Anti-TCR antibody molecules and uses thereof

Abstract

To provide antibodies that avoid or reduce cytokine release syndrome (CRS) and / or neurotoxicity (NT).SOLUTION: Compositions comprising molecules comprising an antigen binding domain that binds to a T cell receptor beta variable (TCR β V) region are provided.SELECTED DRAWING: Figure 108C

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 957,024, filed January 3, 2020, and U.S. Provisional Application No. 63 / 070,596, filed August 26, 2020, the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] Current 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, this approach has limitations. Previous studies have shown, for example, that low doses of anti-CD3e monoclonal antibodies (mAbs) can cause T cell dysfunction and produce immunosuppressive effects. In addition, anti-CD3e mAbs bind to all T cells and thus activate large numbers of T cells. Such non-physiological, massive activation of T cells by these anti-CD3e mAbs can lead to the production of pro-inflammatory cytokines, such as IFN-gamma, IL-1-beta, IL-6, IL-10, and TNF-alpha, causing a "cytokine storm," also known as cytokine release syndrome (CRS) and associated with neurotoxicity (NT). Therefore, it would be advantageous to develop antibodies that avoid or reduce CRS and / or NT. Summary of the Invention [Means for solving the problem]

[0003] Disclosed herein, inter alia, are antibody molecules directed against the variable chain of the beta subunit of the TCR (TCRβV) that bind to, e.g., activate or expand, T cells, e.g., a subset of T cells. In some embodiments, the anti-TCRβV antibody molecules disclosed herein result in a cytokine profile, e.g., a cytokine secretion profile, that differs from that of T cell engagers that bind to receptors or molecules other than the TCRβV region ("non-TCRβV-binding T cell engagers"). In some embodiments, the anti-TCRβV antibody molecules disclosed herein result in reduced, minimal, or no production of cytokines associated with cytokine release syndrome (CRS), e.g., IL-6, IL-1 beta, IL-10, and TNF alpha, and enhanced and / or delayed production of IL-2 and IFN-gamma. In some embodiments, the anti-TCRβV antibodies disclosed herein result in the expansion of immune cells, e.g., T cells, tumor-infiltrating lymphocytes (TILs), NK cells, or other immune cells (e.g., as described herein). Also disclosed herein are methods of making the anti-TCRβV antibody molecules, as well as methods of using the anti-TCRβV antibody molecules, including methods of using the anti-TCRβV antibody molecules to expand immune cells or immune cell populations, and methods of using the anti-TCRβV antibody molecules to treat cancer, including use as a combination therapy with TILs and immune checkpoint therapies. The present disclosure further provides multispecific, e.g., bispecific, molecules comprising the anti-TCRβV antibody molecules. In some embodiments, compositions comprising the anti-TCRβV antibody molecules of the present disclosure can be used to activate and / or redirect T cells, e.g., to promote tumor cell lysis for cancer immunotherapy. In some embodiments, compositions comprising the anti-TCRβV antibody molecules disclosed herein limit the undesirable side effects of CRS and / or NT, e.g., CRS and / or NT associated with anti-CD3e targeting.

[0004] In some embodiments, the anti-TCRβV antibody molecules disclosed herein result in reduced, minimal, or no production of cytokines associated with cytokine release syndrome (CRS), e.g., IL-6, IL-1 beta, IL-10, and TNF alpha, and enhanced and / or delayed production of IL-2 and IFN-gamma, compared to anti-CD3 antibody molecules (e.g., low-affinity anti-CD3 antibody molecules). In some embodiments, administration of the anti-TCRβV antibody molecules disclosed herein in a subject results in reduced cytokine release syndrome (CRS) (e.g., shorter duration or absence of CRS), reduced severity of CRS (e.g., absence of severe CRS, e.g., CRS grade 4 or 5), reduced neurotoxicity (NT), or reduced severity of NT, compared to similar administration of an anti-CD3 antibody molecule (e.g., low-affinity anti-CD3 antibody molecule).

[0005] Thus, provided herein are anti-TCRβ antibody molecules, multispecific or multifunctional molecules (e.g., multispecific or multifunctional antibody molecules) comprising anti-TCRβ antibody molecules (also referred to herein as "compositions"), nucleic acids encoding the same, methods of producing the foregoing molecules, pharmaceutical compositions comprising the foregoing molecules, and methods of treating diseases or disorders, e.g., cancer, using the foregoing molecules. The antibody molecules and pharmaceutical compositions disclosed herein can be used (alone or in combination with other agents or therapeutic modalities), for example, to treat, prevent, and / or diagnose the disorders and conditions described herein, e.g., cancer.

[0006] In one aspect, the present disclosure provides, e.g., a non-murine, e.g., human-like antibody molecule (e.g., a human or humanized antibody molecule) that binds, e.g., specifically binds, to a T cell receptor beta variable (TCRβV) region.

[0007] In some embodiments, the anti-TCRBV antibody molecule comprises the antigen-binding domain of an antibody disclosed in any of Tables 1-2 or 10-13, or a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. In some embodiments, the anti-TCRBV antibody molecule comprises a leader sequence comprising the amino acid sequence of SEQ ID NO: 3288. In some embodiments, the anti-TCRBV antibody molecule does not comprise a leader sequence comprising the amino acid sequence of SEQ ID NO: 3288.

[0008] In some embodiments, binding of an anti-TCRβV antibody molecule to the TCRβV region results in a cytokine profile, e.g., a cytokine secretion profile (e.g., comprising one or more cytokines and / or one or more chemokines), that differs from that of a T cell engager that binds to a receptor or molecule other than the TCRβV region (a "non-TCRβV-binding T cell engager").

[0009] In some embodiments, the cytokine profile, e.g., cytokine secretion profile, is one of the following: (i) an increase in the level, e.g., expression level, and / or activity, of IL-2; (ii) a reduction in the level, e.g., expression level, and / or activity of IL-1β; (iii) a reduction in the level, e.g., expression level, and / or activity of IL-6; (iv) a reduction in the level, e.g., expression level, and / or activity of TNFα; (v) a reduction in the level, e.g., expression level, and / or activity, of IL-10; (vi) a delay in the increase in the level, e.g., expression level, and / or activity of IL-2, e.g., a delay of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or more; (vii) a delay in the increase in the level, e.g., expression level, and / or activity of IFN-gamma, e.g., at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours; 7, 8, 9, or 10 hour delays, or (viii) an increase in the level, e.g., expression level, and / or activity, of IL-15; For example, (i) to (viii) are compared with the cytokine profile, e.g., cytokine secretion profile, of a non-TCRβV-binding T cell engager.

[0010] In some embodiments, binding of the anti-TCRBV antibody to the TCRβV region results in a reduced cytokine storm, e.g., reduced cytokine release syndrome (CRS) and / or neurotoxicity (NT), compared to the cytokine storm induced by a non-TCRβV-binding T cell engager, as measured by the assay of Example 3.

[0011] In some embodiments, the binding of the anti-TCRBV antibody to the TCRβV region is (ix) reduced T cell proliferation kinetics; (x) cell killing, e.g., target cell killing, e.g., cancer cell killing, e.g., as measured by the assay of Example 4; (xi) natural killer (NK) cell proliferation, e.g., increased expansion, or (xii) an expansion of a population of T cells having a memory-like phenotype, e.g., at least about a 1.1- to 10-fold expansion (e.g., at least about a 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold expansion), e.g., as described herein. Bringing about one, two, three or all of the For example, (ix) to (xii) are compared with non-TCRβV-binding T cell engagers.

[0012] In some embodiments, the anti-TCRβV antibody molecules disclosed herein recognize (e.g., bind to) a structurally conserved domain on the TCRβV protein (e.g., indicated by the circled region in Figure 24A).

[0013] In some embodiments, the anti-TCRVβ antibodies disclosed herein comprise an Fc region, e.g., as described herein. In some embodiments, the Fc region is a wild-type Fc region, e.g., a wild-type human Fc region. In some embodiments, the Fc region comprises a variant, e.g., an Fc region that includes an addition, substitution, or deletion of at least one amino acid residue in the Fc region that results in reduced affinity for and / or binding to at least one Fc receptor. In some embodiments, the reduced affinity is compared to an otherwise similar antibody having a wild-type Fc region.

[0014] In some embodiments, an anti-TCRVβ antibody comprising a variant Fc region has one or more of the following properties: (1) reduced effector function (e.g., reduced ADCC, ADCP, and / or CDC), (2) reduced binding to one or more Fc receptors, and / or (3) reduced binding to C1q complement. In some embodiments, the reduction in any one or all of properties (1)-(3) is relative to an otherwise similar antibody having a wild-type Fc region.

[0015] In some embodiments, anti-TCRVβ antibodies comprising a variant Fc region have reduced affinity for human Fc receptors, e.g., FcγRI, FcγRII, and / or FcγRII. In some embodiments, anti-TCRVβ antibodies comprising a variant Fc region comprise a human IgG1 region or a human IgG4 region.

[0016] In some embodiments, the anti-TCRVβ antibodies disclosed herein comprise an Fc region variant, e.g., any one or all, or any combination of mutations, disclosed in Table 21. In some embodiments, the anti-TCRVβ antibodies disclosed herein comprise an Asn297Ala (N297A) mutation. In some embodiments, the anti-TCRVβ antibodies disclosed herein comprise a Leu234Ala / Leu235Ala (LALA) mutation.

[0017] In some embodiments, the anti-TCRβV antibody molecules disclosed herein do not recognize, eg, do not bind to, the interface of the TCRβV:TCR alpha complex. In some embodiments, the anti-TCRβV antibody molecules disclosed herein do not recognize, e.g., do not bind to, the constant region of the TCRβV protein. An exemplary antibody that binds to the constant region of the TCRβV region is JOVI.1, described in Viney et al., (Hybridoma. 1992 December;11(6):701-13).

[0018] In some embodiments, the anti-TCRβV antibody molecules disclosed herein do not recognize, e.g., do not bind to, one or more (e.g., all) of the complementarity determining regions (e.g., CDR1, CDR2, and / or CDR3) of the TCRβV protein.

[0019] In some embodiments, binding of the anti-TCRβV antibody molecule to the TCRβV region is determined by: (i) a reduction in the level, e.g., expression level, and / or activity of IL-1β; (ii) a reduction in the level, e.g., expression level, and / or activity, of IL-6; (iii) a reduction in the level, e.g., expression level, and / or activity of TNFα; (iv) an increase in the level, e.g., expression level, and / or activity, of IL-2; (v) a delay in the increase in the level, e.g., expression level, and / or activity of IL-2, e.g., a delay of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or more; (vi) a delay in the increase in the level, e.g., expression level, and / or activity of IFN-gamma, e.g., a delay of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours; (vii) reduced T cell proliferation kinetics; (viii) a reduction in cytokine storm, e.g., cytokine release syndrome (CRS) and / or neurotoxicity (NT), e.g., as measured by the assay of Example 3; (ix) cell killing, e.g., target cell killing, e.g., cancer cell killing, e.g., as measured by the assay of Example 4; (x) an increase in the level, e.g., expression level, and / or activity of IL-15, or (xi) an increase in natural killer (NK) cell proliferation, e.g., expansion. yielding one, two, three, four, five, six, seven, eight, nine, ten, or more (e.g., all) of the

[0020] In some embodiments, any one or all of (i)-(xi), or any combination thereof, produced by an anti-TCRβV antibody molecule disclosed herein is compared to an antibody that binds to a CD3 molecule, e.g., a CD3 epsilon (CD3e) molecule, or a TCR alpha (TCRα) molecule.

[0021] In some embodiments, binding of the anti-TCRβV antibody molecule to the TCRβV region results in the secretion, eg, production, of perforin and / or granzyme B. In one aspect, the present disclosure provides an antibody molecule that binds, e.g., specifically binds, a T cell receptor beta variable chain (TCRβV) region, wherein the anti-TCRβV antibody molecule comprises: (a) a light chain variable region (VL), (i) (e.g., three) light chain complementarity determining region 1 (LC CDR1), light chain complementarity determining region 2 (LC CDR2), and light chain complementarity determining region 3 (LC CDR4) of SEQ ID NO: 10 or SEQ ID NO: 11 one, two, or all of region 3 (LC CDR3), and (ii) a light chain variable region (VL) comprising framework regions (FR) that are at least 95% identical to one, two, three, or all of (e.g., four) non-mouse germline framework region 1 (FR1), non-mouse germline framework region 2 (FR2), non-mouse germline framework region 3 (FR3), and non-mouse germline framework region 4 (FR4); and / or (b) a heavy chain variable region (VH), (i) one, two, or all of (e.g., three) heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 9; and (ii) a heavy chain variable region (VH) comprising a framework region (FR) that is at least 95% identical to one, two, three, or all of (e.g., four) non-mouse germline framework region 1 (FR1), non-mouse germline framework region 2 (FR2), non-mouse germline framework region 3 (FR3), and non-mouse germline framework region 4 (FR4); The present invention provides an antibody molecule comprising an antigen-binding domain comprising:

[0022] In some embodiments, the VL comprises a sequence having the consensus sequence of SEQ ID NO: 230 or 3289. In some embodiments, the VH comprises a sequence having the consensus sequence of SEQ ID NO: 231 or 3290.

[0023] In some embodiments, the anti-TCRβ antibody molecule is TCRβ V6, e.g., 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.

[0024] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 1 or SEQ ID NO: 9, or the amino acid sequences listed in Table 1; or (ii) LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 2, SEQ ID NO: 10, or SEQ ID NO: 11, or the amino acid sequences listed in Table 1 The antigen-binding domain comprises:

[0025] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a light chain variable region (VL) comprising one, two, or all (e.g., three) of the LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 2, SEQ ID NO: 10, or SEQ ID NO: 11, or the amino acid sequences listed in Table 1.

[0026] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two, or all (e.g., three) of the HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 1 or SEQ ID NO: 9, or the amino acid sequences listed in Table 1.

[0027] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) the LC CDR1 amino acid sequence of SEQ ID NO: 6 (or an amino acid sequence having one, two, three, or four or fewer modifications, e.g., substitutions, additions, or deletions), the LC CDR2 amino acid sequence of SEQ ID NO: 7 (or an amino acid sequence having one, two, three, or four or fewer modifications, e.g., substitutions, additions, or deletions), and / or the sequence a VL comprising the LC CDR3 amino acid sequence of No. 8 (or an amino acid sequence having one, two, three, or no more than four alterations, e.g., substitutions, additions, or deletions thereof); and / or (ii) a VH comprising the HC CDR1 amino acid sequence of SEQ ID NO: 3 (or an amino acid sequence having one, two, three, or four or fewer modifications, e.g., substitutions, additions, or deletions), the HC CDR2 amino acid sequence of SEQ ID NO: 4 (or an amino acid sequence having one, two, three, or four or fewer modifications, e.g., substitutions, additions, or deletions), and / or the HC CDR3 amino acid sequence of SEQ ID NO: 5 (or an amino acid sequence having one, two, three, or four or fewer modifications, e.g., substitutions, additions, or deletions). The antigen-binding domain comprises:

[0028] In some embodiments, the anti-TCRβV antibody molecule comprises: a variable heavy chain (VH) of an amino acid sequence listed in Table 1, e.g., SEQ ID NO: 9, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to an amino acid sequence listed in Table 1, e.g., SEQ ID NO: 9 or SEQ ID NO: 1312; and / or A variable light chain (VL) of an amino acid sequence listed in Table 1, e.g., SEQ ID NO: 10 or SEQ ID NO: 11, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to an amino acid sequence listed in Table 1, e.g., SEQ ID NO: 10 or SEQ ID NO: 11 or SEQ ID NO: 1314. The antigen-binding domain comprises:

[0029] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) the VH amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 1312; (ii) an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:1312; (iii) the VL amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 1314, and / or (iv) an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 1314. The antigen-binding domain comprises:

[0030] In one embodiment, an antibody molecule that binds to, e.g., specifically binds to, a T cell receptor beta variable chain (TCRβV) region, wherein the anti-TCRβV antibody molecule is (a) a light chain variable region (VL), (i) one, two, or all (e.g., three) of the light chain complementarity determining region 1 (LC CDR1), the light chain complementarity determining region 2 (LC CDR2), and the light chain complementarity determining region 3 (LC CDR3) of a humanized BH light chain (LC) of Table 2; and (ii) a light chain variable region (VL) comprising framework regions (FR) having at least 95% identity to one, two, three, or all (e.g., four) of framework region 1 (FR1), framework region 2 (FR2), framework region 3 (FR3), and framework region 4 (FR4) of a humanized BH LC of Table 2; and / or (b) a heavy chain variable region (VH), (i) one, two, or all (e.g., three) of heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3) of a humanized BH heavy chain (HC) of Table 2; and (ii) a heavy chain variable region (VH) comprising framework regions (FR) having at least 95% identity to one, two, three, or all (e.g., four) of framework region 1 (FR1), framework region 2 (FR2), framework region 3 (FR3), and framework region 4 (FR4) of a humanized BH HC of Table 2; Provided herein are antibody molecules comprising an antigen-binding domain comprising:

[0031] In some embodiments, the anti-TCRBV binds to TCRβ V12, eg, TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01, or a variant thereof.

