Multifunctional molecules binding to TCR and uses thereof

Description

MULTIFUNCTIONAL MOLECULES BINDING TO TCR AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application 63 / 688,706 filed on August 29, 2024, which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] Currently available molecules designed to redirect T cells to promote tumor cell lysis for cancer immunotherapy typically target the CD3 epsilon (CD3e) subunit of the T cell receptor (TCR). However, there are limitations to this approach. Previous studies have shown that, e.g., low doses of anti-CD3e monoclonal antibody (mAb) can cause T cell dysfunction and exert immunosuppressive effects. In addition, anti-CD3e mAbs bind to all T cells and thus activate a large number of T cells. Such non- physiological massive activation of T cells by these anti-CD3e mAbs can result in the production of proinflammatory cytokines such as IFN-gamma, IL- 1 -beta, IL-6, IL- 10 and TNF-alpha, causing a “cytokine storm” known as the cytokine release syndrome (CRS), which is also associated with neurotoxicity (NT). Thus, there is a need for improved T cell receptor-binding molecules that redirect T cells for cancer immunotherapy.SUMMARY

[0003] In an aspect, provided herein is, inter aha, a multispecific molecule comprising:(a) a tumor-associated antigen binding moiety, wherein the tumor-associated antigen binding moiety comprises a HER-2 binding moiety;(b) a molecule that binds to a co-stimulatory receptor of a T cell; and(c) a TCRβV-binding moiety, wherein the HER-2 binding moiety comprises an antibody domain or an antigen binding domain comprising:(i) a heavy chain variable region (VH) comprising a heavy chain complementarity-determining region 3 (HC CDR3) sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 628, 642, 643, 644, and 650; and / or(ii) a light chain variable region (VL) comprising a light chain complementarity-determining region 3(LC CDR3) sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 631, 640, and 653.

[0004] In some embodiments, the TCRβV-binding moiety is covalently linked to the molecule that binds to a co-stimulatory receptor of a T cell.

[0005] In some embodiments, the molecule that binds to a co-stimulatory receptor of a T cell activates the co-stimulatory receptor when the molecule that binds to a co-stimulatory receptor of a T cell binds to the co-stimulatory receptor.

[0006] In some embodiments, the molecule that binds to a co-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof.

[0007] In some embodiments, the molecule that binds to a co-stimulatory receptor of a T cell comprises an antibody molecule, an antigen binding domain, a ligand, an extracellular domain of a receptor, or any combination thereof.

[0008] In some embodiments, the antigen binding domain comprises any one selected from the group consisting of a full-length antibody, a Fab, a F(ab')2, an Fv, a single chain Fv, a camelid antibody, a VHH, a half arm antibody, a diabody, a bivalent antibody, a monovalent antibody, or a bispecific antibody, and any combination thereof.

[0009] In some embodiments, the HER-2 binding moiety comprises a VH comprising a HC CDR1 sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 626, 634,636, 648, and 656.

[0010] In some embodiments, the HER-2 binding moiety comprises a VH comprising a HC CDR2 sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 627, 635,637, 649, 657, and 658.

[0011] In some embodiments, the HER-2 binding moiety comprises a VH comprising a HC CDR1 sequence, a HC CDR2 sequence, and a HC CDR3 sequence comprising the sequences of:(i) SEQ ID NOs: 626, 627, and 628, respectively;(ii) SEQ ID NOs: 634, 635, and 628, respectively;(iii) SEQ ID NOs: 636, 637, and 628, respectively;(iv) SEQ ID NOs: 636, 637, and 642, respectively;(v) SEQ ID NOs: 636, 637, and 643, respectively;(vi) SEQ ID NOs: 636, 637, and 644, respectively;(vii) SEQ ID NOs: 648, 649, and 650, respectively;(viii) SEQ ID NOs: 656, 657, and 650, respectively; or(viii) SEQ ID NOs: 656, 658, and 650, respectively.

[0012] In some embodiments, the HER-2 binding moiety comprises a VL comprising a LC CDR1 sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 629, 632,638, 641, 651, 654, and 659.

[0013] In some embodiments, the HER-2 binding moiety comprises a VL comprising a LC CDR2 sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 630, 633,639, 652, 655, and 660.

[0014] In some embodiments, the HER-2 binding moiety comprises a VL comprising a LC CDR1 sequence, a LC CDR2 sequence, and a LC CDR3 sequence comprising the sequences of:(i) SEQ ID NOs: 629, 630, and 631, respectively;(ii) SEQ ID NOs: 632, 633, and 631, respectively;(iii) SEQ ID NOs: 638, 639, and 631, respectively;(iv) SEQ ID NOs: 629, 630, and 640, respectively;(v) SEQ ID NOs: 641, 639, and 631, respectively;(vi) SEQ ID NOs: 651, 652, and 653, respectively;(vii) SEQ ID NOs: 654, 655, and 653, respectively; or(vii) SEQ ID NOs: 659, 660, and 653, respectively;

[0015] In some embodiments, the HER-2 binding moiety comprises a VH and a VL, respectively, comprising a HC CDR1 sequence, a HC CDR2 sequence, and a HC CDR3 sequence, and a LC CDR1 sequence, a LC CDR2 sequence, and a LC CDR3 sequence comprising the sequences of:(i) SEQ ID NOs: 626, 627, 628, 629, 630, and 631, respectively;(ii) SEQ ID NOs: 626, 627, 628, 632, 633, and 631, respectively;(iii) SEQ ID NOs: 634, 635, 628, 629, 630, and 631, respectively;(iv) SEQ ID NOs: 634, 635, 628, 632, 633, and 631, respectively;(v) SEQ ID NOs: 636, 637, 628, 632, 633, and 631, respectively;(vi) SEQ ID NOs: 634, 635, 628, 638, 639, and 631, respectively;(vii) SEQ ID NOs: 636, 637, 628, 638, 639, and 631, respectively;(viii) SEQ ID NOs: 626, 627, 628, 629, 630, and 640, respectively;(ix) SEQ ID NOs: 636, 637, 628, 641, 639, and 631, respectively;(x) SEQ ID NOs: 636, 637, 642, 641, 639, and 631, respectively;(xi) SEQ ID NOs: 636, 637, 643, 641, 639, and 631, respectively;(xii) SEQ ID NOs: 636, 637, 644, 641, 639, and 631, respectively;(xiii) SEQ ID NOs: 648, 649, 650, 651, 652, and 653, respectively;(xiv) SEQ ID NOs: 648, 649, 650, 654, 655, and 653, respectively;(xv) SEQ ID NOs: 656, 657, 650, 651, 652, and 653, respectively;(xvi) SEQ ID NOs: 656, 657, 650, 654, 655, and 653, respectively;(xvii) SEQ ID NOs: 656, 658, 650, 654, 655, and 653, respectively;(xviii) SEQ ID NOs: 656, 657, 650, 659, 660, and 653, respectively; or(xix) SEQ ID NOs: 656, 658, 650, 659, 660, and 653, respectively;

[0016] In some embodiments, the HER-2 binding moiety comprises a VH comprising a sequence having at least 70% sequence identity to any one sequence selected from the group consisting of SEQ ID NOs:600, 603, 604, 607, 609, 610, 611, 616, 619, and 620.

[0017] In some embodiments, the HER-2 binding moiety comprises a VH comprising any one sequence selected from the group consisting of SEQ ID NOs: 600, 603, 604, 607, 609, 610, 611, 616, 619, and 620.

[0018] In some embodiments, the HER-2 binding moiety comprises a VL comprising a sequence having at least 70% sequence identity to any one sequence selected from the group consisting of SEQ ID NOs:601, 602, 605, 606, 608, 617, 618, and 621.

[0019] In some embodiments, the HER-2 binding moiety comprises a VL comprising any one sequence selected from the group consisting of SEQ ID NOs: 601, 602, 605, 606, 608, 617, 618, and 621.

[0020] In some embodiments, the HER-2 binding moiety comprises:(i) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 600, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ IDNO: 601;(ii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 600, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 602;(iii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 603, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 601;(iv) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:603, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 602;(v) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:604, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 602;(vi) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:603, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 605;(vii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:604, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 605;(viii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 600, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 606;(ix) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 607, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608;(x) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:609, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608;(xi) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:610, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608;(xii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:611, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608;(xiii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 616, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 617;(xiv) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:616, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 618;(xv) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 619, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 617;(xvi) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:619, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 618;(xvii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:620, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 618;(xviii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 619, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 621; or(xix) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 620, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 621.

[0021] In some embodiments, the HER-2 binding moiety comprises:(i) a VH comprising the sequence of SEQ ID NO: 600, and a VL comprising the sequence of SEQ ID NO: 601;(ii) a VH comprising the sequence of SEQ ID NO: 600, and a VL comprising the sequence of SEQ ID NO: 602;(iii) a VH comprising the sequence of SEQ ID NO: 603, and a VL comprising the sequence of SEQ ID NO: 601;(iv) a VH comprising the sequence of SEQ ID NO: 603, and a VL comprising the sequence of SEQ ID NO: 602;(v) a VH comprising the sequence of SEQ ID NO: 604, and a VL comprising the sequence of SEQ ID NO: 602;(vi) a VH comprising the sequence of SEQ ID NO: 603, and a VL comprising the sequence of SEQ ID NO: 605;(vii) a VH comprising the sequence of SEQ ID NO: 604, and a VL comprising the sequence of SEQ ID NO: 605;(viii) a VH comprising the sequence of SEQ ID NO: 600, and a VL comprising the sequence of SEQ ID NO: 606;(ix) a VH comprising the sequence of SEQ ID NO: 607, and a VL comprising the sequence of SEQ ID NO: 608;(x) a VH comprising the sequence of SEQ ID NO: 609, and a VL comprising the sequence of SEQ ID NO: 608;(xi) a VH comprising the sequence of SEQ ID NO: 610, and a VL comprising the sequence of SEQ ID NO: 608;(xii) a VH comprising the sequence of SEQ ID NO: 611, and a VL comprising the sequence of SEQ ID NO: 608;(xiii) a VH comprising the sequence of SEQ ID NO: 616, and a VL comprising the sequence of SEQ ID NO: 617;(xiv) a VH comprising the sequence of SEQ ID NO: 616, and a VL comprising the sequence of SEQ ID NO: 618;(xv) a VH comprising the sequence of SEQ ID NO: 619, and a VL comprising the sequence of SEQ ID NO: 617;(xvi) a VH comprising the sequence of SEQ ID NO: 619, and a VL comprising the sequence of SEQ ID NO: 618;(xvii) a VH comprising the sequence of SEQ ID NO: 620, and a VL comprising the sequence of SEQ ID NO: 618;(xviii) a VH comprising the sequence of SEQ ID NO: 619, and a VL comprising the sequence of SEQ ID NO: 621; or(xix) a VH comprising the sequence of SEQ ID NO: 620, and a VL comprising the sequence of SEQ ID NO: 621.

[0022] In some embodiments, the HER-2 binding moiety comprises:(i) a VH comprising a combination of a HC CDR1, a HC CDR2 and a HC CDR3 listed in Table 24 or 21;(ii) a VL comprising a combination of a LC CDR1, a LC CDR2, and a LC CDR3 listed in Table 24 or 21; or(iii) any combination thereof.

[0023] In some embodiments, the HER-2 binding moiety comprises:(i) a VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 of any one of the heavy chain variable domain amino acid sequences listed in Table 24 or 21;(ii) a VL comprising a LC CDR1, a LC CDR2, and a LC CDR3 of any one of the light chain variable domain amino acid sequences listed in Table 24 or 21; or(iii) any combination thereof.

[0024] In some embodiments, the HER-2 binding moiety comprises:(i) a VH comprising a sequence having at least 70% sequence identity to any one of the heavy chain variable domain amino acid sequences listed in Table 24 or 21;(ii) a VL comprising a sequence having at least 70% sequence identity to any one of the light chain variable domain amino acid sequences listed in Table 24 or 21;(iii) a combination thereof.

[0025] In some embodiments, the HER-2 binding moiety comprises:(i) a VH comprising any one of the heavy chain variable domain amino acid sequences listed in Table 24 or 21;(ii) a VL comprising any one of the light chain variable domain amino acid sequences listed in Table 24 or 21;(iii) a combination thereof.

[0026] In some embodiments, the HER-2 binding moiety has a lower affinity for HER-2 relative to a HER-2 binding moiety that comprises a VH comprising a HC CDR1 sequence, a HC CDR2 sequence, and a HC CDR3 sequence of SEQ ID NOs: 626, 627, and 628, respectively, and a VL comprising a LC CDR1 sequence, a LC CDR2 sequence, and a LC CDR3 sequence of SEQ ID NOs: 629, 630, and 631, respectively.

[0027] In some embodiments, the HER-2 binding moiety has lower affinity for HER-2 relative to a HER-2 binding moiety that comprises a VH comprising the sequence of SEQ ID NO: 600, and a VL comprising the sequence of SEQ ID NO: 601.

[0028] In some embodiments, the HER-2 binding moiety has a higher affinity for HER-2 relative to a HER-2 binding moiety that comprises a VH comprising a HC CDR1 sequence, a HC CDR2 sequence, and a HC CDR3 sequence of SEQ ID NOs: 626, 627, and 628, respectively, and a VL comprising a LC CDR1 sequence, a LC CDR2 sequence, and a LC CDR3 sequence of SEQ ID NOs: 629, 630, and 631, respectively.

[0029] In some embodiments, the HER-2 binding moiety has higher affinity for HER-2 relative to a HER-2 binding moiety that comprises a VH comprising the sequence of SEQ ID NO: 600, and a VL comprising the sequence of SEQ ID NO: 601.

[0030] In some embodiments, the HER-2 binding moiety has a lower affinity for HER-2 relative to a HER-2 binding moiety that comprises a VH comprising a HC CDR1 sequence, a HC CDR2 sequence, and a HC CDR3 sequence of SEQ ID NOs: 648, 649, and 650, respectively, and a VL comprising a LC CDR1 sequence, a LC CDR2 sequence, and a LC CDR3 sequence of SEQ ID NOs: 651, 652, and 653, respectively.

[0031] In some embodiments, the HER-2 binding moiety has lower affinity for HER-2 relative to a HER-2 binding moiety that comprises a VH comprising the sequence of SEQ ID NO: 616, and a VL comprising the sequence of SEQ ID NO: 617.

[0032] In some embodiments, the HER-2 binding moiety has a higher affinity for HER-2 relative to a HER-2 binding moiety that comprises a VH comprising a HC CDR1 sequence, a HC CDR2 sequence, and a HC CDR3 sequence of SEQ ID NOs: 648, 649, and 650, respectively, and a VL comprising a LC CDR1 sequence, a LC CDR2 sequence, and a LC CDR3 sequence of SEQ ID NOs: 651, 652, and 653, respectively.

[0033] In some embodiments, the HER-2 binding moiety has higher affinity for HER-2 relative to a HER-2 binding moiety that comprises a VH comprising the sequence of SEQ ID NO: 616, and a VL comprising the sequence of SEQ ID NO: 617.

[0034] In some embodiments, the TCRβV-binding moiety comprises an antibody domain or an antigen binding domain, wherein the antibody domain or the antigen binding domain comprises any one selected from the group consisting of a full-length antibody, a Fab, a F(ab')2, an Fv, a single chain Fv, a camelidantibody, a VHH, a half arm antibody, a diabody, a bivalent antibody, a monovalent antibody, or a bispecific antibody, and any combination thereof.

[0035] In some embodiments, the tumor-associated antigen binding moiety comprises a VHH, an Fab, or an scFv.

[0036] In some embodiments, the TCRβV-binding moiety comprises a VHH, an Fab, or an scFv.

[0037] In some embodiments, the TCRβV-binding moiety binds to a TCRβV region of TCRβV1, TCRβV2, TCRβV3, TCRβV4, TCRβV5, TCRβV6, TCRβV7, TCRβV8, TCRβV9, TCRβVIO, TCRβV11, TCRβV12, TCRβV19, TCRβV20, TCRβV21, TCRβV23, TCRβV24, TCRβV25, TCRβV26, TCRβV27, TCRβV28, TCRβV29, or TCRβV30.

[0038] In some embodiments, the TCRβV-binding moiety binds to a TCRβV region of TCRβV2, TCRβV4-1, TCRβV4-2, TCRβV5-1, TCRβV5-5, TCRβV5-6, TCRβV6, TCRβV6-5, TCRβV6-6, TCRβV6-9, TCRβV7-2, TCRβV7-3, TCRβV7-8, TCRβV7-9, TCRβV9, TCRβV10-1, TCRβV10-2, TCRβV10-3, TCRβV11-2, TCRβV12-3, TCRβV12-4, TCRβV12-5, TCRβV19, TCRβV20-1, TCRβV21, TCRβV24-1, TCRβV25-1, or TCRβV28.

[0039] In some embodiments, the TCRβV-binding moiety binds to a TCRβV region of TCRβV2, TCRβV3-1, TCRβV4-1, TCRβV4-2, TCRβV5-1, TCRβV5-4, TCRβV5-5, TCRβV5-6, TCRβV6-1, TCRβV6-5, TCRβV6-6, TCRβV7-3, TCRβV7-6, TCRβV7-8, TCRβV9, TCRβVl l-2, TCRβV19, TCRβV20-1, TCRβV24-1, TCRβV27, TCRβV28, TCRβV29-1, or TCRβV30.

[0040] In some embodiments, the TCRβV-binding moiety binds to a TCRβV region of TCRβV5, TCRβV6, TCRβVIO, TCRβV 12, or TCRβV20.

[0041] In some embodiments, the TCRβV-binding moiety comprises a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) sequence comprising any one of the HC CDR1 sequences listed in Table 1, 2, 10, 12, 13, or 21, a heavy chain complementarity determining region 2 (HC CDR2) sequence comprising any one of the HC CDR2 sequences listed in Tables 1, 2, 10, 12, 13, 21, 22, 23, 24, or 25, and a heavy chain complementarity determining region 3 (HC CDR3) sequence of comprising any one of the HC CDR3 sequences listed in Table 1, 2, 10, 12, 13, or 21.

[0042] In some embodiments, the TCRβV-binding moiety comprises a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) sequence comprising any one of the LC CDR1 sequences listed in Tablesl, 2, 10, 12, 13, 21, 22, 23, 24, or 25, a light chain complementarity determining region 2 (LC CDR2) sequence comprising any one of the LC CDR2 sequences listed in Table 1, 2, 10, 12, 13, or 21, and a light chain complementarity determining region 3 (LC CDR3) sequence of comprising any one of the LC CDR3 sequences listed in Table 1, 2, 10, 12, 13, or 21.

[0043] In some embodiments, the TCRβV-binding moiety comprises:(i) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) sequence comprising any one of the HC CDR1 sequences listed in Table 1, 2, 10, 12, 13, or 21, a heavy chain complementarity determining region 2 (HC CDR2) sequence comprising any one ofthe HC CDR2 sequences listed in Table 1, 2, 10, 12, 13, or 21, and a heavy chain complementarity determining region 3 (HC CDR3) sequence of comprising any one of the HC CDR3 sequences listed in Table 1, 2, 10, 12, 13, or 21.; and(ii) a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) sequence comprising any one of the LC CDR1 sequences listed in Table 1, 2, 10, 12, 13, or 21, a light chain complementarity determining region 2 (LC CDR2) sequence comprising any one of the LC CDR2 sequences listed in Table 1, 2, 10, 12, 13, or 21, and a light chain complementarity determining region 3 (LC CDR3) sequence of comprising any one of the LC CDR3 sequences listed in Table 1, 2, 10, 12, 13, or 21.

[0044] In some embodiments, the TCRβV-binding moiety comprises a VH comprising an amino acid sequence having at least 70% sequence identity to any one of the VH sequences listed in Table 1, 2, 10, 12, 13, or 21.

[0045] In some embodiments, the TCRβV-binding moiety comprises a VL comprising an amino acid sequence having at least 70% sequence identity to any one of the VL sequences listed in Table 1, 2, 10, 12, 13, or 21.

[0046] In some embodiments, the TCRβV-binding moiety comprises a VH comprising an amino acid sequence having at least 70% sequence identity to any one of the VH sequences listed in Table 1, 2, 10, 12, 13, or 21; and a VL comprising an amino acid sequence having at least 70% sequence identity to any one of the VL sequences listed in Table 1, 2, 10, 12, 13, or 21.

[0047] In some embodiments, the TCRβV-binding moiety comprises a VH comprising any one of the VH sequences listed in Table 1, 2, 10, 12, 13, or 21.

[0048] In some embodiments, the TCRβV-binding moiety comprises a VL comprising any one of the VL sequences listed in Table 1, 2, 10, 12, 13, or 21

[0049] In some embodiments, the TCRβV-binding moiety comprises a VH comprising any one of the VH sequences listed in Table 1, 2, 10, 12, 13, or 21; and a VL comprising any one of the VL sequences listed in Table 1, 2, 10, 12, 13, or 21.

[0050] In some embodiments, the TCRβV-binding moiety comprises a VH comprising a HC CDR1 comprising the sequence GHDFRLTYIH (SEQ ID NO: 3650), a HC CDR2 comprising the sequence RVSAGSGNVKYNEKFKG (SEQ ID NO: 3651), and a HC CDR3 comprising the sequence SYYSYDVLDY (SEQ ID NO: 47).

[0051] In some embodiments, the TCRβV-binding moiety comprises a VL comprising a LC CDR1 comprising the sequence KASQNVADRVV (SEQ ID NO: 3655), a LC CDR2 comprising the sequence SSSHRYK (SEQ ID NO: 3653), and a LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 8).

[0052] In some embodiments, the TCRβV-binding moiety comprises:(i) a VH comprising a HC CDR1 comprising the sequence GHDFRLTYIH (SEQ ID NO: 3650), a HC CDR2 comprising the sequence RVSAGSGNVKYNEKFKG (SEQ ID NO: 3651), and a HC CDR3 comprising the sequence SYYSYDVLDY (SEQ ID NO: 5); and(ii) a VL comprising a LC CDR1 comprising the sequence KASQNVADRVV (SEQ ID NO: 3655), a LC CDR2 comprising the sequence SSSHRYK (SEQ ID NO: 3653), and a LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 8).

[0053] In some embodiments, the TCRβV-binding moiety comprises a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1346.

[0054] In some embodiments, the TCRβV-binding moiety comprises a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1349.

[0055] In some embodiments, the TCRβV-binding moiety comprises a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1346, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1349.

[0056] In some embodiments, the TCRβV-binding moiety comprises a VH comprising the sequence of SEQ ID NO: 1346.

[0057] In some embodiments, the TCRβV-binding moiety comprises a VL comprising the sequence of SEQ ID NO: 1349.

[0058] In some embodiments, the TCRβV-binding moiety comprises a VH comprising the sequence of SEQ ID NO: 1346, and a VL comprising the sequence of SEQ ID NO: 1349.

[0059] In some embodiments, the TCRβV-binding moiety comprises a single chain Fv (scFv) comprising an amino acid sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 140, 153, 168, 183, 195, or 1331.

[0060] In some embodiments, the TCRβV-binding moiety comprises a scFv comprising the sequence of SEQ ID NO: 140, 153, 168, 183, 195, or 1331.

[0061] In some embodiments, the TCRβV-binding moiety comprises a VL comprising a LC CDR1 comprising the sequence RASQNVADRVV (SEQ ID NO: 673), a LC CDR2 comprising the sequence AASSLQS (SEQ ID NO: 639), and a LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 8).

[0062] In some embodiments, the TCRβV-binding moiety comprises:(i) a VH comprising a HC CDR1 comprising the sequence GHDFRLTYIH (SEQ ID NO: 3650), a HC CDR2 comprising the sequence RVSAGSGNVKYNEKFKG (SEQ ID NO: 3651), and a HC CDR3 comprising the sequence SYYSYDVLDY (SEQ ID NO: 5); and(ii) a VL comprising a LC CDR1 comprising the sequence RASQNVADRVV (SEQ ID NO: 673), a LC CDR2 comprising the sequence AASSLQS (SEQ ID NO: 639), and a LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 8).

[0063] In some embodiments, the TCRβV-binding moiety comprises a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1346.

[0064] In some embodiments, the TCRβV-binding moiety comprises a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 672.

[0065] In some embodiments, the TCRβV-binding moiety comprises a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1346, and a VL comprising asequence having at least 70% sequence identity to the sequence of SEQ ID NO: 672.

[0066] In some embodiments, the TCRβV-binding moiety comprises a VH comprising the sequence of SEQ ID NO: 1346.

[0067] In some embodiments, the TCRβV-binding moiety comprises a VL comprising the sequence of SEQ ID NO: 672.

[0068] In some embodiments, the TCRβV-binding moiety comprises a VH comprising the sequence of SEQ ID NO: 1346, and a VL comprising the sequence of SEQ ID NO: 672.

[0069] In some embodiments, the molecule that binds to a co-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof, and the at least one cytokine molecule or a functional fragment or functional variant thereof is selected from the group consisting of interleukin-2 (IL-2) or a functional fragment or functional variant thereof, interleukin-7 (IL- 7) or a functional fragment or functional variant thereof, interleukin- 12 (IL- 12) or a functional fragment or functional variant thereof, interleukin- 15 (IL- 15) or a functional fragment or functional variant thereof, interleukin- 18 (IL- 18) or a functional fragment or functional variant thereof, interleukin-21 (IL-21) or a functional fragment or functional variant thereof, or interferon gamma or a functional fragment or functional variant thereof, or any combination thereof.

[0070] In some embodiments, the molecule that binds to a co-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof, and the at least one cytokine molecule or a functional fragment or functional variant thereof comprises interleukin-2 (IL-2) or a functional fragment or functional variant thereof.

[0071] In some embodiments, the at least one cytokine molecule or a functional fragment or functional variant thereof is an IL-2 variant comprising a substitution mutation.

[0072] In some embodiments, the at least one cytokine molecule or a functional fragment or functional variant thereof is an IL-2 variant comprising C125A mutation.

[0073] In some embodiments, the at least one cytokine molecule or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2270 or the sequence of SEQ ID NO: 2191.

[0074] In some embodiments, the at least one cytokine molecule or a functional fragment or functional variant thereof comprises the sequence of SEQ ID NO: 2270 or the sequence of SEQ ID NO: 2191.

[0075] In some embodiments, the molecule that binds to a co-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof, and the at least one cytokine molecule or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to any one of the cytokine sequences listed in Table 21.

[0076] In some embodiments, the molecule that binds to a co-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof, and the at least one cytokine molecule or a functional fragment or functional variant thereof comprises any one of the cytokine sequences listed in Table 21.

[0077] In some embodiments, the at least one cytokine molecule or a functional fragment or functionalvariant thereof comprises:(i) IL-7 or a functional fragment or functional variant thereof, wherein the IL-7 or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3540;(ii) IL-12 or a functional fragment or functional variant thereof, wherein:(a) the IL-12 or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2290, SEQ ID NO: 3542, SEQ ID NO: 3543, SEQ ID NO: 3545, or any combination thereof; or(b) the IL-12 or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3543 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3545;(iii) IL- 15 or a functional fragment or functional variant thereof, wherein the IL- 15 or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2320 or the sequence of SEQ ID NO: 2170, optionally, wherein the IL- 15 or a functional fragment or functional variant thereof is operatively linked to an IL15Ralpha dimerizing domain comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2180 or an IL15Ralpha sushi domain comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3523; or optionally, wherein the at least one cytokine molecule or a functional fragment or functional variant thereof comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3799 or the sequence of SEQ ID NO: 3810;(iv) IL- 18 or a functional fragment or functional variant thereof, wherein the IL- 18 or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2192;(v) IL-21 or a functional fragment or functional variant thereof, wherein the IL-21 or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2193; or(vi) interferon gamma or a functional fragment or functional variant thereof, wherein the interferon gamma or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2194, or(vii) any combination thereof

[0078] In some embodiments, the at least one cytokine molecule or a functional fragment or functional variant thereof comprises:(i) IL-7 or a functional fragment or functional variant thereof, wherein the IL-7 or a functional fragment or functional variant thereof comprises the sequence of SEQ ID NO: 3540;(ii) IL-12 or a functional fragment or functional variant thereof, wherein:(a) the IL-12 or a functional fragment or functional variant thereof comprises the sequence of SEQ ID NO: 2290, SEQ ID NO: 3542, SEQ ID NO: 3543, SEQ ID NO: 3545, or any combination thereof; or(b) the IL-12 or a functional fragment or functional variant thereof comprises the sequence of SEQ ID NO: 3543 operatively linked to the sequence of SEQ ID NO: 3545;(iii) IL- 15 or a functional fragment or functional variant thereof, wherein the IL- 15 or a functional fragment or functional variant thereof comprises the sequence of SEQ ID NO: 2320 or the sequence of SEQ ID NO: 2170, optionally, wherein the IL- 15 or a functional fragment or functional variant thereof is operatively linked to an IL15Ralpha dimerizing domain comprising the sequence of SEQ ID NO: 2180 or an IL15Ralpha sushi domain comprising the sequence of SEQ ID NO: 3523; or optionally, wherein the at least one cytokine molecule or a functional fragment or functional variant thereof comprising the sequence of SEQ ID NO: 3799 or the sequence of SEQ ID NO: 3810;(iv) IL- 18 or a functional fragment or functional variant thereof, wherein the IL- 18 or a functional fragment or functional variant thereof comprises the sequence of SEQ ID NO: 2192;(v) IL-21 or a functional fragment or functional variant thereof, wherein the IL-21 or a functional fragment or functional variant thereof comprises the sequence of SEQ ID NO: 2193; or(vi) interferon gamma or a functional fragment or functional variant thereof, wherein the interferon gamma or a functional fragment or functional variant thereof comprises the sequence of SEQ ID NO: 2194, or(vii) any combination thereof.

[0079] In some embodiments, the molecule that binds to a co-stimulatory receptor of a T cell binds to CD2, 4- IBB, CD27, CD28, or any combination thereof.

[0080] In some embodiments, the multispecific molecule comprises a first polypeptide chain comprising a first portion of a dimerization module, and a second polypeptide chain comprising a second portion of the dimerization module; wherein the first polypeptide chain and the second polypeptide chain are non-contiguous, and wherein the tumor-associated antigen binding moiety is linked to the first portion of the dimerization module, and the TCRβV-binding moiety and / or the molecule that binds to a co-stimulatory receptor of a T cell are independently linked to the first portion of the dimerization module, the second portion of the dimerization module, or a combination thereof.

[0081] In some embodiments, (i) the tumor-associated antigen binding moiety is linked to the N- terminus of the first portion of the dimerization module, and the TCRβV-binding moiety is linked to the C-terminus of the first portion of the dimerization module, the N-terminus of the second portion of the dimerization module, the C-terminus of the second portion of the dimerization module, or any combination thereof; or(ii) the tumor-associated antigen binding moiety is linked to the C-terminus of the first portion of the dimerization module, and the molecule that binds to a co-stimulatory receptor of a T cell is linked to the N-terminus of the first portion of the dimerization module, the N-terminus of the second portion of the dimerization module, the C-terminus of the second portion of the dimerization module, or any combination thereof.

[0082] In some embodiments, (i) the tumor-associated antigen binding moiety is linked to the N- terminus of the first portion of the dimerization module, and the molecule that binds to a co-stimulatory receptor of a T cell is linked to the C-terminus of the first portion of the dimerization module, the N- terminus of the second portion of the dimerization module, the C-terminus of the second portion of the dimerization module, or any combination thereof; or(ii) the tumor-associated antigen binding moiety is linked to the C-terminus of the first portion of the dimerization module, and the molecule that binds to a co-stimulatory receptor of a T cell is linked to the N-terminus of the first portion of the dimerization module, the N-terminus of the second portion of the dimerization module, the C-terminus of the second portion of the dimerization module, or any combination thereof.

[0083] In some embodiments, the TCRβV-binding moiety and the molecule that binds to a co- stimulatory receptor of a T cell is within a single contiguous polypeptide chain of the first polypeptide chain or the second polypeptide chain.

[0084] In some embodiments, the TCRβV-binding moiety comprises a first portion of the TCRβV- binding moiety, and wherein the multispecific molecule further comprises a third polypeptide chain comprising a second portion of the TCRβV-binding moiety, wherein the third polypeptide chain is non-contiguous with the first polypeptide chain and the second polypeptide chain.

[0085] In some embodiments, t the TCRβV-binding moiety comprises a VH and a VL, or a single domain antibody.

