Multifunctional molecules binding to TCR and uses thereof

Abstract

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

Description

WSGR Docket No.53676-766.601 MULTIFUNCTIONAL MOLECULES BINDING TO TCR AND USES THEREOF CROSS REFERENCE

[0001] This application claims the benefit of U.S. provisional Application No.63 / 497,952 filed April 24, 2023, 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 molecule comprising an antigen binding domain that binds to a T cell receptor beta variable region (TCRβV), wherein the antigen binding domain comprises a light chain variable region (VL) comprising: (i) a light chain complementarity determining region 1 (LC CDR1) amino acid sequence of KASQNVADRVV (SEQ ID NO: 3354), (ii) a light chain complementarity determining region 2 (LC CDR2) amino acid sequence of AASYLQS (SEQ ID NO: 3443), and (iii) a light chain complementarity determining region 3 (LC CDR3) amino acid sequence of QQFKSYPLT (SEQ ID NO: 3356).

[0004] In some embodiments, the antigen binding domain comprises a heavy chain variable region (VH) comprising: (i) a heavy chain complementarity determining region 1 (HC CDR1) amino acid sequence of LTYIH (SEQ ID NO: 3421), FRLTYIH (SEQ ID NO: 3702), or GHDFRLTYIH (SEQ ID NO: 3351); (ii) a heavy chain complementarity determining region 2 (HC CDR2) amino acid sequence of RVSAGSGNVKYNEKFKG (SEQ ID NO: 3352); (iii) a heavy chain complementarity determining region 3 (HC CDR3) amino acid sequence of SYYSYDVLDY (SEQ ID NO: 3353); orWSGR Docket No.53676-766.601 (iv) any combination thereof.

[0005] In some embodiments, the antigen binding domain comprises a VH comprising: (i) a HC CDR1 amino acid sequence of LTYIH (SEQ ID NO: 3421), FRLTYIH (SEQ ID NO: 3702), or GHDFRLTYIH (SEQ ID NO: 3351); (ii) a HC CDR2 amino acid sequence of RVSAGSGNVKYNEKFKG (SEQ ID NO: 3352); and (iii) a HC CDR3 amino acid sequence of SYYSYDVLDY (SEQ ID NO: 3353).

[0006] In some embodiments, the antigen binding domain comprises a VL comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3475 or SEQ ID NO: 3476.

[0007] In some embodiments, the antigen binding domain comprises a VL comprising the sequence of SEQ ID NO: 3475 or SEQ ID NO: 3476.

[0008] In some embodiments, the antigen binding domain comprises a VH comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 1346.

[0009] In some embodiments, the antigen binding domain comprises a VH comprising the sequence of SEQ ID NO: 1346.

[0010] In some embodiments, the antigen binding domain comprises a VH comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 1346 and a VL comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3475.

[0011] In some embodiments, the antigen binding domain comprises a VH comprising the sequence of SEQ ID NO: 1346 and a VL comprising the sequence of SEQ ID NO: 3475.

[0012] In some embodiments, the antigen binding domain comprises a VH comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 1346 and a VL comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3476.

[0013] In some embodiments, the antigen binding domain comprises a VH comprising the sequence of SEQ ID NO: 1346 and a VL comprising the sequence of SEQ ID NO: 3476.

[0014] In some embodiments, the antigen binding domain is a full antibody or antigen-binding fragment thereof, a bivalent antibody, bispecific antibody, or a biparatopic antibody.

[0015] In some embodiments, the antigen binding domain is a Fab, F(ab')2, Fv, a single chain Fv (scFv), a diabody, a single domain antibody, or a camelid antibody.

[0016] In some embodiments, the antigen binding domain is a Fab or a scFv.

[0017] In some embodiments, the antigen binding domain comprises one or more heavy chain constant regions selected from the group consisting of IgG1 heavy chain constant region or functional fragment thereof, IgG2 heavy chain constant region or functional fragment thereof,WSGR Docket No.53676-766.601 IgG3 heavy chain constant region or functional fragment thereof, IgGA1 heavy chain constant region or functional fragment thereof, IgGA2 heavy chain constant region or functional fragment thereof, IgG4 heavy chain constant region or functional fragment thereof, IgJ heavy chain constant region or functional fragment thereof, IgM heavy chain constant region or functional fragment thereof, IgD heavy chain constant region or functional fragment thereof, and IgE heavy chain constant region or functional fragment thereof.

[0018] In some embodiments, the one or more heavy chain constant regions comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 73, the sequence of SEQ ID NO: 76, the sequence of SEQ ID NO: 74, the sequence of SEQ ID NO: 75, the sequence of SEQ ID NO: 41, or the sequence of SEQ ID NO: 3645.

[0019] In some embodiments, the antigen binding domain comprises a kappa light chain constant region or functional fragment thereof, a lambda light chain constant region or functional fragment thereof, or a combination thereof.

[0020] In some embodiments, the kappa light chain constant region comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 39 or SEQ ID NO: 3644.

[0021] In some embodiments, the antigen binding domain binds to the TCRβV6.

[0022] In some embodiments, the molecule is a multifunctional molecule.

[0023] In some embodiments, the molecule is a multispecific molecule.

[0024] In some embodiments, the multifunctional molecule comprises a first polypeptide, a second polypeptide, and at least one cytokine molecule, wherein the first polypeptide and the second polypeptide are non-contiguous, wherein: (i) the first polypeptide comprises a first portion of a dimerization module linked to (A) the antigen binding domain comprising the VH and the VL, or (B) a first portion of the antigen binding domain comprising the VH, wherein when the first polypeptide comprises the first portion of the antigen binding domain, the multifunctional molecule further comprises a third polypeptide comprising a second portion of the antigen binding domain comprising the VL, wherein the third polypeptide is non-contiguous with the first polypeptide and the second polypeptide; and (ii) the second polypeptide comprises a second portion of the dimerization module, and wherein the at least one cytokine molecule is covalently linked to the second polypeptide or the first polypeptide.

[0025] In some embodiments, the multifunctional molecule comprises a first polypeptide, a second polypeptide, and at least one cytokine molecule, wherein the first polypeptide and the second polypeptide are non-contiguous, wherein:WSGR Docket No.53676-766.601 (i) the first polypeptide comprises a first portion of a dimerization module linked to a first portion of the antigen binding domain comprising the VH, wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the antigen binding domain comprising the VL, wherein the third polypeptide is non-contiguous with the first polypeptide and the second polypeptide; and (ii) the second polypeptide comprises a second portion of the dimerization module, and wherein the at least one cytokine molecule is covalently linked to the second polypeptide.

[0026] In some embodiments, the first portion of the dimerization module and the second portion of the dimerization module are dimerized.

[0027] In some embodiments, the first polypeptide comprises: (A) the antigen binding domain comprising the VH and the VL, wherein the antigen binding domain further comprises a heavy chain constant domain 1 (CH1) linked to the VH; or (B) the first portion of the antigen binding domain comprising the VH, wherein the first portion of the antigen binding domain further comprises a CH1 linked to the VH.

[0028] In some embodiments, the CH1 is linked to the C-terminus of the VH.

[0029] In some embodiments, the multifunctional molecule comprises: (1) the first polypeptide comprising the antigen binding domain that comprises the VH and the VL, wherein the antigen binding domain further comprises a light chain constant domain (CL) linked to the VL; or (2) the first polypeptide comprising the first portion of the antigen binding domain and the third polypeptide comprising the second portion of the antigen binding domain, wherein the second portion of the antigen binding domain further comprises a CL linked to the VL of the antigen binding domain.

[0030] In some embodiments, the CL is linked to the C-terminus of the VL.

[0031] In some embodiments, the first portion of the dimerization module is linked to the C- terminus of (A) the antigen binding domain comprising the VH and the VL, or the C-terminus of (B) the first portion of the antigen binding domain comprising the VH.

[0032] In some embodiments, the at least one cytokine molecule is covalently linked to the N- terminus of the second polypeptide, the C-terminus of the second polypeptide, or a combination thereof.

[0033] In some embodiments, the at least one cytokine molecule is within a single contiguous polypeptide chain of the second polypeptide.

[0034] In some embodiments, the at least one cytokine molecule is linked to the N-terminus of the first polypeptide, the C-terminus of the first polypeptide, the N-terminus of the secondWSGR Docket No.53676-766.601 polypeptide, the C-terminus of the second polypeptide, the N-terminus of the third polypeptide, the C-terminus of the third polypeptide, or any combination thereof.

[0035] In some embodiments, the at least one cytokine molecule is within a single contiguous polypeptide chain of the first polypeptide, the second polypeptide, or the third cytokine polypeptide to which the at least one cytokine molecule is linked.

[0036] In some embodiments, the multifunctional molecule further comprises: (i) a linker between the first portion of the dimerization module and the antigen binding domain comprising the VH and the VL, or the first portion of the antigen binding domain comprising the VH; (ii) a linker between the VH and the VL; (iii) a linker between the CH1 and the VH; (iv) a linker between the CL and the VL; (v) a linker between the at least one cytokine molecule and the first polypeptide, a linker between the at least one cytokine molecule and the second polypeptide, a linker between the at least one cytokine molecule and the third polypeptide, or any combination thereof; or (vi) any combination thereof.

[0037] In some embodiments, the linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non-helical linker.

[0038] In some embodiments, the linker is the peptide linker, and wherein the linker comprises the sequence of SEQ ID NO: 3308 or SEQ ID NO: 3473.

[0039] In some embodiments, the multifunctional molecule comprises: (i) the first polypeptide comprising the first portion of the dimerization module linked to the C- terminus of the first portion of the antigen binding domain; (ii) the second polypeptide comprising the second portion of the dimerization module; (iii) the third polypeptide comprising the second portion of the antigen binding domain; and (iv) the at least one cytokine molecule covalently linked to the N-terminus of the second polypeptide.

[0040] In some embodiments, the first portion of the dimerization module comprises a first immunoglobulin constant region (Fc region) and the second portion of the dimerization module comprises a second Fc region.

[0041] In some embodiments, the first Fc region, the second Fc region, or a combination thereof is selected from the group consisting of an IgG1 Fc region or a functional fragment thereof, an IgG2 Fc region or a functional fragment thereof, an IgG3 Fc region or a functional fragment thereof, an IgGA1 Fc region or a functional fragment thereof, an IgGA2 Fc region or aWSGR Docket No.53676-766.601 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.

[0042] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises an Fc interface with one or more of: a paired cavity-protuberance, an electrostatic interaction, or a strand-exchange, wherein the dimerization of the first Fc region and the second Fc region is enhanced as indicated by a greater ratio of heteromultimer:homomultimer forms relative to a dimerization of Fc regions with a non-engineered interface.

[0043] 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.

[0044] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 3645, SEQ ID NO: 3646, SEQ ID NO: 3647, SEQ ID NO:3648, SEQ ID NO: 3649, SEQ ID NO: 3452, SEQ ID NO: 3447 or SEQ ID NO: 3453.

[0045] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO:3648, SEQ ID NO: 3447, or SEQ ID NO: 3453.

[0046] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises the sequence of SEQ ID NO:3648, SEQ ID NO: 3447, or SEQ ID NO: 3453.

[0047] In some embodiments, the at least one cytokine molecule comprises interleukin-15 (IL- 15) or a functional fragment or variant thereof.

[0048] In some embodiments, the IL-15 or a functional fragment or variant thereof comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 2170, SEQ ID NO: 3670, or SEQ ID NO: 3673.

[0049] In some embodiments, the IL-15 or a functional fragment or variant thereof comprises the sequence of SEQ ID NO: 2170, SEQ ID NO: 3670, or SEQ ID NO: 3673.

[0050] In some embodiments, the at least one cytokine molecule further comprises an IL15Ralpha dimerizing domain covalently linked the IL-15 or a functional fragment or variant thereof.

[0051] In some embodiments, the IL15Ralpha dimerizing domain comprises an IL-15 receptor alpha sushi domain or a functional fragment or variant thereof.

[0052] In some embodiments, the IL15Ralpha dimerizing domain comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3472.WSGR Docket No.53676-766.601

[0053] In some embodiments, the IL15Ralpha dimerizing domain comprises the sequence of SEQ ID NO: 3472.

[0054] In some embodiments, the IL-15 or a functional fragment or variant thereof is covalently linked to the IL15Ralpha dimerizing domain via a linker.

[0055] In some embodiments, the IL-15 or a functional fragment or variant thereof is covalently linked to the IL15Ralpha dimerizing domain via a linker comprising the sequence of SEQ ID NO: 3473.

[0056] In some embodiments, the at least one cytokine molecule comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3474, SEQ ID NO: 3671, or SEQ ID NO: 3674.

[0057] In some embodiments, the at least one cytokine molecule comprises the sequence of SEQ ID NO: 3474, SEQ ID NO: 3671, or SEQ ID NO: 3674.

[0058] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the VH of the antigen binding domain, and a first immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising an IL15Ralpha dimerizing domain, an IL-15 or a functional fragment or variant thereof, and a second immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising the VL of the antigen binding domain, and an immunoglobulin light chain constant region.

[0059] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the VH of the antigen binding domain operatively linked to a first immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, an IL15Ralpha dimerizing domain operatively linked to an IL-15 or a functional fragment or variant thereof operatively linked to a second immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the VL of the antigen binding domain operatively linked to an immunoglobulin light chain constant region.

[0060] In some embodiments, the IL15Ralpha dimerizing domain is operatively linked to the IL- 15 or a functional fragment or variant thereof via a linker.

[0061] In some embodiments, the IL15Ralpha dimerizing domain is operatively linked to the IL- 15 or a functional fragment or variant thereof via a linker comprising the sequence of SEQ ID NO: 3473

[0062] In some embodiments, the IL-15 or a functional fragment or variant thereof is operatively linked to the second immunoglobulin heavy chain constant region via a linker.WSGR Docket No.53676-766.601

[0063] In some embodiments, the IL-15 or a functional fragment or variant thereof is operatively linked to the second immunoglobulin heavy chain constant region via a linker comprising the sequence of SEQ ID NO: 3308.

[0064] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 2170, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

[0065] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

[0066] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3473 operatively linked to the sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

[0067] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3474, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

[0068] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3474 operatively linked to the sequence of SEQ ID NO: 3648; andWSGR Docket No.53676-766.601 (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

[0069] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 2170, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

[0070] In some embodiments, the multifunctional molecule comprises: a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

[0071] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3474 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

[0072] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3428.

[0073] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3428.

[0074] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517;WSGR Docket No.53676-766.601 (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517.

[0075] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3517.

[0076] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3670, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

[0077] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

[0078] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3670, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

[0079] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649;WSGR Docket No.53676-766.601 (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

[0080] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3473 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

[0081] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3671, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

[0082] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

[0083] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3671, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

[0084] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3648; andWSGR Docket No.53676-766.601 (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

[0085] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

[0086] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3428.

[0087] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3428.

[0088] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517.

[0089] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3517.

[0090] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3673, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

[0091] In some embodiments, the multifunctional molecule comprises:WSGR Docket No.53676-766.601 (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

[0092] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3673, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

[0093] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

[0094] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3473 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

[0095] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3674, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

[0096] In some embodiments, the multifunctional molecule comprises:WSGR Docket No.53676-766.601 (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

[0097] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3674, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

[0098] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

[0099] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

[0100] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3428.

[0101] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3428.

[0102] In some embodiments, the multifunctional molecule comprises:WSGR Docket No.53676-766.601 (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517.

[0103] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3517.

[0104] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 2170, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

[0105] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

[0106] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 2170, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

[0107] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649;WSGR Docket No.53676-766.601 (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

[0108] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3473 operatively linked to the sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

[0109] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3474, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

[0110] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3474 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

[0111] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3474, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

[0112] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3474 operatively linked to the sequence of SEQ ID NO: 3648; andWSGR Docket No.53676-766.601 (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

[0113] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3474 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

[0114] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3437.

[0115] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3437.

[0116] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3437.

[0117] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3437.

[0118] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3670, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

[0119] In some embodiments, the multifunctional molecule comprises:WSGR Docket No.53676-766.601 (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

[0120] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3670, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

[0121] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

[0122] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3473 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to and the sequence of SEQ ID NO: 3648.

[0123] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3671, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

[0124] In some embodiments, the multifunctional molecule comprises:WSGR Docket No.53676-766.601 (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

[0125] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3671, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

[0126] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3648; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

[0127] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

[0128] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3437.

[0129] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3437.

[0130] In some embodiments, the multifunctional molecule comprises:WSGR Docket No.53676-766.601 (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3437.

[0131] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3437.

[0132] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3673, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

[0133] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

[0134] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3673, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

[0135] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649;WSGR Docket No.53676-766.601 (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

[0136] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3473 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

[0137] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3674, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

[0138] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

[0139] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3674, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

[0140] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3648; andWSGR Docket No.53676-766.601 (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

[0141] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

[0142] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3437.

[0143] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3437.

[0144] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3437.

[0145] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3437.

[0146] In another aspect, provided herein is a multifunctional molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, and at least one cytokine molecule, wherein the first polypeptide, the second polypeptide, and the third polypeptide are non- contiguous, wherein: (i) the first polypeptide comprises a first portion of a dimerization module linked to a first portion of an antigen binding domain that binds to a T cell receptor beta variable region (TCRβV) comprising a heavy chain variable region (VH) of the antigen binding domain;WSGR Docket No.53676-766.601 (ii) the second polypeptide comprises a second portion of the dimerization module, wherein the at least one cytokine molecule is covalently linked to the second polypeptide; and (iii) the third polypeptide comprises a second portion of the antigen binding domain comprising a light chain variable region (VL) of the antigen binding domain; wherein the first portion of the dimerization module comprises a first immunoglobulin constant region (Fc region) comprising the sequence of SEQ ID NO: 3453, and the second portion of the dimerization module comprises a second Fc region comprising the sequence of SEQ ID NO: 3648; and wherein the antigen binding domain comprises: (A) a VH comprising: (i) a heavy chain complementarity determining region 1 (HC CDR1) amino acid sequence of LTYIH (SEQ ID NO: 3421), FRLTYIH (SEQ ID NO: 3702), or GHDFRLTYIH (SEQ ID NO: 3351); (ii) a heavy chain complementarity determining region 2 (HC CDR2) amino acid sequence of RVSAGSGNVKYNEKFKG (SEQ ID NO: 3352); and (iii) a heavy chain complementarity determining region 3 (HC CDR3) amino acid sequence of SYYSYDVLDY (SEQ ID NO: 3353); and (B) a VL comprising: (i) a light chain complementarity determining region 1 (LC CDR1) amino acid sequence of KASQNVADRVV (SEQ ID NO: 3354), (ii) a light chain complementarity determining region 2 (LC CDR2) amino acid sequence of SSSHRYK (SEQ ID NO: 3355), and (iii) a light chain complementarity determining region 3 (LC CDR3) amino acid sequence of QQFKSYPLT (SEQ ID NO: 3356).

[0147] In another aspect, provided herein is a multifunctional molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, and at least one cytokine molecule, wherein the first polypeptide, the second polypeptide, and the third polypeptide are non- contiguous, wherein: (i) the first polypeptide comprises a first portion of a dimerization module linked to a first portion of an antigen binding domain that binds to a T cell receptor beta variable region (TCRβV) comprising a heavy chain variable region (VH) of the antigen binding domain; (ii) the second polypeptide comprises a second portion of the dimerization module, wherein the at least one cytokine molecule is covalently linked to the second polypeptide; and (iii) the third polypeptide comprises a second portion of the antigen binding domain comprising a light chain variable region (VL) of the antigen binding domain;WSGR Docket No.53676-766.601 wherein the first portion of the dimerization module comprises a first immunoglobulin constant region (Fc region) comprising the sequence of SEQ ID NO: 3447, and the second portion of the dimerization module comprises a second Fc region comprising the sequence of SEQ ID NO: 3648; and wherein the antigen binding domain comprises: (A) a VH comprising: (i) a heavy chain complementarity determining region 1 (HC CDR1) amino acid sequence of LTYIH (SEQ ID NO: 3421), FRLTYIH (SEQ ID NO: 3702), or GHDFRLTYIH (SEQ ID NO: 3351); (ii) a heavy chain complementarity determining region 2 (HC CDR2) amino acid sequence of RVSAGSGNVKYNEKFKG (SEQ ID NO: 3352); and (iii) a heavy chain complementarity determining region 3 (HC CDR3) amino acid sequence of SYYSYDVLDY (SEQ ID NO: 3353); and (B) a VL comprising: (i) a light chain complementarity determining region 1 (LC CDR1) amino acid sequence of KASQNVADRVV (SEQ ID NO: 3354), (ii) a light chain complementarity determining region 2 (LC CDR2) amino acid sequence of SSSHRYK (SEQ ID NO: 3355), and (iii) a light chain complementarity determining region 3 (LC CDR3) amino acid sequence of QQFKSYPLT (SEQ ID NO: 3356).

[0148] In some embodiments, the at least one cytokine molecule comprises an IL15Ralpha dimerizing domain covalently linked to IL-15 or a functional fragment or variant thereof via a linker comprising the sequence of SEQ ID NO: 3473.

[0149] In another aspect, provided herein is a multifunctional molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, and at least one cytokine molecule, wherein the first polypeptide, the second polypeptide, and the third polypeptide are non- contiguous, wherein: (i) the first polypeptide comprises a first portion of a dimerization module linked to a first portion of an antigen binding domain that binds to a T cell receptor beta variable region (TCRβV) comprising a heavy chain variable region (VH) of the antigen binding domain; (ii) the second polypeptide comprises a second portion of the dimerization module, wherein the at least one cytokine molecule is covalently linked to the second polypeptide; and (iii) the third polypeptide comprises a second portion of the antigen binding domain comprising a light chain variable region (VL) of the antigen binding domain;WSGR Docket No.53676-766.601 wherein the first portion of the dimerization module comprises a first immunoglobulin constant region (Fc region), and the second portion of the dimerization module comprises a second Fc region; wherein the at least one cytokine molecule comprises an IL15Ralpha dimerizing domain covalently linked to IL-15 or a functional fragment or variant thereof via a linker comprising the sequence of SEQ ID NO: 3473; and wherein the antigen binding domain comprises: (A) a VH comprising: (i) a heavy chain complementarity determining region 1 (HC CDR1) amino acid sequence of LTYIH (SEQ ID NO: 3421), FRLTYIH (SEQ ID NO: 3702), or GHDFRLTYIH (SEQ ID NO: 3351); (ii) a heavy chain complementarity determining region 2 (HC CDR2) amino acid sequence of RVSAGSGNVKYNEKFKG (SEQ ID NO: 3352); and (iii) a heavy chain complementarity determining region 3 (HC CDR3) amino acid sequence of SYYSYDVLDY (SEQ ID NO: 3353); and (B) a VL comprising: (i) a light chain complementarity determining region 1 (LC CDR1) amino acid sequence of KASQNVADRVV (SEQ ID NO: 3354), (ii) a light chain complementarity determining region 2 (LC CDR2) amino acid sequence of SSSHRYK (SEQ ID NO: 3355), and (iii) a light chain complementarity determining region 3 (LC CDR3) amino acid sequence of QQFKSYPLT (SEQ ID NO: 3356).