[0032] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) the HC CDR1, HC CDR2, and HC CDR3 of antibody B listed in Table 2, or (ii) LC CDR1, LC CDR2, and LC CDR3 of Antibody B listed in Table 2 The antigen-binding domain comprises:

[0033] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a light chain variable region (VL) comprising one, two or all (e.g., three) of the LC CDR1, LC CDR2 and LC CDR3 of a humanized BH antibody listed in Table 2.

[0034] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two, or all (e.g., three) of the HC CDR1, HC CDR2, and HC CDR3 of a humanized BH antibody listed in Table 2.

[0035] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a light chain variable region (VL) comprising one, two, or all (e.g., three) of the LC CDR1, LC CDR2, and LC CDR3 of a humanized BH antibody listed in Table 2.

[0036] In some embodiments, the anti-TCRβV antibody molecule comprises: a VH sequence of a humanized BH antibody listed in Table 2, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VH of a humanized BH antibody listed in Table 2; and / or A VL sequence of a humanized BH antibody listed in Table 2, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VL of a humanized BH antibody listed in Table 2. Includes:

[0037] In some embodiments, the anti-TCRβV antibody molecule comprises a framework region (FR) having at least 95% identity to one of FR1, FR2, FR3, and FR4 of the humanized BH LC of Table 2.

[0038] In some embodiments, the anti-TCRβV antibody molecule comprises a framework region (FR) having at least 95% identity to any two of FR1, FR2, FR3, and FR4 of the humanized BH LC of Table 2.

[0039] In some embodiments, the anti-TCRβV antibody molecule comprises a framework region (FR) having at least 95% identity to any three of FR1, FR2, FR3, and FR4 of the humanized BH LC of Table 2.

[0040] In some embodiments, the anti-TCRβV antibody molecule comprises a framework region (FR) having at least 95% identity to all of FR1, FR2, FR3, and FR4 of the humanized BH LC of Table 2.

[0041] In some embodiments, the anti-TCRβV antibody molecule comprises a framework region (FR) having at least 95% identity to one of FR1, FR2, FR3, and FR4 of the humanized BH HC of Table 2.

[0042] In some embodiments, the anti-TCRβV antibody molecule comprises a framework region (FR) having at least 95% identity to any two of FR1, FR2, FR3, and FR4 of the humanized BH HC of Table 2.

[0043] In some embodiments, the anti-TCRβV antibody molecule comprises framework regions (FRs) having at least 95% identity to any three of FR1, FR2, FR3, and FR4 of a humanized BH HC in Table 2.

[0044] In some embodiments, the anti-TCRβV antibody molecule comprises a framework region (FR) having at least 95% identity to all of FR1, FR2, FR3, and FR4 of a humanized BH HC in Table 2.

[0045] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) the HC CDR1, HC CDR2 and HC CDR3 of Antibody C listed in Table 10; or (ii) LC CDR1, LC CDR2, and LC CDR3 of Antibody C listed in Table 10 The antigen-binding domain comprises:

[0046] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two or all (e.g., three) of the HC CDR1, HC CDR2 and HC CDR3 of an antibody C or humanized CH antibody listed in Table 10.

[0047] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a light chain variable region (VL) comprising one, two, or all (e.g., three) of the LC CDR1, LC CDR2, and LC CDR3 of an antibody C or humanized CH antibody listed in Table 10.

[0048] In some embodiments, the anti-TCRβV antibody molecule comprises: a VH sequence of a humanized CH antibody listed in Table 10, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VH of a humanized CH antibody listed in Table 10; and / or A VL sequence of a humanized CH antibody listed in Table 10, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to the VL of a humanized CH antibody listed in Table 10. Includes:

[0049] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) the HC CDR1, HC CDR2 and HC CDR3 of Antibody E listed in Table 11, or (ii) LC CDR1, LC CDR2, and LC CDR3 of Antibody E listed in Table 11 The antigen-binding domain comprises:

[0050] In some embodiments, the anti-TCRβ antibody molecule is an antibody E or a human antibody listed in Table 11. The antibody comprises an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two or all (e.g., three) of HC CDR1, HC CDR2 and HC CDR3 of a modified EH antibody.

[0051] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a light chain variable region (VL) comprising one, two, or all (e.g., three) of the LC CDR1, LC CDR2, and LC CDR3 of antibody E or a humanized EH antibody listed in Table 11.

[0052] In some embodiments, the anti-TCRβV antibody molecule comprises: a VH sequence of a humanized EH antibody listed in Table 11, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VH of a humanized EH antibody listed in Table 11; and / or A VL sequence of a humanized EH antibody listed in Table 11, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VL of a humanized EH antibody listed in Table 11. Includes:

[0053] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) the HC CDR1, HC CDR2 and HC CDR3 of antibody D listed in Table 12, or (ii) LC CDR1, LC CDR2, and LC CDR3 of Antibody D listed in Table 12 The antigen-binding domain comprises:

[0054] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two, or all (e.g., three) of the HC CDR1, HC CDR2, and HC CDR3 of antibody D or a humanized DH antibody listed in Table 12.

[0055] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a light chain variable region (VL) comprising one, two, or all (e.g., three) of the LC CDR1, LC CDR2, and LC CDR3 of antibody D or a humanized DH antibody listed in Table 12.

[0056] In some embodiments, the anti-TCRβV antibody molecule comprises: a VH sequence of a humanized DH antibody listed in Table 12, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VH of a humanized DH antibody listed in Table 12; and / or A VL sequence of a humanized DH antibody listed in Table 12, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VL of a humanized DH antibody listed in Table 12. Includes:

[0057] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) the HC CDR1, HC CDR2 and HC CDR3 of antibody G listed in Table 13, or (ii) LC CDR1, LC CDR2, and LC CDR3 of antibody G listed in Table 13 The antigen-binding domain comprises:

[0058] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two or all (e.g., three) of the HC CDR1, HC CDR2 and HC CDR3 of antibody G or a humanized GH antibody listed in Table 13.

[0059] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a light chain variable region (VL) comprising one, two or all (e.g., three) of the LC CDR1, LC CDR2 and LC CDR3 of antibody G or a humanized GH antibody listed in Table 13.

[0060] In some embodiments, the anti-TCRβV antibody molecule comprises: a VH sequence of a humanized GH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VH of a humanized GH antibody listed in Table 13; and / or A VL sequence of a humanized GH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VL of a humanized GH antibody listed in Table 13. Includes:

[0061] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) the HC CDR1, HC CDR2 and HC CDR3 of antibody H listed in Table 13, or (ii) LC CDR1, LC CDR2, and LC CDR3 of Antibody H listed in Table 13 The antigen-binding domain comprises:

[0062] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two, or all (e.g., three) of the HC CDR1, HC CDR2, and HC CDR3 of an antibody H or humanized HH antibody listed in Table 13.

[0063] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a light chain variable region (VL) comprising one, two, or all (e.g., three) of the LC CDR1, LC CDR2, and LC CDR3 of an antibody H or humanized HH antibody listed in Table 13.

[0064] In some embodiments, the anti-TCRβV antibody molecule comprises: a VH sequence of a humanized HH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VH of a humanized HH antibody listed in Table 13; and / or A VL sequence of a humanized HH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VL of a humanized HH antibody listed in Table 13. Includes:

[0065] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) the HC CDR1, HC CDR2 and HC CDR3 of Antibody I listed in Table 13, or (ii) the LC CDR1, LC CDR2, and LC CDR3 of Antibody I listed in Table 13 DR3 The antigen-binding domain comprises:

[0066] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two, or all (e.g., three) of the HC CDR1, HC CDR2, and HC CDR3 of antibody I or a humanized IH antibody listed in Table 13.

[0067] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a light chain variable region (VL) comprising one, two, or all (e.g., three) of the LC CDR1, LC CDR2, and LC CDR3 of an antibody I or a humanized IH antibody listed in Table 13.

[0068] In some embodiments, the anti-TCRβV antibody molecule comprises: a VH sequence of a humanized IH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VH of a humanized IH antibody listed in Table 13; and / or A VL sequence of a humanized IH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VL of a humanized IH antibody listed in Table 13. Includes:

[0069] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) the HC CDR1, HC CDR2 and HC CDR3 of antibody J listed in Table 13, or (ii) LC CDR1, LC CDR2, and LC CDR3 of Antibody J listed in Table 13 The antigen-binding domain comprises:

[0070] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two, or all (e.g., three) of the HC CDR1, HC CDR2, and HC CDR3 of an antibody J or humanized JH antibody listed in Table 13.

[0071] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a light chain variable region (VL) comprising one, two, or all (e.g., three) of the LC CDR1, LC CDR2, and LC CDR3 of an antibody J or a humanized JH antibody listed in Table 13.

[0072] In some embodiments, the anti-TCRβV antibody molecule comprises: a VH sequence of a humanized JH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VH of a humanized JH antibody listed in Table 13; and / or A VL sequence of a humanized JH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VL of a humanized JH antibody listed in Table 13. Includes:

[0073] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) HC CDR1, HC CDR2 and HC CDRs of Antibody K listed in Table 13 3, or (ii) LC CDR1, LC CDR2, and LC CDR3 of Antibody K listed in Table 13 The antigen-binding domain comprises:

[0074] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two, or all (e.g., three) of the HC CDR1, HC CDR2, and HC CDR3 of an antibody K or humanized KH antibody listed in Table 13.

[0075] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a light chain variable region (VL) comprising one, two, or all (e.g., three) of the LC CDR1, LC CDR2, and LC CDR3 of an antibody K or humanized KH antibody listed in Table 13.

[0076] In some embodiments, the anti-TCRβV antibody molecule comprises: a VH sequence of a humanized GH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to the VH of a humanized KH antibody listed in Table 13; and / or A VL sequence of a humanized GH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to the VL of a humanized KH antibody listed in Table 13. Includes:

[0077] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) the HC CDR1, HC CDR2 and HC CDR3 of antibody L listed in Table 13, or (ii) the LC CDR1, LC CDR2, and LC CDR3 of antibody L listed in Table 13 The antigen-binding domain comprises:

[0078] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two or all (e.g., three) of the HC CDR1, HC CDR2 and HC CDR3 of an antibody L or humanized LH antibody listed in Table 13.

[0079] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a light chain variable region (VL) comprising one, two or all (e.g., three) of the LC CDR1, LC CDR2 and LC CDR3 of an antibody L or a humanized LH antibody listed in Table 13.

[0080] In some embodiments, the anti-TCRβV antibody molecule comprises: a VH sequence of a humanized LH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VH of a humanized LH antibody listed in Table 13; and / or A VL sequence of a humanized LH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VL of a humanized LH antibody listed in Table 13. Includes:

[0081] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) the HC CDR1, HC CDR2 and HC CDR3 of Antibody M listed in Table 13, or (ii) the LC CDR1, LC CDR2, and LC CDR3 of Antibody M listed in Table 13 The antigen-binding domain comprises:

[0082] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two or all (e.g., three) of the HC CDR1, HC CDR2 and HC CDR3 of antibody M or a humanized MH antibody listed in Table 13.

[0083] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a light chain variable region (VL) comprising one, two or all (e.g., three) of the LC CDR1, LC CDR2 and LC CDR3 of antibody M or a humanized MH antibody listed in Table 13.

[0084] In some embodiments, the anti-TCRβV antibody molecule comprises: a VH sequence of a humanized MH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VH of a humanized MH antibody listed in Table 13; and / or A VL sequence of a humanized MH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VL of a humanized MH antibody listed in Table 13. Includes:

[0085] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) the HC CDR1, HC CDR2 and HC CDR3 of Antibody N listed in Table 13, or (ii) LC CDR1, LC CDR2, and LC CDR3 of Antibody N listed in Table 13 The antigen-binding domain comprises:

[0086] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two, or all (e.g., three) of the HC CDR1, HC CDR2, and HC CDR3 of antibody N or a humanized NH antibody listed in Table 13.

[0087] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a light chain variable region (VL) comprising one, two, or all (e.g., three) of the LC CDR1, LC CDR2, and LC CDR3 of antibody N or a humanized NH antibody listed in Table 13.

[0088] In some embodiments, the anti-TCRβV antibody molecule comprises: a VH sequence of a humanized NH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VH of a humanized NH antibody listed in Table 13; and / or A VL sequence of a humanized NH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VL of a humanized NH antibody listed in Table 13. Includes:

[0089] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) the HC CDR1, HC CDR2 and HC CDR3 of Antibody O listed in Table 13, or (ii) the LC CDR1, LC CDR2, and LC CDR3 of Antibody O listed in Table 13 The antigen-binding domain comprises:

[0090] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two, or all (e.g., three) of the HC CDR1, HC CDR2, and HC CDR3 of antibody O or a humanized OH antibody listed in Table 13.

[0091] In some embodiments, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a light chain variable region (VL) comprising one, two, or all (e.g., three) of the LC CDR1, LC CDR2, and LC CDR3 of antibody O or a humanized OH antibody listed in Table 13.

[0092] In some embodiments, the anti-TCRβV antibody molecule comprises: a VH sequence of a humanized OH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VH of a humanized OH antibody listed in Table 13; and / or A VL sequence of a humanized OH antibody listed in Table 13, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VL of a humanized OH antibody listed in Table 13. Includes:

[0093] In another aspect, the present disclosure provides non-murine, e.g., human-like, antibody molecules (e.g., human or humanized antibody molecules) that bind, e.g., specifically bind, to the T cell receptor beta variable (TCRβV) region. In some embodiments, binding of the anti-TCRβV antibody molecule results in an expansion, e.g., at least about 1.1-50 fold expansion (e.g., at least about 1.5-40 fold, 2-35 fold, 3-30 fold, 5-25 fold, 8-20 fold, or 10-15 fold expansion), of a T cell population, e.g., T cells with a memory-like phenotype, e.g., a CD45RA+ CCR7- T cell population. In some embodiments, the T cell population with a memory-like phenotype comprises CD4+ and / or CD8+ T cells. In some embodiments, the T cell population with a memory-like phenotype comprises memory T cells, e.g., T effector memory (T EM ) cells, e.g., T cells expressing CD45RA EM Cell (T EMRA ) cells, e.g., CD4+ or CD8+ T cells EMRA In some embodiments, the T cell population with a memory-like phenotype does not express a senescence marker, such as CD57. In some embodiments, the T cell population with a memory-like phenotype does not express an inhibitory receptor, such as OX40, 4-1BB, and / or ICOS.

[0094] In some embodiments, the T cell population with a memory-like phenotype is a CD45RA+ CCR7- CD57- T cell population. In some embodiments, the T cell population with a memory-like phenotype does not express inhibitory receptors, e.g., OX40, 4-1BB, and / or ICOS.

[0095] In some embodiments, a population of T cells having a memory-like phenotype, e.g., as described herein, can be compared to a reference cell population, e.g., a population of T cells that have not been contacted with an anti-TCRβV antibody. have increased proliferative capacity compared to similar cell populations.

[0096] In some embodiments, the expansion is at least about 1.1 to 10-fold expansion (e.g., at least about 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold expansion).

[0097] In some embodiments, T cells with a memory-like phenotype, e.g., memory effector T cells, e.g., T EM Cells, e.g., T EMRA cells, e.g., CD4+ or CD8+ T cells EMRA The expansion of the cell population is compared to the expansion of a similar cell population using an antibody that binds to a CD3 molecule, eg, a CD3 epsilon (CD3e) molecule, or a TCR alpha (TCRα) molecule.

[0098] In some embodiments, the expanded T cells with a memory-like phenotype, e.g., a T effector memory cell population, comprise T cells, e.g., CD3+, CD8+, or CD4+ T cells. In some embodiments, the expanded T cells with a memory-like phenotype, e.g., a T effector memory cell population, comprise CD3+ and CD8+ T cells. In some embodiments, the expanded T cells with a memory-like phenotype, e.g., a T effector memory cell population, comprise CD3+ and CD4+ T cells.

[0099] In some embodiments, expanded T cells with a memory-like phenotype, T effector memory (T EM ) The cell population comprises T cells, e.g., CD3+, CD8+, or CD4+ T cells, that express or re-express CD45RA, e.g., CD45RA+. In some embodiments, the population comprises CD45RA-expressing T EM Cells, e.g., T EMRAIn some embodiments, the T EMRA cells, e.g., CD4+ or CD8+ T cells EMRA Expression of CD45RA on cells can be detected by methods disclosed herein, for example, flow cytometry.

[0100] In some embodiments, T cells with a memory-like phenotype, e.g., T EMRA The cell population may have low or no expression of CCR7, e.g., CCR7- or CCR7 In some embodiments, T EMRA Expression of CCR7 on cells cannot be detected by the methods disclosed herein, for example, flow cytometry.

[0101] In some embodiments, T cells with a memory-like phenotype, e.g., T EMRA The cell population expresses CD95, e.g., is CD95+. In some embodiments, the T EMRA Expression of CD95 on cells can be detected by methods disclosed herein, for example, flow cytometry.