[0086] In some embodiments, the first portion of the TCRβV-binding moiety comprises a VH of the TCRβV-binding moiety and the second portion of the TCRβV-binding moiety comprises a VL of the TCRβV-binding moiety, or the first portion of the TCRβV-binding moiety comprises a VL of the TCRβV-binding moiety and the second portion of the TCRβV-binding moiety comprises a VH of the TCRβV-binding moiety.

[0087] In some embodiments, the tumor-associated antigen binding moiety comprises a VH and a VL, or a single domain antibody.

[0088] In some embodiments, the tumor-associated antigen binding moiety comprises a first portion of the tumor-associated antigen binding moiety, and wherein the multispecific molecule further comprises a fourth polypeptide chain comprising a second portion of the tumor-associated antigen binding moiety, wherein the fourth polypeptide chain is noncontiguous with the first polypeptide chain, the second polypeptide chain, and the third polypeptide chain.

[0089] In some embodiments, the first portion of the tumor-associated antigen binding moiety comprises a VH of the tumor-associated antigen binding moiety and the second portion of the tumor-associated antigen binding moiety comprises a VL of the tumor-associated antigen binding moiety, or the first portion of the tumor-associated antigen binding moiety comprises a VL of the tumor-associated antigen binding moiety and the second portion of the tumor-associated antigen binding moiety comprises a VHof the tumor-associated antigen binding moiety.

[0090] In some embodiments, the first portion of the dimerization module and the second portion of the dimerization module associates to form a dimer.

[0091] In some embodiments, the first portion of the dimerization module comprises a first immunoglobulin constant region (Fc region) and the second portion of the dimerization module comprises a second Fc region.

[0092] 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.

[0093] 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.

[0094] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises an Fc interface with one or more of: a paired cavity-protuberance, an electrostatic interaction, or a strand-exchange, wherein the dimerization of the first Fc region and the second Fc region is enhanced as indicated by a greater ratio of heteromultimerhomomultimer forms relative to a dimerization of Fc regions with a non-engineered interface.

[0095] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises an amino acid substitution listed in Table 3, 4, 14, 27, or 21.

[0096] In some embodiments, (i) the first Fc region comprises a mutation that decreases Fc receptor binding relative to a Fc region without the mutation;(ii) the second Fc region comprise a mutation that decreases Fc receptor binding relative to a Fc region without the mutation; or(iii) a combination thereof.

[0097] In some embodiments, the mutation that decreases Fc receptor binding is an N297A mutation according to EU Numbering in a heavy chain constant region.

[0098] 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.

[0099] In some embodiments, the first Fc region and the second Fc region comprise an Fc interface with one or more of: a knob-in-a hole, an electrostatic interaction, or a strand-exchange.

[0100] In some embodiments, the first Fc region is an engineered Fc region comprising a knob and the second Fc region is an engineered Fc region comprising a hole, or the first Fc region is an engineered Fc region comprising a hole and the second Fc region is an engineered Fc region comprising a knob.

[0101] In some embodiments, (A)(i) the first Fc region comprises:(a) Y349C mutation according to EU Numbering,(b) T366S mutation according to EU Numbering,(c) L368A mutation according to EU Numbering, and(d) Y407V mutation according to EU Numbering; and(ii) the second Fc region comprises:(a) S354C mutation according to EU Numbering, and(b) T366W mutation according to EU Numbering; or(B)(i) the first Fc region comprises:(a) S354C mutation according to EU Numbering, and(b) T366W mutation according to EU Numbering; and(ii) the second Fc region comprises:(a) Y349C mutation according to EU Numbering,(b) T366S mutation according to EU Numbering,(c) L368A mutation according to EU Numbering, and(d) Y407V mutation according to EU Numbering.

[0102] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises a sequence having at least 70% sequence identity to any one sequence selected from the group consisting of SEQ ID NOs: 40, 41, 42, 550, 3645, 3646, 3647, 3648, 3649, 5038-5051, 5108, 5109, 5111, 5112, and 5113.

[0103] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises any one sequence selected from the group consisting of SEQ ID NOs: 40, 41, 42, 550, 3645, 3646, 3647, 3648, 3649, 5038-5051, 5108, 5109, 5111, 5112, and 5113.

[0104] In some embodiments, the first Fc region comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649, SEQ ID NO: 5113, SEQ ID NO: 550, or SEQ ID NO: 5051, and the second Fc region comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116, or the first Fc region comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116 and the second Fc region comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649, SEQ ID NO: 5113, SEQ ID NO: 550, or SEQ ID NO: 5051.

[0105] In some embodiments, the first Fc region comprises the sequence of SEQ ID NO: 3649, SEQ ID NO: 5113, SEQ ID NO: 550, or SEQ ID NO: 5051, and the second Fc region comprises the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116, or the first Fc region comprises the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116 and the second Fc region comprises the sequence of SEQ ID NO: 3649, SEQ ID NO: 5113, SEQ ID NO: 550, or SEQ ID NO: 5051.

[0106] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises a sequence having at least 70% sequence identity to any one of the Fc region sequences or the heavy chain constant region sequences listed in Table 3, 4, 14, 27, or 21.

[0107] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises any one of the Fc region sequences or the heavy chain constant region sequences listed inTable 3, 4, 14, 27, or 21.

[0108] In some embodiments, (i) the tumor-associated antigen binding moiety further comprises a heavy chain constant domain 1 (CHI) linked to the VH of the tumor-associated antigen binding moiety;(ii) the TCRβV-binding moiety further comprises a heavy chain constant domain 1 (CHI) linked to the VH of the TCRβV-binding moiety; or(iii) a combination thereof.

[0109] In some embodiments, (i) the tumor-associated antigen binding moiety further comprises a light chain constant domain (CL) linked to the VL of the tumor-associated antigen binding moiety;(ii) the TCRβV-binding moiety further comprises a light chain constant domain (CL) linked to the VL of the TCRβV-binding moiety; or(iii) a combination thereof.

[0110] In some embodiments, (i) the CL linked to the VL of the tumor-associated antigen binding moiety comprises a light chain constant region or a fragment thereof;(ii) the CL linked to the VL of the TCRβV-binding moiety comprises a light chain constant region or a fragment thereof; or(iii) a combination thereof.

[0111] In some embodiments, the light chain constant region or a fragment thereof comprises a kappa chain constant domain or a fragment thereof or a lambda chain constant domain or a fragment thereof.

[0112] In some embodiments, the light chain constant region or a fragment thereof comprises any one of the light chain constant region sequences listed in Table 3 or 21.

[0113] In some embodiments, the light chain constant region or a fragment thereof comprise a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 39 or SEQ ID NO: 3644.

[0114] In some embodiments, the light chain constant region or a fragment thereof comprise the sequence of SEQ ID NO: 39 or SEQ ID NO: 3644.

[0115] In some embodiments, the multispecific molecule as described herein further comprises:(i) a linker between the first portion of the dimerization module and the tumor-associated antigen binding moiety or the first portion of the tumor-associated antigen;(ii) a linker between the molecule that binds to a co-stimulatory receptor of a T cell and the first portion of the dimerization module, a linker between the molecule that binds to a co-stimulatory receptor of a T cell and the second portion of the dimerization module, or a combination thereof;(iii) a linker between the molecule that binds to a co-stimulatory receptor of a T cell and the TCRβV- binding moiety or the first portion of the TCRβV-binding moiety;(iv) a linker between the VH and the VL of the tumor-associated antigen binding moiety;(v) a linker between the VH and the VL of the TCRβV-binding moiety;(vi) a linker between the CHI and the VH of the tumor-associated antigen binding moiety;(vii) a linker between the CHI and the VH of the TCRβV-binding moiety;(viii) a linker between the CL and the VL of the tumor-associated antigen binding moiety;(ix) a linker between the CL and the VL of the TCRβV-binding moiety; or(x) any combination thereof.

[0116] 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.

[0117] In some embodiments, the multispecific molecule is an isolated multispecific molecule.

[0118] In some embodiments, the multispecific molecule comprises:(i) a first polypeptide chain comprising a VH of the HER-2 binding moiety operatively linked to a first Fc region;(ii) a second polypeptide chain comprising the TCRβV-binding moiety operatively linked to the molecule that binds to a co-stimulatory receptor of a T cell operatively linked to a second Fc region; and(iii) a third polypeptide chain comprising a VL of the HER-2 binding moiety operatively linked to a light chain constant region; wherein the VH of the HER-2 binding moiety and the VL of the HER-2 binding moiety are assembled and form the first domain.

[0119] In some embodiments, the TCRβV-binding moiety comprises a scFv comprising a VH of the TCRβV-binding moiety operatively linked to a VL of the TCRβV-binding moiety.

[0120] In some embodiments, the second polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1346 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1349 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2270 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116.

[0121] In some embodiments, (i) the sequence having 70% sequence identity to the sequence of SEQ ID NO: 1346 is operatively linked to the sequence having 70% sequence identity to the sequence of SEQ ID NO: 1349 via the sequence of SEQ ID NO: 3801; (ii) the sequence having 70% sequence identity to the sequence of SEQ ID NO: 1349 is operatively linked to the sequence having 70% sequence identity to the sequence of SEQ ID NO: 2270 via the sequence of SEQ ID NO: 3309; (iii) the sequence having 70% sequence identity to the sequence of SEQ ID NO: 2270 is operatively linked to the sequence having 70% sequence identity to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116 via the sequence of SEQ ID NO: 3308; or (iv) any combination thereof.

[0122] In some embodiments, the TCRβV-binding moiety comprises a scFv comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1331.

[0123] In some embodiments, the second polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3800 or SEQ ID NO: 678.

[0124] In some embodiments, the second polypeptide chain comprises the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 2270 operatively linked to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116.

[0125] In some embodiments, (i) the sequence of SEQ ID NO: 1346 is operatively linked to the sequence of SEQ ID NO: 1349 via the sequence of SEQ ID NO: 3801;(ii) the sequence of SEQ ID NO: 1349 is operatively linked to the sequence of SEQ ID NO: 2270 via the sequence of SEQ ID NO: 3309;(iii) the sequence of SEQ ID NO: 2270 is operatively linked to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116 via the sequence of SEQ ID NO: 3308; or(iv) any combination thereof.

[0126] In some embodiments, the TCRβV-binding moiety comprises a scFv comprising the sequence of SEQ ID NO: 1331.

[0127] In some embodiments, the second polypeptide chain comprises the sequence of SEQ ID NO: 3800 or SEQ ID NO: 678.

[0128] In some embodiments, the second polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1346 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 672 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2270 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116.

[0129] In some embodiments, (i) the sequence having 70% sequence identity to the sequence of SEQ ID NO: 1346 is operatively linked to the sequence having 70% sequence identity to the sequence of SEQ ID NO: 672 via the sequence of SEQ ID NO: 3801; (ii) the sequence having 70% sequence identity to the sequence of SEQ ID NO: 672 is operatively linked to the sequence having 70% sequence identity to the sequence of SEQ ID NO: 2270 via the sequence of SEQ ID NO: 3309; (iii) the sequence having 70% sequence identity to the sequence of SEQ ID NO: 2270 is operatively linked to the sequence having 70% sequence identity to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116 via the sequence of SEQ ID NO: 3308; or (iv) any combination thereof.

[0130] In some embodiments, the TCRβV-binding moiety comprises a scFv comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 699.

[0131] In some embodiments, the second polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 697 or SEQ ID NO: 698.

[0132] In some embodiments, the second polypeptide chain comprises the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 672 operatively linked to the sequence of SEQ ID NO: 2270 operatively linked to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116.

[0133] In some embodiments, (i) the sequence of SEQ ID NO: 1346 is operatively linked to the sequence of SEQ ID NO: 672 via the sequence of SEQ ID NO: 3801; (ii) the sequence of SEQ ID NO: 672 is operatively linked to the sequence of SEQ ID NO: 2270 via the sequence of SEQ ID NO: 3309; (iii) the sequence of SEQ ID NO: 2270 is operatively linked to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116 via the sequence of SEQ ID NO: 3308; or (iv) any combination thereof.

[0134] In some embodiments, the TCRβV-binding moiety comprises a scFv comprising the sequence of SEQ ID NO: 699.

[0135] In some embodiments, the second polypeptide chain comprises the sequence of SEQ ID NO: 697 or SEQ ID NO: 698.

[0136] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 607 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 607 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

[0137] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 675 or SEQ ID NO: 676; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 677.

[0138] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 607 operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or the sequence of SEQ ID NO: 607 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 608 operatively linked to the sequence of SEQ ID NO: 3644.

[0139] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 675 or SEQ ID NO: 676; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 677.

[0140] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 604 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 604 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 602 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

[0141] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 679 or SEQ ID NO: 680; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 681.

[0142] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 604operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or the sequence of SEQ ID NO: 604 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 602 operatively linked to the sequence of SEQ ID NO: 3644.

[0143] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 679 or SEQ ID NO: 680; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 681.

[0144] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 603 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 603 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 605 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

[0145] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 682 or SEQ ID NO: 683; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 684.

[0146] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 603 operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or the sequence of SEQ ID NO: 603 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 605 operatively linked to the sequence of SEQ ID NO: 3644.

[0147] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 682 or SEQ ID NO: 683; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 684

[0148] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 604 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 604 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 605 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

[0149] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 679 or SEQ ID NO: 680; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 684.

[0150] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 604 operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or the sequence of SEQ ID NO: 604 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 605 operatively linked to the sequence of SEQ ID NO: 3644.

[0151] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 679 or SEQ ID NO: 680; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 684.

[0152] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 609 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 609 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

[0153] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 685 or SEQ ID NO: 686; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 677.

[0154] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 609 operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or the sequence of SEQ ID NO: 609 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 608 operatively linked to the sequence of SEQ ID NO: 3644.

[0155] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 685 or SEQ ID NO: 686; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 677.

[0156] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 610 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 610 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

[0157] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 687 or SEQ ID NO: 688; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 677.

[0158] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 610 operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or the sequence of SEQ ID NO: 610 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 608 operatively linked to the sequence of SEQ ID NO: 3644.

[0159] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 687 or SEQ ID NO: 688; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 677.

[0160] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 611 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 611 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

[0161] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 689 or SEQ ID NO: 690; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 677.

[0162] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 611 operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or the sequence of SEQ ID NO: 611 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 608 operatively linked to the sequence of SEQ ID NO: 3644.

[0163] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 689 or SEQ ID NO: 690; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 677.

[0164] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 619 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 619 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 618 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

[0165] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 691 or SEQ ID NO: 692; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 693.

[0166] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 619 operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or the sequence of SEQ ID NO: 619 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 618 operatively linked to the sequence of SEQ ID NO: 3644.

[0167] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 691 or SEQ ID NO: 692; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 693.

[0168] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 620 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 620 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO:5051; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 621 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

[0169] In some embodiments, (i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 694 or SEQ ID NO: 695; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 696.

[0170] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 620 operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or the sequence of SEQ ID NO: 620 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 621 operatively linked to the sequence of SEQ ID NO: 3644.

[0171] In some embodiments, (i) the first polypeptide chain comprises the sequence of SEQ ID NO: 694 or SEQ ID NO: 695; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 696.

[0172] In some embodiments, the multispecific molecule comprises a polypeptide chain comprising a sequence having at least 70% sequence identity to any one of the polypeptide chain sequences listed in Table 21.

[0173] In some embodiments, the multispecific molecule comprises a polypeptide chain comprising any one of the polypeptide chain sequences listed in Table 21.

[0174] In some embodiments, the multispecific molecule comprises:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to any one of the polypeptide chain sequences listed in Table 21;(ii) the second polypeptide chain comprises a sequence having at least 70% sequence identity to any one of the polypeptide chain sequences listed in Table 21; and(iii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to any one of the polypeptide chain sequences listed in Table 21.

[0175] In some embodiments, the multispecific molecule comprises:(i) the first polypeptide chain comprises any one of the polypeptide chain sequences listed in Table 21;(ii) the second polypeptide chain comprises any one of the polypeptide chain sequences listed in Table21 ; and(iii) the third polypeptide chain comprises any one of the polypeptide chain sequences listed in Table 21.

[0176] In some embodiments, the multispecific molecule comprises:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to any one of the first polypeptide chain sequences listed in Table 21;(ii) the second polypeptide chain comprises a sequence having at least 70% sequence identity to any oneof the second polypeptide chain sequences listed in Table 21 ; and(iii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to any one of the third polypeptide chain sequences listed in Table 21.

[0177] In some embodiments, the multispecific molecule comprises:(i) the first polypeptide chain comprises any one of the first polypeptide chain sequences listed in Table 21;(ii) the second polypeptide chain comprises any one of the second polypeptide chain sequences listed in Table 21; and(iii) the third polypeptide chain comprises any one of the third polypeptide chain sequences listed in Table 21.

[0178] In another aspect, provided herein is an anti-HER-2 antibody or an anti-HER2 antigen binding domain comprising:(i) a heavy chain variable region (VH) comprising a heavy chain complementarity-determining region 3 (HC CDR3) sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 628, 642, 643, 644, and 650; and / or(ii) a light chain variable region (VL) comprising a light chain complementarity-determining region 3(LC CDR3) sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 631, 640, and 653.

[0179] In some embodiments, the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VH comprising a HC CDR1 sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 626, 634, 636, 648, and 656.

[0180] In some embodiments, the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VH comprising a HC CDR2 sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 627, 635, 637, 649, 657, and 658.

[0181] In some embodiments, the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VH comprising a HC CDR1 sequence, a HC CDR2 sequence, and a HC CDR3 sequence comprising the sequences of:(i) SEQ ID NOs: 626, 627, and 628, respectively;(ii) SEQ ID NOs: 634, 635, and 628, respectively;(iii) SEQ ID NOs: 636, 637, and 628, respectively;(iv) SEQ ID NOs: 636, 637, and 642, respectively;(v) SEQ ID NOs: 636, 637, and 643, respectively;(vi) SEQ ID NOs: 636, 637, and 644, respectively;(vii) SEQ ID NOs: 648, 649, and 650, respectively;(viii) SEQ ID NOs: 656, 657, and 650, respectively; or(ix) SEQ ID NOs: 656, 658, and 650, respectively.

[0182] In some embodiments, the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VL comprising a LC CDR1 sequence comprising any one sequence selected from the groupconsisting of SEQ ID NOs: 629, 632, 638, 641, 651, 654, and 659.

[0183] In some embodiments, the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VL comprising a LC CDR2 sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 630, 633, 639, 652, 655, and 660.

[0184] In some embodiments, the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VL comprising a LC CDR1 sequence, a LC CDR2 sequence, and a LC CDR3 sequence comprising the sequences of:(i) SEQ ID NOs: 629, 630, and 631, respectively;(ii) SEQ ID NOs: 632, 633, and 631, respectively;(iii) SEQ ID NOs: 638, 639, and 631, respectively;(iv) SEQ ID NOs: 629, 630, and 640, respectively;(v) SEQ ID NOs: 641, 639, and 631, respectively;(vi) SEQ ID NOs: 651, 652, and 653, respectively;(vii) SEQ ID NOs: 654, 655, and 653, respectively; or(viii) SEQ ID NOs: 659, 660, and 653, respectively.

[0185] In some embodiments, the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VH and a VL, respectively, comprising a HC CDR1 sequence, a HC CDR2 sequence, and a HC CDR3 sequence, and a LC CDR1 sequence, a LC CDR2 sequence, and a LC CDR3 sequence comprising the sequences of:(i) SEQ ID NOs: 626, 627, 628, 632, 633, and 631, respectively;(ii) SEQ ID NOs: 634, 635, 628, 629, 630, and 631, respectively;(iii) SEQ ID NOs: 634, 635, 628, 632, 633, and 631, respectively;(iv) SEQ ID NOs: 636, 637, 628, 632, 633, and 631, respectively;(v) SEQ ID NOs: 634, 635, 628, 638, 639, and 631, respectively;(vi) SEQ ID NOs: 636, 637, 628, 638, 639, and 631, respectively;(vii) SEQ ID NOs: 626, 627, 628, 629, 630, and 640, respectively;(viii) SEQ ID NOs: 636, 637, 628, 641, 639, and 631, respectively;(ix) SEQ ID NOs: 636, 637, 642, 641, 639, and 631, respectively;(x) SEQ ID NOs: 636, 637, 643, 641, 639, and 631, respectively;(xi) SEQ ID NOs: 636, 637, 644, 641, 639, and 631, respectively;(xii) SEQ ID NOs: 648, 649, 650, 654, 655, and 653, respectively;(xiii) SEQ ID NOs: 656, 657, 650, 651, 652, and 653, respectively;(xiv) SEQ ID NOs: 656, 657, 650, 654, 655, and 653, respectively;(xv) SEQ ID NOs: 656, 658, 650, 654, 655, and 653, respectively;(xvi) SEQ ID NOs: 656, 657, 650, 659, 660, and 653, respectively; or(xvii) SEQ ID NOs: 656, 658, 650, 659, 660, and 653, respectively.

[0186] In some embodiments, the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VH comprising a sequence having at least 70% sequence identity to any one sequenceselected from the group consisting of SEQ ID NOs: 600, 603, 604, 607, 609, 610, 611, 616, 619, and 620.

[0187] In some embodiments, the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VH comprising any one sequence selected from the group consisting of SEQ ID NOs: 600, 603, 604, 607, 609, 610, 611, 616, 619, and 620.

[0188] In some embodiments, the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VL comprising a sequence having at least 70% sequence identity to any one sequence selected from the group consisting of SEQ ID NOs: 601, 602, 605, 606, 608, 617, 618, and 621.

[0189] In some embodiments, the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VL comprising any one sequence selected from the group consisting of SEQ ID NOs: 601,602, 605, 606, 608, 617, 618, and 621.

[0190] In some embodiments, the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises:(i) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 600, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 602;(ii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:603, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 601;(iii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:603, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 602;(iv) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:604, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 602;(v) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:603, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 605;(vi) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:604, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 605;(vii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 600, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 606;(viii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 607, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608;(ix) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:609, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608;(x) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:610, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608;(xi) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:611, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608;(xii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 616, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 618;(xiii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 619, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 617;(xiv) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:619, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 618;(xv) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:620, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 618;(xvi) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:619, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 621; or(xvii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO:620, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 621.

[0191] In some embodiments, the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises:(i) a VH comprising the sequence of SEQ ID NO: 600, and a VL comprising the sequence of SEQ ID NO: 602;(ii) a VH comprising the sequence of SEQ ID NO: 603, and a VL comprising the sequence of SEQ ID NO: 601;(iii) a VH comprising the sequence of SEQ ID NO: 603, and a VL comprising the sequence of SEQ ID NO: 602;(iv) a VH comprising the sequence of SEQ ID NO: 604, and a VL comprising the sequence of SEQ ID NO: 602;(v) a VH comprising the sequence of SEQ ID NO: 603, and a VL comprising the sequence of SEQ ID NO: 605;(vi) a VH comprising the sequence of SEQ ID NO: 604, and a VL comprising the sequence of SEQ ID NO: 605;(vii) a VH comprising the sequence of SEQ ID NO: 600, and a VL comprising the sequence of SEQ ID NO: 606;(viii) a VH comprising the sequence of SEQ ID NO: 607, and a VL comprising the sequence of SEQ ID NO: 608;(ix) a VH comprising the sequence of SEQ ID NO: 609, and a VL comprising the sequence of SEQ ID NO: 608;(x) a VH comprising the sequence of SEQ ID NO: 610, and a VL comprising the sequence of SEQ ID NO: 608;(xi) a VH comprising the sequence of SEQ ID NO: 611, and a VL comprising the sequence of SEQ ID NO: 608;(xii) a VH comprising the sequence of SEQ ID NO: 616, and a VL comprising the sequence of SEQ ID NO: 618;(xiii) a VH comprising the sequence of SEQ ID NO: 619, and a VL comprising the sequence of SEQ ID NO: 617;(xiv) a VH comprising the sequence of SEQ ID NO: 619, and a VL comprising the sequence of SEQ ID NO: 618;(xv) a VH comprising the sequence of SEQ ID NO: 620, and a VL comprising the sequence of SEQ ID NO: 618;(xvi) a VH comprising the sequence of SEQ ID NO: 619, and a VL comprising the sequence of SEQ ID NO: 621; or(xvii) a VH comprising the sequence of SEQ ID NO: 620, and a VL comprising the sequence of SEQ ID NO: 621.

[0192] In another aspect, provided herein is an anti-TCRβV antibody or an anti-TCRβV antigen binding domain comprising:(i) a VH comprising a HC CDR1 comprising the sequence GHDFRLTYIH (SEQ ID NO: 3650), a HC CDR2 comprising the sequence RVSAGSGNVKYNEKFKG (SEQ ID NO: 3651), and a HC CDR3 comprising the sequence SYYSYDVLDY (SEQ ID NO: 5); and(ii) a VL comprising a LC CDR1 comprising the sequence RASQNVADRVV (SEQ ID NO: 673), a LC CDR2 comprising the sequence AASSLQS (SEQ ID NO: 639), and a LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 8).

[0193] In some embodiments, the anti-TCRβV antibody or the anti-TCRβV antigen binding domain comprises a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1346.

[0194] In some embodiments, the anti-TCRβV antibody or the anti-TCRβV antigen binding domain comprises a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 672.

[0195] In some embodiments, the anti-TCRβV antibody or the anti-TCRβV antigen binding domain comprises a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1346, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 672.

[0196] In some embodiments, the anti-TCRβV antibody or the anti-TCRβV antigen binding domain comprises a VH comprising the sequence of SEQ ID NO: 1346.

[0197] In some embodiments, the anti-TCRβV antibody or the anti-TCRβV antigen binding domain comprises a VL comprising the sequence of SEQ ID NO: 672.

[0198] In some embodiments, the anti-TCRβV antibody or the anti-TCRβV antigen binding domain comprises a VH comprising the sequence of SEQ ID NO: 1346, and a VL comprising the sequence of SEQ ID NO: 672.

[0199] In another aspect, provided herein is a composition comprising the multispecific molecule as described herein, the anti-HER-2 antibody or the anti-HER2 antigen binding domain as described herein, or the anti-TCRβV binding antibody or the anti-TCRβV antigen binding domain as described herein.

[0200] In another aspect, provided herein is a polynucleotide comprising a sequence encoding the multispecific molecule as described herein, the anti-HER-2 antibody or the anti-HER2 antigen binding domain as described herein, the anti-TCRβV binding antibody or the anti-TCRβV antigen binding domain as described herein.

[0201] In some embodiments, the polynucleotide is an isolated nucleic acid molecule.

[0202] In another aspect, provided herein is a vector comprising one or more of the polynucleotide as described herein.

[0203] In another aspect, provided herein is a cell comprising the polynucleotide as described herein or the vector as described herein.

[0204] In another aspect, provided herein is a method of making the multispecific molecule as described herein comprising culturing a host cell comprising a recombinant polynucleotide comprising a sequence encoding the multispecific molecule or a vector comprising the recombinant polynucleotide under conditions suitable for gene expression and / or homo- or heterodimerization.

[0205] In another aspect, provided herein is a pharmaceutical composition comprising the multispecific molecule as described herein, the anti-HER-2 antibody or the anti-HER2 antigen binding domain as described herein, the anti-TCRβV binding antibody or the anti-TCRβV antigen binding domain as described herein, the composition as described herein, the polynucleotide as described herein, the vector as described herein, or the cell as described herein, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0206] In another aspect, provided herein is a method of treating a condition or disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the multispecific molecule as described herein, the anti-HER-2 antibody or the anti-HER2 antigen binding domain as described herein, the anti-TCRβV binding antibody or the anti-TCRβV antigen binding domain as described herein, the composition as described herein, the polynucleotide as described herein,the vector as described herein, the cell as described herein, the pharmaceutical composition as described herein, or any combination thereof, wherein the administering is effective to treat the condition or disease in the subject.

[0207] In another aspect, provided herein is the use of the multispecific molecule as described herein, the anti-HER-2 antibody or the anti-HER2 antigen binding domain as described herein, the anti-TCRβV binding antibody or the anti-TCRβV antigen binding domain as described herein, the composition as described herein, the polynucleotide as described herein, the vector as described herein, the cell as described herein, the pharmaceutical composition as described herein, or any combination thereof for treating a condition or disease in a subject in need thereof comprising administering to the subject, wherein the multispecific molecule, the anti-HER-2 antibody or the anti-HER2 antigen binding domain, the anti-TCRβV binding antibody or the anti-TCRβV antigen binding domain, the composition, the polynucleotide, the vector, the cell, the pharmaceutical composition, or any combination thereof is formulate in a therapeutically effective amount to treat the condition or disease in the subject.

[0208] In some embodiments, the condition or disease is cancer.

[0209] In some embodiments, the cancer is a solid tumor, a hematological cancer, a metastatic cancer, a soft tissue tumor, or any combination thereof.

[0210] In some embodiments, the cancer is the solid tumor selected from the group consisting of melanoma, pancreatic cancer, breast cancer, colorectal cancer, lung cancer, skin cancer, ovarian cancer, liver cancer, and any combination thereof.

[0211] In some embodiments, the cancer is the 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.

[0212] 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 any combination thereof.

[0213] In some embodiments, the T-cell lymphoma is peripheral T-cell lymphoma.

[0214] In some embodiments, the cancer is characterized by a cancer antigen present on the cancer.

[0215] In some embodiments, the cancer antigen is a tumor antigen, a stromal antigen, or a hematological antigen.

[0216] In some embodiments, the cancer antigen is selected from the group consisting of CD 19, CD 123, CD22, CD30, CD171, CS-1, C-type lectin-like molecule-1, CD33, epidermal growth factor receptor variant III (EGFRvIII), ganglioside G2 (GD2), ganglioside GD3, TNF receptor family member B cell maturation (BCMA), Tn antigen ((Tn Ag) or (GalNAca-Ser / Thr)), prostate -specific membrane antigen (PSMA), Receptor tyrosine kinase-like orphan receptor 1 (ROR1), Fms-Like Tyrosine Kinase 3 (FLT3), Tumor-associated glycoprotein 72 (TAG72), CD38, CD44v6, Carcinoembryonic antigen (CEA), Epithelial cell adhesion molecule (EPCAM), B7H3 (CD276), KIT (CD117), Interleukin- 13 receptorsubunit alpha-2, mesothelin, Interleukin 11 receptor alpha (IL-1 IRa), prostate stem cell antigen (PSCA), Protease Serine 21, vascular endothelial growth factor receptor 2 (VEGFR2), Lewis(Y) antigen, CD24, Platelet-derived growth factor receptor beta (PDGFR-beta), Stage-specific embryonic antigen-4 (SSEA- 4), CD20, Folate receptor alpha, Receptor tyrosine-protein kinase ERBB2 (Her2 / neu), Mucin 1, cell surface associated (MUC1), epidermal growth factor receptor (EGFR), neural cell adhesion molecule (NCAM), Prostase, prostatic acid phosphatase (PAP), elongation factor 2 mutated (ELF2M), Ephrin B2, fibroblast activation protein alpha (FAP), insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX), Proteasome (Prosome, Macropain) Subunit, Beta Type, 9 (LMP2), glycoprotein 100 (gpl00 / pmell7), oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr-abl), tyrosinase, ephrin type-A receptor 2 (EphA2), Fucosyl GM1, sialyl Lewis adhesion molecule (sLe), ganglioside GM3, transglutaminase 5 (TGS5), high molecular weight-melanoma-associated antigen (HMWMAA), o-acetyl-GD2 ganglioside (OAcGD2), Folate receptor beta, tumor endothelial marker 1 (TEM1 / CD248), tumor endothelial marker 7-related (TEM7R), claudin 6 (CLDN6), thyroid stimulating hormone receptor (TSHR), G protein- coupled receptor class C group 5, member D (GPRC5D), chromosome X open reading frame 61 (CXORF61), CD97, CD179a, anaplastic lymphoma kinase (ALK), Polysialic acid, placenta-specific 1 (PLAC1), hexasaccharide portion of globoH glycoceramide (GloboH), mammary gland differentiation antigen (NY -BR-1), uroplakin 2 (UPK2), Hepatitis A virus cellular receptor 1 (HAVCR1), adrenoceptor beta 3 (ADRB3), pannexin 3 (PANX3), G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex, locus K 9 (LY6K), Olfactory receptor 51E2 (OR 1E2), TCR Gamma Alternate Reading Frame Protein (TARP), Wilms tumor protein (WT1), Cancer / testis antigen 1 (NY-ESO-l / LAGE-1), Cancer / testis antigen 2 (LAGE-la), Melanoma-associated antigen 1 (MAGE-A1), ETS translocationvariant gene 6, located on chromosome 12p (ETV6-AML), sperm protein 17 (SPA17), X Antigen Family, Member 1A (XAGE1), angiopoietin-binding cell surface receptor 2 (Tie 2), melanoma cancer testis antigen-1 (MAD-CT-1), melanoma cancer testis antigen-2 (MAD-CT-2), Fos-related antigen 1, tumor protein p53 (p53), p53 mutant, prostein, Survivin, telomerase, prostate carcinoma tumor antigen-1, melanoma antigen recognized by T cells 1, Rat sarcoma (Ras) mutant, human Telomerase reverse transcriptase (hTERT), sarcoma translocation breakpoints, melanoma inhibitor of apoptosis (ML-IAP), ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene), N-Acetyl glucosaminyl- transferase V (NA 17), paired box protein Pax-3 (PAX3), Androgen receptor, Cyclin Bl, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), Ras Homolog Family Member C (RhoC), Tyrosinase-related protein 2 (TRP-2), Cytochrome P450 1B1 (CYP1B1), CCCTC- Binding Factor (Zinc Finger Protein) -Like, Squamous Cell Carcinoma Antigen Recognized By T Cells 3 (SART3), Paired box protein Pax-5 (PAX5), proacrosin binding protein sp32 (OY-TES1), lymphocytespecific protein tyrosine kinase (LCK), A kinase anchor protein 4 (AKAP-4), synovial sarcoma, X breakpoint 2 (SSX2), Receptor for Advanced Glycation Endproducts (RAGE-1), renal ubiquitous 1 (RU1), renal ubiquitous 2 (RU2), legumain, human papilloma virus E6 (HPV E6), human papilloma virus E7 (HPV E7), intestinal carboxyl esterase, heat shock protein 70-2 mutated (mut hsp70-2), CD79a,CD79b, CD72, Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), Fc fragment of IgA receptor (FCAR or CD89), Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2), CD300 molecule-like family member f (CD300LF), C-type lectin domain family 12 member A (CLEC12A), bone marrow stromal cell antigen 2 (BST2), EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2), lymphocyte antigen 75 (LY75), Glypican-3 (GPC3), Fc receptor-like 5 (FCRL5), FcRH5, PDL1, CD47, prostate specific membrane antigen (PMSA), prostate -specific antigen (PSA), Ron Kinase, c-Met, Immature laminin receptor, TAG-72, BING-4, Calcium-activated chloride channel 2, Cyclin-Bl, 9D7, Ep-CAM, EphA3, SAP-1, PRAME, SSX-2, Melan-A / MART-1, TRPl / gp75, MC1R, β-catenin, BRCA1 / 2, CDK4, CML66, Fibronectin, Ras, TGF-B receptor, AFP, ETA, MAGE, CA-125, BAGE, GAGE, CDC27, a actinin-4, gangliosides, MART-2, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RU11, RU12, SAGE, TRG, TSTA, Ll-CAM, gpA33, GM2, VEGFR, Integrins, carbohydrates, TRAILR1, TRAILR2, RANKL, TGF-beta, hyaluronic acid, collagen, tenascin C, tenascin W, and immunoglobulin lambda-like polypeptide 1 (IGLL1).