[0150] In some embodiments, the Fc region comprises the sequence of SEQ ID NO: 3447, and the second Fc region comprise the sequence of SEQ ID NO: 3648.

[0151] In some embodiments, the Fc region comprises the sequence of SEQ ID NO: 3453, and the second Fc region comprise the sequence of SEQ ID NO: 3648.

[0152] In some embodiments, the antigen binding domain comprises a VH comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 1346.

[0153] In some embodiments, the antigen binding domain comprises a VH comprising the sequence of SEQ ID NO: 1346.

[0154] In some embodiments, the antigen binding domain comprises a VL comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 1349.

[0155] In some embodiments, the antigen binding domain comprises a VL comprising the sequence of SEQ ID NO: 1349.WSGR Docket No.53676-766.601

[0156] In some embodiments, the antigen binding domain comprises a VH comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 1346 and a VL comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 1349.

[0157] In some embodiments, the antigen binding domain comprises a VH comprising the sequence of SEQ ID NO: 1346 and a VL comprising the sequence of SEQ ID NO: 1349.

[0158] In some embodiments, the first polypeptide further comprises a heavy chain constant domain 1 (CH1) linked to the C-terminus of the VH.

[0159] In some embodiments, the third polypeptide further comprises a light chain constant domain (CL) linked to the C-terminus of the VL.

[0160] In some embodiments, the at least one cytokine molecule is within a single contiguous polypeptide chain of the second polypeptide.

[0161] In some embodiments, the multifunctional molecule comprises: (i) the first polypeptide comprising the first portion of the dimerization module linked to the C- terminus of the first portion of the antigen binding domain; (ii) the second polypeptide comprising the second portion of the dimerization module; (iii) the third polypeptide comprising the second portion of the antigen binding domain; and (iv) the at least one cytokine molecule covalently linked to the N-terminus of the second polypeptide.

[0162] In some embodiments, the IL-15 or a functional fragment or variant thereof comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 2170, SEQ ID NO: 3670, or SEQ ID NO: 3673.

[0163] In some embodiments, the IL-15 or a functional fragment or variant thereof comprises the sequence of SEQ ID NO: 2170, SEQ ID NO: 3670, or SEQ ID NO: 3673.

[0164] In some embodiments, the IL15Ralpha dimerizing domain comprises an IL-15 receptor alpha sushi domain or a functional fragment or variant thereof.

[0165] In some embodiments, the IL15Ralpha dimerizing domain comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3472.

[0166] In some embodiments, the IL15Ralpha dimerizing domain comprises the sequence of SEQ ID NO: 3472.

[0167] In some embodiments, the at least one cytokine molecule comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3474, SEQ ID NO: 3671, or SEQ ID NO: 3674.

[0168] In some embodiments, the at least one cytokine molecule comprises the sequence of SEQ ID NO: 3474, SEQ ID NO: 3671, or SEQ ID NO: 3674.WSGR Docket No.53676-766.601

[0169] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the VH of the antigen binding domain, and a first immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising an IL15Ralpha dimerizing domain, an IL-15 or a functional fragment or variant thereof, and a second immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising the VL of the antigen binding domain, and an immunoglobulin light chain constant region.

[0170] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the VH of the antigen binding domain operatively linked to a first immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, an IL15Ralpha dimerizing domain operatively linked to an IL-15 or a functional fragment or variant thereof operatively linked to a second immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the VL of the antigen binding domain operatively linked to an immunoglobulin light chain constant region.

[0171] In some embodiments, the IL-15 or a functional fragment or variant thereof is operatively linked to the second immunoglobulin heavy chain constant region via a linker.

[0172] In some embodiments, the IL-15 or a functional fragment or variant thereof is operatively linked to the second immunoglobulin heavy chain constant region via a linker comprising the sequence of SEQ ID NO: 3308.

[0173] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 2170, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

[0174] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.WSGR Docket No.53676-766.601

[0175] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 2170, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

[0176] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

[0177] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3473 operatively linked to the sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

[0178] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3474, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

[0179] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3474 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

[0180] In some embodiments, the multifunctional molecule comprises:WSGR Docket No.53676-766.601 (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3474, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

[0181] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3474 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

[0182] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3474 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

[0183] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3349.

[0184] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3349.

[0185] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3349.

[0186] In some embodiments, the multifunctional molecule comprises:WSGR Docket No.53676-766.601 (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3349.

[0187] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3670, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

[0188] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

[0189] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3670, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

[0190] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

[0191] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO:WSGR Docket No.53676-766.601 3473 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

[0192] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3671, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

[0193] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

[0194] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3671, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

[0195] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

[0196] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

[0197] In some embodiments, the multifunctional molecule comprises:WSGR Docket No.53676-766.601 (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3349.

[0198] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3349.

[0199] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3349.

[0200] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3349.

[0201] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3673, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

[0202] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3648; andWSGR Docket No.53676-766.601 (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

[0203] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3673, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

[0204] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

[0205] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3473 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

[0206] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3674, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

[0207] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.WSGR Docket No.53676-766.601

[0208] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3674, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

[0209] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

[0210] In some embodiments, the second polypeptide comprises, from the N-terminus to the C- terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

[0211] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3349.

[0212] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3349.

[0213] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3349.WSGR Docket No.53676-766.601

[0214] In some embodiments, the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3349.

[0215] In some embodiments, the antigen binding domain binds to the TCRβV6.

[0216] In another aspect, provided herein is a recombinant polynucleotide molecule comprising polynucleotide sequences encoding the molecule as provided herein or the multifunctional molecule as provided herein.

[0217] In some embodiments, the recombinant polynucleotide molecule is an isolated recombinant polynucleotide molecule.

[0218] In another aspect, provided herein is a vector comprising the recombinant polynucleotide molecule as provided herein.

[0219] In another aspect, provided herein is a cell comprising the recombinant polynucleotide molecule as provided herein, or the vector as provided herein.

[0220] In another aspect, provided herein is a pharmaceutical composition comprising the molecule as provided herein, the multifunctional molecule as provided herein, recombinant polynucleotide molecule as provided herein, the vector as provided herein, or the cell as provided herein, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0221] In another aspect, provided herein is a method of treating a condition or disease in a subject in need therefor comprising administering to the subject a therapeutically effective amount of the molecule as provided herein, the multifunctional molecule as provided herein, recombinant polynucleotide molecule as provided herein, the vector as provided herein, the cell as provided herein, or the pharmaceutical composition as provided herein, or a combination thereof, thereby treating the condition or disease in the subject.

[0222] In some embodiments, the condition or disease is cancer.

[0223] In some embodiments, the cancer is a solid tumor, a hematological cancer, a metastatic cancer, a soft tissue tumor, or a combination thereof.

[0224] In some embodiments, 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.

[0225] 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.WSGR Docket No.53676-766.601

[0226] 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.

[0227] In some embodiments, the T-cell lymphoma is peripheral T-cell lymphoma.

[0228] In some embodiments, the cancer is characterized by a cancer antigen present on the cancer.

[0229] In some embodiments, the cancer antigen is a tumor antigen, a stromal antigen, or a hematological antigen.

[0230] In some embodiments, the cancer antigen is selected from the group consisting of BCMA, CD19, CD20, CD22, FcRH5, PDL1, CD47, ganglioside 2 (GD2), prostate stem cell antigen (PSCA), prostate specific membrane antigen (PMSA), prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), Ron Kinase, c-Met, Immature laminin receptor, TAG-72, BING-4, Calcium-activated chloride channel 2, Cyclin-B1, 9D7, Ep-CAM, EphA3, Her2 / neu, Telomerase, SAP-1, Survivin, NY-ESO-1 / LAGE-1, PRAME, SSX-2, Melan-A / MART-1, Gp100 / pmel17, Tyrosinase, MC1R, β-catenin, BRCA1 / 2, CDK4, CML66, Fibronectin, p53, Ras, TGF-Β receptor, AFP, ETA, MAGE, CA-125, BAGE, GAGE, CDC27, α actinin-4, TRP1 / gp75, TRP2, gangliosides, WT1, Epidermal growth factor receptor (EGFR), MART-2, MUC1, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RU11, RU12, SAGE, TRG, TSTA, Folate receptor alpha, L1-CAM, CAIX, gpA33, GD3, GM2, VEGFR, Integrins, Carbohydrates, IGF1R, TRAILR1, TRAILR2, RANKL, FAP, TGF-beta, hyaluronic acid, collagen, tenascin C, and tenascin W.

[0231] In some embodiments, the method as provided herein further comprises administering a second therapeutic agent or therapy to the subject.

[0232] In some embodiments, the second therapeutic agent or therapy comprises a chemotherapeutic agent, a biologic agent, a hormonal therapy, radiation, or surgery.

[0233] In some embodiments, the second therapeutic agent or therapy is administered in combination with the molecule as provided herein, the multifunctional molecule as provided herein, recombinant polynucleotide molecule as provided herein, the vector as provided herein, the cell as provided herein, or the pharmaceutical composition as provided herein, sequentially, simultaneously, or concurrently. BRIEF DESCRIPTION OF THE DRAWINGS

[0234] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained byWSGR Docket No.53676-766.601 reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0235] FIGS.1-25 depict exemplary embodiments of multifunctional molecules as described herein.

[0236] FIGS.1, 2, and 3 depict exemplary embodiments of multifunctional molecules containing multiple, e.g., two, molecules of a cytokine molecule linked to an antibody molecule that binds to a T cell receptor beta variable region (TCRβV) (“anti-TCRβV antibody molecule”).

[0237] FIGS.4, 5, and 6 depict exemplary embodiments of multifunctional molecules containing a single molecule of a cytokine molecule linked to an anti-TCRβV antibody molecule.

[0238] FIGS.7, 8, 9, and 10 depict exemplary embodiments of multifunctional molecules containing a cytokine molecule linked to a first dimerization module.

[0239] FIGS.11, 12, and 13 depict exemplary embodiments of multifunctional molecules containing an exemplary dimerization module, e.g., an Fc region comprising a N297A mutation, and multiple, e.g., two, molecules of a cytokine molecule linked to an anti-TCRβV antibody molecule.

[0240] FIGS.14, 15, and 16 depict exemplary embodiments of multifunctional molecules containing an exemplary dimerization module, e.g., an Fc region comprising a N297A mutation (Knob-in-hole), and a single molecule of a cytokine molecule linked to an anti-TCRβV antibody molecule.

[0241] FIGS.17, 18, 19, and 20 depict exemplary embodiments of multifunctional molecules containing an exemplary dimerization module, e.g., an Fc region comprising a N297A mutation (Knob-in-hole), and a cytokine molecule linked to the exemplary dimerization module.

[0242] FIG.21 shows an exemplary embodiment of multifunctional molecules comprising a TCRβV-binding moiety and a cytokine molecule (“cytokine”) as described herein.

[0243] FIGS.22, 23, 24, and 25 show exemplary embodiments of multifunctional molecules comprising a first TCRβV-binding moiety, a second TCRβV-binding moiety, and two cytokine molecules as described herein.

[0244] In some embodiments, the cytokine molecule comprises IL-2 or a functional fragment or variant thereof, IL2-C125A or a functional fragment or variant thereof, IL-15 or a functional fragment or variant thereof, IL-7 or a functional fragment or variant thereof, IL-12 or a functional fragment or variant thereof, or IL-21 or a functional fragment or variant thereof. In some embodiments, the cytokine molecule further comprises a cytokine receptor or a functional fragment or variant thereof. In some embodiments, the cytokine molecule comprises IL-15 or a functional fragment or variant thereof. In some embodiments, the cytokine molecule furtherWSGR Docket No.53676-766.601 comprises an IL15Ralpha dimerizing domain. In some embodiments, the cytokine molecule further comprises an IL15Ralpha dimerizing domain linked the IL-15 or a functional fragment or variant thereof. In some embodiments, the cytokine molecule further comprises an IL15Ralpha dimerizing domain covalently linked the IL-15 or a functional fragment or variant thereof. In some embodiments, the cytokine molecule comprises IL-15 linked to an IL-15Ra. In some embodiments, the cytokine molecule further comprises an IL15Ralpha dimerizing domain non-covalently linked the IL-15 or a functional fragment or variant thereof. In some embodiments, the IL15Ralpha dimerizing domain comprises an IL-15 receptor alpha sushi domain or a functional fragment or variant thereof. In some embodiments, the IL-15 or a functional fragment or variant thereof is covalently linked to the IL15Ralpha dimerizing domain via a linker. In some embodiments, the cytokine molecule comprises IL-15 linked to an IL-15Ra sushi domain. In some embodiments, the cytokine molecule comprises a cytokine dimer. In some embodiments, the cytokine molecule comprises an IL-12 beta subunit linked to an IL-12 alpha subunit.

[0245] FIGS.26A and 26B show 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.26A shows VH sequences for murine Antibody A (SEQ ID NO: 1) and humanized Antibody A-H (SEQ ID NO: 9). FIG.26B shows VL sequences for murine Antibody A (SEQ ID NO: 2) and humanized Anti-body A-H (SEQ ID NO: 10 and SEQ ID NO: 11).

[0246] FIG.27 shows CD25+ CD8+ T cells as a percentage of total CD8+ T cells (left) and CD25+ CD4+ T cells as a percentage of total CD4+ T cells (right) in hPBMCs stimulated with BMM0306 or BMM0354 for 5 days.

[0247] FIG.28 shows relative abundance of TRBV6-5, TRBV6-1, TRBV6-2, and TRBV10-3 in human purified T cells after treatment of BMM0306 or BMM0354.

[0248] FIGs.29A-29B show targeted TRBV T cell expansion. FIG.29A shows the percentage of CD25+ TRBV6 / TRBV10+ CD8+ cells after BMM0306 or BMM0354 treatment. FIG.29B shows the percentage of CD25+ TRBV6 / TRBV10- CD8+cells after BMM0306 or BMM0354 treatment.

[0249] FIG.30 shows CD25+ CD8+ T cells as a percentage of total CD3+ T cells in murine splenocytes stimulated with BMM0310 or BMM0347 for 96h.

[0250] FIG.31 shows IFN-γ production by murine splenocytes after stimulation of BMM0310 for 96h.WSGR Docket No.53676-766.601

[0251] FIG.32A-32B show anti-tumor activity in a CT-26 tumor model. FIG.32A shows tumor volume in mice treated with BMM0347 or BMM0310. FIG.32B shows tumor-volume in cured-mice re-challenged with CT-26 tumor cells treated with BMM0310 or BMM0347 as compared to CT-26 naive animals.

[0252] FIGs.33A-33B show CD8+ mTCRVβ13+ T cells in the B16F10 tumor. FIG.33A shows the concentration of CD8+ mTCRVβ13+ T cells in tumors treated with BMM0310 or BMM0347 as compared to vehicle controls. FIG.33B shows the concentration of Granzyme B+ T cells in tumors treated with BMM0310 or BMM0347 as compared to vehicle controls.

[0253] FIG.34A-34B show targeted TRBV T cell expansion and cytokine induction in cynomolgus PBMCs. FIG.34A shows CD25+ CD8+ T cells in cynomolgus PBMCs stimulated with BMM0306 or BMM0354 for 120h. FIG.34B shows IFN-γ production by cynomolgus PBMCs stimulated with BMM0306 or BMM0354 for 120h.

[0254] FIG.35A-35B show pharmacokinetic analyses of BMM0306 and BMM0354 in cynomolgus monkeys. Fig.35A depicts the assay format utilized for the analyses. Fig.35B shows serum concentration of BMM0306 or BMM0354 in cynomolgus monkeys that received intravenous infusion of BMM0306 or BMM0354.

[0255] FIGs.36A-36C show TCRVβ+ T cells expansion in peripheral blood. FIG.36A shows frequency of TCRVβ+ CD3+ T cells in cynomolgus monkeys treated with BMM0306 or BMM0354. FIG.36B shows frequency of TCRVβ+ CD4+ T cells in cynomolgus monkeys treated with BMM0306 or BMM0354. FIG.36C shows frequency of TCRVβ+ cytotoxic T cells in cynomolgus monkeys treated with BMM0306 or BMM0354.

[0256] FIGs.37A-37C show cytokines released by BMM0306 or BMM0354 treatment. FIG. 37A shows serum concentration of TNFα in cynomolgus monkeys treated with BMM0306 or BMM0354. FIG.37B shows serum concentration of IL-6 in cynomolgus monkeys treated with BMM0306 or BMM0354. FIG.37C shows serum concentration of IFNγ in cynomolgus monkeys treated with BMM0306 or BMM0354. INCORPORATION BY REFERENCE

[0257] 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.

[0258] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrativeWSGR Docket No.53676-766.601 embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which: DETAILED DESCRIPTION DEFINITION

[0259] 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.

[0260] 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.

[0261] 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.”

[0262] It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0263] 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.

[0264] 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.

[0265] 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 aWSGR Docket No.53676-766.601 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.

[0266] “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’)2fragments, and single chain variable fragments (scFvs). In some embodiments, the antibody molecule is an antibody mimetic. In some embodiments, the antibody molecule is, or comprises, an antibody-like framework or scaffold, such as, fibronectins, ankyrin repeats (e.g., designed ankyrin repeat proteins (DARPins)), avimers, affibody affinity ligands, anticalins, or affilin molecules.

[0267] 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% sequenceWSGR Docket No.53676-766.601 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.

[0268] 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.

[0269] 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.

[0270] “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 canWSGR Docket No.53676-766.601 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.

[0271] 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. Each variable chain (e.g., variable heavy chain and variable light chain) is typically made up of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the amino acid order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0272] 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.

[0273] “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 immuneWSGR Docket No.53676-766.601 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.

[0274] 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.

[0275] 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.

[0276] The terms “nucleic acid,” “nucleic acid sequence,” “nucleotide sequence,” or “polynucleotide sequence,” and “polynucleotide” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. The polynucleotide may be either single-stranded or double-stranded, and if single-stranded may be the coding strand or non-coding (antisense) strand. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. The nucleic acid may be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semisynthetic, or synthetic origin which either does not occur in nature or is linked to another polynucleotide in a non-natural arrangement.

[0277] 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.WSGR Docket No.53676-766.601

[0278] 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.

[0279] 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 TCRβV variant can bind to TCRα and form a TCR α:β complex.

[0280] 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.

[0281] 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 someWSGR Docket No.53676-766.601 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.

[0282] 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”).

[0283] The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol.48:444-453 ) algorithm which has been incorporated into the GAP program in the GCG software package (available at http: / / www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at http: / / www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and the one that should be used unless otherwise specified) are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.

[0284] 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 beenWSGR Docket No.53676-766.601 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.

[0285] 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.

[0286] The term “amino acid” is intended to embrace all molecules, whether natural or synthetic, which include both an amino functionality and an acid functionality and capable of being included in a polymer of naturally-occurring amino acids. Exemplary amino acids include naturally-occurring amino acids; analogs, derivatives and congeners thereof; amino acid analogs having variant side chains; and all stereoisomers of any of any of the foregoing. As used herein the term “amino acid” includes both the D- or L- optical isomers and peptidomimetics.

[0287] 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).

[0288] 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.WSGR Docket No.53676-766.601

[0289] 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.

[0290] “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.

[0291] In some embodiments, the terms TCRvB, TCRBV, TCRβV, and TCRVβ are interchangeably used. Anti-TCRβV antibodies Human T cell receptor (TCR) complex

[0292] TCR is a disulfide-linked membrane-anchored heterodimeric protein normally consisting of the highly variable alpha (α) and beta (β) chains expressed as part of a complex with the invariant CD3 chain molecules. TCR on αβ T cells is formed by a heterodimer of one alpha chain and one beta chain. Each alpha or beta chain consists of a constant domain and a highly variable domain classified as the Immunoglobulin superfamily (IgSF) fold. The TCRβV chains can be further classified into 30 subfamilies (TRBV1-30). Despite their high structural and functional homology, the amino acid sequence homology in the TRBV genes is very low. Only 4 amino acids out of approximately 95 are identical while 10 additional amino acids are conserved among all subfamilies. Nevertheless, TCRs formed between alpha and beta chains of highly diverse sequences show a remarkable structural homology and elicit a similar function, e.g., activation of T cells.WSGR Docket No.53676-766.601

[0293] T cell receptors (TCR) can be found on the surface of T cells. TCRs recognize antigens, e.g., peptides, presented on, e.g., bound to, major histocompatibility complex (MHC) molecules on the surface of cells, e.g., antigen-presenting cells. TCRs are heterodimeric molecules and can comprise an alpha chain, a beta chain, a gamma chain or a delta chain. TCRs comprising an alpha chain and a beta chain are also referred to as TCRαβ. The TCR beta chain consists of the following regions (also known as segments): variable (V), diversity (D), joining (J) and constant (C) (see Mayer G. and Nyland J. (2010) Chapter 10: Major Histocompatibility Complex and T- cell Receptors-Role in Immune Responses. In: Microbiology and Immunology on-line, University of South Carolina School of Medicine). The TCR alpha chain consists of V, J and C regions. The rearrangement of the T-cell receptor (TCR) through somatic recombination of V (variable), D (diversity), J (joining), and C (constant) regions is a defining event in the development and maturation of a T cell. TCR gene rearrangement takes place in the thymus.

[0294] 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., CD3δ / ε, and / or CD3γ / ε.

[0295] As used herein, the term “T cell receptor beta variable chain” or “TCRβV,” 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 TCRβV includes isoforms, mammalian, e.g., human TCRβV, species homologs of human and analogs comprising at least one common epitope with TCRβV. Human TCRβV comprises a gene family comprising subfamilies including, but not limited to: a TCRβ V6 subfamily, a TCRβ V10 subfamily, a TCRβ V12 subfamily, a TCRβ V5 subfamily, a TCRβ V7 subfamily, a TCRβ V11 subfamily, a TCRβ V14 subfamily, a TCRβ V16 subfamily, a TCRβ V18 subfamily, a TCRβ V9 subfamily, a TCRβ V13 subfamily, a TCRβ V4 subfamily, a TCRβ V3 subfamily, a TCRβ V2 subfamily, a TCRβ V15 subfamily, a TCRβ V30 subfamily, a TCRβ V19 subfamily, a TCRβ V27 subfamily, a TCRβ V28 subfamily, a TCRβ V24 subfamily, a TCRβ V20 subfamily, TCRβ V25 subfamily, a TCRβ V29 subfamily, a TCRβ V1 subfamily, a TCRβ V17 subfamily, a TCRβ V21 subfamily, a TCRβ V23 subfamily, or a TCRβ V26 subfamily, as well as family members of said subfamilies, and variants thereof (e.g., a structural or functional variant thereof). In some embodiments, the TCRβ V6 subfamily comprises: TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01 or TCRβ V6-1*01. In some embodiments, TCRβV comprises TCRβ V6-5*01, or a variant thereof, e.g., a variant having 85%, 90%, 95%, 99% or more identity the naturally-occurring sequence. TCRβ V6-5*01 is also known as TRBV65; TCRBV6S5; TCRBV13S1, or TCRβ V13.1. The amino acid sequence of TCRβ V6-5*01, e.g., human TCRβ V6-5*01, is known in that art, e.g., as provided by IMGT IDWSGR Docket No.53676-766.601 L36092. In some embodiments, TCRβ V6-5*01 is encoded by the nucleic acid sequence of SEQ ID NO: 43, or a sequence having 85%, 90%, 95%, 99% or more identity thereof. In some embodiments, TCRβ V6-5*01 comprises the amino acid sequence of SEQ ID NO: 44, or a sequence having 85%, 90%, 95%, 99% or more identity thereof.