[0102] In some embodiments, T cells with a memory-like phenotype, e.g., T EMRA The cell population expresses CD45RA, e.g., CD45RA+, has low or no CCR7 expression, e.g., CCR7- or CCR7 low, and expresses CD95, e.g., CD95+. In some embodiments, T cells with a memory-like phenotype, e.g., T EMRA The cell population may be identified as CD45RA+, CCR7-, and CD95+ cells. In some embodiments, T cells with a memory-like phenotype, e.g., T EMRA The cell population includes CD3+, CD4+, or CD8+ T cells (e.g., CD3+ T cells, CD3+ CD8+ T cells, or CD3+ CD4+ T cells).

[0103] In some embodiments, the T cell population with a memory-like phenotype does not express a senescence marker, for example, CD57. In some embodiments, the T cell population having a memory-like phenotype is a T cell that is capable of expressing an inhibitory receptor, e.g., Does not express OX40, 4-1BB, and / or ICOS.

[0104] In some embodiments, binding of the anti-TCRβV antibody molecule results in an expansion of a subpopulation of T cells, e.g., at least about a 1.1-50 fold expansion (e.g., at least about a 1.5-40 fold, 2-35 fold, 3-30 fold, 5-25 fold, 8-20 fold, or 10-15 fold expansion). In some embodiments, the subpopulation of T cells activated (e.g., expanded) by the anti-TCRβV antibody molecule exhibits a higher T cell population in terms of higher expression of CD45RA and / or lower expression of CCR7. EMRAIn some embodiments, a subpopulation of T cells activated (e.g., expanded) by anti-TCRβV antibody molecules does not exhibit upregulation of the senescence markers CD57 and / or KLRG1. In some embodiments, a subpopulation of T cells activated (e.g., expanded) by anti-TCRβV antibody molecules does not exhibit upregulation of the costimulatory molecules CD27 and / or CD28. In some embodiments, a subpopulation of T cells activated (e.g., expanded) by anti-TCRβV antibody molecules is highly proliferative. In some embodiments, a subpopulation of T cells activated (e.g., expanded) by anti-TCRβV antibody molecules secretes IL-2. In some embodiments, the expression of surface markers on T cells can be detected by methods disclosed herein, e.g., flow cytometry. In some embodiments, the proliferative capacity of T cells can be detected by methods disclosed herein, e.g., the method described in Example 4. In some embodiments, cytokine expression of T cells can be detected by methods disclosed herein, e.g., the method described in Examples 10 and 21. In some embodiments, the expansion is at least about a 1.1-10 fold expansion (e.g., at least about a 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold expansion). In some embodiments, the expansion is compared to the expansion of a similar cell population using an antibody that binds to a CD3 molecule, e.g., a CD3 epsilon (CD3e) molecule, or a TCR alpha (TCRα) molecule.

[0105] In some embodiments, the binding of the anti-TCRβV antibody molecule to the TCRβV region, compared to an antibody that binds a CD3 molecule, e.g., a CD3 epsilon (CD3e) molecule, or a TCR alpha (TCRα) molecule, is as follows: (i) a reduction in the level, e.g., expression level, and / or activity of IL-1β; (ii) a reduction in the level, e.g., expression level, and / or activity, of IL-6; (iii) a reduction in the level, e.g., expression level, and / or activity of TNFα; (iv) an increase in the level, e.g., expression level, and / or activity, of IL-2; (v) a delay in the increase in the level, e.g., expression level, and / or activity of IL-2, e.g., a delay of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or more; (vi) a delay in the increase in the level, e.g., expression level, and / or activity of IFNg, e.g., a delay of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours; (vii) reduced T cell proliferation kinetics; (viii) a reduction in cytokine storm, e.g., cytokine release syndrome (CRS) and / or neurotoxicity (NT), e.g., as measured by the assay of Example 3; (ix) cell killing, e.g., target cell killing, e.g., cancer cell killing, e.g., as measured by the assay of Example 4; (x) an increase in the level, e.g., expression level, and / or activity of IL-15, or (xi) an increase in natural killer (NK) cell proliferation, e.g., expansion. yielding one, two, three, four, five, six, seven, eight, nine, ten, or more (e.g., all) of the

[0106] In some embodiments of any of the compositions disclosed herein, binding of the anti-TCRβV antibody molecule to the TCRβV region results in a 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or 200-fold, or at least a 2- to 200-fold (e.g., 5- to 150-fold, 10- to 100-fold, 20- to 50-fold) reduction in IL-1β expression levels and / or activity as measured by the assay of Example 3.

[0107] In some embodiments of any of the compositions disclosed herein, binding of the anti-TCRβV antibody molecule to the TCRβV region results in a 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold, or at least 2- to 1000-fold (e.g., 5- to 900-fold, 10- to 800-fold, 20- to 700-fold, 50- to 600-fold, 100- to 500-fold, or 200- to 400-fold) reduction in IL-6 expression levels and / or activity as measured by the assay of Example 3.

[0108] In some embodiments of any of the compositions disclosed herein, binding of the anti-TCRβV antibody molecule to the TCRβV region is at least 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 60-fold, or greater than the expression level and / or activity of TNFα, as measured by the assay of Example 3. or less, or at least 2-2000 fold (e.g., 5-1000 fold, 10-900 fold, 20-800 fold, 50-700 fold, 100-600 fold, 200-500 fold, or 300-400 fold).

[0109] In some embodiments of any of the compositions disclosed herein, binding of the anti-TCRβV antibody molecule to the TCRβV region results in an increase in IL-2 expression level and / or activity by at least 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1000-fold, or 2000-fold, or at least 2-2000-fold (e.g., 5-1000-fold, 10-900-fold, 20-800-fold, 50-700-fold, 100-600-fold, 200-500-fold, or 300-400-fold), as measured by the assay of Example 3.

[0110] In some embodiments of any of the compositions disclosed herein, binding of the anti-TCRβV antibody molecule to the TCRβV region results in at least a 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1000-fold, or 2000-fold, or at least a 2- to 2000-fold (e.g., 5- to 1000-fold, 10- to 900-fold, 20- to 800-fold, 50- to 700-fold, 100- to 600-fold, 200- to 500-fold, or 300- to 400-fold) increase in IL-15 expression level and / or activity as measured by the assay of Example 4.

[0111] In some embodiments of any of the compositions disclosed herein, binding of the anti-TCRβV antibody molecule results in proliferation, e.g., expansion, e.g., at least about a 1.1-50 fold expansion (e.g., at least about a 1.5-40 fold, 2-35 fold, 3-30 fold, 5-25 fold, 8-20 fold, or 10-15 fold expansion) of a natural killer (NK) cell population. In some embodiments, the expansion of NK cells results in at least about a 1.1-30 fold expansion (e.g., at least about a 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, or at least about 1.1-5-fold, 5-10-fold, 10-15-fold, 15-20-fold, 20-25-fold, or 25-30-fold expansion). In some embodiments, NK cell expansion is measured by the assay of Example 4. In some embodiments, NK cell expansion by, e.g., by binding of, an anti-TCRβV antibody molecule is compared to expansion of an otherwise similar population not contacted with the anti-TCRβV antibody molecule.

[0112] In some embodiments of any of the compositions disclosed herein, binding of the anti-TCRβV antibody molecule results in cell killing, e.g., targeted cell killing, e.g., cancer cell killing. In some embodiments, the cancer cell is a blood cancer cell or a solid tumor cell. In some embodiments, the cancer cell is a multiple myeloma cell. In some embodiments, binding of the anti-TCRβV antibody molecule results in cell killing in vitro or in vivo. In some embodiments, cell killing is measured by the assay of Example 4.

[0113] In some embodiments of any of the compositions disclosed herein, the binding of the anti-TCRβ antibody molecule to the TCRβ region is at least 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1000-fold, or 2000-fold, or at least 2-2000-fold (e.g., 5-1000-fold, 10-900-fold, 20-800-fold, 50-700-fold, 100-600-fold, 200- or a decrease of 2-fold or more, 5-fold or more, 10-fold or more, 20-fold or more, 50-fold or more, 100-fold or more, 200-fold or less, 300-fold or less, 400-fold or less, 500-fold or less, 600-fold or less, 700-fold or less, 800-fold or less, 900-fold or less, 1000-fold or less, or 2000-fold or more (e.g., 5-1000-fold or less, 10-900-fold or less, 20-800-fold or less, 50-700-fold or less, 100-600-fold or less, 200-500-fold or less, or 300-400-fold or more).

[0114] In one embodiment, an antibody molecule that binds to, e.g., specifically binds to, a T cell receptor beta variable chain (TCRβV) region (an anti-TCRβV antibody molecule), (i) specifically binds to an epitope on TCRβV, e.g., an epitope that is the same as or similar to an epitope recognized by an anti-TCRβV antibody molecule described herein, e.g., a second anti-TCRβV antibody molecule; (ii) exhibits the same or similar binding affinity or specificity, or both, as an anti-TCRβ antibody molecule described herein, e.g., a second anti-TCRβ antibody molecule; (iii) inhibits, e.g., competitively inhibits, binding of an anti-TCRβ antibody molecule described herein, e.g., a second anti-TCRβ antibody molecule; (iv) binds to the same or overlapping epitope as an anti-TCRβ antibody molecule described herein, e.g., a second anti-TCRβ antibody molecule; or (v) competes for binding with and / or binds to the same epitope as an anti-TCRβ antibody molecule described herein, e.g., a second anti-TCRβ antibody molecule; Antibody molecules are provided herein.

[0115] In some embodiments, the second anti-TCRβ antibody molecule comprises an antigen-binding domain selected from Table 1 or Table 2, or a sequence substantially identical thereto. In some embodiments, the second anti-TCRβ antibody molecule comprises: Heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and / or heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 1 or SEQ ID NO: 9 3), and / or light chain complementarity determining region 1 (LC CDR1), light chain complementarity determining region 2 (LC CDR2), and / or light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO:2, SEQ ID NO:10, or SEQ ID NO:11 The antigen-binding domain comprises:

[0116] In some embodiments of any of the compositions disclosed herein, binding of the anti-TCRβV antibody molecule to the TCRβV region results in a differential change, e.g., at least a 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold increase, or a 2-fold, 5-fold, 10-fold, 20-fold, or 100-fold decrease, in any (e.g., one, two, three, four, or all) of (i) to (v) compared to the activity of the 16G8 or TM23 murine antibody, or a humanized version thereof, described in U.S. Patent No. 5,861,155.

[0117] In some embodiments of any of the compositions disclosed herein, the anti-TCRβV antibody molecule binds to a TCRBV family (e.g., gene family), e.g., a TCRBV gene family, including, by way of example, the subfamilies described herein. In some embodiments, the TCRBV family, e.g., gene family, is selected from the group consisting of TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, TCRβ V29 subfamily, TCRβ V23 subfamily, TCRβ V21 subfamily, TCRβ V1 subfamily, TCRβ V17 subfamily, or TCRβ V26 subfamily.

[0118] In some embodiments, the anti-TCRβV antibody binds to a TCRβ V6 subfamily selected from TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01, or TCRβ V6-1*01. In some embodiments, the TCRβ V6 subfamily includes TCRβ V6-5*01.

[0119] In some embodiments, the anti-TCRβV antibody binds to a TCRβ V10 subfamily selected from TCRβ V10-1*01, TCRβ V10-1*02, TCRβ V10-3*01, or TCRβ V10-2*01.

[0120] In some embodiments, the anti-TCRβV antibody binds to a TCRβ V12 subfamily selected from TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01.

[0121] In some embodiments of any of the compositions disclosed herein, the anti-TCRβ antibody molecule does not bind to TCRβ V12 or binds to TCRβ V12 with an affinity and / or binding specificity that is less (e.g., less than about 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, or less than about half-, five-, or ten-fold less) than the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155. β Binds to V12.

[0122] In some embodiments of any of the compositions disclosed herein, the anti-TCRβ antibody molecule binds to TCRβ V12 with an affinity and / or binding specificity that exceeds (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 2-fold, 5-fold, or 10-fold greater) than that of the 16G8 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155.

[0123] In some embodiments of any of the compositions disclosed herein, the anti-TCRβ antibody molecule binds to a TCRβ V region other than TCRβ V12 (e.g., a TCRβ V region described herein, e.g., the TCRβ V6 subfamily (e.g., TCRβ V6-5*01)) with an affinity and / or binding specificity that exceeds (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 2-fold, 5-fold, or 10-fold greater than) the affinity and / or binding specificity of the 16G8 murine antibody described in U.S. Pat. No. 5,861,155, or a humanized version thereof.

[0124] In some embodiments of any of the compositions disclosed herein, the anti-TCRβV antibody molecule does not comprise at least one CDR of antibody B. In some embodiments of any of the compositions disclosed herein, the anti-TCRβV antibody molecule does not comprise a CDR of antibody B.

[0125] In some embodiments of any of the compositions disclosed herein, the anti-TCRβV antibody binds to a TCRβ V5 subfamily selected from TCRβ V5-5*01, TCRβ V5-6*01, TCRβ V5-4*01, TCRβ V5-8*01, and TCRβ V5-1*01.

[0126] In some embodiments of any of the compositions disclosed herein, the anti-TCRβV antibody binds to a TCRβ V5 subfamily selected from TCRβ V5-5*01, TCRβ V5-6*01, TCRβ V5-4*01, TCRβ V5-8*01, and TCRβ V5-1*01.

[0127] In some embodiments of any of the compositions disclosed herein, the anti-TCRβ antibody molecule does not bind to TCRβ V5-5*01 or TCRβ V5-1*01, or binds to TCRβ V5-5*01 or TCRβ V5-1*01 with an affinity and / or binding specificity that is less (e.g., less than about 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, or less than about half-, five-, or ten-fold less) than the affinity and / or binding specificity of the TM23 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155.

[0128] In some embodiments of any of the compositions disclosed herein, the anti-TCRβ antibody molecule binds to TCRβ V5-5*01 or TCRβ V5-1*01 with an affinity and / or binding specificity that exceeds (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 2-fold, 5-fold, or 10-fold greater) than that of the TM23 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155.

[0129] In some embodiments of any of the compositions disclosed herein, the anti-TCRβV antibody molecule is the TM23 murine antibody described in U.S. Pat. No. 5,861,155 or binds to a TCRβ V region other than TCRβ V5-5*01 or TCRβ V5-1*01 (e.g., a TCRβ V region described herein, e.g., the TCRβ V6 subfamily (e.g., TCRβ V6-5*01)) with an affinity and / or binding specificity that exceeds (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 2-fold, 5-fold, or 10-fold greater than) that of the humanized version.

[0130] In some embodiments of any of the compositions disclosed herein, the anti-TCRβV antibody molecule does not comprise at least one CDR of the TM23 murine antibody. In some embodiments of any of the compositions disclosed herein, the anti-TCRβV antibody molecule does not comprise a CDR of the TM23 murine antibody.

[0131] In some embodiments of any of the compositions disclosed herein, the anti-TCRβV antibody molecule disclosed herein does not include the sequence of the mouse anti-rat TCR antibody R73, e.g., as disclosed in J Exp Med. 1989 Jan 1;169(1):73-86, which is incorporated herein by reference in its entirety. In some embodiments of any of the compositions disclosed herein, the multispecific antibody molecule disclosed herein does not include the sequence of the mouse anti-rat TCR antibody R73, e.g., as disclosed in J Immunol. 1993 Mar 15;150(6):2305-15, which is incorporated herein by reference in its entirety.

[0132] In some embodiments of any of the compositions disclosed herein, the anti-TCRβV antibody molecule disclosed herein is selected from the group consisting of antibodies, e.g., those described in Oncoimmunology. 2016; 5(1): e1052930, which is incorporated herein by reference in its entirety. In some embodiments of any of the compositions disclosed herein, the multispecific antibody molecule disclosed herein does not comprise a viral peptide-MHC complex, for example, as disclosed in Oncoimmunology. 2016; 5(1): e1052930, which is incorporated herein by reference in its entirety.