[0217] In some embodiments, the cancer antigen is HER-2.

[0218] In some embodiments, the cancer is a HER-2 associated cancer.

[0219] In some embodiments, the cancer comprises breast cancer, lung cancer, pancreatic cancer, head and neck cancer, bladder cancer, urothelial cancer, ovarian cancer, gallbladder cancer, gastric cancer, esophageal cancer, hepatocellular cancer, epithelial cancer, or any combination thereof.

[0220] In some embodiments, the cancer comprises breast cancer, pancreatic cancer, lung cancer, or any combination thereof.

[0221] In some embodiments, the cancer comprises a solid cancer selected from the group consisting of colon cancer, breast cancer, renal cancer, melanoma, prostate cancer, lung cancer, rectal cancer, colorectal cancer, cervical cancer, and any combination thereof.

[0222] In some embodiments, the cancer comprises an anti-PDl therapy resistant cancer.

[0223] In some embodiments, the cancer comprises an anti-PDl therapy resistant solid cancer.

[0224] In some embodiments, the cancer comprises an HPV-positive cancer.

[0225] In some embodiments, the cancer comprises an HPV-positive solid cancer.

[0226] In some embodiments, the cancer comprises a cancer with a high tumor mutation burden.

[0227] In some embodiments, the method as described herein or the use as described herein further comprises administering a second therapeutic agent or therapy to the subject.

[0228] In some embodiments, the second therapeutic agent or therapy comprises a chemotherapeutic agent, a biologic agent, a hormonal therapy, radiation, or surgery.

[0229] In some embodiments, the second therapeutic agent or therapy is administered in combination with the multispecific molecule as described herein, the anti-HER-2 antibody or the anti-HER2 antigen binding domain as described herein, the anti-TCRβV binding antibody or the anti-TCRβV antigen binding domain as described herein, the composition as described herein, the polynucleotide as described herein, the vector as described herein, the cell as described herein, the pharmaceutical composition as described herein, or any combination thereof, sequentially, simultaneously, or concurrently.INCORPORATION BY REFERENCE

[0230] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0231] 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:

[0232] FIGS. 1A-1T depict exemplary embodiments of multifunctional molecules as described herein. FIGS. 1A, 1B and 1C 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 (TCRβV) (“anti-TCRβV antibody molecule”). FIGS. 1D, IE and IF depict exemplary embodiments of multifunctional molecules containing a single molecule of an exemplary cytokine, IL-2, linked to an anti-TCRβV antibody molecule. FIGS. 1G, 1H, 1I, and 1 J depict exemplary embodiments of multifunctional molecules containing an exemplary cytokine, IL-2, linked to a first dimerization module. FIGS. 1K, 1L and 1M 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- TCRβV antibody molecule. FIGS. 1N, 1O and 1P 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-TCRβV antibody molecule. FIGS. IQ, 1R, 1S and 1T 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. The “IL2” as shown in FIGs. 1A-1T is an exemplary embodiment of at least one cytokine molecule or a functional fragment or functional variant thereof as described herein, which is an exemplary embodiment of the molecule that binds to a co-stimulatory receptor of a T cell as described herein. In some embodiments, the multifunctional molecules as provided herein further comprises a tumor-associated antigen binding moiety (e.g., a HER-2 binding moiety). In some embodiments, the multifunctional molecules as provided herein comprises a tumor-associated antigen binding moiety (e.g., a HER-2 binding moiety), a molecule that binds to a co-stimulatory receptor of a T cell, and a TCRβV-binding moiety. In some embodiments, the multifunctional molecules as provided herein comprises a tumor- associated antigen binding moiety (e.g., a HER-2 binding moiety) and a TCRβV-binding moiety, instead of two TCRβV-binding moieties, and a molecule that binds to a co-stimulatory receptor of a T cell. In some embodiments, one of anti-TCRβV-binding moieties as shown in FIGs. 1A-1F, 1I-1P, and 1S-11T is replaced with a tumor-associated antigen binding moiety (e.g., a HER-2 binding moiety). In some embodiments, the tumor-associated antigen binding moiety comprises a HER-2 binding moiety. In someembodiments, the molecule that binds to a co-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof. In some embodiments, the molecule that binds to a co-stimulatory receptor of a T cell comprises an antibody molecule, an antigen binding domain, a ligand, an extracellular domain of a receptor, or any combination thereof. In some embodiments, the molecule that binds to a co-stimulatory receptor of a T cell binds to CD2, 4-1BB, CD27, CD28, or any combination thereof.

[0233] FIGS. 2A and 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).

[0234] FIGS. 3A-3C shows the alignment of the Antibody B source mouse VH and VL framework 1, CDR 1, framework 2, CDR 2, framework 3, CDR3, and framework 4 regions with their respective humanized sequences. Kabat CDRs are shown in bold, Chothia CDRs are shown in italics, and combined CDRs are shown in boxes. The framework positions that were back mutated are double underlined. FIG. 3A shows the VH sequence for murine Antibody B (SEQ ID NO: 15) and humanized VH sequences B- H.1A to B-H.1C (SEQ ID NOs: 23-25). FIG. 3B shows the VL sequence for murine Antibody B (SEQ ID NO: 16) and humanized VL sequences B-H.1D to B-H.1H (SEQ ID NOs: 26-30). FIG. 3C 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), continued from FIG. 3B.

[0235] FIG. 4 depicts the phylogenetic tree of TCRBV gene family and subfamilies with corresponding antibodies mapped. Subfamily identities are as follows: Subfamily A: TCRβ V6; Subfamily B: TCRβ V10; Subfamily C: TCRβ V12; Subfamily D: TCRβ V5; Subfamily E: TCRβ V7; Subfamily F: TCRβ V11; Subfamily G: TCRβ V14; Subfamily H: TCRβ V16; Subfamily I:TCRβ V18; Subfamily J:TCRβ V9; Subfamily K: TCRβ V13; Subfamily L: TCRβ V4; Subfamily M:TCRβ V3; Subfamily N:TCRβ V2; Subfamily O:TCRβ V15; Subfamily P: TCRβ V30; Subfamily Q: TCRβ V19; Subfamily R:TCRβ V27; Subfamily S:TCRβ V28; Subfamily T: TCRβ V24; Subfamily U: TCRβ V20; Subfamily V: TCRβ V25; and Subfamily W:TCRβ V29 subfamily. Subfamily members are described in detail herein in the Section titled “TCR beta V (TCRβV)”.

[0236] FIGS. 5A and 5B show the structure and sequence of eight TCRβV proteins from seven different subfamilies: TCRβV6 subfamily (TCRβV6-5 and TCRβV6-4 are shown), TCRβV28 subfamily, TCRβV19 subfamily, TCRβV9 subfamily, TCRβV5 subfamily, TCRβV20 subfamily and TCRβV12 subfamily. FIG. 5A shows the structural alignment of the different TCRβV proteins. The circled area represents the outward facing region comprising the proposed binding site for the anti -TCRβV antibodies as described herein. FIG. 5B shows the amino acid sequence alignment of the proteins shown in FIG. 5A (SEQ ID NOS 3449-3456, respectively, in order of appearance). The various TCRβV proteins (from 7different TCRβV subfamilies) have diverse sequences but share a conserved (similar) structure and function.

[0237] FIG. 6 shows the relative representations of 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). The data show that the anti-TCRVβ antibody stimulation does not induce proliferation of specific T cell clones within the TRBV6-5 positive population, as the relative difference in clonal representation in that population is comparable to the TRBV6-5 negative population as well as total TRAV usage.

[0238] FIG. 7 shows a graphical representation of the relation of sequences between different TCRVB clonotype subfamilies.

[0239] FIG. 8 is a schematic of the experimental design for the pharmacokinetic (PK) profile and dosing strategy of the multifunctional polypeptide molecule as described herein.

[0240] FIG. 9A, 9B, and 9C show 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.

[0241] FIG. 10 shows alignment of affinity matured humanized Antibody A-H VL sequences (SEQ ID NOS: 3377-3389, respectively, in order of appearance).

[0242] FIGs. 11A, 11B, and 11C show alignment of affinity matured humanized Antibody A-H VH sequences (SEQ ID NOS: 3390-3436, respectively, in order of appearance).

[0243] FIG. 12A shows an exemplary embodiment (e.g., BKM0186) of multifunctional molecules comprising a TCRβV-binding moiety and a cytokine polypeptide (e.g., IL2 or IL2-C125A) as described herein. FIG. 12B shows an exemplary embodiment of multifunctional molecules comprising a TCRβV- binding moiety and a cytokine polypeptide as described herein. FIGs. 12C, 12D, 12E, and 12F show exemplary embodiments of multifunctional molecules comprising a first TCRβV-binding moiety, a second TCRβV-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 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. The ”cytokine” as shown in FIGs. 12B-12F represents at least one cytokine molecule or a functional fragment or functional variant thereof as described herein, which is an exemplary embodiment of the molecule that binds to a costimulatory receptor of a T cell as described herein. Similarly, the “IL2-C125A” as shown in FIG. 12A isan exemplary embodiment of at least one cytokine molecule or a functional fragment or functional variant thereof as described herein, which is an exemplary embodiment of the molecule that binds to a co-stimulatory receptor of a T cell as described herein. In some embodiments, the multifunctional molecules as provided herein further comprises a tumor-associated antigen binding moiety (e.g., a HER-2 binding moiety). In some embodiments, the multifunctional molecules as provided herein comprises a tumor-associated antigen binding moiety, a molecule that binds to a co-stimulatory receptor of a T cell, and a TCRβV -binding moiety. In some embodiments, the multifunctional molecules as provided herein comprises a tumor-associated antigen binding moiety (e.g., a HER-2 binding moiety) and a TCRβV- binding moiety, instead of two TCRβV -binding moieties, and a molecule that binds to a co-stimulatory receptor of a T cell. In some embodiments, one of anti-TCRβV-binding moieties as shown in FIGs. 12C- 12F is replaced with a tumor-associated antigen binding moiety (e.g., a HER-2 binding moiety). In some embodiments, the tumor-associated antigen binding moiety (e.g., a HER-2 binding moiety) comprises a HER-2 binding moiety. In some embodiments, the molecule that binds to a co-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof. In some embodiments, the molecule that binds to a co-stimulatory receptor of a T cell comprises an antibody molecule, an antigen binding domain, a ligand, an extracellular domain of a receptor, or any combination thereof. In some embodiments, the molecule that binds to a co-stimulatory receptor of a T cell binds to CD2, 4-1BB, CD27, CD28, or any combination thereof.

[0244] FIG. 13 shows in vitro TCR sequencing. PBMCs were incubated with 100nM of BKM0186 for 5 days and T cells were sequenced for TCR P chain V (TRBV) genes. Compared to unstimulated T cells (grey), BKM0186 selectively expanded T cells bearing TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-5, and TRBV 10-3.

[0245] FIG. 14 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.

[0246] FIGs. 15A and 15B show exemplary embodiments of multifunctional molecules comprising a TCRβV-binding moiety and a cytokine molecule (e.g., wild-type human IL2 or IL15-IL15R sushi fusion) as described herein. FIGs. 15C-15T show exemplary embodiments of multifunctional molecules, e.g., exemplary multifunctional molecules comprising a HER-2 binding moiety, which is an exemplary embodiment of a tumor-associated antigen binding moiety, a TCRβV-binding moiety, and at least one cytokine molecule or a functional fragment or functional variant thereof, which is an exemplary embodiment of the molecule that binds to a co-stimulatory receptor of a T cell as described herein, as described herein. In some embodiments, a HER-2 -binding moiety and / or a TCRβV-binding moiety are antibody, an antigen binding fragment thereof, an antibody fragment, or antigen binding domain. In some embodiments, an antigen binding fragment, an antibody fragment or antigen binding domain comprises Fab, Fab', F(ab')2, F(ab)2, variable fragment (Fv), domain antibody (dAb), or single chain variable fragment (scFv). In some embodiments, the at least one cytokine molecule or a functional fragment or functional variant thereof is selected from the group consisting of interleukin-2 (IL-2) or a functionalfragment or functional variant thereof, interleukin-7 (IL-7) or a functional fragment or functional variant thereof, interleukin- 12 (IL- 12) or a functional fragment or functional variant thereof, interleukin- 15 (IL- 15) or a functional fragment or functional variant thereof, interleukin- 18 (IL- 18) or a functional fragment or functional variant thereof, interleukin-21 (IL-21) or a functional fragment or functional variant thereof, or interferon gamma or a functional fragment or functional variant thereof, or a combination thereof. In some embodiments, exemplary embodiments of multifunctional molecules, e.g., multifunctional molecules comprising a HER-2 -binding moiety, a TCRβV-binding moiety, and at least one cytokine molecule or a functional fragment or functional variant thereof as described herein comprises a dimerization module comprising an Fc region comprising N297A mutation. FIGs. 15C-15H show exemplary embodiments of multifunctional molecules, e.g., multifunctional molecules comprising a HER-2 -binding moiety, a TCRβV-binding moiety, and at least one cytokine molecule or a functional fragment or functional variant thereof as described herein, wherein the multifunctional molecules comprise an exemplary dimerization module, e.g., an Fc region comprising Knob-in-hole mutations and disulfide bridges. FIGs. 15I-15N show exemplary embodiments of multifunctional molecules, e.g., multifunctional molecules comprising a HER-2 -binding moiety, a TCRβV-binding moiety, and at least one cytokine molecule or a functional fragment or functional variant thereof as described herein, wherein the multifunctional molecules comprise an exemplary dimerization module, e.g., an Fc region comprising disulfide bridges, but not comprising Knob-in-hole mutations. FIGs. 15O-15T show exemplary embodiments of multifunctional molecules, e.g., multifunctional molecules comprising a HER-2 -binding moiety, a TCRβV-binding moiety, and at least one cytokine molecule or a functional fragment or functional variant thereof as described herein, wherein the multifunctional molecules comprise an exemplary dimerization module, e.g., an Fc region not comprising disulfide bridges nor Knob-in-hole mutations. FIGs. 15C-15E, 15I-15K, and 15O-15Q show exemplary embodiments of multifunctional molecules, e.g., multifunctional molecules comprising a HER-2 -binding moiety, a TCRβV-binding moiety, and at least one cytokine molecule or a functional fragment or functional variant thereof as described herein, wherein the TCRβV-binding moiety comprises an scFv. FIGs. 15F-15H, 15L-15N, and 15R-15T show exemplary embodiments of multifunctional molecules, e.g., multifunctional molecules comprising a HER-2 -binding moiety, a TCRβV-binding moiety, and at least one cytokine molecule or a functional fragment or functional variant thereof as described herein, wherein the TCRβV- binding moiety comprises an Fab. FIG. 15U shows an exemplary embodiment of multifunctional molecules, e.g., multifunctional molecules comprising a HER-2 -binding moiety, a TCRβV-binding moiety, and at least one cytokine molecule or a functional fragment or functional variant thereof as described herein, wherein the multifunctional molecule comprise two HER-2 -binding moieties. In some embodiments, the at least one cytokine molecule or a functional fragment or functional variant thereof is interleukin-7 (IL-7) or a functional fragment or functional variant thereof, interleukin- 12 (IL- 12) or a functional fragment or functional variant thereof, interleukin- 15 (IL- 15) or a functional fragment or functional variant thereof, interleukin- 18 (IL- 18) or a functional fragment or functional variant thereof, interleukin-21 (IL-21) or a functional fragment or functional variant thereof, or interferon gamma or afunctional fragment or functional variant thereof, or a combination thereof instead of interleukin-2 (IL-2) or a functional fragment or functional variant thereof as indicated as “IL2”. The “hIL2wt” “hIL15- IL15Rsu” “IL2” as shown represents at least one cytokine molecule or a functional fragment or functional variant thereof as described herein, which is an exemplary embodiment of the molecule that binds to a co-stimulatory receptor of a T cell as described herein. In some embodiments, the tumor- associated antigen binding moiety (“a-TAA”) comprises a HER-2 binding moiety. In some embodiments, the molecule that binds to a co-stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof. In some embodiments, the molecule that binds to a co-stimulatory receptor of a T cell comprises an antibody molecule, an antigen binding domain, a ligand, an extracellular domain of a receptor, or any combination thereof. In some embodiments, the molecule that binds to a co-stimulatory receptor of a T cell binds to CD2, 4-1BB, CD27, CD28, or any combination thereof.

[0247] FIG. 16A and FIG. 16B demonstrate the affinity of exemplary anti-HER2 antibodies, Trastuzumab & Pertuzumab, tuned, while increasing humanness & developability. FIG. 16A shows that Trastuzumab variants with 10-700-fold lower affinities compared with the parent Trastuzumab were identified. FIG. 16B shows that Pertuzumab variants with higher degree of humanization and fewer liability motifs were identified. For example, affinity-tuning up to 6-fold was achieved

[0248] FIG. 17A shows the affinity-tuning and derisking of an exemplary anti-HER2 antibody, Trastuzumab, a % homology to the closest human germline up to CDR3; b Remaining liability, which is also part of the commercial molecule, likely hard to remove due to being at the binding interface; c Genentech affinity-tuned Trastuzumab (VL H91A mutant, reported Kd 50 nM, ); d Multi-cycle kinetics.

[0249] FIG. 17B shows the affinity-tuning and derisking of an exemplary anti-HER2 antibody, Pertuzumab. a % homology to the closest human germline excluding up to CDR3; b Remaining liability, which is also part of the commercial molecule, likely hard to remove due to being at the binding interface. BNM0346 could be the high-affinity option of the matrix.DETAILED DESCRIPTIONDEFINITION

[0250] 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.

[0251] 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.

[0252] 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 consistentwith the meaning of “one or more,” “at least one,” and “one or more than one.”

[0253] It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] “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), antibody fragments, and antigen binding domains. In some embodiments, an antibody molecule comprises an antigen binding or functional fragment of a full length antibody, an antigen binding domain, or a full length immunoglobulin chain. For example, a full-length antibody is an immunoglobulin (Ig) molecule (e.g., an IgG antibody) that is naturally occurring or formed by normal immunoglobulin gene fragment recombinatorial processes). In embodiments, an antibody molecule refers to an immunologically active, antigen-binding portion of an immunoglobulin molecule, such as an antibody fragment. An antibody fragment, e.g., functional fragment, is a portion of an antibody, e.g , Fab, Fab', F(ab')2, F(ab)2, variable fragment (Fv), domain antibody (dAb), or single chain variable fragment (scFv). An antigen binding domain can be Fab, Fab', F(ab')2, F(ab)2, variable fragment (Fv), domain antibody (dAb), or single chain variable fragment (scFv). A functional antibody fragment or antigen binding domain binds to the same antigen as that recognized by the intact (e.g., full-length) antibody. The terms “antibody fragment” or“functional fragment” or “antigen binding domain” 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 or an antigen binding domain does not include portions of antibodies without antigen binding activity, such as Fc fragments or single amino acid residues. In some embodiments, an antibody fragment or an antigen binding domain includes portions of antibodies without antigen binding activity, such as Fc fragments or single amino acid residues. Exemplary antibody molecules or antigen binding domains include full length antibodies and antibody fragments, e.g., dAb (domain antibody), single chain, Fab, Fab’, and F(ab’)2 fragments, and single chain variable fragments (scFvs). In some embodiments, the antibody molecule or the antigen binding domain is an antibody mimetic. In some embodiments, the antibody molecule or the antigen binding domain 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.

[0258] 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.

[0259] 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.

[0260] In embodiments, an antibody molecule is monospecific, e.g., it comprises binding specificity for a single epitope. In some embodiments, an antibody molecule is multispecific, e.g., it comprises a plurality of immunoglobulin variable domain sequences, where a first immunoglobulin variable domain sequence has binding specificity for a first epitope and a second immunoglobulin variable domain sequence has binding specificity for a second epitope. In some embodiments, an antibody molecule is a bispecific antibody molecule. “Bispecific antibody molecule” as used herein refers to an antibody molecule that has specificity for more than one (e.g. , two, three, four, or more) epitope and / or antigen.

[0261] “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.

[0262] 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.

[0263] As used herein, an “immune cell” refers to any of various cells that function in the immune system, e.g., to protect against agents of infection and foreign matter. In embodiments, this term includes leukocytes, e.g., neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Innate leukocytes include phagocytes (e.g., macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells. Innate leukocytes identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms, and are mediators in the activation of an adaptive immune response. The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are important types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immuneresponse, whereas T cells are involved in cell-mediated immune response. The term “immune cell” includes immune effector cells.

[0264] “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.

[0265] 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.

[0266] 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.

[0267] 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.

[0268] The term “isolated,” as used herein, refers to material that is removed from its original or native environment (e.g., the natural environment if it is naturally occurring). For example, a naturally- occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide, separated by human intervention from some or all of the co-existing materials in the natural system, is isolated. Such polynucleotides could be part of a vector and / or such polynucleotides or polypeptides could be part of a composition, and still be isolated in that such vector or composition is not part of the environment in which it is found in nature. An isolated polynucleotide (ribonucleic acid (RNA), deoxyribonucleic acid (DNA)), or polypeptide is free of the genes / nucleic acids or sequence s / amino acids that flank it in its naturally-occurring state.

[0269] 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 anamino 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.

[0270] The term “variant” refers to a polypeptide that has a substantially identical amino acid sequence to a reference amino acid sequence, or is encoded by a substantially identical nucleotide sequence. In some embodiments, the variant is a functional variant. In some embodiments, a TCRβV variant can bind to TCRa and form a TCR a: [3 complex. . In some embodiments, a TCRαV variant can bind to TCRa and form a TCR a: [3 complex

[0271] 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.

[0272] Calculations of homology or sequence identity between sequences (the terms are used interchangeably herein) are performed as follows. To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g. , gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”).

[0273] 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 mathematicalalgorithm. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453 ) algorithm which has been incorporated into the GAP program in the GCG software package (available at http: / / www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at http: / / www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and the one that should be used unless otherwise specified) are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.

[0274] 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.

[0275] 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.

[0276] The term “amino acid” is intended to embrace all molecules, whether natural or synthetic, which include both an amino functionality and an acid functionality and capable of being included in a polymer of naturally-occurring amino acids. Exemplary amino acids include naturally-occurring amino acids; analogs, derivatives and congeners thereof; amino acid analogs having variant side chains; and all stereoisomers of any of any of the foregoing. As used herein the term “amino acid” includes both the D- or L- optical isomers and peptidomimetics.

[0277] 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-branchedside chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0278] 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.

[0279] 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.

[0280] “Interleukin-2” also known as IL2, IL-2, IL 2, TCGF, lymphokine, and interleukin 2, as referred to herein, includes any of the recombinant or naturally-occurring forms of IL-2 or variants or homologs thereof that have or maintain IL-2 activity (e.g., at least 40% 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity). In some aspects, the variants or homologs have at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring IL-2. In some embodiments, IL-2 is substantially identical to the protein identified by the UniProt reference number P60568 or a variant or homolog having substantial identity thereto.

[0281] “HER2” also known as Receptor tyrosine-protein kinase erbB-2, ERBB2, CD340, HER-2, HER- 2 / neu, MLN 19, NEU, NGL, TKR1, as erb-b2 receptor tyrosine kinase 2, as referred to herein, includes any of the recombinant or naturally-occurring forms of HER2 or variants or homologs thereof that have or maintain HER2 activity (e.g., at least 40% 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity). In some aspects, the variants or homologs have at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring HER2. In some embodiments, HER2 is substantially identical to the protein identified by the UniProt reference number P04626 or a variant or homolog having substantial identity thereto.

[0282] The term “triple negative breast cancer,” as used herein, refers to the breast cancer of which cancer cells do not have estrogen or progesterone receptors (ER or PR) and also do not make any or too much of the HER2 protein.

[0283] The term “co-stimulatory receptor,” as used herein, refers to the cell surface molecules that canpositively induce a secondary signal to fully activate T cells with TCR signaling and cytokine stimulation. In some embodiments, exemplary co-stimulatory receptors include, but are not limited to, CD2, CD27, CD28, ICOS (CD278), 4-1BB (CD137), 0X40 (CD134), CD40, CD40L, Toll-like receptors (TLRs), or any combination thereof.Anti-TCRβV antibodiesHuman T cell receptor (TCR) complex

[0284] TCR is a disulfide-linked membrane -anchored heterodimeric protein normally consisting of the highly variable alpha (α) and beta (β) chains expressed as part of a complex with the invariant CD3 chain molecules. TCR on αβ T cells is formed by a heterodimer of one alpha chain and one beta chain. Each alpha or beta chain consists of a constant domain and a highly variable domain classified as the Immunoglobulin superfamily (IgSF) fold. The TCRβV chains can be further classified into 30 subfamilies (TRBV1-30). Despite their high structural and functional homology, the amino acid sequence homology in the TRBV genes is very low. Only 4 amino acids out of approximately 95 are identical while 10 additional amino acids are conserved among all subfamilies (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. 5A and 5B) and elicit a similar function, e.g., activation of T cells.

[0285] T cell receptors (TCR) can be found on the surface of T cells. TCRs recognize antigens, e.g., peptides, presented on, e.g., bound to, major histocompatibility complex (MHC) molecules on the surface of cells, e.g , antigen-presenting cells. TCRs are heterodimeric molecules and can comprise an alpha chain, a beta chain, a gamma chain or a delta chain. TCRs comprising an alpha chain and a beta chain are also referred to as TCRαβ. The TCR beta chain consists of the following regions (also known as segments): variable (V), diversity (D), joining (J) and constant (C) (see Mayer G. and Nyland J. (2010) Chapter 10: Major Histocompatibility Complex and T-cell Receptors-Role in Immune Responses. In: Microbiology and Immunology on-line, University of South Carolina School of Medicine). The TCR alpha chain consists of V, J and C regions. The rearrangement of the T-cell receptor (TCR) through somatic recombination of V (variable), D (diversity), J (joining), and C (constant) regions is a defining event in the development and maturation of a T cell. TCR gene rearrangement takes place in the thymus.

[0286] TCRs can comprise a receptor complex, known as the TCR complex, which comprises a TCR heterodimer comprising of an alpha chain and a beta chain, and dimeric signaling molecules, e.g., CD3 co-receptors, e.g., CD3δ / ε. and / or CD3γ / ε.

[0287] As used herein, the term “T cell receptor beta variable chain” or “TCRβV,” refers to an extracellular region of the T cell receptor beta chain which comprises the antigen recognition domain of the T cell receptor. The term TCRβV includes isoforms, mammalian, e.g., human TCRβV, species homologs of human and analogs comprising at least one common epitope with TCRβV. Human TCRβV comprises a gene family comprising subfamilies including, but not limited to: a TCRβ V6 subfamily, a TCRβ V10 subfamily, a TCRβ V12 subfamily, a TCRβ V5 subfamily, a TCRβ V7 subfamily, a TCRβVI 1 subfamily, a TCRβ V14 subfamily, a TCRβ V16 subfamily, a TCRβ V18 subfamily, a TCRβ V9 subfamily, a TCRβ V13 subfamily, a TCRβ V4 subfamily, a TCRβ V3 subfamily, a TCRβ V2 subfamily, a TCRβ V15 subfamily, a TCRβ V30 subfamily, a TCRβ V19 subfamily, a TCRβ V27 subfamily, a TCRβ V28 subfamily, a TCRβ V24 subfamily, a TCRβ V20 subfamily, TCRβ V25 subfamily, a TCRβ V29 subfamily, a TCRβ VI subfamily, a TCRβ VI 7 subfamily, a TCRβ V21 subfamily, a TCRβ V23 subfamily, or a TCRβ V26 subfamily, as well as family members of said subfamilies, and variants thereof (e.g., a structural or functional variant thereof). In some embodiments, the TCRβ V6 subfamily comprises: TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01 or TCRβ V6-l*01. In some embodiments, TCRβV comprises TCRβ V6-5*01, or a variant thereof, e.g., a variant having 85%, 90%, 95%, 99% or more identity the naturally-occurring sequence. TCRβ V6-5*01 is also known as TRBV65; TCRBV6S5; TCRBV13S1, or TCRβ V13.1. The amino acid sequence of TCRβ V6-5*01, e.g., human TCRβ V6-5*01, is known in that art, e.g., as provided by IMGT ID L36092. In some embodiments, TCRβ V6-5*01 is encoded by the nucleic acid sequence of SEQ ID NO: 43, or a sequence having 85%, 90%, 95%, 99% or more identity thereof. In some embodiments, TCRβ V6-5*01 comprises the amino acid sequence of SEQ ID NO: 44, or a sequence having 85%, 90%, 95%, 99% or more identity thereof.

[0288] SEQ ID NO: 43ATGAGCATCGGCCTCCTGTGCTGTGCAGCCTTGTCTCTCCTGTGGGCAGGTCCAGTGAATGC TGGTGTCACTCAGACCCCAAAATTCCAGGTCCTGAAGACAGGACAGAGCATGACACTGCAG TGTGCCCAGGATATGAACCATGAATACATGTCCTGGTATCGACAAGACCCAGGCATGGGGC TGAGGCTGATTCATTACTCAGTTGGTGCTGGTATCACTGACCAAGGAGAAGTCCCCAATGGC TACAATGTCTCCAGATCAACCACAGAGGATTTCCCGCTCAGGCTGCTGTCGGCTGCTCCCTC CCAGACATCTGTGTACTTCTGTGCCAGCAGTTACTC

[0289] SEQ ID NO: 44MSIGLLCCAALSLLWAGPVNAGVTQTPKFQVLKTGQSMTLQCAQDMNHEYMSWYRQDPGMG LRLIHY-SVGAGITDQGEVPNGYNVSRSTTEDFPLRLLSAAPSQTSVYFCASSYTCR beta V (TCRRV)

[0290] 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.