[0296] SEQ ID NO: 43 ATGAGCATCGGCCTCCTGTGCTGTGCAGCCTTGTCTCTCCTGTGGGCAGGTCCAGTG AATGCTGGTGTCACTCAGACCCCAAAATTCCAGGTCCTGAAGACAGGACAGAGCAT GACACTGCAGTGTGCCCAGGATATGAACCATGAATACATGTCCTGGTATCGACAAG ACCCAGGCATGGGGCTGAGGCTGATTCATTACTCAGTTGGTGCTGGTATCACTGACC AAGGAGAAGTCCCCAATGGCTACAATGTCTCCAGATCAACCACAGAGGATTTCCCG CTCAGGCTGCTGTCGGCTGCTCCCTCCCAGACATCTGTGTACTTCTGTGCCAGCAGT TACTC

[0297] SEQ ID NO: 44 MSIGLLCCAALSLLWAGPVNAGVTQTPKFQVLKTGQSMTLQCAQDMNHEYMSWYRQ DPGMGLRLIHY-SVGAGITDQGEVPNGYNVSRSTTEDFPLRLLSAAPSQTSVYFCASSY TCR beta V (TCRβV)

[0298] 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.

[0299] 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.

[0300] Provided herein are, inter alia, antibody molecules and fragments thereof, that bind, e.g., specifically bind, to a human TCR beta V chain (TCRβV), e.g., a TCRβV gene family (also referred to as a group), e.g., a TCRβV subfamily (also referred to as a subgroup), e.g., as described herein. TCR beta V families and subfamilies are known in the art, e.g., as described in Yassai et al., (2009) 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.

[0301] The terms TCRBV, TCRVB, TRBV, TCRβV, TCRVβ or TRβV are used interchangeably herein and refer to a TCR beta V chain, e.g., as described herein.WSGR Docket No.53676-766.601

[0302] In some embodiments, provided herein is an anti-TCRβV antibody molecule that binds to human TCRβV, e.g., a TCRβV family, e.g., gene family or a variant thereof. In some embodiments a TCRBV gene family comprises one or more subfamilies, e.g., as described herein Table 8A or Table 8B. In some embodiments, the TCRβV gene family comprises: a TCRβ V6 subfamily, a TCRβ V10 subfamily, a TCRβ V12 subfamily, a TCRβ V5 subfamily, a TCRβ V7 subfamily, a TCRβ V11 subfamily, a TCRβ V14 subfamily, a TCRβ V16 subfamily, a TCRβ V18 subfamily, a TCRβ V9 subfamily, a TCRβ V13 subfamily, a TCRβ V4 subfamily, a TCRβ V3 subfamily, a TCRβ V2 subfamily, a TCRβ V15 subfamily, a TCRβ V30 subfamily, a TCRβ V19 subfamily, a TCRβ V27 subfamily, a TCRβ V28 subfamily, a TCRβ V24 subfamily, a TCRβ V20 subfamily, TCRβ V25 subfamily, a TCRβ V29 subfamily, a TCRβ V1 subfamily, a TCRβ V17 subfamily, a TCRβ V21 subfamily, a TCRβ V23 subfamily, or a TCRβ V26 subfamily.

[0303] In some embodiments, TCRβ V6 subfamily is also known as TCRβ V13.1. In some embodiments, the TCRβ V6 subfamily comprises: TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6- 9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01 or TCRβ V6-1*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-4*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6- 4*02, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-9*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-8*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-5*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-6*02, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-6*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-2*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-3*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-1*01, or a variant thereof.

[0304] In some embodiments, TCRβ V6 comprises TCRβ V6-5*01, or a variant thereof. In some embodiments, TCRβ V6, e.g., TCRβ V6-5*01, is recognized, e.g., bound, by SEQ ID NO: 1 and / or SEQ ID NO: 2. In some embodiments, TCRβ V6, e.g., TCRβ V6-5*01, is recognized, e.g., bound, by SEQ ID NO: 9 and / or SEQ ID NO: 10. In some embodiments, TCRβ V6 is recognized, e.g., bound, by SEQ ID NO: 9 and / or SEQ ID NO: 11.

[0305] In some embodiments, TCRβ V10 subfamily is also known as TCRβ V12. In some embodiments, the TCRβ V10 subfamily comprises: TCRβ V10-1*01, TCRβ V10-1*02, TCRβ V10-3*01 or TCRβ V10-2*01, or a variant thereof.

[0306] In some embodiments, TCRβ V12 subfamily is also known as TCRβ V8.1. In some embodiments, the TCRβ V12 subfamily comprises: TCRβ V12-4*01, TCRβ V12-3*01, orWSGR Docket No.53676-766.601 TCRβ V12-5*01, or a variant thereof. In some embodiments, TCRβ V12 is recognized, e.g., bound, by SEQ ID NO: 15 and / or SEQ ID NO: 16. In some embodiments, TCRβ V12 is recognized, e.g., bound, by any one of SEQ ID NOs 23-25, and / or any one of SEQ ID NO: 26- 30:

[0307] In some embodiments, the TCRβ V5 subfamily is chosen from: TCRβ V5-5*01, TCRβ V5-6*01, TCRβ V5-4*01, TCRβ V5-8*01, TCRβ V5-1*01, or a variant thereof.

[0308] In some embodiments, the TCRβ V7 subfamily comprises TCRβ V7-7*01, TCRβ V7- 6*01, TCRβ V7 -8*02, TCRβ V7 -4*01, TCRβ V7-2*02, TCRβ V7-2*03, TCRβ V7-2*01, TCRβ V7-3*01, TCRβ V7-9*03, or TCRβ V7-9*01, or a variant thereof.

[0309] In some embodiments, the TCRβ V11 subfamily comprises: TCRβ V11-1*01, TCRβ V11-2*01 or TCRβ V11-3*01, or a variant thereof. In some embodiments, the TCRβ V14 subfamily comprises TCRβ V14*01, or a variant thereof. In some embodiments, the TCRβ V16 subfamily comprises TCRβ V16*01, or a variant thereof. In some embodiments, the TCRβ V18 subfamily comprises TCRβ V18*01, or a variant thereof. In some embodiments, the TCRβ V9 subfamily comprises TCRβ V9*01 or TCRβ V9*02, or a variant thereof. In some embodiments, the TCRβ V13 subfamily comprises TCRβ V13*01, or a variant thereof. In some embodiments, the TCRβ V4 subfamily comprises TCRβ V4-2*01, TCRβ V4-3*01, or TCRβ V4-1*01, or a variant thereof. In some embodiments, the TCRβ V3 subfamily comprises TCRβ V3-1*01, or a variant thereof. In some embodiments, the TCRβ V2 subfamily comprises TCRβ V2*01, or a variant thereof. In some embodiments, the TCRβ V15 subfamily comprises TCRβ V15*01, or a variant thereof. In some embodiments, the TCRβ V30 subfamily comprises TCRβ V30*01, or TCRβ V30*02, or a variant thereof. In some embodiments, the TCRβ V19 subfamily comprises TCRβ V19*01, or TCRβ V19*02, or a variant thereof. In some embodiments, the TCRβ V27 subfamily comprises TCRβ V27*01, or a variant thereof. In some embodiments, the TCRβ V28 subfamily comprises TCRβ V28*01, or a variant thereof. In some embodiments, the TCRβ V24 subfamily comprises TCRβ V24-1*01, or a variant thereof. In some embodiments, the TCRβ V20 subfamily comprises TCRβ V20-1*01, or TCRβ V20-1*02, or a variant thereof. In some embodiments, the TCRβ V25 subfamily comprises TCRβ V25-1*01, or a variant thereof. In some embodiments, the TCRβ V29 subfamily comprises TCRβ V29-1*01, or a variant thereof.

[0310] Exemplary amino acid sequences for TCRβV subfamily members can be found on the ImMunoGeneTics Information System website: http: / / www.imgt.org / , or in a similar resource.

[0311] Anti-TCRβV antibodies

[0312] Current bispecific constructs designed to redirect T cells to promote tumor cell lysis for cancer immunotherapy typically utilize antibody fragments (Fab, scFv, VH, single domainWSGR Docket No.53676-766.601 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 (IFNγ). This excess amount of IFNγ in turn activates macrophages which then overproduce proinflammatory cytokines such as IL-1beta, IL-6, IL-10 and TNF-alpha, causing a “cytokine storm” known as the cytokine release syndrome (CRS) (Shimabukuro-Vornhagen et al., J Immunother Cancer.2018 Jun 15;6(1):56, herein incorporated by reference in its entirety). Thus, the need exists for developing antibodies that are capable of binding and activating only a subset of effector T cells, e.g., to re-duce the CRS and / or neurotoxicity (NT).

[0313] Described herein are molecules targeting the TCRβV chain of TCR and methods thereof. Without wishing to be bound by theory, such molecules are capable of binding, activating, and / or expanding only a subset of T cells, avoiding or reducing CRS and / or NT and minimizing potential immunosuppressive effects of anti-CD3 mAbs.

[0314] Described herein is a class of antibodies, i.e., anti-TCRβV antibody molecules as described herein, which despite having low sequence similarity (e.g., low sequence identity among the different antibody molecules that recognize different TCRβV subfamilies), recognize a structurally conserved, yet sequence-wise variable, region, e.g., domain, on the TCRβV protein and have a similar function (e.g., activation of T cells and a similar cytokine profile as described herein). Thus, the anti-TCRβV antibody molecules as described herein share a structure-function relationship.

[0315] Without wishing to be bound by theory, in some embodiments, the anti-TCRβV antibody molecules as described herein bind to an outward facing epitope of a TCRβV protein when it is in a complex with a TCRalpha protein. In some embodiments, the anti-TCRβV antibody molecules as described herein recognize (e.g., bind to), a domain (e.g., an epitope) on the TCRβV protein that is: (1) structurally conserved among different TCRβV subfamilies; and (2) has minimal sequence identity among the different TCRβV subfamilies. TCRβV proteins from the different TCRBV subfamilies share minimal sequence similarity. However, TCRβV proteins which have minimal sequence similarity, share a similar 3D conformation and structure.

[0316] The alignment of TCRBV amino acid sequences underscores the diversity of TCR sequences. In particular, the TRBV sequences from different subfamilies are considerably different from each other.WSGR Docket No.53676-766.601

[0317] In some embodiments, the anti-TCRβV antibody molecules as described herein do not recognize, e.g., bind to, an interface of a TCRβV:TCRalpha complex. In some embodiments, the anti-TCRβV antibody molecules as described herein do not recognize, e.g., bind to, a constant region of a TCRβV protein. An exemplary antibody that binds to a constant region of a TCRBV region is JOVI.1 as de-scribed in Viney et al., (Hybridoma.1992 Dec;11(6):701-13). In some embodiments, the anti-TCRβV antibody molecules as described herein do not recognize, e.g., bind to, one or more (e.g., all) of a complementarity determining region (e.g., CDR1, CDR2 and / or CDR3) of a TCRβV protein.

[0318] Provided herein are, inter alia, antibody molecules directed to the variable chain of the beta subunit of TCR (TCRβV) which bind and, e.g., activate a subset of T cells. The anti- TCRβV antibody molecules as described herein result in lesser or no production of cytokines associated with CRS, e.g., IL-6, IL-1beta, IL-10 and TNF alpha; and enhanced and / or delayed production of IL-2 and IFNγ. In some embodiments, the anti-TCRβV antibodies as described herein have a cytokine profile, e.g., as described herein, which differs from a cytokine profile of a T cell engager that binds to a receptor or molecule other than a TCRβV region (“a non- TCRβV-binding T cell engager”). In some embodiments, the non-TCRβV-binding T cell engager comprises an antibody that binds to a CD3 molecule (e.g., CD3 epsilon (CD3e) molecule); or a TCR alpha (TCRα) molecule. In some embodiments, the non-TCRβV-binding T cell engager is an OKT3 antibody or an SP34-2 antibody.

[0319] In some embodiments, the anti-TCRβV antibodies as described herein result in expansion of TCRβV+ T cells, e.g., a subset of memory effector T cells known as TEMRA. Without wishing to be bound by theory, it is believed that in some embodiments, TEMRA cells can promote tumor cell lysis but not CRS. Accordingly, provided herein are methods of making said anti-TCRβV antibody molecules and uses thereof. Also described herein are multispecific molecules, e.g., bispecific molecules comprising said anti-TCRβV antibody molecules. In some embodiments, compositions comprising anti-TCRβV antibody molecules of the present disclosure, can be used, e.g., to: (1) activate and redirect T cells to promote tumor cell lysis for cancer immuno-therapy; and / or (2) expand TCRβV+ T cells. In some embodiments, compositions comprising anti-TCRβV antibody molecules as described herein limit the harmful side-effects of CRS and / or NT, e.g., CRS and / or NT associated with anti-CD3e targeting.

[0320] In some embodiments, the anti-TCRβV antibody molecule binds to one or more of TRBV2, TRBV3-1, TRBV4-1, TRBV4-2, TRBV4-3, TRBV5-1, TRBV5-4, TRBV5-5, TRBV5- 6, TRBV5-8, TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8, TRBV6-9, TRBV7-2, TRBV7-3, TRBV7-4, TRBV7-6, TRBV7-7, TRBV7-8, TRBV7-9, TRBV9, TRBV10-1, TRBV10-2, TRBV10-3, TRBV11-1, TRBV11-2, TRBV11-3, TRBV12-3,WSGR Docket No.53676-766.601 TRBV12-4, TRBV12-5, TRBV13, TRBV14, TRBV15, TRBV16, TRBV18, TRBV19, TRBV20-1, TRBV24-1, TRBV25-1, TRBV27, TRBV28, TRBV29-1 and TRBV30. In some embodiments, the anti-TCRβV antibody molecule binds to one or more of TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8 and TRBV6-9. In some embodiments, the anti-TCRβV antibody molecule is an anti-TRBV2, anti-TRBV3-1, anti-TRBV4-1, anti- TRBV4-2, anti-TRBV4-3, anti-TRBV5-1, anti-TRBV5-4, anti-TRBV5-5, anti-TRBV5-6, anti- TRBV5-8, anti-TRBV6-1, anti-TRBV6-2, anti-TRBV6-3, anti-TRBV6-4, anti-TRBV6-5, anti- TRBV6-6, anti-TRBV6-8, anti-TRBV6-9, anti-TRBV7-2, anti-TRBV7-3, anti-TRBV7-4, anti- TRBV7-6, anti-TRBV7-7, anti-TRBV7-8, anti-TRBV7-9, anti-TRBV9, anti-TRBV10-1, anti- TRBV10-2, anti-TRBV10-3, anti-TRBV11-1, anti-TRBV11-2, anti-TRBV11-3, anti-TRBV12- 3, anti-TRBV12-4, anti-TRBV12-5, anti-TRBV13, anti-TRBV14, anti-TRBV15, anti-TRBV16, anti-TRBV18, anti-TRBV19, anti-TRBV20-1, anti-TRBV24-1, anti-TRBV25-1, anti-TRBV27, anti-TRBV28, anti-TRBV29-1, or anti-TRBV30. Exemplary anti-TCRβV antibody molecules and the corresponding TCRβV subfamilies recognized by said anti-TCRβV antibody molecules are disclosed in Table 10A.

[0321] In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV2, TRBV3-1, TRBV4-1, TRBV4-2, TRBV4-3, TRBV5-1, TRBV5-4, TRBV5-5, TRBV5-6, TRBV5-8, TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8, TRBV6-9, TRBV7-2, TRBV7-3, TRBV7-4, TRBV7-6, TRBV7-7, TRBV7-8, TRBV7-9, TRBV9, TRBV10-1, TRBV10-2, TRBV10-3, TRBV11-1, TRBV11-2, TRBV11-3, TRBV12-3, TRBV12-4, TRBV12-5, TRBV13, TRBV14, TRBV15, TRBV16, TRBV18, TRBV19, TRBV20-1, TRBV24-1, TRBV25-1, TRBV27, TRBV28, TRBV29-1 or TRBV30. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-1. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-2. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-3. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-4. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-5. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-6. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-8. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-9.

[0322] In some embodiments, the anti-TCRβV antibody molecule does not bind to TCRβ V12, or binds to TCRβ V12 with an affinity and / or binding specificity that is less than (e.g., less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof as de- scribed in US Patent 5,861,155.WSGR Docket No.53676-766.601

[0323] In some embodiments, the anti-TCRβV antibody molecule binds to TCRβ 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.

[0324] In some embodiments, the anti-TCRβV antibody molecule binds to a TCRβV region other than TCRβ V12 (e.g., TCRβV region as described herein, e.g., TCRβ V6 subfamily (e.g., TCRβ V6-5*01) with an affinity and / or binding specificity that is greater than (e.g., greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof as de- scribed in US Patent 5,861,155.

[0325] In some embodiments, the anti-TCRβV antibody molecule does not comprise the CDRs of the Antibody B murine antibody.

[0326] In some embodiments, the anti-TCRβV antibody molecule does not bind to TCRβ V5- 5*01 or TCRβ V5-1*01, or binds to TCRβ V5-5*01 or TCRβ V5-1*01 with an affinity and / or binding specificity that is less than (e.g., less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the TM23 murine antibody or a humanized version thereof as described in US Patent 5,861,155.

[0327] In some embodiments, the anti-TCRβV antibody molecule binds to TCRβ V5-5*01 or TCRβ V5-1*01with an affinity and / or binding specificity that is greater than (e.g., greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the TM23 murine antibody or a humanized version thereof as de- scribed in US Patent 5,861,155.

[0328] In some embodiments, the anti-TCRβV antibody molecule binds to a TCRβV region other than TCRβ V5-5*01 or TCRβ V5-1*01 (e.g., TCRβV region as described herein, e.g., TCRβ V6 subfamily (e.g., TCRβ V6-5*01) with an affinity and / or binding specificity that is greater than (e.g., greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the TM23 murine antibody or a humanized version thereof as described in US Patent 5,861,155.

[0329] In some embodiments, the anti-TCRβV antibody molecule does not comprise the CDRs of the TM23 murine antibody.

[0330] 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-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule can be chosen from: (a) a light or heavy chain variable framework including at least 80%, 85%, 87% 90%,WSGR Docket No.53676-766.601 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.

[0331] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.1, A-H.2 or A-H.68, e.g., the amino acid sequence of the FR region in the entire variable region, e.g., in SEQ ID NO: 9.

[0332] Alternatively, or in combination with the heavy chain substitutions described herein, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more amino acid changes, e.g., amino acid substitutions or deletions, from an amino acid sequence of any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, e.g., the amino acid sequence of the FR region in the entire variable region, e.g., SEQ ID NO: 10 or SEQ ID NO: 11.

[0333] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes one, two, three, or four heavy chain framework regions or a sequence substantially identical thereto.

[0334] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes one, two, three, or four light chain framework regions or a sequence substantially identical thereto.

[0335] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the light chain framework region 1 of A-H.1 or A-H.2.WSGR Docket No.53676-766.601

[0336] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the light chain framework region 2 of A-H.1 or A-H.2.

[0337] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the light chain framework region 3 of A-H.1 or A-H.2.

[0338] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the light chain framework region 4 of A-H.1 or A-H.2.

[0339] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain 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.

[0340] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain 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.

[0341] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain 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.

[0342] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain comprising:WSGR Docket No.53676-766.601 (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.

[0343] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain 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.

[0344] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain 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.

[0345] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the heavy chain framework region 1 of A- H.1 or A-H.2. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the heavy chain framework region 2 of A-H.1 or A-H.2. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6WSGR Docket No.53676-766.601 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the heavy chain framework region 3 of A-H.1 or A-H.2. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the heavy chain framework region 4 of A-H.1 or A-H.2.

[0346] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.

[0347] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.

[0348] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the heavy chain framework regions 1-4 of A-H.1 or A-H.2, e.g., SEQ ID NO: 9. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the light chain framework regions 1-4 of A-H.1, e.g., SEQ ID NO: 10. In some embodiments, the anti- TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the light chain framework regions 1-4 of A-H.2, e.g., SEQ ID NO: 11. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6- 5*01) antibody molecule, comprises the heavy chain framework regions 1-4 of A-H.1, e.g., SEQ ID NO: 9; and the light chain framework regions 1-4 of A-H.1, e.g., SEQ ID NO: 10. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6- 5*01) antibody molecule, comprises the heavy chain framework regions 1-4 of A-H.2, e.g., SEQ ID NO: 9; and the light chain framework regions 1-4 of A-H.2, e.g., SEQ ID NO: 11.

[0349] In some embodiments, the heavy or light chain variable domain, or both, of the anti- TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes an amino acid sequence, which is substantially identical to an amino acid as describedWSGR Docket No.53676-766.601 herein, e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical to a variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or as described in Table 1, or encoded by the nucleotide sequence in Table 1; or which differs at least 1 or 5 residues, but less than 40, 30, 20, or 10 residues, from a variable region of an antibody described herein.

[0350] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes a VH and / or VL domain encoded by a nucleic acid having a nucleotide sequence as set forth in Table 1, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Table 1.

[0351] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.

[0352] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.WSGR Docket No.53676-766.601

[0353] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule is a monoclonal antibody or an antibody with single specificity. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, can also be a humanized, chimeric, camelid, shark, or an inantibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a humanized antibody molecule. The heavy and light chains of the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, can be full-length (e.g., an antibody can include at least one, and preferably two, complete heavy chains, and at least one, and preferably two, complete light chains) or can include an antigen-binding fragment (e.g., a Fab, F(ab')2, Fv, a single chain Fv fragment, a single domain antibody, a diabody (dAb), a bivalent antibody, or bispecific antibody or fragment thereof, a single domain variant thereof, or a camelid antibody).

[0354] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is in the form of a multispecific molecule, e.g., a bispecific molecule, e.g., as described herein.

[0355] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, has a heavy chain constant region (Fc) chosen from, e.g., the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE. In some embodiments, the Fc region is chosen from the heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4. In some embodiments, the Fc region is chosen from the heavy chain constant region of IgG1 or IgG2 (e.g., human IgG1, or IgG2). In some embodiments, the heavy chain constant region is human IgG1. In some embodiments, the Fc region comprises a Fc region variant, e.g., as described herein.

[0356] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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- TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function). For example, the constant region is mutated at positions 296 (M to Y), 298 (S to T), 300 (T to E), 477 (H to K) and 478 (N to F) to alter Fc receptor binding (e.g., the mutated positions correspond to positionsWSGR Docket No.53676-766.601 132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K) and 314 (N to F) of SEQ ID NOs: 212 or 214; or positions 135 (M to Y), 137 (S to T), 139 (T to E), 316 (H to K) and 317 (N to F) of SEQ ID NOs: 215, 216, 217 or 218), e.g., relative to human IgG1.

