Multifunctional molecules binding to TCR and uses thereof

Abstract

Provided herein are multifunctional molecules comprising a first domain that binds to a first target molecule, wherein the first target molecule is a T cell receptor alpha (TCRα) chain; and a second domain that binds to a second target molecule, wherein the second target molecule is a T cell receptor beta (TCRβ) chain, and methods of using thereof.

Description

CROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 624,887, filed January 25, 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 cancer immunotherapy 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. In addition, anti-CD3e mAbs bind to all T cells and thus activate a large number of T cells. Such non-physiological massive activation of T cells by these anti-CD3e mAbs can result in the production of proinflammatory cytokines such as IFN-gamma, IL-1-beta, IL-6, IL-10 and TNF-alpha, causing a “cytokine storm” known as the cytokine release syndrome (CRS), which is also associated with neurotoxicity (NT). Thus, there is a need for improved T cell receptor-binding molecules that redirect T cells for cancer immunotherapy. SUMMARY

[0003] In an aspect, provided herein is, inter alia, a multifunctional molecule comprising (a) a first domain that binds to a first target molecule, wherein the first target molecule is a T cell receptor alpha (TCRa) chain; and (b) a second domain that binds to a second target molecule, wherein the second target molecule is a T cell receptor beta (TCR[3) chain.

[0004] In some embodiments, the TCRa chain is a human TCRa .

[0005] In some embodiments, the TCR[3 chain is a human TCR[3 chain.

[0006] In some embodiments, the first domain is a TCRaV-binding domain that binds to a variable region of the human TCRa chain (TCRaV).

[0007] In some embodiments, the second domain is a TCR[3V-binding domain that binds to a variable region of the human TCRP chain (TCRpV).

[0008] In some embodiments, the multifunctional molecule comprises at least two non-contiguous polypeptides comprising a first polypeptide chain and a second polypeptide chain; wherein the first polypeptide chain comprises a first portion of a dimerization module; wherein the second polypeptide chain comprises a second portion of the dimerization module; and wherein the first polypeptide chain and the second polypeptide chain form a dimer via association of the first portion of the dimerization module and the second portion of the dimerization module.

[0009] In some embodiments, the first domain is an antibody molecule.

[0010] In some embodiments, the second domain is an antibody molecule.

[0011] In some embodiments, the antibody molecule is selected from the group consisting of a fulllength antibody, an Fab, an Fab', an F(ab')2, an F(ab)2, a variable fragment (Fv), a single domain antibody, a diabody, a camelid antibody, a nanobody, and a single chain variable fragment (scFv).

[0012] In some embodiments, the first domain is a scFv or a single domain antibody.

[0013] In some embodiments, the first domain is an Fab comprising a first portion of the first domain and a second portion of the first domain; wherein the first portion of the first domain and the second portion of the first domain assemble and form the first domain of the multifunctional molecule; wherein the multifunctional molecule further comprises a polypeptide chain comprising the second portion of the first domain, wherein the polypeptide chain comprising the second portion of the first domain is noncontiguous with the first polypeptide chain and the second polypeptide chain.

[0014] In some embodiments, the first portion of the first domain comprises a heavy chain variable region (VH) of the Fab and the second portion of the first domain comprises a light chain variable region (VL) of the Fab, or the first portion of the first domain comprises the VL of the Fab and the second portion of the first domain comprises the VH of the Fab.

[0015] In some embodiments, the second domain is a scFv or a single domain antibody.

[0016] In some embodiments, the second domain is an Fab comprising a first portion of the second domain and a second portion of the second domain; wherein the first portion of the second domain and the second portion of the second domain assemble and form the second domain of the multifunctional molecule; wherein the multifunctional molecule further comprises a polypeptide chain comprising the second portion of the second domain, wherein the polypeptide chain comprising the second portion of the second domain is non-contiguous with the first polypeptide chain, the second polypeptide chain, and the polypeptide chain comprising the second portion of the first domain.

[0017] In some embodiments, the first portion of the second domain comprises a heavy chain variable region (VH) of the Fab and the second portion of the second domain comprises a light chain variable region (VL) of the Fab, or the first portion of the second domain comprises the VL of the Fab and the second portion of the second domain comprises the VH of the Fab.

[0018] In some embodiments, the first portion of the dimerization module is linked to the first domain or the first portion of the first domain.

[0019] In some embodiments, the N-terminus of the first portion of the dimerization module is linked to the C-terminus of the first domain or the C-terminus of the first portion of the first domain.

[0020] In some embodiments, the C-terminus of the first portion of the dimerization module is linked to the N-terminus of the first domain or the N-terminus of the first portion of the first domain.

[0021] In some embodiments, the first portion of the dimerization module is linked to the second domain or the first portion of the second domain.

[0022] In some embodiments, the N-terminus of the first portion of the dimerization module is linked to the C-terminus of the first domain or the C-terminus of the first portion of the first domain, and the C-terminus of the first portion of the dimerization module is linked to the N-terminus of the second domain or the N-terminus of the first portion of the second domain.

[0023] In some embodiments, the C-terminus of the first portion of the dimerization module is linked to the N-terminus of the first domain or the N-terminus of the first portion of the first domain, and the N-terminus of the first portion of the dimerization module is linked to the C-terminus of the second domain or the C-terminus of the first portion of the second domain.

[0024] In some embodiments, the second portion of the dimerization module is linked to the second domain or the first portion of the second domain.

[0025] In some embodiments, the N-terminus of the second portion of the dimerization module is linked to the C-terminus of the second domain or the C-terminus of the first portion of the second domain.

[0026] In some embodiments, the C-terminus of the second portion of the dimerization module is linked to the N-terminus of the second domain or the N-terminus of the first portion of the second domain.

[0027] In some embodiments, the N-terminus of the first portion of a dimerization module is linked to the C-terminus of the first domain or the C-terminus of the first portion of the first domain, and the N-terminus of the second portion of the dimerization module is linked to the C-terminus of the second domain or the C-terminus of the first portion of the second domain.

[0028] In some embodiments, the N-terminus of the first portion of the dimerization module is linked to the C-terminus of the first domain or the C-terminus of the first portion of the first domain, and the C-terminus of the second portion of the dimerization module is linked to the N-terminus of the second domain or the N-terminus of the first portion of the second domain.

[0029] In some embodiments, the C-terminus of the first portion of the dimerization module is linked to the N-terminus of the first domain or the N-terminus of the first portion of the first domain, and the C-terminus of the second portion of the dimerization module is linked to the N-terminus of the second domain or the N-terminus of the first portion of the second domain.

[0030] In some embodiments, the C-terminus of the first portion of the dimerization module is linked to the N-terminus of the first domain or the N-terminus of the first portion of the first domain, and the N-terminus of the second portion of the dimerization module is linked to the C-terminus of the second domain or the C-terminus of the first portion of the second domain.

[0031] In some embodiments, the multifunctional molecule comprises at least three non-contiguous polypeptide chains, wherein: (i) the first polypeptide chain comprising the first portion of the dimerization module linked to a first portion of the first domain; (ii) the second polypeptide chain comprising the second portion of the dimerization module; and (iii) a polypeptide chain comprising a second portion of the first domain, and wherein the second domain is linked to the first portion of the dimerization module or the second portion of the dimerization module.

[0032] In some embodiments, the multifunctional molecule comprises at least three non-contiguous polypeptide chains, wherein: (i) the first polypeptide chain comprising the first portion of the dimerization module linked to the first domain; (ii) the second polypeptide chain comprising the second portion of the dimerization module; and (iii) a polypeptide chain comprising a second portion of the second domain, and wherein a first portion of the second domain is linked to the first portion of the dimerization module or the second portion of the dimerization module.

[0033] In some embodiments, the multifunctional molecule comprises at least four non-contiguous polypeptide chains, wherein: (i) the first polypeptide chain comprising the first portion of the dimerization module linked to a first portion of the first domain; (ii) the second polypeptide chain comprising the second portion of the dimerization module;(iii) a polypeptide chain comprising a second portion of the first domain; and (iv) a polypeptide chain comprising a second portion of the second domain, and wherein a first portion of the second domain is linked to the first portion of the dimerization module or the second portion of the dimerization module.

[0034] In some embodiments, the multifunctional molecule comprises at least two non-contiguous polypeptide chains, wherein: the first polypeptide chain comprising the first portion of the dimerization module linked to the first domain; and the second polypeptide chain comprising the second portion of the dimerization module; and wherein the second domain is linked to the first portion of the dimerization module or the second portion of the dimerization module.

[0035] In some embodiments, the multifunctional molecule further comprises at least one cytokine or a functional fragment or variant thereof.

[0036] In some embodiments, the at least one cytokine or a functional fragment or variant thereof is linked to the first portion of the dimerization module, the second portion of the dimerization module, or any combination thereof.

[0037] In some embodiments, the at least one cytokine or a functional fragment or variant thereof is linked to the N-terminus of the first portion of the dimerization module, 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.

[0038] In some embodiments, the at least one cytokine or a functional fragment or variant thereof is linked to the first domain, the first portion of the first domain, the second portion of the first domain, the second domain, the first portion of the second domain, the second portion of the second domain, or any combination thereof.

[0039] In some embodiments, the at least one cytokine or a functional fragment or variant thereof is linked to the N-terminus of the first domain, the C-terminus of the first domain, the N-terminus of the first portion of the first domain, the C-terminus of the first portion of the first domain, the N-terminus of the second portion of the first domain, the C-terminus of the second portion of the first domain, the N-terminus of the second domain, the C-terminus of the second domain, the N-terminus of the first portion of the second domain, the C-terminus of the first portion of the second domain, the N-terminus of the second portion of the second domain, the C-terminus of the second portion of the second domain, or any combination thereof.

[0040] In some embodiments, the at least one cytokine or a functional fragment or variant thereof 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.

[0041] In some embodiments, the at least one cytokine or a functional fragment or variant thereof comprises interleukin-2 (IL-2) or functional variant thereof.

[0042] In some embodiments, the interleukin-2 (IL-2) or functional variant thereof comprises a sequence with at least 70% sequence identity to the sequence of SEQ ID NO: 2270 or SEQ ID NO: 2191.

[0043] In some embodiments, the interleukin-2 (IL-2) or functional variant thereof comprises the sequence of SEQ ID NO: 2270 or SEQ ID NO: 2191.

[0044] In some embodiments, the at least one cytokine or a functional fragment or variant thereof comprises interleukin-15 (IL-15) or functional variant thereof.

[0045] In some embodiments, the interleukin-15 (IL-15) or functional variant thereof comprises a sequence with at least 70% sequence identity to the sequence of SEQ ID NO: 2170.

[0046] In some embodiments, the interleukin-15 (IL-15) or functional variant thereof comprises the sequence of SEQ ID NO: 2170.

[0047] In some embodiments, the at least one cytokine or a functional fragment or variant thereof further comprises an IL15Ralpha dimerizing domain covalently linked the interleukin-15 (IL-15) or functional variant thereof.

[0048] In some embodiments, the IL15Ralpha dimerizing domain comprises an IL-15 receptor alpha sushi domain or functional variant thereof.

[0049] In some embodiments, the IL15Ralpha dimerizing domain comprises a sequence with at least 70% sequence identity to the sequence of SEQ ID NO: 3472.

[0050] The multifunctional molecule of any one of claims 45-47, wherein the IL15Ralpha dimerizing domain comprises the sequence of SEQ ID NO: 3472.

[0051] In some embodiments, the interleukin-15 (IL-15) or functional variant thereof is covalently linked to the IL15Ralpha dimerizing domain via a linker.

[0052] In some embodiments, the interleukin-15 (IL-15) or functional variant thereof is covalently linked to the IL15Ralpha dimerizing domain via a linker comprising the sequence of SEQ ID NO: 3473.

[0053] In some embodiments, the at least one cytokine or a functional fragment or variant thereof comprises a sequence with at least 70% sequence identity to the sequence of SEQ ID NO: 3474.

[0054] In some embodiments, the at least one cytokine or a functional fragment or variant thereof comprises the sequence of SEQ ID NO: 3474.

[0055] In some embodiments, the multifunctional molecule further comprises a linker between the first domain or the first portion of the first domain and the first portion of the dimerization module.

[0056] In some embodiments, the multifunctional molecule further comprises a linker between the second domain or the first portion of the second domain and the first portion of a dimerization module.

[0057] In some embodiments, the multifunctional molecule further comprises a linker between the second domain or the first portion of the second domain and the second portion of a dimerization module.

[0058] In some embodiments, the multifunctional molecule further comprises a linker between the at least one cytokine or a functional fragment or variant thereof and the first portion of the dimerization module.

[0059] In some embodiments, the multifunctional molecule further comprises a linker between the at least one cytokine or a functional fragment or variant thereof and the first portion of the dimerization module of the first polypeptide chain.

[0060] In some embodiments, the multifunctional molecule further comprises a linker between the at least one cytokine or a functional fragment or variant thereof and the first domain, a linker between the at least one cytokine or a functional fragment or variant thereof and the first portion of the first domain, a linker between the at least one cytokine or a functional fragment or variant thereof and the second portion of the first domain, a linker between the at least one cytokine or a functional fragment or variant thereof and the second domain, a linker between the at least one cytokine or a functional fragment or variant thereof and the first portion of the second domain, a linker between the at least one cytokine or a functional fragment or variant thereof and the second portion of the second domain, or any combination thereof.

[0061] In some embodiments, the multifunctional molecule further comprises a tumor-targeting moiety.

[0062] In some embodiments, the tumor-targeting moiety binds to a cancer antigen.

[0063] In some embodiments, the tumor-targeting moiety binds to a cancer antigen 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 (GalNAca-Ser / Thr)), prostate-specific membrane antigen (PSMA), Receptor tyrosine kinase-like orphan receptor 1 (R0R1), 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-1 IRa), 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), Stagespecific 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 (gp 100) / pmell7, oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abi) (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), Poly sialic 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-la), 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 (NA 17), paired box protein Pax-3 (PAX3), Androgen receptor, Cyclin Bl, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), Ras Homolog Family Member C (RhoC), Tyrosinase-related protein 2 (TRP-2), Cytochrome P450 1B1 (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), prostatespecific antigen (PSA), Ron Kinase, c-Met, Immature laminin receptor, TAG-72, BING-4, Calcium-activated chloride channel 2, Cyclin-Bl, 9D7, Ep-CAM, EphA3, SAP-1, PRAME, Melan-A / MART-1, TRPl / gp75, MC1R, p-catenin, BRCA1 / 2, CDK4, CML66, Fibronectin, Ras, TGF-B receptor, TGF-p receptor, AFP, ETA, MAGE, CA-125, BAGE, GAGE, CDC27, a actinin-4, gangliosides, MART-2, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RUI 1, RU12, SAGE, TRG, TSTA, Ll-CAM, gpA33, GM2, VEGFR, Intergrins, carbohydrates, IGF1R, TRAILRI, TRAILR2, RANKL, TGF-beta, hyaluronic acid, collagen, tenascin C, tenascin W, and immunoglobulin lambda-like polypeptide 1 (IGLL1).

[0064] In some embodiments, the tumor-targeting moiety is an antibody molecule.

[0065] In some embodiments, the antibody molecule is selected from the group consisting of a fulllength antibody, an Fab, an Fab', an F(ab')2, an F(ab)2, a variable fragment (Fv), a single domain antibody, a diabody, a camelid antibody, a nanobody, and a single chain variable fragment (scFv).

[0066] In some embodiments, the multifunctional molecule further comprises a stromal modifying moiety.

[0067] In some embodiments, the multifunctional molecule further comprises an immune cell engager.

[0068] In some embodiments, 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, the macrophage cell engager, and any combination thereof.

[0069] In some embodiments, immune cell engager is an antibody molecule.

[0070] In some embodiments, the antibody molecule is selected from the group consisting of a fulllength antibody, an Fab, an Fab', an F(ab')2, an F(ab)2, a variable fragment (Fv), a single domain antibody, a diabody, a camelid antibody, a nanobody, and a single chain variable fragment (scFv).

[0071] In some embodiments, the first portion of the dimerization module of the first polypeptide chain is a first Fc region or variant thereof.

[0072] In some embodiments, the second portion of the dimerization module of the second polypeptide chain is a second Fc region or variant thereof.

[0073] In some embodiments, the first portion of the dimerization module, the second portion of the dimerization module, or a combination thereof is selected from the group consisting of an IgGl Fc region or a functional fragment thereof, an IgG2 Fc region or a functional fragment thereof, an IgG3 Fc region or a functional fragment thereof, an IgGAl Fc region or a functional fragment thereof, an IgGA2 Fc region or a functional fragment thereof, an IgG4 Fc region or a functional fragment thereof, an IgJ Fc region or a functional fragment thereof, an IgM Fc region or a functional fragment thereof, an IgD Fc region or a functional fragment thereof, and an IgE Fc region or a functional fragment thereof.

[0074] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises an engineered Fc interface with one or more of: a paired cavity-protuberance, an electrostatic interaction, or a strand-exchange, wherein 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 dimerization of Fc regions without the engineered interface.

[0075] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises a Cys at position 349, a Ser at position 366, an Ala at position 368, a Vai at position 407, a Cys at position 354, a Trp at position 366, or any combination thereof in a heavy chain constant region according to EU Numbering.

[0076] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises (i) a Cys at position 349, a Ser at position 366, an Ala at position 368, and a Vai at position 407 in a heavy chain constant region according to EU Numbering; (ii) a Cys at position 354 and a Trp at position 366 in a heavy chain constant region according to EU Numbering; or (iii) a combination thereof.

[0077] In some embodiments, (i) the first Fc region comprises: (a) a Cys at position 349 in a heavy chain constant region according to EU Numbering, (b) a Ser at position 366 in a heavy chain constant region according to EU Numbering, (c) an Ala at position 368 in a heavy chain constant region according to EU Numbering, and (d) a Vai at position 407 in a heavy chain constant region according to EU Numbering; and (ii) the second Fc region comprises: (a) a Cys at position 354 in a heavy chain constant region according to EU Numbering, and (b) a Trp at position 366 in a heavy chain constant region according to EU Numbering.

[0078] In some embodiments, (i) the first Fc region comprises:(a) a Cys at position 354 in a heavy chain constant region according to EU Numbering, and (b) a Trp at position 366 in a heavy chain constant region according to EU Numbering(ii) the second Fc region comprises: (a) a Cys at position 349 in a heavy chain constant region according to EU Numbering, (b) a Ser at position 366 in a heavy chain constant region according to EU Numbering, (c) an Ala at position 368 in a heavy chain constant region according to EU Numbering, and (d) a Vai at position 407 in a heavy chain constant region according to EU Numbering.

[0079] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprise one or more mutations that result in reduced or ablated affinity for at least one Fc receptor relative to a Fc region without the one or more mutations.

[0080] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises an Asn297Ala (N297A) mutation or a Leu234Ala / Leu235Ala (LALA) mutation, or a combination thereof according to EU Numbering.

[0081] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 3901, SEQ ID NO: 3645, SEQ ID NO: 3902, SEQ ID NO: 3646, SEQ ID NO: 3647, SEQ ID NO: 3903, SEQ ID NO:206, SEQ ID NO: 207, SEQ ID NO: 3904, SEQ ID NO: 3452, SEQ ID NO: 3447, or SEQ ID NO: 3453.

[0082] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises the sequence of SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 3901, SEQ ID NO: 3645, SEQ ID NO: 3902, SEQ ID NO: 3646, SEQ ID NO: 3647, SEQ ID NO: 3903, SEQ ID NO:206, SEQ ID NO: 207, SEQ ID NO: 3904, SEQ ID NO: 3452, SEQ ID NO: 3447, or SEQ ID NO: 3453.

[0083] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:206, SEQ ID NO: 3447, or SEQ ID NO: 3453.

[0084] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises the sequence of SEQ ID NO:206, SEQ ID NO: 3447, or SEQ ID NO: 3453.

[0085] In some embodiments, the multifunctional the molecule comprises the following configuration: A-[first portion of dimerization module]-C, B-[second portion of dimerization module]-D, wherein: (a) the dimerization module comprises a first immunoglobulin chain constant region and a second immunoglobulin chain constant region; (b) A and C are linked to the first immunoglobulin chain constant region; and B and D are linked to the second immunoglobulin chain constant region; (c) A, B, C, and D are independently (i) absent; (ii) the first domain; (iii) the second domain, (iv) the at least one cytokine or a functional fragment or variant thereof, (v) the tumor targeting moiety, (vi) the stromal modifying moiety; or (vii) the immune cell engager; wherein at least one of A or C are the first domain, and wherein when A is the first domain, at least one of B, C, or D is the second domain, and when C is the first domain, at least one of A, B, or D is the second domain.

[0086] In some embodiments, the multifunctional molecule is not immobilized to a solid-phase.

[0087] In some embodiments, the multifunctional molecule is not immobilized to a solid-phase.

[0088] In some embodiments, the second domain binds to one or more of a TCRpV subfamily selected from the group consisting of TCRP VI subfamily, TCRP V2 subfamily, TCRP V3 subfamily, TCRP V4 subfamily, TCRP V5 subfamily, TCRP V6 subfamily, TCRP V7 subfamily, TCRP V8 subfamily, TCRP V9 subfamily, TCRP V10 subfamily, TCRP Vil subfamily, TCRP V12 subfamily, TCRP V13 subfamily, TCRP VI4 subfamily, TCRP V15 subfamily, TCRP VI6 subfamily, TCRP V17 subfamily, TCRP VI8 subfamily, TCRP V19, TCRP V20 subfamily, TCRP V21 subfamily, TCRP V22 subfamily TCRP V23 subfamily, TCRP V24 subfamily, TCRP V25 subfamily, TCRP V26 subfamily, TCRP V27 subfamily, TCRP V28 subfamily, TCRP V29 subfamily, and TCRP V30 subfamily.

[0089] In some embodiments, the second domain binds to one or more of a TCRpV subfamily selected from the group consisting of: TCRP VI subfamily comprising TCRP Vl*01; TCRP V2 subfamily comprising one or more selected from TCRP V2*01, TCRP V2*02, and TCRP V2*03; TCRP V3 subfamily comprising one or more selected from TCRP V3-l*01 and TCRP V3-l*02; TCRP V4 subfamily comprising one or more selected from TCRP V4-l*01, TCRP V4-l*02, TCRP V4-2*01, TCRP V4-2*02, TCRP V4-3*01, TCRP V4-3*02, TCRP V4-3*03, and TCRP V4-3*04; TCRP V5 subfamily comprising one or more selected from TCRP V5-l*01, TCRP V5-l*02, TCRP V5-3*01, TCRP V5-3*02, TCRP V5-4*01, TCRP V5-4*02, TCRP V5-4*03, TCRP V5-4*04, TCRP V5-5*01, TCRP V5-5*02, TCRP V5-5*03, TCRP V5-6*01, TCRP V5-7*01, TCRP V5-8*01, and TCRP V5-8*02; TCRP V6 subfamily comprising one or more selected from TCRP V6-l*01, TCRP V6-2*01, TCRP V6-3*01, TCRP V6-4*01, TCRP V6-4*02, TCRP V6-5*01, TCRP V6-6*01, TCRP V6-6*02, TCRP V6-6*03, TCRP V6-6*04, TCRP V6-6*05, TCRP V6-7*01, TCRP V6-8*01, and TCRP V6-9*01; TCRP V7 subfamily comprising one or more selected from TCRP V7-l*01, TCRP V7-2*01, TCRP V7-2*02, TCRP V7-2*03, TCRP V7-2*04, TCRP V7-3*01, TCRP V7-3*02, TCRP V7-3*03, TCRP V7-3*04, TCRP V7-3*05, TCRP V7-4*01, TCRP V7-4*02, TCRP V7-6*01, TCRP V7-6*02, TCRP V7-7*01, TCRP V7-7*02, TCRP V7-8*01, TCRP V7-8*02, TCRP V7-8*03, TCRP V7-9*01, TCRP V7-9*02, TCRP V7-9*03, TCRP V7-9*04, TCRP V7-9*05, TCRP V7-9*06, and TCRP V7-9*07; TCRP V8 subfamily comprising one or more selected from TCRP V8-l*01, TCRP V8-l*02, TCRP V8-2*01, and TCRP V8-2*02; TCRP V9 subfamily comprising one or more selected from TCRP V9-l*01, TCRP V9- 1*02, and TCRP V9-l*03; TCRP V10 subfamily comprising one or more selected from TCRP V10-1*01, TCRP V10-l*02, TCRP V10-l*03, TCRP V10-2*01, TCRP V10-2*02, TCRP V10-3*01, TCRP V10-3*02, TCRP V10-3*03, and TCRP V10-3*04; TCRP Vil subfamily comprising TCRP VI 1-1*01, TCRP VI 1-2*01, TCRP VI 1-2*02, TCRP VI 1-2*03, TCRP VI 1-3*01, TCRP VI 1-3*02, TCRP VI1-3*03, and TCRP VI 1-3*04; TCRP V12 subfamily comprising one or more selected from TCRP V12-3*01, TCRP V12-4*01, TCRP V12-4*02, and TCRP V12-5*01; TCRP V13 subfamily comprising one or more selected from TCRP V13*01 and TCRP V13*02; TCRP V14 subfamily comprising one or more comprising from TCRP V14*01 and TCRP V14*02; TCRP V15 subfamily comprising one or more selected from TCRP V15*01, TCRP V15*02, and TCRP V15*03; TCRP V16 subfamily comprising one or more selected from TCRP V16*01, TCRP V16*02, and TCRP V16*03; TCRP V17 subfamily comprising TCRP V17*01;TCRp V18 subfamily comprising TCRP V18*01; TCRP V19 subfamily comprising one or more selected from TCRP V19*01, TCRP VI9*02, and TCRP VI9* 03; TCRP V20 subfamily comprising one or more selected from TCRP V20-l*01, TCRP V20-l*02, TCRP V20-l*03, TCRP V20-l*04, TCRP V20-l*05, TCRP V20-l*06, and TCRP V20-l*07;TCRp V21 subfamily comprising one or more selected from TCRP V21-l*01 and TCRP V21-1*O2;TCRP V22 subfamily comprising TCRP V22-l*01;TCRp V23 subfamily comprising TCRP V23-l*01;TCRp V24 subfamily comprising TCRP V24-l*01;TCRp V25 subfamily comprising TCRP V25-l*01;TCRp V26 subfamily comprising TCRP V26-l*01;TCRp V27 subfamily comprising TCRP V27*01;TCRp V28 subfamily comprising TCRP V28*01;TCRp V29 subfamily comprising one or more selected from TCRP V29-1*01, TCRP V29-l*02, and TCRP V29-l*03; and TCRP V30 subfamily comprising one or more selected from TCRP V30*01, TCRP V30*02, TCRP V30*03, TCRP V30*04, and TCRP V30*05.

[0090] In some embodiments, the second domain binds to TCRP V4 subfamily, TCRP V6 subfamily, TCRP V20 subfamily, or TCRP V25 subfamily.

[0091] In some embodiments, the second domain binds to TCRB V4-1, TCRB V6-1, TCRB V6-2, TCRB V6-3, TCRB V6-4, TCRB V6-5, TCRB V6-6, TCRB V6-7, TCRB V6-8, TCRB V6-9, TCRB V20-I, or TCRB V25-1.