[0291] 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.

[0292] Provided herein are, inter alia, antibody molecules and fragments thereof, that bind, e.g., specifically bind, to a human TCR beta V chain (TCRβV), e.g. , a TCRβV gene family (also referred to asa group), e.g. , a TCRβV subfamily (also referred to as a subgroup), e.g. , as described herein. TCR beta V families and subfamilies are known in the art, e.g., as described in Yassai et al., (2009) Immunogenetics 61(7)pp:493-502; Wei S. and Concannon P. (1994) Human Immunology 41(3) pp: 201-206. The antibodies described herein can be recombinant antibodies, e.g., recombinant non-murine antibodies, e.g., recombinant human or humanized antibodies.

[0293] The terms TCRBV, TCRVB, TRBV, TCRβV, TCRVβ or TRpV are used interchangeably herein and refer to a TCR beta V chain, e.g., as described herein.

[0294] In some embodiments, provided herein is an anti-TCRβV antibody molecule that binds to human TCRβV, e.g. , a TCRβV family, e.g. , gene family or a variant thereof. In some embodiments a TCRBV gene family comprises one or more subfamilies, e.g., as described herein, e.g., in FIG. 4, Table 8A or Table 8B. In some embodiments, the TCRβV gene family comprises: a TCRβ V6 subfamily, a TCRβ V10 subfamily, a TCRβ V12 subfamily, a TCRβ V5 subfamily, a TCRβ V7 subfamily, a TCRβ V11 subfamily, a TCRβ V14 subfamily, a TCRβ V16 subfamily, a TCRβ V18 subfamily, a TCRβ V9 subfamily, a TCRβ V13 subfamily, a TCRβ V4 subfamily, a TCRβ V3 subfamily, a TCRβ V2 subfamily, a TCRβ V15 subfamily, a TCRβ V30 subfamily, a TCRβ V19 subfamily, a TCRβ V27 subfamily, a TCRβ V28 subfamily, a TCRβ V24 subfamily, a TCRβ V20 subfamily, TCRβ V25 subfamily, a TCRβ V29 subfamily, a TCRβ V1 subfamily, a TCRβ V17 subfamily, a TCRβ V21 subfamily, a TCRβ V23 subfamily, or a TCRβ V26 subfamily.

[0295] In some embodiments, TCRβ V6 subfamily is also known as TCRβ V13.1. In some embodiments, the TCRβ V6 subfamily comprises: TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01 or TCRβ V6-1*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-4*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-4*02, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-9*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-8*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-5*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-6*02, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-6*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-2*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-3*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-l*01, or a variant thereof.

[0296] In some embodiments, TCRβ V6 comprises TCRβ V6-5*01, or a variant thereof. In some embodiments, TCRβ V6, e.g., TCRβ V6-5*01, is recognized, e.g., bound, by SEQ ID NO: 1 and / or SEQ ID NO: 2. In some embodiments, TCRβ V6, e.g., TCRβ V6-5*01, is recognized, e.g., bound, by SEQ ID NO: 9 and / or SEQ ID NO: 10. In some embodiments, TCRβ V6 is recognized, e.g., bound, by SEQ ID NO: 9 and / or SEQ ID NO: 11.

[0297] In some embodiments, TCRβ V10 subfamily is also known as TCRβ V12. In some embodiments, the TCRβ V10 subfamily comprises: TCRβ V10-l*01, TCRβ V10-l*02, TCRβ V10-3*01 or TCRβ V10-2*01, or a variant thereof.

[0298] In some embodiments, TCRβ V12 subfamily is also known as TCRβ V8.1. In some embodiments, the TCRβ V12 subfamily comprises: TCRβ VI2-4*01, TCRβ V12-3*0I, or TCRβ V12- 5*01, or a variant thereof. In some embodiments, TCRβ V12 is recognized, e.g., bound, by SEQ ID NO: 15 and / or SEQ ID NO: 16. In some embodiments, TCRβ V12 is recognized, e.g., bound, by any one of SEQ ID NOs 23-25, and / or any one of SEQ ID NO: 26-30:

[0299] In some embodiments, the TCRβ V5 subfamily is chosen from: TCRβ V5-5*0I, TCRβ V5-6*01, TCRβ V5-4*01, TCRβ V5-8*01, TCRβ V5-1*01, or a variant thereof.

[0300] In some embodiments, the TCRβ V7 subfamily comprises TCRβ V7-7*01, TCRβ V7-6*01, TCRβ V7 -8*02, TCRβ V7 -4*01, TCRβ V7-2*02, TCRβ V7-2*03, TCRβ V7-2*01, TCRβ V7-3*01, TCRβ V7-9*03, or TCRβ V7-9*01, or a variant thereof.

[0301] In some embodiments, the TCRβ V 11 subfamily comprises: TCRβ V11-1*01, TCRβ V11-2*01 or TCRβ V11-3*01, or a variant thereof. In some embodiments, the TCRβ V14 subfamily comprises TCRβ VI4*01, or a variant thereof. In some embodiments, the TCRβ V16 subfamily comprises TCRβ V16*01, or a variant thereof. In some embodiments, the TCRβ VI 8 subfamily comprises TCRβ VI 8*01, or a variant thereof. In some embodiments, the TCRβ V9 subfamily comprises TCRβ V9*01 or TCRβ V9*02, or a variant thereof. In some embodiments, the TCRβ V13 subfamily comprises TCRβ VI3*01, or a variant thereof. In some embodiments, the TCRβ V4 subfamily comprises TCRβ V4-2*01, TCRβ V4-3*01, or TCRβ V4-1*01, or a variant thereof. In some embodiments, the TCRβ V3 subfamily comprises TCRβ V3-1*01, or a variant thereof. In some embodiments, the TCRβ V2 subfamily comprises TCRβ V2*0I, or a variant thereof. In some embodiments, the TCRβ V15 subfamily comprises TCRβ V15*0I, or a variant thereof. In some embodiments, the TCRβ V30 subfamily comprises TCRβ V30*0I, or TCRβ V30*02, or a variant thereof. In some embodiments, the TCRβ V19 subfamily comprises TCRβ V19*0I, or TCRβ VI9*02, or a variant thereof. In some embodiments, the TCRβ V27 subfamily comprises TCRβ V27*01, or a variant thereof. In some embodiments, the TCRβ V28 subfamily comprises TCRβ V28*01, or a variant thereof. In some embodiments, the TCRβ V24 subfamily comprises TCRβ V24-1*01, or a variant thereof. In some embodiments, the TCRβ V20 subfamily comprises TCRβ V20-1*01, or TCRβ V20-1*02, or a variant thereof. In some embodiments, the TCRβ V25 subfamily comprises TCRβ V25-1*01, or a variant thereof. In some embodiments, the TCRβ V29 subfamily comprises TCRβ V29-1*01, or a variant thereof.

[0302] Exemplary amino acid sequences for TCRβV subfamily members can be found on the ImMunoGeneTics Information System website: http: / / www.imgt.org / , or in a similar resource.Anti-TCRBV antibodies

[0303] 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 (IFNγ). This excess amount of IFNγ in turn activates macrophages which then overproduce proinflammatory cytokines such as IL-lbeta, IL-6, IL- 10 and TNF-alpha, causing a “cytokine storm” known as the cytokine release syndrome (CRS) (Shimabukuro-Vomhagen et al., J Immunother Cancer. 2018 Jun 15 ;6( 1) :56, herein incorporated by reference in its entirety). Thus, the need exists for developing antibodies that are capable of binding and activating only a subset of effector T cells, e.g., to re-duce the CRS and / or neurotoxicity (NT).

[0304] Described herein are molecules targeting the TCRβV chain of TCR and methods thereof. Without wishing to be bound by theory, such molecules are capable of binding, activating, and / or expanding only a subset of T cells, avoiding or reducing CRS and / or NT and minimizing potential immunosuppressive effects of anti-CD3 mAbs.

[0305] Described herein is a class of antibodies, i.e., anti-TCRβV antibody molecules as described herein, which despite having low sequence similarity (e.g., low sequence identity among the different antibody molecules that recognize different TCRβV subfamilies), recognize a structurally conserved, yet sequence-wise variable, region, e.g., domain, on the TCRβV protein (as denoted by the circled area in FIG. 5 A) and have a similar function (e.g., activation of T cells and a similar cytokine profile as described herein). Thus, the anti-TCRβV antibody molecules as described herein share a structurefunction relationship.

[0306] Without wishing to be bound by theory, in some embodiments, the anti-TCRβV antibody molecules as described herein bind to an outward facing epitope of a TCRβV protein when it is in a complex with a TCRalpha protein, e.g., as denoted by the circled area in FIG. 5A. In some embodiments, the anti-TCRβV antibody molecules as described herein recognize (e.g., bind to), a domain (e.g., an epitope) on the TCRβV protein that is: (1) structurally conserved among different TCRβV subfamilies; and (2) has minimal sequence identity among the different TCRβV subfamilies. As shown in Table 9, TCRβV proteins from the different TCRBV subfamilies share minimal sequence similarity. However, as shown in FIG. 5A-5B, TCRβV proteins which have minimal sequence similarity, share a similar 3D conformation and structure.

[0307] 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.

[0308] In some embodiments, the anti-TCRβV antibody molecules as described herein do not recognize, e.g., bind to, an interface of a TCRβV: TCRalpha complex. In some embodiments, the anti-TCRβV antibody molecules as described herein do not recognize, e.g., bind to, a constant region of a TCRβV protein. An exemplary antibody that binds to a constant region of a TCRBV region is JOVI. 1 as described in Viney et al., (Hybridoma. 1992 Dec;l 1 (6) : 701 - 13) . In some embodiments, the anti-TCRβV antibody molecules as described herein do not recognize, e.g., bind to, one or more (e.g., all) of acomplementarity determining region (e.g., CDR1, CDR2 and / or CDR3) of a TCRβV protein.

[0309] Provided herein are, inter alia, antibody molecules directed to the variable chain of the beta subunit of TCR (TCRβV) which bind and, e.g., activate a subset of T cells. The anti-TCRβV antibody molecules as described herein result in lesser or no production of cytokines associated with CRS, e.g., IL- 6, IL-lbeta, IL- 10 and TNF alpha; and enhanced and / or delayed production of IL-2 and IFNγ. In some embodiments, the anti-TCRβV antibodies as described herein have a cytokine profile, e.g., as described herein, which differs from a cytokine profile of a T cell engager that binds to a receptor or molecule other than a TCRβV region (“a non-TCRβV-binding T cell engager”). In some embodiments, the non-TCRβV- binding T cell engager comprises an antibody that binds to a CD3 molecule (e.g., CD3 epsilon (CD3e) molecule). In some embodiments, the non-TCRβV-binding T cell engager is an OKT3 antibody or an SP34-2 antibody.

[0310] In some embodiments, the anti-TCRβV antibodies as described herein result in expansion of TCRβV+ T cells, e.g., a subset of memory effector T cells known as TEMRA. Without wishing to be bound by theory, it is believed that in some embodiments, TEMRA cells can promote tumor cell lysis but not CRS. Accordingly, provided herein are methods of making said anti-TCRβV antibody molecules and uses thereof. Also described herein are multispecific molecules, e.g., bispecific molecules comprising said anti-TCRβV antibody molecules. In some embodiments, compositions comprising anti-TCRβV antibody molecules of the present disclosure, can be used, e.g., to: (1) activate and redirect T cells to promote tumor cell lysis for cancer immuno-therapy; and / or (2) expand TCRβV+ T cells. In some embodiments, compositions comprising anti-TCRβV antibody molecules as described herein limit the harmful side-effects of CRS and / or NT, e.g., CRS and / or NT associated with anti-CD3e targeting.

[0311] In some embodiments, the anti-TCRβV antibody molecule binds to one or more of TRBV2, TRBV3-1, TRBV4-1, TRBV4-2, TRBV4-3, TRBV5-1, TRBV5-4, TRBV5-5, TRBV5-6, TRBV5-8, TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8, TRBV6-9, TRBV7-2, TRBV7-3, TRBV7-4, TRBV7-6, TRBV7-7, TRBV7-8, TRBV7-9, TRBV9, TRBV10-1, TRBV10-2, TRBV10-3, TRBV11-1, TRBV11-2, TRBV11-3, TRBV12-3, TRBV12-4, TRBV12-5, TRBV13, TRBV14, TRBV15, TRBV16, TRBV18, TRBV19, TRBV20-1, TRBV24-1, TRBV25-1, TRBV27, TRBV28, TRBV29-1 and TRBV30. In some embodiments, the anti-TCRβV antibody molecule binds to one or more of TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8 and TRBV6-9. In some embodiments, the anti-TCRβV antibody molecule is an anti-TRBV2, anti-TRBV3-1, anti-TRBV4-1, anti-TRBV4-2, anti-TRBV4-3, anti-TRBV5-1, anti-TRBV5-4, anti-TRBV5-5, anti- TRBV5-6, anti-TRBV5-8, anti-TRBV6-1, anti-TRBV6-2, anti-TRBV6-3, anti-TRBV6-4, anti-TRBV6-5, anti-TRBV6-6, anti-TRBV6-8, anti-TRBV6-9, anti-TRBV7-2, anti-TRBV7-3, anti-TRBV7-4, anti- TRBV7-6, anti-TRBV7-7, anti-TRBV7-8, anti-TRBV7-9, anti-TRBV9, anti-TRBVl 0-1, anti-TRBVlO- 2, anti-TRBVl 0-3, anti-TRBVl 1-1, anti-TRBVl 1-2, anti-TRBVl 1-3, anti-TRBV12-3, anti-TRBV12-4, anti-TRBV12-5, anti-TRBV13, anti-TRBV14, anti-TRBV15, anti-TRBV16, anti-TRBV18, anti- TRBV19, anti-TRBV20-1, anti-TRBV24-1, anti-TRBV25-1, anti-TRBV27, anti-TRBV28, anti- TRBV29-1, or anti-TRBV30. Exemplary anti-TCRβV antibody molecules and the correspondingTCRβV subfamilies recognized by said anti-TCRβV antibody molecules are disclosed in Table 10.

[0312] In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV2, TRBV3-1, TRBV4-1, TRBV4-2, TRBV4-3, TRBV5-1, TRBV5-4, TRBV5-5, TRBV5-6, TRBV5-8, TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8, TRBV6-9, TRBV7-2, TRBV7-3, TRBV7-4, TRBV7-6, TRBV7-7, TRBV7-8, TRBV7-9, TRBV9, TRBV10-1, TRBV10-2, TRBV10-3, TRBV11-1, TRBV11-2, TRBV11-3, TRBV12-3, TRBV12-4, TRBV12-5, TRBV13, TRBV14, TRBV15, TRBV16, TRBV18, TRBV19, TRBV20-1, TRBV24-1, TRBV25-1, TRBV27, TRBV28, TRBV29-1 or TRBV30. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-1. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-2. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-3. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-4. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-5. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-6. In some embodiments, the anti- TCRβV antibody molecule binds specifically to TRBV6-8. In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRBV6-9.

[0313] In some embodiments, the anti-TCRβV antibody molecule does not bind to TCRβ V12, or binds to TCRβ V12 with an affinity and / or binding specificity that is less than (e.g., less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof as de-scribed in US Patent 5,861,155.

[0314] In some embodiments, the anti-TCRβV antibody molecule binds to TCRβ V 12 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.

[0315] In some embodiments, the anti-TCRβV antibody molecule binds to a TCRβV region other than TCRβ V12 (e.g., TCRβV region as described herein, e.g., TCRβ V6 subfamily (e.g., TCRβ V6-5*01) with an affinity and / or binding specificity that is greater than (e.g., greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof as de-scribed in US Patent 5,861,155.

[0316] In some embodiments, the anti-TCRβV antibody molecule does not comprise the CDRs of the Antibody B murine antibody.

[0317] In some embodiments, the anti-TCRβV antibody molecule does not bind to TCRβ V5-5*01 or TCRβ V5-l*01, or binds to TCRβ V5-5*01 or TCRβ 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.

[0318] In some embodiments, the anti-TCRβV antibody molecule binds to TCRβ V5-5*01 or TCRβ V5- l*01with an affinity and / or binding specificity that is greater than (e.g., greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificityof the TM23 murine antibody or a humanized version thereof as de-scribed in US Patent 5,861,155.

[0319] In some embodiments, the anti-TCRβV antibody molecule binds to a TCRβV region other than TCRβ V5-5*01 or TCRβ V5-l*01 (e.g., TCRβV region as described herein, e.g., TCRβ V6 subfamily (e.g., TCRβ V6-5*01) with an affinity and / or binding specificity that is greater than (e.g., greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and / or binding specificity of the TM23 murine antibody or a humanized version thereof as described in US Patent 5,861,155.

[0320] In some embodiments, the anti-TCRβV antibody molecule does not comprise the CDRs of the TM23 murine antibody.

[0321] In some embodiments, the light or the heavy chain variable framework (e.g., the region encompassing at least FR1, FR2, FR3, and optionally FR4) of the anti-TCRβV antibody molecule, e.g., anti -TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule can be chosen from: (a) a light or heavy chain variable framework including at least 80%, 85%, 87% 90%, 92%, 93%, 95%, 97%, 98%, or 100% of the amino acid residues from a human light or heavy chain variable framework, e.g. , a light or heavy chain variable framework residue from a human mature antibody, a human germline sequence, or a human consensus sequence; (b) a light or heavy chain variable framework including from 20% to 80%, 40% to 60%, 60% to 90%, or 70% to 95% of the amino acid residues from a human light or heavy chain variable framework, e.g., a light or heavy chain variable framework residue from a human mature antibody, a human germline sequence, or a human consensus sequence; (c) a non-human framework (e.g. , a rodent framework); or (d) a non-human framework that has been modified, e.g. , to remove antigenic or cytotoxic determinants, e.g , deimmunized, or partially humanized. In some embodiments, the light or heavy chain variable framework region (particularly FR1, FR2 and / or FR3) includes a light or heavy chain variable framework sequence at least 70, 75, 80, 85, 87, 88, 90, 92, 94, 95, 96, 97, 98, 99% identical or identical to the frameworks of a VL or VH segment of a human germline gene.

[0322] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a heavy chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more changes, e.g , amino acid substitutions or deletions, from an amino acid sequence of any one of A-H. 1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, e.g., the amino acid sequence of the FR region in the entire variable region, e.g., shown in FIG. 2A, or in SEQ ID NO: 9.

[0323] Alternatively, or in combination with the heavy chain substitutions described herein, the anti- TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more amino acid changes, e.g., amino acid substitutions or deletions, from an amino acid sequence of any one of A-H.1 to A-H.85, e.g., A-H. 1, A-H.2 or A-H.68, e.g. , the amino acid sequence of the FR region in the entire variable region, e.g., shown in FIG. 2B, or in SEQ ID NO: 10 or SEQ ID NO: 11.

[0324] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes one, two, three, or four heavy chain framework regions shown inFIG. 2A, or a sequence substantially identical thereto.

[0325] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes one, two, three, or four light chain framework regions shown in FIG. 2B, or a sequence substantially identical thereto.

[0326] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the light chain framework region 1 of A-H.1 or A-H.2, e.g., as shown in FIG. 2B.

[0327] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the light chain framework region 2 of A-H.1 or A-H.2, e.g., as shown in FIG. 2B.

[0328] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the light chain framework region 3 of A-H.1 or A-H.2, e.g., as shown in FIG. 2B.

[0329] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the light chain framework region 4 of A-H.1 or A-H.2, e.g., as shown in FIG. 2B.

[0330] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain comprising a framework region, e.g., framework region 1 (FR1), comprising a change, e.g., a substitution (e.g., a conservative substitution) at position 10 according to Kabat numbering. In some embodiments, the FR1 comprises a Phenylalanine at position 10, e.g., a Serine to Phenylalanine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0331] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a 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.

[0332] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain comprising a framework region, e.g., framework region 3 (FR3), comprising a change, e.g., a substitution (e.g., a conservative substitution) at a position as described herein according to Kabat numbering. In some embodiments, FR3 comprises a Phenylalanine at position 87, e.g., a substitution at position 87 according to Kabat numbering, e.g., a Tyrosine to Phenylalanine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0333] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain comprising: (a) a framework region 1 (FR1) comprising a Phenylalanine at position 10, e.g., a substitution at position 10 according to Kabat numbering, e.g., a Serine to Phenylalanine substitution; (b) a framework region 2 (FR2) comprising a Histidine at position 36, e.g., a substitution at position 36 according to Kabat numbering, e.g., a Tyrosine to Histidine substitution, and a Alanine at position 46, e.g., a substitution at position 46 according to Kabat numbering, e.g., a Arginine to Alanine substitution; and (c) a framework region 3 (FR3) comprising a Phenylalanine at position 87, e.g., a substitution at position 87 according to Kabat numbering, e.g., a Tyrosine to Phenylalanine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 10. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0334] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain comprising: (a) a framework region 2 (FR2) comprising a Histidine at position 36, e.g., a substitution at position 36 according to Kabat numbering, e.g., a Tyrosine to Histidine substitution, and a Alanine at position 46, e.g., a substitution at position 46 according to Kabat numbering, e.g., a Arginine to Alanine substitution; and (b) a framework region 3 (FR3) comprising a Phenylalanine at position 87, e.g., a substitution at position 87 according to Kabat numbering, e.g., a Tyrosine to Phenylalanine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 11. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0335] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain comprising: (a) a framework region 1 (FR1) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all) positions as described herein according to Kabat numbering; (b) a framework region 2 (FR2) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all) position as described herein according to Kabat numbering and (c) a framework region 3 (FR3) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all) position as described herein according to Kabat numbering. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0336] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the heavy chain framework region 1 of A-H.1 or A-H.2, e.g., as shown in FIG. 2A. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the heavy chain framework region 2 of A-H.1 or A- H.2, e.g., as shown in FIG. 2A. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti- TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the heavy chain framework region 3 of A-H.1 or A-H.2, e.g., as shown in FIG. 2A. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the heavy chain framework region 4 of A-H.1 or A-H.2, e.g. , as shown in FIG. 2A.

[0337] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a heavy chain variable domain comprising a framework region, e.g., framework region 3 (FR3), comprising a change, e.g., a substitution (e.g., a conservative substitution) at a position as described herein according to Kabat numbering. In some embodiments, FR3 comprises a Threonine at position 73, e.g., a substitution at position 73 according to Kabat numbering, e.g., a Glutamic Acid to Threonine substitution. In some embodiments, FR3 comprises a Glycine at position 94, e.g., a substitution at position 94 according to Kabat numbering, e.g , an Arginine to Glycine substitution. In some embodiments, the substitution is relative to a human germline heavy chain framework region sequence.

[0338] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a heavy chain variable domain comprising a framework region 3 (FR3) comprising a Threonine at position 73, e.g., a substitution at position 73 according to Kabat numbering, e.g., a Glutamic Acid to Threonine substitution, and a Glycine at position 94, e.g., a substitution at position 94 according to Kabat numbering, e.g., a Arginine to Glycine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 10.

[0339] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the heavy chain framework regions 1-4 of A-H.1 or A-H.2, e.g., SEQ ID NO: 9, or as shown in FIGs. 2A and 2B. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the light chain framework regions 1-4 of A-H.1, e.g., SEQ ID NO: 10, or as shown in FIGs. 2A and 2B. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the light chain framework regions 1-4 of A-H.2, e.g., SEQ ID NO: 11, or as shown in FIGs. 2A and 2B. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti- TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the heavy chain framework regions 1-4 of A-H.1, e.g., SEQ ID NO: 9; and the light chain framework regions 1-4 of A-H.1, e.g., SEQ ID NO: 10, or as shown in FIGs. 2A and 2B. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the heavy chain framework regions 1-4 of A-H.2, e.g., SEQ ID NO: 9; and the light chain framework regions 1-4 of A-H.2, e.g., SEQ ID NO: 11, or as shown in FIGs. 2A and 2B.

[0340] In some embodiments, the heavy or light chain variable domain, or both, of the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes an amino acid sequence, which is substantially identical to an amino acid as described herein, e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical to a variable region of an antibody described herein, e.g. , an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or as described in Table 1, or encoded by the nucleotide sequence in Table 1; or which differs at least 1 or 5 residues, but less than 40, 30, 20, or 10 residues, from a variable region of an antibody described herein.

[0341] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one, two, three, or four antigen-binding regions, e.g.,variable regions, having an amino acid sequence as set forth in Table 1, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the sequences shown in Table 1. In another embodiment, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes a VH and / or VL domain encoded by a nucleic acid having a nucleotide sequence as set forth in Table 1, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Table 1.

[0342] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises: a 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.

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

[0344] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule is a full antibody or fragment thereof (e.g., a Fab, F(ab')2, Fv, single domain antibody, or a single chain Fv fragment (scFv)). In embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule is a monoclonal antibody or an antibody with single specificity. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti- TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, can also be a humanized, chimeric, camelid, shark, or an in vitro-generated antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a humanized antibody molecule. The heavy and light chains of the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, can be full-length (e.g , an antibody can include at least one, and preferably two, complete heavy chains, and at least one, and preferably two, complete light chains) or can include an antigen-binding fragment (e.g , a Fab, F(ab')2, Fv, a single chain Fv fragment, a single domain antibody, a diabody (dAb), a bivalent antibody, or bispecific antibody or fragment thereof, a single domain variant thereof, a VHH, or a camelid antibody).

[0345] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is in the form of a multispecific molecule, e.g , a bispecific molecule, e.g., as described herein.

[0346] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, has a heavy chain constant region (Fc) chosen from, e.g., the heavy chain constant regions of 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.

[0347] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, has a light chain constant region chosen from, e.g., the light chain constant regions of kappa or lambda, preferably kappa (e.g., human kappa). In some embodiments, the constant region is altered, e.g., mutated, to modify the properties of the anti-TCRβV antibody molecule, e.g., anti- TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule (e.g , to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function). For example, the constant region is mutated at positions 296 (M to Y), 298 (S to T), 300 (T to E), 477 (H to K) and 478 (N to F) to alter Fc receptor binding (e.g. , the mutated positions correspond to positions 132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K) and 314 (N to F) of SEQ ID NOs: 212 or 214; or positions 135 (M to Y), 137 (S to T), 139 (T to E), 316 (H to K) and 317 (N to F) of SEQ ID NOs: 215, 216, 217 or 218), e.g., relative to human IgGl.

[0348] 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.

[0349] Additional exemplary humanized anti-TCRB V6 antibodies are provided in Table 1. In some embodiments, the anti-TCRβ V6 is antibody A, e.g., humanized antibody A (antibody A-H), as provided in Table 1 . In some embodiments, the anti-TCRβV antibody comprises one or more (e.g., all three) of a LC CDR1, LC CDR2, and LC CDR3 provided in Table 1; and / or one or more (e.g., all three) of a HC CDR1, HC CDR2, and HC CDR3 provided in Table 1, or a sequence with at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity thereto. In some embodiments, antibody A comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 1, or a sequence with at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity thereto.

[0350] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises a VH of A-H.1, A-H.2, A-H.3, A-H.4, A-H.5, A-H.6, A-H.7, A- H.8, A-H.9, A-H.10, A-H.1 l, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16, A-H.17, A-H.18, A-H.19, A- H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A- H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.1, A-H.42, A-H.43, A- H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A- H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A- H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A- H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0351] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises a VL of A-H.1, A-H.2, A-H.3, A-H.4, A-H.5, A-H.6, A-H.7, A- H.8, A-H.9, A-H.10, A-H.1 l, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16, A-H.17, A-H.18, A-H.19, A- H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A- H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.1, A-H.42, A-H.43, A- H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A- H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A- H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A- H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0352] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises a VH of A-H.1, A-H.2, A-H.3, A-H.4, A-H.5, A-H.6, A-H.7, A- H.8, A-H.9, A-H.10, A-H.1 l, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16, A-H.17, A-H.18, A-H.19, A- H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A- H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.1, A-H.42, A-H.43, A- H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A- H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A- H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A- H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto; and a VL of A-H.1, A-H.2, A-H.3, A-H.4, A-H.5, A-H.6, A-H.7, A-H.8, A-H.9, A-H.10, A-H.1 l, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16, A-H.17, A-H.18, A- H.19, A-H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A- H.31, A-H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.1, A-H.42, A- H.43, A-H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A- H.55, A-H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A- H.67, A-H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A- H.79, A-H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0353] Exemplary anti-TCRβV antibody molecules and the corresponding TCRβV subfamilies recognized by said anti-TCRβV antibody molecules are disclosed in Table 10.

[0354] The various TCRβV subfamilies and / or subfamily members can be expressed at different levels in individuals, e.g., healthy individuals, as disclosed in Kitaura K. et al (2016), BMC Immunology vol 17: 38, the entire contents of which are hereby incorporated by reference. For example, TCRβ V6-5 is represented in approximately 3-6% healthy donors.

[0355] The representation of various TCRBV subfamilies and / or subfamily members can also be different in cancer cells. For example, TCRβV is present in about 3-6% of tumor infdtrating T cells irrespective of tumor type (see Li B. et al., Nature Genetics, 2016, vol:48(7):725-32 the entire contents of which are hereby incorporated by references). Li et al., also disclose that TCRβ V6-5 is present at a high frequency in tumor cells.Anti-TCRβ V6 antibodies

[0356] In one aspect, provided herein is an anti-TCRβV antibody molecule that binds to human TCRβ V6, e.g., a TCRβ V6 subfamily comprising: TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01 or TCRβ V6-l*01. In some embodiments the TCRβ V6 subfamily comprises TCRβ V6-5*01 or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-4*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-4*02, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-9*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-8*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-5*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-6*02, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-6*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-2*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-3*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-l*01, or a variant thereof.

[0357] In some embodiments, TCRβ V6-5*01 is encoded by the nucleic acid sequence of SEQ ID NO: 43, or a sequence having 85%, 90%, 95%, 99% or more identity thereof. In some embodiments, TCRβ V6-5*01 comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence having 85%, 90%, 95%, 99% or more identity thereof.

[0358] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a non-murine antibody molecule, e.g., a human or humanized antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti- TCRβ V6-5*01) antibody molecule is a human antibody molecule. In some embodiments, the anti- TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule is a humanized antibody molecule.

[0359] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is isolated or recombinant.

[0360] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβV6-5*01) antibody molecule, comprises at least one antigen-binding region, e.g., a variable region or an antigen-binding fragment thereof, from an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H. 1, A-H.2 or A-H.68, or an antibody described in Table 1, or encoded by a nucleotide sequence in Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0361] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one, two, three or four variable regions from an antibody described herein, e.g , an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, 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.

[0362] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one or two heavy chain variable regions from an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody molecule described in Table 1, or encoded by a nucleotide sequence in TableI, 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.

[0363] In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain variable region (VH) having a consensus sequence of SEQ ID NO: 231 or 3290.

[0364] SEQ ID NO: 231 - Consensus VHQVQLVQSGAEVKKPGSSVKVSCKASGH / T / G / YD / T / SFH / R / D / K / TL / D / K / T / NW / F / T / I / Y / GYIHWV RQAPGQGLEWMGR / WV / I / FF / S / YA / PGSGN / ST / V / Y / IK / RYNEKFKGRVTITADTSTSTAYMELSS LRSEDTAVYYCAG / VSY / IYSY / AD / GVLDYWGQGTTVTVSS

[0365] SEQ ID NO: 3290 - Consensus VHQVQLVQSGAEVKKPGSSVKVSCKASGX1X2FX3X4X5YIHWVRQAPGQGLEWMGX6X7X8X9GSGX10X11X12YNEKFKGRVTITADTSTSTAYMELSSLRSEDTAVYYCAX13SX14YSX15X16VLDYWGQGT TVTVSS, 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; XI 1 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.

[0366] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one or two light chain variable regions from an antibody described herein, e.g , an antibody chosen from any one of A-H.1 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.

[0367] In some embodiments, the anti-TCRβV antibody molecule comprises a light chain variable region (VL) having a consensus sequence of SEQ ID NO: 230 or 3289.

[0368] SEQ ID NO: 230 - Consensus VLDIQMTQSPSFLSASVGDRVTITCKASQNVG / E / A / DN / DR / KVAWY / HQQKPGKAPKALIYSSSHRY K / SGVPSRFSGSGSGTEFTLTISSLQPEDFATYFCQQFKSYPLTFGQGTKLEIK

[0369] 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

[0370] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a heavy chain constant region for an IgG4, e.g., a human IgG4. In still another embodiment, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes a heavy chain constant region for an IgGl, e.g., a human IgGl. In some embodiments, the heavy chain constant region comprises an amino sequence set forth in Table 3, 21, or 22, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto.

