Multifunctional molecules binding to TCR and uses thereof

Abstract

Provides herein are multifunctional polypeptide molecules comprising T cell receptor variable beta-binding moieties and cytokines and methods of treating conditions or diseases in a subject using the

Description

23 12 25

[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 a first aspect the present invention relates to a bispecific polypeptide molecule comprising a T cell receptor beta chain variable region (TCRpV)-binding moiety and at least one cytokine polypeptide or a functional fragment or variant thereof; wherein the TCRpV-binding moiety binds to a human TCRpV; wherein the bispecific polypeptide molecule comprises a first polypeptide and a second polypeptide; 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 TCRpV-binding moiety, wherein the TCRpV-binding moiety comprises a heavy chain variable domain (VH) and a light chain variable domain (VL), or a single domain antibody, or 23 12 25 (B) a first portion of the TCRpV-binding moiety comprising a VH of the TCRpV binding moiety, wherein the bispecific polypeptide molecule further comprises a third polypeptide comprising a second portion of the TCRpV-binding moiety comprising a VL of the TCRpV-binding moiety, 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, wherein the at least one cytokine polypeptide or a functional fragment or variant thereof is covalently linked to the second portion of the dimerization module; and wherein the at least one cytokine polypeptide or a functional fragment or variant thereof comprises, from N-terminus to C-terminus, the sequence of SEQ ID NO: 3523 operatively linked to the sequence of SEQ ID NO: 2170.

[0004] In a second aspect, the present invention relates to a recombinant polynucleotide comprising a sequence encoding the bispecific polypeptide molecule of the first aspect.

[0005] In a third aspect, the present invention relates to a medicament comprising the bispecific polypeptide molecule of the first aspect or the recombinant polynucleotide of the second aspect, and a pharmaceutically acceptable carrier, excipient, diluent, or stabilizer.

[0006] In a forth aspect, the present invention relates to a pharmaceutical composition for use in treating cancer in a subject in need thereof, wherein the pharmaceutical composition comprises a therapeutically effective amount of the bispecific polypeptide molecule of the first aspect, the recombinant polynucleotide of the second aspect, or the medicament of the third aspect for treating cancer in the subject when administered to the subject; and optionally, wherein the cancer is a solid tumor, a hematological cancer, a metastatic cancer, a soft tissue tumor, or any combination thereof.

[0007] Preferred embodiments of the present invention are set out in the dependent claims herein.

[0008] Described herein 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 comprises a first portion of a dimerization module linked to (A) a first TCRpV-binding moiety comprising a first heavy chain variable domain (VH) and a first light chain variable domain (VL), or a single domain antibody, or (B) a first portion of a first TCRpV-binding moiety comprising a VH of the first TCRpV-binding moiety, wherein when the first polypeptide comprises the first portion of the first TCRpV-binding moiety, the multifunctional polypeptide molecule further comprises a third polypeptide comprising a second portion of the first TCRpV-binding moiety comprising a VL of the first TCRpV-binding moiety, 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; wherein (a) the multifunctional polypeptide molecule comprises a single TCRpV-binding moiety and the at least one cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the second polypeptide, or (b) the multifunctional polypeptide molecule further 23 12 25 comprises a second TCRpV-binding moiety and 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 when the multifunctional polypeptide molecule further comprises the third polypeptide, or a combination thereof.

[0009] In some embodiments, the multifunctional polypeptide molecule comprises the second TCRpV-binding moiety, and the second portion of the dimerization module is linked to: (A) a second TCRpV-binding moiety comprising a second VH and a second VL, or a single domain antibody, or (B) a first portion of a second TCRpV-binding moiety comprising a VH of the second TCRpV-binding moiety, wherein when the second polypeptide comprises the first portion of the second TCRpV-binding moiety, the multifunctional polypeptide molecule further comprises a fourth polypeptide comprising a second portion of the second TCRpV-binding moiety comprising a VL of the second TCRpV-binding moiety, wherein the fourth polypeptide is non-contiguous with the first polypeptide, the second polypeptide, and the third polypeptide; 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 when the multifunctional polypeptide molecule further comprises the fourth polypeptide, or a combination thereof.

[0010] Described herein is 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 comprises a first portion of a dimerization module linked to a first portion of a first TCRpV-binding moiety comprising a VH of the first TCRpV-binding moiety, wherein the multifunctional polypeptide molecule further comprises a third polypeptide comprising a second portion of the first TCRpV-binding moiety comprising a VL of the first TCRpV-binding moiety, 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, wherein the at least one cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the second polypeptide.

[0011] In some embodiments, the first portion of the dimerization module and the second portion of the dimerization module are dimerized.

[0012] In some embodiments, the first polypeptide comprises: (A) the first TCRpV-binding moiety comprising the first VH and the first VL, wherein the first TCRpV-binding moiety further comprises a first heavy chain constant domain 1 (CHI) linked to the first VH; or (B) the first portion of the first TCRpV-binding moiety comprising the VH of the first TCRpV-binding moiety, wherein the first portion of the first TCRpV-binding moiety further comprises a first CHI linked to the VH of the first TCRpV-binding moiety.

[0013] In some embodiments, the first CHI is linked to the C-terminus of the first VH or the C-terminus of the VH of the first TCRpV-binding moiety. 23 12 25

[0014] In some embodiments, the second polypeptide comprises: (A) the second TCRpV-binding moiety comprising the second VH and the second VL, wherein the second TCRpV-binding moiety further comprises a second CHI linked to the second VH; or (B) the first portion of the second TCRpV-binding moiety comprising the VH of the second TCRpV-binding moiety, wherein the first portion of the second TCRpV-binding moiety further comprises a second CHI linked to the VH of the second TCRpV-binding moiety.

[0015] In some embodiments, the second CHI is linked to the C-terminus of the second VH or the C-terminus of the VH of the second TCRpV-binding moiety.

[0016] In some embodiments, the multifunctional polypeptide molecule comprises: (1) the first polypeptide comprising the first TCRpV-binding moiety that comprises the first VH and the first VL, wherein the first TCRpV-binding moiety further comprises a first light chain constant domain (CL) linked to the first VL; or (2) the first polypeptide comprising the first portion of the first TCRpV-binding moiety and the third polypeptide comprising the second portion of the first TCRpV-binding moiety, wherein the second portion of the first TCRpV-binding moiety further comprises a first CL linked to the VL of the first TCRpV-binding moiety.

[0017] In some embodiments, the first CL is linked to the C-terminus of the first VL or the C-terminus of the VL of the first TCRpV-binding moiety.

[0018] In some embodiments, the multifunctional polypeptide molecule comprises: (1) the second polypeptide comprising the second TCRpV-binding moiety that comprises the second VH and the second VL, wherein the second TCRpV-binding moiety further comprises a second CL linked to the second VL; or (2) the second polypeptide comprising the first portion of the second TCRpV-binding moiety and the fourth polypeptide comprising the second portion of the second TCRpV-binding moiety, wherein the second portion of the second TCRpV-binding moiety further comprises a second CL linked to the VL of the second TCRpV-binding moiety.

[0019] In some embodiments, the second CL is linked to the C-terminus of the second VL or the C-terminus of the VL of the second TCRpV-binding moiety.

[0020] In some embodiments, the first portion of the dimerization module is linked to the C-terminus of (A) the first TCRpV-binding moiety comprising the first VH and the first VL or the single domain antibody, or the C-terminus of (B) the first portion of the first TCRpV-binding moiety comprising the VH of the first TCRpV-binding moiety.

[0021] In some embodiments, the multifunctional polypeptide molecule comprises the second TCRpV-binding moiety, and the second portion of the dimerization module is linked to the C-terminus of (A) the second TCRpV-binding moiety comprising the second VH and the second VL or the single domain antibody, or the C-terminus of (B) the first portion of the second TCRpV-binding moiety comprising the VH of the second TCRpV-binding moiety.

[0022] In some embodiments, the multifunctional polypeptide molecule comprises a single TCRpV-binding moiety, and the at least one cytokine polypeptide or a functional fragment or a functional variant 23 12 25 thereof is covalently linked to the N-terminus of the second polypeptide, the C-terminus of the second polypeptide, or a combination thereof.

[0023] In some embodiments, the at least one cytokine polypeptide or a functional fragment or a functional variant thereof is within a single contiguous polypeptide chain of the second polypeptide.

[0024] In some embodiments, (a) the N-terminus of the first polypeptide is linked to a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to a 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 cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to a 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 cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to a 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 cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to an cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; or (e) a combination thereof.

[0025] In some embodiments, (a-1) the N-terminus of the first polypeptide is linked to a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to a 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 a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to a 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 a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to a 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 a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to a 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 a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to a cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (c-2) the N-terminus of the fourth polypeptide is linked to a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to a 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 a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to a cytokine polypeptide or a functional fragment or a functional 23 12 25 variant thereof; or a combination thereof; and (d-2) the N-terminus of the third polypeptide is linked to a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to a 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 a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to a 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 a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to a 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 a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to a 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 a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to a cytokine polypeptide or a functional fragment or a functional variant thereof.

[0026] In some embodiments, (a-1) the N-terminus of the first polypeptide is linked to a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to a 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 a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to a 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 a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to a 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 a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to a 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 a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to a 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 a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to a 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 a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to a 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 a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third 23 12 25 polypeptide is linked to a 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 a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to a cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof.

[0027] In some embodiments, the N-terminus of the first polypeptide is linked to a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to a cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; the N-terminus of the second polypeptide is linked to a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to a cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; the N-terminus of the third polypeptide is linked to a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to a cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and the N-terminus of the fourth polypeptide is linked to a cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to a cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof.

[0028] In some embodiments, the cytokine polypeptide or a functional fragment or a functional variant thereof is within a single contiguous polypeptide chain of the first polypeptide, the second polypeptide, the third cytokine polypeptide, or the fourth cytokine polypeptide to which the cytokine polypeptide or a functional fragment or a functional variant thereof is linked.

[0029] In some embodiments, the multifunctional polypeptide molecule further comprises: (i) a linker between the first portion of the dimerization module and the first TCRpV-binding moiety comprising the first VH and the first VL or the single domain antibody, or the first portion of the first TCRpV-binding moiety comprising the VH of the first TCRpV-binding moiety; (ii) a linker between the second portion of the dimerization module and the second TCRpV-binding moiety comprising the second VH and the second VL or the single domain antibody, or the first portion of the second TCRpV-binding moiety comprising the VH of the second TCRpV-binding moiety; (iii) a linker between the first VH and the first VL; (iv) a linker between the second VH and the second VL; (v) a linker between the first CHI and the first VH, or the VH of the first TCRpV-binding moiety; (vi) a linker between the second CHI and the second VH, or the VH of the second TCRpV-binding moiety; (vii) a linker between the first CL and the first VL, or the VL of the first TCRpV-binding moiety; (vii) a linker between the second CL and the second VL, or the VL of the second TCRpV-binding moiety; (viii) 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 23 12 25 cytokine polypeptide or a functional fragment or a functional variant thereof and the fourth polypeptide, or a combination thereof; or (ix) a combination thereof.

[0030] 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.

[0031] In some embodiments, the linker is the peptide linker and the linker comprises the sequence of SEQ ID NO: 3308 or SEQ ID NO: 3643.

[0032] In some embodiments, the multifunctional polypeptide molecule is an isolated multifunctional polypeptide molecule.

[0033] In some embodiments, the multifunctional polypeptide 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 first TCRpV-binding moiety; (ii) the second polypeptide comprising the second portion of the dimerization module; (iii) the third polypeptide comprising the second portion of the first TCRpV-binding moiety; and (iv) a cytokine polypeptide or a functional fragment or a functional variant thereof covalently linked to the N-terminus of the second polypeptide, wherein the multifunctional polypeptide molecule comprises a single TCRpV-binding moiety.

[0034] In some embodiments, the multifunctional polypeptide 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 first TCRpV-binding moiety; (ii) the second polypeptide comprising the second portion of the dimerization module linked to the C-terminus of the first portion of the second TCRpV-binding moiety; (iii) the third polypeptide comprising the second portion of the first TCRpV-binding moiety; (iv) the fourth polypeptide comprising the second portion of the second TCRpV-binding moiety; (v) a cytokine polypeptide or a functional fragment or a functional variant thereof covalently linked to the C-terminus of the third polypeptide, and (vi) a cytokine polypeptide or a functional fragment or a functional variant thereof covalently linked to the C-terminus of the fourth polypeptide.

[0035] In some embodiments, the multifunctional polypeptide 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 first TCRpV-binding moiety; (ii) the second polypeptide comprising the second portion of the dimerization module linked to the C-terminus of the first portion of the second TCRpV-binding moiety; (iii) the third polypeptide comprising the second portion of the first TCRpV-binding moiety; (iv) the fourth polypeptide comprising the second portion of the second TCRpV-binding moiety; and (v) a cytokine polypeptide or a functional fragment or a functional variant thereof covalently linked to the C-terminus of the third polypeptide or the C-terminus of the fourth polypeptide, but not to both.

[0036] In some embodiments, the multifunctional polypeptide 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 first TCRpV-binding moiety; (ii) the second polypeptide comprising the second portion of the dimerization module linked to the C-terminus of the first portion of the second TCRpV-binding 23 12 25 moiety; (iii) the third polypeptide comprising the second portion of the first TCR[3V-binding moiety; (iv) the fourth polypeptide comprising the second portion of the second TCRpV-binding moiety; and (v) a cytokine polypeptide or a functional fragment or a functional variant thereof covalently linked to the C-terminus of the first polypeptide or the C-terminus of the second polypeptide, but not to both.

[0037] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises any one selected from the group consisting of a Fab, a F(ab')2, an Fv, a single chain Fv (scFv), a single domain antibody, a diabody (dAb), a camelid antibody, and a combination thereof.

[0038] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises the Fab or the scFv.

[0039] In some embodiments, the TCRpV-binding moiety is the sole antigen-binding moiety of the multifunctional polypeptide molecule.

[0040] In some embodiments, the multifunctional polypeptide molecule comprises two or more of the at least one cytokine polypeptides.

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

[0042] In some embodiments, the at least one cytokine polypeptide comprises a sequence having at least 75%sequence identity to the sequence ofSEQ ID NO: 2191.

[0043] In some embodiments, the variant is an IL-2 variant comprising a substitution mutation.

[0044] In some embodiments, the variant is an IL-2 variant comprising C125A mutation.

[0045] In some embodiments, the variant comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 2270.

[0046] In some embodiments, the first portion of the dimerization module comprises a first immunoglobulin constant regions (Fc regions) and the second portion of the dimerization module comprises a second Fc region.

[0047] In some embodiments, the first Fc region, the second Fc region, or a combination thereof is selected from the group consisting of an IgGl Fc region or a fragment thereof, an IgG2 Fc region or a fragment thereof, an IgG3 Fc region or a fragment thereof, an IgGAl Fc region or a fragment thereof, an IgGA2 Fc region or a fragment thereof, an IgG4 Fc region or a fragment thereof, an IgJ Fc region or a fragment thereof, an IgM Fc region or a fragment thereof, an IgD Fc region or a fragment thereof, and an IgE Fc region or a fragment thereof.

[0048] In some embodiments, the first Fc region, the second Fc region, or a combination thereof is selected from the group consisting of a human IgGl 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.

[0049] 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 23 12 25 as indicated by a greater ratio of heteromultimer :homomultimer forms relative to a dimerization of Fc regions with a non-engineered interface.

[0050] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises an amino acid substitution listed in Table 14.

[0051] 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.

[0052] 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, or SEQ ID NO: 3649.

[0053] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof binds to one or more of a TCRpV subfamily selected from the group consisting of: (i) TCRP V2 subfamily comprising TCRP V2*01; (ii) TCRP V3 subfamily comprising TCRP V3-l*01; (iii) TCRP V4 subfamily comprising one or more selected from TCRP V4-1, TCRP V4-2, and TCRP V4-3; (iv) TCRP V5 subfamily comprising one or more selected from TCRP V5-6*01, TCRP V5-4*01, TCRP V5-l*01, and TCRP V5-8*01; (v) the TCRP V6 subfamily comprising one or more selected from TCRP V6-4*01, TCRP V6-4*02, TCRP V6-9*01, TCRP V6-8*01, TCRP V6-5*01, TCRP V6-6*02, TCRP V6-6*01, TCRP V6-2*01, TCRP V6-3*01, and TCRP V6-l*01; (vi) TCRP V9 subfamily; (vii) TCRP V10 subfamily comprising one or more selected from TCRP V10-l*01, TCRP VI0-1 *02, TCRP V10-3*01, and TCRP V10-2*01; (viii) TCRP VI1 subfamily comprising TCRP VI1-2; (ix) TCRP V12 subfamily comprising one or more selected from TCRP V12-4*01, TCRP V12-3*01, and TCRP V12-5*01; (x) TCRP V13 subfamily comprising TCRP V13*01; (xi) TCRP V16 subfamily comprising TCRP V16*01; (xii) TCRP V19 subfamily comprising one or more selected from TCRP VI9*01 and TCRP VI9*02; (xiii) TCRP V21 subfamily; (xiv) TCRP V23 subfamily; (xv) TCRP V27 subfamily; and (xvi) TCRP V28 subfamily.

[0054] In some embodiments, the multifunctional polypeptide molecule comprises the first TCRpV-binding moiety and the second TCRpV-binding moiety, and the first TCRpV-binding moiety and the second TCRpV-binding moiety are same.

[0055] In some embodiments, the multifunctional polypeptide molecule comprises the first TCRpV-binding moiety and the second TCRpV-binding moiety, and the first TCRpV-binding moiety and the second TCRpV-binding moiety are different.

[0056] In some embodiments, the first TCRpV-binding moiety and the second TCRpV-binding moiety binds: (i) one or more of a TCRP V6 subfamily member and one or more of a TCRP V10 subfamily member, respectively; (ii) one or more of a TCRP V6 subfamily member and one or more of a TCRP V5 subfamily member, respectively; (iii) one or more of a TCRP V6 subfamily member and one or more of a TCRP V12 subfamily member, respectively; (iv) one or more of a TCRP V10 subfamily member and one or more of a TCRP V5 subfamily member, respectively; (v) one or more of a TCRP V10 subfamily 23 12 25 member and one or more of a TCR[3 V12 subfamily member, respectively; or (vi) one or more of a TCRP V5 subfamily member and one or more of a TCRP V12 subfamily member, respectively.

[0057] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-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% 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% sequence identity to any one of the CDR1, CDR2, and CDR3 the sequences listed in Table 1; or (iii) a combination thereof.

[0058] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-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% sequence identity to a non-murine germline FR1, a non-murine germline FR2, a nonmurine 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% sequence identity to 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.

[0059] 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; or (iii) a combination thereof.

[0060] In some embodiments, the VL comprises the FR1 comprising a Phenyalanine at position 10 according to Kabat numbering.

[0061] 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.

[0062] In some embodiments, the VL comprises the FR3 comprising a Phenyalanine at position 87 according to Kabat numbering.

[0063] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-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% 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% sequence identity to any one of the CDR1, CDR2, and CDR3 sequences listed in Table 2; or (iii) a combination thereof.

[0064] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-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% sequence identity to 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% 23 12 25 sequence identity to a FR1, a FR2, a FR3, and a FR4 of a humanized B-H LC of Table 2; or (iii) a combination thereof.

[0065] In some embodiments, the first TCR[3V-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises: (i) a VH comprising a sequence having at least 75% 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 75% sequence identity to the VL sequence of a humanized Antibody B-H listed in Table 2; or (iii) a combination thereof.

[0066] In some embodiments, the first polypeptide, the second polypeptide, or a combination thereof comprises a heavy chain constant region having a sequence having at least 75% sequence identity to any one of the sequences listed in Table 3 or a combination thereof.

[0067] In some embodiments, the first polypeptide, the second polypeptide, or a combination thereof comprises a heavy chain constant region of an IgM or a fragment thereof.

[0068] In some embodiments, the heavy chain constant region of the IgM comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 73.

[0069] In some embodiments, the first polypeptide, the second polypeptide, or a combination thereof comprises a heavy chain constant region of an IgJ or a fragment thereof.

[0070] In some embodiments, the heavy chain constant region of the IgJ comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 76.

[0071] In some embodiments, the first polypeptide, the second polypeptide, a combination thereof comprises a heavy chain constant region of an IgGAl or a fragment thereof.

[0072] In some embodiments, the heavy chain constant region of the IgGAl comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 74.

[0073] In some embodiments, the first polypeptide, the second polypeptide, or a combination thereof comprises a heavy chain constant region of an IgGA2 or a fragment thereof.

[0074] In some embodiments, the heavy chain constant region of the IgGA2 comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 75.

[0075] In some embodiments, the first polypeptide, the second polypeptide, or a combination thereof comprises a heavy chain constant region of an IgGl or a fragment thereof.

[0076] In some embodiments, the heavy chain constant region of the IgGl comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 41 or SEQ ID NO: 3645.

[0077] 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% sequence identity to any one of the sequences listed in Table 3 or a combination thereof.

[0078] 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. 23 12 25

[0079] In some embodiments, the light chain constant region of a kappa chain comprises a light chain constant region sequence listed in Table 3.

[0080] In some embodiments, the light chain constant region of the kappa chain comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 39 or SEQ ID NO: 3644.

[0081] In some embodiments, the first TCR[3V-binding moiety, the second TCRpV-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% 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% 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.

[0082] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-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.

[0083] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-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.

[0084] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof binds to an outward facing region on a TCRpV protein.

[0085] In some embodiments, the outward facing region on the TCRpV protein comprises a structurally conserved region of TCRpV having a similar structure across one or more TCRpV subfamilies.

[0086] In some embodiments, the first polypeptide, the second polypeptide, or a combination thereof comprises (i) a first sequence selected from the group consisting of SEQ ID NOS: 80, 83, 86, 89, 92, 95, 98, 101, 104, 107, 110, 110, 113, 116, 119, 122, 125, 128, 131, 134, 137, 140, 143, 146, 149, 153, 156, 159, 162, 165, 168, 171, 174, 177, 180, 183, 186, 189, 192, 195, 198, 201, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 1309, 1326, 1327, 1328, 1329, 1330, 1331, 1332, 1333, 1334, 1335, 1336, 1337, 1338, 1339, 1340, 1341, 1342, 3281, and 3642; and (ii) a second sequence selected from the group consisting of SEQ ID NOS: 40, 41, 42, 73, 74, 75, 76, 3645, 3646, 3647, 3648, and 3649; wherein the first sequence is linked to the second sequence.