[0092] In some embodiments, the multifunctional molecule comprises a single TCRpV-binding domain.

[0093] In some embodiments, the first domain binds to one or more of a TCRaV subfamily selected from the group consisting of: a TCRaVl subfamily, a TCRa V2 subfamily, a TCRa V3 subfamily, a TCRa V4 subfamily, a TCRa V5 subfamily, a TCRa V6 subfamily, a TCRa V7 subfamily, a TCRa V8 subfamily, a TCRa V9 subfamily, a TCRa V10 subfamily, a TCRa V12 subfamily, a TCRa V13 subfamily, a TCRa V14 subfamily, a TCRa V16 subfamily, a TCRa V17 subfamily, a TCRa V18 subfamily, a TCRa V19 subfamily, a TCRa V20 subfamily, a TCRa V21 subfamily, a TCRa V22 subfamily, a TCRa V23 subfamily, a TCRa V24 subfamily, TCRa V25 subfamily, a TCRa V26 subfamily, a TCRa V27 subfamily, a TCRa V29 subfamily, a TCRa V30 subfamily, a TCRa V34 subfamily, a TCRa V35 subfamily, a TCRa V36 subfamily, a TCRa V38 subfamily, a TCRa V39 subfamily, a TCRa V40 subfamily, and a TCRa V41 subfamily.

[0094] In some embodiments, the first domain binds to one or more of a TCRaV subfamily selected from the group consisting of: TCRaVl subfamily comprising one or more selected from TCRa Vl-l*01, TCRa Vl-l*02, TCRa Vl-2*01, and TCRa Vl-2*02;TCRa V2 subfamily comprising one or more selected from TCRa V2*01 and TCRa V2*02;TCRa V3 subfamily comprising TCRa V3*01;TCRa V4 subfamily comprising TCRa V4*01;TCRa V5 subfamily comprising TCRa V5*01TCRa V6 subfamily comprising one or more selected from TCRa V6*01, TCRa V6*02, TCRa V6*03, TCRa V6*04, TCRa V6*05, and TCRa V6*06;TCRa V7 subfamily comprising TCRa V7*01;TCRa V8 subfamily comprising one or more selected from TCRa V8-l*01, TCRa V8-l*02, TCRa V8-2*01, TCRa V8-2*02, TCRa V8-3*01, TCRa V8-3*02, TCRa V8-3*03, TCRa V8-4*01, TCRa V8-4*02, TCRa V8-4*03, TCRa V8-4*04, TCRa V8-4*05, TCRa V8-4*06, TCRa V8-4*07, TCRa V8-6*01, TCRa V8-6*02, and TCRa V8-7*01; TCRaV9 subfamily comprising one ormore selected from TCRaV9-l*01, TCRa V9-2*01, TCRa V9-2*02, TCRa V9-2*03, and TCRa V9-2*04; TCRa V10 subfamily comprising TCRa V10*01;TCRa V12 subfamily comprising one or more selected from TCRa V12-l*01, TCRa V12-l*02, TCRa V12-2*01, TCRa V12-2*02, TCRa V12-2*03, TCRa V12-3*01, and TCRa V12-3*02;TCRaV13 subfamily comprising one ormore selected from TCRa V13-l*01, TCRa V13-l*02, TCRa V13-1*03, TCRa V13-2*01, and TCRa V13-2*02;TCRa V14 subfamily comprising one ormore selected from TCRa V14*01, TCRa V14*02, TCRa V14*03, and TCRa V14*04;TCRa V16 subfamily comprising TCRa V16*01;TCRa V17 subfamily comprising TCRa V17*01;TCRa V18 subfamily comprising TCRa VI 8*01 ;TCRa V19 subfamily comprising TCRa V19*01TCRa V20 subfamily comprising one ormore selected from TCRa V20*01, TCRa V20*02, TCRa V20*03, and TCRa V20*04;TCRa V21 subfamily comprising one ormore selected from TCRa V21*01 and TCRa V20*02;TCRa V22 subfamily comprising TCRa V22*01;TCRa V23 subfamily comprising one or more selected from TCRa V23*01, TCRa V23*02, TCRa V23*03, and TCRa V23*04;TCRa V24 subfamily comprising one or more selected from TCRa V23*01 and TCRa V23*02;TCRa V25 subfamily comprising TCRa V25*01;TCRa V26 subfamily comprising one or more selected from TCRa V26-1*01, TCRa V26-l*02, TCRa V26-l*03, TCRa V26-2*01, and TCRa V26-2*02;TCRa V27 subfamily comprising one or more selected from TCRa V27*01, TCRa V27*02, and TCRa V27*03;TCRa V29 subfamily comprising one or more selected from TCRa V29*01 and TCRa V27*02;TCRa V30 subfamily comprising one or more selected from TCRa V30*01, TCRa V30*02, TCRa V30*03, and TCRa V30*04;TCRa V34 subfamily comprising TCRa V34*01;TCRa V35 subfamily comprising one or more selected from TCRa V35*01 and TCRa V35*02;TCRa V36 subfamily comprising one or more selected from TCRa V36*01, TCRa V36*02, TCRa V36*03, and TCRa V36*04;TCRa V38 subfamily comprising one ormore selected from TCRa V38-l*01, TCRa V38-l*02, TCRa V38-l*03, TCRa V38-1*04, and TCRa V38-2*01;TCRa V39 subfamily comprising TCRa V39*01;TCRa V40 subfamily comprising TCRa V40*01; and TCRa V41 subfamily comprising TCRa V41*01.

[0095] In some embodiments, the second domain binds to TCRa V12 subfamily, TCRa VI3 subfamily, TCRa V19 subfamily, TCRa V21 subfamily, or TCRa V30 subfamily.

[0096] In some embodiments, the second domain binds to TCRa VI subfamily, TCRa V10 subfamily, TCRa V17 subfamily, or TCRa VI9 subfamily.

[0097] In some embodiments, the second domain binds to TCRa Vl-2, TCRa V10, or TCRa V17.

[0098] In some embodiments, the first domain and the second domain bind to: TCRa VI and TCRp V6, respectively; TCRa VI and TCRp V20, respectively; TCRa V10 and TCRp V25, respectively; TCRa VI and TCRp V4, respectively; TCRa V17 and TCRp V4, respectively; or TCRa V17 and TCRp V6, respectively.

[0099] In some embodiments, the first domain and the second domain bind to: TCRa Vl-2 and TCRp V6-1, respectively; TCRa Vl-2 and TCRp V6-2, respectively; TCRa Vl-2 and TCRp V6-3, respectively; TCRa Vl-2 and TCRp V6-4, respectively; TCRa Vl-2 and TCRp V6-5, respectively; TCRa Vl-2 and TCRP V6-6, respectively; TCRa Vl-2 and TCRp V6-7, respectively; TCRa Vl-2 and TCRp V6-8, respectively; TCRa Vl-2 and TCRp V6-9, respectively; TCRa Vl-2 and TCRp V20-1, respectively; TCRa V10 and TCRp V25-1, respectively; TCRa Vl-2 and TCRp V4-1, respectively; TCRa V17 and TCRp V4-1, respectively; or TCRa V17 and TCRp V6-2, respectively.

[0100] In some embodiments, the first domain comprises an antibody molecule that binds to the TCRaV comprising (i) a VH comprising a combination of a HC CDR1, a HC CDR2 and a HC CDR3 listed in Table 22; (ii) a VL comprising a combination of a LC CDR1, a LC CDR2, and a LC CDR3 listed in Table 22; or (iii) a combination thereof.

[0101] In some embodiments, the first domain comprises an antibody molecule that binds to the TCRaV comprising (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 Table 22; (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 Table 22; or (iii) a combination thereof.

[0102] In some embodiments, the first domain comprises an antibody molecule that binds to the TCRaV comprising (i) a VH comprising a sequence having at least 70% sequence identity to any one of the heavy chain variable domain amino acid sequences listed in Table 22; (i) a VL comprising a sequence having at least 70% sequence identity to any one of the light chain variable domain amino acid sequences listed in Table 22; or (iii) a combination thereof.

[0103] In some embodiments, the first domain comprises an antibody molecule that binds to the TCRaV comprising (i) a VH comprising any one of the heavy chain variable domain amino acid sequences listed in Table 22; (ii) a VL comprising any one of the light chain variable domain amino acid sequences listed in Table 22; or (iii) a combination thereof.

[0104] In some embodiments, the first domain comprises any one of antibody molecules that binds to the TCRaV listed in Table 22.

[0105] In some embodiments, the second domain comprises an antibody molecule that binds to the TCRpV comprising (i) a VH comprising a combination of a HC CDR1, a HC CDR2 and a HC CDR3 listed in Tables 1,2, 10A,10B, IOC, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26; (ii)aVL comprising a combination of a LC CDR1, a LC CDR2, and a LC CDR3 listed in Tables 1, 2, 10A,10B, IOC, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26; or (iii) a combination thereof.

[0106] In some embodiments, the second domain comprises an antibody molecule that binds to the TCRpV comprising (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, 10A,10B, IOC, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26; (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, 10A, 10B, IOC, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26; or (iii) a combination thereof.

[0107] In some embodiments, the second domain comprises an antibody molecule that binds to the TCRpV comprising (i) a VH comprising a sequence having at least 70% sequence identity to any one of the heavy chain variable domain amino acid sequences listed in Tables 1, 2, 10A,10B, 10C, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26; (i) a VL comprising a sequence having at least 70% sequence identity to any one of the light chain variable domain amino acid sequences listed in Tables 1, 2, 10A,10B, 10C, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26; or (iii) a combination thereof.

[0108] In some embodiments, the second domain comprises an antibody molecule that binds to the TCRpV comprising (i) a VH comprising any one of the heavy chain variable domain amino acid sequences listed in Tables 1,2, 10A,10B, 10C, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26; (ii) a VL comprising any one of the light chain variable domain amino acid sequences listed in Tables 1, 2, 10A,10B, 10C, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26; or (iii) a combination thereof.

[0109] In some embodiments, the second domain comprises any one of antibody molecules that binds to the TCRPV listed in Tables 1,2, 10A,10B, 10C, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26.

[0110] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises one or more mutations listed in tables 4 and 14 according to EU numbering. [OlH] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises a sequence having at least 70% sequence identity to any one of the heavy chain constant region sequences listed in Tables 1, 2, 3, 10C, 11, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, or 26.

[0112] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises any one of the heavy chain constant region sequences listed in Tables 1, 2, 3, 10C, 11, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, or 26.

[0113] In some embodiments, the multifunctional molecule further comprises one or more immunoglobulin light chain constant regions.

[0114] In some embodiments, the one or more immunoglobulin light chain constant region is linked to the first domain, the first portion of the first domain, or the second portion of the first domain.

[0115] In some embodiments, the one or more immunoglobulin light chain constant region is linked to the second domain, the first portion of the second domain, or the second portion of the second domain.

[0116] In some embodiments, the one or more immunoglobulin light chain constant region is linked to the at least one cytokine or a functional fragment or variant thereof.

[0117] In some embodiments, the one or more immunoglobulin light chain constant region comprises a kappa light chain constant region, a lambda light chain constant region, or a combination thereof.

[0118] In some embodiments, the one or more immunoglobulin light chain constant region comprises a sequence having at least 70% sequence identity to any one of the light chain constant region sequences listed in Tables 1,2, 3, IOC, 11, 15, 16, 17, 18, 19, 20,21,22, 23,25, or 26.

[0119] In some embodiments, the one or more immunoglobulin light chain constant region comprises any one of the light chain constant region sequences listed in Tables 1, 2, 3, IOC, 11, 15, 16, 17, 18, 19, 20,21,22, 23, 25, or 26.

[0120] In some embodiments, the at least one cytokine or a functional fragment or variant thereof comprises a sequence having at least 70% sequence identity to any one of the cytokine sequences listed in Tables 10C, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, or 26.

[0121] In some embodiments, the at least one cytokine or a functional fragment or variant thereof comprises any one of the cytokine sequences listed in Tables 10C, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, or 26.

[0122] In some embodiments, the tumor-targeting moiety comprises a sequence having at least 70% sequence identity to any one of the antibody sequences listed in Table 24.

[0123] In some embodiments, the tumor-targeting moiety comprises any one of the antibody sequences listed in Table 24.

[0124] In some embodiments, the multifunctional molecule does not comprise an anti-CD3 binding domain.

[0125] In some embodiments, the multifunctional molecule is a polypeptide molecule.

[0126] In some embodiments, the multifunctional molecule is a multispecific molecule.

[0127] In another aspect, provided herein is a polynucleotide comprising a sequence encoding the multifunctional molecule as described herein.

[0128] In some embodiments, the polynucleotide is an isolated nucleic acid molecule.

[0129] In another aspect, provided herein is a vector comprising the polynucleotide as described herein.

[0130] In another aspect, provided herein is a cell comprising the multifunctional molecule as described herein, the polynucleotide as described herein, or the vector as described herein.

[0131] In another aspect, provided herein is a method of making the multifunctional molecule as described herein comprising: culturing a cell comprising the polynucleotide as described herein or the vector as described herein under conditions suitable for expression of the multifunctional molecule. Also provided herein is a method of making the multifunctional molecule as described herein comprising: culturing the cell as described herein under conditions suitable for expression of the multifunctional molecule.

[0132] In another aspect, provided herein is a composition comprising the multifunctional molecule as described herein.

[0133] In another aspect, provided herein is a pharmaceutical composition comprising the multifunctional molecule as described herein, the polynucleotide as described herein, the vector as described herein, the cell as described herein, or the composition as described herein, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0134] In another aspect, provided herein is a method of treating a condition or disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the multifunctional molecule as described herein, the polynucleotide as described herein, the vector as described herein, the cell as described herein, the composition as described herein, the pharmaceutical composition as described herein, or a combination thereof, wherein the administering is effective to treat the condition or disease in the subject.

[0135] In some embodiments, the condition or disease is cancer.

[0136] In some embodiments, the cancer is a solid tumor, a hematological cancer, a metastatic cancer, a soft tissue tumor, or a combination thereof.

[0137] In some embodiments, wherein the cancer is the solid tumor, and wherein the solid tumor is selected from the group consisting of melanoma, pancreatic cancer, breast cancer, colorectal cancer, lung cancer, skin cancer, ovarian cancer, liver cancer, and a combination thereof.

[0138] In some embodiments, 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.

[0139] In some embodiments, the Non-Hodgkin’s lymphoma is selected 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.

[0140] In some embodiments, the T-cell lymphoma is peripheral T-cell lymphoma.

[0141] In some embodiments, the cancer is characterized by a cancer antigen present on the cancer.

[0142] In some embodiments, the cancer antigen present on the cancer is a tumor antigen, a stromal antigen, or a hematological antigen.

[0143] In some embodiments, the cancer antigen is selected from the group consisting of CD 19, CD 123, 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 (GalNAca-Ser / Thr)), prostate-specific membrane antigen (PSMA), Receptor tyrosine kinase-like orphan receptor 1 (R0R1), 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-1 IRa), 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 (gplOO) / pmell7, oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abi) (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-la), Melanoma-associated antigen 1 (MAGE-A1), ETS translocationvariant 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 (NA 17), paired box protein Pax-3 (PAX3), Androgen receptor, Cyclin Bl, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), Ras Homolog Family Member C (RhoC), Tyrosinase-related protein 2 (TRP-2), Cytochrome P450 1B1 (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), lymphocytespecific 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 (RUI), 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-Bl, 9D7, Ep-CAM, EphA3, SAP-1, PRAME, Melan-A / MART-1, TRPl / gp75, MC1R, P-catenin, BRCA1 / 2, CDK4, CML66, Fibronectin, Ras, TGF-B receptor, TGF-P receptor, AFP, ETA, MAGE, CA-125, BAGE, GAGE, CDC27, a actinin-4, gangliosides, MART-2, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, 0A1, OGT, RCC, RUI 1, RU12, SAGE, TRG, TSTA, Ll-CAM, gpA33, GM2, VEGFR, Intergrins, carbohydrates, IGF1R, TRAILRI, TRAILR2, RANKL, TGF-beta, hyaluronic acid, collagen, tenascin C, tenascin W, and immunoglobulin lambda-like polypeptide 1 (IGLL1).

[0144] In some embodiments, the method as described herein further comprises administering a second therapeutic agent or therapy to the subject.

[0145] In some embodiments, the second therapeutic agent or therapy comprises a chemotherapeutic agent, a biologic agent, a hormonal therapy, radiation, or surgery.

[0146] In some embodiments, the second therapeutic agent or therapy is administered in combination with the multifunctional molecule as described herein, the polynucleotide as described herein, the vector as described herein, the cell as described herein, the composition as described herein, or the pharmaceutical composition as described herein, sequentially, simultaneously, or concurrently.

[0147] In another aspect, provided herein is a method of expansion of a subset of T cells in a T cell population comprising contacting the T cell population with the multifunctional molecule as described herein or the composition as described herein, thereby expanding the subset of T cells in the T cell population.

[0148] In some embodiments, the T cell population is a human T cell population.

[0149] In some embodiments, the subset of T cells are a subset of human T cells.

[0150] In some embodiments, the subset of T cells express a T cell receptor (TCR) comprising a TCR[3 chain that comprises the TCR[3V to which the second domain binds.

[0151] In some embodiments, the subset of T cells express a TCR comprising a TCRa chain that comprises the TCRaV to which the first domain binds.

[0152] In some embodiments, the TCR is a human TCR.

[0153] In some embodiments, the multispecific molecule is an agonist of the TCR.

[0154] In some embodiments, the T cell population is an in vivo T cell population.

[0155] In some embodiments, the T cell population is an ex vivo T cell population. INCORPORATION BY REFERENCE

[0156] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0157] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0158] FIGs. 1A-1T depict exemplary embodiments of the multifunctional molecules as described herein. In some embodiments, exemplary multifunctional molecules as described herein comprise a first domain as described herein and a second domain as described herein, and further comprises at least one cytokine or a functional fragment or variant thereof (e.g., IL2 or a functional fragment or variant thereof). FIGs. 1A, IB and IC depict exemplary embodiments of the multifunctional molecules as described herein containing multiple, e.g., two, molecules of a cytokine or a functional fragment or variant thereof (e.g., interleukin-2 (IL-2) or a functional fragment or variant thereof), linked to a first domain as described herein and a second domain as described herein. FIGs. ID, IE and IF depict exemplary embodiments of the multifunctional molecules as described herein containing a single molecule of a cytokine or a functional fragment or variant thereof (e.g.. interleukin-2 (IL-2) or a functional fragment or variant thereof) linked to a first domain as described herein or a second domain as described herein. FIGs. 1G, 1H, II, and 1J depict exemplary embodiments of the multifunctional molecules as described herein containing at least one molecule of a cytokine or a functional fragment or variant thereof (e.g.. interleukin-2 (IL-2) or a functional fragment or variant thereof) linked to the dimerization module. In some embodiments, the cytokine or a functional fragment or variant thereof is linked to a first portion of the dimerization module. In some embodiments, the cytokine or a functional fragment or variant thereof is linked to a second portion of the dimerization module. In some embodiments, the cytokine or a functional fragment or variant thereof is linked to a first portion of the dimerization module and a second portion of the dimerization module. FIGs. IK, IL and IM depict exemplary embodiments of the multifunctional molecules as described herein containing an exemplary dimerization module, e.g., an Fc region comprising a N297A mutation, and multiple, e.g., two, molecules of a cytokine or a functional fragment or variant thereof (e.g., interleukin-2 (IL-2) or a functional fragment or variant thereof) linked to a first domain as described herein and a second domain as described herein. FIGs. IN, IO and IP depict exemplary embodiments of the multifunctional molecules as described herein containing an exemplary dimerization module, e.g., an Fc region comprising aN297A mutation (Knob-in-hole), and a single molecule of a cytokine or a functional fragment or variant thereof (e.g., interleukin-2 (IL-2) or a functional fragment or variant thereof) linked to a first domain as described herein or a second domain as described herein. FIGs. IQ, 1R, IS and IT depict exemplary embodiments of the multifunctional molecules as described herein containing an exemplary dimerization module, e.g., an Fc region comprising a N297A mutation (Knob-in-hole), and a cytokine or a functional fragment or variant thereof (e.g., interleukin-2 (IL-2) or a functional fragment or variant thereof) linked to the exemplary dimerization module. In some embodiments, the cytokine or a functional fragment or variant thereof is linked to a first portion of the dimerization module. In some embodiments, the cytokine or a functional fragment or variant thereof is linked to a second portion of the dimerization module. In some embodiments, the cytokine or a functional fragment or variant thereof is linked to a first portion of the dimerization module and a second portion of the dimerization module. In some embodiments, a first domain as described herein binds to a T cell receptor alpha (TCRa) chain. In some embodiments, a second domain as described herein binds to a second domain that binds to a T cell receptor beta (TCRP) chain. In some embodiments, a first domain as described herein binds to a T cell receptor alpha (TCRa) chain, and a second domain as described herein binds to a second domain that binds to a T cell receptor beta (TCRP) chain. In some embodiments, a first domain as described herein binds to a T cell receptor beta (TCRP) chain. In some embodiments, a second domain as described herein binds to a second domain that binds to a T cell receptor alpha (TCRa) chain. In some embodiments, a first domain as described herein binds to a T cell receptor beta (TCRP) chain, and a second domain as described herein binds to a second domain that binds to a T cell receptor alpha (TCRa) chain. In some embodiments, the exemplary multifunctional molecules as described herein do not comprise at least one cytokine or a functional fragment or variant thereof.

[0159] FIGs. 2A-2B shows the alignment of the Antibody A source mouse VH and VL framework 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. 2A shows VH sequences for murine Antibody A (SEQ ID NO: 1) and humanized Antibody A-H (SEQ ID NO: 9). FIG. 2B shows VL sequences for murine Antibody A (SEQ ID NO: 2) and humanized Antibody A-H (SEQ ID NO: 10 and SEQ ID NO: 11).

[0160] FIGs. 3A-3B shows the alignment of the Antibody B source mouse VH and VL framework 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. 3A shows the VH sequence for murine Antibody B (SEQ ID NO: 15) and humanized VH sequences B-H.1A to B-H.1C (SEQ ID NOs: 23-25). FIG. 3B shows the VL sequence formurine Antibody B (SEQ ID NO: 16) and humanized VL sequences B-H.1D to B-H.1H (SEQ ID NOs: 26-30).

[0161] FIG. 4 depicts the phylogenetic tree of TCRBV gene family and subfamilies with corresponding antibodies mapped. Subfamily identities are as follows: Subfamily A: TCRP V6; Subfamily B: TCRP V10; Subfamily C: TCRP V12; Subfamily D: TCRP V5; Subfamily E: TCRP V7; Subfamily F: TCRP Vil; Subfamily G: TCRP V14; Subfamily H: TCRP V16; Subfamily LTCRp V18; Subfamily J:TCRp V9; Subfamily K: TCRP V13; Subfamily L: TCRP V4; Subfamily M:TCRp V3; Subfamily N:TCRp V2; Subfamily O:TCRp V15; Subfamily P: TCRP V30; Subfamily Q: TCRP V19; Subfamily R:TCRp V27; Subfamily S:TCRp V28; Subfamily T: TCRP V24; Subfamily U: TCRP V20; Subfamily V: TCRP V25; and Subfamily W:TCRP V29 subfamily. Subfamily members are described in detail herein in the Section titled “TCR beta V (TCRpV)”.

[0162] FIGs. 5A-5C show human CD3+ T cells activated by anti-TCR Vpi3.1 antibody (A-H. 1) for 6-days. Human CD3+ T cells were isolated using magnetic-bead separation (negative selection) and activated with immobilized (plate-coated) anti-TCR VP 13.1 (A-H.l) or anti-CD3e (OKT3) antibodies at 100 nM for 6 days. FIG. 5A shows two scatter plots (left: activated with OKT3; and right: activated with A-H.l) of expanded T cells assessed for TCR Vpi3.1 surface expression using anti-TCR Vpi3.1 (A-H.l) followed by a secondary fluorochrome- conjugated antibody for flow cytometry analysis. FIG. 5B shows percentage (%) of TCR VP 13.1 positive T cells activated by anti-TCR VP 13.1 (A-H. 1) or anti-CD3e (0KT3) plotted against total T cells (CD3+). FIG. 5C shows relative cell count acquired by counting the number of events in each T cell subset gate (CD3 or TCR VP 13.1) for 20 seconds at a constant rate of 60pl / min. Data shown as mean value from 3 donors.

[0163] FIGs. 6A-6B show cytolytic activity of human CD3+ T cells activated by anti-TCR Vpi3.1 antibody (A-H.l) against transformed cell line RPMI 8226. FIG. 6A depicts target cell lysis of human CD3+ T cells activated with A-H. lor 0KT3. Human CD3+ T cells were isolated using magnetic-bead separation (negative selection) and activated with immobilized (plate-coated) A-H. 1 or 0KT3 at the indicated concentrations for 4 days prior to co-culture with RPMI 8226 cells at a (E:T) ratio of 5:1 for 2 days. Samples were next analyzed for cell lysis of RPMI 8226 cells by FACS staining for CFSE / CD138-labeled, and membrane-impermeable DNA dyes (DRAQ7) using flow cytometry analysis. FIG. 6B shows target cell lysis of human CD3+ T cells activated with A-H.l or 0KT3 incubated with RPMI-8226 at a (E:T) ratio of 5:1 for 6 days followed by cell lysis analysis of RPMI 8226 cells as described above. Percentage (%) target cell lysis was determined by normalizing to basal target cell lysis (i.e., without antibody treatment) using the following formula, [(x - basal) / (100% - basal), where x is cell lysis of sample]. Data shown is a representative of n=l donor.

[0164] FIGs. 7A-7B show IFNy production by human PBMCs activated with the indicated antibodies. Human PBMCs were isolated from whole blood from the indicated number of donors, followed by solidphase (plate-coated) stimulation with the indicated antibodies at lOONm. Supernatant was collected on Days 1, 2, 3, 5, or 6. FIG. 7A is a graph comparing the production of IFNy in human PBMCs activated with the antibodies indicated activated with anti-TCR VP 13.1 antibodies (A-H. 1 or A-H.2) or anti-CD3e antibodies (OKT3 or SP34-2) on Day 1, 2, 3, 5, or 6 post-activation. FIG. 7B shows IFNy production in human PBMCs activated with the antibodies indicated activated with the indicated anti-TCR Vpi3.1 antibodies or anti-CD3e antibody (OKT3) on Day 1, 2, 3, 5, or 6 post-activation.

[0165] FIGs. 8A-8B show IL-2 production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described for FIGs. 7A-7B was used.

[0166] FIGs. 9A- 9B show IL-6 production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described for FIGs. 7A-7B was used.

[0167] FIGs. 10A-10Bshow TNF-alpha production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described for FIGs. 7A-7B was used.

[0168] FIGs. 11A-11Bshow IL-lbeta production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described for FIGs. 7A-7B was used.

[0169] FIGs. 12A-12B are graphs showing delayed kinetics of IFNy secretion in human PMBCs activated by anti-TCR VP 13.1 antibody A-H.l when compared to PBMCs activated by anti-CD3e antibody OKT3. FIG. 12A shows IFNy secretion data from 4 donors. FIG. 12B shows IFNy secretion data from 4 additional donors. Data shown is representative of n=8 donors.