[0133] In some embodiments of any of the compositions disclosed herein, the anti-TCRβV antibody molecule is selected from the following TCRβV subfamilies: (i) a TCRβ fragment, including, for example, one or more of 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; V6 subfamily, (ii) For example, TCRβ V10-1*01, TCRβ V10-1*02, TCRβ TCRβ V10 subfamily, including one or more of TCRβ V10-3*01, or TCRβ V10-2*01; (iii) the TCRβ V5 subfamily, including, for example, one or more of TCRβ V5-6*01, TCRβ V5-4*01, or TCRβ V5-8*01; (iv) the TCRβ V12 subfamily, including, for example, one or more of TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01; (v) For example, TCRβ V7-7*01, TCRβ V7-6*01, TCRβ V7 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, Rβ V7 subfamily, (vi) the TCRβ V11 subfamily, including, for example, one or more of TCRβ V11-1*01, TCRβ V11-2*01, or TCRβ V11-3*01; (vii) the TCRβ V14 subfamily, including TCRβ V14*01; (viii) TCRβ V16 subfamily, including TCRβ V16*01; (ix) TCRβ V18 subfamily, including TCRβ V18*01; (x) the TCRβ V9 subfamily, including, for example, one or more of TCRβ V9*01 or TCRβ V9*02; (xi) TCRβ V13 subfamily, including TCRβ V13*01; (xii) the TCRβ V4 subfamily, including, for example, one or more of TCRβ V4-2*01, TCRβ V4-3*01, or TCRβ V4-1*01; (xiii) TCRβ V3 subfamily, including TCRβ V3-1*01; (xiv) TCRβ V2 subfamily, including TCRβ V2*01; (xv) TCRβ V15 subfamily, including TCRβ V15*01; (xvi) the TCRβ V30 subfamily, including, for example, one or more of TCRβ V30*01 or TCRβ V30*02; (xvii) the TCRβ V19 subfamily, including, for example, one or more of TCRβ V19*01 or TCRβ V19*02; (xviii) TCRβ V27 subfamily, including TCRβ V27*01; (xix) TCRβ V28 subfamily, including TCRβ V28*01; (xx) TCRβ V24 subfamily, including TCRβ V24-1*01; (xxi) the TCRβ V20 subfamily, including, for example, one or more of TCRβ V20-1*01 or TCRβ V20-1*02; (xxii) the TCRβ V25 subfamily, including TCRβ V25-1*01; or (xxiii) TCRβ V29 subfamily, including TCRβ V29-1*01; (xxiv) TCRβ V21 subfamily; (xxv) TCRβ V1 subfamily, (xxvi) TCRβ V17 subfamily, (xvii) TCRβ V23 subfamily, or (xviii) TCRβ V26 subfamily Binds to one or more (e.g., all) of

[0134] In some embodiments of any of the compositions disclosed herein, the anti-TCRβV antibody molecule is selected from the following TCRβV subfamilies: (i) TCRβ V6, e.g., one or more of 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; (ii) TCRβ V10, e.g., one or more of TCRβ V10-1*01, TCRβ V10-1*02, TCRβ V10-3*01, or TCRβ V10-2*01; (iii) TCRβ V12, e.g., one or more of TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01; or (iv) TCRβ V5, e.g., one or more of TCRβ V5-5*01, TCRβ V5-6*01, TCRβ V5-4*01, TCRβ V5-8*01, TCRβ V5-1*01 Binds to one or more (e.g., all) of

[0135] In some embodiments, the anti-TCRβ antibody molecule binds to TCRβ V6, e.g., one or more of TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01, or TCRβ V6-1*01. In some embodiments, the anti-TCRβ antibody molecule binds to TCRβ V6-5*01.

[0136] In some embodiments, the anti-TCRβV antibody molecule does not bind to TCRβ V12. In some embodiments, the anti-TCRβV antibody molecule does not bind to TCRβ V5-5*01 or TCRβ V5-1*01.

[0137] In certain aspects, provided herein are multispecific molecules (e.g., bispecific molecules) that comprise a first portion (e.g., a first immune cell engager) that comprises an antibody molecule that binds to (e.g., specifically binds to) a T cell receptor beta variable region (TCRβV) (an "anti-TCRβV antibody molecule").

[0138] In some embodiments, the multispecific molecule comprises a second portion that comprises one or more of a tumor-targeting moiety, a cytokine molecule, a stromal-modifying moiety, or an anti-TCRβV antibody molecule other than the first portion.

[0139] In some embodiments, binding of the first portion to the TCRβV region results in a cytokine profile, e.g., a cytokine secretion profile, that differs from that of a T cell engager that binds to a receptor or molecule other than the TCRβV region (a "non-TCRβV-binding T cell engager").

[0140] In another aspect, the present disclosure provides multispecific, e.g., bispecific, molecules comprising the anti-TCRβV antibody molecules disclosed herein. In some embodiments, the multispecific molecule further comprises a tumor-targeting moiety, a cytokine molecule, an immune cell engager, eg, a second immune cell engager, and / or a stromal-modifying moiety.

[0141] In yet another aspect, (i) a first portion comprising a first immune cell engager comprising an anti-TCRβV antibody molecule disclosed herein; and (ii) a second moiety comprising one or more of a tumor-targeting moiety, a second immune cell engager, a cytokine molecule, or a stromal-modifying moiety; Disclosed herein are multispecific, e.g., bispecific, molecules comprising:

[0142] In another aspect, the present disclosure provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding an anti-TCRβV antibody molecule disclosed herein, or a nucleotide sequence having at least 75%, 80%, 85%, 90%, 95%, or 99% identity thereto.

[0143] In another aspect, the disclosure provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding a multispecific molecule disclosed herein, or a nucleotide sequence having at least 75%, 80%, 85%, 90%, 95%, or 99% identity thereto.

[0144] In yet another aspect, the present disclosure provides a method for producing a TCRβ antibody molecule encoding the anti-TCRβ antibody molecule disclosed herein.

[0013] The present invention provides vectors, e.g., expression vectors, comprising a nucleotide sequence identical to, or having at least 75%, 80%, 85%, 90%, 95%, or 99% identity thereto.

[0145] In another aspect, the disclosure provides a vector, e.g., an expression vector, comprising a nucleotide sequence encoding a multispecific molecule disclosed herein, or a nucleotide sequence having at least 75%, 80%, 85%, 90%, 95%, or 99% identity thereto.

[0146] In one aspect, the present disclosure provides a cell, e.g., a host cell, e.g., a population of cells, comprising a nucleic acid molecule encoding an anti-TCRβV antibody molecule disclosed herein, or a nucleotide sequence having at least 75%, 80%, 85%, 90%, 95%, or 99% identity thereto. In some embodiments, a cell or cell population comprising a nucleic acid molecule encoding an anti-TCRβV antibody molecule comprises (i) a heavy chain comprising a variable region (VH), e.g., a VH listed in Tables 1-2 or 10-13, or a sequence having at least 75%, 80%, 85%, 90%, 95%, or 99% identity thereto, and one or more heavy chain constant regions, e.g., as described herein, and / or (ii) a light chain comprising a variable region (VL), e.g., a VL listed in Tables 1-2 or 10-13, or a sequence having at least 75%, 80%, 85%, 90%, 95%, or 99% identity thereto, and a light chain constant region, e.g., as described herein, e.g., a kappa chain constant region comprising the sequence of SEQ ID NO: 39, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto. In some embodiments, the cell or cell population further comprises an IgJ heavy chain constant region, or a fragment thereof. In some embodiments, the IgJ heavy chain constant region comprises the sequence of SEQ ID NO: 76, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto. In some embodiments, the IgJ is contained in, e.g., expressed in, the same cell or cell population that comprises, e.g., expresses, the heavy and / or light chain of the anti-TCRβV antibody molecule, e.g., the anti-TCRβV antibody molecule. In some embodiments, the IgJ is expressed in a cell or cell population that is different from the cell or cell population that comprises, e.g., expresses, the heavy and / or light chain of the anti-TCRβV antibody molecule, e.g., the anti-TCRβV antibody molecule.

[0147] In one aspect, the present disclosure provides a cell, e.g., a host cell, e.g., a population of cells, comprising a nucleic acid molecule encoding a multispecific molecule disclosed herein, or a nucleotide sequence having at least 75%, 80%, 85%, 90%, 95%, or 99% identity thereto.

[0148] In one aspect, disclosed herein is an anti-TCRβV antibody molecule for use in the manufacture of a medicament for treating a disease, e.g., cancer, in a subject. In one aspect, disclosed herein is a multispecific molecule comprising an anti-TCRβV antibody molecule for use in the manufacture of a medicament for treating a disease, e.g., cancer, in a subject.

[0149] In another aspect, the disclosure provides methods of making, e.g., producing, an anti-TCRβV antibody molecule, a multispecific molecule described herein, comprising culturing a host cell described herein under suitable conditions. In some embodiments of the methods of making a multispecific molecule, the conditions include, e.g., conditions suitable for gene expression and / or homo- or heterodimerization.

[0150] In another aspect, the present disclosure provides a pharmaceutical composition comprising an anti-TCRβV antibody molecule or multispecific molecule described herein and a pharmaceutically acceptable carrier, excipient, or stabilizer.

[0151] In certain aspects, the present disclosure provides a method of modulating, e.g., enhancing, an immune response in a subject, the method comprising administering to the subject an effective amount of an antibody molecule that binds (e.g., specifically binds) to a T cell receptor beta variable region (TCRβV) (an "anti-TCRβV antibody molecule").

[0152] In certain aspects, the present disclosure provides a method of modulating, e.g., enhancing, an immune response in a subject, comprising administering to the subject an effective amount of a multispecific molecule disclosed herein.

[0153] In some embodiments, the method includes expanding a population of immune cells, e.g., increasing their number, in the subject. In certain aspects, the present disclosure provides methods for expanding, e.g., increasing the number of, an immune cell population, comprising contacting the immune cell population with an effective amount of an antibody molecule that binds (e.g., specifically binds) to a T cell receptor beta variable region (TCRβV) (an "anti-TCRβV antibody molecule").

[0154] In certain aspects, the present disclosure provides methods of expanding, e.g., increasing the number of, an immune cell population, comprising contacting the immune cell population with an effective amount of a multispecific molecule disclosed herein.

[0155] In some embodiments, expansion occurs in vivo or ex vivo (eg, in vitro). In some embodiments, the immune cell population comprises cells that express TCRβV, e.g., TCRβV+ cells.

[0156] In some embodiments, the TCRβV-expressing cell is a T cell, eg, a CD8+ T cell, a CD3+ T cell, or a CD4+ T cell. In some embodiments, the immune cell population comprises T cells (e.g., CD4 T cells or CD8 T cells). In some embodiments, the immune cell population comprises T cells with a memory-like phenotype, e.g., CD45RA+ CCR7-. In some embodiments, the immune cell population comprises effector T cells or memory T cells (e.g., memory effector T cells (e.g., TEM cells, e.g., TEMRA cells), or tumor-infiltrating lymphocytes (TILs)).

[0157] In some embodiments, the immune cell population comprises T cells, natural killer cells, B cells, or myeloid cells. In some embodiments, the immune cell population is obtained from a healthy subject.

[0158] In certain aspects, provided herein are methods of treating a disease, e.g., cancer, in a subject, comprising administering to the subject an effective amount, e.g., a therapeutically effective amount, of an anti-TCRβ antibody molecule or a multispecific molecule comprising an anti-TCRβ antibody molecule disclosed herein, thereby treating the disease.

[0159] In a related aspect, provided herein is a composition comprising an anti-TCRβV antibody molecule or a multispecific molecule comprising an anti-TCRβV antibody molecule disclosed herein for use in treating a disease, e.g., cancer, in a subject.

[0160] In some embodiments, the disease is cancer, e.g., a solid tumor, or a hematological cancer, or a metastatic lesion. In some embodiments, the method further comprises administering a second agent, e.g., a therapeutic agent, e.g., as described herein. In some embodiments, the second agent comprises a therapeutic agent (e.g., a chemotherapeutic agent, a biological agent, a hormone therapy), radiation, or surgery. In some embodiments, the therapeutic agent is selected from a chemotherapeutic agent or a biological agent.

[0161] In another aspect, provided herein is a method of targeting, e.g., directing or redirecting, therapy, e.g., treatment, to T cells, e.g., in a subject having, e.g., a disease, e.g., cancer, comprising administering an effective amount of (i) an anti-TCRβ antibody disclosed herein, and (ii) e.g., a therapy described herein, e.g., a tumor-targeted therapy (e.g., an antibody that binds to a cancer antigen), thereby targeting T cells.

[0162] In some embodiments, (i) and (ii) are conjugated, eg, linked. In some embodiments, (i) and (ii) are administered simultaneously or concurrently.

[0163] In some embodiments, the method results in (ii) a reduction in cytokine release syndrome (CRS) (e.g., shorter duration or absence of CRS) or a reduction in severity of CRS (e.g., absence of severe CRS, e.g., CRS grade 4 or 5) compared to administration alone. In some embodiments, CRS is assessed by the assay of Example 3. In some embodiments, the method results in (ii) a reduction in neurotoxicity (NT) (e.g., shorter duration or absence of NT) or a reduction in severity of NT (e.g., absence of severe NT) compared to administration alone.

[0164] In yet another aspect, the present disclosure provides a method of targeting T cells, e.g., in a subject having a disease, e.g., cancer, using an anti-TCRβ antibody disclosed herein or a multispecific molecule comprising an anti-TCRβ antibody disclosed herein.

[0165] In another aspect, the present disclosure provides a method of treating, e.g., preventing or reducing, cytokine release syndrome (CRS) and / or neurotoxicity (NT), e.g., CRS and / or NT associated with a treatment, e.g., a previously administered treatment, in a subject, comprising administering to the subject an effective amount of an anti-TCRβ antibody disclosed herein or a multispecific molecule comprising an anti-TCRβ antibody disclosed herein, wherein the subject has a disease, e.g., cancer, thereby treating, e.g., preventing or reducing CRS and / or NT in the subject.

[0166] In a related aspect, the present disclosure provides a composition comprising an anti-TCRβ antibody disclosed herein or a multispecific molecule comprising an anti-TCRβ antibody disclosed herein for use in treating, e.g., preventing or reducing, cytokine release syndrome (CRS) and / or neurotoxicity (NT), e.g., CRS and / or NT associated with a previously administered treatment, in a subject, comprising administering to the subject an effective amount of an anti-TCRβ antibody, wherein the subject has a disease, e.g., cancer.

[0167] In some embodiments of the methods or compositions for use disclosed herein, the anti-TCRβV antibody is administered concurrently with or following administration of a treatment associated with CRS and / or NT.

[0168] In another aspect, a method of expanding, e.g., increasing the number of, a population of immune cells is provided, comprising: binding the population of immune cells to an antibody molecule, e.g., a humanized antibody molecule (e.g., a humanized antibody molecule described herein), that binds, e.g., specifically binds, a T cell receptor beta variable chain (TCRβV) region. Provided herein are methods for expanding an immune cell population, comprising contacting the immune cell population with an anti-TCRβ antibody molecule or a multispecific molecule comprising an anti-TCRβ antibody molecule described herein.

[0169] In some embodiments, expansion occurs in vivo or ex vivo (eg, in vitro). In one aspect, provided herein is a method of assessing a subject having cancer, comprising obtaining a value for TCRβV molecule status for the subject, wherein the value comprises a measure of the presence, e.g., level or activity, of the TCRβV molecule in a sample obtained from the subject, and wherein the value for TCRβV molecule status is higher, e.g., increased, in the sample obtained from the subject compared to a reference value, e.g., a value obtained from a healthy subject, e.g., a subject without cancer.

[0170] In another aspect, the present disclosure provides a method of treating a subject having cancer, the method comprising: (i) obtaining a value of TCRβV molecule status for the subject, wherein the value comprises a measure of the presence, e.g., level or activity, of the TCRβV molecule in a sample obtained from the subject; and (ii) administering to the subject an effective amount of an anti-TCRβV antibody molecule (e.g., a TCRβV agonist) described herein in response to the value, thereby treating the cancer.

[0171] In some embodiments, the value is higher, e.g., increased, in a sample from a subject compared to a reference value, e.g., a value obtained from a healthy subject, e.g., a subject without cancer. In a related aspect, the present disclosure provides a composition comprising an anti-TCRβV antibody molecule for use in treating a subject with cancer, comprising the steps of: (i) obtaining a value of TCRβV molecule status for the subject, wherein the value comprises a measure of the presence, e.g., level or activity, of the TCRβV molecule in a sample from the subject; and (ii) administering to the subject an effective amount of an anti-TCRβV antibody molecule (e.g., a TCRβV agonist) described herein in response to the value.

[0172] In one aspect, there is provided a method of evaluating a subject for the presence of cancer, comprising: (i) obtaining a value for the status of one or more TCRβV molecules for a subject, e.g., in a biological sample derived from the subject, wherein the value comprises a measure of the presence, e.g., level or activity, of the TCRβV molecule in the sample obtained from the subject; and (ii) determining whether the value of the one or more TCRβV molecules is higher, e.g., increased, in the sample derived from the subject compared to a reference value, e.g., a value obtained from a healthy subject, e.g., a subject without cancer. wherein a high, e.g., increased, value in the subject compared to a reference, e.g., a healthy subject, indicates the presence of cancer in the subject.

[0173] In another aspect, the present disclosure provides a method of treating a subject having cancer, comprising: (i) obtaining a value for the status of one or more TCRβV molecules for a subject, e.g., in a biological sample derived from the subject, wherein the value comprises a measure of the presence, e.g., level or activity, of the TCRβV molecule in the sample obtained from the subject; and (ii) determining whether the value of the one or more TCRβV molecules is higher, e.g., increased, in the sample derived from the subject compared to a reference value, e.g., a value obtained from a healthy subject, e.g., a subject without cancer. (iii) if a high, e.g., increased, value is determined in the subject compared to the reference value, administering to the subject an effective amount of, e.g., an anti-TCRβ antibody molecule (e.g., a TCRβ agonist), e.g., as described herein; thereby treating cancer.