[0087] In some embodiments, the first polypeptide, the second polypeptide, or a combination thereof further comprises a third sequence selected from the group consisting of SEQ ID NO: 2191 and SEQ ID NO: 2270, wherein the third sequence is linked to the first sequence, the second sequence, or a combination thereof.

[0088] In some embodiments, the third sequence is linked to the N-terminus of the first sequence.

[0089] In some embodiments, the third sequence is linked to the C-terminus of the second sequence. 23 12 25

[0090] In some embodiments, the first polypeptide, the second polypeptide, or a combination thereof comprises (i) a first sequence selected from the group consisting of SEQ ID NOS: 1, 9, 15, 23, 25, 82, 85, 88, 91, 94, 97, 100, 103, 106, 109, 112, 115, 118, 121, 124, 127, 130, 133, 136, 139, 142, 145, 148, 151, 155, 158, 161, 164, 167, 170, 173, 176, 179, 182, 185, 188, 191, 194, 197, 200, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 1100, 1310, 1311, 1312, 1344, 1346, 1348, 1350, 1356, 1360, 1362, 1370, and 3438; and (ii) a second sequence selected from the group consisting of SEQ ID NOS: 40, 41, 42, 73, 74, 75, 76, 3645, 3646, 3647, 3648, and 3649; wherein the first sequence is linked to the second sequence.

[0091] In some embodiments, the first polypeptide, the second polypeptide, or a combination thereof further comprises a third sequence selected from the group consisting of SEQ ID NO: 2191 and SEQ ID NO: 2270, wherein the third sequence is linked to the first sequence, the second sequence, or a combination thereof.

[0092] In some embodiments, the third sequence is linked to the N-terminus of the first sequence.

[0093] In some embodiments, the third sequence is linked to the C-terminus of the second sequence.

[0094] In some embodiments, the third polypeptide, the fourth polypeptide, or a combination thereof comprises (i) a fourth sequence selected from the group consisting of SEQ ID NOS: 2, 10, 11, 16, 26, 27, 28, 29, 30, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 111, 114, 117, 120, 123, 126, 129, 132, 135, 138, 141, 144, 147, 150, 154, 157, 160, 163, 166, 169, 172, 175, 178, 181, 184, 187, 190, 193, 196, 199, 202, 1101, 1313, 1314, 1347, 1349, 1351, 1353, 1357, 1361, 1365, 1367, 1369, and 3279; and (ii)afifth sequence selected from the group consisting of SEQ ID NOS: 39 and 3644, wherein the fourth sequence is linked to the fifth sequence.

[0095] In some embodiments, the third polypeptide, the fourth polypeptide, or a combination thereof further comprises the third sequence, wherein the third sequence is linked to the fourth sequence, the fifth sequence, or a combination thereof.

[0096] In some embodiments, the third sequence is linked to the N-terminus of the fourth sequence.

[0097] In some embodiments, the third sequence is linked to the C-terminus of the fifth sequence.

[0098] In some embodiments, the first polypeptide, the second polypeptide, or a combination thereof comprises: a first sequence of SEQ ID NO: 1 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 1 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 1 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 1 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 1 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 1 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 1 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 9 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 9 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 9 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 9 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 9 linked to a second sequence of SEQ ID NO: 3646; a first sequence of 23 12 25 SEQ ID NO: 9 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 9 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 25 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 25 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 25 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 25 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 25 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 25 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 25 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 82 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 82 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 82 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 82 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 82 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 82 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 82 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 91 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 91 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 91 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 91 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 91 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 91 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 91 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 103 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 103 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 103 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 103 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 103 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 103 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 103 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 118 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 118 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 118 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 118 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 118 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 118 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 118 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 130 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 130 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 130 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 130 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 130 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 130 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 130 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 142 linked to a second sequence of SEQ 23 12 25 ID NO: 40; a first sequence of SEQ ID NO: 142 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 142 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 142 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 142 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 142 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 142 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 151 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 151 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 151 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 151 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 151 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 151 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 151 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 167 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 167 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 167 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 167 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 167 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 167 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 167 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 182 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 182 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 182 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 182 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 182 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 182 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 182 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 197 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 197 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 197 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 197 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 197 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 197 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 197 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 203 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 203 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 203 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 203 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 203 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 203 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 203 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 209 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 209 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 209 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID 23 12 25 NO: 209 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 209 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 209 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 209 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 215 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 215 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 215 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 215 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 215 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 215 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 215 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 221 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 221 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 221 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 221 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 221 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 221 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 221 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 1100 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 1100 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 1100 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 1100 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 1100 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 1100 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 1100 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 1310 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 1310 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 1310 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 1310 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 1310 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 1310 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 1310 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 1346 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 1346 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 1346 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 1346 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 1346 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 1346 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 1346 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 1350 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 1350 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 1350 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 1350 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 1350 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 1350 linked to a 23 12 25 second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 1350 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 1360 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 1360 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 1360 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 1360 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 1360 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 1360 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 1360 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 1370 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 1370 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 1370 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 1370 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 1370 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 1370 linked to a second sequence of SEQ ID NO: 3648; or a first sequence of SEQ ID NO: 1370 linked to a second sequence of SEQ ID NO: 3649.

[0099] In some embodiments, the first polypeptide, the second polypeptide, or a combination thereof further comprises a third sequence selected from the group consisting of SEQ ID NO: 2191 and SEQ ID NO: 2270, wherein the third sequence is linked to the first sequence, the second sequence, or a combination thereof.

[00100] In some embodiments, the third sequence is linked to the N-terminus of the first sequence.

[00101] In some embodiments, the third sequence is linked to the C-terminus of the second sequence.

[00102] In some embodiments, the third polypeptide, the fourth polypeptide, or a combination thereof comprises: a fourth sequence of SEQ ID NO: 2 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 2 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 10 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 10 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 16 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 16 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 28 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 28 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 87 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 87 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 90 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 90 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 96 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 96 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 105 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 105 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 117 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 117 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 120 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 120 23 12 25 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 129 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 129 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 132 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 132 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 141 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 141 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 150 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 150 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 154 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 154 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 163 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 163 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 169 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 169 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 175 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 175 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 181 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 181 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 187 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 187 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 193 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 193 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 202 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 202 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 1101 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 1101 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 1349 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 1349 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 1313 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 1313 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 1361 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 1361 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 1367 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 1367 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 1367 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 1367 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 3279 linked to a fifth sequence of SEQ ID NO: 3644; or a fourth sequence of SEQ ID NO: 3279 linked to a fifth sequence of SEQ ID NO: 39.

[00103] In some embodiments, the third polypeptide, the fourth polypeptide, or a combination thereof further comprises the third sequence, wherein the third sequence is linked to the fourth sequence, the fifth sequence, or a combination thereof.

[00104] In some embodiments, the third sequence is linked to the N-terminus of the fourth sequence. 23 12 25

[00105] In some embodiments, the third sequence is linked to the C-terminus of the fifth sequence.

[00106] In some embodiments, the first polypeptide comprises: a first sequence of SEQ ID NO: 1 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 1 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 1 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 1 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 1 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 1 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 1 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 9 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 9 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 9 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 9 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 9 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 9 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 9 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 25 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 25 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 25 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 25 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 25 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 25 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 25 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 82 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 82 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 82 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 82 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 82 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 82 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 82 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 91 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 91 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 91 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 91 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 91 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 91 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 91 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 103 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 103 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 103 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 103 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 103 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 103 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 103 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 118 linked to a second sequence of SEQ ID NO: 40; a first 23 12 25 sequence of SEQ ID NO: 118 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 118 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 118 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 118 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 118 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 118 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 130 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 130 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 130 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 130 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 130 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 130 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 130 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 142 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 142 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 142 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 142 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 142 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 142 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 142 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 151 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 151 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 151 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 151 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 151 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 151 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 151 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 167 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 167 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 167 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 167 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 167 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 167 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 167 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 182 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 182 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 182 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 182 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 182 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 182 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 182 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 197 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 197 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 197 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 197 linked to a 23 12 25 second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 197 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 197 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 197 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 203 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 203 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 203 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 203 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 203 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 203 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 203 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 209 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 209 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 209 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 209 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 209 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 209 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 209 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 215 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 215 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 215 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 215 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 215 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 215 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 215 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 221 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 221 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 221 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 221 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 221 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 221 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 221 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 1100 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 1100 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 1100 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 1100 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 1100 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 1100 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 1100 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 1310 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 1310 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 1310 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 1310 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 1310 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 1310 linked to a second sequence 23 12 25 of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 1310 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 1346 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 1346 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 1346 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 1346 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 1346 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 1346 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 1346 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 1350 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 1350 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 1350 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 1350 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 1350 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 1350 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 1350 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 1360 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 1360 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 1360 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 1360 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 1360 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 1360 linked to a second sequence of SEQ ID NO: 3648; a first sequence of SEQ ID NO: 1360 linked to a second sequence of SEQ ID NO: 3649; a first sequence of SEQ ID NO: 1370 linked to a second sequence of SEQ ID NO: 40; a first sequence of SEQ ID NO: 1370 linked to a second sequence of SEQ ID NO: 42; a first sequence of SEQ ID NO: 1370 linked to a second sequence of SEQ ID NO: 74; a first sequence of SEQ ID NO: 1370 linked to a second sequence of SEQ ID NO: 3645; a first sequence of SEQ ID NO: 1370 linked to a second sequence of SEQ ID NO: 3646; a first sequence of SEQ ID NO: 1370 linked to a second sequence of SEQ ID NO: 3648; or a first sequence of SEQ ID NO: 1370 linked to a second sequence of SEQ ID NO: 3649.

[00107] In some embodiments, the second polypeptide comprises: the sequence of SEQ ID NO: 2191 linked to the sequence of SEQ ID NO: 40; the sequence of SEQ ID NO: 2191 linked to the sequence of SEQ ID NO: 42; the sequence of SEQ ID NO: 2191 linked to the sequence of SEQ ID NO: 74; the sequence of SEQ ID NO: 2191 linked to the sequence of SEQ ID NO: 3645; the sequence of SEQ ID NO: 2191 linked to the sequence of SEQ ID NO: 3646; the sequence of SEQ ID NO: 2191 linked to the sequence of SEQ ID NO: 3648; the sequence of SEQ ID NO: 2191 linked to the sequence of SEQ ID NO: 3649; the sequence of SEQ ID NO: 2270 linked to the sequence of SEQ ID NO: 40; the sequence of SEQ ID NO: 2270 linked to the sequence of SEQ ID NO: 42; the sequence of SEQ ID NO: 2270 linked to the sequence of SEQ ID NO: 74; the sequence of SEQ ID NO: 2270 linked to the sequence of SEQ ID NO: 3645; the sequence of SEQ ID NO: 2270 linked to the sequence of SEQ ID NO: 3646; the sequence of 23 12 25 SEQ ID NO: 2270 linked to the sequence of SEQ ID NO: 3648; or the sequence of SEQ ID NO: 2270 linked to the sequence of SEQ ID NO: 3649.

[00108] In some embodiments, the third polypeptide comprises: a fourth sequence of SEQ ID NO: 2 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 2 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 10 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 10 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 16 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 16 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 28 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 28 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 87 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 87 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 90 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 90 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 96 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 96 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 105 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 105 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 117 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 117 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 120 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 120 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 129 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 129 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 132 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 132 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 141 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 141 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 150 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 150 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 154 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 154 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 163 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 163 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 169 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 169 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 175 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 175 linked to a fifth sequence ofSEQIDNO: 39; a fourth sequence of SEQ ID NO: 181 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 181 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 187 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 187 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 193 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 193 23 12 25 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 202 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 202 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 1101 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 1101 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 1349 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 1349 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 1313 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 1313 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 1361 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 1361 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 1367 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 1367 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 1367 linked to a fifth sequence of SEQ ID NO: 3644; a fourth sequence of SEQ ID NO: 1367 linked to a fifth sequence of SEQ ID NO: 39; a fourth sequence of SEQ ID NO: 3279 linked to a fifth sequence of SEQ ID NO: 3644; or a fourth sequence of SEQ ID NO: 3279 linked to a fifth sequence of SEQ ID NO: 39.

[00109] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising an anti-TCRv[3 antibody heavy chain variable region, and an immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising an IL-15 receptor alpha sushi domain or a functional fragment or a functional variant thereof, an IL-15 molecule or a functional fragment or a functional variant thereof, and an immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising an anti-TCRv[3 antibody light chain variable region, and an immunoglobulin light chain constant region.

[00110] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, an anti-TCRv[3 antibody heavy chain variable region operatively linked to an immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, an IL-15 receptor alpha sushi domain or a functional fragment or a functional variant thereof operatively linked to an IL-15 molecule or a functional fragment or a functional variant thereof operatively linked to an immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, an anti-TCRv[3 antibody light chain variable region operatively linked to an immunoglobulin light chain constant region.

[00111] In some embodiments, the IL-15 receptor alpha sushi domain is operatively linked to the IL-15 molecule or a functional fragment or a functional variant thereof via a linker, the IL-15 molecule or a functional fragment or a functional variant thereof is operatively linked to the immunoglobulin heavy chain constant region via a linker, or a combination thereof.

[00112] In some embodiments, the multifunctional polypeptide 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: 3523, the sequence of SEQ ID NO: 2170, and the 23 12 25 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.

[00113] In some embodiments, the multifunctional polypeptide 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: 3523 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: 1349 operatively linked to the sequence of SEQ ID NO: 3644.

[00114] In some embodiments, the sequence of SEQ ID NO: 3523 is operatively linked to the sequence of SEQ ID NO: 2170 via the sequence of SEQ ID NO: 3524, the sequence of SEQ ID NO: 2170 is operatively linked to the sequence of SEQ ID NO: 3648 via the sequence of SEQ ID NO: 3308, or a combination thereof.

[00115] In some embodiments, the bispecific polypeptide molecule comprises: (i) a first polypeptide comprising, from N-terminus to C-terminus, a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 1346 operatively linked to a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 3649; (ii) a second polypeptide comprising, from N-terminus to C-terminus, the sequence of SEQ ID NO: 3523 operatively linked to a sequence having the sequence of SEQ ID NO: 2170, optionally, via a Gly-Ser linker comprising the sequence of SEQ ID NO: 3524, wherein the sequence of SEQ ID NO: 2170 is operatively linked to a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 3648, optionally, via the sequence of SEQ ID NO: 3308; and (iii) a third polypeptide comprising, from N-terminus to C-terminus, a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 1349 operatively linked to a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 3644; optionally, wherein: (i) the first polypeptide comprises, from N-terminus to C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649; (ii) the second polypeptide comprises, from N-terminus to C-terminus, the sequence of SEQ ID NO: 3523 operatively linked to the sequence of SEQ ID NO: 2170, optionally, via a Gly-Ser linker comprising the sequence of SEQ ID NO: 3524, wherein the sequence of SEQ ID NO: 2170 is operatively linked to the sequence of SEQ ID NO: 3648, optionally, via the sequence of SEQ ID NO: 3308; and (iii) the third polypeptide comprises, from N-terminus to C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644; and wherein: 23 12 25 (i) the VH comprises a HC CDR1 comprising the sequence of SEQ ID NO: 3650, a HC CDR2 comprising the sequence of SEQ ID NO: 3651, and a HC CDR3 comprising the sequence of SEQ ID NO: 5; and (ii) a VL comprising a LC CDR1 comprising the sequence of SEQ ID NO: 3655, a LC CDR2 comprising the sequence of SEQ ID NO: 3653, and a LC CDR3 comprising the sequence of SEQ ID NO: 8.

[00116] In some embodiments, the multifunctional polypeptide 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: 3519; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3518.

[00117] In some embodiments, the bispecific polypeptide molecule comprises: (i) a first polypeptide comprising a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 3517; (ii) a second polypeptide comprising a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 3519; and (iii) a third polypeptide comprising a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 3518.

[00118] In some embodiments, the multifunctional polypeptide 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: 3519; and (iii) a third polypeptide comprising to the sequence of SEQ ID NO: 3518.

[00119] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising an anti-TCRv[3 antibody heavy chain variable region, and an immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising an IL-15 molecule or a functional fragment or a functional variant thereof, and an immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising an anti-TCRv[3 antibody light chain variable region, and an immunoglobulin light chain constant region.

[00120] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, an anti-TCRv[3 antibody heavy chain variable region operatively linked to an immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, an IL-15 molecule or a functional fragment or a functional variant thereof operatively linked to an immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, an anti-TCRv[3 antibody light chain variable region operatively linked to an immunoglobulin light chain constant region.

[00121] In some embodiments, the IL-15 molecule or a functional fragment or a functional variant thereof is operatively linked to the immunoglobulin heavy chain constant region via a linker.

[00122] In some embodiments, the multifunctional polypeptide 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: 2170, and the sequence of SEQ ID NO: 3648; and 23 12 25 (iii) a third polypeptide comprising the sequence of SEQ ID NO: 1349, and the sequence of SEQ ID NO: 3644.

[00123] In some embodiments, the multifunctional polypeptide 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: 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.

[00124] In some embodiments, the sequence of SEQ ID NO: 2170 is operatively linked to the sequence of SEQ ID NO: 3648 via the sequence of SEQ ID NO: 3308, or a combination thereof.

[00125] In some embodiments, the multifunctional polypeptide 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: 3520; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3518.

[00126] In some embodiments, the multifunctional polypeptide 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: 3520; and (iii) a third polypeptide comprising to the sequence of SEQ ID NO: 3518.

[00127] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising an anti-TCRv[3 antibody heavy chain variable region, and an immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising an IL-2 molecule or a functional fragment or a functional variant thereof or an IL-2 Cl25A mutant molecule or a functional fragment or a functional variant thereof, and an immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising an anti-TCRv[3 antibody light chain variable region, and an immunoglobulin light chain constant region.

[00128] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, an anti-TCRv[3 antibody heavy chain variable region operatively linked to an immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, an IL-2 molecule or a functional fragment or a functional variant thereof or an IL-2 Cl25A mutant molecule or a functional fragment or a functional variant thereof operatively linked to an immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, an anti-TCRv[3 antibody light chain variable region operatively linked to an immunoglobulin light chain constant region.

[00129] In some embodiments, the IL-2 molecule or a functional fragment or a functional variant thereof or the IL-2 Cl 25 A mutant molecule or a functional fragment or a functional variant thereof is operatively linked to the immunoglobulin heavy chain constant region via a linker. 23 12 25

[00130] In some embodiments, the multifunctional polypeptide 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: 2270, 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.

[00131] In some embodiments, the multifunctional polypeptide 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: 2270 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.

[00132] In some embodiments, the sequence of SEQ ID NO: 2270 is operatively linked to the sequence of SEQ ID NO: 3648 via the sequence of SEQ ID NO: 3308, or a combination thereof.

[00133] In some embodiments, the multifunctional polypeptide 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: 3521; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3518.

[00134] In some embodiments, the multifunctional polypeptide 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: 3521; and (iii) a third polypeptide comprising to the sequence of SEQ ID NO: 3518.

[00135] In some embodiments, the multifunctional polypeptide molecule comprises the second polypeptide comprising an immunoglobulin heavy chain constant region comprising L234A, L235A, and P329G mutations, the third polypeptide comprising an immunoglobulin light chain constant region comprising L234A, L235A, and P329G mutations, or a combination thereof.

[00136] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3530, and the sequence of SEQ ID NO: 3531; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 2191, and the sequence of SEQ ID NO: 3533; and (iii) a third polypeptide comprising the sequence of SEQ ID NO: 3527, and the sequence of SEQ ID NO: 3528.

[00137] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3530 operatively linked to the sequence of SEQ ID NO: 3531; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 2191 operatively linked to the sequence of SEQ ID NO: 3533; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3527 operatively linked to the sequence of SEQ ID NO: 3528. 23 12 25

[00138] In some embodiments, the sequence of SEQ ID NO: 2191 is operatively linked to the sequence of SEQ ID NO: 3533 via the sequence of SEQ ID NO: 3308, or a combination thereof.

[00139] In some embodiments, the first polypeptide further comprises the sequence of SEQ ID NO: 3547 operatively linked to the sequence of SEQ ID NO: 3531, the second polypeptide further comprises the sequence of SEQ ID NO: 3534 operatively linked to the sequence of SEQ ID NO: 3533, or a combination thereof.

[00140] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3529 or the sequence of SEQ ID NO: 3548; (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3532 or the sequence of SEQ ID NO: 3549; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3526.

[00141] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3529 or the sequence of SEQ ID NO: 3548; (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3532 or the sequence of SEQ ID NO: 3549; and (iii) a third polypeptide comprising to the sequence of SEQ ID NO: 3526.

[00142] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising an anti-TCRv[3 antibody heavy chain variable region, and an immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising an IL-7 molecule or a functional fragment or a functional variant thereof, and an immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising an anti-TCRv[3 antibody light chain variable region, and an immunoglobulin light chain constant region.

[00143] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, an anti-TCRv[3 antibody heavy chain variable region operatively linked to an immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, an IL-7 molecule or a functional fragment or a functional variant thereof operatively linked to an immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, an anti-TCRv[3 antibody light chain variable region operatively linked to an immunoglobulin light chain constant region.

[00144] In some embodiments, the IL-7 molecule or a functional fragment or a functional variant thereof is operatively linked to the immunoglobulin heavy chain constant region via a linker.

[00145] In some embodiments, the multifunctional polypeptide 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: 3540, 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. 23 12 25

[00146] In some embodiments, the multifunctional polypeptide 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: 3540 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.

[00147] In some embodiments, the sequence of SEQ ID NO: 3540 is operatively linked to the sequence of SEQ ID NO: 3648 via the sequence of SEQ ID NO: 3308, or a combination thereof.

[00148] In some embodiments, the multifunctional polypeptide 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: 3539; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3518.

[00149] In some embodiments, the multifunctional polypeptide 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: 3539; and (iii) a third polypeptide comprising to the sequence of SEQ ID NO: 3518.