[0170] FIG. 13 depicts increased CD8+ TSCM and Temra T cell subsets in human PBMCs activated by anti-TCR Vpi3.1 antibodies (A-H. 1 or A-H.2) compared to PBMCs activated by anti-CD3e antibodies (0KT3 or SP34-2).

[0171] FIGs. 14A-14F show characterization of an anti-TCRVb antibody. FIG. 14A is a graph depicting proliferation of T cells activated with anti-CD3 (0KT3) antibody or anti-TCRVb antibody. FIG. 14B shows selective expansion of CD45RA+ effector memory CD8+ and CD4+ T cells (TEMRA) cells with anti- TCRVb antibodies. Tn= naive T cell; Tscm= stem cell memory T cell; Tcm= central memory T cell; Tem=effector memory T cell; Temra=effector memory CD45RA+ T cell. FIG. 14C is a graph showing IFN-g secretion by PBMCs stimulated with an anti-TCRVb antibody, or anti-CD3 antibodies. FIG. 14D shows target cell lysis by T cells stimulated with an anti-TCRVb antibody, or anti-CD3 antibodies. Cells were stimulated for 4 days followed by 2 days incubation with multiple myeloma target cells for assessment of cell killing. FIG. 14E is a graph showing perforin secretion by T cells stimulated with an anti-TCRVb antibody, or an anti-CD3 antibody. Perforin was analyzed by FACS staining in TCRVB-positive and TCRVB-negative T cells in PBMCs after 5 days of stimulation with lOOng / ml plate-bound antibody. FIG. 14F is a graph showing Granzyme B by T cells stimulated with an anti-TCRVb antibody, or an anti-CD3 antibody. Granzyme B was analyzed by FACS staining in TCRVB-positive and TCRVB-negative T cells in PBMCs after 5 days of stimulation with lOOng / ml plate-bound antibody.

[0172] FIGs. 15A-15B show production of IL-2 and IL-15 and expansion of human NK cells by stimulation of PBMCs with anti-TCRVb antibody for 6 days at a dose of lOOnM. FIG. 15A shows secretion of IL-2 or IL-15 in T cells stimulated with an anti-TCRVb antibody, or anti-CD3 antibodies. FIG. 15B depicts flow cytometry dot plots showing NKp46 staining vs CD56 antibody staining in cells stimulated with an anti-TCRVb antibody or an anti-CD3 antibody or a control sample.

[0173] FIGs. 16A-16C show secretion of cytokines in PBMCs stimulated with an anti-TCRVb antibody, or anti-CD3 antibodies.

[0174] FIGs. 17A-17B show killing of MM cells by dual targeting BCMA-TCRvb antibody molecules. FIG. 17A shows in vitro killing by one of the following dual-targeting antibody molecules: BCMA-TCRVb (Molecule I), BCMA-CD3, or Control-TCRVb; or an isotype control. FIG. 17B shows in vivo killing of MM cells by a dual-targeting BCM-TCRVb antibody (Molecule I).

[0175] FIG. 18 shows lysis of MM target cells with a dual targeting antibody (Molecule E) which recognized FcRH5 on one arm and TCRVb on the other arm.

[0176] FIGs. 19A-19B demonstrate cytokine production from human PBMCs activated by anti-TCR Vp8a antibodies (B-H.l) when compared to those activated by anti-CD3e antibodies (OKT3 or SP34-2). FIG. 19A shows that human PBMCs activated by anti-TCR Vp8a antibodies (B-H. 1) produce similar or reduced levels of IFNy. FIG. 19B shows human PBMCs activated by anti-TCR Vp8a antibodies (B-H. 1) produce higher levels of IL-2 when compared to those activated by anti-CD3e antibodies (OKT3 or SP34-2). Data shown is representative of n = 6 donors.

[0177] FIGs. 20A-20C demonstrate cytokine production from human PBMCs activated by anti-TCR V[38a antibodies (B-H.l). Human PBMCs activated by anti-TCR Vp8a antibodies (B-H.l) do not significantly produce IL-6 (FIG. 20A), IL 1 p (FIG. 20B), and less TNFa (FIG. 20C), when compared to PBMCs activated by anti-CD3e antibodies (0KT3 or SP34-2). Data shown is representative of n = 6 donors.

[0178] FIGs. 21A-21E demonstrate cytokine production from human PBMCs activated by anti-TCRpV Antibody D antibody compared to control anti-CD3e antibody (0KT3). FIG. 21A shows that human PBMCs activated by anti-TCRpV Antibody D antibody produce similar or reduced levels of IFNy. FIG. 21B shows human PBMCs activated by anti-TCRpV Antibody D antibody produce higher levels of IL-2 when compared to those activated by anti-CD3e antibodies (0KT3). Human PBMCs activated by anti-TCRpV Antibody D antibody do not significantly produce IL-lbeta (FIG. 21C), IL-6, (FIG. 21D), or TNFalpha (FIG. 21E). Data shown is representative of n = 4 donors.

[0179] FIGs. 22A-22B demonstrate cytokine production from human PBMCs activated by anti-TCR Vp5 antibody (Antibody E). FIG. 22A shows that human PBMCs activated by anti-TCR Vp5 antibody produce similar or reduced levels of IFNy compared to PBMCS activated by anti-CD3e antibodies (0KT3 or SP34-2). FIG. 22B shows human PBMCs activated by the anti- TCR Vp5 1 antibody produce higher levels of IL-2 when compared to those activated by anti-CD3e antibodies (0KT3 or SP34-2). Data shown is representative of n = 4 donors.

[0180] FIGs. 23A-23D demonstrate cytokine production from human PBMCs activated by an anti-TCR V[35 antibody (Antibody E). Human PBMCs activated by anti-TCR Vp5 antibody do not significantly produce IL-lbeta (FIG. 23A), IL-6, (FIG. 23B), TNFalpha (FIG. 23C), or IL-10 (FIG. 23D) as compared to PBMCs activated by anti-CD3e antibodies (0KT3 or SP34-2). Data shown is representative of n = 4 donors.

[0181] FIGs. 24A-24F demonstrate cytokine production from human PBMCs activated by a dual targeting (bispecific molecule) comprising an anti-TCRpV binding moiety and a BCMA binding moiety. FIG. 24A shows that human PBMCs activated by the bispecific molecule produce similar or reduced levels of IFNy as PBMCS activated by anti-CD3e antibodies (0KT3). FIG. 24B shows human PBMCs activated by the bispecific molecule produce higher levels of IL-2 when compared to PBMCs activated by anti-CD3e antibodies (0KT3). Human PBMCs activated by the bispecific molecule do not significantly produce IL-lbeta (FIG. 24C), IL-6, (FIG. 24D), TNFalpha (FIG. 24E), or IL-10 (FIG. 24F). Data shown is representative of n = 3 donors.

[0182] FIGs. 25A-25B show the structure and sequence of eight TCRpV proteins from seven different subfamilies: TCRPV6 subfamily (TCRPV6-5 and TCRPV6-4 are shown), TCRPV28 subfamily, TCRPV19 subfamily, TCRPV9 subfamily, TCRPV5 subfamily, TCRPV20 subfamily and TCRPV12 subfamily. FIG. 25A shows the structural alignment of the different TCRpV proteins. The circled area represents the outward facing region comprising the proposed binding site for the anti-TCR[3V antibodies as described herein. FIG. 25B shows the amino acid sequence alignment of the proteins shown in FIG. 25A (SEQ ID NOS 3449-3456, respectively, in order of appearance). The various TCRpV proteins (from 7 different TCRpV subfamilies) have diverse sequences but share a conserved (similar) structure and function.

[0183] FIGs. 26A-26J show cytokine or chemokine secretion of PBMCs activated with anti-TCRVb antibodies (A-H.l, B-H.l), a bispecific molecule comprising an anti-TCRVb antibody (Molecule H), control isotype (122) or anti-CD3e antibody (0KT3). Data shown is representative of n = 2 donors and representative of 2 independent experiments. FIG. 26A shows when plate-bound anti-TCR VP antibodies or anti-CD3e antibodies (0KT3) were used to activate human PBMCs, the T cell cytokine IFNg was induced. With respect to IL-2 production, PBMCs activated with anti-TCR VP antibodies resulted in increased IL-2 production with delayed kinetics (FIG. 26B) as compared to PBMCs activated with anti-CD3e antibody (0KT3). While IL-lbeta (FIG. 26C), IL-6 (FIG. 26D), IL-10 (FIG. 26E), IL-4 (FIG. 26F), TNFalpha (FIG. 26G), and IL-12p70 (FIG. 26H) were induced by anti-CD3e antibody (0KT3), no or little induction of these cytokines or chemokines was observed with PBMCs activated with anti-TCRVb antibodies. PBMCs activated with anti-TCR VP antibodies demonstrated induction of IL-13 (FIG. 261) and IL-8 (FIG. 26J).

[0184] FIGs. 27A-27H show cytokine or chemokine secretion of PBMCs activated with anti-TCRVb antibodies (A-H.l, B-H.l), a bispecific molecule comprising an anti-TCRVb antibody (Molecule H), control isotype (122) or anti-CD3e antibody (0KT3). Data shown is representative of n = 2 donors and representative of 2 independent experiments. PBMCs activated with anti-TCR VP antibodies demonstrated induction of Eotaxin (FIG. 27A), Eotaxin 3 (FIG. 27B), IL-8 or IL-18 (FIG. 27C), MCP-1 (FIG. 27E), MCP-4 (FIG. 27F), MDC (FIG. 27G), and MIPla (FIG. 27H). While IP-10 (FIG. 27D) were induced by anti-CD3e antibody (0KT3), no or little induction of these cytokines or chemokines was observed with PBMCs activated with anti-TCRVb antibodies.

[0185] FIGs. 28A-28L show cytokine or chemokine secretion of PBMCs activated with anti-TCRVb antibodies (A-H.l, B-H.l), a bispecific molecule comprising an anti-TCRVb antibody (Molecule H), control isotype (122) or anti-CD3e antibody (0KT3). Data shown is representative of n = 2 donors and representative of 2 independent experiments. PBMCs activated with anti-TCR VP antibodies demonstrated induction of MIP1B (FIG. 28A), TARC (FIG. 28B), GM-CSF (FIG. 28C), IL-15 (FIG. 28E), IL-16 (FIG. 28F), and IL-15 (FIG. 281), and IL-7 (FIG. 28J). While IL-12-23p40 (FIG. 28D), IL-17A (FIG. 28G), and IL-la (FIG. 28H), were induced by anti-CD3e antibody (0KT3), no or little induction of these cytokines or chemokines was observed with PBMCs activated with anti-TCRVb antibodies.

[0186] FIG. 29 is a graph depicting mean tumor volume in NOD / SCID / IL-2Rynull (NSG) mice engrafted with Raji-luc cells at days 10 to 28. The Star denotes PBMC implantation. Open triangles denote antibody treatment with the indicated antibodies.

[0187] FIGs. 30A-30F are graphs showing cytokine secretion stimulated by anti-TRBCl (Antibody F) or anti-CD3 (0KT3) at Days 2 and 5. Cytokines examined include: IFNy (FIG. 30A), IL-2 (FIG. 30B), IL-ip (FIG. 30C), IL-6 (FIG. 30D), IL-10 (FIG. 30E), and TNFa (FIG. 31F).

[0188] FIG. 31 is a FACS plot showing the expansion of TCRvb 6-5+ T cells over 8 days using anti-TCRvb 6-5 vl.

[0189] FIG. 32 is a bar graph showing the expansion of TCRvb 6-5+ CD4+ T cells and TCRvb 6-5+ CD8+ T cells over 8 days using the anti-CD3a antibody OKT3 (lOOnM).

[0190] FIG. 33 is a bar graph showing the expansion of TCRvb 6-5+ CD4+ T cells and TCRvb 6-5+ CD8+ T cells over 8 days using the anti-TCRvb 6-5 vl antibody (lOOnM).

[0191] FIG. 34 is a FACS plot showing the showing the expansion of TCRvb 6-5+ T cells over 8 days using anti-TCRvb 6-5 vl or the anti-CD3s antibody OKT3.

[0192] FIG. 35A is a bar graph showing the percentage of TCR[3V 6-5+ T cells in PBMC cultures after 8 days of culture with the indicated antibody. Data for 5 replicates are shown. FIG. 35B is a bar graph showing the percentage of TCRpV 6-5+ T cells in purified T cell cultures after 8 days of culture with the indicated antibody. Data for 5 replicates are shown.

[0193] FIG. 36A is a bar graph showing the relative count of TCRpV 6-5+ T cells in PBMC culture after 8 days of culture with the indicated antibody. FIG. 36B is a bar graph showing the relative count of TCRpV 6-5+ T cells in PBMC culture after 8 days of culture with the indicated antibody.

[0194] FIG. 37A is a bar graph showing the relative count of TCRpV 6-5+ T cells in a purified T cell culture after 8 days of culture with the indicated antibody. FIG. 37B is a bar graph showing the relative count of TCRPV 6-5+ T cells in a purified T cell culture after 8 days of culture with the indicated antibody.

[0195] FIG. 38 is a line graph showing the total CD3+ T cell count (fold increase) after 8 days of T cell culture with either the anti-CD3s antibody OKT3 or the anti-TCRvb 6-5 vl antibody.

[0196] FIG. 39 is a series of line graphs showing the kinetics of target cells by TCRpV 6-5 vl activated T cells or anti-CD3a (OKT3) activated T cells. T cells from three different donors were utilized (donor 6769, donor 9880, donor 5411).

[0197] FIG. 40A is a scatter plot showing the percent of target cell lysis by T cells by TCRpV 6-5 vl activated T cells or anti-CD3s (OKT3) activated T cells without T cell pre activation. The data is presented at day 6 of co-culture between target cells and effector T cells. FIG. 40B is a scatter plot showing the percent of target cell lysis by T cells by TCRpV 6-5 vl activated T cells or anti-CD3s (OKT3) activated T cells with 4 days of T cell pre activation. The data is presented at day 2 of co-culture between target cells and effector T cells (after 4 days of T cell pre-activation).

[0198] FIG. 41 is a scatter plot showing the percent of target cell lysis by T cells by TCRpV 6-5 vl activated T cells or anti-CD3s (OKT3) activated T cells with 4 days of T cell pre activation. The data is presented at day 2 of co-culture between target cells and effector T cells (after 4 days of T cell preactivation).

[0199] FIG. 42 is a bar graph showing target cell lysis by T cells by TCRJ3V 6-5 vl activated T cells or anti-CD3a (OKT3) activated T cells (lOOnM each antibody). The data includes seven replicates of each experimental condition.

[0200] FIG. 43 is a series of FACS plots that show the cell surface expression of CD3s on CD4+ TCRJ3V 6-5' or CD4+ TCRpV 6-5+ T cells activated with either SP34-2 (anti-CD3a antibody) or anti-TCRpV 6-5 vl (anti- TCRpV 6-5 antibody) at days 0, 1,2, 4, 6, or 8 post antibody activation.

[0201] FIG. 44 is a series of FACS plots that show the cell surface expression of CD3a on CD8+ TCRpV 6-5' or CD8+ TCRpV 6-5+ T cells activated with either SP34-2 (anti-CD3a antibody) or anti-TCRpV 6-5 vl (anti- TCRpV 6-5 antibody) at days 0, 1,2, 4, 6, or 8 post antibody activation.

[0202] FIG. 45 is a series of FACS plots that show the cell surface expression of TCRpV on CD4+ TCRpV 6-5' or CD4+ TCRpV 6-5+ T cells activated with either SP34-2 (anti-CD3a antibody) or anti-TCRpV 6-5 vl (anti- TCRpV 6-5 antibody) at days 0, 1,2, 4, 6, or 8 post antibody activation.

[0203] FIG. 46 is a series of FACS plots that show the cell surface expression of TCRpV on CD8+ TCRpV 6-5' or CD8+ TCRpV 6-5+ T cells activated with either SP34-2 (anti-CD3a antibody) or anti-TCRpV 6-5 vl (anti- TCRpV 6-5 antibody) at days 0, 1,2, 4, 6, or 8 post antibody activation.

[0204] FIG. 47A shows FACS plot of TCRpV 6-5+ cynomolgus T cell expansion either unstimulated (left) or stimulated with anti-TCRpV 6-5 vl (right) 7 days post activation of cynomolgus PBMCs. PBMCs from Donor DW8N (fresh PBMC sample, male, age 8, weight 7.9 kgs) were used. FIG. 47B shows FACS plot of TCRPV 6-5+ cynomolgus T cell expansion either unstimulated (left) or stimulated with anti-TCRpV 6-5 vl (right) 7 days post activation of cynomolgus PBMCs. PBMCs from Donor G709 (cryopreserved sample, male, age 6, weight 4.7 kgs) were used.

[0205] FIG. 48 shows FACS plot and corresponding microscopy images of TCRpV 6-5+ cynomolgus T cell expansion either unstimulated (left), stimulated with SP34-2 (anti-CD3a antibody) (middle); or stimulated with anti-TCRpV 6-5 vl (right) post activation of cryopreserved donor DW8N cynomolgus PBMCs. The microscopy images show the cell cluster formation (indicated by circles).

[0206] FIG. 49 shows a schematic of FACS plot showing the FACS gating / staining of PBMCs prior y5 T cell purification.

[0207] FIG. 50 shows a schematic of FACS plot showing the FACS gating / staining of purified y5 T cell population.

[0208] FIG. 51 show activation of purified y5 T cell population with anti-CD3s antibody (SP34-2) (left) or anti-TCRpV antibody (anti-TCRpV 6-5 vl) (right).

[0209] FIG. 52A shows the release of IFNy from purified y5 T cell populations activated with anti-CD3a antibody (SP34-2), anti-TCRpV antibody (anti-TCRpV 6-5 vl), or unstimulated. FIG. 52B shows the release of TNFa from purified y5 T cell populations activated with anti-CD3s antibody (SP34-2), anti-TCRpV antibody (anti-TCRpV 6-5 vl), or unstimulated. FIG. 52C shows the release of IL-2 from purified y5 T cell populations activated with anti-CD3s antibody (SP34-2), anti-TCRpV antibody (anti-TCRpV 6-5 vl), or unstimulated. FIG. 52D shows the release of IL-17A from purified y5 T cell populations activated with anti-CD3a antibody (SP34-2), anti-TCRpV antibody (anti-TCRpV 6-5 vl), or unstimulated. FIG. 52E shows the release of IL-la from purified y5 T cell populations activated with anti-CD3a antibody (SP34-2), anti-TCRpV antibody (anti-TCRpV 6-5 vl), or unstimulated. FIG. 52F shows the release of IL-ip from purified y5 T cell populations activated with anti-CD3s antibody (SP34- 2), anti-TCRpV antibody (anti-TCRpV 6-5 vl), or unstimulated. FIG. 52G shows the release of IL-6 from purified y5 T cell populations activated with anti-CD3s antibody (SP34-2), anti-TCRpV antibody (anti-TCRpV 6-5 vl), or unstimulated. FIG. 52H shows the release of IL-10 from purified y5 T cell populations activated with anti-CD3e antibody (SP34-2), anti-TCRpV antibody (anti-TCRpV 6-5 vl), or unstimulated.

[0210] FIG. 53 shows the relative representations of all TCR alpha V segments (TRAV group of genes) and their variants (top), all TCR beta V segment 6-5 variants (TRBV6-5 gene) (bottom left), and all TCR beta V segments and variants excluding 6-5 (bottom right).

[0211] FIG. 54A is a FACS plot showing phenotypic markers of CD4+ T cells expanded with anti-TCRpV antibody (anti-TCRpV 6-5 vl). Defined phenotypes include TEMRA (top left), Naive / TSCM (top right), TEM (bottom left), and TCM (bottom right). FIG. 54B is a FACS plot showing phenotypic markers of CD4+ T cells expanded with anti-CD3e antibody (0KT3). Defined phenotypes include TEMRA (top left), Naive / TSCM (top right), TEM (bottom left), and TCM (bottom right).

[0212] FIG. 55A is a FACS plot showing phenotypic markers of CD8+ T cells expanded with anti-TCRJ3V antibody (anti-TCRpV 6-5 vl). Defined phenotypes include TEMRA (top left), Naive / TSCM (top right), TEM (bottom left), and TCM (bottom right). FIG. 55B is a FACS plot showing phenotypic markers of CD8+ T cells expanded with anti-CD3e antibody (0KT3). Defined phenotypes include TEMRA (top left), Naive / TSCM (top right), TEM (bottom left), and TCM (bottom right).

[0213] FIG. 56A is a bar graph showing the percentage of PD1 expressing CD4+ T cells from T cell cultures activated with anti-TCRpV antibody (anti-TCRpV 6-5 vl), anti-CD3s antibody (0KT3), or unstimulated. FIG. 56B is a bar graph showing the percentage of PD1 expressing CD8+ T cells from T cell cultures activated with anti-TCRpV antibody (anti-TCRpV 6-5 vl), anti-CD3s antibody (0KT3), or unstimulated.

[0214] FIG. 57A is a bar graph showing the expression of Ki-67 by CD4+ T cells from T cell cultures activated with anti-TCRpV antibody (anti-TCRpV 6-5 vl), anti-CD3s antibody (0KT3), or unstimulated. FIG. 57B is a bar graph showing the expression of Ki-67 by CD8+ T cells from T cell cultures activated with anti-TCRpV antibody (anti-TCRpV 6-5 vl), anti-CD3s antibody (0KT3), or unstimulated.

[0215] FIG. 58A is a FACS plot showing the percentage of TEMRA-like CD8+ T cells activated using anti-TCRpV antibody (anti-TCRpV 6-5 vl) that express CD57 (18.7%). FIG. 58B is a FACS plot showing the percentage of TEM-like CD8+ T cells activated using anti-CD3e antibody (0KT3) that express CD57 (46.8%) and the percentage of TCM-like CD8+ T cells activated using anti-CD3s antibody (0KT3) that express CD57 (18.9%).

[0216] FIG. 59 shows a series of FACS plots showing the expression of expression of CD27 and by CD4+ (top) or CD8+ (bottom) T cells from T cell cultures activated with anti-TCRpV antibody (anti-TCRpV 6-5 vl), anti-CD3s antibody (0KT3), or unstimulated.

[0217] FIG. 60 shows a series of FACS plots showing the expression of expression of OX40, 4 IBB, and ICOS by CD4+ (top) or CD8+ (bottom) T cells from T cell cultures activated with anti-TCRpV antibody (anti-TCRpV 6-5 vl), anti-CD3s antibody (0KT3), or unstimulated.

[0218] FIG. 61 shows a series of FACS plots showing the percentage of CD3+ (CD4 gated) TCRpV 65+ T cells 1, 2, 3, 4, 5, 6, and 8 days port activation with BCMA and the anti-TCR VP antibody anti-TCR VP 6-5 vl.

[0219] FIG. 62A shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgGl N297A), anti-TCRpV (anti-TCR VP 6-5 vl), or anti-CD3a (0KT3) antibodies on day 0 post activation. FIG. 62B shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgGl N297A), anti-TCRpV (anti-TCR VP 6-5 vl), or anti-CD3s (0KT3) antibodies on day 1 post activation. FIG. 62C shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgGl N297A), anti-TCRpV (anti-TCR VP 6-5 vl), or anti-CD3a (0KT3) antibodies on day 2 post activation. FIG. 62D shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgGl N297A), anti-TCRpV (anti-TCR VP 6-5 vl), or anti-CD3a (0KT3) antibodies on day 3 post activation. FIG. 62E shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgGl N297A), anti-TCRpV (anti-TCR VP 6-5 vl), or anti-CD3a (0KT3) antibodies on day 4 post activation. FIG. 62F shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgGl N297A), anti-TCRpV (anti-TCR VP 6-5 vl), or anti-CD3s (0KT3) antibodies on day 5 post activation. FIG. 62G shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgGl N297A), anti-TCRpV (anti-TCR VP 6-5 vl), or anti-CD3a (0KT3) antibodies on day 6 post activation. FIG. 62H shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgGl N297A), anti-TCRpV (anti-TCR VP 6-5 vl), or anti-CD3a (0KT3) antibodies on day 8 post activation.

[0220] FIG. 63A is a bar graph showing ATP production from glycolysis of T cell cultures activated with the indicated antibodies. FIG. 63B is a bar graph showing ATP production from oxidative phosphorylation of T cell cultures activated with the indicated antibodies.

[0221] FIG. 64 is a line graph showing the oxygen consumption rate (OCR) of T cells from about 0 to 75 minutes activated with the indicated antibody.

[0222] FIG. 65A shows the oxygen consumption rate (OCR) of T cells activated with the indicated antibody during basal respiration. FIG. 65B shows the oxygen consumption rate (OCR) of T cells activated with the indicated antibody during maximal respiration. FIG. 65C shows the oxygen consumption rate (OCR) of T cells activated with the indicated antibody during spare respiratory capacity. FIG. 65D is a line graph indicates the areas of basal respiration and maximal respiration as shown in FIG. 64A and FIG. 64B, respectively.

[0223] FIG. 66A is a bar graph showing ATP production from glycolysis of T cell cultures activated with anti-TCR[3V 6-5 vl and re-stimulated with the indicated antibody. FIG. 66B is a bar graph showing ATP production from oxidative phosphorylation of T cell cultures activated with anti-TCRpV 6-5 vl and re-stimulated with the indicated antibody.

[0224] FIGs. 67A-67G are graphs showing expression of IFNy (FIG. 67A), TNFa (FIG. 67E), IL-la (FIG. 67B), IL-ip (FIG. 67C), IL-6 (CRS and neurotoxicity associated cytokines) (FIG. 67D) with BHM1710 (anti TCRVB), a reduced affinity anti CD3 antibody (TB) and the SP34 anti CD3e antibody. IL-10 (FIG. 67F), IL-17A (FIG. 67G).

[0225] FIG. 68 is a FACS plot showing the percentage of NK cells expanded from T cell cultures activated with the indicated antibody.

[0226] FIG. 69 is a bar graph showing the number of NK cells expanded from T cell cultures activated with the indicated antibody.

[0227] FIG. 70 shows a series of FACS plots showing NK cell proliferation induced by T cell cultures activated with the indicated antibody.

[0228] FIG. 71 is a schematic showing an assay described in Example for determining NK cell mediated lysis of target K562 cells.

[0229] FIG. 72 is a bar graph showing the percent target cell lysis mediated by NK cells activated by PBMCs activated with the indicated antibody.

[0230] FIG. 73 shows a series of FACS plots showing the proliferation of NK cells from PBMC cultures activated / expanded with the indicated antibody (isotype control or 0KT3). PBMCs from three donors (DI, D2, and D3) were analyzed.

[0231] FIG. 74 shows a series of FACS plots showing the proliferation of NK cells from PBMC cultures activated / expanded with the indicated antibody (anti-TCRvP 12-3 / 4 vl or anti-TCRvP 12-3 / 4 v2). PBMCs from three donors (DI, D2, and D3) were analyzed.

[0232] FIG. 75 shows a series of FACS plots showing the proliferation of NK cells from PBMC cultures activated / expanded with the indicated antibody (anti-TCRvP 12-3 / 4 v3 or SP34-2). PBMCs from three donors (DI, D2, and D3) were analyzed.

[0233] FIG. 76 is a bar graph showing the level of secreted IFNy by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, OKT3, or SP34) and cultured with said antibody for the indicated number of days (1, 3, or 5).