[0371] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes a kappa light chain constant region, e.g., a human kappa light chain constant region. In some embodiments, the light chain constant region comprises an amino sequence set forth in Table 3, 21, or 22, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto.

[0372] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region (VH) of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, 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.

[0373] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[0374] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes at least one, two, or three complementarity determining regions (CDRs) from a light chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or an antibody described in Table 1, 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.

[0375] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Table 1, 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.

[0376] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 1, 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.

[0377] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, molecule includes all six CDRs from an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H. 1, A-H.2 or A-H.68, or an antibody described in Table 1, 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-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, may include any CDR described herein.

[0378] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Table 1) 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 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.

[0379] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Table 1) 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 orfour 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.

[0380] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes at least one, two, three, four, five, or six CDRs according to Kabat et al. (e.g., at least one, two, three, four, five, or six CDRs according to the Kabat definition as set out in Table 1) 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.

[0381] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes all six CDRs according to Kabat et al. (e.g., all six CDRs according to the Kabat definition as set out in Table 1) 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-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, may include any CDR described herein.

[0382] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes at least one, two, or three hypervariable loops that have the same canonical structures as the corresponding hypervariable loop of an antibody described herein, e.g., an antibody chosen from chosen from any one of A-H.1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, e.g., the same canonical structures as at least loop 1 and / or loop 2 of the heavy and / or light chain variable domains of an antibody described herein. See, e.g , Chothia et al., (1992) J. Mol. Biol. 227:799-817; Tomlinson et al., (1992) J. Mol. Biol. 227:776-798 for descriptions of hypervariable loop canonical structures. These structures can be determined by inspection of the tables described in these references.

[0383] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes at least one, two, or three 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.1, A-H.2 or A-H.68, or as described in Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or fouralterations (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.

[0384] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes at least one, two, or three CDRs 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, or three CDRs according to Chothia et al. shown in Table 1.

[0385] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes at least one, two, three, four, five, or six CDRs 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. 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 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.

[0386] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, includes all six CDRs according to Chothia et al. (e.g., all six CDRs according to the Chothia definition as set out in Table 1) 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 Chothia et al. shown in Table 1. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, may include any CDR described herein.

[0387] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, molecule includes a combination of CDRs or hypervariable loops defined according to Kabat et al., Chothia et al., by ImMunoGeneTics (IMGT) numbering system or as described in Table 1.

[0388] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, can contain any combination of CDRs or hypervariable loops according tothe Kabat and Chothia definitions, or by ImMunoGeneTics (IMGT) numbering system.

[0389] In some embodiments, a combined CDR as set out in Table 1 is a CDR that comprises a Kabat CDR and a Chothia CDR.

[0390] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, molecule includes a combination of CDRs or hypervariable loops identified as combined CDRs in Table 1. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, can contain any combination of CDRs or hypervariable loops according the “combined” CDRs are described in Table 1.

[0391] In some embodiments, e.g., an embodiment comprising a variable region, a CDR (e.g., a combined CDR, Chothia CDR or Kabat CDR, or by ImMunoGeneTics (IMGT) numbering system), or other sequence referred to herein, e.g., in Table 1, the antibody molecule is a monospecific antibody molecule, a bispecific antibody molecule, a bivalent antibody molecule, a biparatopic antibody molecule, or an antibody molecule that comprises an antigen binding fragment of an antibody, e.g., a half antibody or antigen binding fragment of a half antibody. In certain embodiments the antibody molecule comprises a multispecific molecule, e.g , a bispecific molecule, e.g., as described herein.

[0392] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule includes: (i) one, two or all of a light chain complementarity determining region 1 (LC CDR1), a light chain complementarity determining region 2 (LC CDR2), and a light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO: 2, SEQ ID NO: 10 or SEQ ID NO: 11, and / or (ii) one, two or all of a heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 1 or SEQ ID NO: 9.

[0393] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises a LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 2, and a HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 1.

[0394] In some embodiments the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises a LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 10, and a HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 9.

[0395] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises a LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 11, and a HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 9.

[0396] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 6, a LC CDR2 amino acid sequence of SEQ ID NO: 7, or a LC CDR3 amino acid sequence of SEQ ID NO: 8; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 3, a HC CDR2 amino acid sequence of SEQ ID NO: 4, or a HC CDR3 amino acid sequence of SEQ ID NO: 5.

[0397] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1amino 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.

[0398] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 51, a LC CDR2 amino acid sequence of SEQ ID NO: 52, or a LC CDR3 amino acid sequence of SEQ ID NO: 53; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 45, a HC CDR2 amino acid sequence of SEQ ID NO: 46, or a HC CDR3 amino acid sequence of SEQ ID NO: 47.

[0399] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1 amino acid sequence of SEQ ID NO: 51, a LC CDR2 amino acid sequence of SEQ ID NO: 52, or a LC CDR3 amino acid sequence of SEQ ID NO: 53; and / or (ii) a heavy chain variable region (VH) comprising a HC CDR1 amino acid sequence of SEQ ID NO: 45, a HC CDR2 amino acid sequence of SEQ ID NO: 46, or a HC CDR3 amino acid sequence of SEQ ID NO: 47.

[0400] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 54, a LC CDR2 amino acid sequence of SEQ ID NO: 55, or a LC CDR3 amino acid sequence of SEQ ID NO: 56; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 48, a HC CDR2 amino acid sequence of SEQ ID NO: 49, or a HC CDR3 amino acid sequence of SEQ ID NO: 50.

[0401] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1 amino acid sequence of SEQ ID NO: 54, a LC CDR2 amino acid sequence of SEQ ID NO: 55, or a LC CDR3 amino acid sequence of SEQ ID NO: 56; and / or (ii) a heavy chain variable region (VH) comprising a HC CDR1 amino acid sequence of SEQ ID NO: 48, a HC CDR2 amino acid sequence of SEQ ID NO: 49, or a HC CDR3 amino acid sequence of SEQ ID NO: 50.

[0402] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises a 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.

[0403] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises a 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.

[0404] 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.

[0405] 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 Tor 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-TCRβ V12 antibodies

[0406] In one aspect, provided herein is an anti-TCRβV antibody molecule that binds to human TCRβ V12, e.g., a TCRβ V12 subfamily comprising: TCRβ V12-4*01, TCRβ V12-3*01 or TCRβ V12-5*01. In some embodiments the TCRβ V12 subfamily comprises TCRβ V12-4*01. In some embodiments the TCRβ V12 subfamily comprises TCRβ V12-3*01.

[0407] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule, is a non-murine antibody molecule, e.g., a human or humanized antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule is a human antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule is a humanized antibody molecule.

[0408] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule, is isolated or recombinant.

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

[0410] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule, comprises at least one, two, three or four variable regions from an antibody described herein, e.g., an antibody as described in Table 2, or encoded by a nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0411] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 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.

[0412] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ 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.

[0413] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibodymolecule, comprises a heavy chain constant region for an IgG4, e.g. , a human IgG4. In still another embodiment, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule, includes a heavy chain constant region for an IgGl, e.g., a human IgGl. In some embodiments, the heavy chain constant region comprises an amino sequence set forth in Table 3, 21, or 22, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto.

[0414] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ 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, 21, or 22, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto.

[0415] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ 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.

[0416] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ 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.

[0417] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ 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.

[0418] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ 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.

[0419] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ 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 (orcollectively 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.

[0420] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ 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-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule, may include any CDR described herein.

[0421] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule includes at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Table 2) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen as described in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Kabat et al. shown in Table 2.

[0422] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule includes at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Table 2) from a light chain variable region of an antibody described herein, e.g., an antibody as described in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Kabat et al. shown in Table 2.

[0423] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ 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.

[0424] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ 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 describedherein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2; or encoded by the nucleotide sequence in Table 2; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to all six CDRs according to Kabat et al. shown in Table 2. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti- TCRβ V12 antibody molecule may include any CDR described herein.

[0425] In some embodiments, the anti—TCRβV antibody molecule, e.g., anti— TCRβ 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.

[0426] In some embodiments, the anti— TCRβV antibody molecule, e.g., anti— TCRβ 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 heavy chain variable region of an antibody described herein, e.g., an antibody chosen as described in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Chothia et al. shown in Table 2.

[0427] In some embodiments, the anti— TCRβV antibody molecule, e.g. , anti— TCRβ 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.

[0428] In some embodiments, the anti— TCRβV antibody molecule, e.g., anti— TCRβ V12 antibody molecule includes at least one, two, three, four, five, or six CDRs according to Chothia et al. (e.g., at least one, two, three, four, five, or six CDRs according to the Chothia definition as set out in Table 2) 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 toone, two, three, four, five, or six CDRs according to Chothia et al. shown in Table 2.

[0429] In some embodiments, the anti— TCRβV antibody molecule, e.g., anti— TCRβ V12 antibody molecule includes all six CDRs according to Chothia et al. (e.g, all six CDRs according to the Chothia definition as set out in Table 2) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2; or encoded by the nucleotide sequence in Table 2; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to all six CDRs according to Chothia et al. shown in Table 2. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti- TCRβ V12 antibody molecule may include any CDR described herein.

[0430] In some embodiments, the anti— TCRβV antibody molecule, e.g., anti— TCRβ V12 antibody molecule includes at least one, two, or three CDRs according to a combined CDR (e.g., at least one, two, or three CDRs according to the combined CDR definition as set out in Table 2) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen as described in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to combined CDR shown in Table 2.

[0431] In some embodiments, the anti— TCRβV antibody molecule, e.g., anti— TCRβ V12 antibody molecule includes at least one, two, or three CDRs according to a combined CDR (e.g., at least one, two, or three CDRs according to the combined CDR definition as set out in Table 2) from a light chain variable region of an antibody described herein, e.g., an antibody as described in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to a combined CDR shown in Table 2.

[0432] In some embodiments, the anti— TCRβV antibody molecule, e.g., anti— TCRβ V12 antibody molecule includes at least one, two, three, four, five, or six CDRs according to a combined CDR. (e.g., at least one, two, three, four, five, or six CDRs according to the combined CDR definition as set out in Table 2) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, three, four, five, or six CDRs according to a combined CDR shown in Table 2.

[0433] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule includes all six CDRs according to a combined CDR (e.g., all six CDRs according to thecombined CDR definition as set out in Table 2) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2; or encoded by the nucleotide sequence in Table 2; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to all six CDRs according to a combined CDR shown in Table 2. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule may include any CDR described herein.

[0434] In some embodiments, a combined CDR as set out in Table 1 is a CDR that comprises a Kabat CDR and a Chothia CDR or by ImMunoGeneTics (IMGT) numbering system.

[0435] In some embodiments, the anti-TCRβV antibody molecule, e e.g., anti-TCRβ V12 antibody molecule, molecule includes a combination of CDRs or hypervariable loops identified as combined CDRs in Table 1. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule, can contain any combination of CDRs or hypervariable loops according the “combined” CDRs are described in Table 1.

[0436] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule includes a combination of CDRs or hypervariable loops defined according to the Kabat et al. and Chothia et al., by ImMunoGeneTics (IMGT) numbering system, or as described in Table 1.

[0437] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule can contain any combination of CDRs or hypervariable loops according to the Kabat and Chothia definitions, or by ImMunoGeneTics (IMGT) numbering system.

[0438] In some embodiments, e.g., an embodiment comprising a variable region, a CDR (e.g., a combined CDR, Chothia CDR or Kabat CDR, or by ImMunoGeneTics (IMGT) numbering system), or other sequence referred to herein, e.g., in Table 2, the antibody molecule is a monospecific antibody molecule, a bispecific antibody molecule, a bivalent antibody molecule, a biparatopic antibody molecule, or an antibody molecule that comprises an antigen binding fragment of an antibody, e.g., a half antibody or antigen binding fragment of a half antibody. In certain embodiments the antibody molecule comprises a multispecific molecule, e.g., a bispecific molecule, e.g., as described herein.

[0439] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule includes: (i) one, two or all of a light chain complementarity determining region 1 (LC CDR1), a light chain complementarity determining region 2 (LC CDR2), and a light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO: 16, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29 or SEQ ID NO: 30, and / or (ii) one, two or all of a heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 15, SEQ ID NO: 23, SEQ ID NO: 24 or SEQ ID NO: 25.

[0440] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 20, a LC CDR2 amino acidsequence of SEQ ID NO: 21, or a LC CDR3 amino acid sequence of SEQ ID NO: 22; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 17, a HC CDR2 amino acid sequence of SEQ ID NO: 18, or a HC CDR3 amino acid sequence of SEQ ID NO: 19.

[0441] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1 amino acid sequence of SEQ ID NO: 20, a LC CDR2 amino acid sequence of SEQ ID NO: 21, and a LC CDR3 amino acid sequence of SEQ ID NO: 2; and / or (ii) a heavy chain variable region (VH) comprising a HC CDR1 amino acid sequence of SEQ ID NO: 17, a HC CDR2 amino acid sequence of SEQ ID NO: 18, and a HC CDR3 amino acid sequence of SEQ ID NO: 19.

[0442] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 63, a LC CDR2 amino acid sequence of SEQ ID NO: 64, or a LC CDR3 amino acid sequence of SEQ ID NO: 65; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 57, a HC CDR2 amino acid sequence of SEQ ID NO: 58, or a HC CDR3 amino acid sequence of SEQ ID NO: 59.

[0443] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1 amino acid sequence of SEQ ID NO: 63, a LC CDR2 amino acid sequence of SEQ ID NO: 64, or a LC CDR3 amino acid sequence of SEQ ID NO: 65; and / or (ii) a heavy chain variable region (VH) comprising a HC CDR1 amino acid sequence of SEQ ID NO: 57, a HC CDR2 amino acid sequence of SEQ ID NO: 58, or a HC CDR3 amino acid sequence of SEQ ID NO: 59.

[0444] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 66, a LC CDR2 amino acid sequence of SEQ ID NO: 67, or a LC CDR3 amino acid sequence of SEQ ID NO: 68; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 60, a HC CDR2 amino acid sequence of SEQ ID NO: 61, or a HC CDR3 amino acid sequence of SEQ ID NO: 62.

[0445] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1 amino acid sequence of SEQ ID NO: 63, a LC CDR2 amino acid sequence of SEQ ID NO: 64, or a LC CDR3 amino acid sequence of SEQ ID NO: 65; and / or (ii) a heavy chain variable region (VH) comprising a HC CDR1 amino acid sequence of SEQ ID NO: 57, a HC CDR2 amino acid sequence of SEQ ID NO: 58, or a HC CDR3 amino acid sequence of SEQ ID NO: 59.

[0446] In some embodiments, the light or the heavy chain variable framework (e.g., the region encompassing at least FR1, FR2, FR3, and optionally FR4) of the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule can be chosen from: (a) a light or heavy chain variable framework including at least 80%, 85%, 87% 90%, 92%, 93%, 95%, 97%, 98%, or 100% of the amino acid residues from a human light or heavy chain variable framework, e.g., a light or heavy chain variable framework residue from a human mature antibody, a human germline sequence, or a human consensus sequence; (b) a light or heavy chain variable framework including from 20% to 80%, 40% to 60%, 60% to 90%, or70% to 95% of the amino acid residues from a human light or heavy chain variable framework, e.g. , a light or heavy chain variable framework residue from a human mature antibody, a human germline sequence, or a human consensus sequence; (c) a non-human framework (e.g., a rodent framework); or (d) a non-human framework that has been modified, e.g., to remove antigenic or cytotoxic determinants, e.g., deimmunized, or partially humanized. In some embodiments, the light or heavy chain variable framework region (particularly FR1, FR2 and / or FR3) includes a light or heavy chain variable framework sequence at least 70, 75, 80, 85, 87, 88, 90, 92, 94, 95, 96, 97, 98, 99% identical or identical to the frameworks of a VL or VH segment of a human germline gene.

[0447] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule, comprises a heavy chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more changes, e.g., amino acid substitutions or deletions, from an amino acid sequence described in Table 2, e.g. , the amino acid sequence of the FR region in the entire variable region, e.g., shown in FIGs. 3 A and 3B, or in SEQ ID NOs: 23-25.

[0448] Alternatively, or in combination with the heavy chain substitutions described herein the anti- TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises a light chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more amino acid changes, e.g., amino acid substitutions or deletions, from an amino acid sequence of an antibody described herein, e.g., the amino acid sequence of the FR region in the entire variable region, e.g., shown in FIGs. 3A and 3B, or in SEQ ID NOs: 26-30.

[0449] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule includes one, two, three, or four heavy chain framework regions shown in FIG. 3 A, or a sequence substantially identical thereto.

[0450] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule includes one, two, three, or four light chain framework regions shown in FIG. 3B, or a sequence substantially identical thereto. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises the light chain framework region 1 e.g., as shown in FIG. 3B. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises the light chain framework region 2 e.g., as shown in FIG. 3B. In some embodiments, the anti- TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises the light chain framework region 3, e.g., as shown in FIG. 3B. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti- TCRβ V12 antibody molecule comprises the light chain framework region 4, e.g., as shown in FIG. 3B.

[0451] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 1 (FR1), comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more, e.g., all, position as described herein according to Kabat numbering. In some embodiments, FR1 comprises an Aspartic Acid at position 1, e.g., a substitution at position 1 according to Kabat numbering, e.g., an Alanine to Aspartic Acid substitution. In some embodiments, FR1 comprises an Asparagine at position 2, e.g., a substitution at position 2 according to Kabat numbering, e.g., an Isoleucine to Asparaginesubstitution, Serine to Asparagine substitution or Tyrosine to Asparagine substitution. In some embodiments, FR1 comprises a Leucine at position 4, e.g., a substitution at position 4 according to Kabat numbering, e.g., a Methionine to Leucine substitution.

[0452] In some embodiments, the anti— TCRβV antibody molecule, e.g. , anti— TCRβ V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 1 (FR1), comprising a substitution at position 1 according to Kabat numbering, e.g., an Alanine to Aspartic Acid substitution, a substitution at position 2 according to Kabat numbering, e.g. , an Isoleucine to Asparagine substitution, Serine to Asparagine substitution or Tyrosine to Asparagine substitution, and a substitution at position 4 according to Kabat numbering, e.g., a Methionine to Leucine substitution. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V 12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 1 (FR1), comprising a substitution at position 1 according to Kabat numbering, e.g., an Alanine to Aspartic Acid substitution, and a substitution at position 2 according to Kabat numbering, e.g., an Isoleucine to Asparagine substitution, Serine to Asparagine substitution or Tyrosine to Asparagine substitution. In some embodiments, the anti- TCRβV antibody molecule, e.g., anti-TCRβ V 12 antibody molecule comprises a light chain comprising a framework region, e.g , framework region 1 (FR1), comprising a substitution at position 1 according to Kabat numbering, e.g., an Alanine to Aspartic Acid substitution, and a substitution at position 4 according to Kabat numbering, e.g., a Methionine to Leucine substitution. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 1 (FR1), comprising a substitution at position 2 according to Kabat numbering, e.g., an Isoleucine to Asparagine substitution, Serine to Asparagine substitution or Tyrosine to Asparagine substitution, and a substitution at position 4 according to Kabat numbering, e.g., a Methionine to Leucine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0453] In some embodiments, the anti— TCRβV antibody molecule, e.g., anti— TCRβ V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 3 (FR3), comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more, e.g., all, position as described herein according to Kabat numbering. In some embodiments, FR3 comprises a Glycine at position 66, e.g., a substitution at position 66 according to Kabat numbering, e.g., a Lysine to Glycine substitution, or a Serine to Glycine substitution. In some embodiments, FR3 comprises an Asparagine at position 69, e.g., a substitution at position 69 according to Kabat numbering, e.g., a Tyrosine to Asparagine substitution. In some embodiments, FR3 comprises a Tyrosine at position 71, e.g., a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, or an Alanine to Tyrosine substitution.

[0454] In some embodiments, the anti— TCRβV antibody molecule, e.g., anti— TCRβ V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 3 (FR3), comprising a substitution at position 66 according to Kabat numbering, e.g., a Lysine to Glycine substitution, or a Serine to Glycine substitution, and a substitution at position 69 according to Kabatnumbering, e.g., a Tyrosine to Asparagine substitution. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 3 (FR3), comprising a substitution at position 66 according to Kabat numbering, e.g., Lysine to Glycine substitution, or a Serine to Glycine substitution, and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, or an Alanine to Tyrosine substitution. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V 12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 3 (FR3), comprising a substitution at position 69 according to Kabat numbering, e.g., a Tyrosine to Asparagine substitution and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, or an Alanine to Tyrosine substitution. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 3 (FR3), comprising a substitution at position 66 according to Kabat numbering, e.g., a Lysine to Glycine substitution, or a Serine to Glycine substitution, a substitution at position 69 according to Kabat numbering, e.g., a Tyrosine to Asparagine substitution and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, or an Alanine to Tyrosine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0455] In some embodiments, the anti— TCRβV antibody molecule, e.g. , anti— TCRβ V12 antibody molecule comprises a light chain comprising: a framework region 1 (FR1) comprising a substitution at position 2 according to Kabat numbering, e.g., a Isoleucine to Asparagine substitution; and a framework region 3 (FR3), comprising a substitution at position 69 according to Kabat numbering, e.g., a Threonine to Asparagine substitution and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 26. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0456] In some embodiments, the anti— TCRβV antibody molecule, e.g. , anti— TCRβ V12 antibody molecule comprises a light chain comprising: (a) a framework region 1 (FR1) comprising a substitution at position 1 according to Kabat numbering, e.g., a Alanine to Aspartic Acid substitution, and a substitution at position 2 according to Kabat numbering, e.g., a Isoleucine to Asparagine substitution; and (b) a framework region 3 (FR3), comprising a substitution at position 69 according to Kabat numbering, e.g., a Threonine to Asparagine substitution and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 27 In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0457] In some embodiments, the anti— TCRβV antibody molecule, e.g. , anti— TCRβ V12 antibody molecule comprises a light chain comprising: (a) a framework region 1 (FR1) comprising a substitution at position 2 according to Kabat numbering, e.g., a Serine to Asparagine substitution; and a substitution at position 4 according to Kabat numbering, e.g., a Methionine to Leucine substitution; and (b) aframework region 3 (FR3), comprising a substitution at position 69 according to Kabat numbering, e.g., a Threonine to Asparagine substitution and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 28 In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0458] In some embodiments, the anti— TCRβV antibody molecule, e.g. , anti— TCRβ V12 antibody molecule comprises a light chain comprising: (a) a framework region 1 (FR1) comprising a substitution at position 2 according to Kabat numbering, e.g., a Serine to Asparagine substitution; and (b) a framework region 3 (FR3) comprising a substitution at position 66 according to Kabat numbering, e.g., a Lysine to Glycine substitution; a substitution at position 69 according to Kabat numbering, e.g., a Threonine to Asparagine substitution; and a substitution at position 71 according to Kabat numbering, e.g., a Alanine to Tyrosine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 29. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0459] In some embodiments, the anti— TCRβV antibody molecule, e.g. , anti— TCRβ V12 antibody molecule comprises a light chain comprising: (a) a framework region 1 (FR1) comprising a substitution at position 2 according to Kabat numbering, e.g., a Tyrosine to Asparagine substitution; and (b) a framework region 3 (FR3) comprising a substitution at position 66 according to Kabat numbering, e.g., a Serine to Glycine substitution; a substitution at position 69 according to Kabat numbering, e.g., a Threonine to Asparagine substitution; and a substitution at position 71 according to Kabat numbering, e.g., a Alanine to Tyrosine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 29. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0460] In some embodiments, the anti— TCRβV antibody molecule, e.g. , anti— TCRβ V12 antibody molecule comprises a light chain variable domain comprising: (a) a framework region 1 (FR1) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all) positions as described herein according to Kabat numbering, and (b) a framework region 3 (FR3) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all) position as described herein according to Kabat numbering. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0461] In some embodiments, the anti— TCRβV antibody molecule, e.g. , anti— TCRβ V12 antibody molecule comprises the heavy chain framework region 1, e.g., as shown in FIG. 3A. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V 12 antibody molecule comprises the heavy chain framework region 2, e.g., as shown in FIG. 3A. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises the heavy chain framework region 3, e.g., as shown in FIG. 3A. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises the heavy chain framework region 4, e.g., as shown in FIG. 3A. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ VI 2 antibody moleculecomprises the heavy chain framework regions 1-4, e.g., SEQ ID NOS: 20-23, or as shown in FIG. 3A. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ VI 2 antibody molecule comprises the light chain framework regions 1-4, e.g., SEQ ID NOs: 26-30, or as shown in FIG. 3B.

[0462] In some embodiments, the anti— TCRβV antibody molecule, e.g., anti— TCRβ V12 antibody molecule comprises the heavy chain framework regions 1-4, e.g., SEQ ID NOs: 23-25; and the light chain framework regions 1-4, e.g., SEQ ID NOs: 26-30, or as shown in FIGs. 3A and 3B.

[0463] In some embodiments, the heavy or light chain variable domain, or both, of, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule includes an amino acid sequence, which is substantially identical to an amino acid as described herein, e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical to a variable region of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2; or which differs at least 1 or 5 residues, but less than 40, 30, 20, or 10 residues, from a variable region of an antibody described herein.

[0464] In some embodiments, the anti— TCRβV antibody molecule, e.g., anti— TCRβ V12 antibody molecule comprises at least one, two, three, or four antigen-binding regions, e.g., variable regions, having an amino acid sequence as set forth in Table 2, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the sequences shown in Table 2. In another embodiment, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule includes a VH and / or VL domain encoded by a nucleic acid having a nucleotide sequence as set forth in Table 2, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Table 2.

[0465] In some embodiments, the anti— TCRβV antibody molecule, e.g., anti— TCRβ V12 antibody molecule comprises: a VH domain comprising an amino acid sequence chosen from the amino acid sequence of SEQ ID NO: 23, SEQ ID NO:24 or SEQ ID NO:25, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, SEQ ID NO:24 or SEQ ID NO:25, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 23, SEQ ID NO:24 or SEQ ID NO:25; and / or a VL domain comprising an amino acid sequence chosen from the amino acid sequence of SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29 or SEQ ID NO: 30, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29 or SEQ ID NO: 30, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29 or SEQ ID NO: 30. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acidsequence of SEQ ID NO: 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 26, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 26, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 26.

[0466] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 27, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 27, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 27.

[0467] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 28, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 28, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 28.

[0468] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 29, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 29, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 29.

[0469] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 30, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 30, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 30.

[0470] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 24 or 25, anamino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 24 or 25, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 24 or 25; and a VL domain comprising the amino acid sequence of SEQ ID NO: 26, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 26, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 26.

[0471] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 24 or 25, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 24 or 25, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 24 or 25; and a VL domain comprising the amino acid sequence of SEQ ID NO: 27, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 27, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 27.

[0472] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 24 or 25, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 24 or 25, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 24 or 25; and a VL domain comprising the amino acid sequence of SEQ ID NO: 28, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 28, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 28.

[0473] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 24 or 25, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 24 or 25, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 24 or 25; and a VL domain comprising the amino acid sequence of SEQ ID NO: 29, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 29, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 29.

[0474] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 24 or 25, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 24 or 25, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 24 or 25; and a VL domain comprising the amino acid sequence of SEQ ID NO: 30, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 30, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 30.

[0475] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 25 or 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 25 or 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 25 or 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 26, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 26, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 26.

[0476] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 25 or 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 25 or 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 25 or 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 27, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 27, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 27.

[0477] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 25 or 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 25 or 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 25 or 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 28, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 28, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 28.

[0478] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 25 or 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 25 or 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 25 or 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 29, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 29, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 29.

[0479] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 25 or 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 25 or 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 25 or 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 30, an amino acid sequence at least about 85%, 90%, 95%, 99% ormore identical to the amino acid sequence SEQ ID NO: 30, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 30.

[0480] In some embodiments, the anti—TCRβV antibody molecule, e.g., anti—TCRβ V12 antibody molecule is a full antibody or fragment thereof (e.g , a Fab, F(ab')2, Fv, or a single chain Fv fragment (scFv)). In embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6- 5*01) antibody molecule is a monoclonal antibody or an antibody with single specificity. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V 12 antibody molecule, can also be a humanized, chimeric, camelid, shark, or an in vitro-generated antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule is a humanized antibody molecule. The heavy and light chains of the anti-TCRβV antibody molecule, e.g., anti-TCRβ VI 2 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, a VHH, or a camelid antibody).

[0481] In some embodiments, the anti— TCRβV antibody molecule, e.g., anti— TCRβ V12 antibody molecule is in the form of a multispecific molecule, e.g , a bispecific molecule, e.g., as described herein.

[0482] In some embodiments, the anti— TCRβV antibody molecule, e.g., anti— TCRβ V12 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.

[0483] In some embodiments, the anti— TCRβV antibody molecule, e.g., anti— TCRβ V12 antibody molecule has a light chain constant region chosen from, e.g., the light chain constant regions of kappa or lambda, preferably kappa (e.g., human kappa). In some embodiments, the constant region is altered, e.g., mutated, to modify the properties of the anti-TCRβV antibody molecule, e.g., anti-TCRβ V12 antibody molecule (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function). For example, the constant region is mutated at positions 296 (M to Y), 298 (S to T), 300 (T to E), 477 (H to K) and 478 (N to F) to alter Fc receptor binding (e.g. , the mutated positions correspond to positions 132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K) and 314 (N to F) of SEQ ID NOs: 212 or 214; or positions 135 (M to Y), 137 (S to T), 139 (T to E), 316 (H to K) and 317 (N to F) of SEQ ID NOs: 215, 216, 217 or 218).

[0484] Antibody B-H.1 comprises a first chain comprising the amino acid sequence of SEQ ID NO: 3280 and a second chain comprising the amino acid sequence of SEQ ID NO: 3281.

[0485] Additional exemplary anti-TCRβ V12 antibodies are provided in Table 2. In some embodiments, the anti-TCRβ V12 is antibody B, e.g., humanized antibody B (antibody B-H), as provided in Table 2. In some embodiments, the anti-TCRβV antibody comprises one or more (e.g., all three) of a LC CDR1, LCCDR2, and LC CDR3 provided in Table 2; and / or one or more (e.g., all three) of a HC CDR1, HC CDR2, and HC CDR3 provided in Table 2, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody B comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 2, or a sequence with at least 95% sequence identity thereto.

[0486] In some embodiments, the anti-TCRVB 12 antibody molecule (e.g., anti-TCRVB 12-3 or anti- TCRVB 12-4 antibody molecule) comprises a VH of B-H. 1A, B-H. IB, B-H. 1C, B-H. ID, B-H. IE, B- H.1F, B-H.1G, B-H. 1H, B-H.1, B-H.2, B-H.3, B-H.4, B-H.5, or B-H.6, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0487] In some embodiments, the anti-TCRVB 12 antibody molecule (e.g., anti-TCRVB 12-3 or anti- TCRVB 12-4 antibody molecule) comprises a VL of B-H.1A, B-H. IB, B-H.1C, B-H. ID, B-H. IE, B- H.1F, B-H.1G, B-H. 1H, B-H.1, B-H.2, B-H.3, B-H.4, B-H.5, or B-H.6, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0488] In some embodiments, the anti-TCRVB 12 antibody molecule (e.g., anti-TCRVB 12-3 or anti- TCRVB 12-4 antibody molecule) comprises a VH of B-H. 1A, B-H. IB, B-H. 1C, B-H. ID, B-H. IE, B- H.1F, B-H.1G, B-H. 1H, B-H.1, B-H.2, B-H.3, B-H.4, B-H.5, or B-H.6, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto; and a VL of B-H.1A, B-H.1B, B-H.1C, B-H. ID, B-H. IE, B-H. IF, B-H.1G, B-H.1H, B-H.1, B-H.2, B-H.3, B-H.4, B-H.5, or B-H.6, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.Anti-TCRβ V5 antibodies

[0489] In one aspect, provided herein is an anti-TCRβV antibody molecule that binds to human TCRβ V5. In some embodiments, the TCRβ V5 subfamily comprises TCRβ V5-5*01, TCRβ V5-6*01, TCRβ V5-4*01, TCRβ V5-8*01, TCRβ V5-l*01, or a variant thereof.Anti-TCRβ V10 antibodies

[0490] In one aspect, provided herein is an anti-TCRβV antibody molecule that binds to a human TCRβ V10 subfamily member. In some embodiments, TCRβ V10 subfamily is also known as TCRβ V12. In some embodiments, the TCRβ V10 subfamily comprises: TCRβ V10-1*01, TCRβ V10-1*02, TCRβ V10-3*01 or TCRβ V10-2*01, or a variant thereof.