[00150] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising an anti-TCRv[3 antibody heavy chain variable region, and an immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising an IL-12 molecule or a functional fragment or a functional variant thereof, and an immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising an anti-TCRv[3 antibody light chain variable region, and an immunoglobulin light chain constant region.

[00151] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, an anti-TCRv[3 antibody heavy chain variable region operatively linked to an immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, an IL-12 molecule or a functional fragment or a functional variant thereof operatively linked to an immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, an anti-TCRv[3 antibody light chain variable region operatively linked to an immunoglobulin light chain constant region.

[00152] In some embodiments, the IL-12 molecule or a functional fragment or a functional variant thereof comprises an IL-12 beta subunit or a functional fragment or a functional variant thereof and a IL-12 alpha subunit or a functional fragment or a functional variant thereof.

[00153] In some embodiments, the IL-12 molecule or a functional fragment or a functional variant thereof comprises, from the N-terminus to the C-terminus, an IL-12 beta subunit or a functional fragment or a functional variant thereof operatively linked to a IL-12 alpha subunit or a functional fragment or a functional variant thereof. 23 12 25

[00154] In some embodiments, the IL-12 beta subunit or a functional fragment or a functional variant thereof is operatively linked to the IL-12 alpha subunit or a functional fragment or a functional variant thereof via a linker, the IL-12 alpha subunit or a functional fragment or a functional variant thereof is operatively linked to the immunoglobulin heavy chain constant region via a linker, or a combination thereof.

[00155] In some embodiments, the multifunctional polypeptide 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: 3542, 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.

[00156] In some embodiments, the multifunctional polypeptide 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: 3542 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.

[00157] In some embodiments, the IL-12 molecule or a functional fragment or a functional variant thereof comprises the sequence of SEQ ID NO: 3543 and the sequence of SEQ ID NO: 3545.

[00158] In some embodiments, the IL-12 molecule or a functional fragment or a functional variant thereof comprises, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3543 operatively linked to the sequence of SEQ ID NO:3545.

[00159] In some embodiments, the sequence of SEQ ID NO: 3543 is operatively linked to the sequence of SEQ ID NO: 3545 via the sequence of SEQ ID NO: 3544, the sequence of SEQ ID NO: 3545 is operatively linked to the sequence of SEQ ID NO: 3648 via the sequence of SEQ ID NO: 3308, or a combination thereof.

[00160] In some embodiments, the multifunctional polypeptide 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: 3541; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3518.

[00161] In some embodiments, the multifunctional polypeptide 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: 3541;and (iii) a third polypeptide comprising to the sequence of SEQ ID NO: 3518.

[00162] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising an anti-TCRv[3 antibody heavy chain variable region, and an immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising an IL-21 molecule or a functional fragment or a functional variant thereof, and an immunoglobulin heavy chain constant region; and (iii) a third 23 12 25 polypeptide comprising an anti-TCRvP antibody light chain variable region, and an immunoglobulin light chain constant region.

[00163] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, an anti-TCRvP antibody heavy chain variable region operatively linked to an immunoglobulin heavy chain constant region; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, an IL-21 molecule or a functional fragment or a functional variant thereof operatively linked to an immunoglobulin heavy chain constant region; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, an anti-TCRvP antibody light chain variable region operatively linked to an immunoglobulin light chain constant region.

[00164] In some embodiments, the IL-21 molecule or a functional fragment or a functional variant thereof is operatively linked to the immunoglobulin heavy chain constant region via a linker, or a combination thereof.

[00165] In some embodiments, the multifunctional polypeptide 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: 2193, 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.

[00166] In some embodiments, the multifunctional polypeptide 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: 2193 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.

[00167] In some embodiments, the sequence of SEQ ID NO: 2193 is operatively linked to the sequence of SEQ ID NO: 3648 via the sequence of SEQ ID NO: 3308.

[00168] In some embodiments, the multifunctional polypeptide 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: 3546; and (iii) a third polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3518.

[00169] In some embodiments, the multifunctional polypeptide 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: 3546; and (iii) a third polypeptide comprising to the sequence of SEQ ID NO: 3518.

[00170] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising an anti-TCRv[3 antibody heavy chain variable region, and an immunoglobulin heavy chain constant region; and (ii) a second polypeptide comprising an anti-TCRv[3 antibody light chain variable 23 12 25 region, an immunoglobulin light chain constant region, and an IL-2 molecule or a functional fragment or a functional variant thereof.

[00171] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, an anti-TCRvP antibody heavy chain variable region operatively linked to an immunoglobulin heavy chain constant region; and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, an anti-TCRvP antibody light chain variable region operatively linked to an immunoglobulin light chain constant region operatively linked to an IL-2 molecule or a functional fragment or a functional variant thereof.

[00172] In some embodiments, the immunoglobulin light chain constant region is operatively linked to the IL-21 molecule or a functional fragment or a functional variant thereof via a linker.

[00173] In some embodiments, the multifunctional polypeptide molecule comprises two first polypeptides and two second polypeptides.

[00174] In some embodiments, the multifunctional polypeptide molecule comprises the first polypeptide comprising an immunoglobulin heavy chain constant region comprising L234A, L235A, and P329G mutations.

[00175] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3530 and the sequence of SEQ ID NO: 3537; and (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3527, the sequence of SEQ ID NO: 3528, and the sequence of SEQ ID NO: 2191.

[00176] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3530 operatively linked to the sequence of SEQ ID NO: 3537; and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, the sequence of SEQ ID NO: 3527 operatively linked to the sequence of SEQ ID NO: 3528 operatively linked to the sequence of SEQ ID NO: 2191.

[00177] In some embodiments, the sequence of SEQ ID NO: 3528 is operatively linked to the sequence of SEQ ID NO: 2191 via the sequence of SEQ ID NO: 3309.

[00178] In some embodiments, the multifunctional polypeptide molecule comprises two first polypeptides and two second polypeptides.

[00179] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3536; and (ii) a second polypeptide comprising a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3535.

[00180] In some embodiments, the multifunctional polypeptide molecule comprises: (i) a first polypeptide comprising the sequence of SEQ ID NO: 3536; and (ii) a second polypeptide comprising the sequence of SEQ ID NO: 3535.

[00181] Described herein is an antibody comprising an anti-T cell receptor beta variable chain (TCRpV) binding domain comprising: (i) a heavy chain variable region (VH) comprising a heavy chain 23 12 25 complementarity determining region 1 (HC CDR1), a heavy chain complementarity determining region 2 (HC CDR2), and a heavy chain complementarity determining region 3 (HC CDR3) comprising an amino acid sequence having at least 75% sequence identity to SEQ ID NO: 3650, SEQ ID NO: 3651, and SEQ ID NO: 5, respectively; (ii) a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1), a light chain complementarity determining region 2 (LC CDR2), and a light chain complementarity determining region 3 (LC CDR3) comprising an amino acid sequence having at least 75% sequence identity to SEQ ID NO: 3655, SEQ ID NO: 3653, and SEQ ID NO: 8, respectively; or (iii) a combination thereof.

[00182] In some embodiments, the TCR[3V binding domain comprising: (i) a VH comprising a HC CDR1, a HC CDR2, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 3650, SEQ ID NO: 3651, and SEQ ID NO: 5, respectively; (ii) a VL comprising a LC CDR1, a LC CDR2, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 3655, SEQ ID NO: 3653, and SEQ ID NO: 8, respectively; or (iii) a combination thereof.

[00183] In some embodiments, the TCRpV binding domain comprising: (i) a VH comprising an amino acid sequence having at least 75% sequence identity to SEQ ID NO: 1346; (ii) a VL comprising an amino acid sequence having at least 75% sequence identity to SEQ ID NO: 1349; or (iii) a combination thereof.

[00184] In some embodiments, the TCRpV binding domain comprising: (i) a VH comprising the amino acid sequence of SEQ ID NO: 1346; (ii) a VL comprising the amino acid sequence of SEQ ID NO: 1349; or (iii) a combination thereof.

[00185] Described herein is a nucleic acid molecule comprising a nucleotide sequence encoding the multifunctional polypeptide molecule as described herein or the antibody as described herein.

[00186] In some embodiments, the nucleic acid molecule is an isolated nucleic acid molecule.

[00187] Described herein is a vector comprising one or more of the nucleic acid molecules as described herein.

[00188] Described herein is a cell comprising the nucleic acid molecules as described herein, or the vector as described herein.

[00189] Described herein is a pharmaceutical composition comprising the multifunctional polypeptide molecule as described herein, the antibody as described herein, the nucleic acid molecules as described herein, the vector as described herein, or the cell as described herein, and a pharmaceutically acceptable carrier, excipient, or diluent.

[00190] Described herein is a multifunctional polypeptide molecule as described herein, an antibody as described herein, a nucleic acid molecules as described herein, a vector as described herein, a cell as described herein, a pharmaceutical composition as described herein, or a combination thereof, for use in a method of treating a condition or disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount, the multifunctional polypeptide molecule, the antibody, the nucleic acid molecules, the vector, the cell, the pharmaceutical composition, or a combination thereof wherein the administering is effective to treat the condition or disease in the subject. 23 12 25

[00191] In some embodiments, the condition or disease is cancer.

[00192] In some embodiments, the cancer is a solid tumor, a hematological cancer, a metastatic cancer, a soft tissue tumor, or a combination thereof.

[00193] In some embodiments, the cancer is the solid tumor, and 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.

[00194] In some embodiments, the cancer is the hematological cancer, and 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.

[00195] 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.

[00196] In some embodiments, the T-cell lymphoma is peripheral T-cell lymphoma.

[00197] In some embodiments, the cancer is characterized by a cancer antigen present on the cancer.

[00198] In some embodiments, the cancer antigen is a tumor antigen, a stromal antigen, or a hematological antigen.

[00199] In some embodiments, the cancer antigen is selected from the group consisting of BCMA, CD 19, CD20, CD22, FcRH5, PDL1, CD47, gangloside 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-Bl, 9D7, Ep-CAM, EphA3, Her2 / neu, Telomerase, SAP-1, Survivin, NY-ESO-l / LAGE-1, PRAME, SSX-2, Melan-A / MART-1, Gpl00 / pmell7, Tyrosinase, TRP-1 / -2, MC1R, P-catenin, BRCA1 / 2, CDK4, CML66, Fibronectin, p53, Ras, TGF-B receptor, AFP, ETA, MAGE, MUC-1, CA-125, BAGE, GAGE, NY-ESO-1, P-catenin, CDK4, CDC27, a actinin-4, TRPl / gp75, TRP2, gplOO, Melan-A / MARTl, gangliosides, WT1, EphA3, Epidermal growth factor receptor (EGFR), MART-2, MART-1, MUC1, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RUI1, RUI2, SAGE, TRG, TRP1, TSTA, Folate receptor alpha, LI-CAM, CAIX, gpA33, GD3, GM2, VEGFR, Intergrins, carbohydrates, IGF1R, EPHA3, TRAILRI, TRAILR2, RANKL, FAP, TGF-beta, hyaluronic acid, collagen, tenascin C, and tenascin W.

[00200] In some embodiments, the method further comprises administering a second therapeutic agent or therapy to the subject.

[00201] In some embodiments, the second therapeutic agent or therapy comprises a chemotherapeutic agent, a biologic agent, a hormonal therapy, radiation, or surgery.

[00202] In some embodiments, the second therapeutic agent or therapy is administered in combination with the multifunctional polypeptide molecule as described herein, the antibody as described herein, the 23 12 25 nucleic acid molecules as described herein, the vector as described herein, the cell as described herein, the pharmaceutical composition as described herein, sequentially, simultaneously, or concurrently. BRIEF DESCRIPTION OF THE DRAWINGS

[00203] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[00204] FIGS. 1A-1T depict exemplary embodiments of multifunctional molecules as described herein. FIGS. 1A, IB and IC depict exemplary embodiments of multifunctional molecules containing multiple, e.g., two, molecules of an exemplary cytokine, interleukin-2 (IL-2), linked to an antibody molecule that binds to a T cell receptor beta variable region (TCR[3V) (“anti-TCR[3V antibody molecule”). FIGS. ID, IE and IF depict exemplary embodiments of multifunctional molecules containing a single molecule of an exemplary cytokine, IL-2, linked to an anti-TCRpV antibody molecule. FIGS. 1G, 1H, II, and 1J depict exemplary embodiments of multifunctional molecules containing an exemplary cytokine, IL-2, linked to a first dimerization module. FIGS. IK, IL and IM 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 an exemplary cytokine, IL-2, linked to an anti-TCRpV antibody molecule. FIGS. IN, IO and IP depict exemplary embodiments of multifunctional molecules containing an exemplary dimerization module, e.g., an Fc region comprising aN297A mutation (Knob-in-hole), and a single molecule of an exemplary cytokine, IL-2, linked to an anti-TCRpV antibody molecule. FIGS. IQ, 1R, IS and IT depict exemplary embodiments of multifunctional molecules containing an exemplary dimerization module, e.g., an Fc region comprising aN297A mutation (Knob-in-hole), and an exemplary cytokine, IL-2, linked to the exemplary dimerization module.

[00205] FIGS. 2A-2B shows the alignment of the Antibody A source mouse VH and VL framework 1, CDR 1, framework 2, CDR 2, framework 3, CDR3, and framework 4 regions with their respective humanized sequences. Kabat CDRs are shown in bold, Chothia CDRs are shown in italics, and combined CDRs are shown in boxes. The framework positions that were back mutated are double underlined. FIG. 2A shows VH sequences for murine Antibody A (SEQ ID NO: 1) and humanized Antibody A-H (SEQ ID NO: 9). FIG. 2B shows VL sequences for murine Antibody A (SEQ ID NO: 2) and humanized Antibody A-H (SEQ ID NO: 10 and SEQ ID NO: 11).

[00206] FIGS. 3A-3B shows the alignment of the Antibody B source mouse VH and VL framework 1, CDR 1, framework 2, CDR 2, framework 3, CDR3, and framework 4 regions with their respective humanized sequences. Kabat CDRs are shown in bold, Chothia CDRs are shown in italics, and combined CDRs are shown in boxes. The framework positions that were back mutated are double underlined. FIG. 3A shows the VH sequence for murine Antibody B (SEQ ID NO: 15) and humanized VH sequences B-H. 1A to B-H. IC (SEQ ID NOs: 23-25). FIG. 3B shows the VL sequence for murine Antibody B (SEQ ID NO: 16) and humanized VL sequences B-H. ID to B-H.1H (SEQ ID NOs: 26-30). 23 12 25

[00207] FIG. 4 depicts the phylogenetic tree of TCRBV gene family and subfamilies with corresponding antibodies mapped. Subfamily identities are as follows: Subfamily A: TCRp V6; Subfamily B: TCRp V10; Subfamily C: TCRp V12; Subfamily D: TCRp V5; Subfamily E: TCRp V7; Subfamily F: TCRp Vil; Subfamily G: TCRp V14; Subfamily H: TCRp V16; Subfamily ETCRp V18; Subfamily J:TCRp V9; Subfamily K: TCRp V13; Subfamily L: TCRp V4; Subfamily M:TCRp V3; Subfamily N:TCRp V2; Subfamily O:TCRp V15; Subfamily P: TCRp V30; Subfamily Q: TCRp V19; Subfamily R:TCRp V27; Subfamily S:TCRp V28; Subfamily T: TCRp V24; Subfamily U: TCRp V20; Subfamily V: TCRp V25; and Subfamily W:TCRP V29 subfamily. Subfamily members are described in detail herein in the Section titled “TCR beta V (TCRpV)”.

[00208] FIGS. 5A-5C show human CD3+ T cells activated by anti-TCR Vpi3.1 antibody (A-H. 1) for 6-days. Human CD3+ T cells were isolated using magnetic-bead separation (negative selection) and activated with immobilized (plate-coated) anti-TCR VP 13.1 (A-H.l) or anti-CD3e (OKT3) antibodies at 100 nM for 6 days. FIG. 5A shows two scatter plots (left: activated with OKT3; and right: activated with A-H.l) of expanded T cells assessed for TCR VP 13.1 surface expression using anti-TCR VP 13.1 (A-H.l) followed by a secondary fluorochrome- conjugated antibody for flow cytometry analysis. FIG. 5B shows percentage (%) of TCR Vpi3.1 positive T cells activated by anti-TCR VP 13.1 (A-H.l) or anti-CD3e (OKT3) plotted against total T cells (CD3+). FIG. 5C shows relative cell count acquired by counting the number of events in each T cell subset gate (CD3 or TCR VP 13.1) for 20 seconds at a constant rate of 60pl / min. Data shown as mean value from 3 donors.

[00209] FIGS. 6A-6B show cytolytic activity ofhuman CD3+ T cells activated by anti-TCR VP 13.1 antibody (A-H.l) against transformed cell line RPMI 8226. FIG. 6A depicts target cell lysis ofhuman CD3+ T cells activated with A-H. lor OKT3. Human CD3+ T cells were isolated using magnetic-bead separation (negative selection) and activated with immobilized (plate-coated) A-H. 1 or OKT3 at the indicated concentrations for 4 days prior to co-culture with RPMI 8226 cells at a (E:T) ratio of 5:1 for 2 days. Samples were next analyzed for cell lysis of RPMI 8226 cells by FACS staining for CFSE / CD138-labeled, and membrane-impermeable DNA dyes (DRAQ7) using flow cytometry analysis. FIG. 6B shows target cell lysis ofhuman CD3+ T cells activated with A-H. 1 or OKT3 incubated with RPMI-8226 at a (E:T) ratio of 5:1 for 6 days followed by cell lysis analysis of RPMI 8226 cells as described above. Percentage (%) target cell lysis was determined by normalizing to basal target cell lysis (i.e. without antibody treatment) using the following formula, [(x - basal) / (100% - basal), where x is cell lysis of sample]. Data shown is a representative of n=l donor.

[00210] FIGS. 7A-7B show IFNy production by human PBMCs activated with the indicated antibodies. Human PBMCs were isolated from whole blood from the indicated number of donors, followed by solidphase (plate-coated) stimulation with the indicated antibodies at lOONm. Supernatant was collected on Days 1, 2, 3, 5, or 6. FIG. 7A is a graph comparing the production of IFNy in human PBMCs activated with the antibodies indicated activated with anti-TCR Vpi3.1 antibodies (A-H. 1 or A-H.2) or anti-CD3e antibodies (OKT3 or SP34-2) on Day 1, 2, 3, 5, or 6 post-activation. FIG. 7B shows IFNy production in 23 12 25 human PBMCs activated with the antibodies indicated activated with the indicated anti-TCR VP 13.1 antibodies or anti-CD3e antibody (0KT3) on Day 1, 2, 3, 5, or 6 post-activation.

[00211] FIGS. 8A-8B show IL-2 production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described for FIGS. 7A-7B was used.

[00212] FIGS. 9A- 9B show IL-6 production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described for FIGS. 7A-7B was used.

[00213] FIGS. 10A-10B show TNF-alpha production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described for FIGS. 7A-7B was used.

[00214] FIGS. 11 A- 11B show IL-lbeta production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described for FIGS. 7A-7B was used.

[00215] FIGS. 12A-12B are graphs showing delayed kinetics of IFNy secretion in human PMBCs activated by anti-TCR VP 13.1 antibody A-H. 1 when compared to PBMCs activated by anti-CD3e antibody OKT3. FIG. 12A shows IFNy secretion data from 4 donors. FIG. 12B shows IFNy secretion data from 4 additional donors. Data shown is representative of n=8 donors.

[00216] FIG. 13 depicts increased CD8+ TSCM and Temra T cell subsets in human PBMCs activated by anti-TCR VP 13.1 antibodies (A-H.l or A-H.2) compared to PBMCs activated by anti-CD3e antibodies (OKT3 or SP34-2).

[00217] FIGS. 14A-14F show characterization of an anti-TCRVb antibody. FIG. 14A is a graph depicting proliferation of T cells activated with anti-CD3 (OKT3) antibody or anti-TCRVb antibody. FIG. 14B shows selective expansion of CD45RA+ effector memory CD8+ and CD4+ T cells (TEMRA) cells with anti- TCRVb antibodies. Tn= naive T cell; Tscm= stem cell memory T cell; Tcm= central memory T cell; Tem=effector memory T cell; Temra=effector memory CD45RA+ T cell. FIG. 14C is a graph showing IFN-g secretion by PBMCs stimulated with an anti-TCRVb antibody, or anti-CD3 antibodies. FIG. 14D shows target cell lysis by T cells stimulated with an anti-TCRVb antibody, or anti-CD3 antibodies. Cells were stimulated for 4 days followed by 2 days incubation with multiple myeloma target cells for assessment of cell killing. FIG. 14E is a graph showing perforin secretion by T cells stimulated with an anti-TCRVb antibody, or an anti-CD3 antibody. Perforin was analyzed by FACS staining in TCRVB-positive and TCRVB-negative T cells in PBMCs after 5 days of stimulation with lOOng / ml plate-bound antibody. FIG. 14F is a graph showing Granzyme B by T cells stimulated with an anti-TCRVb antibody, or an anti-CD3 antibody. Granzyme B was analyzed by FACS staining in TCRVB-positive and TCRVB-negative T cells in PBMCs after 5 days of stimulation with lOOng / ml plate-bound antibody.

[00218] FIGS. 15A-15B show production of IL-2 and IL-15 and expansion of human NK cells by stimulation of PBMCs with anti-TCRVb antibody for 6 days at a dose of lOOnM. FIG. 15A shows secretion of IL-2 or IL-15 in T cells stimulated with an anti-TCRVb antibody, or anti-CD3 antibodies. FIG. 15B depicts flow cytometry dot plots showing NKp46 staining vs CD56 antibody staining in cells stimulated with an anti-TCRVb antibody or an anti-CD3 antibody or a control sample. 23 12 25

[00219] FIGS. 16A-16C show secretion of cytokines in PBMCs stimulated with an anti-TCRVb antibody, or anti-CD3 antibodies.