[0234] FIG. 77 is a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, 0KT3, or SP34) and cultured with said antibody for the indicated number of days (1, 3, or 5).

[0235] FIG. 78 is a bar graph showing the level of secreted IL-15 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, 0KT3, or SP34) and cultured with said antibody for the indicated number of days (1, 3, or 5).

[0236] FIG. 79 is a bar graph showing the level of secreted IL-1 p by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, 0KT3, or SP34) and cultured with said antibody for the indicated number of days (1, 3, or 5).

[0237] FIG. 80 is a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, 0KT3, or SP34) and cultured with said antibody for the indicated number of days (1, 3, or 5).

[0238] FIG. 81 is a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, OKT3, or SP34) and cultured with said antibody for the indicated number of days (1, 3, or 5).

[0239] FIG. 82 is a bar graph showing the level of the indicated cytokine secreted by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or SP34). The data includes use of 17 individual PBMC donors.

[0240] FIG. 83A is a bar graph showing the level of secreted IFNy by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or 0KT3) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 83B is a bar graph showing the level of secreted IL- ip by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or 0KT3) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 83C is a bar graph showing the level of secreted IL-4 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or 0KT3) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 83D is a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or 0KT3) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 83E is a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or 0KT3) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 83F is a bar graph showing the level of secreted TNFa by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or 0KT3) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 83G is a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or 0KT3) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6).

[0241] FIG. 84A is a bar graph showing the level of secreted IFNy by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, SP34-2, or isotype control) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 84B is a bar graph showing the level of secreted IL-1 p by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, SP34-2, or isotype control) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 84C is a bar graph showing the level of secreted IL-4 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, SP34-2, or isotype control) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 84D is a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, SP34-2, or isotype control) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 84E is a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, SP34-2, or isotype control) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 84F is a bar graph showing the level of secreted TNFa by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, OKT3, SP34-2, or isotype control) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 84G is a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, SP34-2, or isotype control) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6).

[0242] FIG. 85A is a bar graph showing the level of secreted IFNy by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 85B is a bar graph showing the level of secreted IL- ip by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 85C is a bar graph showing the level of secreted IL-4 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 85D is a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 85E is a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, OKT3, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 85F is a bar graph showing the level of secreted TNFa by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 85G is a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8).

[0243] FIG. 86A is a bar graph showing the level of secreted IL-17A by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (2, 5, or 7). FIG. 86B is a bar graph showing the level of secreted IL-17A by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (2, 5, or 8). FIG. 86C is a bar graph showing the level of secreted IL-17A by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, OKT3, or SP34-2) and cultured with said antibody for the indicated number of days (2, 5, or 7). FIG. 86D is a bar graph showing the level of secreted IL-17A by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or SP34-2) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7).

[0244] FIG. 87A is a bar graph showing the level of secreted IFNy by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87B is a bar graph showing the level of secreted IL-1 p by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87C is a bar graph showing the level of secreted IL-4 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87D is a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87E is a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87F is a bar graph showing the level of secreted TNFa by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87G is a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87H is a bar graph showing the level of secreted IL-12p70 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 871 is a bar graph showing the level of secreted IL-13 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87J is a bar graph showing the level of secreted IL-8 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87K is a bar graph showing the level of secreted exotaxin by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87L is a bar graph showing the level of secreted exotoxin-3 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87M is a bar graph showing the level of secreted IL-8 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87N is a bar graph showing the level of secreted IP-10 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 870 is a bar graph showing the level of secreted MCP-1 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87P is a bar graph showing the level of secreted MCP-4 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87Q is a bar graph showing the level of secreted MDC by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87R is a bar graph showing the level of secreted MIP-la by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87S is a bar graph showing the level of secreted MIP-lb by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87T is a bar graph showing the level of secreted TARC by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87U is a bar graph showing the level of secreted GMCSF by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87V is a bar graph showing the level of secreted IL-12-23p40 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87W is a bar graph showing the level of secreted IL-15 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87X is a bar graph showing the level of secreted IL-16 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87Y is a bar graph showing the level of secreted IL-17a by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87Z is a bar graph showing the level of secreted IL-la by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87AA is a bar graph showing the level of secreted IL-5 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87BB is a bar graph showing the level of secreted IL-7 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87CC is a bar graph showing the level of secreted TNF-B by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87DD is a bar graph showing the level of secreted VEGF by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8).

[0245] FIG. 88 shows a graphical representation of the relation of sequences between different TCRVB clonotype subfamilies.

[0246] FIG. 89A is a bar graph showing the percentage of cytokine release from PBMCs activated / expanded for eight days using the indicated antibody (anti-TCRpV 12-3 / 4 vl or SP34-2). FIG. 89B is a bar graph showing the percentage of cytokine release from PBMCs activated / expanded for eight days using the indicated antibody (anti-TCRpV 5 or SP34-2). FIG. 89C is a bar graph showing the percentage of cytokine release from PBMCs activated / expanded for eight days using the indicated antibody (anti-TCRpV 10 or SP34-2).

[0247] FIG. 90A a bar graph showing the level of secreted IFNy by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 90B a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 90C a bar graph showing the level of secreted IL-17A by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 90D a bar graph showing the level of secreted IL-la by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 90E a bar graph showing the level of secreted IL-ip by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 90F a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 90G a bar graph showing the level of secreted TNFa by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 90H a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6).

[0248] FIG. 91 is a bar graph summarizing data from FACS analysis of PBMCs activated / expanded for 6 days using the indicated anti-TCRVp antibody.

[0249] FIG. 92A a bar graph showing the level of secreted IFNy by T cells activated / expanded with the indicated antibody for the indicated number of days (1, 3, 5, or 7). FIG. 92B a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody for the indicated number of days (1, 3, 5, or 7). FIG. 92C a bar graph showing the level of secreted IL-17A by T cells activated / expanded with the indicated antibody for the indicated number of days (1, 3, 5, or 7). FIG. 92D a bar graph showing the level of secreted IL-la by T cells activated / expanded with the indicated antibody for the indicated number of days (1, 3, 5, or 7). FIG. 92E a bar graph showing the level of secreted IL-ip by T cells activated / expanded with the indicated antibody for the indicated number of days (1, 3, 5, or 7). FIG. 92F a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody for the indicated number of days (1, 3, 5, or 7). FIG. 92G a bar graph showing the level of secreted IL-4 by T cells activated / expanded with the indicated antibody for the indicated number of days (1, 3, 5, or 7). FIG. 92H a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody for the indicated number of days (1, 3, 5, or 7).

[0250] FIG. 93 is a bar graph summarizing data from FACS analysis of PBMCs activated / expanded for 7 days using the indicated anti-TCRVp antibody.

[0251] FIG. 94A is a bar graph showing the level of secreted IFNy by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 94B a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 94C a bar graph showing the level of secreted IL-17A by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 94D a bar graph showing the level of secreted IL-la by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 94E a bar graph showing the level of secreted IL- ip by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 94F a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 94G a bar graph showing the level of secreted IL-4 by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 94H a bar graph showing the level of secreted TNFa by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 941 a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6).

[0252] FIG. 95A is a bar graph showing the level of secreted IFN-y by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CTOs (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95B is a bar graph showing the level of secreted IFN-y by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 65 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95C is a bar graph showing the level of secreted IL-lb by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95D is a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95E is a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3a (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95F is a bar graph showing the level of secreted IL-15 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95G is a bar graph showing the level of secreted IL-17A by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3a (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95H is a bar graph showing the level of secreted IL-la by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 951 is a bar graph showing the level of secreted IL-lb by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 65 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95J is a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95K is a bar graph showing the level of secreted IL-4 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95L is a bar graph showing the level of secreted TNF-a by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3a (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7).

[0253] FIG. 96 is a FACS plot showing the showing the ability of MH3-2 to bind PBMCs from one of two donors when the PBMCs are either preincubated with TM23 or not (MH3-2 Alone).

[0254] FIG. 97 is a FACS plot showing the ability of MH3-2 to bind PBMCs from one of two donors when the PBMCs are either preincubated with TM23 or not (MH3-2 Alone).

[0255] FIG. 98A is a bar graph showing the polyfunctional strength index (PSI) of PBMC CD4+ T cells, CD4+ T cells expanded with anti-CD3 antibody, (CD3 Expanded T cells), and CD4+ T cells expanded with anti-TCRVP 6-5 antibody (Drug Expanded T cells). The Effector mediators are Granzyme B, IFNy, MIP-la, perforin, TNFa, and TNFp. The Stimulatory mediators are IL-5. The Chemoattractive mediators are MIP-lb. FIG. 98B is a bar graph showing the polyfunctional strength index (PSI) of PBMC CD8+ T cells, CD8+ T cells expanded with anti-CD3 antibody, (CD3 Expanded T cells), and CD8+ T cells expanded with anti-TCRVp 6-5 antibody (Drug Expanded T cells). The Effector mediators are Granzyme B, IFNy, MIP-la, perforin, and TNFp. The Chemoattractive mediators are MIP-lb and RANTES.

[0256] FIG. 99 is a schematic of the experimental design for the pharmacokinetic (PK) profde and dosing strategy of the multifunctional polypeptide molecule as described herein.

[0257] FIG. 100 shows Table 9, which depicts alignment of TCRBV amino acid sequences (SEQ ID NOS 3457-3516, 3669-3673, 3522, 3674-3675, 3525, 3676-3687, 3538, 3688-3698, 3550-3639 and 3699-3790, respectively, in order of appearance). The alignment of TCRBV amino acid sequences in Table 9 underscores the diversity of TCR sequences. In particular, the TRBV sequences from different subfamilies are considerably different from each other.

[0258] FIG. 101 shows alignment of affinity matured humanized Antibody A-H VL sequences (SEQ ID NOS: 3377-3389, respectively, in order of appearance).

[0259] FIG. 102 shows alignment of affinity matured humanized Antibody A-H VH sequences (SEQ ID NOS: 3390-3436, respectively, in order of appearance).

[0260] FIG. 103A shows an exemplary embodiment (e.g., BKM0186) of the multifunctional molecules as described herein comprising a first domain as described herein or a second domain as described herein and at least one cytokine or a functional fragment or variant thereof (e.g., IL2 or a functional fragment or variant thereof or IL2-C125A or a functional fragment or variant thereof) as described herein. FIG. 103B shows an exemplary embodiment of the multifunctional molecules as described herein comprising a first domain as described herein or a second domain as described herein and at least one cytokine or a functional fragment or variant thereof as described herein. FIGs. 103C, 103D, 103E, and 103F show exemplary embodiments of the multifunctional molecules as described herein comprising a first domain, a second domain, and two molecules of a cytokine or a functional fragment or variant thereof as described herein. In some embodiments, the cytokine or a functional fragment or variant thereof comprises IL-2 or a functional fragment or a functional variant thereof, IL2-C125A or a functional fragment or a functional variant thereof, IL-15 or a functional fragment or a functional variant thereof, IL-7 or a functional fragment or a functional variant thereof, IL-12 or a functional fragment or a functional variant thereof, or IL-21 or a functional fragment or a functional variant thereof. In embodiments, the cytokine polypeptide further comprises a cytokine receptor. In some embodiments, the cytokine polypeptide comprises IL-15 linked to a IL-15Ra. In some embodiments, the cytokine or a functional fragment or variant thereof as described herein comprises IL-15 or a functional fragment or variant thereof linked to a IL-15Ra sushi domain. In some embodiments, the cytokine or a functional fragment or variant thereof as described herein comprises a cytokine dimer. In some embodiments, the cytokine or a functional fragment or variant thereof as described herein comprises an IL-12 beta subunit or a functional fragment or variant thereof linked to an IL-12 alpha subunit or a functional fragment or variant thereof. In some embodiments, a first domain as described herein binds to a T cell receptor alpha (TCRa) chain. In some embodiments, a second domain as described herein binds to a second domain that binds to a T cell receptor beta (TCRP) chain. In some embodiments, a first domain as described herein binds to a T cell receptor alpha (TCRa) chain, and a second domain as described herein binds to a second domain that binds to a T cell receptor beta (TCRP) chain. In some embodiments, a first domain as described herein binds to a T cell receptor beta (TCRP) chain. In some embodiments, a second domain as described herein binds to a second domain that binds to a T cell receptor alpha (TCRa) chain. In some embodiments, a first domain as described herein binds to a T cell receptor beta (TCRP) chain, and a second domain as described herein binds to a second domain that binds to a T cell receptor alpha (TCRa) chain. In some embodiments, the exemplary multifunctional molecules as described herein do not comprise at least one cytokine or a functional fragment or variant thereof.

[0261] FIG. 104 shows FACS plots showing binding of BKM0186 to different immune cell populations in Human PBMCs.

[0262] FIG. 105 shows binding of BKM0186 to pure human T cells expressing either Vp6 or CD25 (IL-2Ra) or both.

[0263] FIG. 106 shows in vitro concentration-effect relationships for BKM0186-mediated in vitro expansion of Vp6 T cells and activated (CD25) Vp6 T cells from human PBMCs at day 5 as a % of total T-Cytotoxic (CD8) and T-helper (CD4) populations. Left graph: T-cytotoxic lymphocytes; right graph: T-helper lymphocytes.

[0264] FIG. 107 shows in vitro TCR sequencing. PBMCs were incubated with lOOnM of BKM0186 for 5 days and T cells were sequenced for TCR P chain V (TRBV) genes. Compared to unstimulated T cells (grey), BKM0186 selectively expanded T cells bearing TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-5, and TRBV10-3.

[0265] FIG. 108A and FIG. 108B show a series of graphs (FIG. 108A) and a series of FACS plots (FIG. 108B) exhibiting activation of CD4+ and CD8+ T cells as assessed by CD25 expression following stimulation with BKM0186, RSV-IL2 and Anti-TCRVp6 control in solution.

[0266] FIG. 109 shows a series of FACS plots demonstrating differentiation of memory T cells mediated by BKM0186 in comparison to unstimulated and the controls RSV-IL2 and anti-TCRVp6. Upper left quadrant represents Central memory (CM), lower left quadrant represents Effector memory (EM), upper right quadrant represents Naive (N) and lower right quadrant represents Effector memory RA (TEMRA).

[0267] FIG. 110 shows in vitro concentration-effect relationships for BKM0186-induced cytokine release from human PBMCs at day 4 using MSD V-plex human cytokine panel.

[0268] FIG. Ill shows BKM0186-mediated killing of human tumor organoids generated from primary, patient-derived tissue from colorectal and NSCLC cancer patients. Vertical bars represent percentage of organoid area reduced relative to isotype control following incubation of organoids with BKM0186 and autologous TILs.

[0269] FIG. 112 shows tumor growth curves of mBKMO 186-treated EMT6 tumor-bearing mice. Studies were performed in randomized mice with tumor volumes of 80-150 mm3. For all models except MC38, mice were dosed for 3 weeks with a weekly dosing of 0.5-1.5 mg / kg and survival was determined based on 2000 mm3 tumor volume end point.

[0270] FIG. 113 shows tumor growth curves of mBKMO 186-treated mice. Studies were performed in randomized mice with tumor volumes of 80-150 mm3. For all models except MC38, mice were dosed for 4 weeks with a weekly dosing of 1-1.5 mg / kg and survival was determined based on 2000 mm3 tumor volume end point. For MC38, mice were given first dose of 3 mg / kg followed by 1 mg / kg for subsequent three weekly (QW) doses.

[0271] FIG. 114 shows Kaplan-Meier survival curves of treated mice. Studies were performed in randomized mice with tumor volumes of 80-150 mm3. For all models except MC38, mice were dosed for 4 weeks with a weekly dosing of 1-1.5 mg / kg and survival was determined based on 2000 mm3 tumor volume end point. For MC38, mice were given first dose of 3 mg / kg followed by 1 mg / kg for subsequent three weekly (QW) doses.

[0272] FIG. 115 shows the experimental design for the tumor rechallenge study. Cured EMT6 tumor bearing mice were rechallenged with EMT6 tumor cells in one flank and CT26 tumor cells in another flank and monitored for tumor growth for 28 days.

[0273] FIG. 116 shows the results of the tumor rechallenge study. While the EMT6 tumors were rejected, CT26 tumors grew, suggesting that the memory response against EMT6 tumors likely mediated through mBKMO 186 treatment has been established.

[0274] FIG. 117 shows immune profiling of T cells in blood and tumor tissue on day 14 post dosing of mBKMO 186.

[0275] FIG. 118 shows tumor growth curves of EMT6 tumors after weekly (QW) treatment of mice bearing 150 mm3 tumors with 1 mg / kg of mBKM0186 with and without depletion of V[3-specific T cells. Filled Triangles indicate dosing intervals of the depleting antibodies and open Triangles indicate dosing intervals of mBKMO 186.

[0276] FIG. 119A and FIG. 119B show Pharmacokinetic profiles of BKM0186 (FIG. 119A) and BKM0281 (FIG. 119B) administered single dose IV in cynomolgus monkeys.

[0277] FIG. 120A shows T cell expansion following a single IV dose of BKM0186. FIG. 120B shows T cell expansion following a single IV dose BKM0281. n=3 Monkeys, n=l monkey vehicle control.

[0278] FIG. 121 shows serum soluble CD25 levels in monkeys administered a single IV dose of BKM0186. Mean values, n=2-3 monkeys per group.

[0279] FIG. 122A shows serum IL-6 levels in monkeys administered a single IV dose of BKM0186. FIG. 122B shows serum IL-6 levels in monkeys administered a single IV dose of BKM0281. Mean values, n=2-3 monkeys per group.

[0280] FIG. 123A shows serum IFN-y levels in monkeys administered a single IV dose of BKM0186. FIG. 123B shows IFN-y levels in monkeys administered a single IV dose of BKM0281. Mean values, n=2-3 monkeys per group. Mean values, n=2-3 monkeys per group.

[0281] FIG. 124 shows in vitro concentration-effect relationships for bispecific-mediated in vitro expansion of V[36 T cells.

[0282] FIGs. 125A and 125B show exemplary embodiments of the multifunctional molecules as described herein comprising a first domain as described herein or a second domain as described herein and at least one cytokine or a functional fragment or variant thereof (e.g., wild-type human IL2 or a functional fragment or variant thereof or IL15-IL15R sushi fusion or a functional fragment or variant thereof) as described herein. FIGs. 125C-125T show exemplary embodiments of the multifunctional molecules as described herein, e.g., the multifunctional molecules comprising a first domain as described herein, a second domain as described herein, and at least one cytokine or a functional fragment or variant thereof as described herein, or the multifunctional molecules comprising a tumor-associated antigen (TAA) binding moiety, a first domain as described herein and / or a second domain as described herein, and at least one cytokine or a functional fragment or variant thereof as described herein. In some embodiments, a tumor-associated antigen (TAA)-binding moiety, a first domain as described herein and / or a second domain as described herein are antibody, an antigen binding fragment thereof or an antibody fragment. In some embodiments, an antigen binding fragment or an antibody fragment comprises Fab, Fab', F(ab')2, F(ab)2, variable fragment (Fv), domain antibody (dAb), or single chain variable fragment (scFv). In some embodiments, the at least one cytokine or a functional fragment or variant thereof is selected from the group consisting of interleukin-2 (IL-2) or functional fragment or functional variant thereof, interleukin-7 (IL-7) or functional fragment or functional variant thereof, interleukin-12 (IL-12) or functional fragment or functional variant thereof, interleukin-15 (IL-15) or functional fragment or functional variant thereof, interleukin-18 (IL-18) or functional fragment or functional variant thereof, interleukin-21 (IL-21) or functional fragment or functional variant thereof, or interferon gamma or functional fragment or functional variant thereof, or any combination thereof. In some embodiments, exemplary embodiments of the multifunctional molecules as described herein, e.g., the multifunctional molecules comprising a first domain as described herein, a second domain as described herein, and at least one cytokine or a functional fragment or variant thereof as described herein, or the multifunctional molecules comprising a tumor-associated antigen (TAA) binding moiety, a first domain as described herein and / or a second domain as described herein, and at least one cytokine or a functional fragment or variant thereof as described herein comprises a dimerization module comprising an Fc region comprising N297A mutation. FIGs. 125C-125H show exemplary embodiments of the multifunctional molecules as described herein, e.g., the multifunctional molecules comprising a first domain as described herein, a second domain as described herein, and at least one cytokine or a functional fragment or variant thereof as described herein, or the multifunctional molecules comprising a tumor-associated antigen (TAA) binding moiety, a first domain as described herein and / or a second domain as described herein, and at least one cytokine or a functional fragment or variant thereof as described herein, wherein the multifunctional molecules comprise an exemplary dimerization module, e.g., an Fc region comprising Knob-in-hole mutations and disulfide bridges. FIGs. 125I-125N show exemplary embodiments of the multifunctional molecules as described herein, e.g., the multifunctional molecules comprising a first domain as described herein, a second domain as described herein, and at least one cytokine or a functional fragment or variant thereof as described herein, or the multifunctional molecules comprising a tumor-associated antigen (TAA) binding moiety, a first domain as described herein and / or a second domain as described herein, and at least one cytokine or a functional fragment or variant thereof as described herein, wherein the multifunctional molecules comprise an exemplary dimerization module, e.g., an Fc region comprising disulfide bridges, but not comprising Knob-in-hole mutations. FIGs. 125O-125T show exemplary embodiments of the multifunctional molecules as described herein, e.g., the multifunctional molecules comprising a first domain as described herein, a second domain as described herein, and at least one cytokine or a functional fragment or variant thereof as described herein, or the multifunctional molecules comprising a tumor-associated antigen (TAA) binding moiety, a first domain as described herein and / or a second domain as described herein, and at least one cytokine or a functional fragment or variant thereof as described herein, wherein the multifunctional molecules comprise an exemplary dimerization module, e.g., an Fc region not comprising disulfide bridges nor Knob-in-hole mutations. FIGs. 125C-125E, 125I-125K, and 125O-135Q show exemplary embodiments of the multifunctional molecules as described herein, e.g., the multifunctional molecules comprising a first domain as described herein, a second domain as described herein, and at least one cytokine or a functional fragment or variant thereof as described herein, or the multifunctional molecules comprising a tumor-associated antigen (TAA) binding moiety, a first domain as described herein and / or a second domain as described herein, and at least one cytokine or a functional fragment or variant thereof as described herein, wherein a second domain as described herein or a first domain as described herein comprises an scFv. FIGs. 125F-125H, 125L-125N, and 125R-135T show exemplary embodiments of the multifunctional molecules as described herein, e.g., the multifunctional molecules comprising a first domain as described herein, a second domain as described herein, and at least one cytokine or a functional fragment or variant thereof as described herein, or the multifunctional molecules comprising a tumor-associated antigen (TAA) binding moiety, a first domain as described herein and / or a second domain as described herein, and at least one cytokine or a functional fragment or variant thereof as described herein, wherein a second domain as described herein or a first domain as described herein comprises an Fab. In some embodiments, exemplary embodiments of the multifunctional molecules as described herein comprises an antibody molecule, an antigen binding domain thereof, or a functional fragment or variant that binds to DLL-3 as an a-TAA. In some embodiments, a first domain as described herein binds to a T cell receptor alpha (TCRa) chain. In some embodiments, a second domain as described herein binds to a second domain that binds to a T cell receptor beta (TCRP) chain. In some embodiments, a first domain as described herein binds to a T cell receptor alpha (TCRa) chain, and a second domain as described herein binds to a second domain that binds to a T cell receptor beta (TCRP) chain. In some embodiments, a first domain as described herein binds to a T cell receptor beta (TCRP) chain. In some embodiments, a second domain as described herein binds to a second domain that binds to a T cell receptor alpha (TCRa) chain. In some embodiments, a first domain as described herein binds to a T cell receptor beta (TCRP) chain, and a second domain as described herein binds to a second domain that binds to a T cell receptor alpha (TCRa) chain. In some embodiments, the exemplary multifunctional molecules as described herein do not comprise at least one cytokine or a functional fragment or variant thereof.

[0283] FIG. 126 depicts exemplary graphs showing the average abundance of each depicted TRAV gene relative to total TRAV gene based on sequencing analysis of samples obtained from 5 healthy individuals. TCR repertoire sequencing was performed from total RNA isolated from healthy human purified T-cells. The MiXCR pipeline was used for alignment of reads to TCR clonotypes / germlines. Each TRAV gene is plotted against relative abundance (where 1 equals 100% of total TRAV gene). The average relative abundance for each TRAV is shown with each individual donor shown as (•). n=5.

[0284] FIG. 127A depicts exemplary flow cytometry results showing expansion of T-cells after stimulation with an anti-TRAV 12-1 antibody. Purified human T-cells isolated from a healthy individual were stimulated for 5 days with plate-bound anti-TCR V alpha 12.1 antibody (6D6.6). The FACS plots show expanded T-cells stained with an AF647-labeled anti-TCR V alpha 12.1 antibody. Unstimulated T-cells were stained for baseline expression. Data from 1 representative donor is shown.

[0285] FIG. 127B depicts exemplary flow cytometry results showing expansion of T-cells after stimulation with an anti-TRAV 12-1 antibody. Purified human T cells isolated from healthy individuals were stimulated for 10 days with 100 nM of plate-bound anti-TCR V alpha 12.1 antibody (6D6.6); followed by an additional 2-days in culture in the presence of 100 U / mL recombinant human IL-2. The FACS plots show expanded T cells stained with an AF647-labeled anti-TCR V alpha 12.1 antibody. Unstimulated T-cells were stained for baseline expression. Data from 2 representative donors are shown.

[0286] FIG. 128A depicts exemplary dot plots showing expansion of human CD4+ CD25+ and CD8+ CD25+ T-cells after stimulation with anti-TCRaV-19 / IL-2 bispecific antibody. Human PBMCs were treated at with 0.001, 0.01, 0.1, 1, 10, or 100 nM of anti-TCRaV-19 / IL-2 for 5 days at 37°C. Cells were stained with anti-CD4, anti-CD25 (IL2RA), and anti-CD8 antibodies and FACS was used to quantify percentage of CD4+ CD25+ and CD8+ CD25+ T-cell populations. Isotype controls were used for baseline comparison.

[0287] FIG. 128B depicts exemplary dot plots showing expansion of murine CD4+ CD25+ and CD8+ CD25+ T-cells after stimulation with anti-TCRaV-14 / IL-2 bispecific antibody. Isolated murine T-cells were treated at with 0.001, 0.01, 0.1, 1, 10, or 100 nM of anti-TCRaV-14 / IL-2 for 4 days at 37°C. Cells were stained with anti-CD4, anti-CD25 (IL2RA), and anti-CD8 antibodies and FACS was used to quantify percentage of CD4+ CD25+ and CD8+ CD25+ T-cell populations. Isotype controls were used for baseline comparison.

[0288] FIG. 128C depicts exemplary dot plots showing expansion of murine CD4+ CD25+ and CD8+ CD25+ T-cells after stimulation with anti-TCRaV-12 / IL-2 bispecific antibody. Isolated murine T-cells were treated at with 0.001, 0.01, 0.1, 1, 10, or 100 nM of anti-TCRaV-12 / IL-2 for 4 days at 37°C. Cells were stained with anti-CD4, anti-CD25 (IL2RA), and anti-CD8 antibodies and FACS was used to quantify percentage of CD4+ CD25+ and CD8+ CD25+ T-cell populations. Isotype controls were used for baseline comparison.