[0357] 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.

[0358] Additional exemplary humanized anti-TCRB V6 antibodies are provided in Table 1. In some embodiments, the anti-TCRβ V6 is antibody A, e.g., humanized antibody A (antibody A- H), as provided in Table 1. In some embodiments, the anti-TCRβV antibody comprises one or more (e.g., all three) of a LC CDR1, LC CDR2, and LC CDR3 provided in Table 1; and / or one or more (e.g., all three) of a HC CDR1, HC CDR2, and HC CDR3 provided in Table 1, or a sequence with at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity thereto. In some embodiments, antibody A comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 1, or a sequence with at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity thereto.

[0359] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.11, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16, A-H.17, A-H.18, A-H.19, A-H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A-H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.1, A-H.42, A-H.43, A-H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A-H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A-H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A-H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0360] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.11, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16,WSGR Docket No.53676-766.601 A-H.17, A-H.18, A-H.19, A-H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A-H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.1, A-H.42, A-H.43, A-H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A-H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A-H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A-H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0361] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.11, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16, A-H.17, A-H.18, A-H.19, A-H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A-H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.1, A-H.42, A-H.43, A-H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A-H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A-H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A-H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto; and a VL of A-H.1, A-H.2, A-H.3, A-H.4, A-H.5, A-H.6, A-H.7, A-H.8, A-H.9, A-H.10, A-H.11, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16, A-H.17, A-H.18, A-H.19, A-H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A-H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.1, A-H.42, A-H.43, A-H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A-H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A-H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A-H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0362] Exemplary anti-TCRβV antibody molecules and the corresponding TCRβV subfamilies recognized by said anti-TCRβV antibody molecules are disclosed in Table 10A.

[0363] The various TCRβV 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, TCRβ V6-5 is represented in approximately 3-6% healthy donors.WSGR Docket No.53676-766.601

[0364] The representation of various TCRBV subfamilies and / or subfamily members can also be different in cancer cells. For example, TCRβV 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 TCRβ V6-5 is present at a high frequency in tumor cells. Anti-TCRβ V6 antibodies

[0365] In one aspect, provided herein is an anti-TCRβV antibody molecule that binds to human TCRβ V6, e.g., a TCRβ V6 subfamily comprising: TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6- 9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01 or TCRβ V6-1*01. In some embodiments the TCRβ V6 subfamily comprises TCRβ V6-5*01 or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-4*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-4*02, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-9*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-8*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-5*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-6*02, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-6*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-2*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6- 3*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-1*01, or a variant thereof.

[0366] In some embodiments, TCRβ V6-5*01 is encoded by the nucleic acid sequence of SEQ ID NO: 43, or a sequence having 85%, 90%, 95%, 99% or more identity thereof. In some embodiments, TCRβ V6-5*01 comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence having 85%, 90%, 95%, 99% or more identity thereof.

[0367] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a non-murine antibody molecule, e.g., a human or humanized antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule is a human antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule is a humanized antibody molecule.

[0368] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is isolated or recombinant.

[0369] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one antigen-binding region, e.g., aWSGR Docket No.53676-766.601 variable region or an antigen-binding fragment thereof, from an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, or encoded by a nucleotide sequence in Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0370] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0371] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody molecule described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0372] In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain variable region (VH) having a consensus sequence of SEQ ID NO: 231 or 3290.

[0373] SEQ ID NO: 231 - Consensus VH QVQLVQSGAEVKKPGSSVKVSCKASGH / T / G / YD / T / SFH / R / D / K / TL / D / K / T / NW / F / T / I / Y / G YIHWVRQAPGQGLEWMGR / WV / I / FF / S / YA / PGSGN / ST / V / Y / IK / RYNEKFKGRVTITADT STSTAYMELSSLRSEDTAVYYCAG / VSY / IYSY / AD / GVLDYWGQGTTVTVSS

[0374] SEQ ID NO: 3290 - Consensus VH QVQLVQSGAEVKKPGSSVKVSCKASGX1X2FX3X4X5YIHWVRQAPGQGLEWMGX6X7X8 X9GSGX10X11X12YNEKFKGRVTITADTSTSTAYMELSSLRSEDTAVYYCAX13SX14YSX15X16VLDYWGQGTTVTVSS, where-in: X1 is H or T or G or Y; X2 is D or T or S; X3 is H or R or D or K or T; X4 is L or D or K or T or N; X5 is W or F or T or I or Y or G; X6 is R or W; X7 is V or I or F; X8 is F or S or Y; X9 is A or P; X10 is N or S; X11 is T or V or Y or I; X12 is K or R; X13 is G or V; X14 is Y or I; X15 is Y or A; and X16 is D or G.

[0375] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.1 toWSGR Docket No.53676-766.601 A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0376] In some embodiments, the anti-TCRβV antibody molecule comprises a light chain variable region (VL) having a consensus sequence of SEQ ID NO: 230 or 3289.

[0377] SEQ ID NO: 230 - Consensus VL DIQMTQSPSFLSASVGDRVTITCKASQNVG / E / A / DN / DR / KVAWY / HQQKPGKAPKALIY SSSHRYK / SGVPSRFSGSGSGTEFTLTISSLQPEDFATYFCQQFKSYPLTFGQGTKLEIK

[0378] SEQ ID NO: 3289 - Consensus VL DIQMTQSPSFLSASVGDRVTITCKASQNVX1X2X3VAWX4QQKPGKAPKALIYSSSHRYX5 GVPSRFSGSGSGTEFTLTISSLQPEDFATYFCQQFKSYPLTFGQGTKLEIK, wherein X1 is G, E, A or D; X2 is N or D; X3 is R or K; X4 is Y or H; and X5 is K or S

[0379] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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-TCRβV antibody molecule, e.g., anti- TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes a heavy chain constant region for an IgG1, e.g., a human IgG1. 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.

[0380] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.

[0381] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.1 to A-H.85, e.g., A-H.1, A-H.2 or A- H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0382] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes at least one, two, or three CDRs (orWSGR Docket No.53676-766.601 collectively all of the CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23.

[0383] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0384] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23.

[0385] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23.

[0386] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23, or closely related CDRs, e.g., CDRsWSGR Docket No.53676-766.601 which are identical or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions). In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, may include any CDR described herein.

[0387] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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, Table 16, or Table 23) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A- H.68, or an antibody described in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Kabat et al. shown in Table 1, Table 16, or Table 23.

[0388] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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, Table 16, or Table 23) from a light chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A- H.68, or an antibody described in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Kabat et al. shown in Table 1, Table 16, or Table 23.

[0389] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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, Table 16, or Table 23) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acidWSGR Docket No.53676-766.601 alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, three, four, five, or six CDRs according to Kabat et al. shown in Table 1, Table 16, or Table 23.

[0390] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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, Table 16, or Table 23) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to all six CDRs according to Kabat et al. shown in Table 1, Table 16, or Table 23. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, may include any CDR described herein.

[0391] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, e.g., the same canonical structures as at least loop 1 and / or loop 2 of the heavy and / or light chain variable domains of an antibody described herein. See, e.g., Chothia et al., (1992) J. Mol. Biol.227:799-817; Tomlinson et al., (1992) J. Mol. Biol.227:776-798 for descriptions of hypervariable loop canonical structures. These structures can be determined by inspection of the tables described in these references.

[0392] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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, Table 16, or Table 23) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or as described in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservativeWSGR Docket No.53676-766.601 substitutions) relative to one, two, or three CDRs according to Chothia et al. shown in Table 1, Table 16, or Table 23.

[0393] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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, Table 16, or Table 23) from a light chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Chothia et al. shown in Table 1, Table 16, or Table 23.

[0394] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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, Table 16, or Table 23) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by the nucleotide sequence in Table 1, Table 16, or Table 23; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, three, four, five, or six CDRs according to Chothia et al. shown in Table 1, Table 16, or Table 23.

[0395] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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, Table 16, or Table 23) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to all sixWSGR Docket No.53676-766.601 CDRs according to Chothia et al. shown in Table 1, Table 16, or Table 23. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6- 5*01) antibody molecule, may include any CDR described herein.

[0396] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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, Table 16, or Table 23.

[0397] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, can contain any combination of CDRs or hypervariable loops according to the Kabat and Chothia definitions.

[0398] In some embodiments, a combined CDR as set out in Table 1, Table 16, or Table 23 is a CDR that comprises a Kabat CDR and a Chothia CDR.

[0399] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, molecule includes a combination of CDRs or hypervariable loops identified as combined CDRs in Table 1, Table 16, or Table 23. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6- 5*01) antibody molecule, can contain any combination of CDRs or hypervariable loops according the “combined” CDRs are described in Table 1, Table 16, or Table 23.

[0400] In some embodiments, e.g., an embodiment comprising a variable region, a CDR (e.g., a combined CDR, Chothia CDR or Kabat CDR), or other sequence referred to herein, e.g., in Table 1, Table 16, or Table 23, the antibody molecule is a monospecific antibody molecule, a bispecific antibody molecule, a bivalent antibody molecule, a biparatopic antibody molecule, or an antibody molecule that comprises an antigen binding fragment of an antibody, e.g., a half antibody or antigen binding fragment of a half antibody. In certain embodiments the antibody molecule comprises a multispecific molecule, e.g., a bispecific molecule, e.g., as described herein.

[0401] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.WSGR Docket No.53676-766.601

[0402] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.

[0403] In some embodiments the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti- TCRβ 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.

[0404] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.

[0405] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.

[0406] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.

[0407] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.

[0408] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.WSGR Docket No.53676-766.601

[0409] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.

[0410] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ 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.

[0411] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises a VH and / or a VL of an antibody described in Table 1, Table 16, or Table 23, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0412] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises a VH and a VL of an antibody described in Table 1, Table 16, or Table 23, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0413] 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.

[0414] 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.WSGR Docket No.53676-766.601 Additional anti-TCRVβ antibodies

[0415] Additional exemplary anti-TCRβV antibodies are provided in Table 2, Table 10B, Table 10C, Table 11, Table 12, Table 13, Table 15, Table 17, Table 18, Table 19, Table 20, and Table 21. In some embodiments, the anti-TCRβV antibody is a humanized antibody, e.g., as provided in Table 2, Table 10B, Table 10C, Table 11, Table 12, Table 13, Table 15, Table 17, Table 18, Table 19, Table 20, and Table 21. In some embodiments, the anti-TCRβV antibody comprises one or more (e.g., all three) of a LC CDR1, LC CDR2, and LC CDR3 provided in Table 2, Table 10B, Table 10C, Table 11, Table 12, Table 13, Table 15, Table 17, Table 18, Table 19, Table 20, and Table 21; and / or one or more (e.g., all three) of a HC CDR1, HC CDR2, and HC CDR3 provided in Table 2, Table 10B, Table 10C, Table 11, Table 12, Table 13, Table 15, Table 17, Table 18, Table 19, Table 20, and Table 21, or a sequence with at least 95% sequence identity thereto. In some embodiments, the anti-TCRβV antibody comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 13, or a sequence with at least 95% sequence identity thereto. Antibody-like Frameworks or Scaffolds

[0416] A wide variety of antibody / immunoglobulin frameworks or scaffolds can be employed in the anti-TCRvb antibody molecules as described herein or multifunctional formats thereof so long as the resulting polypeptide includes at least one binding region which specifically binds to the target antigen, e.g., a TCRvb, a tumor antigen, among others. Such frameworks or scaffolds include the 5 main idiotypes of human immunoglobulins, or fragments thereof, and include immunoglobulins of other animal species, preferably having humanized aspects. Novel frameworks, scaffolds and fragments continue to be discovered and developed by those skilled in the art.

[0417] In some embodiments, the anti-TCRvb antibody molecules as described herein or multifunctional formats thereof include non-immunoglobulin based antibodies using non- immunoglobulin scaffolds onto which CDRs can be grafted. Any non-immunoglobulin frameworks and scaffolds may be employed, as long as they comprise a binding region specific for the target antigen (e.g., TCRvb or a tumor antigen). Exemplary non-immunoglobulin frameworks or scaffolds include, but are not limited to, fibronectin (Compound Therapeutics, Inc., Waltham, MA), ankyrin (Molecular Partners AG, Zurich, Switzerland), domain antibodies (Domantis, Ltd., Cambridge, MA, and Ablynx nv, Zwijnaarde, Belgium), lipocalin (Pieris Proteolab AG, Freising, Germany), small modular immuno-pharmaceuticals (Trubion Pharmaceuticals Inc., Seattle, WA), maxybodies (Avidia, Inc., Mountain View, CA), Protein AWSGR Docket No.53676-766.601 (Affibody AG, Sweden), and affilin (gamma-crystallin or ubiquitin) (Scil Proteins GmbH, Halle, Germany).

[0418] Fibronectin scaffolds are typically based on fibronectin type III domain (e.g., the tenth module of the fibronectin type III (10 Fn3 domain)). The fibronectin type III domain has 7 or 8 beta strands which are distributed between two beta sheets, which themselves pack against each other to form the core of the protein, and further containing loops (analogous to CDRs) which connect the beta strands to each other and are solvent exposed. There are at least three such loops at each edge of the beta sheet sandwich, where the edge is the boundary of the protein perpendicular to the direction of the beta strands (see US 6,818,418). Because of this structure, the non-immunoglobulin antibody mimics antigen binding properties that are similar in nature and affinity to those of antibodies. These scaffolds can be used in a loop randomization and shuffling strategy in vitro that is similar to the process of affinity maturation of antibodies in vivo. These fibronectin-based molecules can be used as scaffolds where the loop regions of the molecule can be replaced with CDRs of the invention using standard cloning techniques.

[0419] The ankyrin technology is based on using proteins with ankyrin derived repeat modules as scaffolds for bearing variable regions which can be used for binding to different targets. The ankyrin repeat module typically is a about 33 amino acid polypeptide consisting of two anti- parallel α-helices and a β-turn. Binding of the variable regions can be optimized by using ribosome display.

[0420] Avimers are used by nature for protein-protein interactions and in human over 250 proteins are structurally based on A-domains. Avimers consist of a number of different “A- domain” monomers (2-10) linked via amino acid linkers. Avimers can be created that can bind to the target antigen using the methodology described in, for example, U.S. Patent Application Publication Nos.20040175756; 20050053973; 20050048512; and 20060008844.

[0421] Affibody affinity ligands are small, simple proteins composed of a three-helix bundle based on the scaffold of one of the IgG-binding domains of Protein A. Protein A is a surface protein from the bacterium Staphylococcus aureus. This scaffold domain consists of 58 amino acids, 13 of which are randomized to generate affibody libraries with a large number of ligand variants (See e.g., US 5,831,012). Affibody molecules mimic antibodies, they have a molecular weight of 6 kDa, compared to the molecular weight of antibodies, which is 150 kDa. In spite of its small size, the binding site of affibody molecules is similar to that of an antibody.

[0422] Anticalins are known commercially, e.g., Pieris ProteoLab AG. They are derived from lipocalins, a widespread group of small and robust proteins that are usually involved in the physiological transport or storage of chemically sensitive or insoluble compounds. Several natural lipocalins occur in human tissues or body liquids. The protein architecture is reminiscentWSGR Docket No.53676-766.601 of immunoglobulins, with hypervariable loops on top of a rigid framework. However, in contrast with antibodies or their recombinant fragments, lipocalins are composed of a single polypeptide chain with 160 to 180 amino acid residues, being just marginally bigger than a single immunoglobulin domain. The set of four loops, which makes up the binding pocket, shows pronounced structural plasticity and tolerates a variety of side chains. The binding site can thus be reshaped in a proprietary process in order to recognize prescribed target molecules of different shape with high affinity and specificity. One protein of lipocalin family, the bilin- binding protein (BBP) of Pieris Brassicae has been used to develop anticalins by mutagenizing the set of four loops. One example of a patent application describing anticalins is in PCT Publication No. WO 199916873.

[0423] Affilin molecules are small non-immunoglobulin proteins which are designed for specific affinities towards proteins and small molecules. New affilin molecules can be very quickly selected from two libraries, each of which is based on a different human derived scaffold protein. Affilin molecules do not show any structural homology to immunoglobulin proteins. Currently, two affilin scaffolds are employed, one of which is gamma crystalline, a human structural eye lens protein and the other is “ubiquitin” superfamily proteins. Both human scaffolds are very small, show high temperature stability and are almost resistant to pH changes and denaturing agents. This high stability is mainly due to the expanded beta sheet structure of the proteins. Examples of gamma crystalline derived proteins are described in WO200104144 and examples of “ubiquitin-like” proteins are described in WO2004106368.

[0424] Protein epitope mimetics (PEM) are medium-sized, cyclic, peptide-like molecules (MW 1-2kDa) mimicking beta-hairpin secondary structures of proteins, the major secondary structure involved in protein-protein interactions.

[0425] Domain antibodies (dAbs) can be used in the anti-TCRvb antibody molecules as described herein or multifunctional formats thereof are small functional binding fragments of antibodies, corresponding to the variable regions of either the heavy or light chains of antibodies. Domain antibodies are well expressed in bacterial, yeast, and mammalian cell systems. Further details of domain antibodies and methods of production thereof are known in the art (see, for example, U.S. Pat. Nos.6,291,158; 6,582,915; 6,593,081; 6,172,197; 6,696,245; European Patents 0368684 & 0616640; WO05 / 035572, WO04 / 101790, WO04 / 081026, WO04 / 058821, WO04 / 003019 and WO03 / 002609. Nanobodies are derived from the heavy chains of an antibody.

[0426] A nanobody typically comprises a single variable domain and two constant domains (CH2 and CH3) and retains antigen-binding capacity of the original antibody. Nanobodies can be prepared by methods known in the art (See e.g., U.S. Pat. No.6,765,087, U.S. Pat. No.WSGR Docket No.53676-766.601 6,838,254, WO 06 / 079372). Unibodies consist of one light chain and one heavy chain of an IgG4 antibody. Unibodies may be made by the removal of the hinge region of IgG4 antibodies. Further details of unibodies and methods of preparing them may be found in WO2007 / 059782. Anti-TCRVβ antibody effector function and Fc variants

[0427] In some embodiments, an anti-TCRVβ antibody as described herein comprises an Fc region, e.g., as described herein. In some embodiments, the Fc region is a wildtype Fc region, e.g., a wildtype human Fc region. In some embodiments, the Fc region comprises a variant, e.g., an Fc region comprising an addition, substitution, or deletion of at least one amino acid residue in the Fc region which results in, e.g., reduced or ablated affinity for at least one Fc receptor.

[0428] The Fc region of an antibody interacts with a number of receptors or ligands including Fc Receptors (e.g., FcγRI, FcγRIIA, FcγRIIIA), the complement protein CIq, and other molecules such as proteins A and G. These interactions are essential for a variety of effector functions and downstream signaling events including: antibody dependent cell-mediated cytotoxicity (ADCC), Antibody-dependent cellular phagocytosis (ADCP) and complement dependent cytotoxicity (CDC).

[0429] In some embodiments, an anti-TCRVβ antibody comprising a variant Fc region has reduced, e.g., ablated, affinity for an Fc receptor, e.g., an Fc receptor described herein. In some embodiments, the reduced affinity is compared to an otherwise similar antibody with a wildtype Fc region.

[0430] In some embodiments, an anti-TCRVβ antibody comprising a variant Fc region has one or more of the following properties: (1) reduced effector function (e.g., reduced ADCC, ADCP and / or CDC); (2) reduced binding to one or more Fc receptors; and / or (3) reduced binding to C1q complement. In some embodiments, the reduction in any one, or all of properties (1)-(3) is compared to an otherwise similar antibody with a wildtype Fc region.

[0431] In some embodiments, an anti-TCRVβ antibody comprising a variant Fc region has reduced affinity to a human Fc receptor, e.g., FcγR I, FcγR II and / or FcγR III. In some embodiments, the anti-TCRVβ antibody comprising a variant Fc region comprises a human IgG1 region or a human IgG4 region.

[0432] In some embodiments, an anti-TCRVβ antibody comprising a variant Fc region activates and / or expands T cells, e.g., as described herein. In some embodiments, an anti-TCRVβ antibody comprising a variant Fc region has a cytokine profile described herein, e.g., a cytokine profile that differs from a cytokine profile of a T cell engager that binds to a receptor or molecule other than a TCRβV region (“a non-TCRβV-binding T cell engager”). In someWSGR Docket No.53676-766.601 embodiments, the non-TCRβV-binding T cell engager comprises an antibody that binds to a CD3 molecule (e.g., CD3 epsilon (CD3e) molecule); or a TCR alpha (TCRα) molecule.

[0433] Exemplary Fc region variants are provided in Table 14 and also disclosed in Saunders O, (2019) Frontiers in Immunology; vol 10, article1296, the entire contents of which is hereby incorporated by reference.

[0434] In some embodiments, an anti-TCRVβ antibody as described herein comprises any one or all, or any combination of Fc region variants disclosed in Table 14.

[0435] In some embodiments, an anti-TCRVβ antibody as described herein comprises any one or all, or any combination of Fc region variants, e.g., mutations, disclosed in Table 14. In some embodiments, an anti-TCRVβ antibody as described herein comprise an Asn297Ala (N297A) mutation. In some embodiments, an anti-TCRVβ antibody as described herein comprise a Leu234Ala / Leu235Ala (LALA) mutation. Multifunctional Molecules

[0436] As used herein, a “multifunctional” or a “multispecific” molecule refers to molecule, e.g., a polypeptide, that has two or more functionalities, e.g., two or more binding specificities. In some embodiments, the functionalities can include one or more immune cell engagers, one or more tumor binding molecules, one or more cytokine molecules, one or more stromal modifiers, and other moieties described herein. In some embodiments, the multispecific molecule is a multispecific antibody molecule, e.g., a bispecific antibody molecule. In some embodiments, the multispecific molecule includes an anti-TCRVb antibody molecule as described herein.

[0437] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, a fourth polypeptide, and at least one cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide, the second polypeptide, the third polypeptide, and the fourth polypeptide are non-contiguous, wherein: (i) the first polypeptide comprising a first portion of a first T cell receptor variable beta (TCRβV)-binding moiety and a first dimerization module linked to the first portion of the first TCRβV-binding moiety; (ii) the second polypeptide comprising a second portion of the first TCRβV-binding moiety; (iii) the third polypeptide comprising a first portion of a second TCRβV-binding moiety and a second dimerization module linked to the first portion of the second TCRβV-binding moiety; and (iv) the fourth polypeptide comprising a second portion of the second TCRβV-binding moiety; and wherein the at least one cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof.WSGR Docket No.53676-766.601

[0438] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, and at least one cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide, the second polypeptide, and the third polypeptide are non-contiguous, wherein: (i) the first polypeptide comprising a first portion of a first TCRβV-binding moiety and a first dimerization module linked to the first portion of the first TCRβV-binding moiety; (ii) the second polypeptide comprising a second portion of the first TCRβV-binding moiety; and (iii) the third polypeptide comprising a second dimerization module; and wherein the at least one cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the first polypeptide, the second polypeptide, the third polypeptide, or a combination thereof.