[00220] FIGS. 17A-17B show killing of MM cells by dual targeting BCMA-TCRvb antibody molecules. FIG. 17A shows in vitro killing by one of the following dual-targeting antibody molecules: BCMA-TCRVb (Molecule I), BCMA-CD3, or Control-TCRVb; or an isotype control. FIG. 17B shows in vivo killing of MM cells by a dual-targeting BCM-TCRVb antibody (Molecule I).

[00221] FIG. 18 shows lysis of MM target cells with a dual targeting antibody (Molecule E) which recognized FcRH5 on one arm and TCRVb on the other arm.

[00222] FIGS. 19A-19B demonstrate cytokine production from human PBMCs activated by anti-TCR V[38a antibodies (B-H.l) when compared to those activated by anti-CD3e antibodies (OKT3 or SP34-2). FIG. 19A shows that human PBMCs activated by anti-TCR Vp8a antibodies (B-H. 1) produce similar or reduced levels of IFNy. FIG. 19B shows human PBMCs activated by anti-TCR Vp8a antibodies (B-H.l) produce higher levels of IL-2 when compared to those activated by anti-CD3e antibodies (OKT3 or SP34-2). Data shown is representative of n = 6 donors.

[00223] FIGS. 20A-20C demonstrate cytokine production from human PBMCs activated by anti-TCR Vp8a antibodies (B-H.l). Human PBMCs activated by anti-TCR Vp8a antibodies (B-H.l) do not significantly produce IL-6 (FIG. 20A), IL 1 p (FIG. 20B), and less TNFa (FIG. 20C), when compared to PBMCs activated by anti-CD3e antibodies (OKT3 or SP34-2). Data shown is representative of n = 6 donors.

[00224] FIGS. 21A-21E demonstrate cytokine production from human PBMCs activated by anti-TCRpV Antibody D antibody compared to control anti-CD3e antibody (OKT3). FIG. 21A shows that human PBMCs activated by anti-TCRpV Antibody D antibody produce similar or reduced levels of IFNy. FIG. 21B shows human PBMCs activated by anti-TCRpV Antibody D antibody produce higher levels of IL-2 when compared to those activated by anti-CD3e antibodies (OKT3). Human PBMCs activated by anti-TCRpV Antibody D antibody do not significantly produce IL-lbeta (FIG. 21C), IL-6, (FIG. 21D), or TNFalpha (FIG. 21E). Data shown is representative of n = 4 donors.

[00225] FIGS. 22A-22B demonstrate cytokine production from human PBMCs activated by anti-TCR Vp5 antibody (Antibody E). FIG. 22A shows that human PBMCs activated by anti-TCR Vp5 antibody produce similar or reduced levels of IFNy compared to PBMCS activated by anti-CD3e antibodies (OKT3 or SP34-2). FIG. 22B shows human PBMCs activated by the anti- TCR Vp5 1 antibody produce higher levels of IL-2 when compared to those activated by anti-CD3e antibodies (OKT3 or SP34-2). Data shown is representative of n = 4 donors.

[00226] FIGS. 23A-23D demonstrate cytokine production from human PBMCs activated by an anti-TCR V[35 antibody (Antibody E). Human PBMCs activated by anti-TCR Vp5 antibody do not significantly produce IL-lbeta (FIG. 23A), IL-6, (FIG. 23B), TNFalpha (FIG. 23C), or IL-10 (FIG. 23D) as compared to PBMCs activated by anti-CD3e antibodies (OKT3 or SP34-2). Data shown is representative of n = 4 donors. 23 12 25

[00227] FIGS. 24A-24F demonstrate cytokine production from human PBMCs activated by a dual targeting (bispecific molecule) comprising an anti-TCRpV binding moiety and a BCMA binding moiety. FIG. 24A shows that human PBMCs activated by the bispecific molecule produce similar or reduced levels of IFNy as PBMCS activated by anti-CD3e antibodies (OKT3). FIG. 24B shows human PBMCs activated by the bispecific molecule produce higher levels of IL-2 when compared to PBMCs activated by anti-CD3e antibodies (OKT3). Human PBMCs activated by the bispecific molecule do not significantly produce IL-lbeta (FIG. 24C), IL-6, (FIG. 24D), TNFalpha (FIG. 24E), or IL-10 (FIG. 24F). Data shown is representative of n = 3 donors.

[00228] FIGS. 25A-25B show the structure and sequence of eight TCRpV proteins from seven different subfamilies: TCRPV6 subfamily (TCRPV6-5 and TCRPV6-4 are shown), TCRPV28 subfamily, TCRPV19 subfamily, TCRPV9 subfamily, TCRPV5 subfamily, TCRPV20 subfamily and TCRPV12 subfamily. FIG. 25A shows the structural alignment of the different TCRpV proteins. The circled area represents the outward facing region comprising the proposed binding site for the anti-TCRpV antibodies as described herein. FIG. 25B shows the amino acid sequence alignment of the proteins shown in FIG. 25A (SEQ ID NOS 3449-3456, respectively, in order of appearance). The various TCRpV proteins (from 7 different TCRpV subfamilies) have diverse sequences but share a conserved (similar) structure and function.

[00229] FIGS. 26A-26J show cytokine or chemokine secretion of PBMCs activated with anti-TCRVb antibodies (A-H.l, B-H.l), a bispecific molecule comprising an anti-TCRVb antibody (Molecule H), control isotype (122) or anti-CD3e antibody (OKT3). Data shown is representative of n = 2 donors and representative of 2 independent experiments.

[00230] FIGS. 27A-27H show cytokine or chemokine secretion of PBMCs activated with anti-TCRVb antibodies (A-H.l, B-H.l), a bispecific molecule comprising an anti-TCRVb antibody (Molecule H), control isotype (122) or anti-CD3e antibody (OKT3). Data shown is representative of n = 2 donors and representative of 2 independent experiments.

[00231] FIGS. 28A-28L show cytokine or chemokine secretion of PBMCs activated with anti-TCRVb antibodies (A-H.l, B-H.l), a bispecific molecule comprising an anti-TCRVb antibody (Molecule H), control isotype (122) or anti-CD3e antibody (OKT3). Data shown is representative of n = 2 donors and representative of 2 independent experiments.

[00232] FIG. 29 is a graph depicting mean tumor volume in NOD / SCID / IL-2Rynull (NSG) mice engrafted with Raji-luc cells at days 10 to 28. The Star denotes PBMC implantation. Open triangles denote antibody treatment with the indicated antibodies.

[00233] FIGS. 30A-30F are graphs showing cytokine secretion stimulated by anti-TRBC 1 (Antibody F) or anti-CD3 (OKT3) at Days 2 and 5. Cytokines examined include: IFNy (FIG. 30A), IL-2 (FIG. 30B), IL-ip (FIG. 30C), IL-6 (FIG. 30D), IL-10 (FIG. 30E), and TNFa (FIG. 31F).

[00234] FIG. 31 is a FACS plot showing the expansion of TCRvb 6-5+ T cells over 8 days using anti-TCRvb 6-5 vl. 23 12 25

[00235] FIG. 32 is a bar graph showing the expansion of TCRvb 6-5+ CD4+ T cells and TCRvb 6-5+ CD 8+ T cells over 8 days using the anti-CD3s antibody OKT3 (lOOnM).

[00236] FIG. 33 is a bar graph showing the expansion of TCRvb 6-5+ CD4+ T cells and TCRvb 6-5+ CD8+ T cells over 8 days using the anti-TCRvb 6-5 vl antibody (lOOnM).

[00237] FIG. 34 is a FACS plot showing the showing the expansion of TCRvb 6-5+ T cells over 8 days using anti-TCRvb 6-5 vl or the anti-CD3s antibody OKT3.

[00238] FIG. 35A is a bar graph showing the percentage of TCR[3V 6-5+ T cells in PBMC cultures after 8 days of culture with the indicated antibody. Data for 5 replicates are shown. FIG. 35B is a bar graph showing the percentage of TCRpV 6-5+ T cells in purified T cell cultures after 8 days of culture with the indicated antibody. Data for 5 replicates are shown.

[00239] FIG. 36A is a bar graph showing the relative count of TCRpV 6-5+ T cells in PBMC culture after 8 days of culture with the indicated antibody. FIG. 36B is a bar graph showing the relative count of TCRpV 6-5+ T cells in PBMC culture after 8 days of culture with the indicated antibody.

[00240] FIG. 37A is a bar graph showing the relative count of TCRpV 6-5+ T cells in a purified T cell culture after 8 days of culture with the indicated antibody. FIG. 37B is a bar graph showing the relative count of TCRPV 6-5+ T cells in a purified T cell culture after 8 days of culture with the indicated antibody.

[00241] FIG. 38 is a line graph showing the total CD3+ T cell count (fold increase) after 8 days of T cell culture with either the anti-CD3s antibody OKT3 or the anti-TCRvb 6-5 vl antibody.

[00242] FIG. 39 is a series of line graphs showing the kinetics of target cells by TCRpV 6-5 vl activated T cells or anti-CD3a (OKT3) activated T cells. T cells from three different donors were utilized (donor 6769, donor 9880, donor 5411).

[00243] FIG. 40A is a scatter plot showing the percent of target cell lysis by T cells by TCRpV 6-5 vl activated T cells or anti-CD3s (OKT3) activated T cells without T cell pre activation. The data is presented at day 6 of co-culture between target cells and effector T cells. FIG. 40B is a scatter plot showing the percent of target cell lysis by T cells by TCRpV 6-5 vl activated T cells or anti-CD3s (OKT3) activated T cells with 4 days of T cell pre activation. The data is presented at day 2 of co-culture between target cells and effector T cells (after 4 days of T cell pre-activation).

[00244] FIG. 41 is a scatter plot showing the percent of target cell lysis by T cells by TCRpV 6-5 vl activated T cells or anti-CD3s (OKT3) activated T cells with 4 days of T cell pre activation. The data is presented at day 2 of co-culture between target cells and effector T cells (after 4 days of T cell preactivation).

[00245] FIG. 42 is a bar graph showing target cell lysis by T cells by TCRJ3V 6-5 vl activated T cells or anti-CD3a (OKT3) activated T cells (lOOnM each antibody). The data includes seven replicates of each experimental condition. 23 12 25

[00246] FIG. 43 is a series of FACS plots that show the cell surface expression of CD3a on CD4+ TCRJ3V 6-5' or CD4+ TCRpV 6-5+ T cells activated with either SP34-2 (anti-CD3a antibody) or anti-TCRpV 6-5 vl (anti- TCRpV 6-5 antibody) at days 0, 1,2, 4, 6, or 8 post antibody activation.

[00247] FIG. 44 is a series of FACS plots that show the cell surface expression of CD3a on CD8+ TCRpV 6-5' or CD8+ TCRpV 6-5+ T cells activated with either SP34-2 (anti-CD3a antibody) or anti-TCRpV 6-5 vl (anti- TCRpV 6-5 antibody) at days 0, 1,2, 4, 6, or 8 post antibody activation.

[00248] FIG. 45 is a series of FACS plots that show the cell surface expression of TCRpV on CD4+ TCRpV 6-5' or CD4+ TCRpV 6-5+ T cells activated with either SP34-2 (anti-CD3a antibody) or anti-TCRpV 6-5 vl (anti- TCRpV 6-5 antibody) at days 0, 1,2, 4, 6, or 8 post antibody activation.

[00249] FIG. 46 is a series of FACS plots that show the cell surface expression of TCRpV on CD8+ TCRpV 6-5' or CD8+ TCRpV 6-5+ T cells activated with either SP34-2 (anti-CD3a antibody) or anti-TCRpV 6-5 vl (anti- TCRpV 6-5 antibody) at days 0, 1,2, 4, 6, or 8 post antibody activation.

[00250] FIG. 47A shows FACS plot of TCRpV 6-5+ cynomolgus T cell expansion either unstimulated (left) or stimulated with anti-TCRpV 6-5 vl (right) 7 days post activation of cynomolgus PBMCs. PBMCs from Donor DW8N (fresh PBMC sample, male, age 8, weight 7.9 kgs) were used. FIG. 47B shows FACS plot of TCRPV 6-5+ cynomolgus T cell expansion either unstimulated (left) or stimulated with anti-TCRpV 6-5 vl (right) 7 days post activation of cynomolgus PBMCs. PBMCs from Donor G709 (cryopreserved sample, male, age 6, weight 4.7 kgs) were used.

[00251] FIG. 48 shows FACS plot and corresponding microscopy images of TCRpV 6-5+ cynomolgus T cell expansion either unstimulated (left), stimulated with SP34-2 (anti-CD3a antibody) (middle); or stimulated with anti-TCR[3V 6-5 vl (right) post activation of cryopreserved donor DW8N cynomolgus PBMCs. The microscopy images show the cell cluster formation (indicated by circles).

[00252] FIG. 49 shows a schematic of FACS plot showing the FACS gating / staining of PBMCs prior y5 T cell purification.

[00253] FIG. 50 shows a schematic of FACS plot showing the FACS gating / staining of purified y5 T cell population.

[00254] FIG. 51 show activation of purified y5 T cell population with anti-CD3s antibody (SP34-2) (left) or anti-TCRpV antibody (anti-TCRpV 6-5 vl) (right).

[00255] FIG. 52A shows the release of IFNy from purified y5 T cell populations activated with anti-CD3a antibody (SP34-2), anti-TCRpV antibody (anti-TCRpV 6-5 vl), or unstimulated. FIG. 52B shows the release of TNFa from purified y5 T cell populations activated with anti-CD3s antibody (SP34-2), anti-TCRpV antibody (anti-TCRpV 6-5 vl), or unstimulated. FIG. 52C shows the release of IL-2 from purified y5 T cell populations activated with anti-CD3s antibody (SP34-2), anti-TCRpV antibody (anti-TCRpV 6-5 vl), or unstimulated. FIG. 52D shows the release of IL-17A from purified y5 T cell populations activated with anti-CD3a antibody (SP34-2), anti-TCRpV antibody (anti-TCRpV 6-5 vl), or unstimulated. FIG. 52E shows the release of IL-la from purified y5 T cell populations activated with anti-CD3s antibody (SP34-2), anti-TCRpV antibody (anti-TCRpV 6-5 vl), or unstimulated. FIG. 52F 23 12 25 shows the release of IL-ip from purified y5 T cell populations activated with anti-CD3s antibody (SP34-2), anti-TCRpV antibody (anti-TCRpV 6-5 vl), or unstimulated. FIG. 52G shows the release of IL-6 from purified y5 T cell populations activated with anti-CD3s antibody (SP34-2), anti-TCRpV antibody (anti-TCRpV 6-5 vl), or unstimulated. FIG. 52H shows the release of IL-10 from purified y5 T cell populations activated with anti-CD3a antibody (SP34-2), anti-TCRpV antibody (anti-TCRpV 6-5 vl), or unstimulated.

[00256] FIG. 53 shows the relative representations of all TCR alpha V segments (TRAV group of genes) and their variants (top), all TCR beta V segment 6-5 variants (TRBV6-5 gene) (bottom left), and all TCR beta V segments and variants excluding 6-5 (bottom right).

[00257] FIG. 54A is a FACS plot showing phenotypic markers of CD4+ T cells expanded with anti-TCRpV antibody (anti-TCRpV 6-5 vl). Defined phenotypes include TEMRA (top left), Naive / TSCM (top right), TEM (bottom left), and TCM (bottom right). FIG. 54B is a FACS plot showing phenotypic markers of CD4+ T cells expanded with anti-CD3a antibody (0KT3). Defined phenotypes include TEMRA (top left), Naive / TSCM (top right), TEM (bottom left), and TCM (bottom right).

[00258] FIG. 55A is a FACS plot showing phenotypic markers of CD8+ T cells expanded with anti-TCRJ3V antibody (anti-TCRpV 6-5 vl). Defined phenotypes include TEMRA (top left), Naive / TSCM (top right), TEM (bottom left), and TCM (bottom right). FIG. 55B is a FACS plot showing phenotypic markers of CD8+ T cells expanded with anti-CD3a antibody (0KT3). Defined phenotypes include TEMRA (top left), Naive / TSCM (top right), TEM (bottom left), and TCM (bottom right).

[00259] FIG. 56A is a bar graph showing the percentage of PD1 expressing CD4+ T cells from T cell cultures activated with anti-TCRpV antibody (anti-TCRpV 6-5 vl), anti-CD3s antibody (0KT3), or unstimulated. FIG. 56B is a bar graph showing the percentage of PD1 expressing CD8+ T cells from T cell cultures activated with anti-TCRpV antibody (anti-TCRpV 6-5 vl), anti-CD3s antibody (0KT3), or unstimulated.

[00260] FIG. 57A is a bar graph showing the expression of Ki-67 by CD4+ T cells from T cell cultures activated with anti-TCRpV antibody (anti-TCRpV 6-5 vl), anti-CD3s antibody (0KT3), or unstimulated. FIG. 57B is a bar graph showing the expression of Ki-67 by CD8+ T cells from T cell cultures activated with anti-TCRpV antibody (anti-TCRpV 6-5 vl), anti-CD3s antibody (0KT3), or unstimulated.

[00261] FIG. 58A is a FACS plot showing the percentage of TEMRA-like CD8+ T cells activated using anti-TCRpV antibody (anti-TCRpV 6-5 vl) that express CD57 (18.7%). FIG. 58B is a FACS plot showing the percentage of TEM-like CD8+ T cells activated using anti-CD3s antibody (0KT3) that express CD57 (46.8%) and the percentage of TCM-like CD8+ T cells activated using anti-CD3s antibody (0KT3) that express CD57 (18.9%).

[00262] FIG. 59 shows a series of FACS plots showing the expression of expression of CD27 and by CD4+ (top) or CD8+ (bottom) T cells from T cell cultures activated with anti-TCRpV antibody (anti-TCRpV 6-5 vl), anti-CD3a antibody (0KT3), or unstimulated. 23 12 25

[00263] FIG. 60 shows a series of FACS plots showing the expression of expression of 0X40, 4 IBB, and ICOS by CD4+ (top) or CD8+ (bottom) T cells from T cell cultures activated with anti-TCRpV antibody (anti-TCRpV 6-5 vl), anti-CD3s antibody (0KT3), or unstimulated.

[00264] FIG. 61 shows a series of FACS plots showing the percentage of CD3+ (CD4 gated) TCRpV 6-5+ T cells 1, 2, 3, 4, 5, 6, and 8 days port activation with BCMA and the anti-TCR VP antibody anti-TCR VP 6-5 vl.

[00265] FIG. 62A shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgGl N297A), anti-TCRpV (anti-TCR VP 6-5 vl), or anti-CD3a (0KT3) antibodies on day 0 post activation. FIG. 62B shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgGl N297A), anti-TCRpV (anti-TCR VP 6-5 vl), or anti-CD3a (0KT3) antibodies on day 1 post activation. FIG. 62C shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgGl N297A), anti-TCRpV (anti-TCR VP 6-5 vl), or anti-CD3a (0KT3) antibodies on day 2 post activation. FIG. 62D shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgGl N297A), anti-TCRpV (anti-TCR VP 6-5 vl), or anti-CD3a (0KT3) antibodies on day 3 post activation. FIG. 62E shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgGl N297A), anti-TCRpV (anti-TCR VP 6-5 vl), or anti-CD3a (0KT3) antibodies on day 4 post activation. FIG. 62F shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgGl N297A), anti-TCRpV (anti-TCR VP 6-5 vl), or anti-CD3s (0KT3) antibodies on day 5 post activation. FIG. 62G shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgGl N297A), anti-TCRpV (anti-TCR VP 6-5 vl), or anti-CD3a (0KT3) antibodies on day 6 post activation. FIG. 62H shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgGl N297A), anti-TCRpV (anti-TCR VP 6-5 vl), or anti-CD3a (0KT3) antibodies on day 8 post activation.

[00266] FIG. 63A is a bar graph showing ATP production from glycolysis of T cell cultures activated with the indicated antibodies. FIG. 63B is a bar graph showing ATP production from oxidative phosphorylation of T cell cultures activated with the indicated antibodies.

[00267] FIG. 64 is a line graph showing the oxygen consumption rate (OCR) of T cells from about 0 to 75 minutes activated with the indicated antibody.

[00268] FIG. 65A shows the oxygen consumption rate (OCR) of T cells activated with the indicated antibody during basal respiration. FIG. 65B shows the oxygen consumption rate (OCR) of T cells activated with the indicated antibody during maximal respiration. FIG. 65C shows the oxygen consumption rate (OCR) of T cells activated with the indicated antibody during spare respiratory capacity. FIG. 65D is a line graph indicates the areas of basal respiration and maximal respiration as shown in FIG. 64A and FIG. 64B, respectively.

[00269] FIG. 66A is a bar graph showing ATP production from glycolysis of T cell cultures activated with anti-TCR[3V 6-5 vl and re-stimulated with the indicated antibody. FIG. 66B is a bar graph showing 23 12 25 ATP production from oxidative phosphorylation of T cell cultures activated with anti-TCRpV 6-5 vl and re-stimulated with the indicated antibody.

[00270] FIGS. 67A-67G are graphs showing expression of IFNy (FIG. 67A), TNFa (FIG. 67E), IL-la (FIG. 67B), IL-1P (FIG. 67C), IL-6 (CRS and neurotoxicity associated cytokines) (FIG. 67D) with BHM1710 (anti TCRVB), a reduced affinity anti CD3 antibody (TB) and the SP34 anti CD3e antibody. IL-10 (FIG. 67F), IL-17A (FIG. 67G).

[00271] FIG. 68 is a FACS plot showing the percentage of NK cells expanded from T cell cultures activated with the indicated antibody.

[00272] FIG. 69 is a bar graph showing the number of NK cells expanded from T cell cultures activated with the indicated antibody.

[00273] FIG. 70 shows a series of FACS plots showing NK cell proliferation induced by T cell cultures activated with the indicated antibody.

[00274] FIG. 71 is a schematic showing an assay described in Example for determining NK cell mediated lysis of target K562 cells.

[00275] FIG. 72 is a bar graph showing the percent target cell lysis mediated by NK cells activated by PBMCs activated with the indicated antibody.

[00276] FIG. 73 shows a series of FACS plots showing the proliferation of NK cells from PBMC cultures activated / expanded with the indicated antibody (isotype control or OKT3). PBMCs from three donors (DI, D2, and D3) were analyzed.