[0491] Exemplary anti-TCRβ V10 antibodies are provided in Table 12. In some embodiments, the anti- TCRβ V10 is antibody D, e.g., humanized antibody D (antibody D-H), as provided in Table 12. In some embodiments, antibody D comprises one or more (e.g., three) light chain CDRs and / or one or more (e.g., three) heavy chain CDRs provided in Table 12, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody D comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 12, or a sequence with at least 95% sequence identity thereto.

[0492] In some embodiments, the anti-TCRβ V10 antibody molecule comprises a VH or a VL of an antibody described in Table 12, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0493] In some embodiments, the anti-TCRβ V10 antibody molecule comprises a VH and a VL of an antibody described in Table 12, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.Additional anti-TCRVβ antibodies

[0494] Additional exemplary anti-TCRβV antibodies are provided in Table 13. In some embodiments, the anti-TCRβV antibody is a humanized antibody, e.g., as provided in Table 13. In some embodiments, the anti-TCRβV antibody comprises one or more (e.g., all three) of a LC CDR1, LC CDR2, and LC CDR3 provided in Table 13; and / or one or more (e.g., all three) of a HC CDR1, HC CDR2, and HC CDR3 provided in Table 13, or a sequence with at least 95% sequence identity thereto. In some embodiments, the anti-TCRβV antibody comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 13, or a sequence with at least 95% sequence identity thereto.Antibody-like Frameworks or Scaffolds

[0495] A wide variety of antibody / immunoglobulin frameworks or scaffolds can be employed in the anti-TCRvb antibody molecules as described herein or multifunctional or multispecific formats thereof so long as the resulting polypeptide includes at least one binding region which specifically binds to the target antigen, e.g., a TCRvb, a tumor antigen, among others. Such frameworks or scaffolds include the 5 main idiotypes of human immunoglobulins, or fragments thereof, and include immunoglobulins of other animal species, preferably having humanized aspects. Novel frameworks, scaffolds and fragments continue to be discovered and developed by those skilled in the art.

[0496] In some embodiments, the anti-TCRvb antibody molecules as described herein or multifunctional or multispecific formats thereof include non-immunoglobulin based antibodies using nonimmunoglobulin scaffolds onto which CDRs can be grafted. Any non-immunoglobulin frameworks and scaffolds may be employed, as long as they comprise a binding region specific for the target antigen (e.g., TCRvb or a tumor antigen). Exemplary non-immunoglobulin frameworks or scaffolds include, but are not limited to, fibronectin (Compound Therapeutics, Inc., Waltham, MA), ankyrin (Molecular Partners AG, Zurich, Switzerland), domain antibodies (Domantis, Ltd., Cambridge, MA, and Ablynx nv, Zwijnaarde, Belgium), lipocalin (Pieris Proteolab AG, Freising, Germany), small modular immunopharmaceuticals (Trubion Pharmaceuticals Inc., Seattle, WA), maxybodies (Avidia, Inc., Mountain View, CA), Protein A (Affibody AG, Sweden), and affilin (gamma-crystallin or ubiquitin) (Scil Proteins GmbH, Halle, Germany).

[0497] Fibronectin scaffolds are typically based on fibronectin type III domain (e.g., the tenth module of the fibronectin type III (10 Fn3 domain)). The fibronectin type III domain has 7 or 8 beta strands which are distributed between two beta sheets, which themselves pack against each other to form the core of the protein, and further containing loops (analogous to CDRs) which connect the beta strands to each other and are solvent exposed. There are at least three such loops at each edge of the beta sheet sandwich, where the edge is the boundary of the protein perpendicular to the direction of the beta strands (see US6,818,418). Because of this structure, the non-immunoglobulin antibody mimics antigen binding properties that are similar in nature and affinity to those of antibodies. These scaffolds can be used in a loop randomization and shuffling strategy in vitro that is similar to the process of affinity maturation of antibodies in vivo. These fibronectin-based molecules can be used as scaffolds where the loop regions of the molecule can be replaced with CD Rs of the invention using standard cloning techniques.

[0498] The ankyrin technology is based on using proteins with ankyrin derived repeat modules as scaffolds for bearing variable regions which can be used for binding to different targets. The ankyrin repeat module typically is a about 33 amino acid polypeptide consisting of two anti-parallel a-helices and a β-tum. Binding of the variable regions can be optimized by using ribosome display.

[0499] Avimers are used by nature for protein-protein interactions and in human over 250 proteins are structurally based on A-domains. Avimers consist of a number of different “A-domain” monomers (2-10) linked via amino acid linkers. Avimers can be created that can bind to the target antigen using the methodology described in, for example, U.S. Patent Application Publication Nos. 20040175756; 20050053973; 20050048512; and 20060008844.

[0500] Affibody affinity ligands are small, simple proteins composed of a three-helix bundle based on the scaffold of one of the IgG-binding domains of Protein A. Protein A is a surface protein from the bacterium Staphylococcus aureus. This scaffold domain consists of 58 amino acids, 13 of which are randomized to generate affibody libraries with a large number of ligand variants (See e.g., US 5,831,012). Affibody molecules mimic antibodies, they have a molecular weight of 6 kDa, compared to the molecular weight of antibodies, which is 150 kDa. In spite of its small size, the binding site of affibody molecules is similar to that of an antibody.

[0501] Anticalins are known commercially, e.g., Pieris ProteoLab AG. They are derived from lipocalins, a widespread group of small and robust proteins that are usually involved in the physiological transport or storage of chemically sensitive or insoluble compounds. Several natural lipocalins occur in human tissues or body liquids. The protein architecture is reminiscent of immunoglobulins, with hypervariable loops on top of a rigid framework. However, in contrast with antibodies or their recombinant fragments, lipocalins are composed of a single polypeptide chain with 160 to 180 amino acid residues, being just marginally bigger than a single immunoglobulin domain. The set of four loops, which makes up the binding pocket, shows pronounced structural plasticity and tolerates a variety of side chains. The binding site can thus be reshaped in a proprietary process in order to recognize prescribed target molecules of different shape with high affinity and specificity. One protein of lipocalin family, the bilin-binding protein (BBP) of Pieris Brassicae has been used to develop anticalins by mutagenizing the set of four loops. One example of a patent application describing anticalins is in PCT Publication No. WO 199916873.

[0502] Affilin molecules are small non-immunoglobulin proteins which are designed for specific affinities towards proteins and small molecules. New affilin molecules can be very quickly selected from two libraries, each of which is based on a different human derived scaffold protein. Affilin molecules do not show any structural homology to immunoglobulin proteins. Currently, two affilin scaffolds areemployed, one of which is gamma crystalline, a human structural eye lens protein and the other is “ubiquitin” superfamily proteins. Both human scaffolds are very small, show high temperature stability and are almost resistant to pH changes and denaturing agents. This high stability is mainly due to the expanded beta sheet structure of the proteins. Examples of gamma crystalline derived proteins are described in W0200104144 and examples of “ubiquitin-like” proteins are described in W02004106368.

[0503] Protein epitope mimetics (PEM) are medium-sized, cyclic, peptide-like molecules (MW l-2kDa) mimicking beta-hairpin secondary structures of proteins, the major secondary structure involved in protein-protein interactions.

[0504] Domain antibodies (dAbs) can be used in the anti-TCRvb antibody molecules as described herein or multifunctional or multispecific formats thereof are small functional binding fragments of antibodies, corresponding to the variable regions of either the heavy or light chains of antibodies. Domain antibodies are well expressed in bacterial, yeast, and mammalian cell systems. Further details of domain antibodies and methods of production thereof are known in the art (see, for example, U.S. Pat. Nos. 6,291,158;6,582,915; 6,593,081; 6,172,197; 6,696,245; European Patents 0368684 & 0616640; WO05 / 035572, W004 / 101790, W004 / 081026, W004 / 058821, W004 / 003019 and W003 / 002609. Nanobodies are derived from the heavy chains of an antibody.

[0505] A nanobody typically comprises a single variable domain and two constant domains (CH2 and CH3) and retains antigen-binding capacity of the original antibody. Nanobodies can be prepared by methods known in the art (See e.g., U.S. Pat. No. 6,765,087, U.S. Pat. No. 6,838,254, WO 06 / 079372). Unibodies consist of one light chain and one heavy chain of an IgG4 antibody. Unibodies may be made by the removal of the hinge region of IgG4 antibodies. Further details of unibodies and methods of preparing them may be found in W02007 / 059782.Anti-TCRVP antibody effector function and Fc variants

[0506] In some embodiments, an anti-TCRVβ antibody as described herein comprises an Fc region, e.g., as described herein. In some embodiments, the Fc region is a wildtype Fc region, e.g., a wildtype human Fc region. In some embodiments, the Fc region comprises a variant, e.g., an Fc region comprising an addition, substitution, or deletion of at least one amino acid residue in the Fc region which results in, e.g., reduced or ablated affinity for at least one Fc receptor.

[0507] The Fc region of an antibody interacts with a number of receptors or ligands including Fc Receptors (e.g., FcγRI, FcγRIIA, FcγRIIIA), the complement protein Clq, and other molecules such as proteins A and G. These interactions are essential for a variety of effector functions and downstream signaling events including: antibody dependent cell-mediated cytotoxicity (ADCC), Antibody-dependent cellular phagocytosis (ADCP) and complement dependent cytotoxicity (CDC).

[0508] In some embodiments, an anti-TCRVβ antibody comprising a variant Fc region has reduced, e.g., ablated, affinity for an Fc receptor, e.g., an Fc receptor described herein. In some embodiments, the reduced affinity is compared to an otherwise similar antibody with a wildtype Fc region.

[0509] In some embodiments, an anti-TCRVβ antibody comprising a variant Fc region has one or moreof the following properties: (1) reduced effector function (e.g., reduced ADCC, ADCP and / or CDC); (2) reduced binding to one or more Fc receptors; and / or (3) reduced binding to Clq complement. In some embodiments, the reduction in any one, or all of properties ( l)-(3) is compared to an otherwise similar antibody with a wildtype Fc region.

[0510] In some embodiments, an anti-TCRVβ antibody comprising a variant Fc region has reduced affinity to a human Fc receptor, e.g., FcγR I, FcγR II and / or FcγR III. In some embodiments, the anti- TCRVβ antibody comprising a variant Fc region comprises a human IgGl region or a human IgG4 region.

[0511] In some embodiments, an anti-TCRVβ antibody comprising a variant Fc region activates and / or expands T cells, e.g., as described herein. In some embodiments, an anti-TCRVβ antibody comprising a variant Fc region has a cytokine profile described herein, e.g., a cytokine profile that differs from a cytokine profile of a T cell engager that binds to a receptor or molecule other than a TCRβV region (“a non-TCRβV-binding T cell engager”). In some embodiments, the non-TCRβV-binding T cell engager comprises an antibody that binds to a CD3 molecule (e.g., CD3 epsilon (CD3e) molecule.

[0512] Exemplary Fc region variants are provided in Table 14 and also disclosed in Saunders O, (2019) Frontiers in Immunology; vol 10, article 1296, the entire contents of which is hereby incorporated by reference.

[0513] In some embodiments, an anti-TCRVβ antibody as described herein comprises any one or all, or any combination of Fc region variants disclosed in Table 14.

[0514] In some embodiments, an anti-TCRVβ antibody as described herein comprises any one or all, or any combination of Fc region variants, e.g., mutations, disclosed in Table 14. In some embodiments, an anti-TCRVβ antibody as described herein comprise an Asn297Ala (N297A) mutation. In some embodiments, an anti-TCRVβ antibody as described herein comprise a Leu234Ala / Leu235Ala (LALA) mutation.Anti-TCRαV antibodiesHuman T cell receptor (TCR) complex

[0515] As used herein, the term “T cell receptor alpha variable chain” or “TCRαV,” or “TRAV,” refers to an extracellular region of the T cell receptor alpha chain which can comprise a portion of the antigen recognition domain of the T cell receptor. The term TCRαV includes isoforms, mammalian, e.g., human TCRαV, species homologs of human and analogs comprising at least one common epitope with TCRαV. Human TCRαV comprises a gene family comprising subfamilies including, but not limited to: a TCRa V12 subfamily, a TCRa V 13 subfamily, a TCRa V 19 subfamily, a TCRa V21 subfamily, or a TCRa V30 subfamily, as well as family members of said subfamilies, and variants thereof (e.g., a structural or functional variant thereof).

[0516] In some embodiments, the TCRa V 12 subfamily comprises: TCRαV 12-1, TCRαV 12-2, or TCRαV 12-3, or a variant thereof.

[0517] In some embodiments, the TCRa V13 subfamily comprises: TCRαV13-l or TCRαV13-2, or avariant thereof.

[0518] Provided herein are, inter alia, antibody molecules and fragments thereof, that bind, e.g., specifically bind, to a human TCR alpha V chain (TCRαV), e.g., a TCRαV gene family (also referred to as a group), e.g., a TCRαV subfamily (also referred to as a subgroup), e.g., as described herein. TCR alpha 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.

[0519] The terms TCRAV, TCRVA, TRAV, TCRαV, TCRVa or TRαV are used interchangeably herein and refer to a TCR alpha V chain, e.g., as described herein.

[0520] In some embodiments, provided herein is an anti-TCRαV antibody molecule that binds to human TCRαV, e.g., a TCRαV family, e.g., gene family or a variant thereof.

[0521] Exemplary amino acid sequences for TCRαV subfamily members can be found on the ImMunoGeneTics Information System website: www.imgt.org / , or in a similar resource.Anti-TCRaV antibodies

[0522] Described herein are molecules targeting the TCRαV 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.

[0523] Described herein is a class of antibodies, i.e., anti-TCRαV antibody molecules as described herein, which despite having low sequence similarity (e.g., low sequence identity among the different antibody molecules that recognize different TCRαV subfamilies), recognize a structurally conserved, yet sequence-wise variable, region, e.g., domain, on the TCRαV protein and have a similar function (e.g., activation of T cells and a similar cytokine profile as described herein). Thus, the anti-TCRαV antibody molecules as described herein share a structure -function relationship.

[0524] In some embodiments, the anti-TCRαV antibody molecules as described herein do not recognize, e.g., bind to, an interface of a TCRβV:TCRalpha complex. In some embodiments, the anti-TCRαV antibody molecules as described herein do not recognize, e.g., bind to, a constant region of a TCRβV protein. In some embodiments, the anti-TCRαV antibody molecules as described herein do not recognize, e.g., bind to, one or more (e.g., all) of a complementarity determining region (e.g., CDR1, CDR2 and / or CDR3) of a TCRβV protein.

[0525] Provided herein are, inter alia, antibody molecules directed to the variable chain of the alpha subunit of TCR (TCRαV) which bind and, e.g., activate a subset of T cells. The anti-TCRαV antibody molecules as described herein result in lesser or no production of cytokines associated with CRS, e.g., IL- 6, IL-lbeta, IL- 10 and TNF alpha; and enhanced and / or delayed production of IL-2 and IFNγ. In some embodiments, the anti-TCRαV antibodies as described herein have a cytokine profile, e.g., as described herein, which differs from a cytokine profile of a T cell engager that binds to a receptor or molecule otherthan a TCRαV region (“a non-TCRαV-binding T cell engager”). In some embodiments, the non-TCRαV- 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-TCRαV-binding T cell engager is an OKT3 antibody or an SP34-2 antibody.

[0526] In some embodiments, the anti-TCRαV antibodies as described herein result in expansion of TCRαV+ 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-TCRαV antibody molecules and uses thereof. Also described herein are multispecific molecules, e.g., bispecific molecules comprising said anti-TCRαV antibody molecules. In some embodiments, compositions comprising anti-TCRαV 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 TCRαV+ T cells. In some embodiments, compositions comprising anti-TCRαV 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.

[0527] In some embodiments, the anti-TCRαV antibody molecule binds to one or more of TRAV12-1, TRAV12-2, TRAV12-3, TRAV13-1, TRAV13-2, TRAV19-1, TRAV21-1, and TRAV30-1. In some embodiments, the anti-TCRαV antibody molecule is an anti-TRAV12-1, anti-TRAV12-2, anti-TRAV12- 3, anti-TRAV13-1, anti-TRAV13-2, anti-TRAV19-1, anti-TRAV21-1, or anti-TRAV30-l.

[0528] In some embodiments, the anti-TCRβV antibody molecule binds specifically to TRAV12-1, TRAV12-2, TRAV12-3, TRAV13-1, TRAV13-2, TRAV19-1, TRAV21-1, or TRAV30-1.

[0529] In some embodiments, the anti-TCRαV antibody molecule is a full antibody or fragment thereof (e.g., a Fab, F(ab')2, Fv, single domain antibody, or a single chain Fv fragment (scFv)). In embodiments, the anti-TCRαV antibody molecule is a monoclonal antibody or an antibody with single specificity. In some embodiments, the anti-TCRαV antibody molecule can also be a humanized, chimeric, camelid, shark, or an in vitro-generated antibody molecule. In some embodiments, the anti-TCRαV antibody molecule is a humanized antibody molecule. The heavy and light chains of the anti-TCRαV 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 antigenbinding 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).

[0530] In some embodiments, the anti-TCRαV antibody molecule is in the form of a multispecific molecule, e.g., a bispecific molecule, e.g., as described herein.

[0531] The various TCRαV subfamilies and / or subfamily members can be expressed at different levels in individuals, e.g., healthy...

Claims

1. CLAIMSWHAT IS CLAIMED IS:

1. A multispecific molecule comprising:(a) a tumor-associated antigen binding moiety, wherein the tumor-associated antigen binding moiety comprises a HER-2 binding moiety;(b) a molecule that binds to a co-stimulatory receptor of a T cell; and(c) a TCRβV-binding moiety, wherein the HER-2 binding moiety comprises an antibody domain or an antigen binding domain comprising:(i) a heavy chain variable region (VH) comprising a heavy chain complementarity-determining region 3 (HC CDR3) sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 628, 642, 643, 644, and 650; and / or(ii) a light chain variable region (VL) comprising a light chain complementarity-determining region 3 (LC CDR3) sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 631, 640, and 653.

2. The multispecific molecule of claim 1, wherein the TCRβV-binding moiety is covalently linked to the molecule that binds to a co-stimulatory receptor of a T cell.

3. The multispecific molecule of claim 1 or 2, wherein the molecule that binds to a co-stimulatory receptor of a T cell activates the co-stimulatory receptor when the molecule that binds to a co- stimulatory receptor of a T cell binds to the co-stimulatory receptor.

4. The multispecific molecule of any one of claims 1 to 3, wherein the molecule that binds to a co- stimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof.

5. The multispecific molecule of any one of claims 1 to 3, wherein the molecule that binds to a co- stimulatory receptor of a T cell comprises an antibody molecule, an antigen binding domain, a ligand, an extracellular domain of a receptor, or any combination thereof.

6. The multispecific molecule of any one of claims 1 to 5, wherein the antigen binding domain comprises any one selected from the group consisting of a full-length antibody, a Fab, a F(ab')2, an Fv, a single chain Fv, a camelid antibody, a VHH, a half arm antibody, a diabody, a bivalent antibody, a monovalent antibody, or a bispecific antibody, and any combination thereof.

7. The multispecific molecule of any one of claims 1 to 6, wherein the HER-2 binding moiety comprises a VH comprising a HC CDR1 sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 626, 634, 636, 648, and 656.

8. The multispecific molecule of any one of claims 1 to 7, wherein the HER-2 binding moiety comprises a VH comprising a HC CDR2 sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 627, 635, 637, 649, 657, and 658.

9. The multispecific molecule of any one of claims 1 to 8, wherein the HER-2 binding moiety comprises a VH comprising a HC CDR1 sequence, a HC CDR2 sequence, and a HC CDR3 sequence comprising the sequences of:(i) SEQ ID NOs: 626, 627, and 628, respectively;(ii) SEQ ID NOs: 634, 635, and 628, respectively;(iii) SEQ ID NOs: 636, 637, and 628, respectively;(iv) SEQ ID NOs: 636, 637, and 642, respectively;(v) SEQ ID NOs: 636, 637, and 643, respectively;(vi) SEQ ID NOs: 636, 637, and 644, respectively;(vii) SEQ ID NOs: 648, 649, and 650, respectively;(viii) SEQ ID NOs: 656, 657, and 650, respectively; or(ix) SEQ ID NOs: 656, 658, and 650, respectively.

10. The multispecific molecule of any one of claims 1 to 9, wherein the HER-2 binding moiety comprises a VL comprising a LC CDR1 sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 629, 632, 638, 641, 651, 654, and 659.

11. The multispecific molecule of any one of claims 1 to 10, wherein the HER-2 binding moiety comprises a VL comprising a LC CDR2 sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 630, 633, 639, 652, 655, and 660.

12. The multispecific molecule of any one of claims 1 to 11, wherein the HER-2 binding moiety comprises a VL comprising a LC CDR1 sequence, a LC CDR2 sequence, and a LC CDR3 sequence comprising the sequences of:(i) SEQ ID NOs: 629, 630, and 631, respectively;(ii) SEQ ID NOs: 632, 633, and 631, respectively;(iii) SEQ ID NOs: 638, 639, and 631, respectively;(iv) SEQ ID NOs: 629, 630, and 640, respectively;(v) SEQ ID NOs: 641, 639, and 631, respectively;(vi) SEQ ID NOs: 651, 652, and 653, respectively;(vii) SEQ ID NOs: 654, 655, and 653, respectively; or(viii) SEQ ID NOs: 659, 660, and 653, respectively.

13. The multispecific molecule of any one of claims 1 to 12, wherein the HER-2 binding moiety comprises a VH and a VL, respectively, comprising a HC CDR1 sequence, a HC CDR2 sequence, and a HC CDR3 sequence, and a LC CDR1 sequence, a LC CDR2 sequence, and a LC CDR3 sequence comprising the sequences of:(i) SEQ ID NOs: 626, 627, 628, 629, 630, and 631, respectively;(ii) SEQ ID NOs: 626, 627, 628, 632, 633, and 631, respectively;(iii) SEQ ID NOs: 634, 635, 628, 629, 630, and 631, respectively;(iv) SEQ ID NOs: 634, 635, 628, 632, 633, and 631, respectively;(v) SEQ ID NOs: 636, 637, 628, 632, 633, and 631, respectively;(vi) SEQ ID NOs: 634, 635, 628, 638, 639, and 631, respectively;(vii) SEQ ID NOs: 636, 637, 628, 638, 639, and 631, respectively;(viii) SEQ ID NOs: 626, 627, 628, 629, 630, and 640, respectively;(ix) SEQ ID NOs: 636, 637, 628, 641, 639, and 631, respectively;(x) SEQ ID NOs: 636, 637, 642, 641, 639, and 631, respectively;(xi) SEQ ID NOs: 636, 637, 643, 641, 639, and 631, respectively;(xii) SEQ ID NOs: 636, 637, 644, 641, 639, and 631, respectively;(xiii) SEQ ID NOs: 648, 649, 650, 651, 652, and 653, respectively;(xiv) SEQ ID NOs: 648, 649, 650, 654, 655, and 653, respectively;(xv) SEQ ID NOs: 656, 657, 650, 651, 652, and 653, respectively;(xvi) SEQ ID NOs: 656, 657, 650, 654, 655, and 653, respectively;(xvii) SEQ ID NOs: 656, 658, 650, 654, 655, and 653, respectively;(xviii) SEQ ID NOs: 656, 657, 650, 659, 660, and 653, respectively; or (xix) SEQ ID NOs: 656, 658, 650, 659, 660, and 653, respectively;14. The multispecific molecule of any one of claims 1 to 13, wherein the HER-2 binding moiety comprises a VH comprising a sequence having at least 70% sequence identity to any one sequence selected from the group consisting of SEQ ID NOs: 600, 603, 604, 607, 609, 610, 611, 616, 619, and 620.

15. The multispecific molecule of any one of claims 1 to 14, wherein the HER-2 binding moiety comprises a VH comprising any one sequence selected from the group consisting of SEQ ID NOs:600, 603, 604, 607, 609, 610, 611, 616, 619, and 620.

16. The multispecific molecule of any one of claims 1 to 15, wherein the HER-2 binding moiety comprises a VL comprising a sequence having at least 70% sequence identity to any one sequence selected from the group consisting of SEQ ID NOs: 601, 602, 605, 606, 608, 617, 618, and 621.

17. The multispecific molecule of any one of claims 1 to 16, wherein the HER-2 binding moiety comprises a VL comprising any one sequence selected from the group consisting of SEQ ID NOs:601, 602, 605, 606, 608, 617, 618, and 621.

18. The multispecific molecule of any one of claims 1 to 17, wherein the HER-2 binding moiety comprises:(i) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 600, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 601;(ii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 600, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 602;(iii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 603, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 601;(iv) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 603, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 602;(v) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 604, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 602;(vi) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 603, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 605;(vii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 604, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 605;(viii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 600, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 606;(ix) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 607, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608;(x) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 609, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608;(xi) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 610, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608;(xii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 611, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608;(xiii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 616, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 617;(xiv) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 616, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 618;(xv) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 619, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 617;(xvi) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 619, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 618;(xvii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 620, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 618;(xviii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 619, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 621; or(xix) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 620, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 621.

19. The multispecific molecule of any one of claims 1 to 18, wherein the HER-2 binding moiety comprises:(i) a VH comprising the sequence of SEQ ID NO: 600, and a VL comprising the sequence of SEQ ID NO: 601;(ii) a VH comprising the sequence of SEQ ID NO: 600, and a VL comprising the sequence of SEQ ID NO: 602;(iii) a VH comprising the sequence of SEQ ID NO: 603, and a VL comprising the sequence of SEQ ID NO: 601;(iv) a VH comprising the sequence of SEQ ID NO: 603, and a VL comprising the sequence of SEQ ID NO: 602;(v) a VH comprising the sequence of SEQ ID NO: 604, and a VL comprising the sequence of SEQ ID NO: 602;(vi) a VH comprising the sequence of SEQ ID NO: 603, and a VL comprising the sequence of SEQ ID NO: 605;(vii) a VH comprising the sequence of SEQ ID NO: 604, and a VL comprising the sequence of SEQ ID NO: 605;(viii) a VH comprising the sequence of SEQ ID NO: 600, and a VL comprising the sequence of SEQ ID NO: 606;(ix) a VH comprising the sequence of SEQ ID NO: 607, and a VL comprising the sequence of SEQ ID NO: 608;(x) a VH comprising the sequence of SEQ ID NO: 609, and a VL comprising the sequence of SEQ ID NO: 608;(xi) a VH comprising the sequence of SEQ ID NO: 610, and a VL comprising the sequence of SEQ ID NO: 608;(xii) a VH comprising the sequence of SEQ ID NO: 611, and a VL comprising the sequence of SEQ ID NO: 608;(xiii) a VH comprising the sequence of SEQ ID NO: 616, and a VL comprising the sequence of SEQ ID NO: 617;(xiv) a VH comprising the sequence of SEQ ID NO: 616, and a VL comprising the sequence of SEQ ID NO: 618;(xv) a VH comprising the sequence of SEQ ID NO: 619, and a VL comprising the sequence of SEQ ID NO: 617;(xvi) a VH comprising the sequence of SEQ ID NO: 619, and a VL comprising the sequence of SEQ ID NO: 618;(xvii) a VH comprising the sequence of SEQ ID NO: 620, and a VL comprising the sequence of SEQ ID NO: 618;(xviii) a VH comprising the sequence of SEQ ID NO: 619, and a VL comprising the sequence ofSEQ ID NO: 621; or(xix) a VH comprising the sequence of SEQ ID NO: 620, and a VL comprising the sequence of SEQ ID NO: 621.

20. The multispecific molecule of any one of claims 1 to 19, wherein the HER-2 binding moiety comprises:(i) a VH comprising a combination of a HC CDR1, a HC CDR2 and a HC CDR3 listed in Table 24 or 21;(ii) a VL comprising a combination of a LC CDR1, a LC CDR2, and a LC CDR3 listed in Table 24 or 21; or(iii) any combination thereof.

21. The multispecific molecule of any one of claims 1 to 20, wherein the HER-2 binding moiety comprises:(i) a VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 of any one of the heavy chain variable domain amino acid sequences listed in Table 24 or 21;(ii) a VL comprising a LC CDR1, a LC CDR2, and a LC CDR3 of any one of the light chain variable domain amino acid sequences listed in Table 24 or 21; or(iii) any combination thereof.

22. The multispecific molecule of any one of claims 1 to 21, wherein the HER-2 binding moiety comprises:(i) a VH comprising a sequence having at least 70% sequence identity to any one of the heavy chain variable domain amino acid sequences listed in Table 24 or 21;(ii) a VL comprising a sequence having at least 70% sequence identity to any one of the light chain variable domain amino acid sequences listed in Table 24 or 21;(iii) a combination thereof.

23. The multispecific molecule of any one of claims 1 to 22, wherein the HER-2 binding moiety comprises:(i) a VH comprising any one of the heavy chain variable domain amino acid sequences listed in Table 24 or 21;(ii) a VL comprising any one of the light chain variable domain amino acid sequences listed in Table 24 or 21;(iii) a combination thereof.

24. The multispecific molecule of any one of claims 1 to 23, wherein the HER-2 binding moiety has a lower affinity for HER-2 relative to a HER-2 binding moiety that comprises a VH comprising a HC CDR1 sequence, a HC CDR2 sequence, and a HC CDR3 sequence of SEQ ID NOs: 626, 627, and 628, respectively, and a VL comprising a LC CDR1 sequence, a LC CDR2 sequence, and a LC CDR3 sequence of SEQ ID NOs: 629, 630, and 631, respectively.

25. The multispecific molecule of any one of claims 1 to 24, wherein the HER-2 binding moiety has lower affinity for HER-2 relative to a HER-2 binding moiety that comprises a VH comprising the sequence of SEQ ID NO: 600, and a VL comprising the sequence of SEQ ID NO: 601.

26. The multispecific molecule of any one of claims 1 to 23, wherein the HER-2 binding moiety has a higher affinity for HER-2 relative to a HER-2 binding moiety that comprises a VH comprising a HC CDR1 sequence, a HC CDR2 sequence, and a HC CDR3 sequence of SEQ ID NOs: 626, 627, and 628, respectively, and a VL comprising a LC CDR1 sequence, a LC CDR2 sequence, and a LC CDR3 sequence of SEQ ID NOs: 629, 630, and 631, respectively.

27. The multispecific molecule of any one of claims 1 to 23 and 26, wherein the HER-2 binding moiety has higher affinity for HER-2 relative to a HER-2 binding moiety that comprises a VH comprising the sequence of SEQ ID NO: 600, and a VL comprising the sequence of SEQ ID NO: 601.

28. The multispecific molecule of any one of claims 1 to 27, wherein the HER-2 binding moiety has a lower affinity for HER-2 relative to a HER-2 binding moiety that comprises a VH comprising a HC CDR1 sequence, a HC CDR2 sequence, and a HC CDR3 sequence of SEQ ID NOs: 648, 649, and 650, respectively, and a VL comprising a LC CDR1 sequence, a LC CDR2 sequence, and a LC CDR3 sequence of SEQ ID NOs: 651, 652, and 653, respectively.

29. The multispecific molecule of any one of claims 1 to 28, wherein the HER-2 binding moiety has lower affinity for HER-2 relative to a HER-2 binding moiety that comprises a VH comprising the sequence of SEQ ID NO: 616, and a VL comprising the sequence of SEQ ID NO: 617.

30. The multispecific molecule of any one of claims 1 to 27, wherein the HER-2 binding moiety has a higher affinity for HER-2 relative to a HER-2 binding moiety that comprises a VH comprising a HC CDR1 sequence, a HC CDR2 sequence, and a HC CDR3 sequence of SEQ ID NOs: 648, 649, and 650, respectively, and a VL comprising a LC CDR1 sequence, a LC CDR2 sequence, and a LC CDR3 sequence of SEQ ID NOs: 651, 652, and 653, respectively.

31. The multispecific molecule of any one of claims 1 to 27 and 30, wherein the HER-2 binding moiety has higher affinity for HER-2 relative to a HER-2 binding moiety that comprises a VHcomprising the sequence of SEQ ID NO: 616, and a VL comprising the sequence of SEQ ID NO: 617.