[0439] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, and at least one cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide, the second polypeptide, and the third polypeptide are non-contiguous, wherein: (i) the first polypeptide comprising a first portion of a first TCRβV-binding moiety and a first dimerization module linked to the first portion of the first TCRβV-binding moiety; (ii) the second polypeptide comprising a second portion of the first TCRβV-binding moiety; and (iii) the third polypeptide comprising a second dimerization module; wherein the at least one cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the first polypeptide, the second polypeptide, the third polypeptide, or a combination thereof; and wherein the multifunctional polypeptide molecule does not comprise an additional TCRβV- binding moiety except the first TCRβV-binding moiety.

[0440] In some embodiments, the first portion of the first TCRβV-binding moiety comprises a first heavy chain variable domain (VH) and a first heavy chain constant domain 1 (CH1) linked to the first VH. In some embodiments, the first CH1 is linked to the C-terminus of the first VH. In some embodiments, the second portion of the first TCRβV-binding moiety comprises a first light chain variable domain (VL) and a first light chain constant domain (CL) linked to the first VL. In some embodiments, first CL is linked to the C-terminus of the first VL. In some embodiments, wherein the first dimerization module is linked to the first portion of the first TCRβV-binding moiety. In some embodiments, the first dimerization module is linked to the C- terminus of the first portion of the first TCRβV-binding moiety. In some embodiments, wherein the first portion of the second TCRβV-binding moiety comprises a second VH and a second CH1 linked to the second VH. In some embodiments, the second CH1 is linked to the C- terminus of the second VH. In some embodiments, the second portion of the second TCRβV- binding moiety comprises a second VL and a second CL linked to the second VL. In someWSGR Docket No.53676-766.601 embodiments, the second CL is linked to the C-terminus of the second VL. In some embodiments, the second dimerization module is linked to the first portion of the second TCRβV-binding moiety. In some embodiments, the second dimerization module is linked to the C-terminus of the first portion of the second TCRβV-binding moiety.

[0441] In some embodiments, (a) the N-terminus of the first polypeptide is linked to a first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to a second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (b) the N-terminus of the second polypeptide is linked to a third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to a fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (c) the N-terminus of the third polypeptide is linked to a fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to a sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (d) the N-terminus of the fourth polypeptide is linked to a seventh cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to an eighth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; or (e) a combination thereof.

[0442] In some embodiments, (a-1) the N-terminus of the first polypeptide is linked to the first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (a-2) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (b-1) the N-terminus of the first polypeptide is linked to the first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (b-2) the N-terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C- terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (c-1) the N-terminus of the first polypeptide is linked to the first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combinationWSGR Docket No.53676-766.601 thereof; and (c-2) the N-terminus of the fourth polypeptide is linked to the seventh cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to the eighth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (d-1) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (d-2) the N- terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (e-1) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (e-2) the N-terminus of the fourth polypeptide is linked to the seventh cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to the eighth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; or (f-1) the N-terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (f-2) the N-terminus of the fourth polypeptide is linked to the seventh cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to the eighth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof.

[0443] In some embodiments, (a-1) the N-terminus of the first polypeptide is linked to the first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (a-2) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (a-3) the N-terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (b-1) the N-terminus of the first polypeptide is linked to the firstWSGR Docket No.53676-766.601 cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (b-2) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (b-3) the N-terminus of the fourth polypeptide is linked to the seventh cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to the eighth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; or (c-1) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C- terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (c-2) the N-terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (c-3) the N-terminus of the fourth polypeptide is linked to the seventh cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to the eighth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof.

[0444] In some embodiments, (1) the N-terminus of the first polypeptide is linked to the first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (2) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (3) the N-terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (4) the N-terminus of the fourth polypeptide is linked to the seventh cytokine polypeptide or a functional fragment or a functional variant thereof; the C- terminus of the fourth polypeptide is linked to the eighth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof.WSGR Docket No.53676-766.601

[0445] In some embodiments, the first cytokine polypeptide, the second cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the first polypeptide, the third cytokine polypeptide, the fourth cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the second polypeptide, the fifth cytokine polypeptide, the sixth cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the third polypeptide, the seventh cytokine polypeptide, the eighth cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the fourth polypeptide, or a combination thereof.

[0446] In some embodiments, (a) the N-terminus of the first polypeptide is linked to a first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to a second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (b) the N-terminus of the second polypeptide is linked to a third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to a fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (c) the N-terminus of the third polypeptide is linked to a fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to a sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; or (d) a combination thereof.

[0447] In some embodiments, (a-1) the N-terminus of the first polypeptide is linked to the first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (a-2) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (b-1) the N-terminus of the first polypeptide is linked to the first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (b-2) the N-terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C- terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; or (c-1) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to the fourthWSGR Docket No.53676-766.601 cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (c-2) the N-terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof.

[0448] In some embodiments, (1) the N-terminus of the first polypeptide is linked to the first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (2) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (3) the N-terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof.

[0449] In some embodiments, the first cytokine polypeptide, the second cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the first polypeptide, the third cytokine polypeptide, the fourth cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the second polypeptide, the fifth cytokine polypeptide, the sixth cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the third polypeptide, or a combination thereof.

[0450] In some embodiments, the multifunctional polypeptide molecule as described herein further comprises a linker between the first portion of the first TCRβV-binding moiety and the first dimerization module, a linker between the first portion of the second TCRβV-binding moiety and the second dimerization module, a linker between the first VH and the first CH1, a linker between the first VL and the first CL, a linker between the second VH and the second CH1, a linker between the second VL and the second CL, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the first polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the second polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the third polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the fourth polypeptide, or a combination thereof.WSGR Docket No.53676-766.601

[0451] In some embodiments, the multifunctional polypeptide molecule as described herein further comprises comprising a linker between the first portion of the first TCRβV-binding moiety and the first dimerization module, a linker between the first VH and the first CH1, a linker between the first VL and the first CL, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the first polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the second polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the third polypeptide, or a combination thereof. In some embodiments, linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non-helical linker. In some embodiments, the linker is the peptide linker and wherein the linker is a GS linker. In some embodiments, the linker is the peptide linker and wherein the linker comprises the sequence of SEQ ID NO: 3308 or SEQ ID NO: 3643.

[0452] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, a fourth polypeptide, a first cytokine polypeptide or a functional fragment or a functional variant thereof, and a second cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide, the second polypeptide, the third polypeptide, and the fourth polypeptide are non- contiguous, wherein: (i) the first polypeptide comprising a first portion of a first TCRβV-binding moiety and a first dimerization module linked to the first portion of the first TCRβV-binding moiety; (ii) the second polypeptide comprising a second portion of the first TCRβV-binding moiety; (iii) the third polypeptide comprising a first portion of a second TCRβV-binding moiety and a second dimerization module linked to the first portion of the second TCRβV-binding moiety; and (iv) the fourth polypeptide comprising a second portion of the second TCRβV- binding moiety; and wherein the first cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the C-terminus of the second polypeptide, and the second cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the C-terminus of the fourth polypeptide.

[0453] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, a fourth polypeptide, a cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide, the second polypeptide, the third polypeptide, and the fourth polypeptide are non- contiguous, wherein: (i) the first polypeptide comprising a first portion of a first TCRβV-binding moiety and a first dimerization module linked to the first portion of the first TCRβV-binding moiety; (ii) the second polypeptide comprising a second portion of the first TCRβV-bindingWSGR Docket No.53676-766.601 moiety; (iii) the third polypeptide comprising a first portion of a second TCRβV-binding moiety and a second dimerization module linked to the first portion of the second TCRβV-binding moiety; and (iv) the fourth polypeptide comprising a second portion of the second TCRβV- binding moiety; and wherein the cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the C-terminus of the second polypeptide or the C- terminus of the fourth polypeptide.

[0454] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, a fourth polypeptide, a cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide, the second polypeptide, the third polypeptide, and the fourth polypeptide are non- contiguous, wherein: (i) the first polypeptide comprising a first portion of a first TCRβV-binding moiety and a first dimerization module linked to the first portion of the first TCRβV-binding moiety; (ii) the second polypeptide comprising a second portion of the first TCRβV-binding moiety; (iii) the third polypeptide comprising a first portion of a second TCRβV-binding moiety and a second dimerization module linked to the first portion of the second TCRβV-binding moiety; and (iv) the fourth polypeptide comprising a second portion of the second TCRβV- binding moiety; and wherein the cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the C-terminus of the first polypeptide or the C-terminus of the third polypeptide.

[0455] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, and a cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide, the second polypeptide, and the third polypeptide are non-contiguous, wherein: (i) the first polypeptide comprising a first portion of a first TCRβV-binding moiety and a first dimerization module linked to the first portion of the first TCRβV-binding moiety; (ii) the second polypeptide comprising a second portion of the first TCRβV-binding moiety; and (iii) the third polypeptide comprising a second dimerization module; wherein the at least one cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the N terminus of the third polypeptide; and wherein the multifunctional polypeptide molecule does not comprise an additional TCRβV-binding moiety except the first TCRβV-binding moiety.

[0456] In some embodiments, the first portion of the first TCRβV-binding moiety comprises a first VH and a first CH1 linked to the first VH. In some embodiments, the first CH1 is linked to the C-terminus of the first VH.WSGR Docket No.53676-766.601

[0457] In some embodiments, the second portion of the first TCRβV-binding moiety comprises a first VL and a first CL linked to the first VL. In some embodiments, first CL is linked to the C- terminus of the first VL.

[0458] In some embodiments, the first dimerization module is linked to the first portion of the first TCRβV-binding moiety. In some embodiments, the first dimerization module is linked to the C-terminus of the first portion of the first TCRβV-binding moiety. In some embodiments, the first portion of the second TCRβV-binding moiety comprises a second VH and a second CH1 linked to the second VH. In some embodiments, the second CH1 is linked to the C- terminus of the second VH. In some embodiments, the second portion of the second TCRβV- binding moiety comprises a second VL and a second CL linked to the second VL. In some embodiments, the second CL is linked to the C-terminus of the second VL. In some embodiments, the second dimerization module is linked to the first portion of the second TCRβV-binding moiety. In some embodiments, the second dimerization module is linked to the C-terminus of the first portion of the second TCRβV-binding moiety.

[0459] In some embodiments, the multifunctional polypeptide molecule as described herein further comprises a linker between the first portion of the first TCRβV-binding moiety and the first dimerization module, a linker between the first portion of the second TCRβV-binding moiety and the second dimerization module, a linker between the first VH and the first CH1, a linker between the first VL and the first CL, a linker between the second VH and the second CH1, a linker between the second VL and the second CL, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the first polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the second polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the third polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the fourth polypeptide, or a combination thereof. In some embodiments, the multifunctional polypeptide molecule as described herein further comprises a linker between the first portion of the first TCRβV-binding moiety and the first dimerization module, a linker between the first VH and the first CH1, a linker between the first VL and the first CL, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the third polypeptide, or a combination thereof. In some embodiments, linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non-helical linker. In some embodiments, the linker is the peptide linker and wherein the linker is a GS linker. In some embodiments, theWSGR Docket No.53676-766.601 linker is the peptide linker and wherein the linker comprises the sequence of SEQ ID NO: 3308 or SEQ ID NO: 3643.

[0460] In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises any one selected from the group consisting of a Fab, F(ab')2, Fv, a single chain Fv (scFv), a single domain antibody, a diabody (dAb), a camelid antibody and a combination thereof. In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises a scFv or a Fab.

[0461] In some embodiments, the multifunctional polypeptide molecule does not comprise an additional antigen-binding moiety except the TCRβV-binding moiety. In some embodiments, the multifunctional polypeptide molecule further comprise an additional antigen-binding moiety that is not the TCRβV-binding moiety.

[0462] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, and at least one cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide and the second polypeptide are non-contiguous, wherein: (i) the first polypeptide comprising a first TCRβV- binding moiety and a first dimerization module linked to the C-terminus of the first TCRβV- binding moiety, wherein the first TCRβV-binding moiety comprises a first VL and a first VH; and (ii) the second polypeptide comprising a second TCRβV-binding moiety and a second dimerization module linked to the C-terminus of the second TCRβV-binding moiety; wherein the at least one cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the first polypeptide, the second polypeptide, or a combination thereof; wherein the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises a scFv; and wherein the multifunctional polypeptide molecule does not comprise an additional antigen-binding moiety except the first TCRβV-binding moiety and the second TCRβV-binding moiety.

[0463] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, and at least one cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide and the second polypeptide are non-contiguous, wherein: (i) the first polypeptide comprising a first TCRβV- binding moiety and a first dimerization module linked to the C-terminus of the first TCRβV- binding moiety, wherein the first TCRβV-binding moiety comprises a first VL and a first VH; and (ii) the second polypeptide comprising a second dimerization module; wherein the at least one cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the first polypeptide, the second polypeptide, or a combination thereof; wherein the first TCRβV-binding moiety comprises a scFv; wherein the multifunctional polypeptideWSGR Docket No.53676-766.601 molecule does not comprise an additional antigen-binding moiety except the first TCRβV- binding moiety; and wherein the multifunctional polypeptide molecule does not comprise an additional TCRβV-binding moiety except the first TCRβV-binding moiety.

[0464] In some embodiments, (a) the N-terminus of the first polypeptide is linked to a first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to a second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (b) the N-terminus of the second polypeptide is linked to a third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to a fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; or (e) a combination thereof.

[0465] In some embodiments, the first cytokine polypeptide, the second cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the first polypeptide, the third cytokine polypeptide, the fourth cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the second polypeptide, or a combination thereof.

[0466] In some embodiments, the multifunctional polypeptide molecule as described herein further comprises a linker between the first TCRβV-binding moiety and the first dimerization module, a linker between the second TCRβV-binding moiety and the second dimerization module, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the first polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the second polypeptide, or a combination thereof.

[0467] In some embodiments, the multifunctional polypeptide molecule as described herein further comprises a linker between the first TCRβV-binding moiety and the first dimerization module, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the first polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the second polypeptide, or a combination thereof. In some embodiments, the linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non-helical linker. In some embodiments, the linker is the peptide linker and wherein the linker is a GS linker. In some embodiments, the linker is the peptide linker and wherein the linker comprises the sequence of SEQ ID NO: 3308 or SEQ ID NO: 3643.

[0468] In some embodiments, the multifunctional polypeptide molecule comprises at least two of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide moleculeWSGR Docket No.53676-766.601 comprises at least three of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises at least four of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises at least five of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises at least six of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises at least seven of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises at least eight of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises two of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises three of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises four of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises five of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises six of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises seven of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises eight of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises two of the cytokine polypeptide, each of which is linked to the first polypeptide and the second polypeptide; the first polypeptide and the third polypeptide;. the first polypeptide and the fourth polypeptide; the second and the third polypeptide; the second polypeptide and the fourth polypeptide; or the third polypeptide and the fourth polypeptide, respectively. In some embodiments, the multifunctional polypeptide molecule comprises three of the cytokine polypeptide, each of which is linked to the first polypeptide, the second polypeptide, and the third polypeptide; the first polypeptide, the second polypeptide, and the fourth polypeptide; the first polypeptide, the third polypeptide, and the fourth polypeptide; or the second polypeptide, the third polypeptide, and the fourth polypeptide, respectively. In some embodiments, the multifunctional polypeptide molecule comprises four of the cytokine polypeptide, each of which is linked to the first polypeptide, the second polypeptide, the third polypeptide, and the fourth polypeptide, respectively. In some embodiments, the cytokine polypeptide is not linked to the polypeptides that comprise the first TCRβV-binding moiety.

[0469] In some embodiments, , the at least one cytokine polypeptide is selected from the group consisting of interleukin-2 (IL-2) or a fragment or a functional fragment or a functional variant thereof, interleukin-7 (IL-7) or a fragment or a functional fragment or a functional variant thereof, interleukin-12 (IL-12) or a fragment or a functional fragment or a functional variant thereof, interleukin-15 (IL-15) or a fragment or a functional fragment or a functional variant thereof, interleukin-18 (IL-18) or a fragment or a functional fragment or a functional variantWSGR Docket No.53676-766.601 thereof, interleukin-21 (IL-21) or a fragment or a functional fragment or a functional variant thereof, or interferon gamma or a fragment or a functional fragment or a functional variant thereof, or a combination thereof.

[0470] In some embodiments, the at least one cytokine polypeptide comprises interleukin-2 (IL- 2) or a fragment thereof. In some embodiments, the at least one cytokine polypeptide is interleukin-2 (IL-2) or a fragment thereof. In some embodiments, the at least one cytokine polypeptide comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 2191. In some embodiments, the at least one cytokine polypeptide comprises the sequence of SEQ ID NO: 2191. In some embodiments, the sequence of the at least one cytokine polypeptide is a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 2191. In some embodiments, the sequence of the at least one cytokine polypeptide is the sequence of SEQ ID NO: 2191.

[0471] In some embodiments, the variant of the at least one cytokine polypeptide comprises an IL-2 variant comprising a mutation. In some embodiments, the mutation comprises an insertion mutation, a deletion mutation, or a substitution mutation. In some embodiments, the mutation comprises the substitution mutation. In some embodiments, the variant comprises an IL-2 variant comprising C125A mutation. In some embodiments, the variant of the at least one cytokine polypeptide is an IL-2 variant comprising a mutation. In some embodiments, the mutation is an insertion mutation, a deletion mutation, or a substitution mutation. In some embodiments, the mutation is the substitution mutation. In some embodiments, the variant is an IL-2 variant comprising C125A mutation. In some embodiments, the variant comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 2270. In some embodiments, the variant comprises the sequence of SEQ ID NO: 2270. In some embodiments, the sequence of the variant is a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 2270. In some embodiments, the sequence of the variant is the sequence of SEQ ID NO: 2270.

[0472] In some embodiments, the first dimerization module comprises a first immunoglobulin constant regions (Fc regions) and the second dimerization module comprises a second Fc region. In some embodiments, the first dimerization module is a first immunoglobulin constant regions (Fc regions) and the second dimerization module is a second Fc region.

[0473] In some embodiments, the first Fc region, the second Fc region, or a combination thereof is selected from an IgG1 Fc region or a fragment thereof, an IgG2 Fc region or a fragment thereof, an IgG3 Fc region or a fragment thereof, an IgGA1 Fc region or a fragment thereof, anWSGR Docket No.53676-766.601 IgGA2 Fc region or a fragment thereof, an IgG4 Fc region or a fragment thereof, an IgJ Fc region or a fragment thereof, an IgM Fc region or a fragment thereof, an IgD Fc region or a fragment thereof, and an IgE Fc region or a fragment thereof.

[0474] In some embodiments, the first Fc region, the second Fc region, or a combination thereof is selected from a human IgG1 Fc region or a fragment thereof, a human IgG2 Fc region or a fragment thereof, and a human IgG4 Fc region or a fragment thereof.

[0475] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises an Fc interface with one or more of: a paired cavity-protuberance, an electrostatic interaction, or a strand-exchange, wherein the dimerization of the first Fc region and the second Fc region is enhanced as indicated by a greater ratio of heteromultimer:homomultimer forms relative to a dimerization of Fc regions with a non-engineered interface. In some embodiments, the dimerization of the first Fc region and the second Fc region is enhanced at least by 1.1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 1.6 fold, 1.7 fold, 1.8 fold, 1.9 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 25 fold, 30 fold, 35 fold, 40 fold, 45 fold, 50 fold, 55 fold, 60 fold, 65 fold, 70 fold, 75 fold, 80 fold, 85 fold, 90 fold, 95 fold, 100 fold, 150 fold, 200 fold, 250 fold, 300 fold, 250 fold, 400 fold, 450 fold, 500 fold, 550 fold, 600 fold, 650 fold, 700 fold, 750 fold, 800 fold, 850 fold, 900 fold, 950 fold, 1000 fold, 2000 fold, 3000 fold, 4000 fold, 5000 fold, 6000 fold, 7000 fold, 8000 fold, 9000 fold, or 10000 fold relative to a dimerization of Fc regions with a non-engineered interface. In some embodiments, the dimerization of the first Fc region and the second Fc region is enhanced at most by 1.1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 1.6 fold, 1.7 fold, 1.8 fold, 1.9 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 25 fold, 30 fold, 35 fold, 40 fold, 45 fold, 50 fold, 55 fold, 60 fold, 65 fold, 70 fold, 75 fold, 80 fold, 85 fold, 90 fold, 95 fold, 100 fold, 150 fold, 200 fold, 250 fold, 300 fold, 250 fold, 400 fold, 450 fold, 500 fold, 550 fold, 600 fold, 650 fold, 700 fold, 750 fold, 800 fold, 850 fold, 900 fold, 950 fold, 1000 fold, 2000 fold, 3000 fold, 4000 fold, 5000 fold, 6000 fold, 7000 fold, 8000 fold, 9000 fold, or 10000 fold relative to a dimerization of Fc regions with a non-engineered interface. In some embodiments, the dimerization of the first Fc region and the second Fc region is enhanced by 1.1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 1.6 fold, 1.7 fold, 1.8 fold, 1.9 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 25 fold, 30 fold, 35 fold, 40 fold, 45 fold, 50 fold, 55 fold, 60 fold, 65 fold, 70 fold, 75 fold, 80 fold, 85 fold, 90 fold, 95 fold, 100 fold, 150 fold, 200 fold, 250 fold, 300 fold, 250 fold, 400 fold, 450 fold, 500 fold, 550 fold, 600 fold, 650 fold, 700 fold, 750 fold, 800 fold, 850 fold, 900 fold, 950 fold, 1000 fold, 2000 fold, 3000 fold, 4000 fold, 5000 fold, 6000 fold, 7000 fold, 8000 fold, 9000 fold, or 10000 fold relative to a dimerization of Fc regions with a non-engineered interface.WSGR Docket No.53676-766.601

[0476] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises an amino acid substitution listed in Table 14.

[0477] 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.

[0478] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 3645, SEQ ID NO: 3646, SEQ ID NO: 3647, SEQ ID NO:3648, or SEQ ID NO: 3649. 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: 3645, SEQ ID NO: 3646, SEQ ID NO: 3647, SEQ ID NO:3648, or SEQ ID NO: 3649.

[0479] In some embodiments, the sequence of the first Fc region, the second Fc region, or a combination thereof is a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 3645, SEQ ID NO: 3646, SEQ ID NO: 3647, SEQ ID NO:3648, or SEQ ID NO: 3649. In some embodiments, the sequence of the first Fc region, the second Fc region, or a combination thereof is the sequence of SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 3645, SEQ ID NO: 3646, SEQ ID NO: 3647, SEQ ID NO:3648, or SEQ ID NO: 3649.