[0174] In a related aspect, (i) obtaining a value for the status of one or more TCRβV molecules for a subject, e.g., in a biological sample derived from the subject, wherein the value comprises a measure of the presence, e.g., level or activity, of the TCRβV molecule in the sample obtained from the subject; and (ii) determining whether the value of the one or more TCRβV molecules is higher, e.g., increased, in the sample derived from the subject compared to a reference value, e.g., a value obtained from a healthy subject, e.g., a subject without cancer. (iii) if a high, e.g., increased, value is determined in the subject compared to the reference value, administering to the subject an effective amount of, e.g., an anti-TCRβ antibody molecule (e.g., a TCRβ agonist), e.g., as described herein; Provided herein is a composition comprising an anti-TCRβV antibody molecule for use in a method of treating a subject with cancer, comprising:

[0175] In some embodiments of any of the methods of treatment or compositions for use disclosed herein, the status indicates that the subject has cancer or a symptom thereof. In some embodiments of any of the methods of treatment or compositions for use disclosed herein, the status indicates responsiveness to a therapy, e.g., a therapy comprising, by way of example, an anti-TCRβV antibody molecule described herein.

[0176] In some embodiments of any of the methods of treatment or compositions for use disclosed herein, the value of the status is determined, e.g., measured, by an assay described herein.

[0177] In yet another aspect, provided herein is a method of treating a subject having cancer, comprising administering to the subject an effective amount of an anti-TCRBV antibody molecule described herein, wherein the subject has, e.g., a high, e.g., increased, level or activity of one or more TCRBV molecules described herein, e.g., compared to a reference level or activity of one or more TCRBV molecules in a healthy subject, e.g., a subject without cancer.

[0178] In an aspect, the present disclosure provides a method of treating a subject having cancer, comprising: (i) isolating a biological sample from a subject, e.g., a peripheral blood sample, a biopsy sample, or a bone marrow sample; (ii) obtaining for the subject, e.g., in a biological sample from the subject, a value for the status of one or more TCRβV molecules, wherein the value comprises a measure of the presence, e.g., level or activity, of the TCRβV molecule in the sample obtained from the subject compared to a reference value, e.g., a sample from a healthy subject; a high, e.g., increased, value in the subject compared to a reference, e.g., a healthy subject, indicates the presence of cancer in the subject; (iii) contacting the biological sample with an anti-TCRβV antibody molecule, e.g., in vitro; (iv) administering the biological sample obtained from step (iii), or a portion thereof, to a subject. The present invention provides a method comprising:

[0179] In another aspect, there is provided a method of expanding a population of immune effector cells from a subject with cancer, comprising: (i) isolating a biological sample, e.g., a peripheral blood sample, a biopsy sample, or a bone marrow sample, from a subject, comprising an immune effector cell population; (ii) obtaining for a subject, e.g., in a biological sample from the subject, a value for the status of one or more TCRβV molecules, wherein the value comprises a measure of the presence, e.g., level or activity, of the TCRβV molecule in the sample from the subject compared to a reference value, e.g., a sample from a healthy subject; a high, e.g., increased, value in the subject compared to a reference, e.g., a healthy subject, indicates the presence of cancer in the subject; (iii) contacting a biological sample containing a population of immune effector cells with an anti-TCRβV antibody molecule; A method is provided herein, comprising:

[0180] In some embodiments, the method further comprises administering to the subject a population of immune effector cells contacted with an anti-TCRβV antibody molecule. In some embodiments, the methods of expansion, or methods of treatment, or compositions for use disclosed herein include measuring T cell function (e.g., cytotoxic activity, cytokine secretion, or degranulation) in the immune effector cell population compared to, e.g., a reference population, e.g., an otherwise similar population not contacted with the anti-TCRβV antibody molecule, or an immune effector cell population obtained from a healthy subject (e.g., a subject without cancer).

[0181] In some embodiments of any of the methods or compositions for use disclosed herein, a biological sample comprising a population of immune effector cells is contacted with an anti-TCRβV antibody molecule that binds to one or more TCRβV molecules (e.g., the same TCRβV molecule) identified as being high, e.g., increased, in the biological sample.

[0182] In some embodiments of any of the methods or compositions for use disclosed herein, a biological sample comprising a population of immune effector cells is contacted with an anti-TCRβV antibody molecule that does not bind to one or more TCRβV molecules (e.g., different TCRβV molecules) identified as being high, e.g., increased, in the biological sample.

[0183] In another aspect, there is provided a method of identifying one or more TCRβV molecules associated with cancer, comprising: (i) obtaining the status of a plurality of TCRβV molecules in a biological sample from a first subject with a disease and in a biological sample from a second subject without the disease; (ii) determining whether the level or activity of one or more TCRβV molecules is higher, e.g., increased, in a first subject compared to a second subject, thereby identifying one or more TCRβV molecules associated with cancer.

[0184] In some embodiments of any of the methods or compositions for use disclosed herein, one or more of the TCRβ V molecules are from the following TCRβ V subfamilies: (i) a TCRβ V molecule, including one or more of 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. V6 subfamily, (ii) For example, TCRβ V10-1*01, TCRβ V10-1*02, TCRβ TCRβ V10 subfamily, including one or more of TCRβ V10-3*01, or TCRβ V10-2*01; (iii) the TCRβ V5 subfamily, including, for example, one or more of TCRβ V5-6*01, TCRβ V5-4*01, or TCRβ V5-8*01; (iv) the TCRβ V12 subfamily, including, for example, one or more of TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01; (v) For example, TCRβ V7-7*01, TCRβ V7-6*01, TCRβ V7 the TCRβ V7 subfamily, including one or more of 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; (vi) the TCRβ V11 subfamily, including, for example, one or more of TCRβ V11-1*01, TCRβ V11-2*01, or TCRβ V11-3*01; (vii) the TCRβ V14 subfamily, including TCRβ V14*01; (viii) TCRβ V16 subfamily, including TCRβ V16*01; (ix) TCRβ V18 subfamily, including TCRβ V18*01; (x) the TCRβ V9 subfamily, including, for example, one or more of TCRβ V9*01 or TCRβ V9*02; (xi) TCRβ V13 subfamily, including TCRβ V13*01; (xii) the TCRβ V4 subfamily, including, for example, one or more of TCRβ V4-2*01, TCRβ V4-3*01, or TCRβ V4-1*01; (xiii) TCRβ V3 subfamily, including TCRβ V3-1*01; (xiv) TCRβ V2 subfamily, including TCRβ V2*01; (xv) TCRβ V15 subfamily, including TCRβ V15*01; (xvi) the TCRβ V30 subfamily, including, for example, one or more of TCRβ V30*01 or TCRβ V30*02; (xvii) the TCRβ V19 subfamily, including, for example, one or more of TCRβ V19*01 or TCRβ V19*02; (xviii) TCRβ V27 subfamily, including TCRβ V27*01; (xix) TCRβ V28 subfamily, including TCRβ V28*01; (xx) TCRβ V24 subfamily, including TCRβ V24-1*01; (xxi) the TCRβ V20 subfamily, including, for example, one or more of TCRβ V20-1*01 or TCRβ V20-1*02; (xxii) the TCRβ V25 subfamily, including TCRβ V25-1*01; or (xxiii) TCRβ V29 subfamily, including TCRβ V29-1*01; (xxiv) TCRβ V21 subfamily; (xxv) TCRβ V1 subfamily, (xxvi) TCRβ V17 subfamily, (xvii) TCRβ V23 subfamily, or (xviii) TCRβ V26 subfamily , including one or more (e.g., all) of:

[0185] In some embodiments of any of the methods or compositions for use disclosed herein, the cancer is a solid tumor, including but not limited to melanoma, pancreatic cancer (e.g., pancreatic adenocarcinoma), breast cancer, colorectal cancer (CRC), lung cancer (e.g., small cell or non-small cell lung cancer), skin cancer, ovarian cancer, or liver cancer.

[0186] In some embodiments of any of the methods or compositions for use disclosed herein, the cancer is a B-cell or T-cell malignancy, e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma (e.g., B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL)), Hematological cancers, including, but not limited to, follicular lymphoma, chronic lymphocytic leukemia (B-CLL), mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia), acute myeloid leukemia (AML), chronic myelogenous leukemia, myelodysplastic syndromes, multiple myeloma, and acute lymphocytic leukemia.

[0187] In some embodiments of the methods of expansion, or methods of treatment, or compositions for use disclosed herein, a high, e.g., increased, level or activity of one or more TCRβV molecules in a subject, e.g., a sample from a subject, indicates a bias, e.g., preferential expansion, e.g., clonal expansion, of T cells expressing said one or more TCRβV molecules in the subject.

[0188] In some embodiments, for example, a subject having a cancer disclosed herein has a high, e.g., increased, level or activity of one or more TCRβV molecules associated with the cancer, hi some embodiments, the TCRβV molecule associates with, e.g., recognizes, a cancer antigen, e.g., a cancer-associated antigen or a neoantigen.

[0189] In some embodiments of any of the methods or compositions for use disclosed herein, the subject has B-CLL. In some embodiments, the subject with B-CLL has one or more TCRβ V molecules, for example, (i) the TCRβ V6 subfamily, including, for example, 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; (ii) the TCRβ V5 subfamily, including TCRβ V5-6*01, TCRβ V5-4*01, or TCRβ V5-8*01; (iii) the TCRβ V3 subfamily, including TCRβ V3-1*01; (iv) the TCRβ V2 subfamily, including TCRβ V2*01; or (v) the TCRβ The level or activity of one or more TCRβV molecules, including the TCRβ V19 subfamily, including V19*01 or TCRβ V19*02, is high, e.g., increased.

[0190] In some embodiments, a subject with B-CLL has elevated, e.g., increased, levels or activity of the TCRβ V6 subfamily, including, for example, TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01, or TCRβ V6-1*01. In some embodiments, the subject is administered an anti-TCRβ V molecule (e.g., an agonistic anti-TCRβ V molecule described herein) that binds to one or more members of the TCRβ V6 subfamily. In some embodiments, administration of the anti-TCRβ V molecule results in the expansion of immune cells expressing one or more members of the TCRβ V6 subfamily.

[0191] In some embodiments, a subject with B-CLL has high, e.g., increased, levels or activity of the TCRβ V5 subfamily, including TCRβ V5-6*01, TCRβ V5-4*01, or TCRβ V5-8*01. In some embodiments, the subject is administered an anti-TCRβ V molecule (e.g., an agonist anti-TCRβ V molecule described herein) that binds to one or more members of the TCRβ V5 subfamily. In some embodiments, administration of the anti-TCRβ V molecule results in expansion of immune cells expressing one or more members of the TCRβ V5 subfamily.

[0192] In some embodiments, the subject with B-CLL has high, e.g., increased, levels or activity of the TCRβ V3 subfamily, including TCRβ V3-1*01. In some embodiments, the subject is administered an anti-TCRβ molecule (e.g., an agonist anti-TCRβ molecule described herein) that binds to one or more members of the TCRβ V3 subfamily. In some embodiments, administration of the anti-TCRβ molecule results in expansion of immune cells that express one or more members of the TCRβ V3 subfamily.

[0193] In some embodiments, a subject with B-CLL has high, e.g., increased, levels or activity of the TCRβ V2 subfamily, including TCRβ V2*01. In some embodiments, the subject is administered an anti-TCRβV molecule (e.g., an agonist anti-TCRβV molecule described herein) that binds to one or more members of the TCRβ V2 subfamily. In some embodiments, administration of the anti-TCRβV molecule results in the expansion of immune cells that express one or more members of the TCRβ V2 subfamily.

[0194] In some embodiments, a subject with B-CLL has high, e.g., increased, levels or activity of the TCRβ V19 subfamily, including TCRβ V19*01 or TCRβ V19*02. In some embodiments, the subject is administered an anti-TCRβV molecule (e.g., an agonist anti-TCRβV molecule described herein) that binds to one or more members of the TCRβ V19 subfamily. In some embodiments, administration of the anti-TCRβV molecule results in expansion of immune cells expressing one or more members of the TCRβ V19 subfamily.

[0195] In some embodiments of any of the methods or compositions for use disclosed herein, the subject has melanoma. In some embodiments, the subject with melanoma has elevated, e.g., increased, levels or activity of one or more TCRβV molecules, e.g., one or more TCRβV molecules comprising the TCRβV subfamily, including TCRβV6-4*01, TCRβV6-4*02, TCRβV6-9*01, TCRβV6-8*01, TCRβV6-5*01, TCRβV6-6*02, TCRβV6-6*01, TCRβV6-2*01, TCRβV6-3*01, or TCRβV6-1*01. In some embodiments, the subject is administered an anti-TCRβV molecule (e.g., an agonistic anti-TCRβV molecule described herein) that binds to one or more members of the TCRβV6 subfamily. In some embodiments, administration of the anti-TCRβ V molecule results in the expansion of immune cells that express one or more members of the TCRβ V6 subfamily.

[0196] In some embodiments of any of the methods or compositions for use disclosed herein, the subject has DLBCL. In some embodiments, the subject with melanoma has high, e.g., increased, levels or activity of one or more TCRβV molecules, for example, one or more TCRβV molecules including (i) the TCRβ V13 subfamily, including TCRβ V13*01, (ii) the TCRβ V3 subfamily, including TCRβ V3-1*01, or (iii) the TCRβ V23 subfamily.

[0197] In some embodiments, the subject with DLBCL has high, e.g., increased, TCRβ The subject has a level or activity of the TCRβ V13 subfamily, including V13*01. In some embodiments, the subject is administered an anti-TCRβV molecule (e.g., an agonist anti-TCRβV molecule described herein) that binds to one or more members of the TCRβ V13 subfamily. In some embodiments, administration of the anti-TCRβV molecule results in the expansion of immune cells that express one or more members of the TCRβ V13 subfamily.

[0198] In some embodiments, the subject with DLBCL has high, e.g., increased, levels or activity of the TCRβ V3 subfamily, including TCRβ V3-1*01. In some embodiments, the subject is administered one or more members of the TCRβ V3 subfamily. An anti-TCRβ molecule (e.g., an agonist anti-TCRβ molecule described herein) that binds is administered. In some embodiments, administration of the anti-TCRβ molecule results in expansion of immune cells that express one or more members of the TCRβ V3 subfamily.

[0199] In some embodiments, the subject with DLBCL has a high, e.g., increased, level or activity of the TCRβ V23 subfamily. In some embodiments, the subject is administered an anti-TCRβV molecule (e.g., an agonist anti-TCRβV molecule described herein) that binds to one or more members of the TCRβ V23 subfamily. In some embodiments, administration of the anti-TCRβV molecule results in the expansion of immune cells that express one or more members of the TCRβ V23 subfamily.

[0200] In some embodiments of any of the methods or compositions for use disclosed herein, the subject has CRC. In some embodiments, the subject with melanoma has high, e.g., increased, levels or activity of one or more TCRβV molecules, for example, one or more TCRβV molecules including (i) the TCRβ V19 subfamily, including TCRβ V19*01 or TCRβ V19*02, (ii) the TCRβ V12 subfamily, including TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01, (iii) the TCRβ V16 subfamily, including TCRβ V16*01, or (iv) the TCRβ V21 subfamily.

[0201] In some embodiments, the subject with CRC is a subject with TCRβ V19*01 or TCRβ The level or activity of the TCRβ V19 subfamily, including V19*02, is high, e.g., increased. In some embodiments, the subject is administered an anti-TCRβV molecule (e.g., an agonist anti-TCRβV molecule described herein) that binds to one or more members of the TCRβ V19 subfamily. In some embodiments, administration of the anti-TCRβV molecule results in the expansion of immune cells that express one or more members of the TCRβ V19 subfamily.

[0202] In some embodiments, the subject with CRC is a TCRβ V12-4*01, TCRβ The level or activity of the TCRβ V12 subfamily, including TCRβ V12-3*01, or TCRβ V12-5*01, is high, e.g., increased. In some embodiments, the subject is administered an anti-TCRβV molecule (e.g., an agonist anti-TCRβV molecule described herein) that binds to one or more members of the TCRβ V12 subfamily. In some embodiments, administration of the anti-TCRβV molecule results in expansion of immune cells expressing one or more members of the TCRβ V12 subfamily.

[0203] In some embodiments, the subject with CRC has a TCRβ gene comprising TCRβ V16*01. The level or activity of the V16 subfamily is high, for example, increased. In some embodiments, the subject is administered an anti-TCRβV molecule (e.g., an agonist anti-TCRβV molecule described herein) that binds to one or more members of the TCRβV16 subfamily. In some embodiments, administration of the anti-TCRβV molecule results in the expansion of immune cells that express one or more members of the TCRβV16 subfamily.

[0204] In some embodiments, the subject with CRC has high, e.g., increased, levels or activity of the TCRβ V21 subfamily. An anti-TCRβ molecule (e.g., an agonist anti-TCRβ molecule described herein) that binds to one or more members of the V21 subfamily is administered. In some embodiments, administration of the anti-TCRβ molecule results in expansion of immune cells that express one or more members of the TCRβ V21 subfamily.

[0205] Alternatively, or in combination with any of the embodiments disclosed herein, (i) specifically binds to an epitope on TCRβV, e.g., an epitope that is the same as or similar to an epitope recognized by an anti-TCRβV antibody molecule described herein, e.g., a second anti-TCRβV antibody molecule; (ii) exhibits the same or similar binding affinity or specificity, or both, as an anti-TCRβ antibody molecule described herein, e.g., a second anti-TCRβ antibody molecule; (iii) inhibits, e.g., competitively inhibits, binding of an anti-TCRβ antibody molecule described herein, e.g., a second anti-TCRβ antibody molecule; (iv) binds to the same or overlapping epitope as an anti-TCRβ antibody molecule described herein, e.g., a second anti-TCRβ antibody molecule; or (v) competes for binding with and / or binds to the same epitope as an anti-TCRβ antibody molecule described herein, e.g., a second anti-TCRβ antibody molecule; Anti-TCRβV antibody molecules are provided herein.