[00277] FIG. 74 shows a series of FACS plots showing the proliferation of NK cells from PBMC cultures activated / expanded with the indicated antibody (anti-TCRvP 12-3 / 4 vl or anti-TCRvP 12-3 / 4 v2). PBMCs from three donors (DI, D2, and D3) were analyzed.

[00278] FIG. 75 shows a series of FACS plots showing the proliferation of NK cells from PBMC cultures activated / expanded with the indicated antibody (anti-TCRvP 12-3 / 4 v3 or SP34-2). PBMCs from three donors (DI, D2, and D3) were analyzed.

[00279] FIG. 76 is a bar graph showing the level of secreted IFNy by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, OKT3, or SP34) and cultured with said antibody for the indicated number of days (1, 3, or 5).

[00280] FIG. 77 is a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, OKT3, or SP34) and cultured with said antibody for the indicated number of days (1, 3, or 5).

[00281] FIG. 78 is a bar graph showing the level of secreted IL-15 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, OKT3, or SP34) and cultured with said antibody for the indicated number of days (1, 3, or 5).

[00282] FIG. 79 is a bar graph showing the level of secreted IL-1 p by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, OKT3, or SP34) and cultured with said antibody for the indicated number of days (1, 3, or 5). 23 12 25

[00283] FIG. 80 is a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, OKT3, or SP34) and cultured with said antibody for the indicated number of days (1, 3, or 5).

[00284] FIG. 81 is a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, 0KT3, or SP34) and cultured with said antibody for the indicated number of days (1, 3, or 5).

[00285] FIG. 82 is a bar graph showing the level of the indicated cytokine secreted by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or SP34). The data includes use of 17 individual PBMC donors.

[00286] FIG. 83A is a bar graph showing the level of secreted IFNy by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or 0KT3) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 83B is a bar graph showing the level of secreted IL-1 p by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or 0KT3) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 83C is a bar graph showing the level of secreted IL-4 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or 0KT3) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 83D is a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or 0KT3) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 83E is a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or 0KT3) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 83F is a bar graph showing the level of secreted TNFa by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or 0KT3) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 83G is a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or 0KT3) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6).

[00287] FIG. 84A is a bar graph showing the level of secreted IFNy by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, SP34-2, or isotype control) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 84B is a bar graph showing the level of secreted IL-1 p by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, SP34-2, or isotype control) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 84C is a bar graph showing the level of secreted IL-4 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, SP34-2, or isotype control) and cultured with said antibody for the indicated number of days (1,2, 3, 5, or 6). FIG. 84D is a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, SP34-2, or isotype control) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 84E is a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody (anti- 23 12 25 TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, SP34-2, or isotype control) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 84F is a bar graph showing the level of secreted TNFa by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, SP34-2, or isotype control) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6). FIG. 84G is a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, SP34-2, or isotype control) and cultured with said antibody for the indicated number of days (1, 2, 3, 5, or 6).

[00288] FIG. 85A is a bar graph showing the level of secreted IFNy by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 85B is a bar graph showing the level of secreted IL-1 p by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 85C is a bar graph showing the level of secreted IL-4 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 85D is a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 85E is a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 85F is a bar graph showing the level of secreted TNFa by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 85G is a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (1,2,3,4,5,6, or 8).

[00289] FIG. 86A is a bar graph showing the level of secreted IL-17A by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (2, 5, or 7). FIG. 86B is a bar graph showing the level of secreted IL-17A by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (2, 5, or 8). FIG. 86C is a bar graph showing the level of secreted IL-17A by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl, 0KT3, or SP34-2) and cultured with said antibody for the indicated number of days (2, 5, or 7). FIG. 86D is a bar graph showing the level of secreted IL-17A by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl or SP34-2) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). 23 12 25

[00290] FIG. 87A is a bar graph showing the level of secreted IFNy by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87B is a bar graph showing the level of secreted IL-1 p by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87C is a bar graph showing the level of secreted IL-4 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87D is a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87E is a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87F is a bar graph showing the level of secreted TNFa by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1,2, 3, 4, 5, 6, or 8). FIG. 87G is a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87H is a bar graph showing the level of secreted IL-12p70 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 871 is a bar graph showing the level of secreted IL-13 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87J is a bar graph showing the level of secreted IL-8 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87K is a bar graph showing the level of secreted exotaxin by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87L is a bar graph showing the level of secreted exotoxin-3 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti- 23 12 25 TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87M is a bar graph showing the level of secreted IL-8 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87N is a bar graph showing the level of secreted IP-10 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 870 is a bar graph showing the level of secreted MCP-1 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87P is a bar graph showing the level of secreted MCP-4 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87Q is a bar graph showing the level of secreted MDC by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87R is a bar graph showing the level of secreted MIP-la by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1,2, 3, 4, 5, 6, or 8). FIG. 87S is a bar graph showing the level of secreted MIP-lb by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87T is a bar graph showing the level of secreted TARC by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87U is a bar graph showing the level of secreted GMCSF by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87V is a bar graph showing the level of secreted IL-12-23p40 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87W is a bar graph showing the level of secreted IL-15 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87X is a bar graph showing the level of secreted IL-16 by T cells 23 12 25 activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87Y is a bar graph showing the level of secreted IL-17a by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87Z is a bar graph showing the level of secreted IL-laby T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87AA is a bar graph showing the level of secreted IL-5 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87BB is a bar graph showing the level of secreted IL-7 by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1,2, 3, 4, 5, 6, or 8). FIG. 87CC is a bar graph showing the level of secreted TNF-B by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). FIG. 87DD is a bar graph showing the level of secreted VEGF by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRpV 6-5 vl with anti-BCMA antibody; anti-TCRpV 6-5 vl; anti-TCRpV 123 / 4 vl, or SP34-2) and cultured with said antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8).

[00291] FIG. 88 shows a graphical representation of the relation of sequences between different TCRVB clonotype subfamilies.

[00292] FIG. 89A is a bar graph showing the percentage of cytokine release from PBMCs activated / expanded for eight days using the indicated antibody (anti-TCRpV 12-3 / 4 vl or SP34-2). FIG. 89B is a bar graph showing the percentage of cytokine release from PBMCs activated / expanded for eight days using the indicated antibody (anti-TCRpV 5 or SP34-2). FIG. 89C is a bar graph showing the percentage of cytokine release from PBMCs activated / expanded for eight days using the indicated antibody (anti-TCRpV 10 or SP34-2).

[00293] FIG. 90A a bar graph showing the level of secreted IFNy by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 90B a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 90C a bar graph showing the level of secreted IL-17A by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 90D a bar graph showing the level of secreted IL-la by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 90E a bar graph showing the level of secreted IL-1 p by T cells activated / expanded 23 12 25 with the indicated antibody for the indicated number of days (3 or 6). FIG. 90F a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 90G a bar graph showing the level of secreted TNFa by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 90H a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6).

[00294] FIG. 91 is a bar graph summarizing data from FACS analysis of PBMCs activated / expanded for 6 days using the indicated anti-TCRVp antibody.

[00295] FIG. 92A a bar graph showing the level of secreted IFNy by T cells activated / expanded with the indicated antibody for the indicated number of days (1, 3, 5, or 7). FIG. 92B a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody for the indicated number of days (1, 3, 5, or 7). FIG. 92C a bar graph showing the level of secreted IL-17A by T cells activated / expanded with the indicated antibody for the indicated number of days (1, 3, 5, or 7). FIG. 92D a bar graph showing the level of secreted IL-la by T cells activated / expanded with the indicated antibody for the indicated number of days (1, 3, 5, or 7). FIG. 92E a bar graph showing the level of secreted IL-1 p by T cells activated / expanded with the indicated antibody for the indicated number of days (1, 3, 5, or 7). FIG. 92F a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody for the indicated number of days (1, 3, 5, or 7). FIG. 92G a bar graph showing the level of secreted IL-4 by T cells activated / expanded with the indicated antibody for the indicated number of days (1, 3, 5, or 7). FIG. 92H a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody for the indicated number of days (1, 3, 5, or 7).

[00296] FIG. 93 is a bar graph summarizing data from FACS analysis of PBMCs activated / expanded for 7 days using the indicated anti-TCRVp antibody.

[00297] FIG. 94A is a bar graph showing the level of secreted IFNy by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 94B a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 94C a bar graph showing the level of secreted IL-17A by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 94D a bar graph showing the level of secreted IL-la by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 94E a bar graph showing the level of secreted IL-1 p by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 94F a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 94G a bar graph showing the level of secreted IL-4 by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 94H a bar graph showing the level of secreted TNFa by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). FIG. 941 a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody for the indicated number of days (3 or 6). 23 12 25

[00298] FIG. 95A is a bar graph showing the level of secreted IFN-y by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95B is a bar graph showing the level of secreted IFN-y by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95C is a bar graph showing the level of secreted IL-lb by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95D is a bar graph showing the level of secreted IL-6 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95E is a bar graph showing the level of secreted IL-10 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3a (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3a (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95F is a bar graph showing the level of secreted IL-15 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3a (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95G is a bar graph showing the level of secreted IL-17A by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3a (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95H is a bar graph showing the level of secreted IL-la by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 951 is a bar graph showing the level of secreted IL-lb by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95J is a bar graph showing the level of secreted IL-2 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95K is a bar graph showing the level of secreted IL-4 by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7). FIG. 95L is a bar graph showing the level of secreted TNF-a by T cells activated / expanded with the indicated antibody (anti-TCRpV 6-5 vl (plate coated), anti-CD3s 23 12 25 (plate coated), anti-TCRpV 6-5 vl (in solution), or anti-CD3s (in solution) and cultured with said antibody for the indicated number of days (1, 3, 5, or 7).

[00299] FIG. 96 is a FACS plot showing the showing the ability of MH3-2 to bind PBMCs from one of two donors when the PBMCs are either preincubated with TM23 or not (MH3-2 Alone).

[00300] FIG. 97 is a FACS plot showing the ability of MH3-2 to bind PBMCs from one of two donors when the PBMCs are either preincubated with TM23 or not (MH3-2 Alone).

[00301] FIG. 98A is a bar graph showing the polyfunctional strength index (PSI) of PBMC CD4+ T cells, CD4+ T cells expanded with anti-CD3 antibody, (CD3 Expanded T cells), and CD4+ T cells expanded with anti-TCRVP 6-5 antibody (Drug Expanded T cells). The Effector mediators are Granzyme B, IFNy, MIP-la, perforin, TNFa, and TNFp. The Stimulatory mediators are IL-5. The Chemoattractive mediators are MIP-lb. FIG. 98B is a bar graph showing the polyfunctional strength index (PSI) of PBMC CD8+ T cells, CD8+ T cells expanded with anti-CD3 antibody, (CD3 Expanded T cells), and CD8+ T cells expanded with anti-TCRVP 6-5 antibody (Drug Expanded T cells). The Effector mediators are Granzyme B, IFNy, MIP-la, perforin, and TNFp. The Chemoattractive mediators are MIP-lb and RANTES.

[00302] FIG. 99 is a schematic of the experimental design for the pharmacokinetic (PK) profde and dosing strategy of the multifunctional polypeptide molecule as described herein.

[00303] FIG. 100 shows Table 9, which depicts alignment of TCRBV amino acid sequences (SEQ ID NOS 3457-3516, 3669-3673, 3522, 3674-3675, 3525, 3676-3687, 3538, 3688-3698, 3550-3639 and 3699-3790, respectively, in order of appearance). The alignment of TCRBV amino acid sequences in Table 9 underscores the diversity of TCR sequences. In particular, the TRBV sequences from different subfamilies are considerably different from each other.

[00304] FIG. 101 shows alignment of affinity matured humanized Antibody A-H VL sequences (SEQ ID NOS: 3377-3389, respectively, in order of appearance).

[00305] FIG. 102 shows alignment of affinity matured humanized Antibody A-H VH sequences (SEQ ID NOS: 3390-3436, respectively, in order of appearance).

[00306] FIG. 103A shows an exemplary embodiment (e.g., BKM0186) of multifunctional molecules comprising a TCRpV-binding moiety and a cytokine polypeptide (e.g., IL2 or IL2-C125A) as described herein. FIG. 103B shows an exemplary embodiment of multifunctional molecules comprising a TCRpV-binding moiety and a cytokine polypeptide as described herein. FIGS. 103C, 103D, 103E, and 103F show exemplary embodiments of multifunctional molecules comprising a first TCRpV-binding moiety, a second TCRpV-binding moiety, and two cytokine polypeptides as described herein. In some embodiments, the cytokine polypeptide comprises IL-2 or a functional fragment or a functional variant thereof, IL2-C125A or a functional fragment or a functional variant thereof, IL-15 or a functional fragment or a functional variant thereof, IL-7 or a functional fragment or a functional variant thereof, IL-12 or a functional fragment or a functional variant thereof, or IL-21 or a functional fragment or a functional variant thereof. In embodiments, the cytokine polypeptide further comprises a cytokine receptor. In some embodiments, the cytokine polypeptide comprises IL-15 linked to a IL-15Ra. In some 23 12 25 embodiments, the cytokine polypeptide comprises IL-15 linked to a IL-15Ra sushi domain. In some embodiments, the cytokine polypeptide comprises a cytokine dimer. In some embodiments, the cytokine polypeptide comprises an IL-12 beta subunit linked to an IL-12 alpha subunit.

[00307] FIG. 104 shows FACS plots showing binding of BKM0186 to different immune cell populations in Human PBMCs.

[00308] FIG. 105 shows binding of BKM0186 to pure human T cells expressing either V|36 or CD25 (IL-2Ra) or both.

[00309] FIG. 106 shows in vitro concentration-effect relationships for BKM0186-mediated in vitro expansion of V|36 T cells and activated (CD25) V|36 T cells from human PBMCs at day 5 as a % of total T-Cytotoxic (CD8) and T-helper (CD4) populations. Left graph: T-cytotoxic lymphocytes; right graph: T-helper lymphocytes.

[00310] FIG. 107 shows in vitro TCR sequencing. PBMCs were incubated with lOOnM of BKM0186 for 5 days and T cells were sequenced for TCR [3 chain V (TRBV) genes. Compared to unstimulated T cells (grey), BKM0186 selectively expanded T cells bearing TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-5, and TRBV10-3.

[00311] FIG. 108A and FIG. 108B show a series of graphs (FIG. 108A) and a series of FACS plots (FIG. 108B) exhibiting activation of CD4+ and CD8+ T cells as assessed by CD25 expression following stimulation with BKM0186, RSV-IL2 and Anti-TCRV[36 control in solution.

[00312] FIG. 109 shows a series of FACS plots demonstrating differentiation of memory T cells mediated by BKM0186 in comparison to unstimulated and the controls RSV-IL2 and anti-TCRV[36. Upper left quadrant represents Central memory (CM), lower left quadrant represents Effector memory (EM), upper right quadrant represents Naive (N) and lower right quadrant represents Effector memory RA (TEMRA).

[00313] FIG. 110 shows in vitro concentration-effect relationships for BKM0186-induced cytokine release from human PBMCs at day 4 using MSD V-plex human cytokine panel.

[00314] FIG. Ill shows BKM0186-mediated killing of human tumor organoids generated from primary, patient-derived tissue from colorectal and NSCLC cancer patients. Vertical bars represent percentage of organoid area reduced relative to isotype control following incubation of organoids with BKM0186 and autologous TILs.

[00315] FIG. 112 shows tumor growth curves of mBKM0186-treated EMT6 tumor-bearing mice. Studies were performed in randomized mice with tumor volumes of 80-150 mm3. For all models except MC38, mice were dosed for 3 weeks with a weekly dosing of 0.5-1.5 mg / kg and survival was determined based on 2000 mm3 tumor volume end point.

[00316] FIG. 113 shows tumor growth curves of mBKM0186-treated mice. Studies were performed in randomized mice with tumor volumes of 80-150 mm3. For all models except MC38, mice were dosed for 4 weeks with a weekly dosing of 1-1.5 mg / kg and survival was determined based on 2000 mm3 tumor volume end point. For MC38, mice were given first dose of 3 mg / kg followed by 1 mg / kg for subsequent three weekly (QW) doses. 23 12 25

[00317] FIG. 114 shows Kaplan-Meier survival curves of treated mice. Studies were performed in randomized mice with tumor volumes of 80-150 mm3. For all models except MC38, mice were dosed for 4 weeks with a weekly dosing of 1-1.5 mg / kg and survival was determined based on 2000 mm3 tumor volume end point. For MC38, mice were given first dose of 3 mg / kg followed by 1 mg / kg for subsequent three weekly (QW) doses.

[00318] FIG. 115 shows the experimental design for the tumor rechallenge study. Cured EMT6 tumor bearing mice were rechallenged with EMT6 tumor cells in one flank and CT26 tumor cells in another flank and monitored for tumor growth for 28 days.

[00319] FIG. 116 shows the results of the tumor rechallenge study. While the EMT6 tumors were rejected, CT26 tumors grew, suggesting that the memory response against EMT6 tumors likely mediated through mBKM0186 treatment has been established.

[00320] FIG. 117 shows immune profiling of T cells in blood and tumor tissue on day 14 post dosing of mBKM0186.

[00321] FIG. 118 shows tumor growth curves of EMT6 tumors after weekly (QW) treatment of mice bearing 150 mm3 tumors with 1 mg / kg of mBKM0186 with and without depletion of V[3-specific T cells. Filled Triangles indicate dosing intervals of the depleting antibodies and open Triangles indicate dosing intervals ofmBKM0186.

[00322] FIG. 119A and FIG. 119B show Pharmacokinetic profiles of BKM0186 (FIG. 119A) and BKM0281 (FIG. 119B) administered single dose IV in cynomolgus monkeys.

[00323] FIG. 120A shows T cell expansion following a single IV dose of BKM0186. FIG. 120B shows T cell expansion following a single IV dose BKM0281. n=3 Monkeys, n=l monkey vehicle control.

[00324] FIG. 121 shows serum soluble CD25 levels in monkeys administered a single IV dose of BKM0186. Mean values, n=2-3 monkeys per group.

[00325] FIG. 122A shows serum IL-6 levels in monkeys administered a single IV dose of BKM0186. FIG. 122B shows serum IL-6 levels in monkeys administered a single IV dose of BKM0281. Mean values, n=2-3 monkeys per group.

[00326] FIG. 123A shows serum IFN-y levels in monkeys administered a single IV dose of BKM0186. FIG. 123B shows IFN-y levels in monkeys administered a single IV dose of BKM0281. Mean values, n=2-3 monkeys per group. Mean values, n=2-3 monkeys per group.

[00327] FIG. 124 shows in vitro concentration-effect relationships for bispecific-mediated in vitro expansion of V|36 T cells. DETAILED DESCRIPTION DEFINITION

[00328] 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. 23 12 25

[00329] 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.

[00330] 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.”

[00331] It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[00332] 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.

[00333] 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.

[00334] The term “acquire” or “acquiring” as the terms are used herein, refer to obtaining possession of a physical entity (e.g., a sample, a polypeptide, a nucleic acid, or a sequence), or a value, e.g., a numerical value, by “directly acquiring” or “indirectly acquiring” the physical entity or value. “Directly acquiring” means performing a process (e.g., performing a synthetic or analytical method) to obtain the physical entity or value. “Indirectly acquiring” refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value). Directly acquiring a physical entity includes performing a process that includes a physical change in a physical substance, e.g., a starting material. Directly acquiring a value includes performing a process that includes a physical change in a sample or another substance, e.g., performing an analytical process which includes a physical change in a substance, e.g., a sample.

[00335] “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 23 12 25 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.

[00336] The term “human-like antibody molecule” as used herein refers to a humanized antibody molecule, human antibody molecule or an antibody molecule having at least 95% sequence identity with a non-murine germline framework region, e.g., FR1, FR2, FR3 and / or FR4. In some embodiments, the human-like antibody molecule comprises a framework region having at least 95% sequence identity to a human germline framework region, e.g., a FR1, FR2, FR3 and / or FR4 of a human germline framework region. In some embodiments, the human-like antibody molecule is a recombinant antibody. In some embodiments, the human-like antibody molecule is a humanized antibody molecule. In some embodiments, the human-like antibody molecule is human antibody molecule. In some embodiments, the human-like antibody molecule is a phage display or a yeast display antibody molecule. In some embodiments, the human-like antibody molecule is a chimeric antibody molecule. In some embodiments, the human-like antibody molecule is a CDR grafted antibody molecule.

[00337] 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.

[00338] 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 23 12 25 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.

[00339] “Antigen” (Ag) as used herein refers to a molecule that can provoke an immune response, e.g., involving activation of certain immune cells and / or antibody generation. Any macromolecule, including almost all proteins or peptides, can be an antigen. Antigens can also be derived from genomic recombinant or DNA. For example, any DNA comprising a nucleotide sequence or a partial nucleotide sequence that encodes a protein capable of eliciting an immune response encodes an “antigen.” In embodiments, an antigen does not need to be encoded solely by a full length nucleotide sequence of a gene, nor does an antigen need to be encoded by a gene at all. In embodiments, an antigen can be synthesized or can be derived from a biological sample, e.g., a tissue sample, a tumor sample, a cell, or a fluid with other biological components. As used, herein a “tumor antigen” or interchangeably, a “cancer antigen” includes any molecule present on, or associated with, a cancer, e.g., a cancer cell or a tumor microenvironment that can provoke an immune response. As used, herein an “immune cell antigen” includes any molecule present on, or associated with, an immune cell that can provoke an immune response.

[00340] 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.

[00341] 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 23 12 25 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.

[00342] ‘‘Immune effector cell,” as that term is used herein, refers to a cell that is involved in an immune response, e.g., in the promotion of an immune effector response. Examples of immune effector cells include, but are not limited to, T cells, e.g., alpha / beta T cells and gamma / delta T cells, B cells, natural killer (NK) cells, natural killer T (NK T) cells, and mast cells.

[00343] 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.

[00344] 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.

[00345] The terms “nucleic acid,” “nucleic acid sequence,” “nucleotide sequence,” or “polynucleotide sequence,” and “polynucleotide” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. The polynucleotide may be either single-stranded or double-stranded, and if single-stranded may be the coding strand or noncoding (antisense) strand. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. The nucleic acid may be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semisynthetic, or synthetic origin which either does not occur in nature or is linked to another polynucleotide in a non-natural arrangement.