32. The multispecific molecule of any one of claims 1 to 31, wherein the TCRβV-binding moiety comprises an antibody domain or an antigen binding domain, wherein the antibody domain or the antigen binding domain comprises any one selected from the group consisting of a full-length antibody, a Fab, a F(ab')2, an Fv, a single chain Fv, a camelid antibody, a VHH, a half arm antibody, a diabody, a bivalent antibody, a monovalent antibody, or a bispecific antibody, and any combination thereof.

33. The multispecific molecule of any one of claims 1 to 32, wherein the tumor-associated antigen binding moiety comprises a VHH, an Fab, or an scFv.

34. The multispecific molecule of any one of claims 1 to 33, wherein the TCRβV-binding moiety comprises a VHH, an Fab, or an scFv.

35. The multispecific molecule of any one of claims 1 to 34, wherein the TCRβV-binding moiety binds to a TCRβV region of TCRβVl, TCRβV2, TCRβV3, TCRβV4, TCRβV5, TCRβV6, TCRβV7, TCRβV8, TCRβV9, TCRβVIO, TCRβV11, TCRβV12, TCRβV19, TCRβV20, TCRβV21, TCRβV23, TCRβV24, TCRβV25, TCRβV26, TCRβV27, TCRβV28, TCRβV29, or TCRβV30.

36. The multispecific molecule of any one of claims 1 to 34, wherein the TCRβV-binding moiety binds to a TCRβV region of TCRβV2, TCRβV4-1, TCRβV4-2, TCRβV5-1, TCRβV5-5, TCRβV5-6, TCRβV6, TCRβV6-5, TCRβV6-6, TCRβV6-9, TCRβV7-2, TCRβV7-3, TCRβV7-8, TCRβV7-9, TCRβV9, TCRβVIO-I, TCRβV10-2, TCRβV10-3, TCRβV11-2, TCRβV12-3, TCRβV12-4, TCRβV12-5, TCRβV19, TCRβV20-1, TCRβV21, TCRβV24-1, TCRβV25-1, or TCRβV28.

37. The multispecific molecule of any one of claims 1 to 34, wherein the TCRβV-binding moiety binds to a TCRβV region of TCRβV2, TCRβV3-1, TCRβV4-1, TCRβV4-2, TCRβV5-1, TCRβV5-4, TCRβV5-5, TCRβV5-6, TCRβV6-1, TCRβV6-5, TCRβV6-6, TCRβV7-3, TCRβV7-6, TCRβV7-8, TCRβV9, TCRβV11-2, TCRβV19, TCRβV20-1, TCRβV24-1, TCRβV27, TCRβV28, TCRβV29- 1, or TCRβV30.

38. The multispecific molecule of claims 1 to 34, wherein the TCRβV-binding moiety binds to a TCRβV region of TCRβV5, TCRβV6, TCRβVIO, TCRβV12, or TCRβV20.

39. The multispecific molecule of any one of claims 1 to 38, wherein the TCRβV-binding moiety comprises a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) sequence comprising any one of the HC CDR1 sequences listed in Table 1, 2, 10, 12, 13, or 21, a heavy chain complementarity determining region 2 (HC CDR2) sequence comprising any one of the HC CDR2 sequences listed in Tablesl, 2, 10, 12, 13, 21, 22, 23, 24, or 25, and a heavy chain complementarity determining region 3 (HC CDR3) sequence of comprising any one of the HC CDR3 sequences listed in Table 1, 2, 10, 12, 13, or 21.

40. The multispecific molecule of any one of claims 1 to 39, wherein the TCRβV-binding moiety comprises a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) sequence comprising any one of the LC CDR1 sequences listed in Tablesl, 2,10, 12, 13, 21, 22, 23, 24, or 25, a light chain complementarity determining region 2 (LC CDR2) sequence comprising any one of the LC CDR2 sequences listed in Table 1, 2, 10, 12, 13, or 21, and a light chain complementarity determining region 3 (LC CDR3) sequence of comprising any one of the LC CDR3 sequences listed in Table 1, 2, 10, 12, 13, or 21.

41. The multispecific molecule of any one of claims 1 to 40, wherein the TCRβV-binding moiety comprises:(i) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) sequence comprising any one of the HC CDR1 sequences listed in Table 1, 2, 10, 12, 13, or 21, a heavy chain complementarity determining region 2 (HC CDR2) sequence comprising any one of the HC CDR2 sequences listed in Table 1, 2, 10, 12, 13, or 21, and a heavy chain complementarity determining region 3 (HC CDR3) sequence of comprising any one of the HC CDR3 sequences listed in Table 1, 2, 10, 12, 13, or 21.; and(ii) a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) sequence comprising any one of the LC CDR1 sequences listed in Table 1, 2, 10, 12, 13, or 21, a light chain complementarity determining region 2 (LC CDR2) sequence comprising any one of the LC CDR2 sequences listed in Table 1, 2, 10, 12, 13, or 21, and a light chain complementarity determining region 3 (LC CDR3) sequence of comprising any one of the LC CDR3 sequences listed in Table 1, 2, 10, 12, 13, or 21.

42. The multispecific molecule of any one of claims 1 to 41, wherein the TCRβV-binding moiety comprises a VH comprising an amino acid sequence having at least 70% sequence identity to any one of the VH sequences listed in Table 1, 2, 10, 12, 13, or 21.

43. The multispecific molecule of any one of claims 1 to 42, wherein the TCRβV-binding moiety comprises a VL comprising an amino acid sequence having at least 70% sequence identity to any one of the VL sequences listed in Table 1, 2, 10, 12, 13, or 21.

44. The multispecific molecule of any one of claims 1 to 43, wherein the TCRβV-binding moiety comprises a VH comprising an amino acid sequence having at least 70% sequence identity to any one of the VH sequences listed in Table 1, 2, 10, 12, 13, or 21; and a VL comprising an amino acid sequence having at least 70% sequence identity to any one of the VL sequences listed in Table 1, 2, 10, 12, 13, or 21.

45. The multispecific molecule of any one of claims 1 to 44, wherein the TCRβV-binding moiety comprises a VH comprising any one of the VH sequences listed in Table 1, 2, 10, 12, 13, or 21.

46. The multispecific molecule of any one of claims 1 to 45, wherein the TCRβV-binding moiety comprises a VL comprising any one of the VL sequences listed in Table 1, 2, 10, 12, 13, or 2147. The multispecific molecule of any one of claims 1 to 46, wherein the TCRβV-binding moiety comprises a VH comprising any one of the VH sequences listed in Table 1, 2, 10, 12, 13, or 21; and a VL comprising any one of the VL sequences listed in Table 1, 2, 10, 12, 13, or 21.

48. The multispecific molecule of any one of claims 1 to 47, wherein the TCRβV-binding moiety comprises a VH comprising a HC CDR1 comprising the sequence GHDFRLTYIH (SEQ ID NO:3650), a HC CDR2 comprising the sequence RVSAGSGNVKYNEKFKG (SEQ ID NO: 3651), and a HC CDR3 comprising the sequence SYYSYDVLDY (SEQ ID NO: 47).

49. The multispecific molecule of any one of claims 1 to 48, wherein the TCRβV-binding moiety comprises a VL comprising a LC CDR1 comprising the sequence KASQNVADRVV (SEQ ID NO: 3655), a LC CDR2 comprising the sequence SSSHRYK (SEQ ID NO: 3653), and a LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 8).

50. The multispecific molecule of any one of claims 1 to 49, wherein the TCRβV-binding moiety comprises:(i) a VH comprising a HC CDR1 comprising the sequence GHDFRLTYIH (SEQ ID NO: 3650), aHC CDR2 comprising the sequence RVSAGSGNVKYNEKFKG (SEQ ID NO: 3651), and a HC CDR3 comprising the sequence SYYSYDVLDY (SEQ ID NO: 5); and(ii) a VL comprising a LC CDR1 comprising the sequence KASQNVADRVV (SEQ ID NO: 3655), a LC CDR2 comprising the sequence SSSHRYK (SEQ ID NO: 3653), and a LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 8).

51. The multispecific molecule of any one of claims 1 to 50, wherein the TCRβV-binding moiety comprises a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1346.

52. The multispecific molecule of any one of claims 1 to 51, wherein the TCRβV-binding moiety comprises a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1349.

53. The multispecific molecule of any one of claims 1 to 52, wherein the TCRβV-binding moiety comprises a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1346, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1349.

54. The multispecific molecule of any one of claims 1 to 53, wherein the TCRβV-binding moiety comprises a VH comprising the sequence of SEQ ID NO: 1346.

55. The multispecific molecule of any one of claims 1 to 54, wherein the TCRβV-binding moiety comprises a VL comprising the sequence of SEQ ID NO: 1349.

56. The multispecific molecule of any one of claims 1 to 55, wherein the TCRβV-binding moiety comprises a VH comprising the sequence of SEQ ID NO: 1346, and a VL comprising the sequence of SEQ ID NO: 1349.

57. The multispecific molecule of any one of claims 1 to 56, wherein the TCRβV-binding moiety comprises a single chain Fv (scFv) comprising an amino acid sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 140, 153, 168, 183, 195, or 1331.

58. The multispecific molecule of any one of claims 1 to 57, wherein the TCRβV-binding moiety comprises a scFv comprising the sequence of SEQ ID NO: 140, 153, 168, 183, 195, or 1331.

59. The multispecific molecule of any one of claims 1 to 48, wherein the TCRβV-binding moiety comprises a VL comprising a LC CDR1 comprising the sequence RASQNVADRVV (SEQ ID NO:673), a LC CDR2 comprising the sequence AASSLQS (SEQ ID NO: 639), and a LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 8).

60. The multispecific molecule of any one of claims 1 to 49 and 59, wherein the TCRβV-binding moiety comprises:(i) a VH comprising a HC CDR1 comprising the sequence GHDFRLTYIH (SEQ ID NO: 3650), aHC CDR2 comprising the sequence RVSAGSGNVKYNEKFKG (SEQ ID NO: 3651), and a HC CDR3 comprising the sequence SYYSYDVLDY (SEQ ID NO: 5); and(ii) a VL comprising a LC CDR1 comprising the sequence RASQNVADRVV (SEQ ID NO: 673), a LC CDR2 comprising the sequence AASSLQS (SEQ ID NO: 639), and a LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 8).

61. The multispecific molecule of any one of claims 1 to 49, 59, and 60, wherein the TCRβV-binding moiety comprises a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1346.

62. The multispecific molecule of any one of claims 1 to 49 and 59 to 61, wherein the TCRβV-binding moiety comprises a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 672.

63. The multispecific molecule of any one of claims 1 to 49 and 59 to 62, wherein the TCRβV-binding moiety comprises a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1346, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 672.

64. The multispecific molecule of any one of claims 1 to 49 and 59 to 63, wherein the TCRβV-binding moiety comprises a VH comprising the sequence of SEQ ID NO: 1346.

65. The multispecific molecule of any one of claims 1 to 49 and 59 to 64, wherein the TCRβV-binding moiety comprises a VL comprising the sequence of SEQ ID NO: 672.

66. The multispecific molecule of any one of claims 1 to 49 and 59 to 65, wherein the TCRβV-binding moiety comprises a VH comprising the sequence of SEQ ID NO: 1346, and a VL comprising the sequence of SEQ ID NO: 672.

67. The multispecific molecule of any one of claims 1 to 66, wherein the molecule that binds to a costimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof, and the at least one cytokine molecule or a functional fragment or functional variant thereof is selected from the group consisting of interleukin-2 (IL-2) or a functional fragment or functional variant thereof, interleukin-7 (IL-7) or a functional fragment or functional variant thereof, interleukin- 12 (IL- 12) or a functional fragment or functional variant thereof, interleukin- 15 (IL- 15) or a functional fragment or functional variant thereof, interleukin- 18 (IL- 18) or a functional fragment or functional variant thereof, interleukin-21 (IL-21) or a functional fragment or functional variant thereof, or interferon gamma or a functional fragment or functional variant thereof, or any combination thereof.

68. The multispecific molecule of any one of claims 1 to 67, wherein the molecule that binds to a costimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof, and the at least one cytokine molecule or a functional fragment or functional variant thereof comprises interleukin-2 (IL-2) or a functional fragment or functional variant thereof.

69. The multispecific molecule of claim 68, wherein the at least one cytokine molecule or a functional fragment or functional variant thereof is an IL-2 variant comprising a substitution mutation.

70. The multispecific molecule of claim 68, wherein the at least one cytokine molecule or a functional fragment or functional variant thereof is an IL-2 variant comprising C125A mutation.

71. The multispecific molecule of any one of claims 68 to 70, wherein the at least one cytokine molecule or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2270 or the sequence of SEQ ID NO: 2191.

72. The multispecific molecule of any one of claims 68 to 71, wherein the at least one cytokine molecule or a functional fragment or functional variant thereof comprises the sequence of SEQ ID NO: 2270 or the sequence of SEQ ID NO: 2191.

73. The multispecific molecule of any one of claims 1 to 72, wherein the molecule that binds to a costimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof, and the at least one cytokine molecule or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to any one of the cytokine sequences listed in Table 21.

74. The multispecific molecule of any one of claims 1 to 73, wherein the molecule that binds to a costimulatory receptor of a T cell comprises at least one cytokine molecule or a functional fragment or functional variant thereof, and the at least one cytokine molecule or a functional fragment or functional variant thereof comprises any one of the cytokine sequences listed in Table 21.

75. The multispecific molecule of claim 67, wherein the at least one cytokine molecule or a functional fragment or functional variant thereof comprises:(i) IL-7 or a functional fragment or functional variant thereof, wherein the IL-7 or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3540;(ii) IL-12 or a functional fragment or functional variant thereof, wherein:(a) the IL-12 or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2290, SEQ ID NO: 3542, SEQ ID NO: 3543, SEQ ID NO: 3545, or any combination thereof; or(b) the IL-12 or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3543 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3545;(iii) IL- 15 or a functional fragment or functional variant thereof, wherein the IL- 15 or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2320 or the sequence of SEQ ID NO: 2170, optionally, wherein the IL- 15 or a functional fragment or functional variant thereof is operatively linked to an IL15Ralpha dimerizing domain comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2180 or an IL15Ralpha sushi domain comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3523; or optionally, wherein the at least one cytokine molecule or a functional fragment or functional variant thereof comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3799 or the sequence of SEQ ID NO: 3810;(iv) IL- 18 or a functional fragment or functional variant thereof, wherein the IL- 18 or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2192;(v) IL-21 or a functional fragment or functional variant thereof, wherein the IL-21 or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2193; or(vi) interferon gamma or a functional fragment or functional variant thereof, wherein the interferon gamma or a functional fragment or functional variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2194, or(vii) any combination thereof76. The multispecific molecule of claim 67 or 75, wherein the at least one cytokine molecule or a functional fragment or functional variant thereof comprises:(i) IL-7 or a functional fragment or functional variant thereof, wherein the IL-7 or a functional fragment or functional variant thereof comprises the sequence of SEQ ID NO: 3540;(ii) IL-12 or a functional fragment or functional variant thereof, wherein:(a) the IL-12 or a functional fragment or functional variant thereof comprises the sequence of SEQ ID NO: 2290, SEQ ID NO: 3542, SEQ ID NO: 3543, SEQ ID NO: 3545, or any combination thereof; or(b) the IL-12 or a functional fragment or functional variant thereof comprises the sequence of SEQ ID NO: 3543 operatively linked to the sequence of SEQ ID NO: 3545;(iii) IL- 15 or a functional fragment or functional variant thereof, wherein the IL- 15 or a functional fragment or functional variant thereof comprises the sequence of SEQ ID NO: 2320 or the sequence of SEQ ID NO: 2170, optionally, wherein the IL- 15 or a functional fragment or functional variant thereof is operatively linked to an IL15Ralpha dimerizing domain comprising the sequence of SEQ ID NO: 2180 or an IL15Ralpha sushi domain comprising the sequence of SEQ ID NO: 3523; oroptionally, wherein the at least one cytokine molecule or a functional fragment or functional variant thereof comprising the sequence of SEQ ID NO: 3799 or the sequence of SEQ ID NO: 3810;(iv) IL- 18 or a functional fragment or functional variant thereof, wherein the IL- 18 or a functional fragment or functional variant thereof comprises the sequence of SEQ ID NO: 2192;(v) IL-21 or a functional fragment or functional variant thereof, wherein the IL-21 or a functional fragment or functional variant thereof comprises the sequence of SEQ ID NO: 2193; or(vi) interferon gamma or a functional fragment or functional variant thereof, wherein the interferon gamma or a functional fragment or functional variant thereof comprises the sequence of SEQ ID NO: 2194, or(vii) any combination thereof.

77. The multispecific molecule of any one of claims 1 to 3 and 5 to 66, wherein the molecule that binds to a co-stimulatory receptor of a T cell binds to CD2, 4-1BB, CD27, CD28, or any combination thereof.

78. The multispecific molecule of any one of claims 1 to 77, wherein the multispecific molecule comprises a first polypeptide chain comprising a first portion of a dimerization module, and a second polypeptide chain comprising a second portion of the dimerization module; wherein the first polypeptide chain and the second polypeptide chain are non-contiguous, and wherein the tumor-associated antigen binding moiety is linked to the first portion of the dimerization module, and the TCRβV-binding moiety and / or the molecule that binds to a costimulatory receptor of a T cell are independently linked to the first portion of the dimerization module, the second portion of the dimerization module, or a combination thereof.

79. The multispecific molecule of claim 78, wherein:(i) the tumor-associated antigen binding moiety is linked to the N-terminus of the first portion of the dimerization module, and the TCRβV-binding moiety is linked to the C-terminus of the first portion of the dimerization module, the N-terminus of the second portion of the dimerization module, the C-terminus of the second portion of the dimerization module, or any combination thereof; or(ii) the tumor-associated antigen binding moiety is linked to the C-terminus of the first portion of the dimerization module, and the molecule that binds to a co-stimulatory receptor of a T cell is linked to the N-terminus of the first portion of the dimerization module, the N-terminus of the second portion of the dimerization module, the C-terminus of the second portion of the dimerization module, or any combination thereof.

80. The multispecific molecule of claim 78 or 79, wherein:(i) the tumor-associated antigen binding moiety is linked to the N-terminus of the first portion of the dimerization module, and the molecule that binds to a co-stimulatory receptor of a T cell is linked to the C-terminus of the first portion of the dimerization module, the N-terminus of thesecond portion of the dimerization module, the C-terminus of the second portion of the dimerization module, or any combination thereof; or(ii) the tumor-associated antigen binding moiety is linked to the C-terminus of the first portion of the dimerization module, and the molecule that binds to a co-stimulatory receptor of a T cell is linked to the N-terminus of the first portion of the dimerization module, the N-terminus of the second portion of the dimerization module, the C-terminus of the second portion of the dimerization module, or any combination thereof.

81. The multispecific molecule of any one of claims 78 to 80, wherein the TCRβV-binding moiety and the molecule that binds to a co-stimulatory receptor of a T cell is within a single contiguous polypeptide chain of the first polypeptide chain or the second polypeptide chain.

82. The multispecific molecule of any one of claims 78 to 81, wherein the TCRβV-binding moiety comprises a first portion of the TCRβV-binding moiety, and wherein the multispecific molecule further comprises a third polypeptide chain comprising a second portion of the TCRβV-binding moiety, wherein the third polypeptide chain is noncontiguous with the first polypeptide chain and the second polypeptide chain.

83. The multispecific molecule of any one of claims 1 to 82, wherein t the TCRβV-binding moiety comprises a VH and a VL, or a single domain antibody.

84. The multispecific molecule of claim 82 or 83, wherein the first portion of the TCRβV-binding moiety comprises a VH of the TCRβV-binding moiety and the second portion of the TCRβV- binding moiety comprises a VL of the TCRβV-binding moiety, or the first portion of the TCRβV- binding moiety comprises a VL of the TCRβV-binding moiety and the second portion of the TCRβV-binding moiety comprises a VH of the TCRβV-binding moiety.

85. The multispecific molecule of any one of claims 1 to 83, wherein the tumor-associated antigen binding moiety comprises a VH and a VL, or a single domain antibody.

86. The multispecific molecule of any one of claims 1 to 85, wherein the tumor-associated antigen binding moiety comprises a first portion of the tumor-associated antigen binding moiety, and wherein the multispecific molecule further comprises a fourth polypeptide chain comprising a second portion of the tumor-associated antigen binding moiety, wherein the fourth polypeptide chain is non-contiguous with the first polypeptide chain, the second polypeptide chain, and the third polypeptide chain.

87. The multispecific molecule of claim 86, wherein the first portion of the tumor-associated antigen binding moiety comprises a VH of the tumor-associated antigen binding moiety and the second portion of the tumor-associated antigen binding moiety comprises a VL of the tumor-associated antigen binding moiety, or the first portion of the tumor-associated antigen binding moiety comprises a VL of the tumor-associated antigen binding moiety and the second portion of the tumor-associated antigen binding moiety comprises a VH of the tumor-associated antigen binding moiety.

88. The multispecific molecule of any one of claims 1 to 87, wherein the first portion of the dimerization module and the second portion of the dimerization module associates to form a dimer.

89. The multispecific molecule of any one of claims 78 to 88, wherein the first portion of the dimerization module comprises a first immunoglobulin constant region (Fc region) and the second portion of the dimerization module comprises a second Fc region.

90. The multispecific molecule of claim 89, wherein 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.

91. The multispecific molecule of claim 89 or 90, wherein 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.

92. The multispecific molecule of any one of claims 89 to 91, wherein the first Fc region, the second Fc region, or a combination thereof comprises an Fc interface with one or more of: a paired cavityprotuberance, an electrostatic interaction, or a strand-exchange, wherein the dimerization of the first Fc region and the second Fc region is enhanced as indicated by a greater ratio of heteromultimer:homomultimer forms relative to a dimerization of Fc regions with a nonengineered interface.

93. The multispecific molecule of any one of claims 89 to 92, wherein the first Fc region, the second Fc region, or a combination thereof comprises an amino acid substitution listed in Table 3, 4, 14, 27, or 21.

94. The multispecific molecule of any one of claims 89 to 93, wherein:(i) the first Fc region comprises a mutation that decreases Fc receptor binding relative to a Fc region without the mutation;(ii) the second Fc region comprise a mutation that decreases Fc receptor binding relative to a Fc region without the mutation; or(iii) a combination thereof.

95. The multispecific molecule of claim 94, wherein the mutation that decreases Fc receptor binding is an N297A mutation according to EU Numbering in a heavy chain constant region.

96. The multispecific molecule of any one of claims 89 to 94, wherein the first Fc region, the second Fc region, or a combination thereof comprises an Asn297Ala (N297A) mutation or a Leu234Ala / Leu235Ala (LALA) mutation.

97. The multispecific molecule of any one of claims 89 to 96, wherein the first Fc region and the second Fc region comprise an Fc interface with one or more of: a knob-in-a hole, an electrostatic interaction, or a strand-exchange.

98. The multispecific molecule of any one of claims 89 to 97, wherein the first Fc region is an engineered Fc region comprising a knob and the second Fc region is an engineered Fc region comprising a hole, or the first Fc region is an engineered Fc region comprising a hole and the second Fc region is an engineered Fc region comprising a knob.

99. The multispecific molecule of any one of claims 89 to 98, wherein:(A)(i) the first Fc region comprises:(a) Y349C mutation according to EU Numbering,(b) T366S mutation according to EU Numbering,(c) L368A mutation according to EU Numbering, and(d) Y407V mutation according to EU Numbering; and(ii) the second Fc region comprises:(a) S354C mutation according to EU Numbering, and(b) T366W mutation according to EU Numbering; or(B)(i) the first Fc region comprises:(a) S354C mutation according to EU Numbering, and(b) T366W mutation according to EU Numbering; and(ii) the second Fc region comprises:(a) Y349C mutation according to EU Numbering,(b) T366S mutation according to EU Numbering,(c) L368A mutation according to EU Numbering, and(d) Y407V mutation according to EU Numbering.

100. The multispecific molecule of any one of claim 89 to 99, wherein the first Fc region, the second Fc region, or a combination thereof comprises a sequence having at least 70% sequence identity to any one sequence selected from the group consisting of SEQ ID NOs: 40, 41, 42, 550, 3645, 3646, 3647, 3648, 3649, 5038-5051, 5108, 5109, 5111, 5112, and 5113.

101. The multispecific molecule of any one of claim 89 to 100, wherein the first Fc region, the second Fc region, or a combination thereof comprises any one sequence selected from the group consisting of SEQ ID NOs: 40, 41, 42, 550, 3645, 3646, 3647, 3648, 3649, 5038-5051, 5108, 5109, 5111,5112, and 5113.

102. The multispecific molecule of any one of claim 89 to 101, wherein the first Fc region comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649, SEQ ID NO:5113, SEQ ID NO: 550, or SEQ ID NO: 5051, and the second Fc region comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116, or the first Fc region comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116 and the second Fc region comprises a sequence havingat least 70% sequence identity to the sequence of SEQ ID NO: 3649, SEQ ID NO: 5113, SEQ ID NO: 550, or SEQ ID NO: 5051.

103. The multispecific molecule of any one of claim 89 to 102, wherein the first Fc region comprises the sequence of SEQ ID NO: 3649, SEQ ID NO: 5113, SEQ ID NO: 550, or SEQ ID NO: 5051, and the second Fc region comprises the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116, or the first Fc region comprises the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116 and the second Fc region comprises the sequence of SEQ ID NO: 3649, SEQ ID NO: 5113, SEQ ID NO: 550, or SEQ ID NO: 5051.

104. The multispecific molecule of any one of claim 89 to 103, wherein the first Fc region, the second Fc region, or a combination thereof comprises a sequence having at least 70% sequence identity to any one of the Fc region sequences or the heavy chain constant region sequences listed in Table 3, 4, 14, 27, or 21.

105. The multispecific molecule of any one of claim 89 to 104, wherein the first Fc region, the second Fc region, or a combination thereof comprises any one of the Fc region sequences or the heavy chain constant region sequences listed in Table 3, 4, 14, 27, or 21.

106. The multispecific molecule of any one of claims 1 to 105, wherein:(i) the tumor-associated antigen binding moiety further comprises a heavy chain constant domain 1 (CHI) linked to the VH of the tumor-associated antigen binding moiety;(ii) the TCRβV-binding moiety further comprises a heavy chain constant domain 1 (CHI) linked to the VH of the TCRβV-binding moiety; or(iii) a combination thereof.

107. The multispecific molecule of any one of claims 1 to 106, wherein:(i) the tumor-associated antigen binding moiety further comprises a light chain constant domain (CL) linked to the VL of the tumor-associated antigen binding moiety;(ii) the TCRβV-binding moiety further comprises a light chain constant domain (CL) linked to the VL of the TCRβV-binding moiety; or(iii) a combination thereof.

108. The multispecific molecule of claim 107, wherein:(i) the CL linked to the VL of the tumor-associated antigen binding moiety comprises a light chain constant region or a fragment thereof;(ii) the CL linked to the VL of the TCRβV-binding moiety comprises a light chain constant region or a fragment thereof; or(iii) a combination thereof.

109. The multispecific molecule of claim 108, wherein the light chain constant region or a fragment thereof comprises a kappa chain constant domain or a fragment thereof or a lambda chain constant domain or a fragment thereof.

110. The multispecific molecule of claim 108 or 109, wherein the light chain constant region or a fragment thereof comprises any one of the light chain constant region sequences listed in Table 3 or 21.

111. The multispecific molecule of any one of claims 108 to 110, wherein the light chain constant region or a fragment thereof comprise a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 39 or SEQ ID NO: 3644.

112. The multispecific molecule of any one of claims 108 to 111, wherein the light chain constant region or a fragment thereof comprise the sequence of SEQ ID NO: 39 or SEQ ID NO: 3644.

113. The multispecific molecule of any one of claims 1 to 112, further comprising:(i) a linker between the first portion of the dimerization module and the tumor-associated antigen binding moiety or the first portion of the tumor-associated antigen;(ii) a linker between the molecule that binds to a co-stimulatory receptor of a T cell and the first portion of the dimerization module, a linker between the molecule that binds to a co-stimulatory receptor of a T cell and the second portion of the dimerization module, or a combination thereof;(iii) a linker between the molecule that binds to a co-stimulatory receptor of a T cell and the TCRβV -binding moiety or the first portion of the TCRβV-binding moiety;(iv) a linker between the VH and the VL of the tumor-associated antigen binding moiety;(v) a linker between the VH and the VL of the TCRβV-binding moiety;(vi) a linker between the CHI and the VH of the tumor-associated antigen binding moiety;(vii) a linker between the CHI and the VH of the TCRβV-binding moiety;(viii) a linker between the CL and the VL of the tumor-associated antigen binding moiety;(ix) a linker between the CL and the VL of the TCRβV-binding moiety; or(x) any combination thereof.

114. The multispecific molecule of claim 113, wherein the linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non-helical linker.

115. The multispecific molecule of any one of claims 1 to 114, wherein the multispecific molecule is an isolated multispecific molecule.

116. The multispecific molecule of any one of claims 1 to 115, wherein the multispecific molecule comprises:(i) a first polypeptide chain comprising a VH of the HER-2 binding moiety operatively linked to a first Ec region;(ii) a second polypeptide chain comprising the TCRβV-binding moiety operatively linked to the molecule that binds to a co-stimulatory receptor of a T cell operatively linked to a secind Fc region; and(iii) a third polypeptide chain comprising a VL of the HER-2 binding moiety operatively linked to a light chain constant region;wherein the VH of the HER-2 binding moiety and the VL of the HER-2 binding moiety are assembled and form the first domain.

117. The multispecific molecule of claim 116, wherein the TCRβV-binding moiety comprises a scFv comprising a VH of the TCRβV-binding moiety operatively linked to a VL of the TCRβV-binding moiety.

118. The multispecific molecule of claim 116 or 117, wherein the second polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1346 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1349 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2270 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116.

119. The multispecific molecule of claim 118, wherein:(i) the sequence having 70% sequence identity to the sequence of SEQ ID NO: 1346 is operatively linked to the sequence having 70% sequence identity to the sequence of SEQ ID NO: 1349 via the sequence of SEQ ID NO: 3801;(ii) the sequence having 70% sequence identity to the sequence of SEQ ID NO: 1349 is operatively linked to the sequence having 70% sequence identity to the sequence of SEQ ID NO: 2270 via the sequence of SEQ ID NO: 3309;(iii) the sequence having 70% sequence identity to the sequence of SEQ ID NO: 2270 is operatively linked to the sequence having 70% sequence identity to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116 via the sequence of SEQ ID NO: 3308; or(iv) any combination thereof.

120. The multispecific molecule of any one of claims 116 to 119, wherein the TCRβV-binding moiety comprises a scFv comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1331.

121. The multispecific molecule of any one of claims 116 to 120, wherein the second polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3800 or SEQ ID NO: 678.

122. The multispecific molecule of any one of claims 116 to 121, wherein the second polypeptide chain comprises the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 1349 operatively linked to the sequence of SEQ ID NO: 2270 operatively linked to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116.

123. The multispecific molecule of claim 122, wherein:(i) the sequence of SEQ ID NO: 1346 is operatively linked to the sequence of SEQ ID NO: 1349 via the sequence of SEQ ID NO: 3801;(ii) the sequence of SEQ ID NO: 1349 is operatively linked to the sequence of SEQ ID NO: 2270 via the sequence of SEQ ID NO: 3309;(iii) the sequence of SEQ ID NO: 2270 is operatively linked to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116 via the sequence of SEQ ID NO: 3308; or(iv) any combination thereof.

124. The multispecific molecule of any one of claims 116 to 123, wherein the TCRβV-binding moiety comprises a scFv comprising the sequence of SEQ ID NO: 1331.

125. The multispecific molecule of any one of claims 116 to 124, wherein the second polypeptide chain comprises the sequence of SEQ ID NO: 3800 or SEQ ID NO: 678.

126. The multispecific molecule of claim 116 or 117, wherein the second polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1346 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 672 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 2270 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116.

127. The multispecific molecule of claim 126, wherein:(i) the sequence having 70% sequence identity to the sequence of SEQ ID NO: 1346 is operatively linked to the sequence having 70% sequence identity to the sequence of SEQ ID NO: 672 via the sequence of SEQ ID NO: 3801;(ii) the sequence having 70% sequence identity to the sequence of SEQ ID NO: 672 is operatively linked to the sequence having 70% sequence identity to the sequence of SEQ ID NO: 2270 via the sequence of SEQ ID NO: 3309;(iii) the sequence having 70% sequence identity to the sequence of SEQ ID NO: 2270 is operatively linked to the sequence having 70% sequence identity to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116 via the sequence of SEQ ID NO: 3308; or(iv) any combination thereof.