[0480] In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof binds to one or more of a TCRβV subfamily selected from the group consisting of: (i) TCRβ V2 subfamily comprising TCRβ V2*01; (ii) TCRβ V3 subfamily comprising TCRβ V3-1*01; (iii) TCRβ V4 subfamily comprising one or more selected from TCRβ V4-1, TCRβ V4-2, and TCRβ V4-3; (iv) TCRβ V5 subfamily comprising one or more selected from TCRβ V5-6*01, TCRβ V5-4*01, TCRβ V5-1*01, and TCRβ V5-8*01; (v) the TCRβ V6 subfamily comprising one or more selected from TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6- 2*01, TCRβ V6-3*01, and TCRβ V6-1*01; (vi) TCRβ V9 subfamily; (vii) TCRβ V10 subfamily comprising one or more selected from TCRβ V10-1*01, TCRβ V10-1*02, TCRβ V10-3*01, and TCRβ V10-2*01; (viii) TCRβ V11 subfamily comprising TCRβ V11-2; (ix) TCRβ V12 subfamily comprising one or more selected from TCRβ V12-4*01, TCRβ V12-3*01, and TCRβ V12-5*01; (x) TCRβ V13 subfamily comprising TCRβ V13*01; (xi) TCRβ V16 subfamily comprising TCRβ V16*01; (xii) TCRβ V19 subfamily comprising one or more selected from TCRβ V19*01 and TCRβ V19*02; (xiii) TCRβ V21 subfamily. (xiv) TCRβ V23 subfamily. (xv) TCRβ V27 subfamily; and (xvi) TCRβ V28 subfamily.WSGR Docket No.53676-766.601

[0481] In some embodiments, the first TCRβV-binding moiety and the second TCRβV-binding moiety are same. In some embodiments, the first TCRβV-binding moiety and the second TCRβV-binding moiety are different.

[0482] In some embodiments, the first TCRβV-binding moiety and the second TCRβV-binding moiety binds: (i) one or more of a TCRβ V6 subfamily member and one or more of a TCRβ V10 subfamily member, respectively; (ii) one or more of a TCRβ V6 subfamily member and one or more of a TCRβ V5 subfamily member, respectively; (iii) one or more of a TCRβ V6 subfamily member and one or more of a TCRβ V12 subfamily member, respectively; (iv) one or more of a TCRβ V10 subfamily member and one or more of a TCRβ V5 subfamily member, respectively; (v) one or more of a TCRβ V10 subfamily member and one or more of a TCRβ V12 subfamily member, respectively; or (vi) one or more of a TCRβ V5 subfamily member and one or more of a TCRβ V12 subfamily member, respectively.

[0483] In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 of an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the CDR1, CDR2, and CDR3 sequences listed in Table 1; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 of an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the CDR1, CDR2, and CDR3 the sequences listed in Table 1; or (iii) a combination thereof. In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 having any one of the CDR1, CDR2, and CDR3 sequences listed in Table 1; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 having any one of the CDR1, CDR2, and CDR3 the sequences listed in Table 1; or (iii) a combination thereof.

[0484] In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 of an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the CDR1, CDR2, and CDR3 sequences listed in Table 1, respectively; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 of an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the CDR1, CDR2, and CDR3 the sequences listed in Table 1, respectively; or (iii) a combination thereof. In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 having any one of the CDR1, CDR2, and CDR3 sequences listed in Table 1, respectively; (ii) aWSGR Docket No.53676-766.601 LC CDR1, a LC CDR2, and a LC CDR3 having any one of the CDR1, CDR2, and CDR3 the sequences listed in Table 1, respectively; or (iii) a combination thereof.

[0485] In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a VH comprising a framework region (FR) comprising a framework 1 (FR1), a framework region 2 (FR2), a framework region 3 (FR3), and a framework region 4 (FR4) that have at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity with a non-murine germline FR1, a non-murine germline FR2, a non- murine germline FR3, and a non-murine germline FR4; (ii) a VL comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity with a non-murine germline FR1, a non-murine germline FR2, a non-murine germline FR3, and a non-murine germline FR4; or (iii) a combination thereof. In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a VH comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 having the sequences of a non-murine germline FR1, a non-murine germline FR2, a non-murine germline FR3, and a non-murine germline FR4; (ii) a VL comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 having the sequences of a non-murine germline FR1, a non-murine germline FR2, a non-murine germline FR3, and a non-murine germline FR4; or (iii) a combination thereof.

[0486] In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a VH comprising a FR1, a FR2, a FR3, and a FR4 that have at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity with a non-murine germline FR1, a non-murine germline FR2, a non-murine germline FR3, and a non-murine germline FR4, respectively; (ii) a VL comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity with a non-murine germline FR1, a non-murine germline FR2, a non-murine germline FR3, and a non-murine germline FR4, respectively; or (iii) a combination thereof. In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a VH comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 having the sequences of a non-murine germline FR1, a non-murine germline FR2, a non-murine germline FR3, and a non-murine germline FR4, respectively; (ii) a VL comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 having the sequences of a non-murine germline FR1, a non-murine germline FR2, a non-murine germline FR3, and a non-murine germline FR4, respectively; or (iii) a combination thereof.

[0487] In some embodiments, the VH comprises the FR3 comprising (i) a Threonine at position 73 according to Kabat numbering; (ii) a Glycine a position 94 according to Kabat numbering; orWSGR Docket No.53676-766.601 (iii) a combination thereof. In some embodiments, the VL comprises the FR1 comprising a Phenylalanine at position 10 according to Kabat numbering. In some embodiments, the VL comprises the FR2 comprising (i) a Histidine at position 36 according to Kabat numbering; (ii) an Alanine at position 46 according to Kabat numbering; or (iii) a combination thereof. In some embodiments, the VL comprises the FR3 comprising a Phenylalanine at position 87 according to Kabat numbering.

[0488] In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 of an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the CDR1, CDR2, and CDR3 sequences listed in Table 2; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 of an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the CDR1, CDR2, and CDR3 sequences listed in Table 2; or (iii) a combination thereof. In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 having any one of the CDR1, CDR2, and CDR3 sequences listed in Table 2; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 having any one of the CDR1, CDR2, and CDR3 sequences listed in Table 2; or (iii) a combination thereof.

[0489] In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 of an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the CDR1, CDR2, and CDR3 sequences listed in Table 2, respectively; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 of an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the CDR1, CDR2, and CDR3 sequences listed in Table 2, respectively; or (iii) a combination thereof. In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 having any one of the CDR1, CDR2, and CDR3 sequences listed in Table 2, respectively; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 having any one of the CDR1, CDR2, and CDR3 sequences listed in Table 2, respectively; or (iii) a combination thereof.

[0490] In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a VH comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity with a FR1, a FR2, a FR3, and a FR4 of a humanized B-H LC of Table 2; (ii) a VL comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have at least 75%, 80%,WSGR Docket No.53676-766.601 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity with a FR1, a FR2, a FR3, and a FR4 of a humanized B-H LC of Table 2; or (iii) a combination thereof. In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a VH comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have the sequence of a FR1, a FR2, a FR3, and a FR4 of a humanized B-H LC of Table 2; (ii) a VL comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have the sequence of a FR1, a FR2, a FR3, and a FR4 of a humanized B-H LC of Table 2; or (iii) a combination thereof.

[0491] In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a VH comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity with a FR1, a FR2, a FR3, and a FR4 of a humanized B-H LC of Table 2, respectively; (ii) a VL comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity with a FR1, a FR2, a FR3, and a FR4 of a humanized B-H LC of Table 2, respectively; or (iii) a combination thereof. In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a VH comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have the sequence of a FR1, a FR2, a FR3, and a FR4 of a humanized B- H LC of Table 2, respectively; (ii) a VL comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have the sequence of a FR1, a FR2, a FR3, and a FR4 of a humanized B-H LC of Table 2, respectively; or (iii) a combination thereof.

[0492] In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a VH comprising a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the VH sequence of a humanized Antibody B-H listed in Table 2; (ii) a VL comprising a sequence having at least at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the VL sequence of a humanized Antibody B-H listed in Table 2; or (iii) a combination thereof. In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a VH comprising the VH sequence of a humanized Antibody B-H listed in Table 2; (ii) a VL comprising the VL sequence of a humanized Antibody B-H listed in Table 2; or (iii) a combination thereof. In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) the VH of a humanized Antibody B-H listed in Table 2; (ii) the VL sequence of a humanized Antibody B-H listed in Table 2; or (iii) a combination thereof.

[0493] In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a heavy chain constantWSGR Docket No.53676-766.601 region having a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the sequences listed in Table 3 or a combination thereof. In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a heavy chain constant region having any one of the sequences listed in Table 3 or a combination thereof. In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a heavy chain constant region of which sequence is a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the sequences listed in Table 3 or a combination thereof. In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a heavy chain constant region having any one of the heavy chain constant region sequences listed in Table 3 or a combination thereof. In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a heavy chain constant region of an IgM or a fragment thereof. In some embodiments, the heavy chain constant region of the IgM comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 73. In some embodiments, the heavy chain constant region of the IgM comprises the sequence of SEQ ID NO: 73. In some embodiments, the sequence of the heavy chain constant region of the IgM is the sequence of SEQ ID NO: 73.

[0494] In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a heavy chain constant region of an IgJ or a fragment thereof. In some embodiments, the heavy chain constant region of the IgJ comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 76. In some embodiments, the heavy chain constant region of the IgJ comprises the sequence of SEQ ID NO: 76. In some embodiments, the sequence of the heavy chain constant region of the IgJ is the sequence of SEQ ID NO: 76.

[0495] In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a heavy chain constant region of an IgGA1 or a fragment thereof. In some embodiments, the heavy chain constant region of the IgGA1comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 74. In some embodiments, the heavy chain constant region of the IgGA1 comprises the sequence of SEQ ID NO: 74. In some embodiments, the sequence of the heavy chain constant region of the IgGA1 is the sequence of SEQ ID NO: 74.WSGR Docket No.53676-766.601

[0496] In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a heavy chain constant region of an IgGA2 or a fragment thereof. In some embodiments, the heavy chain constant region of the IgGA2 comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 75. In some embodiments, the heavy chain constant region of the IgGA2 comprises the sequence of SEQ ID NO: 75. In some embodiments, the sequence of the heavy chain constant region of the IgGA2 is the sequence of SEQ ID NO: 75.

[0497] In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a heavy chain constant region of an IgG1 or a fragment thereof. In some embodiments, the heavy chain constant region of the IgG1 comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 41. In some embodiments, the heavy chain constant region of the IgG1 comprises the sequence of SEQ ID NO: 41. In some embodiments, the sequence of the heavy chain constant region of the IgG1 is the sequence of SEQ ID NO: 41. In some embodiments, the heavy chain constant region of the IgG1 comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 3645. In some embodiments, the heavy chain constant region of the IgG1 comprises the sequence of SEQ ID NO: 3645. In some embodiments, the sequence of the heavy chain constant region of the IgG1 is the sequence of SEQ ID NO: 3645.

[0498] In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a light chain constant region having a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the sequences listed in Table 3 or a combination thereof. In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a light chain constant region having any one of the sequences listed in Table 3 or a combination thereof. In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a light chain constant region having any one of the light chain constant region sequences listed in Table 3 or a combination thereof.

[0499] In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a light chain constant region of a kappa chain or a fragment thereof. In some embodiments, the light chain constant region of a kappa chain comprises a light chain constant region sequence listed in Table 3.WSGR Docket No.53676-766.601

[0500] In some embodiments, the light chain constant region of a kappa chain comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 39 or SEQ ID NO: 3644. In some embodiments, the light chain constant region of a kappa chain comprises the sequence of SEQ ID NO: 39 or SEQ ID NO: 3644. In some embodiments, the sequence of the light chain constant region of a kappa chain is a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 39 or SEQ ID NO: 3644. In some embodiments, the sequence of the light chain constant region of a kappa chain is the sequence of SEQ ID NO: 39 or SEQ ID NO: 3644.

[0501] In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 comprising amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to CDR1, CDR2, and CDR3 sequences of a VH disclosed in Tables 1, 2, 10, 11, 12 or 13; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 comprising an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to CDR1, CDR2, and CDR3 sequences of a VL disclosed in Tables 1, 2, 10, 11, 12 or 13; or (iii) a combination thereof. In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 comprising the CDR1, CDR2, and CDR3 sequences of a VH disclosed in Tables 1, 2, 10, 11, 12 or 13; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 comprising the CDR1, CDR2, and CDR3 sequences of a VL disclosed in Tables 1, 2, 10, 11, 12 or 13; or (iii) a combination thereof. In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 comprising amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to CDR1, CDR2, and CDR3 sequences of a VH disclosed in Tables 1, 2, 10, 11, 12 or 13, respectively; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 comprising an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to CDR1, CDR2, and CDR3 sequences of a VL disclosed in Tables 1, 2, 10, 11, 12 or 13, respectively; or (iii) a combination thereof. In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 comprising the CDR1, CDR2, and CDR3 sequences of a VH disclosed in Tables 1, 2, 10, 11, 12 or 13, respectively; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 comprising the CDR1, CDR2, and CDR3 sequences of a VL disclosed in Tables 1, 2, 10, 11, 12 or 13, respectively; or (iii) a combination thereof. In some embodiments, the first TCRβV-binding moiety, the secondWSGR Docket No.53676-766.601 TCRβV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 of a VH disclosed in Tables 1, 2, 10, 11, 12 or 13; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 of a VL disclosed in Tables 1, 2, 10, 11, 12 or 13; or (iii) a combination thereof.

[0502] In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises a light chain comprising a FR1 comprising: (i) an Aspartic Acid at position 1 according to Kabat numbering; (ii) an Asparagine at position 2 according to Kabat numbering; (iii) a Leucine at position 4 according to Kabat numbering; or (iv) a combination thereof.

[0503] In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof comprises a light chain comprising a FR3 comprising: (i) a Glycine at position 66 according to Kabat numbering; (ii) an Asparagine at position 69 according to Kabat numbering; (iii) a Tyrosine at position 71 according to Kabat numbering; or (iv) a combination thereof.

[0504] In some embodiments, the first TCRβV-binding moiety, the second TCRβV-binding moiety, or a combination thereof binds to an outward facing region on a TCRβV protein. In some embodiments, the outward facing region on the TCRβV protein comprises a structurally conserved region of TCRβV having a similar structure across one or more TCRβV subfamilies. Cytokine Molecules

[0505] In some embodiments, the multifunctional molecule includes a cytokine molecule. As used herein, a “cytokine molecule” or a “cytokine polypeptide” as interchangeably used herein, refers to full length, a fragment or a variant of a cytokine; a cytokine further comprising a receptor domain, e.g., a cytokine receptor dimerizing domain; or an agonist of a cytokine receptor, e.g., an antibody molecule (e.g., an agonistic antibody) to a cytokine receptor, that elicits at least one activity of a naturally-occurring cytokine. In some embodiments, a cytokine molecule refers to a cytokine polypeptide or a functional fragment or variant thereof. In some embodiments the cytokine molecule is chosen from interleukin-2 (IL-2), interleukin-7 (IL-7), interleukin-12 (IL-12), interleukin-10 (IL-10), interleukin-15 (IL-15), interleukin-18 (IL-18), interleukin-21 (IL-21), or interferon gamma, or a fragment or variant thereof, or a combination of any of the aforesaid cytokines. The cytokine molecule can be a monomer or a dimer. In embodiments, the cytokine molecule can further include a cytokine receptor dimerizing domain. In other embodiments, the cytokine molecule is an agonist of a cytokine receptor, e.g., an antibody molecule (e.g., an agonistic antibody) to a cytokine receptor chosen from an IL-15Ra or IL-21R.WSGR Docket No.53676-766.601

[0506] Cytokines are generally polypeptides that influence cellular activity, for example, through signal transduction pathways. Accordingly, a cytokine of the multispecific or multifunctional polypeptide is useful and can be associated with receptor-mediated signaling that transmits a signal from outside the cell membrane to modulate a response within the cell. Cytokines are proteinaceous signaling compounds that are mediators of the immune response. They control many different cellular functions including proliferation, differentiation and cell survival / apoptosis; cytokines are also involved in several pathophysiological processes including viral infections and autoimmune diseases. Cytokines are synthesized under various stimuli by a variety of cells of both the innate (monocytes, macrophages, dendritic cells) and adaptive (T- and B-cells) immune systems. Cytokines can be classified into two groups: pro- and anti- inflammatory. Pro-inflammatory cytokines, including IFNγ, IL-1, IL-6 and TNF-alpha, are predominantly derived from the innate immune cells and Th1 cells. Anti-inflammatory cytokines, including IL-10, IL-4, IL-13 and IL-5, are synthesized from Th2 immune cells.

[0507] Provided herein are, inter alia, multispecific (e.g., bi-, tri-, quad- specific) or multifunctional molecules, that include, e.g., are engineered to contain, one or more cytokine molecules, e.g., immunomodulatory (e.g., proinflammatory) cytokines and variants, e.g., functional variants, thereof. Accordingly, in some embodiments, the cytokine molecule is an interleukin or a variant, e.g., a functional variant thereof. In some embodiments the interleukin is a proinflammatory interleukin. In some embodiments the interleukin is chosen from interleukin- 2 (IL-2), interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-18 (IL-18), interleukin-21 (IL-21), interleukin-7 (IL-7), or interferon gamma. In some embodiments, the cytokine molecule is a proinflammatory cytokine.

[0508] In certain embodiments, the cytokine is a single chain cytokine. In certain embodiments, the cytokine is a multichain cytokine (e.g., the cytokine comprises 2 or more (e.g., 2) polypeptide chains. An exemplary multichain cytokine is IL-12.

[0509] Examples of useful cytokines include, but are not limited to, GM-CSF, IL-1α, IL-1β, IL- 2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-21, IFN-α, IFN-β, IFN-γ, MIP-1α, MIP-1β, TGF-β, TNF-α, and TNFβ. In some embodiments the cytokine of the multispecific or multifunctional polypeptide is a cytokine selected from the group of GM-CSF, IL-2, IL-7, IL-8, IL-10, IL-12, IL-15, IL-21, IFN-α, IFN-γ, MIP-1α, MIP-1β and TGF-β. In some embodiments the cytokine of the i the multispecific or multifunctional polypeptide is a cytokine selected from the group of IL-2, IL-7, IL-10, IL-12, IL-15, IFN-α, and IFN-γ. In certain embodiments the cytokine is mutated to remove N- and / or O-glycosylation sites. Elimination of glycosylation increases homogeneity of the product obtainable in recombinant production.WSGR Docket No.53676-766.601

[0510] In some embodiments, the cytokine of the multispecific or multifunctional polypeptide is IL-2. In a specific embodiment, the IL-2 cytokine can elicit one or more of the cellular responses selected from the group consisting of: proliferation in an activated T lymphocyte cell, differentiation in an activated T lymphocyte cell, cytotoxic T cell (CTL) activity, proliferation in an activated B cell, differentiation in an activated B cell, proliferation in a natural killer (NK) cell, differentiation in a NK cell, cytokine secretion by an activated T cell or an NK cell, and NK / lymphocyte activated killer (LAK) antitumor cytotoxicity. In another particular embodiment the IL-2 cytokine is a mutant IL-2 cytokine having reduced binding affinity to the .alpha.- subunit of the IL-2 receptor. Together with the .beta.- and .gamma.-subunits (also known as CD122 and CD132, respectively), the .alpha.-subunit (also known as CD25) forms the heterotrimeric high-affinity IL-2 receptor, while the dimeric receptor consisting only of the β- and γ-subunits is termed the intermediate-affinity IL-2 receptor. As described in PCT patent application number PCT / EP2012 / 051991, which is incorporated herein by reference in its entirety, a mutant IL-2 polypeptide with reduced binding to the .alpha.-subunit of the IL-2 receptor has a reduced ability to induce IL-2 signaling in regulatory T cells, induces less activation-induced cell death (AICD) in T cells, and has a reduced toxicity profile in vivo, compared to a wild-type IL-2 polypeptide. The use of such a cytokine with reduced toxicity is particularly advantageous in a multispecific or multifunctional polypeptide according to the invention, having a long serum half-life due to the presence of an Fc domain. In some embodiments, the mutant IL-2 cytokine of the multispecific or multifunctional polypeptide according to the invention comprises at least one amino acid mutation that reduces or abolishes the affinity of the mutant IL-2 cytokine to the .alpha.-subunit of the IL-2 receptor (CD25) but preserves the affinity of the mutant IL-2 cytokine to the intermediate-affinity IL-2 receptor (consisting of the β and γ subunits of the IL-2 receptor), compared to the non-mutated IL-2 cytokine. In some embodiments the one or more amino acid mutations are amino acid substitutions. In a specific embodiment, the mutant IL-2 cytokine comprises one, two or three amino acid substitutions at one, two or three position(s) selected from the positions corresponding to residue 42, 45, and 72 of human IL-2. In a more specific embodiment, the mutant IL-2 cytokine comprises three amino acid substitutions at the positions corresponding to residue 42, 45 and 72 of human IL-2. In an even more specific embodiment, the mutant IL-2 cytokine is human IL-2 comprising the amino acid substitutions F42A, Y45A and L72G. In some embodiments the mutant IL-2 cytokine additionally comprises an amino acid mutation at a position corresponding to position 3 of human IL-2, which eliminates the O-glycosylation site of IL-2. Particularly, said additional amino acid mutation is an amino acid substitution replacing a threonine residue by an alanine residue. A particular mutant IL-2 cytokine useful in theWSGR Docket No.53676-766.601 invention comprises four amino acid substitutions at positions corresponding to residues 3, 42, 45 and 72 of human IL-2. Specific amino acid substitutions are T3A, F42A, Y45A and L72G. As demonstrated in PCT patent application number PCT / EP2012 / 051991 and in the appended Examples, said quadruple mutant IL-2 polypeptide (IL-2 qm) exhibits no detectable binding to CD25, reduced ability to induce apoptosis in T cells, reduced ability to induce IL-2 signaling in T.sub.reg cells, and a reduced toxicity profile in vivo. However, it retains ability to activate IL-2 signaling in effector cells, to induce proliferation of effector cells, and to generate IFN-γ as a secondary cytokine by NK cells.

[0511] The IL-2 or mutant IL-2 cytokine according to any of the above embodiments may comprise additional mutations that provide further advantages such as increased expression or stability. For example, the cysteine at position 125 may be replaced with a neutral amino acid such as alanine, to avoid the formation of disulfide-bridged IL-2 dimers. Thus, in certain embodiments the IL-2 or mutant IL-2 cytokine of the multispecific or multifunctional polypeptide according to the invention comprises an additional amino acid mutation at a position corresponding to residue 125 of human IL-2. In some embodiments said additional amino acid mutation is the amino acid substitution C125A.

[0512] In a specific embodiment the IL-2 cytokine of the multispecific or multifunctional polypeptide comprises the polypeptide sequence of SEQ ID NO: 2270 [APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQC LEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLN RWITFAQSIISTLT].

[0513] In another specific embodiment the IL-2 cytokine of the multispecific or multifunctional polypeptide comprises the polypeptide sequence of SEQ ID NO: 2280 [APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFAMPKKATELKHLQC LEEELKPLEEVLNGAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLN RWITFAQSIISTLT].

