises the tumor-associated antigen binding moiety linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 3792, wherein the tumor-associated antigen binding moiety is an scFv that binds to a tumor-associated antigen, and the second polypeptide chain comprises the sequence of SEQ ID NO 3800.

252. The multifunctional molecule of any one of claims 166-248, wherein the multifunctional moleculeconsists of a first polypeptide chain, a second polypeptide chain, and a third polypeptide chain, wherein the first polypeptide chain comprises a first portion of the tumor-associated antigen binding moiety linked to an Fc region, wherein the tumor-associated antigen binding moiety is an Fab that binds to a tumor-associated antigen; the second polypeptide chain comprises the sequence of SEQ ID NO 3800; and the third polypeptide chain comprises a second portion of the tumor-associated antigen binding moiety.

253. The multifunctional molecule of any one of claims 166-248, and 252, wherein the multifunctionalmolecule consists of a first polypeptide chain, a second polypeptide chain, and a third polypeptide chain, wherein the first polypeptide chain comprises a first portion of the tumor-associated antigen binding moiety linked to a sequence having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%,WSGR Docket. No.53676-777.601 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%- sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 3792, wherein the tumor-associated antigen binding moiety is an Fab that binds to a tumor-associated antigen; the second polypeptide chain comprises the sequence of SEQ ID NO 3800; and the third polypeptide chain comprises a second portion of the tumor-associated antigen binding moiety.

254. The multifunctional molecule of any one of claims 166-248, 252, and 253, wherein themultifunctional molecule consists of a first polypeptide chain, a second polypeptide chain, and a third polypeptide chain, wherein the first polypeptide chain comprises a first portion of the tumor- associated antigen binding moiety linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 3792, wherein the tumor-associated antigen binding moiety is an Fab that binds to a tumor-associated antigen; the second polypeptide chain comprises the sequence of SEQ ID NO 3800; and the third polypeptide chain comprises a second portion of the tumor-associated antigen binding moiety.

255. The multifunctional molecule of any one of claims 166-254, wherein the multifunctional moleculeis a polypeptide molecule.

256. The multifunctional molecule of any one of claims 166-255, wherein the TCRβV-binding moietycomprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1346, 541, or 1231.

257. The multifunctional molecule of any one of claims 166-256, wherein the TCRβV-binding moietycomprises a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466.

258. The multifunctional molecule of any one of claims 166-257, wherein the TCRβV-binding moietycomprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1346 and a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1349.

259. The multifunctional molecule of any one of claims 166-257, wherein the TCRβV-binding moietycomprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 541 and a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity the sequence of SEQ ID NO: 3527.

260. The multifunctional molecule of any one of claims 166-257, wherein the TCRβV-binding moietycomprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1346 and a VL comprising a sequence having at least 80%, 81%, 82%,WSGR Docket No.53676-777.601 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity the sequence of SEQ ID NO: 1217.

261. The multifunctional molecule of any one of claims 166-257, wherein the TCRβV-binding moietycomprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1231 and a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity the sequence of SEQ ID NO: 3527.

262. The multifunctional molecule of any one of claims 166-257, wherein the TCRβV-binding moietycomprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1231 and a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity the sequence of SEQ ID NO: 1485.

263. The multifunctional molecule of any one of claims 166-257, wherein the TCRβV-binding moietycomprises a VH comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1346 and a VL comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity the sequence of SEQ ID NO: 1466.

264. The multifunctional molecule of any one of claims 166-263, wherein the TCRβV-binding moietycomprises an scFv comprising the sequence of SEQ ID NO: 1346, 541, or 1231 operatively linked to the sequence of SEQ ID NO: 1349, 1217, 3527, 1485, or 1466 via a linker comprising the sequence of SEQ ID NO: 3801.

265. The multifunctional molecule of any one of claims 166-264, wherein the TCRβV-binding moietycomprises an scFv comprising a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 1331, 1216, 1230, 1376, 1483, or 1701.

266. The multifunctional molecule of any one of claims 166-263, wherein the multifunctional moleculecomprises a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1066, 1067, 1461, 1462, 1464, 1465, 1471, 1472, 1477, 1478, 1481, 1482, 1496, 1497, 1617, 1703, 1705, 1706, 615, or 1661.