[00346] 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 23 12 25 (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.

[00347] 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.

[00348] The term “variant” refers to a polypeptide that has a substantially identical amino acid sequence to a reference amino acid sequence, or is encoded by a substantially identical nucleotide sequence. In some embodiments, the variant is a functional variant. In some embodiments, a TCRpV variant can bind to TCRa and form a TCR a: [3 complex.

[00349] 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.

[00350] 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 23 12 25 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”).

[00351] 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 aNWSgapdna.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.

[00352] The percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The nucleic acid and protein sequences described herein can be used as a “query sequence” to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to a nucleic acid molecule of the invention. BLAST protein searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[00353] 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.

[00354] 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 23 12 25 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.

[00355] 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).

[00356] 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.

[00357] 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.

[00358] ‘‘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). The variants or homologs may 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. Anti-TCRBV antibodies Human T cell receptor (TCR) complex

[00359] TCR is a disulfide-linked membrane-anchored heterodimeric protein normally consisting of the highly variable alpha (a) and beta (P) chains expressed as part of a complex with the invariant CD3 chain 23 12 25 molecules. TCR on aP T cells is formed by a heterodimer of one alpha chain and one beta chain. Each alpha or beta chain consists of a constant domain and a highly variable domain classified as the Immunoglobulin superfamily (IgSF) fold. The TCRpV chains can be further classified into 30 subfamilies (TRBV1-30). Despite their high structural and functional homology, the amino acid sequence homology in the TRBV genes is very low. Only 4 amino acids out of approximately 95 are identical while 10 additional amino acids are conserved among all subfamilies (see, an alignment of TCRBV amino acid sequences in Table 9). Nevertheless, TCRs formed between alpha and beta chains of highly diverse sequences show a remarkable structural homology (FIGS. 25A and 25B) and elicit a similar function, e.g., activation of T cells.

[00360] T cell receptors (TCR) can be found on the surface of T cells. TCRs recognize antigens, e.g., peptides, presented on, e.g., bound to, major histocompatibility complex (MHC) molecules on the surface of cells, e.g., antigen-presenting cells. TCRs are heterodimeric molecules and can comprise an alpha chain, a beta chain, a gamma chain or a delta chain. TCRs comprising an alpha chain and a beta chain are also referred to as TCRap. The TCR beta chain consists of the following regions (also known as segments): variable (V), diversity (D), joining (J) and constant (C) (see Mayer G. and Nyland J. (2010) Chapter 10: Major Histocompatibility Complex and T-cell Receptors-Role in Immune Responses. In: Microbiology and Immunology on-line, University of South Carolina School of Medicine). The TCR alpha chain consists of V, J and C regions. The rearrangement of the T-cell receptor (TCR) through somatic recombination of V (variable), D (diversity), J (joining), and C (constant) regions is a defining event in the development and maturation of a T cell. TCR gene rearrangement takes place in the thymus.

[00361] 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., CD3o / s. and / or CD3y / a.

[00362] As used herein, the term “T cell receptor beta variable chain” or “TCRpV,” refers to an extracellular region of the T cell receptor beta chain which comprises the antigen recognition domain of the T cell receptor. The term TCRpV includes isoforms, mammalian, e.g., human TCRpV, species homologs of human and analogs comprising at least one common epitope with TCRpV. Human TCRpV comprises a gene family comprising subfamilies including, but not limited to: a TCRP V6 subfamily, a TCRP V10 subfamily, a TCRP V12 subfamily, a TCRP V5 subfamily, a TCRP V7 subfamily, a TCRP Vil subfamily, a TCRP V14 subfamily, a TCRP V16 subfamily, a TCRP VI8 subfamily, a TCRP V9 subfamily, a TCRP V13 subfamily, a TCRP V4 subfamily, a TCRP V3 subfamily, a TCRP V2 subfamily, a TCRP V15 subfamily, a TCRP V30 subfamily, a TCRP V19 subfamily, a TCRP V27 subfamily, a TCRP V28 subfamily, a TCRP V24 subfamily, a TCRP V20 subfamily, TCRP V25 subfamily, a TCRP V29 subfamily, a TCRP VI subfamily, a TCRP V17 subfamily, a TCRP V21 subfamily, a TCRP V23 subfamily, or a TCRP V26 subfamily, as well as family members of said subfamilies, and variants thereof (e.g., a structural or functional variant thereof). In some embodiments, the TCRP V6 subfamily comprises: TCRP V6-4*01, TCRP V6-4*02, TCRP V6-9*01, TCRP V6-8*01, TCRP V6-5*01, TCRP 23 12 25 V6-6*02, TCRp V6-6*01, TCRp V6-2*01, TCRp V6-3*01 or TCRp V6-l*01. In some embodiments, TCRpV comprises TCRP V6-5*01, or a variant thereof, e.g., a variant having 85%, 90%, 95%, 99% or more identity the naturally-occurring sequence. TCRP V6-5*01 is also known as TRBV65; TCRBV6S5; TCRBV13S1, or TCRp V13.1. The amino acid sequence of TCRp V6-5*01, e.g., human TCRp V6-5*01, is known in that art, e.g., as provided by IMGT ID L36092. In some embodiments, TCRP V6-5*01 is encoded by the nucleic acid sequence of SEQ ID NO: 43, or a sequence having 85%, 90%, 95%, 99% or more identity thereof. In some embodiments, TCRP V6-5*01 comprises the amino acid sequence of SEQ ID NO: 44, or a sequence having 85%, 90%, 95%, 99% or more identity thereof. SEQ ID NO: 43 ATGAGCATCGGCCTCCTGTGCTGTGCAGCCTTGTCTCTCCTGTGGGCAGGTCCAGTGAATGCT GGTGTCACTCAGACCCCAAAATTCCAGGTCCTGAAGACAGGACAGAGCATGACACTGCAGT GTGCCCAGGATATGAACCATGAATACATGTCCTGGTATCGACAAGACCCAGGCATGGGGCT GAGGCTGATTCATTACTCAGTTGGTGCTGGTATCACTGACCAAGGAGAAGTCCCCAATGGCT ACAATGTCTCCAGATCAACCACAGAGGATTTCCCGCTCAGGCTGCTGTCGGCTGCTCCCTCC CAGACATCTGTGTACTTCTGTGCCAGCAGTTACTC SEQ ID NO: 44 MSIGLLCCAALSLLWAGPVNAGVTQTPKFQVLKTGQSMTLQCAQDMNHEYMSWYRQDPGMG LRLIHY-SVGAGITDQGEVPNGYNVSRSTTEDFPLRLLSAAPSQTSVYFCASSY TCR beta V (TCRBV)

[00363] 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.

[00364] 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.

[00365] Provided herein are, inter alia, antibody molecules and fragments thereof, that bind, e.g., specifically bind, to a human TCR beta V chain (TCRpV), e.g., a TCRpV gene family (also referred to as a group), e.g., a TCRpV subfamily (also referred to as a subgroup), e.g., as described herein. TCR beta V families and subfamilies are known in the art, e.g., as described in Yassai et al., (2009) Immunogenetics 61(7)pp:493-502; Wei S. and Concannon P. (1994) Human Immunology 41(3) pp: 201-206. The antibodies described herein can be recombinant antibodies, e.g., recombinant non-murine antibodies, e.g., recombinant human or humanized antibodies.

[00366] The terms TCRBV, TCRVB, TRBV, TCRpV, TCRVp or TRpV are used interchangeably herein and refer to a TCR beta V chain, e.g., as described herein. 23 12 25

[00367] In some embodiments, provided herein is an anti-TCRpV antibody molecule that binds to human TCR[3V, e.g., a TCRpV family, e.g., gene family or a variant thereof. In some embodiments a TCRBV gene family comprises one or more subfamilies, e.g., as described herein, e.g., in FIG. 4, Table 8A or Table 8B. In some embodiments, the TCRpV gene family comprises: a TCRP V6 subfamily, a TCRP V10 subfamily, a TCRP V12 subfamily, a TCRP V5 subfamily, a TCRP V7 subfamily, a TCRP VI1 subfamily, a TCRP V14 subfamily, a TCRP V16 subfamily, a TCRP VI8 subfamily, a TCRP V9 subfamily, a TCRP V13 subfamily, a TCRP V4 subfamily, a TCRP V3 subfamily, a TCRP V2 subfamily, a TCRP V15 subfamily, a TCRP V30 subfamily, a TCRP V19 subfamily, a TCRP V27 subfamily, a TCRP V28 subfamily, a TCRP V24 subfamily, a TCRP V20 subfamily, TCRP V25 subfamily, a TCRP V29 subfamily, a TCRP VI subfamily, a TCRP V17 subfamily, a TCRP V21 subfamily, a TCRP V23 subfamily, or a TCRP V26 subfamily.

[00368] In some embodiments, TCRP V6 subfamily is also known as TCRP VI3.1. In some embodiments, the TCRP V6 subfamily comprises: TCRP V6-4*01, TCRP V6-4*02, TCRP V6-9*01, TCRP V6-8*01, TCRP V6-5*01, TCRP V6-6*02, TCRP V6-6*01, TCRP V6-2*01, TCRP V6-3*01 or TCRP V6-l*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-4*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-4*02, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-9*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-8*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-5*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-6*02, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-6*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-2*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-3*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-1 * 01, or a variant thereof.

[00369] In some embodiments, TCRP V6 comprises TCRP V6-5*01, or a variant thereof. In some embodiments, TCRP V6, e.g., TCRP V6-5*01, is recognized, e.g., bound, by SEQ ID NO: 1 and / or SEQ ID NO: 2. In some embodiments, TCRP V6, e.g., TCRP V6-5*01, is recognized, e.g., bound, by SEQ ID NO: 9 and / or SEQ ID NO: 10. In some embodiments, TCRP V6 is recognized, e.g., bound, by SEQ ID NO: 9 and / or SEQ ID NO: 11.

[00370] In some embodiments, TCRP V10 subfamily is also known as TCRP VI2. In some embodiments, the TCRP V10 subfamily comprises: TCRP V10-l*01, TCRP VI0-1 *02, TCRP V10-3*01 or TCRP V10-2*01, or a variant thereof.

[00371] In some embodiments, TCRP V12 subfamily is also known as TCRP V8.1. In some embodiments, the TCRP V12 subfamily comprises: TCRP V12-4*01, TCRP V12-3*01, or TCRP V12-5*01, or a variant thereof. In some embodiments, TCRP V12 is recognized, e.g., bound, by SEQ ID NO: 15 and / or SEQ ID NO: 16. In some embodiments, TCRP V12 is recognized, e.g., bound, by any one of SEQ ID NOs 23-25, and / or any one of SEQ ID NO: 26-30: 23 12 25

[00372] In some embodiments, the TCRp V5 subfamily is chosen from: TCRp V5-5*01, TCRp V5-6*01, TCRp V5-4*01, TCRp V5-8*01, TCRp V5-l*01, or a variant thereof

[00373] In some embodiments, the TCRP V7 subfamily comprises TCRP V7-7*01, TCRP V7-6*01, TCRP V7 -8*02, TCRP V7 -4*01, TCRp V7-2*02, TCRp V7-2*03, TCRp V7-2*01, TCRp V7-3*01, TCRP V7-9*03, or TCRP V7-9*01, or a variant thereof.

[00374] In some embodiments, the TCRP Vil subfamily comprises: TCRP VI 1-1*01, TCRP VI 1-2*01 or TCRP Vll-3*01,ora variant thereof. In some embodiments, the TCRP V14 subfamily comprises TCRP V14*01, or a variant thereof. In some embodiments, the TCRP V16 subfamily comprises TCRP V16*01, or a variant thereof. In some embodiments, the TCRP V18 subfamily comprises TCRP V18*01, or a variant thereof. In some embodiments, the TCRP V9 subfamily comprises TCRP V9*01 or TCRP V9*02, or a variant thereof. In some embodiments, the TCRP V13 subfamily comprises TCRP V13*01, or a variant thereof. In some embodiments, the TCRP V4 subfamily comprises TCRP V4-2*01, TCRP V4-3*01, or TCRP V4-l*01, or a variant thereof. In some embodiments, the TCRP V3 subfamily comprises TCRP V3-l*01, or a variant thereof. In some embodiments, the TCRP V2 subfamily comprises TCRP V2*01, or a variant thereof. In some embodiments, the TCRP V15 subfamily comprises TCRP V15*01, or a variant thereof. In some embodiments, the TCRP V30 subfamily comprises TCRP V30*01, or TCRP V30*02, or a variant thereof. In some embodiments, the TCRP V19 subfamily comprises TCRP VI9*01, or TCRP VI9*02, or a variant thereof. In some embodiments, the TCRP V27 subfamily comprises TCRP V27*01, or a variant thereof. In some embodiments, the TCRP V28 subfamily comprises TCRP V28*01, or a variant thereof. In some embodiments, the TCRP V24 subfamily comprises TCRP V24-l*01, or a variant thereof. In some embodiments, the TCRP V20 subfamily comprises TCRP V20-l*01, or TCRP V20-l*02, or a variant thereof. In some embodiments, the TCRP V25 subfamily comprises TCRP V25-l*01, or a variant thereof. In some embodiments, the TCRP V29 subfamily comprises TCRP V29-l*01, or a variant thereof.

[00375] Exemplary amino acid sequences for TCRpV subfamily members can be found on the ImMunoGeneTics Information System website: http: / / www.imgt.org / , or in a similar resource. Anti-TCRRV antibodies

[00376] Current bispecific constructs designed to redirect T cells to promote tumor cell lysis for cancer immunotherapy typically utilize antibody fragments (Fab, scFv, VH, single domain antibody, etc.) that are derived from monoclonal antibodies (mAb) directed against the CD3e subunit of the T cell receptor (TCR). However, there are limitations to this approach which may prevent the full realization of the therapeutic potential for such bispecific constructs. Previous studies have shown that even low “activating” doses of anti-CD3e mAb can cause long-term T cell dysfunction and exert immunosuppressive effects. In addition, anti-CD3e mAbs have been associated with side effects that result from massive T cell activation. The large number of activated T cells secrete substantial amounts of cytokines, the most important of which is Interferon gamma (IFNy). This excess amount of IFNy in turn 23 12 25 activates macrophages which then overproduce proinflammatory cytokines such as IL-lbeta, IL-6, IL-10 and TNF-alpha, causing a “cytokine storm” known as the cytokine release syndrome (CRS) (Shimabukuro-Vornhagen et al., J Immunother Cancer. 2018 Jun 15;6( 1):56). 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).

[00377] Described herein are molecules targeting the TCRpV chain of TCR and methods thereof. Without wishing to be bound by theory, such molecules are capable of binding, activating, and / or expanding only a subset of T cells, avoiding or reducing CRS and / or NT and minimizing potential immunosuppressive effects of anti-CD3 mAbs.

[00378] Described herein is a class of antibodies, i.e., anti-TCRpV antibody molecules as described herein, which despite having low sequence similarity (e.g., low sequence identity among the different antibody molecules that recognize different TCRpV subfamilies), recognize a structurally conserved, yet sequence-wise variable, region, e.g., domain, on the TCRpV protein (as denoted by the circled area in FIG. 25A) and have a similar function (e.g., activation of T cells and a similar cytokine profde as described herein). Thus, the anti-TCRpV antibody molecules as described herein share a structurefunction relationship.

[00379] Without wishing to be bound by theory, in some embodiments, the anti-TCRpV antibody molecules as described herein bind to an outward facing epitope of a TCRpV protein when it is in a complex with a TCRalpha protein, e.g., as denoted by the circled area in FIG. 25A. In some embodiments, the anti-TCRpV antibody molecules as described herein recognize (e.g., bind to), a domain (e.g., an epitope) on the TCRpV protein that is: (1) structurally conserved among different TCRpV subfamilies; and (2) has minimal sequence identity among the different TCRpV subfamilies. As shown in Table 9, TCRpV proteins from the different TCRBV subfamilies share minimal sequence similarity. However, as shown in FIG. 25A-25B, TCRpV proteins which have minimal sequence similarity, share a similar 3D conformation and structure.

[00380] The alignment of TCRBV amino acid sequences in Table 9 underscores the diversity of TCR sequences. In particular, the TRBV sequences from different subfamilies are considerably different from each other.

[00381] In some embodiments, the anti-TCRpV antibody molecules as described herein do not recognize, e.g., bind to, an interface of a TCRpV: TCRalpha complex. In some embodiments, the anti-TCRpV antibody molecules as described herein do not recognize, e.g., bind to, a constant region of a TCRpV protein. An exemplary antibody that binds to a constant region of a TCRBV region is JOVI.l as described in Viney et al., (Hybridoma. 1992 Dec;l 1(6):701-13). In some embodiments, the anti-TCRpV antibody molecules as described herein do not recognize, e.g., bind to, one or more (e.g., all) of a complementarity determining region (e.g., CDR1, CDR2 and / or CDR3) of a TCRpV protein.

[00382] Provided herein are, inter alia, antibody molecules directed to the variable chain of the beta subunit of TCR (TCRpV) which bind and, e.g., activate a subset of T cells. The anti-TCRpV antibody 23 12 25 molecules as described herein result in lesser or no production of cytokines associated with CRS, e.g., IL-6, IL-lbeta, IL-10 and TNF alpha; and enhanced and / or delayed production of IL-2 and IFNy. In some embodiments, the anti-TCRpV antibodies as described herein have a cytokine profde, e.g., as described herein, which differs from a cytokine profde of a T cell engager that binds to a receptor or molecule other than a TCRpV region (“a non-TCRpV-binding T cell engager”). In some embodiments, the non-TCRpV-binding T cell engager comprises an antibody that binds to a CD3 molecule (e.g., CD3 epsilon (CD3e) molecule); or a TCR alpha (TCRa) molecule. In some embodiments, the non-TCRpV-binding T cell engager is an OKT3 antibody or an SP34-2 antibody.

[00383] In some embodiments, the anti-TCRpV antibodies as described herein result in expansion of TCRPV+ T cells, e.g., a subset of memory effector T cells known as TEMRA. Without wishing to be bound by theory, it is believed that in some embodiments, TEMRA cells can promote tumor cell lysis but not CRS. Accordingly, provided herein are methods of making said anti-TCRpV antibody molecules and uses thereof. Also described herein are multispecific molecules, e.g., bispecific molecules comprising said anti-TCRpV antibody molecules. In some embodiments, compositions comprising anti-TCRpV antibody molecules of the present disclosure, can be used, e.g., to: (1) activate and redirect T cells to promote tumor cell lysis for cancer immuno-therapy; and / or (2) expand TCRPV+ T cells. In some embodiments, compositions comprising anti-TCRpV antibody molecules as described herein limit the harmful side-effects of CRS and / or NT, e.g., CRS and / or NT associated with anti-CD3e targeting.

[00384] In some embodiments, the anti-TCRpV antibody molecule binds to one or more of TRBV2, TRBV3-1, TRBV4-1, TRBV4-2, TRBV4-3, TRBV5-1, TRBV5-4, TRBV5-5, TRBV5-6, TRBV5-8, TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8, TRBV6-9, TRBV7-2, TRBV7-3, TRBV7-4, TRBV7-6, TRBV7-7, TRBV7-8, TRBV7-9, TRBV9, TRBV10-1, TRBV10-2, TRBV10-3, TRBV11-1, TRBV11-2, TRBV11-3, TRBV12-3, TRBV12-4, TRBV12-5, TRBV13, TRBV14, TRBV15, TRBV16, TRBV18, TRBV19, TRBV20-1, TRBV24-1, TRBV25-1, TRBV27, TRBV28, TRBV29-1 and TRBV30. In some embodiments, the anti-TCRpV antibody molecule binds to one or more of TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8 and TRBV6-9. In some embodiments, the anti-TCRpV antibody molecule is an anti-TRBV2, anti-TRBV3-l, anti-TRBV4-l, anti-TRBV4-2, anti-TRBV4-3, anti-TRBV5-l, anti-TRBV5-4, anti-TRBV5-5, anti-TRBV5-6, anti-TRBV5-8, anti-TRBV6-l, anti-TRBV6-2, anti-TRBV6-3, anti-TRBV6-4, anti-TRBV6-5, anti-TRBV6-6, anti-TRBV6-8, anti-TRBV6-9, anti-TRBV7-2, anti-TRBV7-3, anti-TRBV7-4, anti-TRBV7-6, anti-TRBV7-7, anti-TRBV7-8, anti-TRBV7-9, anti-TRBV9, anti-TRBV10-l, anti-TRBV10-2, anti-TRBV10-3, anti-TRBVll-1, anti-TRBVll-2, anti-TRBVll-3, anti-TRBV12-3, anti-TRBV12-4, anti-TRBV12-5, anti-TRBV13, anti-TRBV14, anti-TRBV15, anti-TRBV16, anti-TRBV18, anti-TRBV19, anti-TRBV20-l, anti-TRBV24-l, anti-TRBV25-l, anti-TRBV27, anti-TRBV28, anti-TRBV29-1, or anti-TRBV30. Exemplary anti-TCRpV antibody molecules and the corresponding TCRpV subfamilies recognized by said anti-TCRpV antibody molecules are disclosed in Table 10A. 23 12 25

[00385] In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV2, TRBV3-1, TRBV4-1, TRBV4-2, TRBV4-3, TRBV5-1, TRBV5-4, TRBV5-5, TRBV5-6, TRBV5-8, TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8, TRBV6-9, TRBV7-2, TRBV7-3, TRBV7-4, TRBV7-6, TRBV7-7, TRBV7-8, TRBV7-9, TRBV9, TRBV10-1, TRBV10-2, TRBV10-3, TRBV11-1, TRBV11-2, TRBV11-3, TRBV12-3, TRBV12-4, TRBV12-5, TRBV13, TRBV14, TRBV15, TRBV16, TRBV18, TRBV19, TRBV20-1, TRBV24-1, TRBV25-1, TRBV27, TRBV28, TRBV29-1 or TRBV30. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-1. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-2. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-3. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-4. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-5. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-6. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-8. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-9.

[00386] In some embodiments, the anti-TCRpV antibody molecule does not bind to TCRP V12, or binds to TCRP V12 with an affinity and / or binding specificity that is less than (e.g., less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof as de-scribed in US Patent 5,861,155.