[0289] FIGs. 129A-129D depict exemplary embodiments of the multifunctional molecules as described herein, wherein the N-terminus of the first portion of a dimerization module is linked to the C-terminus of the first domain or the C-terminus of the first portion of the first domain, and the N-terminus of the second portion of the dimerization module is linked to the C-terminus of the second domain or the C-terminus of the first portion of the second domain. FIGs. 129A and 129D depict exemplary embodiments of the multifunctional molecules as described herein, wherein a first domain as described herein comprises an scFv. FIGs. 129B and 129C depict exemplary embodiments of the multifunctional molecules as described herein, wherein a first domain as described herein comprises an Fab. FIGs. 129A and 129C depict exemplary embodiments of the multifunctional molecules as described herein, wherein a second domain as described herein comprises an scFv. FIGs. 129B and 129D depict exemplary embodiments of the multifunctional molecules as described herein, wherein a second domain as described herein comprises an Fab. In some embodiments, a first domain as described herein binds to a T cell receptor alpha (TCRa) chain. In some embodiments, a second domain as described herein binds to a second domain that binds to a T cell receptor beta (TCRP) chain. In some embodiments, a first domain as described herein binds to a T cell receptor alpha (TCRa) chain, and a second domain as described herein binds to a second domain that binds to a T cell receptor beta (TCRP) chain. In some embodiments, a first domain as described herein binds to a T cell receptor beta (TCRP) chain. In some embodiments, a second domain as described herein binds to a second domain that binds to a T cell receptor alpha (TCRa) chain. In some embodiments, a first domain as described herein binds to a T cell receptor beta (TCRP) chain, and a second domain as described herein binds to a second domain that binds to a T cell receptor alpha (TCRa) chain.

[0290] FIGs. 130A-130D depict exemplary embodiments of the multifunctional molecules as described herein, wherein the N-terminus of the first portion of the dimerization module is linked to the C-terminus of the first domain or the C-terminus of the first portion of the first domain, and the C-terminus of the second portion of the dimerization module is linked to the N-terminus of the second domain or the N-terminus of the first portion of the second domain. FIGs. 130A and 130C depict exemplary embodiments of the multifunctional molecules as described herein, wherein a first domain as described herein comprises an Fab. FIGs. 130B and 130D depict exemplary embodiments of the multifunctional molecules as described herein, wherein a first domain as described herein comprises an scFv. FIGs. 130A and 130D depict exemplary embodiments of the multifunctional molecules as described herein, wherein a second domain as described herein comprises an Fab. FIGs. 130B and 130C depict exemplary embodiments of the multifunctional molecules as described herein, wherein a second domain as described herein comprises an scFv. In some embodiments, a first domain as described herein binds to a T cell receptor alpha (TCRa) chain. In some embodiments, a second domain as described herein binds to a second domain that binds to a T cell receptor beta (TCRP) chain. In some embodiments, a first domain as described herein binds to a T cell receptor alpha (TCRa) chain, and a second domain as described herein binds to a second domain that binds to a T cell receptor beta (TCRP) chain. In some embodiments, a first domain as described herein binds to a T cell receptor beta (TCRP) chain. In some embodiments, a second domain as described herein binds to a second domain that binds to a T cell receptor alpha (TCRa) chain. In some embodiments, a first domain as described herein binds to a T cell receptor beta (TCRP) chain, and a second domain as described herein binds to a second domain that binds to a T cell receptor alpha (TCRa) chain.

[0291] FIGs. 131A-131D depict exemplary embodiments of the multifunctional molecules as described herein, wherein the C-terminus of the first portion of the dimerization module is linked to the N-terminus of the first domain or the N-terminus of the first portion of the first domain, and the C-terminus of the second portion of the dimerization module is linked to the N-terminus of the second domain or the N-terminus of the first portion of the second domain. FIGs. 131A and 131D depict exemplary embodiments of the multifunctional molecules as described herein, wherein a first domain as described herein comprises an scFv. FIGs. 131B and 131C depict exemplary embodiments of the multifunctional molecules as described herein, wherein a first domain as described herein comprises an Fab. FIGs. 131A and 131B depict exemplary embodiments of the multifunctional molecules as described herein, wherein a second domain as described herein comprises an scFv. FIGs. 131C and 131D depict exemplary embodiments of the multifunctional molecules as described herein, wherein a second domain as described herein comprises an Fab. In some embodiments, a first domain as described herein binds to a T cell receptor alpha (TCRa) chain. In some embodiments, a second domain as described herein binds to a second domain that binds to a T cell receptor beta (TCRP) chain. In some embodiments, a first domain as described herein binds to a T cell receptor alpha (TCRa) chain, and a second domain as described herein binds to a second domain that binds to a T cell receptor beta (TCRP) chain. In some embodiments, a first domain as described herein binds to a T cell receptor beta (TCRP) chain. In some embodiments, a second domain as described herein binds to a second domain that binds to a T cell receptor alpha (TCRa) chain. In some embodiments, a first domain as described herein binds to a T cell receptor beta (TCRP) chain, and a second domain as described herein binds to a second domain that binds to a T cell receptor alpha (TCRa) chain.

[0292] FIGs. 132A-132D depict exemplary embodiments of the multifunctional molecules as described herein, wherein the C-terminus of the first portion of the dimerization module is linked to the N-terminus of the first domain or the N-terminus of the first portion of the first domain, and the N-terminus of the second portion of the dimerization module is linked to the C-terminus of the second domain or the C-terminus of the first portion of the second domain. FIGs. 132A and 132B depict exemplary embodiments of the multifunctional molecules as described herein, wherein a first domain as described herein comprises an Fab. FIGs. 132C and 132D depict exemplary embodiments of the multifunctional molecules as described herein, wherein a first domain as described herein comprises an scFv. FIGs. 132A and 132D depict exemplary embodiments of the multifunctional molecules as described herein, wherein a second domain as described herein comprises an Fab. FIGs. 132B and 132C depict exemplary embodiments of the multifunctional molecules as described herein, wherein a second domain as described herein comprises an scFv. In some embodiments, a first domain as described herein binds to a T cell receptor alpha (TCRa) chain. In some embodiments, a second domain as described herein binds to a second domain that binds to a T cell receptor beta (TCRP) chain. In some embodiments, a first domain as described herein binds to a T cell receptor alpha (TCRa) chain, and a second domain as described herein binds to a second domain that binds to a T cell receptor beta (TCRP) chain. In some embodiments, a first domain as described herein binds to a T cell receptor beta (TCRP) chain. In some embodiments, a second domain as described herein binds to a second domain that binds to a T cell receptor alpha (TCRa) chain. In some embodiments, a first domain as described herein binds to a T cell receptor beta (TCRP) chain, and a second domain as described herein binds to a second domain that binds to a T cell receptor alpha (TCRa) chain. DETAILED DESCRIPTION DEFINITION

[0293] Certain specific details of this description are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the present disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments.

[0294] Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed disclosure.

[0295] 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.”

[0296] It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0297] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below.

[0298] 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.

[0299] The term “acquire” or “acquiring” as the terms are used herein, refer to obtaining possession of a physical entity (e.g., a sample, a polypeptide, a nucleic acid, or a sequence), or a value, e.g., a numerical value, by “directly acquiring” or “indirectly acquiring” the physical entity or value. “Directly acquiring” means performing a process (e.g., performing a synthetic or analytical method) to obtain the physical entity or value. “Indirectly acquiring” refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value). Directly acquiring a physical entity includes performing a process that includes a physical change in a physical substance, e.g., a starting material. Directly acquiring a value includes performing a process that includes a physical change in a sample or another substance, e.g., performing an analytical process which includes a physical change in a substance, e.g., a sample.

[0300] “Antibody molecule” as used herein refers to a protein, e.g., an immunoglobulin chain or fragment thereof, comprising at least one immunoglobulin variable domain structure and / or sequence. An antibody molecule encompasses antibodies (e.g., full-length antibodies) and antibody fragments. In some embodiments, an antibody molecule comprises an antigen binding or functional fragment of a full length antibody, or a full length immunoglobulin chain. For example, a full-length antibody is an immunoglobulin (Ig) molecule (e.g., an IgG antibody) that is naturally occurring or formed by normal immunoglobulin gene fragment recombinatorial processes). In embodiments, an antibody molecule refers to an immunologically active, 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’)2 fragments, a diabody, a VHH antibody, a nanobody, a single domain antibody, a single domain variant, a camelid antibody, 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.

[0301] The term “human-like antibody molecule” as used herein refers to a humanized antibody molecule, human antibody molecule or an antibody molecule having at least 95% sequence identity with a non-murine germline framework region, e.g., FR1, FR2, FR3 and / or FR4. In some embodiments, the human-like antibody molecule comprises a framework region having at least 95% sequence identity to a human germline framework region, e.g., a FR1, FR2, FR3 and / or FR4 of a human germline framework region. In some embodiments, the human-like antibody molecule is a recombinant antibody. In some embodiments, the human-like antibody molecule is a humanized antibody molecule. In some embodiments, the human-like antibody molecule is human antibody molecule. In some embodiments, the human-like antibody molecule is a phage display or a yeast display antibody molecule. In some embodiments, the human-like antibody molecule is a chimeric antibody molecule. In some embodiments, the human-like antibody molecule is a CDR grafted antibody molecule.

[0302] As used herein, an “immunoglobulin variable domain sequence” refers to an amino acid sequence which can form the structure of an immunoglobulin variable domain. For example, the sequence may include all or part of the amino acid sequence of a naturally-occurring variable domain. For example, the sequence may or may not include one, two, or more N- or C-terminal amino acids, or may include other alterations that are compatible with formation of the protein structure.

[0303] In embodiments, an antibody molecule is monospecific, e.g., it comprises binding specificity for a single epitope. In some embodiments, an antibody molecule is multispecific, e.g., it comprises a plurality of immunoglobulin variable domain sequences, where a first immunoglobulin variable domain sequence has binding specificity for a first epitope and a second immunoglobulin variable domain sequence has binding specificity for a second epitope. In some embodiments, an antibody molecule is a bispecific antibody molecule. “Bispecific antibody molecule” as used herein refers to an antibody molecule that has specificity for more than one (e.g., two, three, four, or more) epitope and / or antigen.

[0304] “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.

[0305] The “antigen-binding site,” or “binding portion” of an antibody molecule refers to the part of an antibody molecule, e.g., an immunoglobulin (Ig) molecule, that participates in antigen binding. In embodiments, the antigen binding site is formed by amino acid residues of the variable (V) regions of the heavy (H) and light (L) chains. Three highly divergent stretches within the variable regions of the heavy and light chains, referred to as hypervariable regions, are disposed between more conserved flanking stretches called “framework regions,” (FRs). FRs are amino acid sequences that are naturally found between, and adjacent to, hypervariable regions in immunoglobulins. In embodiments, in an antibody molecule, the three hypervariable regions of a light chain and the three hypervariable regions of a heavy chain are disposed relative to each other in three dimensional space to form an antigen-binding surface, which is complementary to the three-dimensional surface of a bound antigen. The three hypervariable regions of each of the heavy and light chains are referred to as “complementarity-determining regions,” or “CDRs.” The framework region and CDRs have been defined and described, e.g., in Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242, and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917 or by ImMunoGeneTics (IMGT) system. Each variable chain (e.g., heavy chain variable region and light chain variable region) 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.

[0306] As used herein, an “immune cell” refers to any of various cells that function in the immune system, e.g., to protect against agents of infection and foreign matter. In embodiments, this term includes leukocytes, e.g., neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Innate leukocytes include phagocytes (e.g., macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells. Innate leukocytes identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms, and are mediators in the activation of an adaptive immune response. The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are important types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response. The term “immune cell” includes immune effector cells.

[0307] ‘‘Immune effector cell,” as that term is used herein, refers to a cell that is involved in an immune response, e.g., in the promotion of an immune effector response. Examples of immune effector cells include, but are not limited to, T cells, e.g., alpha / beta T cells and gamma / delta T cells, B cells, natural killer (NK) cells, natural killer T (NK T) cells, and mast cells.

[0308] 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.

[0309] The terms “polypeptide”, “peptide” and “protein” (if single chain) are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by 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.

[0310] The terms “nucleic acid,” “nucleic acid sequence,” “nucleotide sequence,” or “polynucleotide sequence,” and “polynucleotide” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. The polynucleotide may be either single-stranded or double-stranded, and if single-stranded may be the coding strand or noncoding (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.

[0311] The term “isolated,” as used herein, refers to material that is removed from its original or native environment (e.g., the natural environment if it is naturally occurring). For example, a naturally-occurring polynucleotide or polypeptide present in a living animal is not isolated, 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.

[0312] The compositions and methods of the present invention encompass polypeptides and nucleic acids having the sequences specified, or sequences substantially identical or similar thereto, e.g., sequences at least 80%, 85%, 90%, 95% identical or higher to the sequence specified. In the context of an amino acid sequence, the term “substantially identical” is used herein to refer to a first amino acid that contains a sufficient or minimum number of amino acid residues that are i) identical to, or ii) conservative substitutions of aligned amino acid residues in a second amino acid sequence such that the first and second amino acid sequences can have a common structural domain and / or common functional activity. For example, amino acid sequences that contain a common structural domain having at least about 80%, 85%, 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99%, 99.5%, 99.9%, or 100% sequence identity to a reference sequence, e.g., a sequence provided herein. In the context of nucleotide sequence, the term “substantially identical” is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimum number of nucleotides that are identical to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide having common functional activity, or encode a common structural polypeptide domain or a common functional polypeptide activity. For example, nucleotide sequences having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99%, 99.5%, 99.9%, or 100% sequence identity to a reference sequence, e.g., a sequence provided herein.

[0313] The term “variant” refers to a polypeptide that has a substantially identical amino acid sequence to a reference amino acid sequence, or is encoded by a substantially identical nucleotide sequence. In some embodiments, the variant is a functional variant. In some embodiments, a TCR[3V variant can bind to TCRa and form a TCR a:P complex.

[0314] The term “functional variant” refers to a polypeptide that has a substantially identical amino acid sequence to a reference amino acid sequence, or is encoded by a substantially identical nucleotide sequence, and is capable of having one or more activities of the reference amino acid sequence.

[0315] The term “functional fragment” refers to a polypeptide that has a partial amino acid sequence of a reference 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.

[0316] Calculations of homology or sequence identity between sequences (the terms are used interchangeably 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”).

[0317] The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453 ) algorithm which has been incorporated into the GAP program in the GCG software package (available at 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 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.

[0318] The percent identity between two amino acid or nucleotide sequences can be determined using the 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 and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[0319] It is understood that the molecules of the present invention may have additional conservative or non-essential amino acid substitutions, which do not have a substantial effect on their functions.

[0320] The term “amino acid” is intended to embrace all molecules, whether natural or synthetic, which include both an amino functionality and an acid functionality and capable of being included in a polymer of naturally-occurring amino acids. Exemplary amino acids include naturally-occurring amino acids; analogs, derivatives and congeners thereof; amino acid analogs having variant side chains; and all stereoisomers of any of any of the foregoing. As used herein the term “amino acid” includes both the Dor L- optical isomers and peptidomimetics.

[0321] A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0322] 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.

[0323] As used herein, the term “mutation” refers to an alteration in the nucleotide sequence of the genome of an organism, virus, or extrachromosomal DNA. In some embodiments, the mutation may be a large-scale mutation, such as amplifications (or gene duplications) or repetitions of a chromosomal segment, deletions of large chromosomal regions, chromosomal rearrangements (e.g., chromosomal translocations, chromosomal inversions, non-homologous chromosomal crossover, and interstitial deletions), and loss of heterozygosity. In some embodiments, the mutation may be a small-scale mutation, such as insertions, deletions, and substitution mutations. As used herein, the term “substitution mutation” refers to the transition that exchange a single nucleotide for another.

[0324] As used herein, the term “linked” and “operatively linked” are interchangeably used.

[0325] ‘‘Interleukin-2” also known as IL2, IL-2, IL 2, TCGF, lymphokine, and interleukin 2, as referred to 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 is substantially identical to the protein identified by the UniProt reference number P60568 or a variant or homolog having substantial identity thereto. Human T cell receptor (TCR) complex

[0326] TCR is a disulfide-linked membrane-anchored heterodimeric protein normally consisting of the highly variable alpha (a) and beta (P) chains expressed as part of a complex with the invariant CD3 chain molecules. TCR on aP T cells is formed by a heterodimer of one alpha chain and one beta chain. Each alpha or beta chain consists of a constant domain and a highly variable domain classified as the Immunoglobulin superfamily (IgSF) fold. The TCRpV chains can be further classified into subfamilies. 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.

[0327] T cell receptors (TCR) can be found on the surface of T cells. TCRs recognize antigens, e.g., peptides, presented on, e.g., bound to, major histocompatibility complex (MHC) molecules on the surface of cells, e.g., antigen-presenting cells. TCRs are heterodimeric molecules and can comprise an alpha chain, a beta chain, a gamma chain or a delta chain. TCRs comprising an alpha chain and a beta chain are also referred to as TCRap. The TCR beta chain consists of the following regions (also known as segments): variable (V), diversity (D), joining (J) and constant (C) (see Mayer G. and Nyland J. (2010) Chapter 10: Major Histocompatibility Complex and T-cell Receptors-Role in Immune Responses. In: Microbiology and Immunology on-line, University of South Carolina School of Medicine). The TCR alpha chain consists of V, J and C regions. The rearrangement of the T-cell receptor (TCR) through somatic recombination of V (variable), D (diversity), J (joining), and C (constant) regions is a defining event in the development and maturation of a T cell. TCR gene rearrangement takes place in the thymus.

[0328] TCRs can comprise a receptor complex, known as the TCR complex, which comprises a TCR heterodimer comprising of an alpha chain and a beta chain, and dimeric signaling molecules, e.g., CD3 co-receptors, e.g., CD35 / a, and / or CD3y / a.

[0329] As used herein, the term “T cell receptor beta variable chain” or “TCRpV,” refers to an extracellular region of the T cell receptor beta chain which comprises the antigen recognition domain of the T cell receptor. The term TCRpV includes isoforms, mammalian, e.g., human TCRpV, species homologs of human and analogs comprising at least one common epitope with TCRpV. Human TCRpV comprises a gene family comprising subfamilies including, but not limited to: a TCRP V6 subfamily, a TCRP V10 subfamily, a TCRP V12 subfamily, a TCRP V5 subfamily, a TCRP V7 subfamily, a TCRP Vil subfamily, a TCRP V14 subfamily, a TCRP V16 subfamily, aTCRP V18 subfamily, a TCRP V9 subfamily, a TCRP V13 subfamily, a TCRP V4 subfamily, a TCRP V3 subfamily, a TCRP V2 subfamily, a TCRP V15 subfamily, a TCRP V30 subfamily, a TCRP V19 subfamily, a TCRP V27 subfamily, a TCRP V28 subfamily, a TCRP V24 subfamily, a TCRP V20 subfamily, TCRP V25 subfamily, a TCRP V29 subfamily, a TCRP VI subfamily, a TCRP VI7 subfamily, a TCRP V21 subfamily, a TCRP V23 subfamily, or a TCRP V26 subfamily, as well as family members of said subfamilies, and variants thereof (e.g., a structural or functional variant thereof). In some embodiments, the TCRP V6 subfamily comprises: TCRP V6-4*01, TCRP V6-4*02, TCRP V6-9*01, TCRP V6-8*01, TCRP V6-5*01, TCRP V6-6*02, TCRP V6-6*01, TCRP V6-2*01, TCRP V6-3*01 or TCRP V6-l*01. In some embodiments, TCRpV comprises TCRP V6-5*01, or a variant thereof, e.g., a variant having 85%, 90%, 95%, 99% or more identity the naturally-occurring sequence. TCRP V6-5*01 is also known as TRBV65; TCRBV6S5; TCRBV13S1, or TCRP V13.1. The amino acid sequence of TCRP V6-5*01, e.g., human TCRP V6-5*01, is known in that art, e.g., as provided by IMGT ID L36092. In some embodiments, TCRP V6-5*01 is encoded by the nucleic acid sequence of SEQ ID NO: 43, or a sequence having 85%, 90%, 95%, 99% or more identity thereof. In some embodiments, TCRP V6-5*01 comprises the amino acid sequence of SEQ ID NO: 44, or a sequence having 85%, 90%, 95%, 99% or more identity thereof.

[0330] SEQ ID NO: 43 ATGAGCATCGGCCTCCTGTGCTGTGCAGCCTTGTCTCTCCTGTGGGCAGGTCCAGTGAATGC TGGTGTCACTCAGACCCCAAAATTCCAGGTCCTGAAGACAGGACAGAGCATGACACTGCAG TGTGCCCAGGATATGAACCATGAATACATGTCCTGGTATCGACAAGACCCAGGCATGGGGC TGAGGCTGATTCATTACTCAGTTGGTGCTGGTATCACTGACCAAGGAGAAGTCCCCAATGGC TACAATGTCTCCAGATCAACCACAGAGGATTTCCCGCTCAGGCTGCTGTCGGCTGCTCCCTC CCAGACATCTGTGTACTTCTGTGCCAGCAGTTACTC

[0331] SEQ ID NO: 44 MSIGLLCCAALSLLWAGPVNAGVTQTPKFQVLKTGQSMTLQCAQDMNHEYMSWYRQDPGMG LRLIHY-SVGAGITDQGEVPNGYNVSRSTTEDFPLRLLSAAPSQTSVYFCASSY TCR beta V (TCR / 3V)

[0332] Diversity in the immune system enables protection against a huge array of pathogens. Since the germline genome is limited in size, diversity is achieved not only by the process of V(D)J recombination but also by junctional (junctions between V-D and D-J segments) deletion of nucleotides and addition of pseudo-random, non-templated nucleotides. The TCR beta gene undergoes gene arrangement to generate diversity.

[0333] The TCR V beta repertoire varies between individuals and populations because of, e.g., 7 frequently occurring inactivating polymorphisms in functional gene segments and a large insertion / deletion-related polymorphism encompassing 2 V beta gene segments.

[0334] Provided herein are, inter alia, antibody molecules and fragments thereof, that bind, e.g., specifically bind, to a human TCR beta V chain (TCRpV). e.g., a TCRpV gene family (also referred to as a group), e.g., a TCRpV subfamily (also referred to as a subgroup), e.g., as described herein. TCR beta V families and subfamilies are known in the art, e.g., as described in Yassai et al., (2009) Immunogenetics 61(7)pp:493-502; Wei S. and Concannon P. (1994) Human Immunology 41(3) pp: 201-206. The antibodies described herein can be recombinant antibodies, e.g., recombinant non-murine antibodies, e.g., recombinant human or humanized antibodies.

[0335] The terms TCRBV, TCRVB, TRBV, TCRpV, TCRVp or TRpV are used interchangeably herein and refer to a TCR beta V chain, e.g., as described herein.

[0336] The terms TCRBV, TCRVB, TRBV, TCRpV, TCRVp or TRpV are used interchangeably herein and refer to a TCR beta V chain, e.g., as described herein.

[0337] In some embodiments, provided herein is an anti-TCRpV antibody molecule that binds to human TCRpV, e.g., a TCRpV family, e.g., gene family or a variant thereof. In some embodiments a TCRBV gene family comprises one or more subfamilies, e.g., as described herein, e.g., Table 8A or Table 8B. In some embodiments, the TCRpV gene family comprises: a TCRP V6 subfamily, a TCRP V10 subfamily, a TCRP V12 subfamily, a TCRP V5 subfamily, a TCRP V7 subfamily, a TCRP VI1 subfamily, a TCRP V14 subfamily, a TCRP V16 subfamily, a TCRP V18 subfamily, a TCRP V9 subfamily, a TCRP V13 subfamily, a TCRP V4 subfamily, a TCRP V3 subfamily, a TCRP V2 subfamily, a TCRP V15 subfamily, a TCRP V30 subfamily, a TCRP V19 subfamily, a TCRP V27 subfamily, a TCRP V28 subfamily, a TCRP V24 subfamily, a TCRP V20 subfamily, TCRP V25 subfamily, a TCRP V29 subfamily, a TCRP VI subfamily, a TCRP V17 subfamily, a TCRP V21 subfamily, a TCRP V23 subfamily, or a TCRP V26 subfamily.

[0338] In some embodiments, TCRP V6 subfamily is also known as TCRP V13.1. In some embodiments, the TCRP V6 subfamily comprises: TCRP V6-4*01, TCRP V6-4*02, TCRP V6-9*01, TCRP V6-8*01, TCRP V6-5*01, TCRP V6-6*02, TCRP V6-6*01, TCRP V6-2*01, TCRP V6-3*01 or TCRP V6-l*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-4*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-4*02, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-9*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-8*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-5*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-6*02, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-6*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-2*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-3*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-l*01,ora variant thereof.

[0339] In some embodiments, TCRP V6 comprises TCRP V6-5*01, or a variant thereof. In some embodiments, TCRP V6, e.g., TCRP V6-5*01, is recognized, e.g., bound, by SEQ ID NO: 1 and / or SEQ ID NO: 2. In some embodiments, TCRP V6, e.g., TCRP V6-5*01, is recognized, e.g., bound, by SEQ ID NO: 9 and / or SEQ ID NO: 10. In some embodiments, TCRP V6 is recognized, e.g., bound, by SEQ ID NO: 9 and / or SEQ ID NO: 11.

[0340] In some embodiments, TCRP V10 subfamily is also known as TCRP V12. In some embodiments, the TCRP V10 subfamily comprises: TCRP V10-l*01, TCRP V10-l*02, TCRP V10-3*01 or TCRP V10-2*01, or a variant thereof.

[0341] In some embodiments, TCRP V12 subfamily is also known as TCRP V8.1. In some embodiments, the TCRP V12 subfamily comprises: TCRP V12-4*01, TCRP V12-3*01, or TCRP V12-5*01, or a variant thereof. In some embodiments, TCRP V12 is recognized, e.g., bound, by SEQ ID NO: 15 and / or SEQ ID NO: 16. In some embodiments, TCRP V12 is recognized, e.g., bound, by any one of SEQ ID NOs 23-25, and / or any one of SEQ ID NO: 26-30:

[0342] In some embodiments, the TCRP V5 subfamily is chosen from: TCRP V5-5*01, TCRP V5-6*01, TCRP V5-4*01, TCRP V5-8*01, TCRP V5-l*01, or a variant thereof.

[0343] In some embodiments, the TCRP V7 subfamily comprises TCRP V7-7*01, TCRP V7-6*01, TCRP V7 -8*02, TCRP V7 -4*01, TCRP V7-2*02, TCRP V7-2*03, TCRP V7-2*01, TCRP V7-3*01, TCRP V7-9*03, or TCRP V7-9*01, or a variant thereof.