267. The multifunctional molecule of any one of claims 166-263, wherein the multifunctional moleculecomprises a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1077 or 1078.WSGR Docket. No.53676-777.601268. The multifunctional molecule of any one of claims 166-263, wherein the multifunctional moleculecomprises a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1081 or 508.

269. The multifunctional molecule of any one of claims 166-263, wherein the multifunctional moleculecomprises: (a) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1066 or 1067, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081; (b) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1461 or 1462, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081; (c) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1464 or 1465, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081; (d) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1471 or 1472, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081;WSGR Docket No.53676-777.601(e) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1477 or 1478, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081;(f) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1481 or 1482, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081;(g) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1496 or 1497, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081;(h) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1617 or 1703, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081;(i) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1705 or 1706, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%,WSGR Docket. No.53676-777.601 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081; or (j) a first polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 615 or 1661, a second polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1077 or 1078, and a third polypeptide chain having a sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 100% sequence identity to SEQ ID NO: 1081.

270. The multifunctional molecule of any one of claims 166-269, wherein the multifunctional moleculeis a multispecific molecule.

271. A polynucleotide comprising a sequence encoding the multifunctional molecule of any one ofclaims 166-270.

272. The polynucleotide of claim 271, wherein the polynucleotide is an isolated nucleic acid molecule.

273. A vector comprising one or more of the polynucleotide of claim 271 or 272.

274. A cell comprising the polynucleotide of claim 271 or 272, or the vector of claim 273.

275. A pharmaceutical composition comprising the multifunctional molecule of any one of claims 166-270, the polynucleotide of claim 271 or 272, the vector of claim 273, or the cell of claim 274, and a pharmaceutically acceptable carrier, excipient, or diluent.

276. A method of treating a condition or disease in a subject in need thereof comprising administering tothe subject a therapeutically effective amount of the multifunctional molecule of any one of claims 166-270, the polynucleotide of claim 271 or 272, the vector of claim 273, the cell of claim 274, the pharmaceutical composition of claim 275, or any combination thereof, wherein the administering is effective to treat the condition or disease in the subject.

277. The method of claim 276, wherein the condition or disease is cancer.

278. The method of claim 277, wherein the cancer is a solid tumor, a hematological cancer, a metastaticcancer, a soft tissue tumor, or any combination thereof.

279. The method, the combination therapy, the composition, or the kit any one of claims 1-165, whereinthe disease or condition is cancer.

280. The method, the combination therapy, the composition, or the kit of claim 279, wherein the canceris a solid tumor, a hematological cancer, a metastatic cancer, a soft tissue tumor, or a combination thereof.

281. The method, the combination therapy, the composition, or the kit of claim 279 or 280, wherein thecancer is the solid tumor, and wherein the solid tumor is selected from the group consisting of breast cancer, colorectal cancer, lung cancer, prostate cancer, and a combination thereof.WSGR Docket No.53676-777.601282. The method, the combination therapy, the composition, or the kit of claim 280, wherein the breastcancer is a Triple-Negative Breast Cancer (TNBC) or a metastatic Triple Negative Breast Cancer (mTNBC).

283. The method or the combination therapy of any one of claims 279-280, wherein the cancer is thehematological cancer, and wherein the hematological cancer is selected from the group consisting of Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia, myelodysplastic syndrome, multiple myeloma, T-cell lymphoma, acute lymphocytic leukemia, and a combination thereof.

284. The method or the combination therapy of claim 283, wherein the Non-Hodgkin’s lymphoma isselected from the group consisting of B cell lymphoma, diffuse large B cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia (B-CLL), mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, and a combination thereof.

285. The method or the combination therapy of claim 284, wherein the T-cell lymphoma is peripheral T-cell lymphoma.

286. The method or the combination therapy of any one of claims 279-285, wherein the cancer ischaracterized by a cancer antigen present on the cancer.

287. The method or the combination therapy of claim 286, wherein the cancer antigen is a tumor antigen,a stromal antigen, or a hematological antigen.