[0206] In some embodiments, the second anti-TCRβ antibody molecule comprises an antigen-binding domain selected from Table 1 or Table 2, or a sequence substantially identical thereto. In some embodiments, the second anti-TCRβ antibody molecule comprises: Heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and / or heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 1 or SEQ ID NO: 9, and / or light chain complementarity determining region 1 (LC CDR1), light chain complementarity determining region 2 (LC CDR2), and / or light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO: 2, SEQ ID NO: 10, or SEQ ID NO: 11 The antigen-binding domain comprises:

[0207] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises: (i) heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and / or heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 1 or SEQ ID NO: 9, or a sequence disclosed in Table 1; or (ii) light chain complementarity determining region 1 (LC CDR1), light chain complementarity determining region 2 (LC CDR2), and / or light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO: 2, SEQ ID NO: 10, or SEQ ID NO: 11, or a sequence disclosed in Table 1 The antigen-binding domain comprises:

[0208] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a light chain variable region (VL) comprising one, two, or all (e.g., three) of the LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 2, SEQ ID NO: 10, or SEQ ID NO: 11.

[0209] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two, or all (e.g., three) of HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 1 or SEQ ID NO: 9.

[0210] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises: (i) the LC CDR1 amino acid sequence of SEQ ID NO: 6 (or an amino acid sequence having one, two, three, or four or fewer modifications, e.g., substitutions, additions, or deletions), the LC CDR2 amino acid sequence of SEQ ID NO: 7 (or an amino acid sequence having one, two, three, or four or fewer modifications, e.g., substitutions, additions, or deletions), and / or SEQ ID NO: a VL comprising the LC CDR3 amino acid sequence of No. 8 (or an amino acid sequence having one, two, three, or no more than four modifications, e.g., substitutions, additions, or deletions thereof); and / or (ii) a VH comprising the HC CDR1 amino acid sequence of SEQ ID NO: 3 (or an amino acid sequence having one, two, three, or four or fewer modifications, e.g., substitutions, additions, or deletions), the HC CDR2 amino acid sequence of SEQ ID NO: 4 (or an amino acid sequence having one, two, three, or four or fewer modifications, e.g., substitutions, additions, or deletions), and / or the HC CDR3 amino acid sequence of SEQ ID NO: 5 (or an amino acid sequence having one, two, three, or four or fewer modifications, e.g., substitutions, additions, or deletions). The antigen-binding domain comprises:

[0211] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises: the variable heavy chain (VH) of SEQ ID NO: 9 or SEQ ID NO: 1312, or a sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto; and / or The variable light chain (VL) of SEQ ID NO: 10 or SEQ ID NO: 11 or SEQ ID NO: 1314, or a sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto. The antigen-binding domain comprises:

[0212] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising the VH amino acid sequence of SEQ ID NO: 9 and the VL amino acid sequence of SEQ ID NO: 10.

[0213] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising the VH amino acid sequence of SEQ ID NO: 9 and the VL amino acid sequence of SEQ ID NO: 11.

[0214] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising the VH amino acid sequence of SEQ ID NO: 1312 and the VL amino acid sequence of SEQ ID NO: 1314.

[0215] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 1337, or a sequence having at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereto.

[0216] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 1500, or a sequence having at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereto.

[0217] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises a heavy chain that includes a framework region, e.g., framework region 3 (FR3), that includes one or both of: (i) a threonine at position 73, e.g., a substitution at position 73 according to Kabat numbering, e.g., a glutamic acid to threonine substitution, or (ii) a glycine at position 94, e.g., an arginine to glycine substitution, e.g., a glutamic acid to threonine substitution, or (ii) a glycine at position 94, e.g., according to Kabat numbering. In some embodiments, the substitution is relative to the human germline heavy chain framework region sequence.

[0218] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises a light chain comprising a framework region, e.g., 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. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0219] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises a light chain that includes a framework region, e.g., framework region 2 (FR2), that includes one or both of: (i) a histidine at position 36, e.g., a substitution at position 36 according to Kabat numbering, e.g., a tyrosine to histidine substitution, or (ii) 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 the human germline light chain framework region sequence.

[0220] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises a light chain comprising a framework region, e.g., 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. In some embodiments, the substitution is relative to the human germline light chain framework region sequence.

[0221] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβ antibody molecule binds to TCRβ V6, e.g., TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01, or TCRβ V6-1*01. In some embodiments, the anti-TCRβ antibody molecule binds to TCRβ V6-5*01.

[0222] In some embodiments, TCRβ V6, e.g., 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 are recognized, e.g., bound, by SEQ ID NO: 1 and / or SEQ ID NO: 2. In some embodiments, TCRβ V6, e.g., 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, is recognized, e.g., bound, by SEQ ID NO:9 and / or SEQ ID NO:10. In some embodiments, TCRβ V6, e.g., 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, is recognized by, e.g., bound by, SEQ ID NO: 9 and / or SEQ ID NO: 11. In some embodiments, TCRβ V6-5*01 is recognized by, e.g., bound by, SEQ ID NO: 9 and / or SEQ ID NO: 10, or a sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto. In some embodiments, TCRβ V6-5*01 is recognized by SEQ ID NO:9 and / or SEQ ID NO:11, or a sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto, e.g., For example, they are combined.

[0223] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises: (i) the heavy chain complementarity determining region (HC CDR1), HC CDR2, and / or HC CDR3 of SEQ ID NO: 15, SEQ ID NO: 23, SEQ ID NO: 24, or SEQ ID NO: 25, or a sequence disclosed in Table 2, and / or (ii) light chain complementarity-determining region 1 (LC CDR1), LC CDR2, and / or 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, or a sequence disclosed in Table 2 The antigen-binding domain comprises:

[0224] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a light chain variable region (VL) comprising one, two, or all of LC CDR1, LC CDR2, and 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.

[0225] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two, or all of HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 15, SEQ ID NO: 23, SEQ ID NO: 24, or SEQ ID NO: 25.

[0226] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises: (i) a VL comprising the LC CDR1 amino acid sequence of SEQ ID NO: 20 (or the amino acid sequence having no more than one, two, three, or four modifications, e.g., substitutions, additions, or deletions), the LC CDR2 amino acid sequence of SEQ ID NO: 21 (or the amino acid sequence having no more than one, two, three, or four modifications, e.g., substitutions, additions, or deletions), and / or the LC CDR3 amino acid sequence of SEQ ID NO: 22 (or the amino acid sequence having no more than one, two, three, or four modifications, e.g., substitutions, additions, or deletions), and / or (ii) a VH comprising the HC CDR1 amino acid sequence of SEQ ID NO: 17 (or an amino acid sequence having no more than one, two, three, or four modifications, e.g., substitutions, additions, or deletions), the HC CDR2 amino acid sequence of SEQ ID NO: 18 (or an amino acid sequence having no more than one, two, three, or four modifications, e.g., substitutions, additions, or deletions), and / or the HC CDR3 amino acid sequence of SEQ ID NO: 19 (or an amino acid sequence having no more than one, two, three, or four modifications, e.g., substitutions, additions, or deletions). The antigen-binding domain comprises:

[0227] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises: a variable heavy chain (VH) of SEQ ID NO: 23, SEQ ID NO: 24, or SEQ ID NO: 25, or a sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto; and / or A variable light chain (VL) of SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, or SEQ ID NO:30, or a sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto. The antigen-binding domain comprises:

[0228] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises a light chain that includes a framework region, e.g., framework region 1 (FR1), that includes one, two, or all (e.g., three) of: (i) 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, or (ii) an asparagine at position 2, e.g., a substitution at position 2 according to Kabat numbering, e.g., an isoleucine to asparagine substitution, a serine to asparagine substitution, or a tyrosine to asparagine substitution, or (iii) a leucine at position 4, e.g., a substitution at position 4 according to Kabat numbering, e.g., a methionine to leucine substitution. In some embodiments, the substitution is with respect to the human germline light chain framework region sequence.

[0229] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises a light chain that includes a framework region, e.g., framework region 3 (FR3), that includes one, two, or all (e.g., three) of: (i) 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, (ii) an asparagine at position 69, e.g., a substitution at position 69 according to Kabat numbering, e.g., a threonine to asparagine substitution, or (iii) 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. In some embodiments, the substitution is relative to the human germline light chain framework region sequence.

[0230] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβ antibody molecule binds to TCRβ V12, e.g., TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01. In some embodiments, the anti-TCRβ antibody molecule binds to TCRβ V12-4*01 or TCRβ V12-3*01.

[0231] In some embodiments, TCRβ V12, e.g., TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01, is recognized by, e.g., bound by, SEQ ID NO: 15 and / or SEQ ID NO: 16. In some embodiments, TCRβ V12, e.g., TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01, is recognized by, e.g., bound by, any one of SEQ ID NOs: 23-25, and / or any one of SEQ ID NOs: 26-30, or an amino acid sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto. In some embodiments, TCR β V12-4*01 is recognized, e.g., bound, by any one of SEQ ID NOs: 23-25 ​​and / or any one of SEQ ID NOs: 26-30, or an amino acid sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto. In some embodiments, TCR β V12-3*01 is recognized, e.g., bound, by any one of SEQ ID NOs: 23-25 ​​and / or any one of SEQ ID NOs: 26-30, or an amino acid sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto.

[0232] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a single-chain Fv (scFv) or a Fab.

[0233] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule binds to a conformational epitope or a linear epitope on a T cell. In some embodiments of any of the compositions or methods disclosed herein, the tumor comprises an antigen, e.g., a tumor antigen, e.g., a tumor-associated antigen or a neoantigen, and the anti-TCRβV antibody molecule recognizes, e.g., binds to, the tumor antigen.

[0234] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule is a full-length antibody (e.g., an antibody comprising at least one, and preferably two, complete heavy chains and at least one, and preferably two, complete light chains), or an antigen-binding fragment (e.g., a Fab, F(ab'), Fv, a single-chain Fv fragment, a single-domain antibody, a diabody (dAb), a bivalent antibody, or a bispecific antibody or fragment thereof, a single-domain variant thereof, a camelid antibody, or a rat-derived VH.

[0235] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises one or more heavy chain constant regions selected from IgG1, IgG2, IgG3, IgGA1, IgGA2, IgM, IgJ, or IgG4, e.g., as disclosed in Table 3, or fragments thereof.

[0236] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises an IgM heavy chain constant region or a fragment thereof, where optionally the IgM heavy chain constant region comprises the sequence of SEQ ID NO: 73, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto. In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprising an IgM constant region further comprises an IgJ heavy chain constant region or a fragment thereof, where optionally the IgJ heavy chain constant region comprises the sequence of SEQ ID NO: 76, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto.

[0237] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises an IgJ heavy chain constant region or a fragment thereof, and optionally the IgJ heavy chain constant region comprises the sequence of SEQ ID NO: 76, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto.

[0238] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises a heavy chain constant region of IgGA1 or a fragment thereof, and optionally the IgGA1 heavy chain constant region comprises the sequence of SEQ ID NO: 74, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto.

[0239] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises a heavy chain constant region of IgGA2 or a fragment thereof, and optionally the IgGA2 heavy chain constant region comprises a sequence listed in Table 3, e.g., the sequence of SEQ ID NO: 75, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto.

[0240] In some embodiments of any of the compositions or methods disclosed herein, binding of an anti-TCRβV antibody molecule to the TCRβV region results in a cytokine profile, e.g., a cytokine secretion profile (e.g., comprising one or more cytokines and / or one or more chemokines), that differs from that of a T cell engager that binds to a receptor or molecule other than the TCRβV region (a "non-TCRβV-binding T cell engager").

[0241] In some embodiments, the cytokine profile, e.g., cytokine secretion profile, comprises one or more cytokines and / or one or more chemokines. (e.g., as described herein) levels and / or activities.In certain embodiments, the cytokine profile, e.g., cytokine secretion profile, is selected from the group consisting of IL-2 (e.g., full length, a variant, or a fragment thereof), IL-1 beta (e.g., full length, a variant, or a fragment thereof), IL-6 (e.g., full length, a variant, or a fragment thereof), TNF alpha (e.g., full length, a variant, or a fragment thereof), IFNg (e.g., full length, a variant, or a fragment thereof), IL-10 (e.g., full length, a variant, or a fragment thereof), IL-4 (e.g., full length, a variant, or a fragment thereof), TNF alpha (e.g., full length, a variant, or a fragment thereof), IL-12p70 (e.g., full length, a variant, or a fragment thereof), IL-13 (e.g., full length, a variant, or a fragment thereof), IL-8 (e.g., full length, or a variant or fragment thereof), eotaxin (e.g., full length, a variant or fragment thereof), eotaxin-3 (e.g., full length, a variant or fragment thereof), IL-8(HA) (e.g., full length, a variant or fragment thereof), IP-10 (e.g., full length, a variant or fragment thereof), MCP-1 (e.g., full length, a variant or fragment thereof), MCP-4 (e.g., full length, a variant or fragment thereof), MDC (e.g., full length, a variant or fragment thereof), MIP-1a (e.g., full length, a variant or fragment thereof), MIP-1b (e.g., full length, a variant or fragment thereof), TARC (e.g., full length, a variant or fragment thereof), GM-CSF (e.g., full length, a variant or fragment thereof), IL-12 The level and / or activity of one or more of 23p40 (e.g., full length, a variant, or a fragment thereof), IL-15 (e.g., full length, a variant, or a fragment thereof), IL-16 (e.g., full length, a variant, or a fragment thereof), IL-17a (e.g., full length, a variant, or a fragment thereof), IL-1a (e.g., full length, a variant, or a fragment thereof), IL-5 (e.g., full length, a variant, or a fragment thereof), IL-7 (e.g., full length, a variant, or a fragment thereof), TNF-beta (e.g., full length, a variant, or a fragment thereof), or VEGF (e.g., full length, a variant, or a fragment thereof).

[0242] In some embodiments, the cytokine profile, e.g., cytokine secretion profile, is one of the following: (i) an increase in the level, e.g., expression level, and / or activity, of IL-2; (ii) a reduction in the level, e.g., expression level, and / or activity of IL-1β; (iii) a reduction in the level, e.g., expression level, and / or activity of IL-6; (iv) a reduction in the level, e.g., expression level, and / or activity of TNFα; (v) a reduction in the level, e.g., expression level, and / or activity, of IL-10; (vi) a delay in the increase in the level, e.g., expression level, and / or activity of IL-2, e.g., a delay of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or more; (vii) a delay in the increase in the level, e.g., expression level, and / or activity of IFNg, e.g., a delay of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or (viii) an increase in the level, e.g., expression level, and / or activity, of IL-15; For example, (i) to (viii) are compared with the cytokine profile, e.g., cytokine secretion profile, of a non-TCRβV-binding T cell engager.

[0243] In some embodiments, binding of the anti-TCRBV antibody to the TCRβV region results in a reduced cytokine storm, e.g., reduced cytokine release syndrome (CRS) and / or neurotoxicity (NT), compared to the cytokine storm induced by a non-TCRβV-binding T cell engager, as measured by the assay of Example 3.

[0244] In some embodiments, the binding of the anti-TCRBV antibody to the TCRβV region is (ix) reduced T cell proliferation kinetics; (x) cell killing, e.g., target cell killing, e.g., cancer cell killing, e.g., as measured by the assay of Example 4; (xi) natural killer (NK) cell proliferation, e.g., increased expansion, or (xii) an expansion of a T cell population having a memory-like phenotype, e.g., at least about a 1.1- to 10-fold expansion (e.g., at least about a 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold expansion). Bringing about one, two, three or all of the For example, (ix) to (xii) are compared with non-TCRβV-binding T cell engagers.

[0245] In some embodiments, the anti-TCRβV antibody molecules disclosed herein recognize (e.g., bind to) a structurally conserved domain on the TCRβV protein (e.g., indicated by the circled region in Figure 24A).

[0246] In some embodiments, the anti-TCRβV antibody molecules disclosed herein do not recognize, eg, do not bind to, the interface of the TCRβV:TCR alpha complex. In some embodiments, the anti-TCRβV antibody molecules disclosed herein do not recognize, e.g., do not bind to, the constant region of the TCRβV protein. An exemplary antibody that binds to the constant region of the TCRβV region is JOVI.1, described in Viney et al., (Hybridoma. 1992 December;11(6):701-13).

[0247] In some embodiments, the anti-TCRβV antibody molecules disclosed herein do not recognize, e.g., do not bind to, one or more (e.g., all) of the complementarity determining regions (e.g., CDR1, CDR2, and / or CDR3) of the TCRβV protein.

[0248] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises a light chain constant region chosen from a kappa or lambda light chain constant region, or a fragment thereof, e.g., as disclosed in Table 3.

[0249] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises a light chain constant region of a kappa chain or a fragment thereof, and optionally the kappa chain constant region comprises the sequence of SEQ ID NO: 39, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto.