[0344] In some embodiments, the TCRP V11 subfamily comprises: TCRP Vll-l*01, TCRP Vll-2*01 or TCRP Vll-3*01,ora variant thereof. In some embodiments, the TCRP V14 subfamily comprises TCRP V14*01, or a variant thereof. In some embodiments, the TCRP V16 subfamily comprises TCRP V16*01, or a variant thereof. In some embodiments, the TCRP VI8 subfamily comprises TCRP VI8*01, or a variant thereof. In some embodiments, the TCRP V9 subfamily comprises TCRP V9*01 or TCRP V9*02, or a variant thereof. In some embodiments, the TCRP V13 subfamily comprises TCRP V13*01, or a variant thereof. In some embodiments, the TCRP V4 subfamily comprises TCRP V4-2*01, TCRP V4-3*01, or TCRP V4-l*01, or a variant thereof. In some embodiments, the TCRP V3 subfamily comprises TCRP V3-l*01, or a variant thereof. In some embodiments, the TCRP V2 subfamily comprises TCRP V2*01, or a variant thereof. In some embodiments, the TCRP V15 subfamily comprises TCRP V15*01, or a variant thereof. In some embodiments, the TCRP V30 subfamily comprises TCRP V30*01, or TCRP V30*02, or a variant thereof. In some embodiments, the TCRP V19 subfamily comprises TCRP V19*01, or TCRP V19*02, or a variant thereof. In some embodiments, the TCRP V27 subfamily comprises TCRP V27*01, or a variant thereof. In some embodiments, the TCRP V28 subfamily comprises TCRP V28*01, or a variant thereof. In some embodiments, the TCRP V24 subfamily comprises TCRP V24-l*01, or a variant thereof. In some embodiments, the TCRP V20 subfamily comprises TCRP V20-l*01, or TCRP V20-l*02, or a variant thereof. In some embodiments, the TCRP V25 subfamily comprises TCRP V25-l*01, or a variant thereof. In some embodiments, the TCRP V29 subfamily comprises TCRP V29-l*01, or a variant thereof.

[0345] Exemplary amino acid sequences for TCRpV subfamily members can be found on the ImMunoGeneTics Information System website: www.imgt.org / , or in a similar resource. Anti-TCRpV antibodies

[0346] Current bispecific constructs designed to redirect T cells to promote tumor cell lysis for cancer immunotherapy typically utilize antibody fragments (Fab, scFv, VH, single domain antibody, etc.) that 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 (IFNy). This excess amount of IFNy in turn activates macrophages which then overproduce proinflammatory cytokines such as IL-lbeta, IL-6, IL-10 and TNF-alpha, causing a “cytokine storm” known as the cytokine release syndrome (CRS) (Shimabukuro-Vomhagen 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).

[0347] Described herein are molecules targeting the TCRpV 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.

[0348] Described herein is a class of antibodies, i.e., anti-TCRpV antibody molecules as described herein, which despite having low sequence similarity (e.g., low sequence identity among the different antibody molecules that recognize different TCRpV subfamilies), recognize a structurally conserved, yet sequence-wise variable, region, e.g., domain, on the TCRpV protein and have a similar function (e.g., activation of T cells and a similar cytokine profile as described herein). Thus, the anti-TCRpV antibody molecules as described herein share a structure-function relationship.

[0349] Without wishing to be bound by theory, in some embodiments, the anti-TCRpV antibody molecules as described herein bind to an outward facing epitope of a TCRpV protein when it is in a complex with a TCRalpha protein. In some embodiments, the anti-TCRpV antibody molecules as described herein recognize (e.g., bind to), a domain (e.g., an epitope) on the TCRpV protein that is: (1) structurally conserved among different TCRpV subfamilies; and (2) has minimal sequence identity among the different TCRpV subfamilies. TCRpV proteins from the different TCRBV subfamilies share minimal sequence similarity. However, TCRpV proteins which have minimal sequence similarity, share a similar 3D conformation and structure.

[0350] The alignment of TCRBV amino acid sequences in ta9 underscores the diversity of TCR sequences. In particular, the TRBV sequences from different subfamilies are considerably different from each other.

[0351] In some embodiments, the anti-TCRpV antibody molecules as described herein do not recognize, e.g., bind to, an interface of a TCRpV: TCRalpha complex. In some embodiments, the anti-TCRpV antibody molecules as described herein do not recognize, e.g., bind to, a constant region of a TCRpV 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;l 1(6):701-13). In some embodiments, the anti-TCRpV 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 TCRpV protein.

[0352] Provided herein are, inter alia, antibody molecules directed to the variable chain of the beta subunit of TCR (TCRpV) which bind and, e.g., activate a subset of T cells. The anti-TCRpV antibody molecules as described herein result in lesser or no production of cytokines associated with CRS, e.g., IL-6, IL-lbeta, IL-10 and TNF alpha; and enhanced and / or delayed production of IL-2 and IFNy. In some embodiments, the anti-TCRpV 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 TCRpV region (“a non-TCRpV-binding T cell engager”). In some embodiments, the non-TCRpV-binding T cell engager comprises an antibody that binds to a CD3 molecule (e.g., CD3 epsilon (CD3e) molecule); or a TCR alpha (TCRa) molecule. In some embodiments, the non-TCRpV-binding T cell engager is an OKT3 antibody or an SP34-2 antibody.

[0353] In some embodiments, the anti-TCRpV antibodies as described herein result in expansion of TCRPV+ 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-TCRpV antibody molecules and uses thereof. Also described herein are multispecific molecules, e.g., bispecific molecules comprising said anti-TCRpV antibody molecules. In some embodiments, compositions comprising anti-TCRpV 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 TCRPV+ T cells. In some embodiments, compositions comprising anti-TCRpV 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.

[0354] In some embodiments, the anti-TCR[3V 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-TCRpV 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-TCRpV antibody molecule is an anti-TRBV2, anti-TRBV3-l, anti-TRBV4-l, anti-TRBV4-2, anti-TRBV4-3, anti-TRBV5-l, anti-TRBV5-4, anti-TRBV5-5, anti-TRBV5-6, anti-TRBV5-8, anti-TRBV6-l, 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-l, anti-TRBVlO-2, anti-TRBV10-3, anti-TRBVl 1-1, anti-TRBVl 1-2, anti-TRBVl 1-3, anti-TRBV12-3, anti-TRBV12-4, anti-TRBV12-5, anti-TRBV13, anti-TRBV14, anti-TRBV15, anti-TRBV16, anti-TRBV18, anti-TRBV19, anti-TRBV20-l, anti-TRBV24-l, anti-TRBV25-l, anti-TRBV27, anti-TRBV28, anti-TRBV29-1, or anti-TRBV30. Exemplary anti-TCRpV antibody molecules and the corresponding TCRpV subfamilies recognized by said anti-TCRpV antibody molecules are disclosed in Table 10A.

[0355] In some embodiments, the anti-TCRpV 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-TCRpV antibody molecule binds specifically to TRBV6-1. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-2. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-3. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-4. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-5. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-6. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-8. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-9.

[0356] In some embodiments, the anti-TCRpV antibody molecule does not bind to TCRP V12, or binds to TCRP 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.

[0357] In some embodiments, the anti-TCRpV antibody molecule binds to TCRP V12 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 described in US Patent 5,861,155.

[0358] In some embodiments, the anti-TCRpV antibody molecule binds to a TCRpV region other than TCRP V12 (e.g., TCRpV region as described herein, e.g., TCRP V6 subfamily (e.g., TCRP 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.

[0359] In some embodiments, the anti-TCRpV antibody molecule does not comprise the CDRs of the Antibody B murine antibody.

[0360] In some embodiments, the anti-TCRpV antibody molecule does not bind to TCRP V5-5*01 or TCRP V5-l*01, or binds to TCRP V5-5*01 or TCRP V5-l*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.

[0361] In some embodiments, the anti-TCRpV antibody molecule binds to TCRP V5-5*01 or TCRP V5-l*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.

[0362] In some embodiments, the anti-TCRpV antibody molecule binds to a TCRpV region other than TCRP V5-5*01 or TCRP V5-l*01 (e.g., TCRpV region as described herein, e.g., TCRP V6 subfamily (e.g., TCRP 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.

[0363] In some embodiments, the anti-TCRpV antibody molecule does not comprise the CDRs of the TM23 murine antibody.

[0364] In some embodiments, the light or the heavy chain variable framework (e.g., the region encompassing at least FR1, FR2, FR3, and optionally FR4) of the anti-TCRpV antibody molecule, e.g., anti-TCRP V6 (e.g., anti-TCRP 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 VU or VH segment of a human germline gene.

[0365] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.l, 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: 9.

[0366] Alternatively, or in combination with the heavy chain substitutions described herein, the anti-TCR[3V antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp 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.

[0367] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes one, two, three, or four heavy chain framework regions, or a sequence substantially identical thereto.

[0368] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes one, two, three, or four light chain framework regions, or a sequence substantially identical thereto.

[0369] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the light chain framework region 1 of A-H.l or A-H.2.

[0370] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the light chain framework region 2 of A-H.l or A-H.2.

[0371] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the light chain framework region 3 of A-H.l or A-H.2.

[0372] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the light chain framework region 4 of A-H.l or A-H.2.

[0373] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.

[0374] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.

[0375] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.

[0376] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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, 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.

[0377] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.

[0378] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.

[0379] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the heavy chain framework region 1 of A-H.l or A-H.2. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the heavy chain framework region 2 of A-H. 1 or A-H.2, e.g. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp 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-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the heavy chain framework region 4 of A-H. 1 or A-H.2.

[0380] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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 at 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.

[0381] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.

[0382] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the light chain framework regions 1-4 of A-H.l, e.g., SEQ ID NO: 10. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp 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-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the heavy chain framework regions 1-4 of A-H.l, 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-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp 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.

[0383] In some embodiments, the heavy or light chain variable domain, or both, of the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp 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.l to A-H.85, e.g., A-H.l, 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.

[0384] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp 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.

[0385] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.

[0386] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.

[0387] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule is a monoclonal antibody or an antibody with single specificity. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, can also be a humanized, chimeric, camelid, shark, or an in w / ro-gcncratcd antibody molecule. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, is a humanized antibody molecule. The heavy and light chains of the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp 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).

[0388] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, is in the form of a multispecific molecule, e.g., a bispecific molecule, e.g., as described herein.

[0389] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, has a heavy chain constant region (Fc) chosen from, e.g., the heavy chain constant regions of IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE. In some embodiments, the Fc region is chosen from the heavy chain constant regions of IgGl, IgG2, IgG3, and IgG4. In some embodiments, the Fc region is chosen from the heavy chain constant region of IgGl or IgG2 (e.g., human IgGl, or IgG2). In some embodiments, the heavy chain constant region is human IgGl. In some embodiments, the Fc region comprises a Fc region variant, e.g., as described herein.

[0390] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp 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 (Hto K) and 314 (N to F) of SEQ ID NOs: 212 or 214; or positions 135 (M to Y), 137 (S to T), 139 (Tto E), 316 (Hto K) and 317 (N to F) of SEQ ID NOs: 215, 216, 217 or 218), e.g., relative to human IgGl.

[0391] 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.

[0392] Additional exemplary humanized anti-TCRB V6 antibodies are provided in Table 1. In some embodiments, the anti-TCRp V6 is antibody A, e.g., humanized antibody A (antibody A-H), as provided in Table 1. In some embodiments, the anti-TCRpV 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 heavy chain variable region (VH) and / or a light chain variable region (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.

[0393] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.ll, 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.l, 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.

[0394] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.ll, 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.l, 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.

[0395] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises a VH of A-H.l, 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.ll, 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.l, 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.l, 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.ll, 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.l, 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.

[0396] Exemplary anti-TCRpV antibody molecules and the corresponding TCRpV subfamilies recognized by said anti-TCRpV antibody molecules are disclosed in Table 10A.

[0397] The various TCRpV subfamilies and / or subfamily members can be expressed at different levels in 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, TCRp V6-5 is represented in approximately 3-6% healthy donors.

[0398] The representation of various TCRBV subfamilies and / or subfamily members can also be different in cancer cells. For example, TCRpV is present in about 3-6% of tumor infiltrating T cells 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 TCRp V6-5 is present at a high frequency in tumor cells. Anti-TCRp V6 antibodies

[0399] In one aspect, provided herein is an anti-TCRpV antibody molecule that binds to human TCRP V6, e.g., a TCRP V6 subfamily comprising: TCRp V6-4*01, TCRp V6-4*02, TCRp V6-9*01, TCRp V6-8*01, TCRP V6-5*01, TCRp V6-6*02, TCRp V6-6*01, TCRp V6-2*01, TCRp V6-3*01 or TCRp V6-l*01. In some embodiments the TCRP V6 subfamily comprises TCRP V6-5*01 or a variant thereof. In some embodiments, TCRp V6 comprises TCRp V6-4*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-4*02, or a variant thereof. In some embodiments, TCRP V6 comprises TCRp V6-9*01, or a variant thereof. In some embodiments, TCRp V6 comprises TCRp V6-8*01, or a variant thereof. In some embodiments, TCRp V6 comprises TCRp V6-5*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-6*02, or a variant thereof. In some embodiments, TCRP V6 comprises TCRp V6-6*01, or a variant thereof. In some embodiments, TCRp V6 comprises TCRp V6-2*01, or a variant thereof. In some embodiments, TCRp V6 comprises TCRp V6-3*01, or a variant thereof. In some embodiments, TCRp V6 comprises TCRp V6-l*01, or a variant thereof.

[0400] In some embodiments, TCRp V6-5*01 is encoded by the nucleic acid sequence of SEQ ID NO: 43, or a sequence having 85%, 90%, 95%, 99% or more identity thereof. In some embodiments, TCRP V6-5*01 comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence having 85%, 90%, 95%, 99% or more identity thereof.

[0401] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, is a non-murine antibody molecule, e.g., a human or humanized antibody molecule. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule is a human antibody molecule. In some embodiments, the anti- TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule is a humanized antibody molecule.

[0402] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, is isolated or recombinant.

[0403] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.l 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.

[0404] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.l to A-H.85, e.g., A-H.l, 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.

[0405] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.l to A-H.85, e.g., A-H.l, A-H.2 or A-H.68, or an antibody molecule 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.

[0406] In some embodiments, the anti-TCRpV antibody molecule comprises a heavy chain variable region (VH) having a consensus sequence of SEQ ID NO: 231 or 3290.

[0407] SEQ ID NO: 231 - Consensus VH QVQLVQSGAEVKKPGSSVKVSCKASGH / 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

[0408] SEQ ID NO: 3290 - Consensus VH QVQLVQSGAEVKKPGSSVKVSCKASGX1X2FX3X4X5YIHWVRQAPGQGLEWMGX6X7X8X9G SGX1 OX 1IX12YNEKFKGRVTITADTSTSTAYMELS SLRSEDTAVYYCAX13 SX14YSX15X16VLD YWGQGTTVTVSS, where-in: XI 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; XI1 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.

[0409] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.l to A-H.85, e.g., A-H.l, 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.

[0410] In some embodiments, the anti-TCRpV antibody molecule comprises a light chain variable region (VL) having a consensus sequence of SEQ ID NO: 230 or 3289.

[0411] SEQ ID NO: 230 - Consensus VL DIQMTQSPSFLSASVGDRVTITCKASQNVG / E / A / DN / DR / KVAWY / HQQKPGKAPKALIYSSSHRY K / SGVPSRFSGSGSGTEFTLTISSLQPEDFATYFCQQFKSYPLTFGQGTKLEIK

[0412] SEQ ID NO: 3289 - Consensus VL DIQMTQSPSFLSASVGDRVTITCKASQNVX1X2X3VAWX4QQKPGKAPKALIYSSSHRYX5GVPS RFSGSGSGTEFTLTISSLQPEDFATYFCQQFKSYPLTFGQGTKLEIK, wherein XI 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

[0413] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises a heavy chain constant region for an IgG4, e.g., a human IgG4. In still another embodiment, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule includes a heavy chain constant region for an IgGl, e.g., a human IgGl. 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.

[0414] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.

[0415] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.l to A-H.85, e.g., A-H.l, 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.

[0416] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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, or encoded by a nucleotide sequence shown in Table 1. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[0417] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.l to A-H.85, e.g., A-H.l, 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.

[0418] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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, or encoded by a nucleotide sequence shown in Table 1. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[0419] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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, or encoded by a nucleotide sequence shown in Table 1. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[0420] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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, or encoded by a nucleotide sequence in Table 1, 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-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, may include any CDR described herein.

[0421] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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) 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.l, A-H.2 or A-H.68, or an antibody described 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; 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.

[0422] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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) 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.l, A-H.2 or A-H.68, or an antibody described 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; 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.

[0423] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, 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 1) 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, 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; 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.

[0424] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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) 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, 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; 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. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, may include any CDR described herein.

[0425] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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.l to A-H.85, e.g., A-H.l, 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 or by ImMunoGeneTics (IMGT) system. These structures can be determined by inspection of the tables described in these references.

[0426] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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) or by ImMunoGeneTics (IMGT) system from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H. 1, A-H.2 or A-H.68, or as described 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; 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 or by ImMunoGeneTics (IMGT) system.

[0427] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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) or by ImMunoGeneTics (IMGT) system from a light chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H.l, A-H.2 or A-H.68, or an antibody described 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; 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 or by ImMunoGeneTics (IMGT) system.

[0428] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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) or by ImMunoGeneTics (IMGT) system 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.l, A-H.2 or A-H.68, or an antibody described in Table 1, or encoded by the 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; 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 or by ImMunoGeneTics (IMGT) system.

[0429] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*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) or by ImMunoGeneTics (IMGT) system from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H.l, 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; 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. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, may include any CDR described herein or by ImMunoGeneTics (IMGT) system.

[0430] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, molecule includes a combination of CDRs or hypervariable loops defined according to Kabat et al., Chothia et al., or as described in Table 1 or by ImMunoGeneTics (IMGT) system.

[0431] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, can contain any combination of CDRs or hypervariable loops according to the Kabat and Chothia definitions or by ImMunoGeneTics (IMGT) system.

[0432] In some embodiments, a combined CDR as set out in Table 1 is a CDR that comprises a Kabat CDR and a Chothia CDR or by ImMunoGeneTics (IMGT) system.

[0433] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, molecule includes a combination of CDRs or hypervariable loops identified as combined CDRs in Table 1. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, can contain any combination of CDRs or hypervariable loops according the “combined” CDRs are described in Table 1.

[0434] In some embodiments, e.g., an embodiment comprising a variable region, a CDR (e.g., a combined CDR, Chothia CDR or Kabat CDR or CDRs by ImMunoGeneTics (IMGT) system), or other sequence referred to herein, e.g., in Table 1, 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.

[0435] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule 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: 2, SEQ ID NO: 10 or SEQ ID NO: 11, 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: 1 or SEQ ID NO: 9.

[0436] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises a LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 2, and a HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 1.

[0437] In some embodiments the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises a LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 10, and a HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 9.

[0438] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises a LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 11, and a HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 9.

[0439] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 6, a LC CDR2 amino acid sequence of SEQ ID NO: 7, or a LC CDR3 amino acid sequence of SEQ ID NO: 8; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 3, a HC CDR2 amino acid sequence of SEQ ID NO: 4, or a HC CDR3 amino acid sequence of SEQ ID NO: 5.

[0440] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1 amino acid sequence of SEQ ID NO: 6, a LC CDR2 amino acid sequence of SEQ ID NO: 7, or a LC CDR3 amino acid sequence of SEQ ID NO: 8; and / or (ii) a heavy chain variable region (VH) comprising a HC CDR1 amino acid sequence of SEQ ID NO: 3, a HC CDR2 amino acid sequence of SEQ ID NO: 4, or a HC CDR3 amino acid sequence of SEQ ID NO: 5.

[0441] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 51, a LC CDR2 amino acid sequence of SEQ ID NO: 52, or a LC CDR3 amino acid sequence of SEQ ID NO: 53; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 45, a HC CDR2 amino acid sequence of SEQ ID NO: 46, or a HC CDR3 amino acid sequence of SEQ ID NO: 47.

[0442] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1 amino acid sequence of SEQ ID NO: 51, a LC CDR2 amino acid sequence of SEQ ID NO: 52, or a LC CDR3 amino acid sequence of SEQ ID NO: 53; and / or (ii) a heavy chain variable region (VH) comprising a HC CDR1 amino acid sequence of SEQ ID NO: 45, a HC CDR2 amino acid sequence of SEQ ID NO: 46, or a HC CDR3 amino acid sequence of SEQ ID NO: 47.

[0443] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 54, a LC CDR2 amino acid sequence of SEQ ID NO: 55, or a LC CDR3 amino acid sequence of SEQ ID NO: 56; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 48, a HC CDR2 amino acid sequence of SEQ ID NO: 49, or a HC CDR3 amino acid sequence of SEQ ID NO: 50.

[0444] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1 amino acid sequence of SEQ ID NO: 54, a LC CDR2 amino acid sequence of SEQ ID NO: 55, or a LC CDR3 amino acid sequence of SEQ ID NO: 56; and / or (ii) a heavy chain variable region (VH) comprising a HC CDR1 amino acid sequence of SEQ ID NO: 48, a HC CDR2 amino acid sequence of SEQ ID NO: 49, or a HC CDR3 amino acid sequence of SEQ ID NO: 50.

[0445] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises a VH and / or a VL of an antibody described in Table 1, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0446] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises a VH and a VL of an antibody described in Table 1, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0447] In some embodiments, an anti-TCRVb antibody as described herein has an antigen binding domain 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.

[0448] In some embodiments, an anti-TCRVb antibody as described herein has an antigen binding domain 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 58 is K or R; position 97 is G or V; position 99 is Y or I; position 102 is Y or A; and / or position 103 is D or G. Anti-TCRp VI2 antibodies

[0449] In one aspect, provided herein is an anti-TCRpV antibody molecule that binds to human TCRp V12, e.g., a TCRP V12 subfamily comprising: TCRp V12-4*01, TCRp V12-3*01 or TCRp V12-5*01. In some embodiments the TCRP V12 subfamily comprises TCRP V12-4*01. In some embodiments the TCRP V12 subfamily comprises TCRP V12-3*01.

[0450] In some embodiments, the anti—TC^RpA / antibody molecule, e.g., anti—TC^Rp A / 12 antibody molecule, is a non-murine antibody molecule, e.g., a human or humanized antibody molecule. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule is a human antibody molecule. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule is a humanized antibody molecule.

[0451] In some embodiments, the anti—TC^RpA / antibody molecule, e.g., anti—TC^Rp A / 12 antibody molecule, is isolated or recombinant.

[0452] In some embodiments, the anti—TC^RpA / antibody molecule, e.g., anti—TC^Rp A / 12 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 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.

[0453] In some embodiments, the anti—TC^RpA / antibody molecule, e.g., anti—TC^Rp A / 12 antibody molecule, 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.

[0454] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp A^12 antibody molecule, 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.

[0455] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp A^12 antibody molecule, 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.

[0456] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp A^12 antibody molecule, comprises a heavy chain constant region for an IgG4, e.g., a human IgG4. In still another embodiment, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, includes a heavy chain constant region for an IgGl, e.g., a human IgGl. 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.

[0457] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp A^12 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.

[0458] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp \^12 antibody molecule, 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.

[0459] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp \^12 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 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.

[0460] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp \^12 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 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.

[0461] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp A^12 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 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.

[0462] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp A^12 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 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.

[0463] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp A^12 antibody molecule, 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-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, may include any CDR described herein.

[0464] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp A^12 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 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.

[0465] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp A^12 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 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.

[0466] In some embodiments, the anti—TC^RpA / antibody molecule, e.g., anti—TC^Rp A / 12 antibody molecule 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.

[0467] In some embodiments, the anti—TC^RpA / antibody molecule, e.g., anti—TC^Rp A / 12 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 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-TCRpV antibody molecule, e.g., anti-TCRP V12 antibody molecule may include any CDR described herein.

[0468] In some embodiments, the anti—TC^RpA / antibody molecule, e.g., anti—TC^Rp A / 12 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 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. 227:799817; 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.

[0469] In some embodiments, the anti—TC^RpA / antibody molecule, e.g., anti—TC^Rp A / 12 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 2) or by ImMunoGeneTics (IMGT) system 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 Chothia et al. shown in Table 2 or by ImMunoGeneTics (IMGT) system.

[0470] In some embodiments, the anti-TC^RpA^ antibody molecule, tyq.. anti-TC^Rp A^12 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 2) or by ImMunoGeneTics (IMGT) system 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 or by ImMunoGeneTics (IMGT) system.

[0471] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp A^12 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 2) or by ImMunoGeneTics (IMGT) system 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 or by ImMunoGeneTics (IMGT) system.

[0472] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp A^12 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 2) or by ImMunoGeneTics (IMGT) system 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 or by ImMunoGeneTics (IMGT) system. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule may include any CDR described herein.

[0473] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule 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.

[0474] In some embodiments, the anti-TC^RpA^ antibody molecule, tyq.. anti-TC^Rp A^12 antibody molecule 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.

[0475] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp A^12 antibody molecule 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.

[0476] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp A^12 antibody molecule 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-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule may include any CDR described herein.

[0477] In some embodiments, a combined CDR as set out in Table 1 is a CDR that comprises a Kabat CDR and a Chothia CDR or CDR by ImMunoGeneTics (IMGT) system.

[0478] In some embodiments, the anti-TC^RpA^ antibody molecule, e e.g., anti-TC^Rp A^12 antibody molecule, molecule includes a combination of CDRs or hypervariable loops identified as combined CDRs in Table 1. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, can contain any combination of CDRs or hypervariable loops according the “combined” CDRs are described in Table 1.

[0479] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp A^12 antibody molecule 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 or by ImMunoGeneTics (IMGT) system.

[0480] In some embodiments, the anti-TC^RpA / antibody molecule, tyq.. anti-TC^Rp A / 12 antibody molecule can contain any combination of CDRs or hypervariable loops according to the Kabat and Chothia definitions or by ImMunoGeneTics (IMGT) system.

[0481] In some embodiments, e.g., an embodiment comprising a variable region, a CDR (e.g., a combined CDR, Chothia CDR or Kabat CDR, or CDR by ImMunoGeneTics (IMGT) 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.

[0482] In some embodiments, the anti-TC^RpA / antibody molecule, e.g., anti-TC^Rp A / 12 antibody molecule 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.

[0483] In some embodiments, the anti-TC^RpA / antibody molecule, e.g., anti-TC^Rp A / 12 antibody molecule 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.

[0484] In some embodiments, the anti-TC^RpA / antibody molecule, e.g., anti-TC^Rp A / 12 antibody molecule 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.

[0485] In some embodiments, the anti-TC^RpA / antibody molecule, e.g., anti-TC^Rp A / 12 antibody molecule 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.

[0486] In some embodiments, the anti-TC^RpA / antibody molecule, e.g., anti-TC^Rp A / 12 antibody molecule 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.

[0487] In some embodiments, the anti—TC^RpA / antibody molecule, c.q.. anti—TC^Rp A / 12 antibody molecule 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.

[0488] In some embodiments, the anti—TC^RpA / antibody molecule, c.q.. anti—TC^Rp A / 12 antibody molecule 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.

[0489] In some embodiments, the light or the heavy chain variable framework (e.g., the region encompassing at least FR1, FR2, FR3, and optionally FR4) of the anti-TCRpV antibody molecule, e.g., anti-TCRp 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.

[0490] In some embodiments, the anti—TC^RpA / antibody molecule, e.g., anti—TC^Rp A / 12 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 described in Table 2 .e.g., the amino acid sequence of the FR region in the entire variable region, e.g., shown in FIGs. 3A and 3B, or in SEQ ID NOs: 23-25.