288. The method of claim 286 or 287, wherein the cancer antigen is selected from the group consisting ofCD19, CD123, CD22, CD30, CD171, CS-1, C-type lectin-like molecule-1, CD33, epidermal growth factor receptor variant III (EGFRvIII), ganglioside G2 (GD2), ganglioside GD3, TNF receptor family member B cell maturation (BCMA), Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr)), prostate-specific membrane antigen (PSMA), Receptor tyrosine kinase-like orphan receptor 1 (ROR1), Fms-Like Tyrosine Kinase 3 (FLT3), Tumor-associated glycoprotein 72 (TAG72), CD38, CD44v6, Carcinoembryonic antigen (CEA), Epithelial cell adhesion molecule (EPCAM), B7H3 (CD276), KIT (CD117), Interleukin-13 receptor subunit alpha-2, mesothelin, Interleukin 11 receptor alpha (IL- 11Ra), prostate stem cell antigen (PSCA), Protease Serine 21, vascular endothelial growth factor receptor 2 (VEGFR2), Lewis(Y) antigen, CD24, Platelet-derived growth factor receptor beta (PDGFR-beta), Stage-specific embryonic antigen-4 (SSEA-4), CD20, Folate receptor alpha, Receptor tyrosine-protein kinase ERBB2 (Her2 / neu), Mucin 1, cell surface associated (MUC1), epidermal growth factor receptor (EGFR), neural cell adhesion molecule (NCAM), Prostase, prostatic acid phosphatase (PAP), elongation factor 2 mutated (ELF2M), Ephrin B2, fibroblast activation protein alpha (FAP), insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX), Proteasome (Prosome, Macropain) Subunit, Beta Type, 9 (LMP2), glycoprotein 100 (gp100 / pmel17), oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr-abl), tyrosinase, ephrin type-A receptor 2 (EphA2), Fucosyl GM1, sialyl Lewis adhesion molecule (sLe), ganglioside GM3,WSGR Docket. No.53676-777.601 transglutaminase 5 (TGS5), high molecular weight-melanoma-associated antigen (HMWMAA), o- acetyl-GD2 ganglioside (OAcGD2), Folate receptor beta, tumor endothelial marker 1 (TEM1 / CD248), tumor endothelial marker 7-related (TEM7R), claudin 6 (CLDN6), thyroid stimulating hormone receptor (TSHR), G protein-coupled receptor class C group 5, member D (GPRC5D), chromosome X open reading frame 61 (CXORF61), CD97, CD179a, anaplastic lymphoma kinase (ALK), Polysialic acid, placenta-specific 1 (PLAC1), hexasaccharide portion of globoH glycoceramide (GloboH), mammary gland differentiation antigen (NY-BR-1), uroplakin 2 (UPK2), Hepatitis A virus cellular receptor 1 (HAVCR1), adrenoceptor beta 3 (ADRB3), pannexin 3 (PANX3), G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex, locus K 9 (LY6K), Olfactory receptor 51E2 (OR51E2), TCR Gamma Alternate Reading Frame Protein (TARP), Wilms tumor protein (WT1), Cancer / testis antigen 1 (NY-ESO-1 / LAGE-1), Cancer / testis antigen 2 (LAGE-1a), Melanoma-associated antigen 1 (MAGE-A1), ETS translocation-variant gene 6, located on chromosome 12p (ETV6-AML), sperm protein 17 (SPA17), X Antigen Family, Member 1A (XAGE1), angiopoietin-binding cell surface receptor 2 (Tie 2), melanoma cancer testis antigen-1 (MAD-CT-1), melanoma cancer testis antigen-2 (MAD-CT-2), Fos-related antigen 1, tumor protein p53 (p53), p53 mutant, prostein, Survivin, telomerase, prostate carcinoma tumor antigen-1, melanoma antigen recognized by T cells 1, Rat sarcoma (Ras) mutant, human Telomerase reverse transcriptase (hTERT), sarcoma translocation breakpoints, melanoma inhibitor of apoptosis (ML-IAP), ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene), N-Acetyl glucosaminyl-transferase V (NA17), paired box protein Pax-3 (PAX3), Androgen receptor, Cyclin B1, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), Ras Homolog Family Member C (RhoC), Tyrosinase-related protein 2 (TRP-2), Cytochrome P4501B1 (CYP1B1), CCCTC-Binding Factor (Zinc Finger Protein)-Like, Squamous Cell Carcinoma Antigen Recognized By T Cells 3 (SART3), Paired box protein Pax-5 (PAX5), proacrosin binding protein sp32 (OY-TES1), lymphocyte-specific protein tyrosine kinase (LCK), A kinase anchor protein 4 (AKAP-4), synovial sarcoma, X breakpoint 2 (SSX2), Receptor for Advanced Glycation Endproducts (RAGE-1), renal ubiquitous 1 (RU1), renal ubiquitous 2 (RU2), legumain, human papilloma virus E6 (HPV E6), human papilloma virus E7 (HPV E7), intestinal carboxyl esterase, heat shock protein 70-2 mutated (mut hsp70-2), CD79a, CD79b, CD72, Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), Fc fragment of IgA receptor (FCAR or CD89), Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2), CD300 molecule-like family member f (CD300LF), C-type lectin domain family 12 member A (CLEC12A), bone marrow stromal cell antigen 2 (BST2), EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2), lymphocyte antigen 75 (LY75), Glypican-3 (GPC3), Fc receptor-like 5 (FCRL5), FcRH5, PDL1, CD47, prostate specific membrane antigen (PMSA), prostate-specific antigen (PSA), Ron Kinase, c- Met, Immature laminin receptor, TAG-72, BING-4, Calcium-activated chloride channel 2, Cyclin- B1, 9D7, Ep-CAM, EphA3, SAP-1, PRAME, SSX-2, Melan-A / MART-1, TRP1 / gp75, MC1R, β- catenin, BRCA1 / 2, CDK4, CML66, Fibronectin, Ras, TGF-Β receptor, AFP, ETA, MAGE, CA-125,WSGR Docket No.53676-777.601 BAGE, GAGE, CDC27, α actinin-4, gangliosides, MART-2, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RU11, RU12, SAGE, TRG, TSTA, L1-CAM, gpA33, GM2, VEGFR, Integrins, carbohydrates, TRAILR1, TRAILR2, RANKL, TGF-beta, hyaluronic acid, collagen, tenascin C, tenascin W, and immunoglobulin lambda-like polypeptide 1 (IGLL1).