[0250] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβV antibody molecule comprises: (i) one or more heavy chain constant regions, including a heavy chain constant region selected from IgG1, IgG2, IgG3, IgGA1, IgGA2, IgG4, IgJ, IgM, IgD, or IgE, e.g., as set forth in Table 3, or a fragment thereof; and (ii) a light chain constant region comprising a light chain constant region selected from the kappa or lambda light chain constant regions, or a fragment thereof, e.g., as set forth in Table 3 Includes:

[0251] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβ antibody molecule, or the cell comprising the anti-TCRβ antibody molecule, (i) a heavy chain comprising a variable region (VH), e.g., the VH of an antibody disclosed herein, and / or one or more heavy chain constant regions, e.g., as disclosed herein; and / or (ii) a variable light chain (VL), e.g., the VL of an antibody disclosed herein, and / or a light chain comprising, e.g., one or more light chain constant regions disclosed herein Includes:

[0252] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβ antibody molecule, or the cell comprising the anti-TCRβ antibody molecule, (i)(a) an IgM heavy chain constant region or fragment thereof comprising the sequence of SEQ ID NO: 73, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto; (b) an IgGA1 heavy chain constant region or a fragment thereof comprising the sequence of SEQ ID NO: 74, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto; or (c) a heavy chain comprising a heavy chain constant region comprising an IgGA2 heavy chain constant region or a fragment thereof comprising the sequence of SEQ ID NO: 75, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto; and (ii) a light chain comprising a light chain constant region comprising a kappa chain constant region comprising the sequence of SEQ ID NO: 39, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto; Including, Optionally, the anti-TCRβV antibody molecule further comprises an IgJ heavy chain constant region or a fragment thereof, wherein the IgJ heavy chain constant region comprises the sequence of SEQ ID NO: 76, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto.

[0253] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβ antibody molecule, or the cell comprising the anti-TCRβ antibody molecule, (i) a VH selected from the VHs of Tables 1-2 or 10-13, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto, and a heavy chain constant region; (a) an IgM heavy chain constant region or fragment thereof comprising the sequence of SEQ ID NO: 73, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto; (b) an IgGA1 heavy chain constant region or a fragment thereof comprising the sequence of SEQ ID NO: 74, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto; or (c) a heavy chain comprising a heavy chain constant region comprising an IgGA2 heavy chain constant region or a fragment thereof comprising the sequence of SEQ ID NO: 75, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto; and (ii) a light chain comprising a VL chosen from the VLs of Tables 1-2 or 10-13, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto, and a light chain constant region comprising a kappa chain constant region comprising the sequence of SEQ ID NO: 39, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto. Including, Optionally, the anti-TCRβV antibody molecule further comprises an IgJ heavy chain constant region or a fragment thereof, wherein the IgJ heavy chain constant region comprises the sequence of SEQ ID NO: 76, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto.

[0254] In some embodiments of any of the methods disclosed herein, the anti-TCRβV antibody molecule is selected from the following TCRβV subfamilies: (i) For example, 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, V6 subfamily, (ii) For example, TCRβ V10-1*01, TCRβ V10-1*02, TCRβ TCRβ V10 subfamily, including one or more of TCRβ V10-3*01, or TCRβ V10-2*01; (iii) the TCRβ V5 subfamily, including, for example, one or more of TCRβ V5-6*01, TCRβ V5-4*01, or TCRβ V5-8*01; (iv) the TCRβ V12 subfamily, including, for example, one or more of TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01; (v) For example, TCRβ V7-7*01, TCRβ V7-6*01, TCRβ V7 the TCRβ V7 subfamily, including one or more of 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; (vi) the TCRβ V11 subfamily, including, for example, one or more of TCRβ V11-1*01, TCRβ V11-2*01, or TCRβ V11-3*01; (vii) the TCRβ V14 subfamily, including TCRβ V14*01; (viii) TCRβ V16 subfamily, including TCRβ V16*01; (ix) TCRβ V18 subfamily, including TCRβ V18*01; (x) the TCRβ V9 subfamily, including, for example, one or more of TCRβ V9*01 or TCRβ V9*02; (xi) TCRβ V13 subfamily, including TCRβ V13*01; (xii) the TCRβ V4 subfamily, including, for example, one or more of TCRβ V4-2*01, TCRβ V4-3*01, or TCRβ V4-1*01; (xiii) TCRβ V3 subfamily, including TCRβ V3-1*01; (xiv) TCRβ V2 subfamily, including TCRβ V2*01; (xv) TCRβ V15 subfamily, including TCRβ V15*01; (xvi) the TCRβ V30 subfamily, including, for example, one or more of TCRβ V30*01 or TCRβ V30*02; (xvii) the TCRβ V19 subfamily, including, for example, one or more of TCRβ V19*01 or TCRβ V19*02; (xviii) TCRβ V27 subfamily, including TCRβ V27*01; (xix) TCRβ V28 subfamily, including TCRβ V28*01; (xx) TCRβ V24 subfamily, including TCRβ V24-1*01; (xxi) the TCRβ V20 subfamily, including, for example, one or more of TCRβ V20-1*01 or TCRβ V20-1*02; (xxii) the TCRβ V25 subfamily, including TCRβ V25-1*01; or (xxiii) TCRβ V29 subfamily, including TCRβ V29-1*01; (xxiv) TCRβ V21 subfamily; (xxv) TCRβ V1 subfamily, (xxvi) TCRβ V17 subfamily, (xvii) TCRβ V23 subfamily, or (xviii) TCRβ V26 subfamily Binds to one or more (e.g., all) of

[0255] In some embodiments of any of the methods disclosed herein, the anti-TCRβV antibody molecule is selected from the following TCRβV subfamilies: (i) TCRβ V6, such as 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, (ii) TCRβ V10, e.g., TCRβ V10-1*01, TCRβ V10-1*02, TCRβ V10-3*01, or TCRβ V10-2*01; (iii) TCRβ V12, e.g., TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01, or (iv) binds to one or more (e.g., all) of TCRβ V5, e.g., TCRβ V5-5*01, TCRβ V5-6*01, TCRβ V5-4*01, TCRβ V5-8*01, TCRβ V5-1*01.

[0256] In some embodiments, the anti-TCRβ antibody molecule binds to TCRβ V6, e.g., TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01, or TCRβ V6-1*01. In some embodiments, the anti-TCRβ antibody molecule binds to TCRβ V6-5*01.

[0257] In some embodiments, the anti-TCRβV antibody molecule does not bind to TCRβ V12. In some embodiments, the anti-TCRβV antibody molecule does not bind to TCRβ V5-5*01 or TCRβ V5-1*01.

[0258] In some embodiments of any of the methods disclosed herein, the anti-TCRβ antibody molecule does not bind to TCRβ V12 or binds to TCRβ V12 with an affinity and / or binding specificity that is less (e.g., less than about 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, or less than about half-, five-, or ten-fold less) than the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155. Binds to V12.

[0259] In some embodiments of any of the methods disclosed herein, the anti-TCRβ antibody molecule binds to TCRβ V12 with an affinity and / or binding specificity that is greater than (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 2-fold, 5-fold, or 10-fold greater than) that of the 16G8 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155.

[0260] In some embodiments of any of the methods disclosed herein, the anti-TCRβ antibody molecule binds to a TCRβ V region other than TCRβ V12 (e.g., a TCRβ V region described herein, e.g., the TCRβ V6 subfamily (e.g., TCRβ V6-5*01)) with an affinity and / or binding specificity that exceeds (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 2-fold, 5-fold, or 10-fold greater than) the affinity and / or binding specificity of the 16G8 murine antibody described in U.S. Pat. No. 5,861,155, or a humanized version thereof.

[0261] In some embodiments of any of the methods disclosed herein, the anti-TCRβ antibody The molecule does not comprise at least one CDR of antibody B. In some embodiments of any of the methods disclosed herein, the anti-TCRβV antibody molecule does not comprise a CDR of antibody B.

[0262] In some embodiments of any of the methods disclosed herein, the anti-TCRβ antibody molecule does not bind to TCRβ V5-5*01 or TCRβ V5-1*01, or binds to TCRβ V5-5*01 or TCRβ V5-1*01 with an affinity and / or binding specificity that is less (e.g., less than about 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, or less than about half-, five-, or ten-fold less) than that of the TM23 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155.

[0263] In some embodiments of any of the methods disclosed herein, the anti-TCRβ antibody molecule binds to TCRβ V5-5*01 or TCRβ V5-1*01 with an affinity and / or binding specificity that exceeds (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 2-fold, 5-fold, or 10-fold greater) than that of the TM23 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155.

[0264] In some embodiments of any of the methods disclosed herein, the anti-TCRβ antibody molecule binds to a TCRβ V region other than TCRβ V5-5*01 or TCRβ V5-1*01 (e.g., a TCRβ V region described herein, e.g., the TCRβ V6 subfamily (e.g., TCRβ V6-5*01)) with an affinity and / or binding specificity that exceeds (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 2-fold, 5-fold, or 10-fold greater than) the affinity and / or binding specificity of the TM23 murine antibody described in U.S. Pat. No. 5,861,155, or a humanized version thereof.

[0265] In some embodiments of any of the methods disclosed herein, the anti-TCRβV antibody molecule does not comprise at least one CDR of the TM23 murine antibody. In some embodiments of any of the methods disclosed herein, the anti-TCRβV antibody molecule does not comprise a CDR of the TM23 murine antibody.

[0266] In some embodiments of any of the methods disclosed herein, the anti-TCRβV antibody molecule disclosed herein is a TCRβV antibody molecule as described in, e.g., J Exp Med. 1989 Jan 1; 169(1):73-86, which is incorporated herein by reference in its entirety. In some embodiments of any of the methods disclosed herein, the multispecific antibody molecule disclosed herein does not include the sequence of the mouse anti-rat TCR antibody R73, e.g., as disclosed in J Immunol. 1993 Mar 15;150(6):2305-15, which is incorporated herein by reference in its entirety.

[0267] In some embodiments of any of the methods disclosed herein, the anti-TCRβV antibody molecule disclosed herein does not comprise a viral peptide-MHC complex, e.g., as disclosed in Oncoimmunology. 2016; 5(1): e1052930, which is incorporated herein by reference in its entirety. In some embodiments of any of the methods disclosed herein, the multispecific antibody molecule disclosed herein does not comprise a viral peptide-MHC complex, e.g., as disclosed in Oncoimmunology. 2016; 5(1): e1052930, which is incorporated herein by reference in its entirety. INCORPORATED INTO THE SPECIFICATION.

[0268] In some embodiments of the methods disclosed herein, the immune cell population comprises T cells, natural killer cells, B cells, antigen-presenting cells, or myeloid cells (e.g., monocytes, macrophages, neutrophils, or granulocytes).

[0269] In some embodiments of the methods disclosed herein, the immune cell population comprises T cells, e.g., CD4+ T cells, CD8+ T cells, TCR alpha-beta T cells, or TCR gamma-delta T cells. In some embodiments, the T cells are memory T cells (e.g., central memory T cells), or effector memory T cells (e.g., T EMRA ), or effector T cells. In some embodiments, the T cells comprise tumor-infiltrating lymphocytes (TILs).

[0270] In some embodiments of the methods disclosed herein, the immune cell population is obtained from a healthy subject. In some embodiments of the methods disclosed herein, the immune cell population is obtained from a subject (e.g., from an apheresis sample from the subject), e.g., a subject with a disease described herein, e.g., cancer. In some embodiments, the immune cell population obtained from the subject with a disease, e.g., cancer, comprises tumor-infiltrating lymphocytes (TILs).

[0271] In some embodiments of the methods disclosed herein, the methods result in at least a 1.1-10 fold expansion (e.g., at least a 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold expansion).

[0272] In some embodiments of the methods disclosed herein, the method further includes contacting the cell population with an agent that promotes, e.g., increases, the expansion of immune cells. In some embodiments, the agent includes, e.g., an immune checkpoint inhibitor described herein. In some embodiments, the agent includes a 4-1BB (CD127) agonist, e.g., an anti-4-1BB antibody.

[0273] In some embodiments of the methods disclosed herein, the method further comprises contacting the population of cells with a population of non-dividing cells, e.g., feeder cells, e.g., irradiated allogeneic human PBMCs.

[0274] In some embodiments of the methods disclosed herein, the expansion methods described herein comprise expanding the cells for a period of at least about 4 hours, 6 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 22 hours, or at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days, or at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks.

[0275] In some embodiments of the methods disclosed herein, the expansion of an immune cell population is compared to the expansion of a similar cell population using an antibody that binds to a CD3 molecule, e.g., a CD3 epsilon (CD3e) molecule, or a TCR alpha (TCRα) molecule.

[0276] In some embodiments of the methods disclosed herein, the expansion of an immune cell population is compared to the expansion of a similar cell population that has not been contacted with the anti-TCRβV antibody molecule. In some embodiments of the methods disclosed herein, memory effector T cells, e.g., T EM Cells, e.g., T EMRA The expansion of the population of cells involves the expression of CD3 molecules, e.g., CD3 This is compared to the expansion of similar cell populations using antibodies that bind to the TCR epsilon (CD3e) molecule, or the TCR alpha (TCRα) molecule.

[0277] In some embodiments of the methods disclosed herein, the methods result in the expansion, e.g., selective or preferential expansion, of T cells expressing a TCR comprising a T cell receptor (TCR) alpha and / or TCR beta molecule, e.g., TCR alpha-beta T cells (αβ T cells).

[0278] In some embodiments of the methods disclosed herein, the methods result in expansion of αβ T cells over expansion of T cells expressing TCRs comprising TCR gamma and / or TCR delta molecules, e.g., TCR gamma-delta T cells (γδ T cells). In some embodiments, expansion of αβ T cells over γδ T cells results in reduced production of cytokines associated with CRS. In some embodiments, expansion of αβ T cells over γδ T cells results in immune cells that have a reduced ability, e.g., are less likely, to induce CRS when administered to a subject.

[0279] In some embodiments of the methods disclosed herein, a population of immune cells (e.g., T cells (e.g., T cells)) cultured in the presence of, e.g., expanded with, an anti-TCRβV antibody disclosed herein is used. EMRA The IL-16 (cells or TILs) or NK cells) do not induce CRS and / or NT when administered to a subject, e.g., a subject having a disease or condition described herein.

[0280] In some embodiments, the anti-TCRβ antibody molecule in the multispecific molecules disclosed herein is the first immune cell engager moiety. In some embodiments, the anti-TCRβ antibody molecule does not bind to TCRβ V12 or binds to TCRβ V12 with an affinity and / or binding specificity that is less (e.g., less than about 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, or less than about half-, five-, or ten-fold less) than that of the 16G8 murine antibody or humanized version thereof described in U.S. Patent No. 5,861,155. In some embodiments, the anti-TCRβ antibody molecule binds to TCRβ V12 with an affinity and / or binding specificity that exceeds (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 2-fold, 5-fold, or 10-fold greater than) that of the 16G8 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155. In some embodiments, the anti-TCRβ antibody molecule binds to a TCRβ region other than TCRβ V12 (e.g., a TCRβ V region described herein, e.g., a TCRβ V6 subfamily (e.g., TCRβ V6-5*01)) with an affinity and / or binding specificity that exceeds (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 2-fold, 5-fold, or 10-fold greater than) the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155. In some embodiments, the anti-TCRβ antibody molecule does not comprise the CDRs of the Antibody B murine antibody.

[0281] In some embodiments, the anti-TCRβ antibody molecule in the multispecific molecules disclosed herein is the first immune cell engager moiety. In some embodiments, the anti-TCRβ antibody molecule does not bind to TCRβ V5-5*01 or TCRβ V5-1*01, or binds to TCRβ V5-5*01 or TCRβ V5-1*01 with an affinity and / or binding specificity that is less (e.g., less than about 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, or less than about half-, five-, or ten-fold less) than the affinity and / or binding specificity of the TM23 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155. 1. In some embodiments, the anti-TCRβ antibody molecule binds to TCRβ V5-5*01 or TCRβ V5-1*01 with an affinity and / or binding specificity that exceeds (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 2-fold, 5-fold, or 10-fold greater than) that of the TM23 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155. In some embodiments, the anti-TCRβ antibody molecule binds to a TCRβ region other than TCRβ V5-5*01 or TCRβ V5-1*01 (e.g., a TCRβ V region described herein, e.g., the TCRβ V6 subfamily (e.g., TCRβ V6-5*01)) with an affinity and / or binding specificity that exceeds (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 2-fold, 5-fold, or 10-fold greater than) the affinity and / or binding specificity of the TM23 murine antibody described in U.S. Pat. No. 5,861,155, or a humanized version thereof. In some embodiments, the anti-TCRβ antibody molecule does not comprise the CDRs of the TM23 murine antibody.

[0282] In some embodiments, the multispecific molecule further comprises a second immune cell engager moiety. In some embodiments, the first and / or second immune cell engager binds to and activates an immune cell, e.g., an effector cell. In some embodiments, the first and / or second immune cell engager binds to but does not activate an immune cell, e.g., an effector cell. In some embodiments, the second immune cell engager is selected from an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, or a combination thereof. In some embodiments, the second immune cell engager comprises a T cell engager that binds to CD3, TCRα, TCRγ, TCRζ, ICOS, CD28, CD27, HVEM, LIGHT, CD40, 4-1BB, OX40, DR3, GITR, CD30, TIM1, SLAM, CD2, or CD226.