[0491] Alternatively, or in combination with the heavy chain substitutions described herein the anti-TCRpV antibody molecule, e.g., anti-TCRp 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 antibody described herein .e.g., the amino acid sequence of the FR region in the entire variable region, e.g., shown in FIGs. 3A and 3B, or in SEQ ID NOs: 26-30.

[0492] In some embodiments, the anti—TC^RpA^ antibody molecule, e.g., anti—TC^Rp A^12 antibody molecule includes one, two, three, or four heavy chain framework regions shown in FIG. 3A, or a sequence substantially identical thereto.

[0493] In some embodiments, the anti—TC^RpA^ antibody molecule, e.g., anti—TC^Rp A^12 antibody molecule includes one, two, three, or four light chain framework regions shown in FIG. 3B, or a sequence substantially identical thereto. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises the light chain framework region 1 e.g., as shown in FIG. 3B. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises the light chain framework region 2 e.g., as shown in FIG. 3B. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises the light chain framework region 3, e.g., as shown in FIG. 3B. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRP V12 antibody molecule comprises the light chain framework region 4, e.g., as shown in FIG. 3B.

[0494] In some embodiments, the anti—TC^RpA^ antibody molecule, e.g., anti—TC^Rp \^12 antibody molecule 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.

[0495] In some embodiments, the anti—TC^RpA^ antibody molecule, e.g., anti—TC^Rp \^12 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, 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-TCRpV antibody molecule, e.g., anti-TCRp 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-TCRpV antibody molecule, e.g., anti-TCRp 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, the anti-TCRpV antibody molecule, e.g., anti-TCRp 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.

[0496] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp \^12 antibody molecule 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.

[0497] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp \^12 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, and a substitution at position 69 according to Kabat numbering, e.g., a Tyrosine to Asparagine substitution. . In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp 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-TCRpV antibody molecule, e.g., anti-TCRp 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-TCRpV antibody molecule, e.g., anti-TCRp 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.

[0498] In some embodiments, the anti-TC^RpA^ antibody molecule, tyq.. anti-TC^Rp A^12 antibody molecule 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.

[0499] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp \^12 antibody molecule 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.

[0500] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp \^12 antibody molecule 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.

[0501] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp \^12 antibody molecule 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.

[0502] In some embodiments, the anti-TC^RpA^ antibody molecule, e.g., anti-TC^Rp \^12 antibody molecule 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) a 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.

[0503] In some embodiments, the anti—TC^RpA^ antibody molecule, e.g., anti—TC^Rp A^12 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, 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.

[0504] In some embodiments, the anti—TC^RpA^ antibody molecule, e.g., anti—TC^Rp A^12 antibody molecule comprises the heavy chain framework region 1, e.g., as shown in FIG. 3A. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises the heavy chain framework region 2, e.g., as shown in FIG. 3A. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises the heavy chain framework region 3, e.g., as shown in FIG. 3A. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises the heavy chain framework region 4, e.g., as shown in FIG. 3A. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp VI2 antibody molecule comprises the heavy chain framework regions 1-4, e.g., SEQ ID NOS: 20-23, or as shown in FIG. 3A. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp VI2 antibody molecule comprises the light chain framework regions 1-4, e.g., SEQ ID NOs: 26-30, or as shown in FIG. 3B.

[0505] In some embodiments, the anti—TC^RpA^ antibody molecule, e.g., anti—TC^Rp \^12 antibody molecule 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, or as shown in FIGs. 3A and 3B.

[0506] In some embodiments, the heavy or light chain variable domain, or both, of, the anti-TCRpV antibody molecule, e.g., anti-TCRp 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.

[0507] In some embodiments, the anti—TC^RpA^ antibody molecule, e.g., anti—TC^Rp \^12 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 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-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule includes a VH and / or VL 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.

[0508] In some embodiments, the anti-TC^RpA / antibody molecule, e.g., anti-TC^Rp A / 12 antibody molecule 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-TCRpV antibody molecule, e.g., anti-TCRp 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.

[0509] In some embodiments, the anti-TC^RpA / antibody molecule, e.g., anti-TC^Rp A / 12 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: 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.

[0510] In some embodiments, the anti-TC^RpA / antibody molecule, e.g., anti-TC^Rp A / 12 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: 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.

[0511] In some embodiments, the anti-TC^R[3A^ antibody molecule, tyq.. anti-TC^R[3 A^12 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: 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.

[0512] In some embodiments, the anti-TC^R[3A^ antibody molecule, tyq.. anti-TC^R[3 A^12 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: 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.

[0513] In some embodiments, the anti-TC^R[3A^ antibody molecule, tyq.. anti-TC^R[3 A^12 antibody molecule 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.

[0514] In some embodiments, the anti-TC^R[3A^ antibody molecule, tyq.. anti-TC^R[3 A^12 antibody molecule 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.

[0515] In some embodiments, the anti-TC^R[3A^ antibody molecule, tyq.. anti-TC^R[3 A^12 antibody molecule 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 ...

Claims

1. A multifunctional molecule comprising:(a) a first domain that binds to a first target molecule, wherein the first target molecule is a T cell receptor alpha (TCRa) chain; and(b) a second domain that binds to a second target molecule, wherein the second target molecule is a T cell receptor beta (TCRP) chain.

2. The multifunctional molecule of claim 1, wherein the TCRa chain is a human TCRa.

3. The multifunctional molecule of claim 1 or 2, wherein the TCRP chain is a human TCRP chain.

4. The multifunctional molecule of any one of claims 1-3, wherein the first domain is a TCRaV-binding domain that binds to a variable region of the human TCRa chain (TCRaV).

5. The multifunctional molecule of any one of claims 1-4, wherein the second domain is a TCRpV-binding domain that binds to a variable region of the human TCRP chain (TCRpV).

6. The multifunctional molecule of any one of claims 1-5, wherein the multifunctional molecule comprises at least two non-contiguous polypeptides comprising a first polypeptide chain and a second polypeptide chain;wherein the first polypeptide chain comprises a first portion of a dimerization module;wherein the second polypeptide chain comprises a second portion of the dimerization module; andwherein the first polypeptide chain and the second polypeptide chain form a dimer via association of the first portion of the dimerization module and the second portion of the dimerization module.

7. The multifunctional molecule of any one of claims 1-6, wherein the first domain is an antibody molecule.

8. The multifunctional molecule of any one of claims 1-7, wherein the second domain is an antibody molecule.

9. The multifunctional molecule of claim 7 or 8, wherein the antibody molecule is selected from the group consisting of a full-length antibody, an Fab, an Fab', an F(ab')2, an F(ab)2, a variable fragment (Fv), a single domain antibody, a diabody, a camelid antibody, a nanobody, and a single chain variable fragment (scFv).

10. The multifunctional molecule of any one of claims 7-9, wherein the first domain is a scFv or a single domain antibody.

11. The multifunctional molecule of any one of claims 7-9, wherein the first domain is an Fab comprising a first portion of the first domain and a second portion of the first domain;wherein the first portion of the first domain and the second portion of the first domain assemble and form the first domain of the multifunctional molecule;wherein the multifunctional molecule further comprises a polypeptide chain comprising the second portion of the first domain, wherein the polypeptide chain comprising the second portion of the first domain is non-contiguous with the first polypeptide chain and the second polypeptide chain.

12. The multifunctional molecule of claim 11, wherein the first portion of the first domain comprises a heavy chain variable region (VH) of the Fab and the second portion of the first domain comprises a light chain variable region (VL) of the Fab, or the first portion of the first domain comprises the VL of the Fab and the second portion of the first domain comprises the VH of the Fab.

13. The multifunctional molecule of any one of claims 7-12, wherein the second domain is a scFv or a single domain antibody.

14. The multifunctional molecule of any one of claims 7-12, wherein the second domain is an Fab comprising a first portion of the second domain and a second portion of the second domain; wherein the first portion of the second domain and the second portion of the second domain assemble and form the second domain of the multifunctional molecule;wherein the multifunctional molecule further comprises a polypeptide chain comprising the second portion of the second domain, wherein the polypeptide chain comprising the second portion of the second domain is non-contiguous with the first polypeptide chain, the second polypeptide chain, and the polypeptide chain comprising the second portion of the first domain.

15. The multifunctional molecule of claim 14, wherein the first portion of the second domain comprises a heavy chain variable region (VH) of the Fab and the second portion of the second domain comprises a light chain variable region (VL) of the Fab, or the first portion of the second domain comprises the VL of the Fab and the second portion of the second domain comprises the VH of the Fab.

16. The multifunctional molecule of any one of claims 6-15, wherein the first portion of the dimerization module is linked to the first domain or the first portion of the first domain.

17. The multifunctional molecule of claim 16, wherein the N-terminus of the first portion of the dimerization module is linked to the C-terminus of the first domain or the C-terminus of the first portion of the first domain.

18. The multifunctional molecule of claim 16, wherein the C-terminus of the first portion of the dimerization module is linked to the N-terminus of the first domain or the N-terminus of the first portion of the first domain.

19. The multifunctional molecule of any one of claims 6-18, wherein the first portion of the dimerization module is linked to the second domain or the first portion of the second domain.

20. The multifunctional molecule of any one of claims 6-19, wherein the N-terminus of the first portion of the dimerization module is linked to the C-terminus of the first domain or the C-terminus of the first portion of the first domain, and the C-terminus of the first portion of the dimerization module is linked to the N-terminus of the second domain or the N-terminus of the first portion of the second domain.

21. The multifunctional molecule of any one of claims 6-19, wherein the C-terminus of the first portion of the dimerization module is linked to the N-terminus of the first domain or the N-terminus of thefirst portion of the first domain, and the N-terminus of the first portion of the dimerization module is linked to the C-terminus of the second domain or the C-terminus of the first portion of the second domain.

22. The multifunctional molecule of any one of claims 6-18, wherein the second portion of the dimerization module is linked to the second domain or the first portion of the second domain.

23. The multifunctional molecule of claim 22, wherein the N-terminus of the second portion of the dimerization module is linked to the C-terminus of the second domain or the C-terminus of the first portion of the second domain.

24. The multifunctional molecule of claim 22, wherein the C-terminus of the second portion of the dimerization module is linked to the N-terminus of the second domain or the N-terminus of the first portion of the second domain.

25. The multifunctional molecule of any one of claims 6-18 and 22-24, wherein the N-terminus of the first portion of a dimerization module is linked to the C-terminus of the first domain or the C-terminus of the first portion of the first domain, and the N-terminus of the second portion of the dimerization module is linked to the C-terminus of the second domain or the C-terminus of the first portion of the second domain.

26. The multifunctional molecule of any one of claims 6-18 and 22-24, wherein the N-terminus of the first portion of the dimerization module is linked to the C-terminus of the first domain or the C-terminus of the first portion of the first domain, and the C-terminus of the second portion of the dimerization module is linked to the N-terminus of the second domain or the N-terminus of the first portion of the second domain.

27. The multifunctional molecule of any one of claims 6-18 and 22-24, wherein the C-terminus of the first portion of the dimerization module is linked to the N-terminus of the first domain or the N-terminus of the first portion of the first domain, and the C-terminus of the second portion of the dimerization module is linked to the N-terminus of the second domain or the N-terminus of the first portion of the second domain.

28. The multifunctional molecule of any one of claims 6-18 and 22-24, wherein the C-terminus of the first portion of the dimerization module is linked to the N-terminus of the first domain or the N-terminus of the first portion of the first domain, and the N-terminus of the second portion of the dimerization module is linked to the C-terminus of the second domain or the C-terminus of the first portion of the second domain.

29. The multifunctional molecule of claims 6-9, 11-13, and 15-28, wherein the multifunctional molecule comprises at least three non-contiguous polypeptide chains, wherein:(i) the first polypeptide chain comprising the first portion of the dimerization module linked to a first portion of the first domain;(ii) the second polypeptide chain comprising the second portion of the dimerization module; and (iii) a polypeptide chain comprising a second portion of the first domain; andwherein the second domain is linked to the first portion of the dimerization module or the second portion of the dimerization module.

30. The multifunctional molecule of claims 6-10 and 14-28, wherein the multifunctional molecule comprises at least three non-contiguous polypeptide chains, wherein:(i) the first polypeptide chain comprising the first portion of the dimerization module linked to the first domain;(ii) the second polypeptide chain comprising the second portion of the dimerization module; and (iii) a polypeptide chain comprising a second portion of the second domain; andwherein a first portion of the second domain is linked to the first portion of the dimerization module or the second portion of the dimerization module.

31. The multifunctional molecule of claims 6-9, 11, 12, and 14-28, wherein the multifunctional molecule comprises at least four non-contiguous polypeptide chains, wherein:(i) the first polypeptide chain comprising the first portion of the dimerization module linked to a first portion of the first domain;(ii) the second polypeptide chain comprising the second portion of the dimerization module;(iii) a polypeptide chain comprising a second portion of the first domain; and(iv) a polypeptide chain comprising a second portion of the second domain; and wherein a first portion of the second domain is linked to the first portion of the dimerization module or the second portion of the dimerization module.

32. The multifunctional molecule of claims 6-10, 13, and 16-28, wherein the multifunctional molecule comprises at least two non-contiguous polypeptide chains, wherein:(i) the first polypeptide chain comprising the first portion of the dimerization module linked to the first domain; and(ii) the second polypeptide chain comprising the second portion of the dimerization module; and wherein the second domain is linked to the first portion of the dimerization module or the second portion of the dimerization module.

33. The multifunctional molecule of any one of claims 1-32, wherein the multifunctional molecule further comprises at least one cytokine or a functional fragment or variant thereof.

34. The multifunctional molecule of claim 33, wherein the at least one cytokine or a functional fragment or variant thereof is linked to the first portion of the dimerization module, the second portion of the dimerization module, or any combination thereof.

35. The multifunctional molecule of claim 33 or 34, wherein the at least one cytokine or a functional fragment or variant thereof is linked to the N-terminus of the first portion of the dimerization module, 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.

36. The multifunctional molecule of any one of claims 33-35, wherein the at least one cytokine or a functional fragment or variant thereof is linked to the first domain, the first portion of the firstdomain, the second portion of the first domain, the second domain, the first portion of the second domain, the second portion of the second domain, or any combination thereof.

37. The multifunctional molecule of claim 36, wherein the at least one cytokine or a functional fragment or variant thereof is linked to the N-terminus of the first domain, the C-terminus of the first domain, the N-terminus of the first portion of the first domain, the C-terminus of the first portion of the first domain, the N-terminus of the second portion of the first domain, the C-terminus of the second portion of the first domain, the N-terminus of the second domain, the C-terminus of the second domain, the N-terminus of the first portion of the second domain, the C-terminus of the first portion of the second domain, the N-terminus of the second portion of the second domain, the C-terminus of the second portion of the second domain, or any combination thereof.

38. The multifunctional molecule of any one of claims 33-37, wherein the at least one cytokine or a functional fragment or variant thereof 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.

39. The multifunctional molecule of claim 38, wherein the at least one cytokine or a functional fragment or variant thereof comprises interleukin-2 (IL-2) or functional variant thereof.

40. The multifunctional molecule of claim 38 or 39, wherein the interleukin-2 (IL-2) or functional variant thereof comprises a sequence with at least 70% sequence identity to the sequence of SEQ ID NO: 2270 or SEQ ID NO: 2191.

41. The multifunctional molecule of any one of claims 38-40, wherein the interleukin-2 (IL-2) or functional variant thereof comprises the sequence of SEQ ID NO: 2270 or SEQ ID NO: 2191.

42. The multifunctional molecule of claim 38, wherein the at least one cytokine or a functional fragment or variant thereof comprises interleukin-15 (IL-15) or functional variant thereof.

43. The multifunctional molecule of claim 38 or 42, wherein the interleukin-15 (IL-15) or functional variant thereof comprises a sequence with at least 70% sequence identity to the sequence of SEQ ID NO: 2170.

44. The multifunctional molecule of any one of claims 38, 42, and 43, wherein the interleukin-15 (IL-15) or functional variant thereof comprises the sequence of SEQ ID NO: 2170.

45. The multifunctional molecule of any one of claims 38 and 42-44, wherein the at least one cytokine or a functional fragment or variant thereof further comprises an IL15Ralpha dimerizing domain covalently linked the interleukin-15 (IL-15) or functional variant thereof.

46. The multifunctional molecule of claim 45, wherein the IL15Ralpha dimerizing domain comprises an IL-15 receptor alpha sushi domain or functional variant thereof.

47. The multifunctional molecule of claim 45 or 46, wherein the IL15Ralpha dimerizing domain comprises a sequence with at least 70% sequence identity to the sequence of SEQ ID NO: 3472.

48. The multifunctional molecule of any one of claims 45-47, wherein the IL15Ralpha dimerizing domain comprises the sequence of SEQ ID NO: 3472.

49. The multifunctional molecule of any one of claims 45-48, wherein the interleukin-15 (IL-15) or functional variant thereof is covalently linked to the IL15Ralpha dimerizing domain via a linker.

50. The multifunctional molecule of claim 49, wherein the interleukin-15 (IL-15) or functional variant thereof is covalently linked to the IL15Ralpha dimerizing domain via a linker comprising the sequence of SEQ ID NO: 3473.

51. The multifunctional molecule of any one of claims 38 and 42-50, wherein the at least one cytokine or a functional fragment or variant thereof comprises a sequence with at least 70% sequence identity to the sequence of SEQ ID NO: 3474.

52. The multifunctional molecule of any one of claims 38 and 42-51, wherein the at least one cytokine or a functional fragment or variant thereof comprises the sequence of SEQ ID NO: 3474.

53. The multifunctional molecule of any one of claims 1-52, wherein the multifunctional molecule further comprises a linker between the first domain or the first portion of the first domain and the first portion of the dimerization module.

54. The multifunctional molecule of any one of claims 1-53, wherein the multifunctional molecule further comprises a linker between the second dom ain or the first portion of the second domain and the first portion of a dimerization module.

55. The multifunctional molecule of any one of claims 1-54, wherein the multifunctional molecule further comprises a linker between the second domain or the first portion of the second domain and the second portion of a dimerization module.

56. Tire multifunctional molecule of any one of claims 33-55, wherein the multifunctional molecule further comprises a linker between the at least one cytokine or a functional fragment or variant thereof and the first portion of the dimerization module.

57. The multi functional molecule of any one of claims 33-56, wherein the multifunctional molecule further comprises a linker between the at least one cytokine or a functional fragment or variant thereof and the first portion of the dimerization module of the first polypeptide chain.

58. The multifunctional molecule of any one of claims 33-57, wherein the multifunctional molecule further comprises a linker between the at least one cytokine or a functional fragment or variant thereof and the first domain, a linker between the at least one cytokine or a functional fragment or variant thereof and the first portion of the first domain, a linker between the at least one cytokine or a functional fragment or variant thereof and the second portion of the first domain, a linker between the at least one cytokine or a functional fragment or variant thereof and the second domain, a linker between the at least one cytokine or a functional fragment or variant thereof and the first portion of the second domain, a linker between the at least one cytokine or a functional fragment or variant thereof and the second portion of the second domain, or any combination thereof.

59. The multifunctional molecule of any one of claims 1-58, wherein the multifunctional molecule further comprises a tumor-targeting moiety.

60. The multifunctional molecule of claim 59, wherein the tumor-targeting moiety binds to a cancer antigen.

61. The multifunctional molecule of claim 59 or 60, wherein the tumor-targeting moiety binds to a cancer antigen 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 (GalNAca-Ser / Thr)), prostate-specific membrane antigen (PSMA), Receptor tyrosine kinase-like orphan receptor 1 (R0R1), 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-1 IRa), 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 (gp 100) / pmell7, oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abi) (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-la), Melanoma-associated antigen 1 (MAGE-A1), ETS translocation-variant gene 6, located on chromosome 12p (ETV6-AML), sperm protein 17 (SPA 17), 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 Telomerasereverse 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 (NA 17), paired box protein Pax-3 (PAX3), Androgen receptor, Cyclin Bl, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), Ras Homolog Family Member C (RhoC), Tyrosinase-related protein 2 (TRP-2), Cytochrome P450 1B1 (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 (RUI), 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-Bl, 9D7, Ep-CAM, EphA3, SAP-1, PRAME, Melan-A / MART-1, TRPl / gp75, MC1R, P-catenin, BRCA1 / 2, CDK4, CML66, Fibronectin, Ras, TGF-B receptor, TGF-p receptor, AFP, ETA, MAGE, CA-125, BAGE, GAGE, CDC27, a actinin-4, gangliosides, MART-2, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RU11, RU12, SAGE, TRG, TSTA, Ll-CAM, gpA33, GM2, VEGFR, Intergrins, carbohydrates, IGF1R, TRAILRI, TRAILR2, RANKL, TGF-beta, hyaluronic acid, collagen, tenascin C, tenascin W, and immunoglobulin lambda-like polypeptide 1 (IGLL1).

62. The multifunctional molecule of any one of claims 59-61, wherein the tumor-targeting moiety is an antibody molecule.

63. The multifunctional molecule of claim 62, wherein the antibody molecule is selected from the group consisting of a full-length antibody, an Fab, an Fab', an F(ab')2, an F(ab)2, a variable fragment (Fv), a single domain antibody, a diabody, a camelid antibody, a nanobody, and a single chain variable fragment (scFv).

64. The multifunctional molecule of any one of claims 1-63, wherein the multifunctional molecule further comprises a stromal modifying moiety.

65. The multifunctional molecule of any one of claims 1-64, wherein the multifunctional molecule further comprises an immune cell engager.

66. The multifunctional molecule of claim 65, 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, the macrophage cell engager, and any combination thereof.

67. The multifunctional molecule of claim 65 or 66, wherein immune cell engager is an antibody molecule.

68. The multifunctional molecule of claim 67, wherein the antibody molecule is selected from the group consisting of a full-length antibody, an Fab, an Fab', an F(ab')2, an F(ab)2, a variable fragment (Fv), a single domain antibody, a diabody, a camelid antibody, a nanobody, and a single chain variable fragment (scFv).

69. The multifunctional molecule of any one of claims 1-68, wherein the first portion of the dimerization module of the first polypeptide chain is a first Fc region or variant thereof.

70. The multifunctional molecule of any one of claims 1-69, wherein the second portion of the dimerization module of the second polypeptide chain is a second Fc region or variant thereof.

71. The multifunctional molecule of claim 69 or 70, wherein the first portion of the dimerization module, the second portion of the dimerization module, or a combination thereof is selected from the group consisting of an IgGl Fc region or a functional fragment thereof, an IgG2 Fc region or a functional fragment thereof, an IgG3 Fc region or a functional fragment thereof, an IgGAl Fc region or a functional fragment thereof, an IgGA2 Fc region or a functional fragment thereof, an IgG4 Fc region or a functional fragment thereof, an IgJ Fc region or a functional fragment thereof, an IgM Fc region or a functional fragment thereof, an IgD Fc region or a functional fragment thereof, and an IgE Fc region or a functional fragment thereof.

72. The multifunctional molecule of any one of claims 69-71, wherein the first Fc region, the second Fc region, or a combination thereof comprises an engineered Fc interface with one or more of: a paired cavity-protuberance, an electrostatic interaction, or a strand-exchange, wherein 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 dimerization of Fc regions without the engineered interface.

73. The multifunctional molecule of any one of claims 69-72, wherein the first Fc region, the second Fc region, or a combination thereof comprises a Cys at position 349, a Ser at position 366, an Ala at position 368, a Vai at position 407, a Cys at position 354, a Trp at position 366, or any combination thereof in a heavy chain constant region according to EU Numbering.

74. The multifunctional molecule of any one of claims 69-73, wherein the first Fc region, the second Fc region, or a combination thereof comprises (i) a Cys at position 349, a Ser at position 366, an Ala at position 368, and a Vai at position 407 in a heavy chain constant region according to EU Numbering; (ii) a Cys at position 354 and a Trp at position 366 in a heavy chain constant region according to EU Numbering; or (iii) a combination thereof.

75. The multifunctional molecule of any one of claims 69-74, wherein:(i) the first Fc region comprises:(a) a Cys at position 349 in a heavy chain constant region according to EU Numbering, (b) a Ser at position 366 in a heavy chain constant region according to EU Numbering, (c) an Ala at position 368 in a heavy chain constant region according to EU Numbering, and (d) a Vai at position 407 in a heavy chain constant region according to EU Numbering; and(ii) the second Fc region comprises:(a) a Cys at position 354 in a heavy chain constant region according to EU Numbering, and(b) a Trp at position 366 in a heavy chain constant region according to EU Numbering.

76. The multifunctional molecule of any one of claims 69-74, wherein:(i) the first Fc region comprises:(a) a Cys at position 354 in a heavy chain constant region according to EU Numbering, and(b) a Trp at position 366 in a heavy chain constant region according to EU Numbering(ii) the second Fc region comprises:(a) a Cys at position 349 in a heavy chain constant region according to EU Numbering,(b) a Ser at position 366 in a heavy chain constant region according to EU Numbering, (c) an Ala at position 368 in a heavy chain constant region according to EU Numbering, and (d) a Vai at position 407 in a heavy chain constant region according to EU Numbering.

77. The multifunctional molecule of any one of claims 69-76, wherein the first Fc region, the second Fc region, or a combination thereof comprise one or more mutations that result in reduced or ablated affinity for at least one Fc receptor relative to a Fc region without the one or more mutations.

78. The multifunctional molecule of any one of claims 69-77, wherein the first Fc region, the second Fc region, or a combination thereof comprises an Asn297Ala (N297A) mutation or a Leu234Ala / Leu235Ala (LALA) mutation, or a combination thereof according to EU Numbering.

79. The multifunctional molecule of any one of claims 69-78, wherein the first Fc region, the second Fc region, or a combination thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 3901, SEQ ID NO: 3645, SEQ ID NO: 3902, SEQ ID NO: 3646, SEQ ID NO: 3647, SEQ ID NO: 3903, SEQ ID NO:206, SEQ ID NO: 207, SEQ ID NO: 3904, SEQ ID NO: 3452, SEQ ID NO: 3447, or SEQ ID NO: 3453.

80. The multifunctional molecule of any one of claims 69-79, wherein the first Fc region, the second Fc region, or a combination thereof comprises the sequence of SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 3901, SEQ ID NO: 3645, SEQ ID NO: 3902, SEQ ID NO: 3646, SEQ ID NO: 3647, SEQ ID NO: 3903, SEQ ID NO:206, SEQ ID NO: 207, SEQ ID NO: 3904, SEQ ID NO: 3452, SEQ ID NO: 3447, or SEQ ID NO: 3453.

81. The multifunctional molecule of any one of claims 69-80, wherein the first Fc region, the second Fc region, or a combination thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:206, SEQ ID NO: 3447, or SEQ ID NO: 3453.

82. The molecule of any one of claims 69-81, wherein the first Fc region, the second Fc region, or a combination thereof comprises the sequence of SEQ ID NO:206, SEQ ID NO: 3447, or SEQ ID NO: 3453.