128. The multispecific molecule of any one of claims 116, 117, 126, and 127, wherein the TCRβV- binding moiety comprises a scFv comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 699.

129. The multispecific molecule of any one of claims 116, 117, and 126 to 128, wherein the second polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 697 or SEQ ID NO: 698.

130. The multispecific molecule of any one of claims 116, 117, and 126 to 129, wherein the second polypeptide chain comprises the sequence of SEQ ID NO: 1346 operatively linked to the sequence of SEQ ID NO: 672 operatively linked to the sequence of SEQ ID NO: 2270 operatively linked to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116.

131. The multispecific molecule of claim 130, wherein:(i) the sequence of SEQ ID NO: 1346 is operatively linked to the sequence of SEQ ID NO: 672 via the sequence of SEQ ID NO: 3801;(ii) the sequence of SEQ ID NO: 672 is operatively linked to the sequence of SEQ ID NO: 2270 via the sequence of SEQ ID NO: 3309;(iii) the sequence of SEQ ID NO: 2270 is operatively linked to the sequence of SEQ ID NO: 3648 or SEQ ID NO: 5116 via the sequence of SEQ ID NO: 3308; or(iv) any combination thereof.

132. The multispecific molecule of any one of claims 116, 117, and 126 to 131, wherein the TCRβV- binding moiety comprises a scFv comprising the sequence of SEQ ID NO: 699.

133. The multispecific molecule of any one of claims 116, 117, and 126 to 132, wherein the second polypeptide chain comprises the sequence of SEQ ID NO: 697 or SEQ ID NO: 698.

134. The multispecific molecule of any one of claims 116 to 133, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 607 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 607 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051 ; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

135. The multispecific molecule of any one of claims 116 to 134, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 675 or SEQ ID NO: 676; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 677.

136. The multispecific molecule of any one of claims 116 to 135, wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 607 operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, orthe sequence ofSEQ ID NO: 607 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 608 operatively linked to the sequence of SEQ ID NO: 3644.

137. The multispecific molecule of any one of claims 116 to 136, wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 675 or SEQ ID NO: 676; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 677.

138. The multispecific molecule of any one of claims 116 to 133, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 604 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70%sequence identity to the sequence of SEQ ID NO: 604 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051 ; and (ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 602 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

139. The multispecific molecule of any one of claims 116 to 133 and 138, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 679 or SEQ ID NO: 680; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 681.

140. The multispecific molecule of any one of claims 116 to 133, 138, and 139 wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 604 operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, orthe sequence ofSEQ ID NO: 604 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 602 operatively linked to the sequence of SEQ ID NO: 3644.

141. The multispecific molecule of any one of claims 116 to 133 and 138 to 140, wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 679 or SEQ ID NO: 680; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 681.

142. The multispecific molecule of any one of claims 116 to 133, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 603 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 603 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051 ; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 605 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

143. The multispecific molecule of any one of claims 116 to 133 and 142, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 682 or SEQ ID NO: 683; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 684.

144. The multispecific molecule of any one of claims 116 to 133, 142, and 143, wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 603 operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, orthe sequence ofSEQ ID NO: 603 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 605 operatively linked to the sequence of SEQ ID NO: 3644.

145. The multispecific molecule of any one of claims 116 to 133 and 142 to 144, wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 682 or SEQ ID NO: 683; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 684146. The multispecific molecule of any one of claims 116 to 133, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 604 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 604 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051 ; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 605 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

147. The multispecific molecule of any one of claims 116 to 133 and 146, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 679 or SEQ ID NO: 680; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 684.

148. The multispecific molecule of any one of claims 116 to 133, 146, and 147, wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 604 operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, orthe sequence ofSEQ ID NO: 604 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 605 operatively linked to the sequence of SEQ ID NO: 3644.

149. The multispecific molecule of any one of claims 116 to 133 and 146 to 148, wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 679 or SEQ ID NO: 680; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 684.

150. The multispecific molecule of any one of claims 116 to 133, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 609 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70%sequence identity to the sequence of SEQ ID NO: 609 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051 ; and (ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

151. The multispecific molecule of any one of claims 116 to 133 and 150, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 685 or SEQ ID NO: 686; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 677.

152. The multispecific molecule of any one of claims 116 to 133, 150, and 151, wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 609 operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, orthe sequence ofSEQ ID NO: 609 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 608 operatively linked to the sequence of SEQ ID NO: 3644.

153. The multispecific molecule of any one of claims 116 to 133 and 150 to 152, wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 685 or SEQ ID NO: 686; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 677.

154. The multispecific molecule of any one of claims 116 to 133, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 610 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 610 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051 ; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

155. The multispecific molecule of any one of claims 116 to 133 and 154, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 687 or SEQ ID NO: 688; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 677.

156. The multispecific molecule of any one of claims 116 to 133, 154, and 155, wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 610 operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, orthe sequence ofSEQ ID NO: 610 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 608 operatively linked to the sequence of SEQ ID NO: 3644.

157. The multispecific molecule of any one of claims 116 to 133 and 154 to 156, wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 687 or SEQ ID NO: 688; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 677.

158. The multispecific molecule of any one of claims 116 to 133, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 611 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 611 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051 ; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

159. The multispecific molecule of any one of claims 116 to 133 and 158, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 689 or SEQ ID NO: 690; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 677.

160. The multispecific molecule of any one of claims 116 to 133, 158, and 159, wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 611 operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or the sequence ofSEQ ID NO: 611 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 608 operatively linked to the sequence of SEQ ID NO: 3644.

161. The multispecific molecule of any one of claims 116 to 133 and 158 to 160, wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 689 or SEQ ID NO: 690; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 677.

162. The multispecific molecule of any one of claims 116 to 133, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 619 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70%sequence identity to the sequence of SEQ ID NO: 619 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051 ; and (ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 618 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

163. The multispecific molecule of any one of claims 116 to 133 and 162, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 691 or SEQ ID NO: 692; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 693.

164. The multispecific molecule of any one of claims 116 to 133, 162, and 163, wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 619 operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, orthe sequence ofSEQ ID NO: 619 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 618 operatively linked to the sequence of SEQ ID NO: 3644.

165. The multispecific molecule of any one of claims 116 to 133 and 162 to 164, wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 691 or SEQ ID NO: 692; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 693.

166. The multispecific molecule of any one of claims 116 to 133, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 620 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, or a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 620 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 549 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051 ; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 621 operatively linked to a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 3644.

167. The multispecific molecule of any one of claims 116 to 133 and 166, wherein:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 694 or SEQ ID NO: 695; and(ii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 696.

168. The multispecific molecule of any one of claims 116 to 133, 166, and 167, wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 620 operatively linked to the sequence of SEQ ID NO: 3649 or SEQ ID NO: 5113, orthe sequence ofSEQ ID NO: 620 operatively linked to the sequence of SEQ ID NO: 549 operatively linked to the sequence of SEQ ID NO: 550 or SEQ ID NO: 5051; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 621 operatively linked to the sequence of SEQ ID NO: 3644.

169. The multispecific molecule of any one of claims 116 to 133 and 166 to 168, wherein:(i) the first polypeptide chain comprises the sequence of SEQ ID NO: 694 or SEQ ID NO: 695; and(ii) the third polypeptide chain comprises the sequence of SEQ ID NO: 696.

170. The multispecific molecule of any one of claims 116 to 169, wherein the multispecific molecule comprises a polypeptide chain comprising a sequence having at least 70% sequence identity to any one of the polypeptide chain sequences listed in Table 21.

171. The multispecific molecule of any one of claims 116 to 170, wherein the multispecific molecule comprises a polypeptide chain comprising any one of the polypeptide chain sequences listed in Table 21.

172. The multispecific molecule of any one of claims 116 to 171, wherein the multispecific molecule comprises:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to any one of the polypeptide chain sequences listed in Table 21 ;(ii) the second polypeptide chain comprises a sequence having at least 70% sequence identity to any one of the polypeptide chain sequences listed in Table 21 ; and(iii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to any one of the polypeptide chain sequences listed in Table 21.

173. The multispecific molecule of any one of claims 116 to 172, wherein the multispecific molecule comprises:(i) the first polypeptide chain comprises any one of the polypeptide chain sequences listed in Table 21;(ii) the second polypeptide chain comprises any one of the polypeptide chain sequences listed in Table 21 ; and(iii) the third polypeptide chain comprises any one of the polypeptide chain sequences listed in Table 21.

174. The multispecific molecule of any one of claims 116 to 173, wherein the multispecific molecule comprises:(i) the first polypeptide chain comprises a sequence having at least 70% sequence identity to any one of the first polypeptide chain sequences listed in Table 21 ;(ii) the second polypeptide chain comprises a sequence having at least 70% sequence identity to any one of the second polypeptide chain sequences listed in Table 21 ; and(iii) the third polypeptide chain comprises a sequence having at least 70% sequence identity to any one of the third polypeptide chain sequences listed in Table 21.

175. The multispecific molecule of any one of claims 116 to 174, wherein the multispecific molecule comprises:(i) the first polypeptide chain comprises any one of the first polypeptide chain sequences listed in Table 21;(ii) the second polypeptide chain comprises any one of the second polypeptide chain sequences listed in Table 21; and(iii) the third polypeptide chain comprises any one of the third polypeptide chain sequences listed in Table 21.

176. An anti-HER-2 antibody or an anti-HER2 antigen binding domain comprising:(i) a heavy chain variable region (VH) comprising a heavy chain complementarity-determining region 3 (HC CDR3) sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 628, 642, 643, 644, and 650; and / or(ii) a light chain variable region (VL) comprising a light chain complementarity-determining region 3 (LC CDR3) sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 631, 640, and 653.

177. The anti-HER-2 antibody or the anti-HER2 antigen binding domain of claim 176, wherein the anti- HER-2 antibody or the anti-HER2 antigen binding domain comprises a VH comprising a HC CDR1 sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 626, 634, 636, 648, and 656.

178. The anti-HER-2 antibody or the anti-HER2 antigen binding domain of claim 176 or 177, wherein the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VH comprising a HC CDR2 sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 627, 635, 637, 649, 657, and 658.

179. The anti-HER-2 antibody or the anti-HER2 antigen binding domain of any one of claims 176 to 178, wherein the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VH comprising a HC CDR1 sequence, a HC CDR2 sequence, and a HC CDR3 sequence comprising the sequences of:(i) SEQ ID NOs: 626, 627, and 628, respectively;(ii) SEQ ID NOs: 634, 635, and 628, respectively;(iii) SEQ ID NOs: 636, 637, and 628, respectively;(iv) SEQ ID NOs: 636, 637, and 642, respectively;(v) SEQ ID NOs: 636, 637, and 643, respectively;(vi) SEQ ID NOs: 636, 637, and 644, respectively;(vii) SEQ ID NOs: 648, 649, and 650, respectively;(viii) SEQ ID NOs: 656, 657, and 650, respectively; or(ix) SEQ ID NOs: 656, 658, and 650, respectively.

180. The anti-HER-2 antibody or the anti-HER2 antigen binding domain of any one of claims 176 to179, wherein the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VL comprising a LC CDR1 sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 629, 632, 638, 641, 651, 654, and 659.

181. The anti-HER-2 antibody or the anti-HER2 antigen binding domain of any one of claims 176 to180, wherein the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VL comprising a LC CDR2 sequence comprising any one sequence selected from the group consisting of SEQ ID NOs: 630, 633, 639, 652, 655, and 660.

182. The anti-HER-2 antibody or the anti-HER2 antigen binding domain of any one of claims 176 to181, wherein the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VL comprising a LC CDR1 sequence, a LC CDR2 sequence, and a LC CDR3 sequence comprising the sequences of:(i) SEQ ID NOs: 629, 630, and 631, respectively;(ii) SEQ ID NOs: 632, 633, and 631, respectively;(iii) SEQ ID NOs: 638, 639, and 631, respectively;(iv) SEQ ID NOs: 629, 630, and 640, respectively;(v) SEQ ID NOs: 641, 639, and 631, respectively;(vi) SEQ ID NOs: 651, 652, and 653, respectively;(vii) SEQ ID NOs: 654, 655, and 653, respectively; or(viii) SEQ ID NOs: 659, 660, and 653, respectively.

183. The anti-HER-2 antibody or the anti-HER2 antigen binding domain of any one of claims 176 to182, wherein the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VH and a VL, respectively, comprising a HC CDR1 sequence, a HC CDR2 sequence, and a HC CDR3 sequence, and a LC CDR1 sequence, a LC CDR2 sequence, and a LC CDR3 sequence comprising the sequences of:(i) SEQ ID NOs: 626, 627, 628, 632, 633, and 631, respectively;(ii) SEQ ID NOs: 634, 635, 628, 629, 630, and 631, respectively;(iii) SEQ ID NOs: 634, 635, 628, 632, 633, and 631, respectively;(iv) SEQ ID NOs: 636, 637, 628, 632, 633, and 631, respectively;(v) SEQ ID NOs: 634, 635, 628, 638, 639, and 631, respectively;(vi) SEQ ID NOs: 636, 637, 628, 638, 639, and 631, respectively;(vii) SEQ ID NOs: 626, 627, 628, 629, 630, and 640, respectively;(viii) SEQ ID NOs: 636, 637, 628, 641, 639, and 631, respectively;(ix) SEQ ID NOs: 636, 637, 642, 641, 639, and 631, respectively;(x) SEQ ID NOs: 636, 637, 643, 641, 639, and 631, respectively;(xi) SEQ ID NOs: 636, 637, 644, 641, 639, and 631, respectively;(xii) SEQ ID NOs: 648, 649, 650, 654, 655, and 653, respectively;(xiii) SEQ ID NOs: 656, 657, 650, 651, 652, and 653, respectively;(xiv) SEQ ID NOs: 656, 657, 650, 654, 655, and 653, respectively;(xv) SEQ ID NOs: 656, 658, 650, 654, 655, and 653, respectively;(xvi) SEQ ID NOs: 656, 657, 650, 659, 660, and 653, respectively; or(xvii) SEQ ID NOs: 656, 658, 650, 659, 660, and 653, respectively.

184. The anti-HER-2 antibody or the anti-HER2 antigen binding domain of any one of claims 176 to183, wherein the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VH comprising a sequence having at least 70% sequence identity to any one sequence selected from the group consisting of SEQ ID NOs: 600, 603, 604, 607, 609, 610, 611, 616, 619, and 620.

185. The anti-HER-2 antibody or the anti-HER2 antigen binding domain of any one of claims 176 to184, wherein the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VH comprising any one sequence selected from the group consisting of SEQ ID NOs: 600, 603, 604, 607, 609, 610, 611, 616, 619, and 620.

186. The anti-HER-2 antibody or the anti-HER2 antigen binding domain of any one of claims 176 to185, wherein the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VL comprising a sequence having at least 70% sequence identity to any one sequence selected from the group consisting of SEQ ID NOs: 601, 602, 605, 606, 608, 617, 618, and 621.

187. The anti-HER-2 antibody or the anti-HER2 antigen binding domain of any one of claims 176 to186, wherein the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises a VL comprising any one sequence selected from the group consisting of SEQ ID NOs: 601, 602, 605, 606, 608, 617, 618, and 621.

188. The anti-HER-2 antibody or the anti-HER2 antigen binding domain of any one of claims 176 to187, wherein the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises:(i) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 600, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 602;(ii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 603, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 601;(iii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 603, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 602;(iv) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 604, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 602;(v) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 603, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 605;(vi) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 604, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 605;(vii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 600, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 606;(viii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 607, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608;(ix) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 609, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608;(x) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 610, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608;(xi) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 611, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 608;(xii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 616, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 618;(xiii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 619, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 617;(xiv) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 619, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 618;(xv) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 620, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 618;(xvi) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 619, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 621; or(xvii) a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 620, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 621.

189. The anti-HER-2 antibody or the anti-HER2 antigen binding domain of any one of claims 176 to 188, wherein the anti-HER-2 antibody or the anti-HER2 antigen binding domain comprises:(i) a VH comprising the sequence of SEQ ID NO: 600, and a VL comprising the sequence of SEQ ID NO: 602;(ii) a VH comprising the sequence of SEQ ID NO: 603, and a VL comprising the sequence of SEQ ID NO: 601;(iii) a VH comprising the sequence of SEQ ID NO: 603, and a VL comprising the sequence ofSEQ ID NO: 602;(iv) a VH comprising the sequence of SEQ ID NO : 604, and a VL comprising the sequence of SEQ ID NO: 602;(v) a VH comprising the sequence of SEQ ID NO: 603, and a VL comprising the sequence of SEQ ID NO: 605;(vi) a VH comprising the sequence of SEQ ID NO: 604, and a VL comprising the sequence of SEQ ID NO: 605;(vii) a VH comprising the sequence of SEQ ID NO: 600, and a VL comprising the sequence of SEQ ID NO: 606;(viii) a VH comprising the sequence of SEQ ID NO: 607, and a VL comprising the sequence of SEQ ID NO: 608;(ix) a VH comprising the sequence of SEQ ID NO: 609, and a VL comprising the sequence of SEQ ID NO: 608;(x) a VH comprising the sequence of SEQ ID NO: 610, and a VL comprising the sequence of SEQ ID NO: 608;(xi) a VH comprising the sequence of SEQ ID NO: 611, and a VL comprising the sequence of SEQ ID NO: 608;(xii) a VH comprising the sequence of SEQ ID NO: 616, and a VL comprising the sequence of SEQ ID NO: 618;(xiii) a VH comprising the sequence of SEQ ID NO: 619, and a VL comprising the sequence of SEQ ID NO: 617;(xiv) a VH comprising the sequence of SEQ ID NO: 619, and a VL comprising the sequence of SEQ ID NO: 618;(xv) a VH comprising the sequence of SEQ ID NO: 620, and a VL comprising the sequence of SEQ ID NO: 618;(xvi) a VH comprising the sequence of SEQ ID NO: 619, and a VL comprising the sequence ofSEQ ID NO: 621; or(xvii) a VH comprising the sequence of SEQ ID NO: 620, and a VL comprising the sequence of SEQ ID NO: 621.

190. An anti-TCRβV antibody or an anti-TCRβV antigen binding domain comprising:(i) a VH comprising a HC CDR1 comprising the sequence GHDFRLTYIH (SEQ ID NO: 3650), a HC CDR2 comprising the sequence RVSAGSGNVKYNEKFKG (SEQ ID NO: 3651), and a HC CDR3 comprising the sequence SYYSYDVLDY (SEQ ID NO: 5); and(ii) a VL comprising a LC CDR1 comprising the sequence RASQNVADRVV (SEQ ID NO: 673), a LC CDR2 comprising the sequence AASSLQS (SEQ ID NO: 639), and a LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 8).

191. The anti-TCRβ V antibody or the anti-TCRβV antigen binding domain of claim 190 composing a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1346.

192. The anti-TCRβV antibody or the anti-TCRβV antigen binding domain of claim 190 or 191 comprising a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 672.

193. The anti-TCRβV antibody or the anti-TCRβV antigen binding domain of any one of claims 190 to192 comprising a VH comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 1346, and a VL comprising a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 672.

194. The anti-TCRβV antibody or the anti-TCRβV antigen binding domain of any one of claims 190 to193 comprising a VH comprising the sequence of SEQ ID NO: 1346.

195. The anti-TCRβV antibody or the anti-TCRβV antigen binding domain of any one of claims 190 to194 comprising a VL comprising the sequence of SEQ ID NO: 672.

196. The anti-TCRβV antibody or the anti-TCRβV antigen binding domain of any one of claims 190 to195 comprising a VH comprising the sequence of SEQ ID NO: 1346, and a VL comprising the sequence of SEQ ID NO: 672.

197. A composition comprising the multispecific molecule of any one of claims 1 to 175, the anti-HER- 2 antibody or the anti-HER2 antigen binding domain of any one of claims 176 to 189, or the anti- TCRβV binding antibody or the anti-TCRβV antigen binding domain of any one of claims 190 to 196.

198. A polynucleotide comprising a sequence encoding the multispecific molecule of any one of claims 1 to 175, the anti-HER-2 antibody or the anti-HER2 antigen binding domain of any one of claims 176 to 189, the anti-TCRβV binding antibody or the anti-TCRβV antigen binding domain of any one of claims 190 to 196.

199. The polynucleotide of claim 198, wherein the polynucleotide is an isolated nucleic acid molecule.

200. A vector comprising one or more of the polynucleotide of claim 198 or 199.

201. A cell comprising the polynucleotide of claim 198 or 199 or the vector of claim 200.

202. A method of making the multispecific molecule of any one claims 1 to 175 comprising culturing a host cell comprising a recombinant polynucleotide comprising a sequence encoding the multispecific molecule or a vector comprising the recombinant polynucleotide under conditions suitable for gene expression and / or homo- or heterodimerization.

203. A pharmaceutical composition comprising the multispecific molecule of any one of claims 1 to 175, the anti-HER-2 antibody or the anti-HER2 antigen binding domain of any one of claims 176 to 189, the anti-TCRβV binding antibody or the anti-TCRβV antigen binding domain of any one ofclaims 190 to 196, the composition of claim 197, the polynucleotide of claim 198 or 199, the vector of claim 200, or the cell of claim 201, and a pharmaceutically acceptable carrier, excipient, or diluent.

204. A method of treating a condition or disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the multispecific molecule of any one of claims 1 to 175, the anti-HER-2 antibody or the anti-HER2 antigen binding domain of any one of claims 176 to 189, the anti-TCRβV binding antibody or the anti-TCRβV antigen binding domain of any one of claims 190 to 196, the composition of claim 197, the polynucleotide of claim 198 or 199, the vector of claim 200, the cell of claim 201, the pharmaceutical composition of claim 203, or any combination thereof, wherein the administering is effective to treat the condition or disease in the subject.

205. Use of the multispecific molecule of any one of claims 1 to 175, the anti-HER-2 antibody or the anti-HER2 antigen binding domain of any one of claims 176 to 189, the anti-TCRβV binding antibody or the anti-TCRβV antigen binding domain of any one of claims 190 to 196, the composition of claim 197, the polynucleotide of claim 198 or 199, the vector of claim 200, the cell of claim 201, the pharmaceutical composition of claim 203, or any combination thereof for treating a condition or disease in a subject in need thereof comprising administering to the subject, wherein the multispecific molecule, the anti-HER-2 antibody or the anti-HER2 antigen binding domain, the anti-TCRβV binding antibody or the anti-TCRβV antigen binding domain, the composition, the polynucleotide, the vector, the cell, the pharmaceutical composition, or any combination thereof is formulate in a therapeutically effective amount to treat the condition or disease in the subject.

206. The method of claim 204 or the use of claim 205, wherein the condition or disease is cancer.

207. The method or the use of claim 206, wherein the cancer is a solid tumor, a hematological cancer, a metastatic cancer, a soft tissue tumor, or any combination thereof.

208. The method or the use of claim 206 or 207, wherein the cancer is the solid tumor selected from the group consisting of melanoma, pancreatic cancer, breast cancer, colorectal cancer, lung cancer, skin cancer, ovarian cancer, liver cancer, and any combination thereof.

209. The method or the use of any one of claims 206 to 208, wherein the cancer is the 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.

210. The method or the use of claim 209, wherein the Non-Hodgkin’s lymphoma is selected from the group consisting of B cell lymphoma, diffuse large B cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia (B-CLL), mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, and any combination thereof.

211. The method or the use of claim 210, wherein the T-cell lymphoma is peripheral T-cell lymphoma.

212. The method or the use of any one of claims 206-211, wherein the cancer is characterized by a cancer antigen present on the cancer.

213. The method or the use of claim 212, wherein the cancer antigen is a tumor antigen, a stromal antigen, or a hematological antigen.

214. The method or the use of claim 212 or 213, wherein the cancer antigen is selected from the group consisting of CD19, CD123, CD22, CD30, CD171, CS-1, C-type lectin-like molecule-1, CD33, epidermal growth factor receptor variant III (EGFRvIII), ganglioside G2 (GD2), ganglioside GD3, TNF receptor family member B cell maturation (BCMA), Tn antigen ((Tn Ag) or (GalNAca- Ser / Thr)), prostate-specific membrane antigen (PSMA), Receptor tyrosine kinase-like orphan receptor 1 (ROR1), Fms-Like Tyrosine Kinase 3 (FLT3), Tumor-associated glycoprotein 72 (TAG72), CD38, CD44v6, Carcinoembryonic antigen (CEA), Epithelial cell adhesion molecule (EPCAM), B7H3 (CD276), KIT (CD117), Interleukin- 13 receptor subunit alpha-2, mesothelin, Interleukin 11 receptor alpha (IL-1 IRa), prostate stem cell antigen (PSCA), Protease Serine 21, vascular endothelial growth factor receptor 2 (VEGFR2), Lewis(Y) antigen, CD24, Platelet- derived growth factor receptor beta (PDGFR-beta), Stage-specific embryonic antigen-4 (SSEA-4), CD20, Folate receptor alpha, Receptor tyrosine-protein kinase ERBB2 (Her2 / neu), Mucin 1, cell surface associated (MUC1), epidermal growth factor receptor (EGFR), neural cell adhesion molecule (NCAM), Prostase, prostatic acid phosphatase (PAP), elongation factor 2 mutated (ELF2M), Ephrin B2, fibroblast activation protein alpha (FAP), insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX), Proteasome (Prosome, Macropain) Subunit, Beta Type, 9 (LMP2), glycoprotein 100 (gpl00 / pmell7), oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr-abl), tyrosinase, ephrin type-A receptor 2 (EphA2), Fucosyl GM1, sialyl Lewis adhesion molecule (sLe), ganglioside GM3, transglutaminase 5 (TGS5), high molecular weight-melanoma-associated antigen (HMWMAA), o-acetyl-GD2 ganglioside (OAcGD2), Folate receptor beta, tumor endothelial marker 1 (TEM1 / CD248), tumor endothelial marker 7-related (TEM7R), claudin 6 (CLDN6), thyroid stimulating hormone receptor (TSHR), G protein-coupled receptor class C group 5, member D (GPRC5D), chromosome X open reading frame 61 (CXORF61), CD97, CD179a, anaplastic lymphoma kinase (ALK), Polysialic acid, placentaspecific 1 (PLAC1), hexasaccharide portion of globoH glycoceramide (GloboH), mammary gland differentiation antigen (NY-BR-1), uroplakin 2 (UPK2), Hepatitis A virus cellular receptor 1 (HAVCR1), adrenoceptor beta 3 (ADRB3), pannexin 3 (PANX3), G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex, locus K 9 (LY6K), Olfactory receptor 51E2 (OR51E2), TCR Gamma Alternate Reading Frame Protein (TARP), Wilms tumor protein (WT1), Cancer / testis antigen 1 (NY -ESO-l / LAGE-1), Cancer / testis antigen 2 (LAGE-la), Melanoma-associated antigen 1 (MAGE-A1), ETS translocation-variant gene 6, located on chromosome 12p (ETV6-AML), sperm protein 17 (SPA17), X Antigen Family, Member 1A (XAGE1), angiopoietin-binding cell surface receptor 2 (Tie 2), melanoma cancer testis antigen-1 (MAD-CT-1), melanoma cancer testisantigen-2 (MAD-CT-2), Fos-related antigen 1, tumor protein p53 (p53), p53 mutant, prostein, Survivin, telomerase, prostate carcinoma tumor antigen- 1, melanoma antigen recognized by T cells 1, Rat sarcoma (Ras) mutant, human Telomerase reverse transcriptase (hTERT), sarcoma translocation breakpoints, melanoma inhibitor of apoptosis (ML-IAP), ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene), N-Acetyl glucosaminyl -transferase V (NA 17), paired box protein Pax-3 (PAX3), Androgen receptor, Cyclin Bl, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), Ras Homolog Family Member C (RhoC), Tyrosinase-related protein 2 (TRP-2), Cytochrome P450 1B1 (CYP1B1), CCCTC- Binding Factor (Zinc Finger Protein)-Like, Squamous Cell Carcinoma Antigen Recognized By T Cells 3 (SART3), Paired box protein Pax-5 (PAX5), proacrosin binding protein sp32 (OY-TES1), lymphocyte-specific protein tyrosine kinase (LCK), A kinase anchor protein 4 (AKAP-4), synovial sarcoma, X breakpoint 2 (SSX2), Receptor for Advanced Glycation Endproducts (RAGE-1), renal ubiquitous 1 (RU1), renal ubiquitous 2 (RU2), legumain, human papilloma virus E6 (HPV E6), human papilloma virus E7 (HPV E7), intestinal carboxyl esterase, heat shock protein 70-2 mutated (mut hsp70-2), CD79a, CD79b, CD72, Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), Fc fragment of IgA receptor (FCAR or CD89), Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2), CD300 molecule-like family member f (CD300LF), C-type lectin domain family 12 member A (CLEC12A), bone marrow stromal cell antigen 2 (BST2), EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2), lymphocyte antigen 75 (LY75), Glypican-3 (GPC3), Fc receptor-like 5 (FCRL5), FcRH5, PDL1, CD47, prostate specific membrane antigen (PMSA), prostate-specific antigen (PSA), Ron Kinase, c-Met, Immature laminin receptor, TAG-72, BING-4, Calcium -activated chloride channel 2, Cyclin-Bl, 9D7, Ep-CAM, EphA3, SAP-1, PRAME, SSX-2, Melan-A / MART-1, TRPl / gp75, MC1R, β-catenin, BRCA1 / 2, CDK4, CML66, Fibronectin, Ras, TGF-B receptor, AFP, ETA, MAGE, CA-125, BAGE, GAGE, CDC27, a actinin-4, gangliosides, MART-2, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RU11, RU12, SAGE, TRG, TSTA, LI -CAM, gpA33, GM2, VEGFR, Integrins, carbohydrates, TRAILR1, TRAILR2, RANKL, TGF-beta, hyaluronic acid, collagen, tenascin C, tenascin W, and immunoglobulin lambda-like polypeptide 1 (IGLL1).

215. The method or the use of claim 212 or 213, wherein the cancer antigen is HER-2.

216. The method or the use of any one of claims 206 to 215, wherein the cancer is a HER-2 associated cancer.

217. The method or the use of any one of claims 206 to 208 and 212 to 216 , wherein the cancer comprises breast cancer, lung cancer, pancreatic cancer, head and neck cancer, bladder cancer, urothelial cancer, ovarian cancer, gallbladder cancer, gastric cancer, esophageal cancer, hepatocellular cancer, epithelial cancer, or any combination thereof.

218. The method or the use of any one of claims 206 to 208 and 212 to 217, wherein the cancer comprises breast cancer, pancreatic cancer, lung cancer, or any combination thereof.

219. The method or the use of claim 206 to 208 and 212 to 218, wherein the cancer comprises a solid cancer selected from the group consisting of colon cancer, breast cancer, renal cancer, melanoma, prostate cancer, lung cancer, rectal cancer, colorectal cancer, cervical cancer, and any combination thereof.

220. The method of any one of claims 204, and 206 to 219 or the use of any one of claims 205 to 219, wherein the cancer comprises an anti-PDl therapy resistant cancer.

221. The method or the use of claim 220, wherein the cancer comprises an anti-PD 1 therapy resistant solid cancer.

222. The method of any one of claims 204, and 206 to 221 or the use of any one of claims 205 to 221, wherein the cancer comprises an HPV-positive cancer.

223. The method or the use of claim 222, wherein the cancer comprises an HPV-positive solid cancer.

224. The method of any one of claims 204, and 206 to 223 or the use of any one of claims 205 to 223, wherein the cancer comprises a cancer with a high tumor mutation burden.

225. The method of any one of claims 204, and 206 to 224 or the use of any one of claims 205 to 224, further comprising administering a second therapeutic agent or therapy to the subject.

226. The method or the use of claim 225, wherein the second therapeutic agent or therapy comprises a chemotherapeutic agent, a biologic agent, a hormonal therapy, radiation, or surgery.

227. The method or the use of claim 225 or 226, wherein the second therapeutic agent or therapy is administered in combination with the multispecific molecule of any one of claims 1 to 175, the anti-HER-2 antibody or the anti-HER2 antigen binding domain of any one of claims 176 to 189, the anti-TCRβV binding antibody or the anti-TCRβ V antigen binding domain of any one of claims 190 to 196, the composition of claim 197, the polynucleotide of claim 198 or 199, the vector of claim 200, the cell of claim 201, the pharmaceutical composition of claim 203, or any combination thereof, sequentially, simultaneously, or concurrently.

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