289. The method of claim 286 or 287, wherein the cancer antigen is TROP-2.

290. The method of claim 277 or 278, wherein the cancer is a TROP-2 associated cancer.

291. The method of any one of claims 277, 278, and 290, wherein the cancer comprises breast cancer,colorectal cancer, lung cancer, prostate cancer, or any combination thereof.

292. The method of any one of claims 277, 278, 290, and 291, wherein the wherein the breast cancer is aTriple-Negative Breast Cancer (TNBC) or a metastatic Triple Negative Breast Cancer (mTNBC).

293. The method of any one of claims 275-292, further comprising administering a second therapeuticagent or therapy to the subject.

294. The method of claim 293, wherein the second therapeutic agent or therapy comprises achemotherapeutic agent, a biologic agent, a hormonal therapy, radiation, or surgery.

295. The method of claim 293 or 294, wherein the second therapeutic agent or therapy is administered incombination with the multifunctional molecule of any one of claims 166-270, the polynucleotide of claim 271 or 272, the vector of claim 273, the cell of claim 274, and / or the pharmaceutical composition of claim 275, sequentially, simultaneously, or concurrently.

296. The method of any one of claims 275-295, wherein the multifunctional molecule of any one ofclaims 166-270, the polynucleotide of claim 271 or 272, the vector of claim 273, the cell of claim 274, and / or the pharmaceutical composition of claim 275 induces T cell mediated cytotoxicity of tumor cells.

297. The method of any one of claims 275-296, wherein the multifunctional molecule of any one ofclaims 166-270, the polynucleotide of claim 271 or 272, the vector of claim 273, the cell of claim 274, and / or the pharmaceutical composition of claim 275 induces T cell activation.

298. The method of any one of claims 275-297, wherein the multifunctional molecule of any one ofclaims 166-270, the polynucleotide of claim 271 or 272, the vector of claim 273, the cell of claim 274, or the pharmaceutical composition of claim 275 induces T cell proliferation.

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