[0514] In another embodiment the cytokine of the multispecific or multifunctional polypeptide is IL-12. In a specific embodiment said IL-12 cytokine is a single chain IL-12 cytokine. In an even more specific embodiment the single chain IL-12 cytokine comprises the polypeptide sequence of SEQ ID NO: 2290 [IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQV KEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYS GRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQED SACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSW EYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYWSGR Docket No.53676-766.601 SSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNM LQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLA SRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQA LNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS]. In some embodiments, the IL-12 cytokine can elicit one or more of the cellular responses selected from the group consisting of: proliferation in a NK cell, differentiation in a NK cell, proliferation in a T cell, and differentiation in a T cell.

[0515] In another embodiment the cytokine of the multispecific or multifunctional polypeptide is IL-10. In a specific embodiment said IL-10 cytokine is a single chain IL-10 cytokine. In an even more specific embodiment the single chain IL-10 cytokine comprises the polypeptide sequence of SEQ ID NO: 2300 [SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKG YLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENK SKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRNGGGGSGGGGSGGGGS GGGGSSPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLL EDFKGYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRF LPCENKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN].

[0516] In another specific embodiment the IL-10 cytokine is a monomeric IL-10 cytokine. In a more specific embodiment the monomeric IL-10 cytokine comprises the polypeptide sequence of SEQ ID NO: 2310 [SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKG YLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENG GGSGGKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN]. In some embodiments, the IL-10 cytokine can elicit one or more of the cellular responses selected from the group consisting of: inhibition of cytokine secretion, inhibition of antigen presentation by antigen presenting cells, reduction of oxygen radical release, and inhibition of T cell proliferation. A multispecific or multifunctional polypeptide according to the invention wherein the cytokine is IL-10 is particularly useful for downregulation of inflammation, e.g. in the treatment of an inflammatory disorder.

[0517] In another embodiment, the cytokine of the multispecific or multifunctional polypeptide is IL-15. In a specific embodiment said IL-15 cytokine is a mutant IL-15 cytokine having reduced binding affinity to the α-subunit of the IL-15 receptor. Without wishing to be bound by theory, a mutant IL-15 polypeptide with reduced binding to the .alpha.-subunit of the IL-15 receptor has a reduced ability to bind to fibroblasts throughout the body, resulting in improved pharmacokinetics and toxicity profile, compared to a wild-type IL-15 polypeptide. The use of anWSGR Docket No.53676-766.601 cytokine with reduced toxicity, such as the described mutant IL-2 and mutant IL-15 effector moieties, is particularly advantageous in a multispecific or multifunctional polypeptide according to the invention, having a long serum half-life due to the presence of an Fc domain. In some embodiments the mutant IL-15 cytokine of the multispecific or multifunctional polypeptide according to the invention comprises at least one amino acid mutation that reduces or abolishes the affinity of the mutant IL-15 cytokine to the .alpha.-subunit of the IL-15 receptor but preserves the affinity of the mutant IL-15 cytokine to the intermediate-affinity IL-15 / IL-2 receptor (consisting of the .beta.- and .gamma.-subunits of the IL-15 / IL-2 receptor), compared to the non-mutated IL-15 cytokine. In some embodiments the amino acid mutation is an amino acid substitution. In a specific embodiment, the mutant IL-15 cytokine comprises an amino acid substitution at the position corresponding to residue 53 of human IL-15. In a more specific embodiment, the mutant IL-15 cytokine is human IL-15 comprising the amino acid substitution E53A. In some embodiments the mutant IL-15 cytokine additionally comprises an amino acid mutation at a position corresponding to position 79 of human IL-15, which eliminates the N- glycosylation site of IL-15. Particularly, said additional amino acid mutation is an amino acid substitution replacing an asparagine residue by an alanine residue. In an even more specific embodiment the IL-15 cytokine comprises the polypeptide sequence of SEQ ID NO: 2320 [NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLASGDASI HDTVENLIILANNSLSSNGAVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS]. In some embodiments, the IL-15 cytokine can elicit one or more of the cellular responses selected from the group consisting of: proliferation in an activated T lymphocyte cell, differentiation in an activated T lymphocyte cell, cytotoxic T cell (CTL) activity, proliferation in an activated B cell, differentiation in an activated B cell, proliferation in a natural killer (NK) cell, differentiation in a NK cell, cytokine secretion by an activated T cell or an NK cell, and NK / lymphocyte activated killer (LAK) antitumor cytotoxicity.

[0518] Mutant cytokine molecules useful as effector moieties in the multispecific or multifunctional polypeptide can be prepared by deletion, substitution, insertion or modification using genetic or chemical methods well known in the art. Genetic methods may include site- specific mutagenesis of the encoding DNA ...

Claims

WSGR Docket No.53676-766.601 CLAIMS WHAT IS CLAIMED IS:

1. A molecule comprising an antigen binding domain that binds to a T cell receptor beta variable region (TCRβV), wherein the antigen binding domain comprises a light chain variable region (VL) comprising: (i) a light chain complementarity determining region 1 (LC CDR1) amino acid sequence of KASQNVADRVV (SEQ ID NO: 3354), (ii) a light chain complementarity determining region 2 (LC CDR2) amino acid sequence of AASYLQS (SEQ ID NO: 3443), and (iii) a light chain complementarity determining region 3 (LC CDR3) amino acid sequence of QQFKSYPLT (SEQ ID NO: 3356).

2. The molecule of claim 1, wherein the antigen binding domain comprises a heavy chain variable region (VH) comprising: (i) a heavy chain complementarity determining region 1 (HC CDR1) amino acid sequence of LTYIH (SEQ ID NO: 3421), FRLTYIH (SEQ ID NO: 3702), or GHDFRLTYIH (SEQ ID NO: 3351); (ii) a heavy chain complementarity determining region 2 (HC CDR2) amino acid sequence of RVSAGSGNVKYNEKFKG (SEQ ID NO: 3352); (iii) a heavy chain complementarity determining region 3 (HC CDR3) amino acid sequence of SYYSYDVLDY (SEQ ID NO: 3353); or (iv) any combination thereof.

3. The molecule of claim 1 or 2, wherein the antigen binding domain comprises a VH comprising: (i) a HC CDR1 amino acid sequence of LTYIH (SEQ ID NO: 3421), FRLTYIH (SEQ ID NO: 3702), or GHDFRLTYIH (SEQ ID NO: 3351); (ii) a HC CDR2 amino acid sequence of RVSAGSGNVKYNEKFKG (SEQ ID NO: 3352); and (iii) a HC CDR3 amino acid sequence of SYYSYDVLDY (SEQ ID NO: 3353).

4. The molecule of any one of claims 1-3, wherein the antigen binding domain comprises a VL comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3475 or SEQ ID NO: 3476.

5. The molecule of any one of claims 1-4, wherein the antigen binding domain comprises a VL comprising the sequence of SEQ ID NO: 3475 or SEQ ID NO: 3476.WSGR Docket No.53676-766.601 6. The molecule of any one of claims 1-5, wherein the antigen binding domain comprises a VH comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 1346.

7. The molecule of any one of claims 1-6, wherein the antigen binding domain comprises a VH comprising the sequence of SEQ ID NO: 1346.

8. The molecule of any one of claims 1-7, wherein the antigen binding domain comprises a VH comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 1346 and a VL comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3475.

9. The molecule of any one of claims 1-8, wherein the antigen binding domain comprises a VH comprising the sequence of SEQ ID NO: 1346 and a VL comprising the sequence of SEQ ID NO: 3475.

10. The molecule of any one of claims 1-7, wherein the antigen binding domain comprises a VH comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 1346 and a VL comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3476.

11. The molecule of any one of claims 1-7 and 10, wherein the antigen binding domain comprises a VH comprising the sequence of SEQ ID NO: 1346 and a VL comprising the sequence of SEQ ID NO: 3476.

12. The molecule of any one of claims 1-11, wherein the antigen binding domain is a full antibody or antigen-binding fragment thereof, a bivalent antibody, bispecific antibody, or a biparatopic antibody.

13. The molecule of any one of claims 1-12, wherein the antigen binding domain is a Fab, F(ab')2, Fv, a single chain Fv (scFv), a diabody, a single domain antibody, or a camelid antibody.

14. The molecule of any one of claims 1-13, wherein the antigen binding domain is a Fab or a scFv.

15. The molecule of any one of claims 1-14, wherein the antigen binding domain comprises one or more heavy chain constant regions selected from the group consisting of IgG1 heavy chain constant region or functional fragment thereof, IgG2 heavy chain constant region or functional fragment thereof, IgG3 heavy chain constant region or functional fragment thereof, IgGA1 heavy chain constant region or functional fragment thereof, IgGA2 heavy chain constant region or functional fragment thereof, IgG4 heavy chain constant region or functional fragment thereof, IgJ heavy chain constant region or functional fragment thereof, IgM heavy chain constant region or functional fragmentWSGR Docket No.53676-766.601 thereof, IgD heavy chain constant region or functional fragment thereof, and IgE heavy chain constant region or functional fragment thereof.

16. The molecule of claim 15, wherein the one or more heavy chain constant regions comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 73, the sequence of SEQ ID NO: 76, the sequence of SEQ ID NO: 74, the sequence of SEQ ID NO: 75, the sequence of SEQ ID NO: 41, or the sequence of SEQ ID NO: 3645.

17. The molecule of any one of claims 1-16, wherein the antigen binding domain comprises a kappa light chain constant region or functional fragment thereof, a lambda light chain constant region or functional fragment thereof, or a combination thereof.

18. The molecule of claim 17, wherein the kappa light chain constant region comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 39 or SEQ ID NO: 3644.

19. The molecule of any one of claims 1-18, wherein the antigen binding domain binds to the TCRβV6.

20. The molecule of any one of claims 1-19, wherein the molecule is a multifunctional molecule.

21. The molecule of any one of claims 1-20, wherein the molecule is a multispecific molecule.

22. The molecule of claim 20 or 21, wherein the multifunctional molecule comprises a first polypeptide, a second polypeptide, and at least one cytokine molecule, wherein the first polypeptide and the second polypeptide are non-contiguous, wherein: (i) the first polypeptide comprises a first portion of a dimerization module linked to (A) the antigen binding domain comprising the VH and the VL, or (B) a first portion of the antigen binding domain comprising the VH, wherein when the first polypeptide comprises the first portion of the antigen binding domain, the multifunctional molecule further comprises a third polypeptide comprising a second portion of the antigen binding domain comprising the VL, wherein the third polypeptide is non-contiguous with the first polypeptide and the second polypeptide; and (ii) the second polypeptide comprises a second portion of the dimerization module, and wherein the at least one cytokine molecule is covalently linked to the second polypeptide or the first polypeptide.

23. The molecule of any one of claims 20-22, wherein the multifunctional molecule comprises a first polypeptide, a second polypeptide, and at least one cytokine molecule, wherein the first polypeptide and the second polypeptide are non-contiguous, wherein:WSGR Docket No.53676-766.601 (i) the first polypeptide comprises a first portion of a dimerization module linked to a first portion of the antigen binding domain comprising the VH, wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the antigen binding domain comprising the VL, wherein the third polypeptide is non-contiguous with the first polypeptide and the second polypeptide; and (ii) the second polypeptide comprises a second portion of the dimerization module, and wherein the at least one cytokine molecule is covalently linked to the second polypeptide.

24. The molecule of claim 22 or 23, wherein the first portion of the dimerization module and the second portion of the dimerization module are dimerized.

25. The molecule of any one of claims 22-24, wherein the first polypeptide comprises: (A) the antigen binding domain comprising the VH and the VL, wherein the antigen binding domain further comprises a heavy chain constant domain 1 (CH1) linked to the VH; or (B) the first portion of the antigen binding domain comprising the VH, wherein the first portion of the antigen binding domain further comprises a CH1 linked to the VH.

26. The molecule of claim 25, wherein the CH1 is linked to the C-terminus of the VH.

27. The molecule of any one of claims 22-26, wherein the multifunctional molecule comprises: (1) the first polypeptide comprising the antigen binding domain that comprises the VH and the VL, wherein the antigen binding domain further comprises a light chain constant domain (CL) linked to the VL; or (2) the first polypeptide comprising the first portion of the antigen binding domain and the third polypeptide comprising the second portion of the antigen binding domain, wherein the second portion of the antigen binding domain further comprises a CL linked to the VL of the antigen binding domain.

28. The molecule of claim 27, wherein the CL is linked to the C-terminus of the VL.

29. The molecule of any one of claims 22-28, wherein the first portion of the dimerization module is linked to the C-terminus of (A) the antigen binding domain comprising the VH and the VL, or the C-terminus of (B) the first portion of the antigen binding domain comprising the VH.

30. The molecule of any one of claims 22-29, wherein the at least one cytokine molecule is covalently linked to the N-terminus of the second polypeptide, the C-terminus of the second polypeptide, or a combination thereof.

31. The molecule of claim 30, wherein the at least one cytokine molecule is within a single contiguous polypeptide chain of the second polypeptide.WSGR Docket No.53676-766.601 32. The molecule of any one of claims 22-31, wherein the at least one cytokine molecule is linked to the N-terminus of the first polypeptide, the C-terminus of the first polypeptide, the N-terminus of the second polypeptide, the C-terminus of the second polypeptide, the N-terminus of the third polypeptide, the C-terminus of the third polypeptide, or any combination thereof.

33. The molecule of claim 32, wherein the at least one cytokine molecule is within a single contiguous polypeptide chain of the first polypeptide, the second polypeptide, or the third cytokine polypeptide to which the at least one cytokine molecule is linked.

34. The molecule of any one of claims 22-33, wherein the multifunctional molecule further comprises: (i) a linker between the first portion of the dimerization module and the antigen binding domain comprising the VH and the VL, or the first portion of the antigen binding domain comprising the VH; (ii) a linker between the VH and the VL; (iii) a linker between the CH1 and the VH; (iv) a linker between the CL and the VL; (v) a linker between the at least one cytokine molecule and the first polypeptide, a linker between the at least one cytokine molecule and the second polypeptide, a linker between the at least one cytokine molecule and the third polypeptide, or any combination thereof; or (vi) any combination thereof.

35. The molecule of claim 34, wherein the linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non-helical linker.

36. The molecule of claim 35, wherein the linker is the peptide linker, and wherein the linker comprises the sequence of SEQ ID NO: 3308 or SEQ ID NO: 3473.

37. The molecule of any one of claims 22-36, wherein the multifunctional molecule comprises: (i) the first polypeptide comprising the first portion of the dimerization module linked to the C-terminus of the first portion of the antigen binding domain; (ii) the second polypeptide comprising the second portion of the dimerization module; (iii) the third polypeptide comprising the second portion of the antigen binding domain; and (iv) the at least one cytokine molecule covalently linked to the N-terminus of the second polypeptide.WSGR Docket No.53676-766.601 38. The molecule of any one of claims 22-37, wherein the first portion of the dimerization module comprises a first immunoglobulin constant region (Fc region) and the second portion of the dimerization module comprises a second Fc region.

39. The molecule of claim 38, wherein the first Fc region, the second Fc region, or a combination thereof is selected from the group consisting of an IgG1 Fc region or a functional fragment thereof, an IgG2 Fc region or a functional fragment thereof, an IgG3 Fc region or a functional fragment thereof, an IgGA1 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.

40. The molecule of claim 38 or 39, wherein the first Fc region, the second Fc region, or a combination thereof comprises an Fc interface with one or more of: a paired cavity- protuberance, an electrostatic interaction, or a strand-exchange, wherein the dimerization of the first Fc region and the second Fc region is enhanced as indicated by a greater ratio of heteromultimer:homomultimer forms relative to a dimerization of Fc regions with a non- engineered interface.

41. The molecule of any one of claims 38-40, 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.

42. The molecule of any one of claims 38-41, wherein the first Fc region, the second Fc region, or a combination thereof comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 3645, SEQ ID NO: 3646, SEQ ID NO: 3647, SEQ ID NO:3648, SEQ ID NO: 3649, SEQ ID NO: 3452, SEQ ID NO: 3447 or SEQ ID NO: 3453.

43. The molecule of any one of claims 38-42, wherein the first Fc region, the second Fc region, or a combination thereof comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO:3648, SEQ ID NO: 3447, or SEQ ID NO: 3453.

44. The molecule of any one of claims 38-43, wherein the first Fc region, the second Fc region, or a combination thereof comprises the sequence of SEQ ID NO:3648, SEQ ID NO: 3447 or SEQ ID NO: 3453.

45. The molecule of any one of claims 22-44, wherein the at least one cytokine molecule comprises interleukin-15 (IL-15) or a functional fragment or variant thereof.WSGR Docket No.53676-766.601 46. The molecule of claim 45, wherein the IL-15 or a functional fragment or variant thereof comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 2170, SEQ ID NO: 3670, or SEQ ID NO: 3673.

47. The molecule of claim 45 or 46, wherein the IL-15 or a functional fragment or variant thereof comprises the sequence of SEQ ID NO: 2170, SEQ ID NO: 3670, or SEQ ID NO: 3673.

48. The molecule of any one of claims 45-47, wherein the at least one cytokine molecule further comprises an IL15Ralpha dimerizing domain covalently linked the IL-15 or a functional fragment or variant thereof.

49. The molecule of claim 48, wherein the IL15Ralpha dimerizing domain comprises an IL-15 receptor alpha sushi domain or a functional fragment or variant thereof.

50. The molecule of claim 48 or 49, wherein the IL15Ralpha dimerizing domain comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3472.

51. The molecule of any one of claims 48-50, wherein the IL15Ralpha dimerizing domain comprises the sequence of SEQ ID NO: 3472.

52. The molecule of any one of claims 48-51, wherein the IL-15 or a functional fragment or variant thereof is covalently linked to the IL15Ralpha dimerizing domain via a linker.

53. The molecule of any one of claims 48-52, wherein the IL-15 or a functional fragment or variant thereof is covalently linked to the IL15Ralpha dimerizing domain via a linker comprising the sequence of SEQ ID NO: 3473.

54. The molecule of any one of claims 22-53, wherein the at least one cytokine molecule comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3474, SEQ ID NO: 3671, or SEQ ID NO: 3674.

55. The molecule of any one of claims 22-54, wherein the at least one cytokine molecule comprises the sequence of SEQ ID NO: 3474, SEQ ID NO: 3671, or SEQ ID NO: 3674.

56. The molecule of any one of claims 20-55, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the VH of the antigen binding domain, and a first immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising an IL15Ralpha dimerizing domain, an IL-15 or a functional fragment or variant thereof, and a second immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising the VL of the antigen binding domain, and an immunoglobulin light chain constant region.WSGR Docket No.53676-766.601 57. The molecule of any one of claims 20-56, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the VH of the antigen binding domain operatively linked to a first immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, an IL15Ralpha dimerizing domain operatively linked to an IL-15 or a functional fragment or variant thereof operatively linked to a second immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the VL of the antigen binding domain operatively linked to an immunoglobulin light chain constant region.

58. The molecule of claim 57, wherein the IL15Ralpha dimerizing domain is operatively linked to the IL-15 or a functional fragment or variant thereof via a linker.

59. The molecule of claim 57 or 58, wherein the IL15Ralpha dimerizing domain is operatively linked to the IL-15 or a functional fragment or variant thereof via a linker comprising the sequence of SEQ ID NO: 3473 60. The molecule of any one of claims 57-59, wherein the IL-15 or a functional fragment or variant thereof is operatively linked to the second immunoglobulin heavy chain constant region via a linker.

61. The molecule of any one of claims 57-60, wherein the IL-15 or a functional fragment or variant thereof is operatively linked to the second immunoglobulin heavy chain constant region via a linker comprising the sequence of SEQ ID NO: 3308.

62. The molecule of any one of claims 20-61, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 2170, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

63. The molecule of any one of claims 20-62, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452;WSGR Docket No.53676-766.601 (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

64. The molecule of any one of claims 20-61, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 2170, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

65. The molecule of any one of claims 20-61 and 64, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

66. The molecule of claim 63 or 65, wherein the second polypeptide comprises, from the N- terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3473 operatively linked to the sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

67. The molecule of any one of claims 20-66, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3474, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.WSGR Docket No.53676-766.601 68. The molecule of any one of claims 20-67, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3474 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

69. The molecule of any one of claims 20-66, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3474, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

70. The molecule of any one of claims 20-66 and 69, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3474 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

71. The molecule of claim 68 or 70, wherein the second polypeptide comprises, from the N- terminus to the C-terminus, the sequence of SEQ ID NO: 3474 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

72. The molecule of any one of claims 20-71, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3428.WSGR Docket No.53676-766.601 73. The molecule of any one of claims 20-72, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3428.

74. The molecule of any one of claims 20-69, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517.

75. The molecule of any one of claims 20-69 and 74, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3517.

76. The molecule of any one of claims 20-61, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3670, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

77. The molecule of any one of claims 20-61 and 76, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.WSGR Docket No.53676-766.601 78. The molecule of any one of claims 20-61, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3670, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

79. The molecule of any one of claims 20-61 and 78, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

80. The molecule of claim 77 or 79, wherein the second polypeptide comprises, from the N- terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3473 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

81. The molecule of any one of claims 20-61 and 76-80, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3671, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

82. The molecule of any one of claims 20-61 and 76-81, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452;WSGR Docket No.53676-766.601 (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

83. The molecule of any one of claims 20-61 and 74-78, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3671, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

84. The molecule of any one of claims 20-61, 74-78, and 83, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

85. The molecule of claim 82 or 84, wherein the second polypeptide comprises, from the N- terminus to the C-terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

86. The molecule of any one of claims 20-61 and 76-85, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3428.

87. The molecule of any one of claims 20-61 and 76-86, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3669; andWSGR Docket No.53676-766.601 (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3428.

88. The molecule of any one of claims 20-61 and 76-83, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517.

89. The molecule of any one of claims 20-61, 76-83, and 88, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3517.

90. The molecule of any one of claims 20-61, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3673, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

91. The molecule of any one of claims 20-61 and 90, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

92. The molecule of any one of claims 20-61, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649;WSGR Docket No.53676-766.601 (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3673, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

93. The molecule of any one of claims 20-61 and 92, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

94. The molecule of claim 91 or 93, wherein the second polypeptide comprises, from the N- terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3473 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

95. The molecule of any one of claims 20-61 and 90-94, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3674, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

96. The molecule of any one of claims 20-61 and 90-95, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.WSGR Docket No.53676-766.601 97. The molecule of any one of claims 20-61 and 88-92, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3674, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3475, and the sequence of SEQ ID NO: 3644.

98. The molecule of any one of claims 20-61, 88-92, and 97, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3475 operatively linked to the sequence of SEQ ID NO: 3644.

99. The molecule of claim 96 or 98, wherein the second polypeptide comprises, from the N- terminus to the C-terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

100. The molecule of any one of claims 20-61 and 90-99, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3428.

101. The molecule of any one of claims 20-61 and 90-100, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3428.

102. The molecule of any one of claims 20-61 and 88-97, wherein the multifunctional molecule comprises:WSGR Docket No.53676-766.601 (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517.