83. The multifunctional molecule of any one of claims 1-82, wherein the multifunctional the molecule comprises the following configuration:A-[first portion of dimerization module]-C,B-[second portion of dimerization module]-D, wherein:(a) the dimerization module comprises a first immunoglobulin chain constant region and a second immunoglobulin chain constant region;(b) A and C are linked to the first immunoglobulin chain constant region; and B and D are linked to the second immunoglobulin chain constant region;(c) A, B, C, and D are independently (i) absent; (ii) the first domain; (iii) the second domain, (iv) the at least one cytokine or a functional fragment or variant thereof, (v) the tumor targeting moiety, (vi) the stromal modifying moiety; or (vii) the immune cell engager;wherein at least one of A or C are the first domain, andwherein when A is the first domain, at least one of B, C, or D is the second domain, and when C is the first domain, at least one of A, B, or D is the second domain.

84. The multifunctional molecule of any one of claims 1-83, wherein the multifunctional molecule is not immobilized to a solid-phase.

85. The multifunctional molecule of any one of claims 1-84, wherein the multifunctional molecule is not immobilized to a solid-phase.

86. The multifunctional molecule any one of claim 1-85, wherein the second domain binds to one or more of a TCRpV subfamily selected from the group consisting of TCRP VI subfamily, TCRP V2 subfamily, TCRP V3 subfamily, TCRP V4 subfamily, TCRP V5 subfamily, TCRP V6 subfamily, TCRP V7 subfamily, TCRP V8 subfamily, TCRP V9 subfamily, TCRP V10 subfamily, TCRP Vil subfamily, TCRP VI2 subfamily, TCRP V13 subfamily, TCRP VI4 subfamily, TCRP V15 subfamily, TCRP VI6 subfamily, TCRP V17 subfamily, TCRP VI8 subfamily, TCRP VI9, TCRP V20 subfamily, TCRP V21 subfamily, TCRP V22 subfamily TCRP V23 subfamily, TCRP V24 subfamily, TCRP V25 subfamily, TCRP V26 subfamily, TCRP V27 subfamily, TCRP V28 subfamily, TCRP V29 subfamily, and TCRP V30 subfamily.

87. The multifunctional molecule of any one of claims 1-86, wherein the second domain binds to one or more of a TCRpV subfamily selected from the group consisting of:(i) TCRP VI subfamily comprising TCRP VI*01;(ii) TCRP V2 subfamily comprising one or more selected from TCRP V2*01, TCRP V2*02, and TCRP V2* 03;(iii) TCRP V3 subfamily comprising one or more selected from TCRP V3-l*01 and TCRP V3-1*02;(iv) TCRP V4 subfamily comprising one or more selected from TCRP V4-l*01, TCRP V4-1*02, TCRP V4-2*01, TCRP V4-2*02, TCRP V4-3*01, TCRP V4-3*02, TCRP V4-3*03, and TCRP V4-3*04;(v) TCRP V5 subfamily comprising one or more selected from TCRP V5-l*01, TCRP V5-1*02, TCRP V5-3*01, TCRP V5-3*02, TCRP V5-4*01, TCRP V5-4*02, TCRP V5-4*03, TCRP V5-4*04, TCRP V5-5*01, TCRP V5-5*02, TCRP V5-5*03, TCRP V5-6*01, TCRP V5-7*01, TCRP V5-8*01, and TCRP V5-8*02;(vi) TCRP V6 subfamily comprising one or more selected from TCRP V6-l*01, TCRP V6-2*01, TCRP V6-3*01, TCRP V6-4*01, TCRP V6-4*02, TCRP V6-5*01, TCRP V6-6*01, TCRP V6-6*02, TCRP V6-6*03, TCRP V6-6*04, TCRP V6-6*05, TCRP V6-7*01, TCRP V6-8*01, and TCRP V6-9*01;(vii) TCRP V7 subfamily comprising one or more selected from TCRP V7-l*01, TCRP V7-2*01, TCRP V7-2*02, TCRP V7-2*03, TCRP V7-2*04, TCRP V7-3*01, TCRP V7-3*02, TCRP V7-3*03, TCRP V7-3*04, TCRP V7-3*05, TCRP V7-4*01, TCRP V7-4*02, TCRP V7-6*01, TCRP V7-6*02, TCRP V7-7*01, TCRP V7-7*02, TCRP V7-8*01, TCRP V7-8*02, TCRP V7-8*03, TCRP V7-9*01, TCRP V7-9*02, TCRP V7-9*03, TCRP V7-9*04, TCRP V7-9*05, TCRP V7-9*06, and TCRP V7-9*07.(viii) TCRP V8 subfamily comprising one or more selected from TCRP V8-l*01, TCRP V8-1*02, TCRP V8-2*01, and TCRP V8-2*02;(ix) TCRP V9 subfamily comprising one or more selected from TCRP V9-l*01, TCRP V9-1*02, and TCRP V9-1*03;(x) TCRP V10 subfamily comprising one or more selected from TCRP V10-l*01, TCRP V10-1*02, TCRP V10-l*03, TCRP V10-2*01, TCRP V10-2*02, TCRP V10-3*01, TCRP V10-3*02, TCRP V10-3*03, and TCRP V10-3*04;(xi) TCRP VI1 subfamily comprising TCRP VI 1-1*01, TCRP VI 1-2*01, TCRP VI 1-2*02, TCRP VI 1-2*03, TCRP VI 1-3*01, TCRP VI 1-3*02, TCRP VI 1-3*03, and TCRP VI1-3*04;(xii) TCRP V12 subfamily comprising one or more selected from TCRP V 12-3*01, TCRP V12-4*01, TCRP V12-4*02, and TCRP V12-5*01;(xiii) TCRP V13 subfamily comprising one or more selected from TCRP V13*01 and TCRP V13*02;(xiv) TCRP V14 subfamily comprising one or more comprising from TCRP V14*01 and TCRP V14*02;(xv) TCRP VI5 subfamily comprising one or more selected from TCRP V15*01, TCRP V15*02, and TCRP V15*03;(xvi) TCRP V16 subfamily comprising one or more selected from TCRP V16*01, TCRP VI6*02, and TCRP VI6*03;(xvii) TCRP V17 subfamily comprising TCRP V17*01;(xviii) TCRP V18 subfamily comprising TCRP V18*01;(xix) TCRP V19 subfamily comprising one or more selected from TCRP V19*01, TCRPVI9*02, and TCRP VI9*03;(xx) TCRP V20 subfamily comprising one or more selected from TCRP V20-l*01, TCRP V20-l*02, TCRP V20-l*03, TCRP V20-l*04, TCRP V20-l*05, TCRP V20-l*06, and TCRP V20-1*07;(xxi) TCRP V21 subfamily comprising one or more selected from TCRP V21-l*01 and TCRP V21-l*02;(xxii) TCRP V22 subfamily comprising TCRP V22-l*01;(xxiii) TCRP V23 subfamily comprising TCRP V23-l*01;(xxiv) TCRP V24 subfamily comprising TCRP V24-l*01;(xxv) TCRP V25 subfamily comprising TCRP V25-l*01;(xxvi) TCRP V26 subfamily comprising TCRP V26-l*01;(xxvii) TCRP V27 subfamily comprising TCRP V27*01;(xxviii) TCRP V28 subfamily comprising TCRP V28*01;(xxix) TCRP V29 subfamily comprising one or more selected from TCRP V29-l*01, TCRP V29-l*02, and TCRP V29-l*03; and(xxx) TCRP V30 subfamily comprising one or more selected from TCRP V30*01, TCRP V30*02, TCRP V30*03, TCRP V30*04, and TCRP V30*05.

88. The multifunctional molecule of any one of claims 1-87, wherein the second domain binds to TCRP V4 subfamily, TCRP V6 subfamily, TCRP V20 subfamily, or TCRP V25 subfamily.

89. The multifunctional molecule of any one of claims 1-88, wherein the second domain binds to TCRB V4-1, TCRB V6-1, TCRB V6-2, TCRB V6-3, TCRB V6-4, TCRB V6-5, TCRB V6-6, TCRB V6-7, TCRB V6-8, TCRB V6-9, TCRB V20-1, or TCRB V25-1.

90. The multifunctional molecule of any one of claims 1-89, wherein the multifunctional molecule comprises a single TCRpV-binding domain.

91. The multifunctional molecule of any one of claims 1-90, wherein the first domain binds to one or more of a TCRaV subfamily selected from the group consisting of: a TCRaVl subfamily, a TCRa V2 subfamily, a TCRa V3 subfamily, a TCRa V4 subfamily, a TCRa V5 subfamily, a TCRa V6 subfamily, a TCRa V7 subfamily, a TCRa V8 subfamily, a TCRa V9 subfamily, a TCRa V10 subfamily, a TCRa V12 subfamily, a TCRa V13 subfamily, a TCRa V14 subfamily, a TCRa V16 subfamily, a TCRa V17 subfamily, a TCRa V18 subfamily, a TCRa V19 subfamily, a TCRa V20 subfamily, a TCRa V21 subfamily, a TCRa V22 subfamily, a TCRa V23 subfamily, a TCRa V24 subfamily, TCRa V25 subfamily, a TCRa V26 subfamily, a TCRa V27 subfamily, a TCRa V29 subfamily, a TCRa V30 subfamily, a TCRa V34 subfamily, a TCRa V35 subfamily, a TCRa V36 subfamily, a TCRa V38 subfamily, a TCRa V39 subfamily, a TCRa V40 subfamily, and a TCRa V41 subfamily.

92. The multifunctional molecule of any one of claims 1-91, wherein the first domain binds to one or more of a TCRaV subfamily selected from the group consisting of:(i) TCRaVl subfamily comprising one or more selected from TCRa Vl-l*01, TCRa Vl-l*02, TCRa VI-2*01, and TCRa VI-2*02;(ii) TCRa V2 subfamily comprising one or more selected from TCRa V2*01 and TCRa V2*02;(iii) TCRa V3 subfamily comprising TCRa V3*01;(iv) TCRa V4 subfamily comprising TCRa V4*01;(v) TCRa V5 subfamily comprising TCRa V5*01(vi) TCRa V6 subfamily comprising one or more selected from TCRa V6*01, TCRa V6*02, TCRa V6*03, TCRa V6*04, TCRa V6*05, and TCRa V6*06;(vii) TCRa V7 subfamily comprising TCRa V7*01;(viii) TCRa V8 subfamily comprising one or more selected from TCRa V8-l*01, TCRa V8-1*02, TCRa V8-2*01, TCRa V8-2*02, TCRa V8-3*01, TCRa V8-3*02, TCRa V8-3*03, TCRa V8-4*01, TCRa V8-4*02, TCRa V8-4*03, TCRa V8-4*04, TCRa V8-4*05, TCRa V8-4*06, TCRaV8-4*07, TCRa V8-6*01, TCRaV8-6*02, and TCRaV8-7*01;(ix) TCRaV9 subfamily comprising one ormore selected from TCRaV9-l*01, TCRa V9-2*01, TCRa V9-2*02, TCRa V9-2*03, and TCRa V9-2*04;(x) TCRa V10 subfamily comprising TCRa V10*01;(xi) TCRa V12 subfamily comprising one or more selected from TCRa V12-l*01, TCRa V12-1*02, TCRa V12-2*01, TCRa V12-2*02, TCRa V12-2*03, TCRa V12-3*01, and TCRa V12-3*02;(xii) TCRa V13 subfamily comprising one or more selected from TCRa V13-l*01, TCRa VI3-1*02, TCRa V13-l*03, TCRa V13-2*01, and TCRa V13-2*02;(xiii) TCRa V14 subfamily comprising one or more selected from TCRa V14*01, TCRa V14*02, TCRa V14*03, and TCRa V14*04;(xiv) TCRa V16 subfamily comprising TCRa V16*01;(xv) TCRa V17 subfamily comprising TCRa V17*01;(xvi) TCRa V18 subfamily comprising TCRa V 18*01;(xvii) TCRa V19 subfamily comprising TCRa V19*01;(xviii) TCRa V20 subfamily comprising one or more selected from TCRa V20*01, TCRa V20*02, TCRa V20*03, and TCRa V20*04;(xix) TCRa V21 subfamily comprising one or more selected from TCRa V21*01 and TCRa V20*02;(xx) TCRa V22 subfamily comprising TCRa V22*01;(xxi) TCRa V23 subfamily comprising one or more selected from TCRa V23*01, TCRa V23*02, TCRa V23*03, and TCRa V23*04;(xxii) TCRa V24 subfamily comprising one or more selected from TCRa V23*01 and TCRa V23*02;(xxiii) TCRa V25 subfamily comprising TCRa V25*01;(xxiv) TCRa V26 subfamily comprising one ormore selected from TCRa V26-l*01, TCRa V26-l*02, TCRa V26-1*03, TCRa V26-2*01, and TCRa V26-2*02;(xxv) TCRa V27 subfamily comprising one or more selected from TCRa V27*01, TCRa V27*02, and TCRa V27*03;(xxvi) TCRa V29 subfamily comprising one or more selected from TCRa V29*01 and TCRa V27*02;(xxvii) TCRa V30 subfamily comprising one or more selected from TCRa V30*01, TCRa V30*02, TCRa V30*03, and TCRa V30*04;(xxviii) TCRa V34 subfamily comprising TCRa V34*01;(xxix) TCRa V35 subfamily comprising one or more selected from TCRa V35*01 and TCRa V35*02;(xxx) TCRa V36 subfamily comprising one or more selected from TCRa V36*01, TCRa V36*02, TCRa V36*03, and TCRa V36*04;(xxxi) TCRa V38 subfamily comprising one or more selected from TCRa V38-l*01, TCRa V38-l*02, TCRa V3 8-1*03, TCRa V38-1*04, and TCRa V38-2*01;(xxxii) TCRa V39 subfamily comprising TCRa V39*01;(xxxiii) TCRa V40 subfamily comprising TCRa V40*01; and(xxxiv) TCRa V41 subfamily comprising TCRa V41*01.

93. The multifunctional molecule of any one of claims 1-92, wherein the second domain binds to TCRa V12 subfamily, TCRa V13 subfamily, TCRa V19 subfamily, TCRa V21 subfamily, or TCRa V30 subfamily.

94. The multifunctional molecule of any one of claims 1-92, wherein the second domain binds to TCRa VI subfamily, TCRa VI0 subfamily, TCRa V17 subfamily, or TCRa V19 subfamily.

95. The multifunctional molecule of any one of claims 1-92, wherein the second domain binds to TCRa Vl-2, TCRa V10, or TCRa V17.

96. The multifunctional molecule of claim 1-95, wherein the first domain and the second domain bind to: TCRa VI and TCRp V6, respectively;TCRa VI and TCRp V20, respectively;TCRa V10 and TCRp V25, respectively;TCRa VI and TCRp V4, respectively;TCRa V17 and TCRp V4, respectively; orTCRa V17 and TCRp V6, respectively.

97. The multifunctional molecule of claim 1-96, wherein the first domain and the second domain bind to:TCRa Vl-2 and TCRp V6-1, respectively;TCRa Vl-2 and TCRp V6-2, respectively;TCRa Vl-2 and TCRp V6-3, respectively;TCRa Vl-2 and TCRp V6-4, respectively;TCRa Vl-2 and TCRp V6-5, respectively;TCRa Vl-2 and TCRp V6-6, respectively;TCRa Vl-2 and TCRp V6-7, respectively;TCRa Vl-2 and TCRp V6-8, respectively;TCRa Vl-2 and TCRp V6-9, respectively;TCRa Vl-2 and TCRp V20-1, respectively;TCRa V10 and TCRp V25-1, respectively;TCRa Vl-2 and TCRp V4-1, respectively;TCRa V17 and TCRp V4-1, respectively; or TCRa V17 and TCRp V6-2, respectively.

98. The multifunctional molecule of any one of claims 1-97, wherein the first domain comprises an antibody molecule that binds to the TCRaV comprising (i) a VH comprising a combination of a HC CDR1, a HC CDR2 and a HC CDR3 listed in Table 22; (ii) a VL comprising a combination of a LC CDR1, a LC CDR2, and a LC CDR3 listed in Table 22; or (iii) a combination thereof.

99. The multifunctional molecule of any one of claims 1-98, wherein the first domain comprises an antibody molecule that binds to the TCRaV comprising (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 Table 22; (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 Table 22; or (iii) a combination thereof.

100. The multifunctional molecule of any one of claims 1-99, wherein the first domain comprises an antibody molecule that binds to the TCRaV comprising (i) a VH comprising a sequence having at least 70% sequence identity to any one of the heavy chain variable domain amino acid sequences listed in Table 22; (i) a VL comprising a sequence having at least 70% sequence identity to any one of the light chain variable domain amino acid sequences listed in Table 22; or (iii) a combination thereof.

101. The multifunctional molecule of any one of claims 1-100, wherein the first domain comprises an antibody molecule that binds to the TCRaV comprising (i) a VH comprising any one of the heavy chain variable domain amino acid sequences listed in Table 22; (ii) a VL comprising any one of the light chain variable domain amino acid sequences listed in Table 22; or (iii) a combination thereof.

102. The multifunctional molecule of any one of claims 1-101, wherein the first domain comprises any one of antibody molecules that binds to the TCRaV listed in Table 22.

103. The multifunctional molecule of any one of claims 1-102, wherein the second domain comprises an antibody molecule that binds to the TCRpV comprising (i) a VH comprising a combination of a HC CDRl,aHC CDR2 andaHC CDR3 listed in Tables 1,2, 10A,10B, 10C, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26; (ii) a VL comprising a combination of a LC CDR1, a LC CDR2, and a LC CDR3 listed in Tables 1,2, 10A,10B, 10C, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26; or (iii) a combination thereof.

104. The multifunctional molecule of any one of claims 1-103, wherein the second domain comprises an antibody molecule that binds to the TCRpV comprising (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, 10A,10B, 10C, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26; (ii) a VL comprisinga 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, 10A,10B, IOC, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26; or (iii) a combination thereof.

105. The multifunctional molecule of any one of claims 1-104, wherein the second domain comprises an antibody molecule that binds to the TCRpV comprising (i) a VH comprising a sequence having at least 70% sequence identity to any one of the heavy chain variable domain amino acid sequences listed in Tables 1,2, 10A,10B, 10C, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26; (i)aVL comprising a sequence having at least 70% sequence identity to any one of the light chain variable domain amino acid sequences listed in Tables 1, 2, 10A,10B, 10C, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26; or (iii) a combination thereof.

106. The multifunctional molecule of any one of claims 1-105, wherein the second domain comprises an antibody molecule that binds to the TCRpV comprising (i) a VH comprising any one of the heavy chain variable domain amino acid sequences listed in Tables 1, 2, 10A,10B, 10C, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26; (ii) a VL comprising any one of the light chain variable domain amino acid sequences listed in Tables 1, 2, 10A,10B, 10C, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26; or (iii) a combination thereof.

107. The multifunctional molecule of any one of claims 1-106, wherein the second domain comprises any one of antibody molecules that binds to the TCRpV listed in Tables 1, 2, 10A,10B, 10C, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 25, or 26.

108. The multifunctional molecule of any one of claims 1-107, wherein the first Fc region, the second Fc region, or a combination thereof comprises one or more mutations listed in tables 4 and 14 according to EU numbering.

109. The multifunctional molecule of any one of claims 1-108, wherein the first Fc region, the second Fc region, or a combination thereof comprises a sequence having at least 70% sequence identity to any one of the heavy chain constant region sequences listed in Tables 1, 2, 3, 10C, 11, 15, 16, 17, 18, 19, 20,21,22, 23, 25, or 26.

110. The multifunctional molecule of any one of claims 1-109, wherein the first Fc region, the second Fc region, or a combination thereof comprises any one of the heavy chain constant region sequences listed in Tables 1,2, 3, 10C, 11, 15, 16, 17, 18, 19, 20,21,22, 23,25, or 26.

111. The multifunctional molecule of any one of claims 1-110, wherein the multifunctional molecule further comprises one or more immunoglobulin light chain constant regions.

112. The multifunctional molecule of claim 111, wherein the one or more immunoglobulin light chain constant region is linked to the first domain, the first portion of the first domain, or the second portion of the first domain.

113. The multifunctional molecule of claim 111 or 112, wherein the one or more immunoglobulin light chain constant region is linked to the second domain, the first portion of the second domain, or the second portion of the second domain.

114. The multifunctional molecule of any one of claims 111-113, wherein the one or more immunoglobulin light chain constant region is linked to the at least one cytokine or a functional fragment or variant thereof.

115. The multifunctional molecule of any one of claims 111-114, wherein the one or more immunoglobulin light chain constant region comprises a kappa light chain constant region, a lambda light chain constant region, or a combination thereof.

116. The multifunctional molecule of any one of claims 111-115, wherein the one or more immunoglobulin light chain constant region comprises a sequence having at least 70% sequence identity to any one of the light chain constant region sequences listed in Tables 1, 2, 3, IOC, 11, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, or 26.

117. The multifunctional molecule of any one of claims 111-116, wherein the one or more immunoglobulin light chain constant region comprises any one of the light chain constant region sequences listed in Tables 1,2,3, IOC, 11, 15, 16, 17, 18, 19, 20,21,22, 23, 25, or 26.

118. The multifunctional molecule of any one of claims 33-117, wherein the at least one cytokine or a functional fragment or variant thereof comprises a sequence having at least 70% sequence identity to any one of the cytokine sequences listed in Tables 10C, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, or 26.

119. The multifunctional molecule of any one of claims 33-118, wherein the at least one cytokine or a functional fragment or variant thereof comprises any one of the cytokine sequences listed in Tables 10C, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, or 26.

120. The multifunctional molecule of any one of claims 59-119, wherein the tumor-targeting moiety comprises a sequence having at least 70% sequence identity to any one of the antibody sequences listed in Table 24.

121. The multifunctional molecule of any one of claims 59-120, wherein the tumor-targeting moiety comprises any one of the antibody sequences listed in Table 24.

122. The multifunctional molecule of any one of claims 1-121, wherein the multifunctional molecule does not comprise an anti-CD3 binding domain.

123. The multifunctional molecule of any one of claims 1-122, wherein the multifunctional molecule is a polypeptide molecule.

124. The multifunctional molecule of any one of claims 1-123, wherein the multifunctional molecule is a multispecific molecule.

125. A polynucleotide comprising a sequence encoding the multifunctional molecule of any one of claims 1-124.

126. The polynucleotide of claim 125, wherein the polynucleotide is an isolated nucleic acid molecule.

127. A vector comprising the polynucleotide of claim 125 or 126.

128. A cell comprising the multifunctional molecule of any one of claims 1-124, the polynucleotide of claim 125 or 126, or the vector of claim 127.

129. A method of making the multifunctional molecule of any one of claims 1-124 comprising: culturing a cell comprising the polynucleotide of claim 125 or 126 or the vector of claim 127 under conditions suitable for expression of the multifunctional molecule.

130. A method of making the multifunctional molecule of any one of claims 1-124 comprising: culturing the cell of claim 128 under conditions suitable for expression of the multifunctional molecule.

131. A composition comprising the multifunctional molecule of any one of claims 1-124.

132. A pharmaceutical composition comprising the multifunctional molecule of any one of claims 1-124, the polynucleotide of claim 125 or 126, the vector of claim 127, the cell of claim 128, or the composition of claim 131, and a pharmaceutically acceptable carrier, excipient, or diluent.

133. A method of treating a condition or disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the multifunctional molecule of any one of claims 1124, the polynucleotide of claim 125 or 126, the vector of claim 127, the cell of claim 128, the composition of claim 131, the pharmaceutical composition of claim 132, or a combination thereof, wherein the administering is effective to treat the condition or disease in the subject.

134. The method of claim 133, wherein the condition or disease is cancer.

135. The method of claim 134, wherein the cancer is a solid tumor, a hematological cancer, a metastatic cancer, a soft tissue tumor, or a combination thereof.

136. The method of claim 134 or 135, wherein the cancer is the solid tumor, and wherein the solid tumor is selected from the group consisting of melanoma, pancreatic cancer, breast cancer, colorectal cancer, lung cancer, skin cancer, ovarian cancer, liver cancer, and a combination thereof.

137. The method of claim 134 or 135, wherein 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.

138. The method of claim 137, wherein the Non-Hodgkin’s lymphoma is selected 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.

139. The method of claim 137, wherein the T-cell lymphoma is peripheral T-cell lymphoma.

140. The method of any one of claims 134-139, wherein the cancer is characterized by a cancer antigen present on the cancer.

141. The method of claim 140, wherein the cancer antigen present on the cancer is a tumor antigen, a stromal antigen, or a hematological antigen.

142. The method of claim 140 or 141, wherein 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 (GalNAca-Ser / Thr)), prostate-specific membrane antigen (PSMA), Receptor tyrosine kinase-like orphan receptor 1 (ROR1), Fms-LikeTyrosine 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-1 IRa), 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 (gp 100) / pmell7, oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abi) (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-la), Melanoma-associated antigen 1 (MAGE-A1), ETS translocation-variant gene 6, located on chromosome 12p (ETV6-AML), sperm protein 17 (SPA 17), 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 (NA 17), paired box protein Pax-3 (PAX3), Androgen receptor, Cyclin Bl, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), Ras Homolog Family Member C (RhoC), Tyrosinase-related protein 2 (TRP-2), Cytochrome P450 1B1 (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 proteinsp32 (0Y-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 (RUI), 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-Bl, 9D7, Ep-CAM, EphA3, SAP-1, PRAME, Melan-A / MART-1, TRPl / gp75, MC1R, P-catenin, BRCA1 / 2, CDK4, CML66, Fibronectin, Ras, TGF-B receptor, TGF-p receptor, AFP, ETA, MAGE, CA-125, BAGE, GAGE, CDC27, a actinin-4, gangliosides, MART-2, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RU11, RU12, SAGE, TRG, TSTA, Ll-CAM, gpA33, GM2, VEGFR, Intergrins, carbohydrates, IGF1R, TRAILRI, TRAILR2, RANKL, TGF-beta, hyaluronic acid, collagen, tenascin C, tenascin W, and immunoglobulin lambda-like polypeptide 1 (IGLL1).

143. The method of any one of claims 134-142, further comprising administering a second therapeutic agent or therapy to the subject.

144. The method of claim 143, wherein the second therapeutic agent or therapy comprises a chemotherapeutic agent, a biologic agent, a hormonal therapy, radiation, or surgery.

145. The method of claim 143 or 144, wherein the second therapeutic agent or therapy is administered in combination with the multifunctional molecule of any one of claims 1-124, the polynucleotide of claim 125 or 126, the vector of claim 127, the cell of claim 128,, the composition of claim 131, or the pharmaceutical composition of claim 132, sequentially, simultaneously, or concurrently.

146. A method of expansion of a subset of T cells in a T cell population comprising contacting the T cell population with the multifunctional molecule of any one of claims 1-124 or the composition of claim 131, thereby expanding the subset of T cells in the T cell population.

147. The method of claim 146, wherein the T cell population is a human T cell population.

148. The method of claim 146 or 147, wherein the subset of T cells are a subset of human T cells.

149. The method of any one of claims 146-148, wherein the subset of T cells express a T cell receptor (TCR) comprising a TCRP chain that comprises the TCRpV to which the second domain binds.

150. The method of any one of claims 146-149, wherein the subset of T cells express a TCR comprising a TCRa chain that comprises the TCRaV to which the first domain binds.

151. The method of claim 149 or 150, wherein the TCR is a human TCR.

152. The method of any one of claims 149-151, wherein the multispecific molecule is an agonist of the TCR.

153. The method of any one of claims 146-152, wherein the T cell population is an in vivo T cell population.

154. The method of any one of claims 146-152, wherein the T cell population is an ex vivo T cell population.

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