[00387] In some embodiments, the anti-TCRpV antibody molecule binds to TCRP V12 with an affinity and / or binding specificity that is greater than (e.g., greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof as described in US Patent 5,861,155.

[00388] In some embodiments, the anti-TCRpV antibody molecule binds to a TCRpV region other than TCRP V12 (e.g., TCRpV region as described herein, e.g., TCRP V6 subfamily (e.g., TCRP V6-5*01) with an affinity and / or binding specificity that is greater than (e.g., greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof as de-scribed in US Patent 5,861,155.

[00389] In some embodiments, the anti-TCRpV antibody molecule does not comprise the CDRs of the Antibody B murine antibody.

[00390] In some embodiments, the anti-TCRpV antibody molecule does not bind to TCRP V5-5*01 or TCRP V5-l*01, or binds to TCRP V5-5*01 or TCRP V5-l*01 with an affinity and / or binding specificity that is less than (e.g., less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the TM23 murine antibody or a humanized version thereof as described in US Patent 5,861,155.

[00391] In some embodiments, the anti-TCRpV antibody molecule binds to TCRP V5-5*01 or TCRP V5-l*01with an affinity and / or binding specificity that is greater than (e.g., greater than about 10%, 20%, 23 12 25 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 ahumanized version thereof as de-scribed in US Patent 5,861,155.

[00392] In some embodiments, the anti-TCRpV antibody molecule binds to a TCRpV region other than TCRp V5-5*01 or TCRp V5-l*01 (e.g., TCRpV region as described herein, e.g., TCRp V6 subfamily (e.g., TCRP V6-5*01) with an affinity and / or binding specificity that is greater than (e.g., greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the TM23 murine antibody or a humanized version thereof as described in US Patent 5,861,155.

[00393] In some embodiments, the anti-TCRpV antibody molecule does not comprise the CDRs of the TM23 murine antibody.

[00394] In some embodiments, the light or the heavy chain variable framework (e.g., the region encompassing at least FR1, FR2, FR3, and optionally FR4) of the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule can be chosen from: (a) a light or heavy chain variable framework including at least 80%, 85%, 87% 90%, 92%, 93%, 95%, 97%, 98%, or 100% of the amino acid residues from a human light or heavy chain variable framework, e.g., a light or heavy chain variable framework residue from a human mature antibody, a human germline sequence, or a human consensus sequence; (b) a light or heavy chain variable framework including from 20% to 80%, 40% to 60%, 60% to 90%, or 70% to 95% of the amino acid residues from a human light or heavy chain variable framework, e.g., a light or heavy chain variable framework residue from a human mature antibody, a human germline sequence, or a human consensus sequence; (c) a non-human framework (e.g., a rodent framework); or (d) a non-human framework that has been modified, e.g., to remove antigenic or cytotoxic determinants, e.g., deimmunized, or partially humanized. In some embodiments, the light or heavy chain variable framework region (particularly FR1, FR2 and / or FR3) includes a light or heavy chain variable framework sequence at least 70, 75, 80, 85, 87, 88, 90, 92, 94, 95, 96, 97, 98, 99% identical or identical to the frameworks of a VU or VH segment of a human germline gene.

[00395] In some embodiments, the anti-TCRpV antibody molecule, e.g, anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises a heavy chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more changes, e.g, amino acid substitutions or deletions, from an amino acid sequence of any one of A-H.l 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, shown in FIG. 2A, or in SEQ ID NO: 9.

[00396] Alternatively, or in combination with the heavy chain substitutions described herein, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises a light chain variable domain 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.l to A-H.85, e.g., A-H.l, A-H.2 or A-H.68, e.g., the amino acid sequence of the FR region in the entire variable region, e.g., shown in FIG. 2B, or in SEQ ID NO: 10 or SEQ ID NO: 11. 23 12 25

[00397] In some embodiments, the anti-TCRpV antibody molecule, e.g, anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes one, two, three, or four heavy chain framework regions shown in FIG. 2A, or a sequence substantially identical thereto.

[00398] In some embodiments, the anti-TCRpV antibody molecule, e.g, anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes one, two, three, or four light chain framework regions shown in FIG. 2B, or a sequence substantially identical thereto.

[00399] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the light chain framework region 1 of A-H. 1 or A-H.2, e.g., as shown in FIG. 2B.

[00400] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the light chain framework region 2 of A-H. 1 or A-H.2, e.g., as shown in FIG. 2B.

[00401] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the light chain framework region 3 of A-H. 1 or A-H.2, e.g., as shown in FIG. 2B.

[00402] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the light chain framework region 4 of A-H. 1 or A-H.2, e.g., as shown in FIG. 2B.

[00403] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises a light chain variable domain comprising a framework region, e.g., framework region 1 (FR1), comprising a change, e.g., a substitution (e.g., a conservative substitution) at position 10 according to Kabat numbering. In some embodiments, the FR1 comprises a Phenylalanine at position 10, e.g., a Serine to Phenyalanine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[00404] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises a light chain variable domain comprising a framework region, e.g., framework region 2 (FR2), comprising a change, e.g., a substitution (e.g., a conservative substitution) at a position as described herein according to Kabat numbering. In some embodiments, FR2 comprises a Histidine at position 36, e.g., a substitution at position 36 according to Kabat numbering, e.g., a Tyrosine to Histidine substitution. In some embodiments, FR2 comprises an Alanine at position 46, e.g., a substitution at position 46 according to Kabat numbering, e.g., an Arginine to Alanine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[00405] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises a light chain variable domain comprising a framework region, e.g., framework region 3 (FR3), comprising a change, e.g., a substitution (e.g., a conservative substitution) at a position as described herein according to Kabat numbering. In some embodiments, FR3 23 12 25 comprises a Phenyalanine at position 87, e.g., a substitution at position 87 according to Kabat numbering, e.g., a Tyrosine to Phenyalanine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[00406] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises a light chain variable domain comprising: (a) a framework region 1 (FR1) comprising a Phenylalanine at position 10, e.g., a substitution at position 10 according to Kabat numbering, e.g., a Serine to Phenyalanine 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 Phenyalanine 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.

[00407] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises a light chain variable domain comprising: (a) a framework region 2 (FR2) comprising a Histidine at position 36, e.g., a substitution at position 36 according to Kabat numbering, e.g., a Tyrosine to Histidine substitution, and a Alanine at position 46, e.g., a substitution at position 46 according to Kabat numbering, e.g., a Arginine to Alanine substitution; and (b) a framework region 3 (FR3) comprising a Phenylalanine at position 87, e.g., a substitution at position 87 according to Kabat numbering, e.g., a Tyrosine to Phenyalanine 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.

[00408] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises a light chain variable domain comprising: (a) a framework region 1 (FR1) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all) positions as described herein according to Kabat numbering, ; (b) a framework region 2 (FR2) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all) position as described herein according to Kabat numbering and (c) a framework region 3 (FR3) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all) position as described herein according to Kabat numbering. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[00409] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the heavy chain framework region 1 ofA-H.l orA-H.2, e.g., as shown in FIG. 2A. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the heavy chain framework region 2 of A-H. 1 or A-H.2, e.g., as shown in FIG. 2A. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti- 23 12 25 TCRP V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the heavy chain framework region 3 of A-H. 1 or A-H.2, e.g., as shown in FIG. 2A. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the heavy chain framework region 4 of A-H.l or A-H.2, e.g., as shown in FIG. 2A.

[00410] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises a heavy chain variable domain comprising a framework region, e.g., framework region 3 (FR3), comprising a change, e.g., a substitution (e.g., a conservative substitution) at a position as described herein according to Kabat numbering. In some embodiments, FR3 comprises a Threonine at position 73, e.g., a substitution at position 73 according to Kabat numbering, e.g., a Glutamic Acid to Threonine substitution. In some embodiments, FR3 comprises a Glycine at position 94, e.g., a substitution at position 94 according to Kabat numbering, e.g., an Arginine to Glycine substitution. In some embodiments, the substitution is relative to a human germline heavy chain framework region sequence.

[00411] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises a heavy chain variable domain comprising a framework region 3 (FR3) comprising a Threonine at position 73, e.g., a substitution at position 73 according to Kabat numbering, e.g., a Glutamic Acid to Threonine substitution, and a Glycine at position 94, e.g., a substitution at position 94 according to Kabat numbering, e.g., a Arginine to Glycine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 10.

[00412] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the heavy chain framework regions 1-4 of A-H. 1 or A-H.2, e.g., SEQ ID NO: 9, or as shown in FIGS. 2A and 2B. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the light chain framework regions 1-4 of A-H.l, e.g., SEQ ID NO: 10, or as shown in FIGS. 2A and 2B. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the light chain framework regions 1-4 of A-H.2, e.g., SEQ ID NO: 11, or as shown in FIGS. 2A and 2B. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the heavy chain framework regions 1-4 of A-H.l, e.g., SEQ ID NO: 9; and the light chain framework regions 1-4 of A-H. 1, e.g., SEQ ID NO: 10, or as shown in FIGS. 2A and 2B. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the heavy chain framework regions 1-4 of A-H.2, e.g., SEQ ID NO: 9; and the light chain framework regions 1-4 of A-H.2, e.g., SEQ ID NO: 11, or as shown in FIGS. 2A and 2B.

[00413] In some embodiments, the heavy or light chain variable domain, or both, of the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes an amino acid sequence, which is substantially identical to an amino acid as described herein, e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical to a variable region of an antibody described 23 12 25 herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H. 1, A-H.2 or A-H.68, or as described in Table 1, or 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.

[00414] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises at least one, two, three, or four antigen-binding regions, e.g., variable regions, having an amino acid sequence as set forth in Table 1, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the sequences shown in Table 1. In another embodiment, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule includes a VH and / or VL domain encoded by a nucleic acid having a nucleotide sequence as set forth in Table 1, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Table 1.

[00415] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 9, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 9, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 9; and / or a VL domain comprising the amino acid sequence of SEQ ID NO: 10, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 10.

[00416] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 9, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 9, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 9; and / or a VL domain comprising the amino acid sequence of SEQ ID NO: 11, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 11, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 11.

[00417] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule is a full antibody or fragment thereof (e.g., aFab, F(ab')2, Fv, single domain antibody, or a single chain Fv fragment (scFv)). In embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule is a monoclonal antibody or an antibody with single specificity. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, can also be a humanized, chimeric, camelid, shark, or an in w / ro-gcncratcd antibody molecule. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, is a humanized antibody 23 12 25 molecule. The heavy and light chains of the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, can be full-length (e.g, an antibody can include at least one, and preferably two, complete heavy chains, and at least one, and preferably two, complete light chains) or can include an antigen-binding fragment (e.g., a Fab, F(ab')2, Fv, a single chain Fv fragment, a single domain antibody, a diabody (dAb), a bivalent antibody, or bispecific antibody or fragment thereof, a single domain variant thereof, or a camelid antibody).

[00418] In some embodiments, the anti-TCRpV antibody molecule, e.g, anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, is in the form of a multispecific molecule, e.g, a bispecific molecule, e.g., as described herein.

[00419] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, has a heavy chain constant region (Fc) chosen from, e.g., the heavy chain constant regions of IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE. In some embodiments, the Fc region is chosen from the heavy chain constant regions of IgGl, IgG2, IgG3, and IgG4. In some embodiments, the Fc region is chosen from the heavy chain constant region of IgGl or IgG2 (e.g., human IgGl, or IgG2). In some embodiments, the heavy chain constant region is human IgGl. In some embodiments, the Fc region comprises a Fc region variant, e.g., as described herein.

[00420] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, has a light chain constant region chosen from, e.g., the light chain constant regions of kappa or lambda, preferably kappa (e.g., human kappa). In some embodiments, the constant region is altered, e.g., mutated, to modify the properties of the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function). For example, the constant region is mutated at positions 296 (M to Y), 298 (S to T), 300 (T to E), 477 (H to K) and 478 (N to F) to alter Fc receptor binding (e.g., the mutated positions correspond to positions 132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K) and 314 (N to F) of SEQ IDNOs: 212 or 214; or positions 135 (MtoY), 137 (S to T), 139(TtoE), 316 (H to K) and 317 (N to F) of SEQ ID NOs: 215, 216, 217 or 218), e.g., relative to human IgGl.

[00421] 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.

[00422] Additional exemplary humanized anti-TCRB V6 antibodies are provided in Table 1. In some embodiments, the anti-TCRp V6 is antibody A, e.g., humanized antibody A (antibody A-H), as provided 23 12 25 in Table 1. In some embodiments, the anti-TCRpV antibody comprises one or more (e.g., all three) of a LC CDR1, LC CDR2, and LC CDR3 provided in Table 1; and / or one or more (e.g., all three) of a HC CDR1, HC CDR2, and HC CDR3 provided in Table 1, or a sequence with at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity thereto. In some embodiments, antibody A comprises a 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.

[00423] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises a VH of A-H.l, A-H.2, A-H.3, A-H.4, A-H.5, A-H.6, A-H.7, A-H.8, A-H.9, A-H.10, A-H.l 1, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16, A-H.17, A-H.18, A-H.19, A-H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A-H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.l, A-H.42, A-H.43, A-H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A-H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A-H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A-H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[00424] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises a VL of A-H.l, A-H.2, A-H.3, A-H.4, A-H.5, A-H.6, A-H.7, A-H.8, A-H.9, A-H.10, A-H.l 1, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16, A-H.17, A-H.18, A-H.19, A-H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A-H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.l, A-H.42, A-H.43, A-H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A-H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A-H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A-H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[00425] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises a VH of A-H.l, A-H.2, A-H.3, A-H.4, A-H.5, A-H.6, A-H.7, A-H.8, A-H.9, A-H.10, A-H.l 1, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16, A-H.17, A-H.18, A-H.19, A-H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A-H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.l, A-H.42, A-H.43, A-H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A-H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A-H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A-H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto; and a VL of A-H.l, A-H.2, A-H.3, A-H.4, A-H.5, A-H.6, 23 12 25 A-H.7, A-H.8, A-H.9, A-H.10, A-H.ll, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16, A-H.17, A-H.18, A-H.19, A-H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A-H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.l, A-H.42, A-H.43, A-H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A-H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A-H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A-H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[00426] Exemplary anti-TCRpV antibody molecules and the corresponding TCRpV subfamilies recognized by said anti-TCRpV antibody molecules are disclosed in Table 10A.

[00427] The various TCRpV subfamilies and / or subfamily members can be expressed at different levels in individuals, e.g., healthy individuals, as disclosed in Kitaura K. et al (2016), BMC Immunology vol 17: 38. For example, TCRP V6-5 is represented in approximately 3-6% healthy donors.

[00428] The representation of various TCRBV subfamilies and / or subfamily members can also be different in cancer cells. For example, TCRpV is present in about 3-6% of tumor infdtrating T cells irrespective of tumor type (see Li B. et al., Nature Genetics, 2016, vol:48(7):725-32). Li et al., also disclose that TCRP V6-5 is present at a high frequency in tumor cells. Anti-TCRB V6 antibodies

[00429] Provided herein is an anti-TCRpV antibody molecule that binds to human TCRP V6, e.g., a TCRP V6 subfamily comprising: TCRP V6-4*01, TCRP V6-4*02, TCRP V6-9*01, TCRP V6-8*01, TCRP V6-5*01, TCRP V6-6*02, TCRP V6-6*01, TCRP V6-2*01, TCRP V6-3*01 or TCRP V6-l*01. In some embodiments the TCRP V6 subfamily comprises TCRP V6-5*01 or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-4*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-4*02, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-9*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-8*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-5*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-6*02, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-6*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-2*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-3*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-l*01, or a variant thereof.

[00430] In some embodiments, TCRP V6-5*01 is encoded by the nucleic acid sequence of SEQ ID NO: 43, or a sequence having 85%, 90%, 95%, 99% or more identity thereof. In some embodiments, TCRP V6-5*01 comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence having 85%, 90%, 95%, 99% or more identity thereof.

[00431] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 {e.g., anti-TCRp V6-5*01) antibody molecule, is a non-murine antibody molecule, e.g., a human or humanized antibody 23 12 25 molecule. In some embodiments, the anti-TCRpV antibody molecule, e.g, anti-TCRp V6 (e.g., anti-TCRP V6-5*01) antibody molecule is a human antibody molecule. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule is a humanized antibody molecule.

[00432] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, is isolated or recombinant.

[00433] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises at least one antigen-binding region, e.g., a variable region or an antigen-binding fragment thereof, from an antibody described herein, e.g., an antibody chosen from any one of A-H. 1 to A-H.85, e.g., A-H.l, A-H.2 or A-H.68, or an antibody described in Table 1, or encoded by 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.

[00434] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises at least one, two, three or four variable regions from an antibody described herein, e.g., an antibody chosen from any one of A-H. 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.

[00435] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises at least one or two heavy chain variable regions from an antibody described herein, e.g., an antibody chosen from any one of A-H. 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, 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.

[00436] In some embodiments, the anti-TCRpV antibody molecule comprises a heavy chain variable region (VH) having a consensus sequence of SEQ ID NO: 231 or 3290.

[00437] SEQ ID NO: 231 - Consensus VH QVQLVQSGAEVKKPGSSVKVSCKASGH / T / G / YD / T / SFH / R / D / K / TL / D / K / T / NW / F / T / I / Y / GYIHWV RQAPGQGLEWMGR / WV / I / FF / S / YA / PGSGN / ST / V / Y / IK / RYNEKFKGRVTITADTSTSTAYMELSSL RSEDTAVYYCAG / VSY / IYSY / AD / GVLDYWGQGTTVTVSS

[00438] SEQ ID NO: 3290 - Consensus VH QVQLVQSGAEVKKPGSSVKVSCKASGXiX2FX3X4X5YIHWVRQAPGQGLEWMGX6X7X8X9GSGXi 0X11X12YNEKFKGRVTITADTSTSTAYMELSSLRSEDTAVYYCAX13SX14YSX15X16VLDYWGQGTT VTVSS, where-in: XI is H or T or G or Y; X2 is D or T or S; X3 is H or R or D or K or T; X4 is L or D or K or T or N; X5 is W or F or T or I or Y or G; X6 is R or W; X7 is V or I or F; X8 is F or S or Y; X9 is A or P; X10 is N or S; XI1 is T or V or Y or I; X12 is K or R; X13 is G or V; X14 is Y or I; X15 is Y or A; and X16 is D or G. 23 12 25

[00439] In some embodiments, the anti-TCRpV antibody molecule, e.g, anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises at least one or two light chain variable regions from an antibody described herein, e.g., an antibody chosen from any one of A-H. 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.

[00440] In some embodiments, the anti-TCRpV antibody molecule comprises a light chain variable region (VL) having a consensus sequence of SEQ ID NO: 230 or 3289.

[00441] SEQ ID NO: 230 - Consensus VL DIQMTQSPSFLSASVGDRVTITCKASQNVG / E / A / DN / DR / KVAWY / HQQKPGKAPKALIYSSSHRY K / SGVPSRFSGSGSGTEFTLTISSLQPEDFATYFCQQFKSYPLTFGQGTKLEIK

[00442] SEQ ID NO: 3289 - Consensus VL DIQMTQSPSFLSASVGDRVTITCKASQNVX1X2X3VAWX4QQKPGKAPKALIYSSSHRYX5GVPSRF SGSGSGTEFTLTISSLQPEDFATYFCQQFKSYPLTFGQGTKLEIK, wherein XI is G, E, A or D; X2 is N or D; X3 is R or K; X4 is Y or H; and X5 is K or S

[00443] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises a heavy chain constant region for an IgG4, e.g., a human IgG4. In still another embodiment, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule includes a heavy chain constant region for an IgGl, e.g., a human IgGl. In some embodiments, the heavy chain constant region comprises an amino sequence set forth in Table 3, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto.

[00444] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes a kappa light chain constant region, e.g., a human kappa light chain constant region. In some embodiments, the light chain constant region comprises an amino sequence set forth in Table 3, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto.

[00445] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region (VH) of an antibody described herein, e.g., an antibody chosen from any one of A-H. 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.

[00446] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1. In some embodiments, one or more of the CDRs (or collectively 23 12 25 all of the CDRs) have one, two, three, four, five, six or more changes, e.g, amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[00447] In some embodiments, the anti-TCRpV antibody molecule, e.g, anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes at least one, two, or three complementarity determining regions (CDRs) from a light chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H.l, A-H.2 or A-H.68, or an antibody described in Table 1, or encoded by a nucleotide sequence in Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[00448] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[00449] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[00450] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, molecule includes all six CDRs from an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H.l, A-H.2 or A-H.68, or an antibody described in Table 1, or encoded by a nucleotide sequence in Table 1, or closely related CDRs, e.g., CDRs which are identical or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions). In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, may include any CDR described herein.

[00451] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule includes at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Table 1) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H. 1 to A-H.85, e.g., A-H. 1, A-H.2 or A-H.68, or an antibody described in Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the 23 12 25 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.

[00452] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule includes at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Table 1) from a light chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H. 1 to A-H.85, e.g., A-H. 1, A-H.2 or A-H.68, or an antibody described in Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Kabat et al. shown in Table 1.

[00453] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes at least one, two, three, four, five, or six CDRs according to Kabat et al. (e.g., at least one, two, three, four, five, or six CDRs according to the Kabat definition as set out in Table 1) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any one of A-H. 1 to A-H.85, e.g., A-H. 1, A-H.2 or A-H.68, or an antibody described in Table 1, or encoded by a nucleotide sequence in Table 1; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, three, four, five, or six CDRs according to Kabat et al. shown in Table 1.

[00454] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes all six CDRs according to Kabat et al. (e.g., all six CDRs according to the Kabat definition as set out in Table 1) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any one of A-H. 1 to A-H.85, e.g., A-H. 1, A-H.2 or A-H.68, or an antibody described in Table 1, or encoded by a nucleotide sequence in Table 1; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to all six CDRs according to Kabat et al. shown in Table 1. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, may include any CDR described herein.