103. The molecule of any one of claims 20-61, 88-100, and 102, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3517.

104. The molecule of any one of claims 20-61, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 2170, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

105. The molecule of any one of claims 20-61 and 104, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

106. The molecule of any one of claims 20-61, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 2170, and the sequence of SEQ ID NO: 3648; andWSGR Docket No.53676-766.601 (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

107. The molecule of any one of claims 20-61 and 106, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

108. The molecule of claim 105 or 107, wherein the second polypeptide comprises, from the N- terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3473 operatively linked to the sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

109. The molecule of any one of claims 20-61 and 104-108, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3474, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

110. The molecule of any one of claims 20-61 and 104-109, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3474 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

111. The molecule of any one of claims 20-61 and 102-106, wherein the multifunctional molecule comprises:WSGR Docket No.53676-766.601 (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3474, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

112. The molecule of any one of claims 20-61, 102-106, and 111, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3474 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

113. The molecule of claim 110 or 112, wherein the second polypeptide comprises, from the N- terminus to the C-terminus, the sequence of SEQ ID NO: 3474 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

114. The molecule of any one of claims 20-61 and 104-113, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3437.

115. The molecule of any one of claims 20-61 and 104-114, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3437.

116. The molecule of any one of claims 20-61 and 102-111, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517;WSGR Docket No.53676-766.601 (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3437.

117. The molecule of any one of claims 20-61, 102-111, and 116, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3437.

118. The molecule of any one of claims 20-61, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3670, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

119. The molecule of any one of claims 20-61 and 118, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

120. The molecule of any one of claims 20-61, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3670, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.WSGR Docket No.53676-766.601 121. The molecule of any one of claims 20-61 and 120, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

122. The molecule of claim 119 or 121, wherein the second polypeptide comprises, from the N- terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3473 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to and the sequence of SEQ ID NO: 3648.

123. The molecule of any one of claims 20-61 and 118-122, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3671, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

124. The molecule of any one of claims 20-61 and 118-123, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

125. The molecule of any one of claims 20-61 and 116-120, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649;WSGR Docket No.53676-766.601 (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3671, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

126. The molecule of any one of claims 20-61, 116-120, and 125, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3648; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

127. The molecule of claim 124 or 126, wherein the second polypeptide comprises, from the N- terminus to the C-terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

128. The molecule of any one of claims 20-61 and 118-127, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3437.

129. The molecule of any one of claims 20-61 and 118-128, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3437.

130. The molecule of any one of claims 20-61 and 116-125, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3669; andWSGR Docket No.53676-766.601 (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3437.

131. The molecule of any one of claims 20-61, 116-125, and 130, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3437.

132. The molecule of any one of claims 20-61, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3673, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

133. The molecule of any one of claims 20-61 and 132, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

134. The molecule of any one of claims 20-61, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3673, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

135. The molecule of any one of claims 20-61 and 134, wherein the multifunctional molecule comprises:WSGR Docket No.53676-766.601 (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

136. The molecule of claim 133 or 135, wherein the second polypeptide comprises, from the N- terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3473 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

137. The molecule of any one of claims 20-61 and 132-136, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3674, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

138. The molecule of any one of claims 20-61 and 132-137, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

139. The molecule of any one of claims 20-61 and 130-134, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3674, and the sequence of SEQ ID NO: 3648; andWSGR Docket No.53676-766.601 (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3476, and the sequence of SEQ ID NO: 3644.

140. The molecule of any one of claims 20-61 and 130-134, and 139, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3476 operatively linked to the sequence of SEQ ID NO: 3644.

141. The molecule of claim 138 or 140, wherein the second polypeptide comprises, from the N- terminus to the C-terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

142. The molecule of any one of claims 20-61 and 132-139, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3437.

143. The molecule of any one of claims 20-61 and 130-142, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3437.

144. The molecule of any one of claims 20-61 and 130-139, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3437.WSGR Docket No.53676-766.601 145. The molecule of any one of claims 20-61, 130-139, and 144, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3437.

146. A multifunctional molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, and at least one cytokine molecule, wherein the first polypeptide, the second polypeptide, and the third polypeptide are non- contiguous, wherein: (i) the first polypeptide comprises a first portion of a dimerization module linked to a first portion of an antigen binding domain that binds to a T cell receptor beta variable region (TCRβV) comprising a heavy chain variable region (VH) of the antigen binding domain; (ii) the second polypeptide comprises a second portion of the dimerization module, wherein the at least one cytokine molecule is covalently linked to the second polypeptide; and (iii) the third polypeptide comprises a second portion of the antigen binding domain comprising a light chain variable region (VL) of the antigen binding domain; wherein the first portion of the dimerization module comprises a first immunoglobulin constant region (Fc region) comprising the sequence of SEQ ID NO: 3453, and the second portion of the dimerization module comprises a second Fc region comprising the sequence of SEQ ID NO: 3648; and wherein the antigen binding domain comprises: (A) a VH comprising: (i) a heavy chain complementarity determining region 1 (HC CDR1) amino acid sequence of LTYIH (SEQ ID NO: 3421), FRLTYIH (SEQ ID NO: 3702), or GHDFRLTYIH (SEQ ID NO: 3351); (ii) a heavy chain complementarity determining region 2 (HC CDR2) amino acid sequence of RVSAGSGNVKYNEKFKG (SEQ ID NO: 3352); and (iii) a heavy chain complementarity determining region 3 (HC CDR3) amino acid sequence of SYYSYDVLDY (SEQ ID NO: 3353); and (B) a VL comprising: (i) a light chain complementarity determining region 1 (LC CDR1) amino acid sequence of KASQNVADRVV (SEQ ID NO: 3354), (ii) a light chain complementarity determining region 2 (LC CDR2) amino acid sequence of SSSHRYK (SEQ ID NO: 3355), andWSGR Docket No.53676-766.601 (iii) a light chain complementarity determining region 3 (LC CDR3) amino acid sequence of QQFKSYPLT (SEQ ID NO: 3356).

147. A multifunctional molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, and at least one cytokine molecule, wherein the first polypeptide, the second polypeptide, and the third polypeptide are non- contiguous, wherein: (i) the first polypeptide comprises a first portion of a dimerization module linked to a first portion of an antigen binding domain that binds to a T cell receptor beta variable region (TCRβV) comprising a heavy chain variable region (VH) of the antigen binding domain; (ii) the second polypeptide comprises a second portion of the dimerization module, wherein the at least one cytokine molecule is covalently linked to the second polypeptide; and (iii) the third polypeptide comprises a second portion of the antigen binding domain comprising a light chain variable region (VL) of the antigen binding domain; wherein the first portion of the dimerization module comprises a first immunoglobulin constant region (Fc region) comprising the sequence of SEQ ID NO: 3447, and the second portion of the dimerization module comprises a second Fc region comprising the sequence of SEQ ID NO: 3648; and wherein the antigen binding domain comprises: (A) a VH comprising: (i) a heavy chain complementarity determining region 1 (HC CDR1) amino acid sequence of LTYIH (SEQ ID NO: 3421), FRLTYIH (SEQ ID NO: 3702), or GHDFRLTYIH (SEQ ID NO: 3351); (ii) a heavy chain complementarity determining region 2 (HC CDR2) amino acid sequence of RVSAGSGNVKYNEKFKG (SEQ ID NO: 3352); and (iii) a heavy chain complementarity determining region 3 (HC CDR3) amino acid sequence of SYYSYDVLDY (SEQ ID NO: 3353); and (B) a VL comprising: (i) a light chain complementarity determining region 1 (LC CDR1) amino acid sequence of KASQNVADRVV (SEQ ID NO: 3354), (ii) a light chain complementarity determining region 2 (LC CDR2) amino acid sequence of SSSHRYK (SEQ ID NO: 3355), and (iii) a light chain complementarity determining region 3 (LC CDR3) amino acid sequence of QQFKSYPLT (SEQ ID NO: 3356).WSGR Docket No.53676-766.601 148. The multifunctional molecule of claim 146 or 147, wherein the at least one cytokine molecule comprises an IL15Ralpha dimerizing domain covalently linked to IL-15 or a functional fragment or variant thereof via a linker comprising the sequence of SEQ ID NO: 3473.

149. A multifunctional molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, and at least one cytokine molecule, wherein the first polypeptide, the second polypeptide, and the third polypeptide are non- contiguous, wherein: (i) the first polypeptide comprises a first portion of a dimerization module linked to a first portion of an antigen binding domain that binds to a T cell receptor beta variable region (TCRβV) comprising a heavy chain variable region (VH) of the antigen binding domain; (ii) the second polypeptide comprises a second portion of the dimerization module, wherein the at least one cytokine molecule is covalently linked to the second polypeptide; and (iii) the third polypeptide comprises a second portion of the antigen binding domain comprising a light chain variable region (VL) of the antigen binding domain; wherein the first portion of the dimerization module comprises a first immunoglobulin constant region (Fc region), and the second portion of the dimerization module comprises a second Fc region; wherein the at least one cytokine molecule comprises an IL15Ralpha dimerizing domain covalently linked to IL-15 or a functional fragment or variant thereof via a linker comprising the sequence of SEQ ID NO: 3473; and wherein the antigen binding domain comprises: (A) a VH comprising: (i) a heavy chain complementarity determining region 1 (HC CDR1) amino acid sequence of LTYIH (SEQ ID NO: 3421), FRLTYIH (SEQ ID NO: 3702), or GHDFRLTYIH (SEQ ID NO: 3351); (ii) a heavy chain complementarity determining region 2 (HC CDR2) amino acid sequence of RVSAGSGNVKYNEKFKG (SEQ ID NO: 3352); and (iii) a heavy chain complementarity determining region 3 (HC CDR3) amino acid sequence of SYYSYDVLDY (SEQ ID NO: 3353); and (B) a VL comprising: (i) a light chain complementarity determining region 1 (LC CDR1) amino acid sequence of KASQNVADRVV (SEQ ID NO: 3354),WSGR Docket No.53676-766.601 (ii) a light chain complementarity determining region 2 (LC CDR2) amino acid sequence of SSSHRYK (SEQ ID NO: 3355), and (iii) a light chain complementarity determining region 3 (LC CDR3) amino acid sequence of QQFKSYPLT (SEQ ID NO: 3356).

150. The multifunctional molecule of claim 149, wherein the Fc region comprises the sequence of SEQ ID NO: 3447, and the second Fc region comprise the sequence of SEQ ID NO: 3648.

151. The multifunctional molecule of claim 149, wherein the Fc region comprises the sequence of SEQ ID NO: 3453, and the second Fc region comprise the sequence of SEQ ID NO: 3648.

152. The multifunctional molecule of any one of claims 146-151, wherein the antigen binding domain comprises a VH comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 1346.

153. The multifunctional molecule of any one of claims 146-152, wherein the antigen binding domain comprises a VH comprising the sequence of SEQ ID NO: 1346.

154. The multifunctional molecule of any one of claims 146-153, wherein the antigen binding domain comprises a VL comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 1349.

155. The multifunctional molecule of any one of claims 146-154, wherein the antigen binding domain comprises a VL comprising the sequence of SEQ ID NO: 1349.

156. The multifunctional molecule of any one of claims 146-155, wherein the antigen binding domain comprises a VH comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 1346 and a VL comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 1349.

157. The multifunctional molecule of any one of claims 146-156, wherein the antigen binding domain comprises a VH comprising the sequence of SEQ ID NO: 1346 and a VL comprising the sequence of SEQ ID NO: 1349.

158. The multifunctional molecule of any one of claims 146-157, wherein the first polypeptide further comprises a heavy chain constant domain 1 (CH1) linked to the C-terminus of the VH.

159. The multifunctional molecule of any one of claims 146-158, wherein the third polypeptide further comprises a light chain constant domain (CL) linked to the C-terminus of the VL.

160. The multifunctional molecule of any one of claims 146-159, wherein the at least one cytokine molecule is within a single contiguous polypeptide chain of the second polypeptide.WSGR Docket No.53676-766.601 161. The multifunctional molecule of any one of claims 146-160, wherein the multifunctional molecule comprises: (i) the first polypeptide comprising the first portion of the dimerization module linked to the C-terminus of the first portion of the antigen binding domain; (ii) the second polypeptide comprising the second portion of the dimerization module; (iii) the third polypeptide comprising the second portion of the antigen binding domain; and (iv) the at least one cytokine molecule covalently linked to the N-terminus of the second polypeptide.

162. The multifunctional molecule of any one of claims 147-161, wherein the IL-15 or a functional fragment or variant thereof comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 2170, SEQ ID NO: 3670, or SEQ ID NO: 3673.

163. The multifunctional molecule of any one of claims 148-162, wherein the IL-15 or a functional fragment or variant thereof comprises the sequence of SEQ ID NO: 2170, SEQ ID NO: 3670, or SEQ ID NO: 3673.

164. The multifunctional molecule of any one of claims 146-163, wherein the IL15Ralpha dimerizing domain comprises an IL-15 receptor alpha sushi domain or a functional fragment or variant thereof.

165. The multifunctional molecule of any one of claims 146-164, wherein the IL15Ralpha dimerizing domain comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3472.

166. The multifunctional molecule of any one of claims 146-165, wherein the IL15Ralpha dimerizing domain comprises the sequence of SEQ ID NO: 3472.

167. The multifunctional molecule of any one of claims 146-166, wherein the at least one cytokine molecule comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3474, SEQ ID NO: 3671, or SEQ ID NO: 3674.

168. The multifunctional molecule of any one of claims 146-167, wherein the at least one cytokine molecule comprises the sequence of SEQ ID NO: 3474, SEQ ID NO: 3671, or SEQ ID NO: 3674.

169. The multifunctional molecule of any one of claims 146-168, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the VH of the antigen binding domain, and a first immunoglobulin heavy chain constant region;WSGR Docket No.53676-766.601 (ii) a second polypeptide comprising an IL15Ralpha dimerizing domain, an IL-15 or a functional fragment or variant thereof, and a second immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising the VL of the antigen binding domain, and an immunoglobulin light chain constant region.

170. The multifunctional molecule of any one of claims 146-169, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the VH of the antigen binding domain operatively linked to a first immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, an IL15Ralpha dimerizing domain operatively linked to an IL-15 or a functional fragment or variant thereof operatively linked to a second immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the VL of the antigen binding domain operatively linked to an immunoglobulin light chain constant region.

171. The multifunctional molecule of any one of claims 146-170, wherein the IL-15 or a functional fragment or variant thereof is operatively linked to the second immunoglobulin heavy chain constant region via a linker.

172. The multifunctional molecule of any one of claims 146-171, wherein the IL-15 or a functional fragment or variant thereof is operatively linked to the second immunoglobulin heavy chain constant region via a linker comprising the sequence of SEQ ID NO: 3308.

173. The multifunctional molecule of any one of claims 146-172, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 2170, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

174. The multifunctional molecule of any one of claims 146-173, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452;WSGR Docket No.53676-766.601 (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

175. The multifunctional molecule of any one of claims 144-172, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 2170, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

176. The multifunctional molecule of any one of claims 144-172 and 175, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

177. The multifunctional molecule of claim 174 or 176, wherein the second polypeptide comprises, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3473 operatively linked to the sequence of SEQ ID NO: 2170 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

178. The multifunctional molecule of any one of claims 146-175, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3474, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.WSGR Docket No.53676-766.601 179. The multifunctional molecule of any one of claims 146-178, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3474 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

180. The multifunctional molecule of any one of claims 144-175, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3474, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

181. The multifunctional molecule of any one of claims 144-175 or 180, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3474 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

182. The multifunctional molecule of claim 179 or 181, wherein the second polypeptide comprises, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3474 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

183. The multifunctional molecule of any one of claims 146-182, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3420; andWSGR Docket No.53676-766.601 (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3349.

184. The multifunctional molecule of any one of claims 146-183, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3349.

185. The multifunctional molecule of any one of claims 144-180, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3349.

186. The multifunctional molecule of any one of claims 144-180 and 185, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3420; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3349.

187. The multifunctional molecule of any one of claims 146-172, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3670, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

188. The multifunctional molecule of any one of claims 146-172 and 187, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to the sequence of SEQ ID NO: 3648; andWSGR Docket No.53676-766.601 (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

189. The multifunctional molecule of any one of claims 146-172, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3670, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

190. The multifunctional molecule of any one of claims 146-172 and 189, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

191. The multifunctional molecule of claim 188 or 190, wherein the second polypeptide comprises, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3473 operatively linked to the sequence of SEQ ID NO: 3670 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

192. The multifunctional molecule of any one of claims 146-172 and 187-191, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3671, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

193. The multifunctional molecule of any one of claims 146-172 and 187-192, wherein the multifunctional molecule comprises:WSGR Docket No.53676-766.601 (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

194. The multifunctional molecule of any one of claims 146-172 and 187-191, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3671, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

195. The multifunctional molecule of any one of claims 146-172, 187-191 and 194, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

196. The multifunctional molecule of claim 193 or 195, wherein the second polypeptide comprises, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3671 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

197. The multifunctional molecule of any one of claims 146-172 and 187-196, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3349.WSGR Docket No.53676-766.601 198. The multifunctional molecule of any one of claims 146-172 and 187-197, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3349.

199. The multifunctional molecule of any one of claims 146-172 and 187-194, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3349.

200. The multifunctional molecule of any one of claims 146-172, 187-194, and 199, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3669; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3349.

201. The multifunctional molecule of any one of claims 146-172, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3673, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

202. The multifunctional molecule of any one of claims 146-172 and 201, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.WSGR Docket No.53676-766.601 203. The multifunctional molecule of any one of claims 146-172, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3472, the sequence of SEQ ID NO: 3673, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

204. The multifunctional molecule of any one of claims 146-172 and 203, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

205. The multifunctional molecule of claim 202 or 204, wherein the second polypeptide comprises, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3472 operatively linked to the sequence of SEQ ID NO: 3473 operatively linked to the sequence of SEQ ID NO: 3673 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

206. The multifunctional molecule of any one of claims 146-172 and 201-205, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3452; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3674, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

207. The multifunctional molecule of any one of claims 146-172 and 201-206, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3452;WSGR Docket No.53676-766.601 (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

208. The multifunctional molecule of any one of claims 144-172 and 199-203, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 1346, and the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3674, and the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

209. The multifunctional molecule of any one of claims 144-172, 199-203, and 208, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3648; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

210. The multifunctional molecule of claim 207 or 209, wherein the second polypeptide comprises, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3674 operatively linked to the sequence of SEQ ID NO: 3308 operatively linked to the sequence of SEQ ID NO: 3648.

211. The multifunctional molecule of any one of claims 146-172 and 201-210, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3348; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3349.

212. The multifunctional molecule of any one of claims 146-172 and 201-211, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3348;WSGR Docket No.53676-766.601 (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3349.

213. The multifunctional molecule of any one of claims 146-172 and 199-208, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3349.

214. The multifunctional molecule of any one of claims 146-172, 199-208, and 213, wherein the multifunctional molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3672; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3349.

215. The multifunctional molecule of any one of claims 146-212, wherein the antigen binding domain binds to the TCRβV6.

216. A recombinant polynucleotide molecule comprising polynucleotide sequences encoding the molecule of any one of claims 1-145 or the multifunctional molecule of any one of claims 146-215.

217. The recombinant polynucleotide molecule of claim 216, wherein the recombinant polynucleotide molecule is an isolated recombinant polynucleotide molecule.

218. A vector comprising the recombinant polynucleotide molecule of claim 216 or 217.

219. A cell comprising the recombinant polynucleotide molecule of claim 216 or 217, or the vector of claim 218.

220. A pharmaceutical composition comprising the molecule of any one of claims 1-143, the multifunctional molecule of any one of claims 146-215, recombinant polynucleotide molecule of claim 216 or 217, the vector of claim 218, or the cell of claim 219, and a pharmaceutically acceptable carrier, excipient, or diluent.

221. A method of treating a condition or disease in a subject in need therefor comprising administering to the subject a therapeutically effective amount of the molecule of any one of claims 1-145, the multifunctional molecule of any one of claims 146-215, recombinant polynucleotide molecule of claim 216 or 217, the vector of claim 218, the cell of claim 219, or the pharmaceutical composition of claim 220, or a combination thereof, thereby treating the condition or disease in the subject.WSGR Docket No.53676-766.601 222. The method of claim 221, wherein the condition or disease is cancer.

223. The method of claim 222, wherein the cancer is a solid tumor, a hematological cancer, a metastatic cancer, a soft tissue tumor, or a combination thereof.

224. The method of claim 223, 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.

225. The method of claim 223, 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.

226. The method of claim 225, 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.

227. The method of claim 226, wherein the T-cell lymphoma is peripheral T-cell lymphoma.

228. The method of any one of claims 222-227, wherein the cancer is characterized by a cancer antigen present on the cancer.

229. The method of claim 228, wherein the cancer antigen is a tumor antigen, a stromal antigen, or a hematological antigen.

230. The method of claim 228 or 229, wherein the cancer antigen is selected from the group consisting of BCMA, CD19, CD20, CD22, FcRH5, PDL1, CD47, ganglioside 2 (GD2), prostate stem cell antigen (PSCA), prostate specific membrane antigen (PMSA), prostate- specific antigen (PSA), carcinoembryonic antigen (CEA), Ron Kinase, c-Met, Immature laminin receptor, TAG-72, BING-4, Calcium-activated chloride channel 2, Cyclin-B1, 9D7, Ep-CAM, EphA3, Her2 / neu, Telomerase, SAP-1, Survivin, NY-ESO-1 / LAGE-1, PRAME, SSX-2, Melan-A / MART-1, Gp100 / pmel17, Tyrosinase, MC1R, β-catenin, BRCA1 / 2, CDK4, CML66, Fibronectin, p53, Ras, TGF-Β receptor, AFP, ETA, MAGE, CA-125, BAGE, GAGE, CDC27, α actinin-4, TRP1 / gp75, TRP2, gangliosides, WT1, Epidermal growth factor receptor (EGFR), MART-2, MUC1, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RU11, RU12, SAGE, TRG, TSTA, Folate receptor alpha, L1-CAM, CAIX, gpA33, GD3, GM2, VEGFR, Integrins, Carbohydrates,WSGR Docket No.53676-766.601 IGF1R, TRAILR1, TRAILR2, RANKL, FAP, TGF-beta, hyaluronic acid, collagen, tenascin C, and tenascin W.

231. The method of any one of claims 221-230, further comprising administering a second therapeutic agent or therapy to the subject.

232. The method of claim 231, wherein the second therapeutic agent or therapy comprises a chemotherapeutic agent, a biologic agent, a hormonal therapy, radiation, or surgery.

233. The method of claim 231 or 232, wherein the second therapeutic agent or therapy is administered in combination with the molecule of any one of claims 1-143, the multifunctional molecule of any one of claims 144-213, recombinant polynucleotide molecule of claim 216 or 217, the vector of claim 218, the cell of claim 219, or the pharmaceutical composition of claim 220, sequentially, simultaneously, or concurrently.

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