[00455] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes at least one, two, or three hypervariable loops that have the same canonical structures as the corresponding hypervariable loop of an antibody described herein, e.g., an antibody chosen from chosen from any one of A-H.l to A-H.85, e.g., A-H. 1, A-H.2 or A-H.68, e.g., the 23 12 25 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.

[00456] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule includes at least one, two, or three CDRs according to Chothia et al. (e.g., at least one, two, or three CDRs according to the Chothia definition as set out in Table 1) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H. 1 to A-H.85, e.g., A-H.l, A-H.2 or A-H.68, or as described in Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Chothia et al. shown in Table 1.

[00457] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule includes at least one, two, orthree 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) 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, 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, orthree CDRs according to Chothia et al. shown in Table 1.

[00458] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes at least one, two, three, four, five, or six CDRs according to Chothia et al. (e.g., at least one, two, three, four, five, or six CDRs according to the Chothia definition as set out in Table 1) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H.l, A-H.2 or A-H.68, or an antibody described in Table 1, or encoded by the nucleotide sequence in Table 1; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, three, four, five, or six CDRs according to Chothia et al. shown in Table 1.

[00459] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes all six CDRs according to Chothia et al. (e.g., all six CDRs according to the Chothia definition as set out in Table 1) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any one of A-H. 1 to A-H.85, e.g., A-H. 1, A-H.2 or A-H.68, or an antibody described in Table 1, or encoded by a nucleotide sequence in Table 1; or 23 12 25 a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to all six CDRs according to Chothia et al. shown in Table 1. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, may include any CDR described herein.

[00460] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, molecule includes a combination of CDRs or hypervariable loops defined according to Kabat et al., Chothia et al., or as described in Table 1.

[00461] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, can contain any combination of CDRs or hypervariable loops according to the Kabat and Chothia definitions.

[00462] In some embodiments, a combined CDR as set out in Table 1 is a CDR that comprises a Kabat CDR and a Chothia CDR.

[00463] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, molecule includes a combination of CDRs or hypervariable loops identified as combined CDRs in Table 1. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, can contain any combination of CDRs or hypervariable loops according the “combined” CDRs are described in Table 1.

[00464] 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, 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.

[00465] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule includes: (i) one, two or all of a light chain complementarity determining region 1 (LC CDR1), a light chain complementarity determining region 2 (LC CDR2), and a light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO: 2, SEQ ID NO: 10 or SEQ ID NO: 11, and / or (ii) one, two or all of a heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 1 or SEQ ID NO: 9.

[00466] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises a LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 2, and a HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 1. 23 12 25

[00467] In some embodiments the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises a LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 10, and a HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 9.

[00468] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises a LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 11, and a HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 9.

[00469] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 6, a LC CDR2 amino acid sequence of SEQ ID NO: 7, or a LC CDR3 amino acid sequence of SEQ ID NO: 8; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 3, a HC CDR2 amino acid sequence of SEQ ID NO: 4, or a HC CDR3 amino acid sequence of SEQ ID NO: 5.

[00470] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1 amino acid sequence of SEQ ID NO: 6, a LC CDR2 amino acid sequence of SEQ ID NO: 7, or a LC CDR3 amino acid sequence of SEQ ID NO: 8; and / or (ii) a heavy chain variable region (VH) comprising a HC CDR1 amino acid sequence of SEQ ID NO: 3, a HC CDR2 amino acid sequence of SEQ ID NO: 4, or a HC CDR3 amino acid sequence of SEQ ID NO: 5.

[00471] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 51, a LC CDR2 amino acid sequence of SEQ ID NO: 52, or a LC CDR3 amino acid sequence of SEQ ID NO: 53; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 45, a HC CDR2 amino acid sequence of SEQ ID NO: 46, or a HC CDR3 amino acid sequence of SEQ ID NO: 47.

[00472] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1 amino acid sequence of SEQ ID NO: 51, a LC CDR2 amino acid sequence of SEQ ID NO: 52, or a LC CDR3 amino acid sequence of SEQ ID NO: 53; and / or (ii) a heavy chain variable region (VH) comprising a HC CDR1 amino acid sequence of SEQ ID NO: 45, a HC CDR2 amino acid sequence of SEQ ID NO: 46, or a HC CDR3 amino acid sequence of SEQ ID NO: 47.

[00473] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 54, a LC CDR2 amino acid sequence of SEQ ID NO: 55, or a LC CDR3 amino acid sequence of SEQ ID NO: 56; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 48, a HC CDR2 amino acid sequence of SEQ ID NO: 49, or a HC CDR3 amino acid sequence of SEQ ID NO: 50.

[00474] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1 amino acid sequence of SEQ ID NO: 54, a LC CDR2 amino acid sequence of SEQ ID NO: 55, or a LC CDR3 amino acid sequence of SEQ ID NO: 56; and / or (ii) a heavy chain variable region (VH) 23 12 25 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.

[00475] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises a VH and / or a VL of an antibody described in Table 1, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[00476] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises a VH and a VL of an antibody described in Table 1, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[00477] 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.

[00478] In some embodiments, an anti-TCRVb antibody as described herein has an antigen binding domain having a VH having a consensus sequence of SEQ ID NO: 231, wherein: position 27 is H or T or G or Y; position 28 is D or T or S; position 30 is H or R or D or K or T; position 31 is L or D or K or T or N; position 32 is W or F or T or I or Y or G; position 49 is R or W; position 50 is V or I or F; position 51 is F or S or Y; position 52 is A or P; position 56 is N or S; position 57 is T or V or Y or I; position 58 is K or R; position 97 is G or V; position 99 is Y or I; position 102 is Y or A; and / or position 103 is D or G. Anti-TCRB VI2 antibodies

[00479] Provided herein is an anti-TCRpV antibody molecule that binds to human TCRp V12, e.g., a TCRp V12 subfamily comprising: TCRp V12-4*01, TCRp V12-3*01 or TCRp V12-5*01. In some embodiments the TCRP V12 subfamily comprises TCRP V12-4*01. In some embodiments the TCRP V12 subfamily comprises TCRP V12-3*01.

[00480] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, is a non-murine antibody molecule, e.g., a human or humanized antibody molecule. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule is a human antibody molecule. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule is a humanized antibody molecule.

[00481] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, is isolated or recombinant.

[00482] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, comprises at least one antigen-binding region, e.g., a variable region or an antigen-binding fragment thereof, from an antibody described herein, e.g., an antibody described in Table 2, or encoded by a nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[00483] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, comprises at least one, two, three or four variable regions from an antibody described herein, 23 12 25 e.g., an antibody as described in Table 2, or encoded by a nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[00484] In some embodiments, the anti-TCR.[W antibody molecule, e.g., anti-TC^Rp A^12 antibody molecule, comprises at least one or two heavy chain variable regions from an antibody described herein, e.g., an antibody as described in Table 2, or encoded by a nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[00485] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, comprises at least one or two light chain variable regions from an antibody described herein, e.g., an antibody as described in Table 2, or encoded by a nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[00486] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, comprises a heavy chain constant region for an IgG4, e.g., a human IgG4. In still another embodiment, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, includes a heavy chain constant region for an IgGl, e.g., a human IgGl. In some embodiments, the heavy chain constant region comprises an amino sequence set forth in Table 3, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto.

[00487] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 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.

[00488] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, includes at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[00489] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, includes at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Table 2, or encoded by a nucleotide sequence shown in Table 2. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 2, or encoded by a nucleotide sequence shown in Table 2. 23 12 25

[00490] In some embodiments, the anti-TCRpV antibody molecule, e.g, anti-TCRp V12 antibody molecule, includes at least one, two, or three complementarity determining regions (CDRs) from a light chain variable region of an antibody described herein, e.g, an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[00491] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, includes at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Table 2, or encoded by a nucleotide sequence shown in Table 2. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 2, or encoded by a nucleotide sequence shown in Table 2.

[00492] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 2, or encoded by a nucleotide sequence shown in Table 2. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 2, or encoded by a nucleotide sequence shown in Table 2.

[00493] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, molecule includes all six CDRs from an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2, or closely related CDRs, e.g., CDRs which are identical or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions). In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, may include any CDR described herein.

[00494] In some embodiments, the anti—TCR]fV antibody molecule, e.g., anti—TC^Rp A^12 antibody molecule includes at least one, two, or three CDRs according to Kabat etal. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Table 2) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen as described in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Kabat et al. shown in Table 2.

[00495] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule includes at least one, two, or three CDRs according to Kabat etal. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Table 2) from a light chain variable region of 23 12 25 an antibody described herein, e.g., an antibody as described in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Kabat et al. shown in Table 2.

[00496] In some embodiments, the anti-TCR[3V antibody molecule, e.g, anti-TCRp V12 antibody molecule includes at least one, two, three, four, five, or six CDRs according to Kabat et al. (e.g., at least one, two, three, four, five, or six CDRs according to the Kabat definition as set out in Table 2) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, three, four, five, or six CDRs according to Kabat et al. shown in Table 2.

[00497] In some embodiments, the anti-TCRpV antibody molecule, e.g, anti-TCRp V12 antibody molecule includes all six CDRs according to Kabat et al. (e.g., all six CDRs according to the Kabat definition as set out in Table 2) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2; or encoded by the nucleotide sequence in Table 2; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to all six CDRs according to Kabat et al. shown in Table 2. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule may include any CDR described herein.

[00498] In some embodiments, the anti-TCRpV antibody molecule, e.g, anti-TCRp V12 antibody molecule includes at least one, two, or three hypervariable loops that have the same canonical structures as the corresponding hypervariable loop of an antibody described herein, e.g., an antibody described in Table 2, e.g., the same canonical structures as at least loop 1 and / or loop 2 of the heavy and / or light chain variable domains of an antibody described herein. See, e.g., Chothia et al., (1992) J. Mol. Biol. 227:799-817; 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.

[00499] In some embodiments, the anti-TCRpV antibody molecule, e.g, anti-TCRp V12 antibody molecule includes at least one, two, or three CDRs according to Chothia etal. (e.g., at least one, two, or three CDRs according to the Chothia definition as set out in Table 2) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen as described in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, 23 12 25 three or four alterations (e.g., substitutions, deletions, or insertions, e.g, conservative substitutions) relative to one, two, or three CDRs according to Chothia et al. shown in Table 2.

[00500] In some embodiments, the anti-TCRpV antibody molecule, e.g, anti-TCRp V12 antibody molecule includes at least one, two, or three CDRs according to Chothia et al. (e.g., at least one, two, or three CDRs according to the Chothia definition as set out in Table 2) from a light chain variable region of an antibody described herein, e.g., an antibody as described in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Chothia et al. shown in Table 2.

[00501] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule includes at least one, two, three, four, five, or six CDRs according to Chothia et al. (e.g....

Claims

26 11 25What is claimed is:

1. A bispecific polypeptide molecule comprising a T cell receptor beta chain variable region(TCRpV)-binding moiety and at least one cytokine polypeptide or a functional fragment or variant thereof;wherein the TCRpV-binding moiety binds to a human TCRPV;wherein the bispecific polypeptide molecule comprises a first polypeptide and a second polypeptide;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 TCRpV-binding moiety, wherein the TCRpV-binding moiety comprises a heavy chain variable domain (VH) and a light chain variable domain (VL), or a single domain antibody, or(B) a first portion of the TCRpV-binding moiety comprising a VH of the TCRPV-binding moiety, wherein the bispecific polypeptide molecule further comprises a third polypeptide comprising a second portion of the TCRpV-binding moiety comprising a VL of the TCRpV-binding moiety, 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, wherein the at least one cytokine polypeptide or a functional fragment or variant thereof is covalently linked to the second portion of the dimerization module; andwherein the at least one cytokine polypeptide or a functional fragment or variant thereof comprises, from N-terminus to C-terminus, the sequence of SEQ ID NO: 3523 operatively linked to the sequence of SEQ ID NO: 2170.

2. The bispecific polypeptide molecule of claim 1, wherein the sequence of SEQ ID NO: 3523is operatively linked to the sequence of SEQ ID NO: 2170 via a Gly-Ser linker.

3. The bispecific polypeptide molecule of claim 2, wherein the Gly-Ser linker comprises the sequence of SEQ ID NO: 3524.

4. The bispecific polypeptide molecule of any one of claims 1 to 3, wherein the at least one cytokine polypeptide or a functional fragment or variant thereof is an agonist of a cytokinereceptor.

5. The bispecific polypeptide molecule of any one of claims 1 to 4, wherein the TCRPV-binding moiety binds to one or more of a human TCRPV subfamily selected from the groupconsisting of TCRPV1 subfamily, TCRPV2 subfamily, TCRPV3 subfamily, TCRPV4 subfamily,TCRPV5 subfamily, TCRPV6 subfamily, TCRPV7 subfamily, TCRPV9 subfamily, TCRPVIOsubfamily, TCRPV11 subfamily, TCRPV12 subfamily, TCRPV19 subfamily, TCRPV20 subfamily, TCRPV24 subfamily, TCRPV25subfamily, TCRPV13 subfamily, TCRPV16 subfamily, TCRPV21 subfamily, TCRPV23 subfamily, TCRPV26 subfamily, TCRPV27subfamily, TCRPV28 subfamily, TCRPV29 subfamily, and TCRPV30 subfamily.26 11 256. The bispecific polypeptide molecule of any one of claims 1 to 5, wherein the TCRPV-binding moiety comprises any one selected from the group consisting of a full antibody, a bivalent antibody, a Fab, a F(ab')2, an Fv, a single chain Fv (scFv), a single domain antibody, and a camelidantibody.

7. The bispecific polypeptide molecule of any one of claims 1 to 6, wherein the TCRPV-binding moiety comprises an Fab, a single domain antibody, or an scFv.

8. The bispecific polypeptide molecule of any one of claims 1 to 7, wherein the first portion of the dimerization module comprises a first immunoglobulin constant region and the second portion of the dimerization module comprises a second immunoglobulin constant region.

9. The bispecific polypeptide molecule of claim 8, wherein the first immunoglobulin constantregion comprises a first Fc region, and the second immunoglobulin constant region comprises a second Fc region, andwherein the first Fc region, the second Fc region, or a combination thereof is selected from the group consisting of an IgGl Fc region or a fragment thereof, an IgG2 Fc region or a fragment thereof, an IgG3 Fc region or a fragment thereof, an IgGAl Fc region or a fragment thereof, an IgGA2 Fc region or a fragment thereof, an IgG4 Fc region or a fragment thereof, an IgJ Fc region or a fragment thereof, an IgM Fc region or a fragment thereof, an IgD Fc region or a fragment thereof, and an IgE Fc region or a fragment thereof.

10. The bispecific polypeptide molecule of claim 9, wherein:26 11 25(i) 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 dimerization of the first Fc region and the second Fc region is enhanced as indicated by a greater ratio of heteromultimer: homomultimer forms relative to dimerization of Fc regions with a non-engineered interface; and / or(ii) the first Fc region, the second Fc region, or a combination thereof comprises an Asn297Ala (N297A) mutation or a Leu234Ala / Leu235Ala (LALA) mutation according to EU Numbering.

11. The bispecific polypeptide molecule of claim 9 or 10, 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: 41, SEQ ID NO: 42, SEQ ID NO: 3531, SEQ ID NO: 3533, SEQ ID NO: 3537, SEQ ID NO: 3645, SEQ ID NO: 3646, SEQ ID NO: 3647, SEQ ID NO: 3648, or SEQ ID NO: 3649; andoptionally, wherein the first Fc region, the second Fc region, or a combination thereof comprises the sequence of SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 3531, SEQ ID NO: 3533, SEQ ID NO: 3537, SEQ ID NO: 3645, SEQ ID NO: 3646, SEQ ID NO: 3647, SEQ ID NO: 3648, or SEQ ID NO: 3649.

12. The bispecific polypeptide molecule of any one of claims 1 to 11, wherein the first portion of the dimerization module comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3649 and the second portion of the dimerization module comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3648; andoptionally, wherein the first portion of the dimerization module comprises the sequence of SEQ ID NO: 3649 and the second portion of the dimerization module comprises the sequence of SEQ ID NO: 3648.

13. The bispecific polypeptide molecule of any one of claims 1 to 12, wherein the bispecific polypeptide molecule further comprises a light chain constant region operatively linked to the VL of the TCRpV-binding moiety; andwherein the light chain constant region is selected from the group consisting of a kappa light chain constant region or a fragment thereof and a lambda light chain constant region or a fragment thereof.26 11 2514. The bispecific polypeptide molecule of claim 13, wherein the light chain constant region comprises a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3644 or the sequence of SEQ ID NO: 3528; andoptionally, wherein the light chain constant region comprises the sequence of SEQ ID NO: 3644 or the sequence of SEQ ID NO: 3528.

15. The bispecific polypeptide molecule of any one of claims 1 to 14, wherein the TCRPV-binding moiety comprises:(i) a VH comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the sequence of SEQ ID NO: 3650, a heavy chain complementarity determining region 2 (HC CDR2) comprising the sequence of SEQ ID NO: 3651, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the sequence of SEQ ID NO: 5; and(ii) a VL comprising a light chain complementarity determining region 1 (LC CDR1) comprising the sequence of SEQ ID NO: 3655, a light chain complementarity determining region 2 (LC CDR2) comprising the sequence of SEQ ID NO: 3653, and a light chain complementarity determining region 3 (LC CDR3) comprising the sequence of SEQ ID NO: 8.

16. The bispecific polypeptide molecule of claim 15, wherein the TCRpV-binding moiety comprises:(i) a VH comprising an amino acid sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 1346; and / or(ii) a VL comprising an amino acid sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 1349; andoptionally, wherein:(i) the VH comprises the sequence of SEQ ID NO: 1346; and / or(ii) the VL comprises the sequence of SEQ ID NO: 1349.

17. The bispecific polypeptide molecule of any one of claims 1 to 16, wherein the bispecific polypeptide molecule comprises:(i) a first polypeptide comprising an anti-TCRpV antibody heavy chain variable region, and a first immunoglobulin heavy chain constant region;26 11 25(ii) a second polypeptide comprising an IL-15 receptor alpha sushi domain or a functional fragment or variant thereof, an IL-15 molecule or a functional fragment or variant thereof, and a second immunoglobulin heavy chain constant region; and(iii) a third polypeptide comprising an anti-TCRpV antibody light chain variable region, and an immunoglobulin light chain constant region; andwherein:(i) the first polypeptide comprises, from N-terminus to C-terminus, the anti-TCRpV antibody heavy chain variable region operatively linked to the first immunoglobulin heavy chain constant region;(ii) the second polypeptide comprises, from N-terminus to C-terminus, the IL-15 receptor alpha sushi domain or a functional fragment or variant thereof operatively linked to the IL-15 molecule or a functional fragment or variant thereof operatively linked to the second immunoglobulin heavy chain constant region; and(iii) the third polypeptide comprises, from N-terminus to C-terminus, the anti-TCRpV antibody light chain variable region operatively linked to the immunoglobulin light chain constant region.

18. The bispecific polypeptide molecule of any one of claims 1 to 17, wherein the bispecific polypeptide molecule comprises:(i) a first polypeptide comprising, from N-terminus to C-terminus, a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 1346 operatively linked to a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 3649;(ii) a second polypeptide comprising, from N-terminus to C-terminus, the sequence of SEQ ID NO: 3523 operatively linked to a sequence having the sequence of SEQ ID NO: 2170, optionally, via a Gly-Ser linker comprising the sequence of SEQ ID NO: 3524, wherein the sequence of SEQ ID NO: 2170 is operatively linked to a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 3648, optionally, via the sequence of SEQ ID NO: 3308; and(iii) a third polypeptide comprising, from N-terminus to C-terminus, a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 1349 operatively linked to a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 3644; optionally, wherein:26 11 25(i) the first polypeptide comprises, from N-terminus to C-terminus, the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 3649;(ii) the second polypeptide comprises, from N-terminus to C-terminus, the sequence of SEQ ID NO: 3523 operatively linked to the sequence of SEQ ID NO: 2170, optionally, via a Gly-Ser linker comprising the sequence of SEQ ID NO: 3524, wherein the sequence of SEQ ID NO: 2170 is operatively linked to the sequence of SEQ ID NO: 3648, optionally, via the sequence of SEQ ID NO: 3308; and(iii) the third polypeptide comprises, from N-terminus to C-terminus, the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 3644; andwherein:(i) the VH comprises a HC CDR1 comprising the sequence of SEQ ID NO: 3650, a HC CDR2 comprising the sequence of SEQ ID NO: 3651, and a HC CDR3 comprising the sequence of SEQ ID NO: 5; and(ii) a VL comprising a LC CDR1 comprising the sequence of SEQ ID NO: 3655, a LC CDR2 comprising the sequence of SEQ ID NO: 3653, and a LC CDR3 comprising the sequence of SEQ ID NO: 8.

19. The bispecific polypeptide molecule of any one of claims 1 to 18, wherein the bispecific polypeptide molecule comprises:(i) a first polypeptide comprising a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 3517;(ii) a second polypeptide comprising a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 3519; and(iii) a third polypeptide comprising a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 3518;optionally, wherein:(i) the first polypeptide comprises the sequence of SEQ ID NO: 3517;(ii) the second polypeptide comprises the sequence of SEQ ID NO: 3519; and(iii) the third polypeptide comprises the sequence of SEQ ID NO: 3518.26 11 2520. A recombinant polynucleotide comprising a sequence encoding the bispecific polypeptide molecule of any one of claims 1 to 19.

21. A medicament comprising the bispecific polypeptide molecule of any one of claims 1 to 19 or the recombinant polynucleotide of claim 20, and a pharmaceutically acceptable carrier, excipient, diluent, or stabilizer.

22. A pharmaceutical composition for use in treating cancer in a subject in need thereof, wherein the pharmaceutical composition comprises a therapeutically effective amount of the bispecific polypeptide molecule of any one of claims 1 to 19, the recombinant polynucleotide of claim 20, or the medicament of claim 21 for treating cancer in the subject when administered to the subject; andoptionally, wherein the cancer is a solid tumor, a hematological cancer, a metastatic cancer, a soft tissue tumor, or any combination thereof.

23. The pharmaceutical composition for use of claim 22, wherein:(i) the cancer is a solid tumor 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; or(ii) the cancer is a hematological cancer 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 any combination thereof.

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