[0283] In some embodiments, the multispecific molecules disclosed herein comprise a tumor-targeting moiety. In some embodiments, the tumor-targeting moiety comprises an antibody molecule (e.g., Fab or scFv), a receptor molecule (e.g., a receptor, a receptor fragment, or a functional variant thereof), or a ligand molecule (e.g., a ligand, a ligand fragment, or a functional variant thereof) that binds to a cancer antigen, or a combination thereof. In some embodiments, the tumor-targeting moiety binds to a cancer antigen present in a cancer, such as a blood cancer, a solid tumor, a metastatic cancer, a soft tissue tumor, a metastatic lesion, or a combination thereof. In some embodiments, the tumor-targeting moiety binds to a cancer antigen, such as BCMA or FcRH5.

[0284] In some embodiments, the tumor-targeting antibody molecule binds to a conformational or linear epitope on a tumor antigen. In some embodiments of any of the compositions or methods disclosed herein, the tumor-targeting moiety is an antigen, e.g., a cancer antigen. In some embodiments, the cancer antigen is a tumor or stromal antigen, or a blood antigen.

[0285] In some embodiments of any of the compositions or methods disclosed herein, the tumor-targeting moiety is selected from the group consisting of BCMA, FcRH5, CD19, CD20, CD22, CD30, CD33, CD38, CD47, CD99, CD123, FcRH5, CLEC12, CD179A, SLAMF7, or NY-ESO1, PDL1, CD47, gangloside 2 (GD2), prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PMSA), prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), Ron kinase, c-Met, immature laminin receptor, TAG-72, BING-4, calcium-activated chloride channel 2, cyclin-B1, 9D7, Ep-CAM, EphA3, Her2 / neu, telomerase, SAP-1, survivin, NY-ESO-1 / LAGE-1, PRAME, SSX-2, Melan-A / MART-1, Gp100 / pmel17, tyrosinase, TRP-1 / -2, MC1R, β-catenin, BRCA1 / 2, CDK4, CML66, fibronectin, p53, Ras, TGF-β receptor, AFP, ETA, MAGE, MUC-1, CA-125, BAGE, GAGE, NY-ESO-1, β-catenin, CDK4, CDC27, α-actinin-4, TRP1 / gp75, TRP2, gp100, Melan-A / MART1, gangliosides, WT1, EphA3, epidermal growth factor receptor (EGFR), MART-2, MART-1, MUC1, MUC2, M Binds to a cancer antigen selected from UM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RUI1, RUI2, SAGE, TRG, TRP1, TSTA, folate receptor alpha, L1-CAM, CAIX, gpA33, GD3, GM2, VEGFR, integrins (integrin alpha V beta 3, integrin alpha 5 beta 1), carbohydrate (Le), IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, (FAP), TGF-beta, hyaluronic acid, collagen, e.g., type IV collagen, tenascin C, or tenascin W.

[0286] In some embodiments of any of the compositions or methods disclosed herein, the cancer is a solid tumor, including but not limited to pancreatic cancer (e.g., pancreatic adenocarcinoma), breast cancer, colorectal cancer, lung cancer (small cell or non-small cell lung cancer), skin cancer, ovarian cancer, or liver cancer.

[0287] In some embodiments of any of the compositions or methods disclosed herein, the cancer antigen or tumor antigen is a blood antigen. In some embodiments, the cancer or tumor antigen is selected from one or more of BCMA, FcRH5, CD19, CD20, CD22, CD30, CD33, CD38, CD47, CD99, CD123, FcRH5, CLEC12, CD179A, SLAMF7, or NY-ESO1. In some embodiments, the tumor targeting moiety binds to one or both of BCMA or FcRH5.

[0288] In some embodiments, the tumor targeting moiety binds to BCMA. In embodiments, the tumor targeting moiety comprises a BCMA targeting moiety. In some embodiments, the tumor targeting moiety comprising a BCMA targeting moiety binds to a BCMA antigen on the surface of a cell, e.g., a cancer cell or a hematopoietic cell. The BCMA antigen may be present in a primary tumor cell or a metastatic lesion thereof. In some embodiments, the cancer is a blood cancer, e.g., multiple myeloma. For example, the BCMA antigen may be present in a tumor, e.g., in a class of tumors that typically have one or more of limited tumor perfusion, vascular compression, or a fibrous tumor stroma. In some embodiments, the tumor targeting moiety, including the BCMA targeting moiety, is selected from the group consisting of U.S. Pat. Nos. 8,920,776, 9,243,058, 9,340,621, 8,846,042, 7,083,785, 9,545,086, 7,276,241, 9,034,324, 7,799,902, 9,387,237, Nos. 8821883, 861745, U.S. Patent Application Publication Nos. 20130273055, 20160176973, 20150368351, 20150376287, 20170022284, 20160015749, 20140242077, 20170037128, European Patent Nos. 20170051068, 20160368988, 20160311915, 20160131654, 20120213768, 20110177093, 20160297885, European Patent Nos. 3137500, 2699259, 2982694, 302 9068, 3023437, WO2016090327, WO2017021450, WO2016110584, WO2016118641, WO2016168149, the contents of all of which are incorporated herein by reference.

[0289] In some embodiments, the BCMA targeting moiety comprises an antibody molecule (e.g., a Fab or scFv) that binds to BCMA. In some embodiments, the antibody molecule against BCMA comprises one, two, or three CDRs from any of the heavy chain variable domain sequences in Table 9, or closely related CDRs, e.g., CDRs with at least one amino acid change but no more than two, three, or four changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) from any of the CDR sequences in Table 9. In some embodiments, the antibody molecule against BCMA comprises a heavy chain variable domain sequence selected from any of the amino acid sequences in Table 9, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or with at least one amino acid change but no more than 5, 10, or 15 changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions)).

[0290] In some embodiments, the tumor targeting moiety binds to FcRH5. In embodiments, the tumor targeting moiety comprises an FcRH5 targeting moiety. In some embodiments, the tumor targeting moiety comprising an FcRH5 targeting moiety binds to an FcRH5 antigen on the surface of a cell, for example, a cancer cell or a hematopoietic cell. The FcRH5 antigen may be present in a primary tumor cell or a metastatic lesion thereof. In some embodiments, the cancer is a blood cancer, for example, multiple myeloma. For example, the FcRH5 antigen may be present in a tumor, for example, in a class of tumors that typically have one or more of limited tumor perfusion, vascular compression, or fibrous tumor stroma. In some embodiments, the tumor targeting moiety comprising an FcRH5 targeting moiety comprises an anti-FcRH5 antibody or antigen-binding fragment thereof described in U.S. Patent No. 7,999,077, the entire contents of which are incorporated herein by reference.

[0291] In some embodiments of any of the compositions or methods disclosed herein, the cancer is a B-cell or T-cell malignancy, e.g., a hematological cancer, including but not limited to Hodgkin's lymphoma, non-Hodgkin's lymphoma (e.g., B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia), acute myeloid leukemia (AML), chronic myelogenous leukemia, myelodysplastic syndrome, multiple myeloma, and acute lymphocytic leukemia. In some embodiments, the hematological cancer is multiple myeloma.

[0292] In some embodiments, the multispecific molecules disclosed herein further comprise a cytokine molecule, e.g., one or two cytokine molecules. In some embodiments, the cytokine molecule is selected from interleukin-2 (IL-2), interleukin-7 (IL-7), interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-18 (IL-18), interleukin-21 (IL-21), or interferon gamma, or a fragment, variant, or combination thereof. In some embodiments, it is a monomer or dimer. In some embodiments, the cytokine molecule further comprises a receptor dimerization domain, e.g., an IL15R alpha dimerization domain. In some embodiments, the cytokine molecule (e.g., IL-15) and the receptor dimerization domain (e.g., the IL15R alpha dimerization domain) are not covalently linked, e.g., are noncovalently associated.

[0293] In some embodiments, the multispecific molecules disclosed herein comprise: (i) an anti-TCRβ antibody molecule (e.g., an anti-TCRβ antibody molecule described herein), and (ii) a tumor-targeting antibody molecule (e.g., as described herein, e.g., BCMA, FcRH5, CD19, CD22, CD33, CD123, FcRH5, CD179a, if The antibodies include antibody molecules that bind to blood antigens selected from one or more of CLEC12 or CLEC13.

[0294] In some embodiments, the multispecific molecules disclosed herein comprise (i) an anti-TCRβV antibody molecule, (ii) a tumor-targeting antibody molecule, and a cytokine molecule described herein, e.g., an IL-12 cytokine molecule.

[0295] In some embodiments, the multispecific molecule comprises an anti-TCRβV antibody molecule described herein and a tumor-targeting antibody molecule that binds to one or both of BCMA or FcRH5. In some embodiments, the multispecific molecule further comprises an IL-12 cytokine molecule. The multispecific molecule can be used to treat hematological cancers that express BCMA or FcRH5, such as multiple myeloma.

[0296] In some embodiments, the multispecific molecule comprises an anti-TCRβV antibody molecule described herein and a tumor-targeting antibody molecule that binds to one or more of CD19, CD22, or CD123. In some embodiments, the multispecific molecule further comprises an IL-12 cytokine molecule. The multispecific molecule can be used to treat hematological cancers that express CD19, CD22, or CD123, such as leukemia or lymphoma. In some embodiments, the CD19, CD22, or CD123-expressing hematological cancer is selected from B-cell or T-cell malignancies, such as Hodgkin's lymphoma, non-Hodgkin's lymphoma (e.g., B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma, hairy cell lymphoma), acute myeloid leukemia (AML), chronic myelogenous leukemia, myelodysplastic syndrome, multiple myeloma, and acute lymphocytic leukemia. In some embodiments, the hematological cancer is multiple myeloma.

[0297] In some embodiments, the multispecific molecules disclosed herein further comprise an immunoglobulin constant region (e.g., Fc region) selected from the heavy chain constant regions of IgG1, IgG2, and IgG4, more particularly, the heavy chain constant region of human IgG1, IgG2, or IgG4. In some embodiments, the immunoglobulin constant region (e.g., Fc region) is linked, e.g., covalently linked, to one or more of a tumor targeting moiety, an immune cell engager, a cytokine molecule, or a stromal-modifying moiety. In some embodiments, the interface of the first and second immunoglobulin chain constant regions (e.g., Fc region) is altered, e.g., mutated, to increase or decrease dimerization, e.g., compared to an unengineered interface. In some embodiments, dimerization of immunoglobulin chain constant regions (e.g., Fc regions) provides one or more of paired holes and protrusions ("knobs-in-holes"), electrostatic interactions, or strand exchange at the Fc interface of the first and second Fc regions, thereby forming a higher ratio of heteromultimers:homomultimers, e.g., compared to an unengineered interface. In some embodiments, the multispecific molecules disclosed herein further comprise a linker, e.g., a linker described herein, optionally selected from a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, or a non-helical linker.

[0298] In some embodiments, the multispecific molecule comprises at least two non-contiguous polypeptide chains. In some embodiments, the multispecific molecule comprises the following composition: A,B-[dimerization module]-C,-D where: (1) The dimerization module is an immunoglobulin constant domain, e.g., a heavy chain constant domain. (e.g., a homodimeric or heterodimeric heavy chain constant region, e.g., an Fc region), or a constant domain of an immunoglobulin variable region (e.g., a Fab region), (2) A, B, C, and D are independently absent, or (i) an antigen-binding domain that preferentially binds to a first immune cell engager comprising an anti-TCRβV antibody molecule disclosed herein, (ii) a tumor-targeting moiety (e.g., a tumor-targeting antibody molecule described herein), (iii) a second immune cell engager selected from a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, (iv) a cytokine molecule, or (v) a stromal-modifying moiety, with the proviso that: At least one, two, or three of A, B, C, and D comprise an antigen-binding domain that preferentially binds to a TCRβV region disclosed herein; and Any of the remaining A, B, C, and D are absent or comprise one of a tumor-targeting moiety, a second immune cell engager, a cytokine molecule, or a stromal-modifying moiety. This is subject to the following conditions.

[0299] In some embodiments, the dimerization module comprises one or more immunoglobulin chain constant regions (e.g., Fc regions) comprising one or more of paired holes and protrusions ("knobs-in-holes"), electrostatic interactions, or strand exchange. In some embodiments, the one or more immunoglobulin chain constant regions (e.g., Fc regions) comprise an amino acid substitution at one or more of positions selected from: 347, 349, 350, 351, 366, 368, 370, 392, 394, 395, 397, 398, 399, 405, 407, or 409 of the Fc region of, for example, a human IgG1. In some embodiments, one or more immunoglobulin constant regions (e.g., Fc regions) comprise an amino acid substitution selected from T366S, L368A, or Y407V (e.g., corresponding to a pore or hole), or T366W (e.g., corresponding to a protrusion or knob), or a combination thereof.

[0300] In some embodiments, the multispecific molecule comprises a linker, for example, between the antigen binding domain of an anti-TCRβ antibody molecule disclosed herein and a tumor targeting moiety, between the antigen binding domain of an anti-TCRβ antibody molecule disclosed herein and a second immune cell engager, between the antigen binding domain of an anti-TCRβ antibody molecule disclosed herein and a cytokine molecule, between the antigen binding domain of an anti-TCRβ antibody molecule disclosed herein and a stromal-modifying moiety, between a second immune cell engager and a cytokine molecule, between a second immune cell engager and a stromal-modifying moiety, a cytokine molecule and the stromal-modifying moiety, between the antigen-binding domain of the anti-TCRβ antibody molecule disclosed herein and the dimerization module, between the second immune cell engager and the dimerization module, between the cytokine molecule and the dimerization module, between the stromal-modifying moiety and the dimerization module, between the tumor targeting moiety and the dimerization module, between the tumor targeting moiety and the cytokine molecule, between the tumor targeting moiety and the second immune cell engager, or between the tumor targeting moiety and the antigen-binding domain of the anti-TCRβ antibody molecule disclosed herein. In some embodiments, the linker is selected from a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, or a non-helical linker. In some embodiments, the linker is a peptide linker. In some embodiments, the peptide linker comprises Gly and Ser. In some embodiments, the peptide linker comprises an amino acid sequence selected from SEQ ID NOs: 142-145 or 175-178.

[0301] In some embodiments of the methods or compositions for use disclosed herein, the disease is selected from a hematological cancer, a solid tumor, a metastatic cancer, a soft tissue tumor, a metastatic lesion, or a combination thereof. It is a cancer of choice.

[0302] In some embodiments of the methods or compositions for use disclosed herein, the cancer is a solid tumor selected from melanoma, pancreatic cancer (e.g., pancreatic adenocarcinoma), breast cancer, colorectal cancer (CRC), lung cancer (e.g., small cell or non-small cell lung cancer), skin cancer, ovarian cancer, or liver cancer. In some embodiments, the cancer is melanoma or CRC.

[0303] In some embodiments of the methods or compositions for use disclosed herein, the cancer is a B-cell or T-cell malignancy, e.g., a hematological cancer selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma (e.g., B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia), acute myeloid leukemia (AML), chronic myelogenous leukemia, myelodysplastic syndrome, multiple myeloma, or acute lymphocytic leukemia. In some embodiments, the hematological cancer is multiple myeloma. In some embodiments, the hematological cancer is CLL or DLBCL.

[0304] In some embodiments of the compositions for use or methods disclosed herein, the subject-derived sample comprises a blood sample, e.g., a peripheral blood sample, a biopsy, e.g., a tumor biopsy, or a bone marrow sample. In some embodiments, the sample comprises a biological sample containing immune effector cells, e.g., T cells or NK cells. In some embodiments, the T cells are CD4 T cells, CD8 T cells (e.g., effector T cells or memory T cells (e.g., memory effector T cells (e.g., T EM Cells, e.g., T EMRA cells), or tumor-infiltrating lymphocytes (TILs).

[0305] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.Methods and materials similar or equivalent to those described herein can be used in the practice or testing of this invention, and suitable methods and materials are described below.All publications, patent applications, patents, and other references described herein are incorporated by reference in their entirety.In the event of any discrepancy, the present specification, including definitions, will prevail.In addition, materials, methods, and examples are merely illustrative and are not intended to be limiting.

[0306] Other features and advantages of the invention will be apparent from the following detailed description and claims. The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with the color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Brief explanation of the drawings]

[0307] [Figure 1A] Figures 1A-1B show alignments of the mouse VH and VL framework 1, CDR1, framework 2, CDR2, framework 3, CDR3, and framework 4 regions of the antibody A source with their respective humanized sequences. Kabat CDRs are shown in bold, Chothia CDRs in italics, and combined CDRs in boxes. Backmutated framework positions are double underlined. Figure 1A shows the VH sequences of mouse antibody A (SEQ ID NO: 1) and humanized antibody AH (SEQ ID NO: 9). Figure 1B shows the VL sequences of mouse antibody A (SEQ ID NO: 2) and humanized antibody AH (SEQ ID NO: 10 and SEQ ID NO: 11). [Figure 1B] FIG. 1B shows the VL sequences of murine antibody A (SEQ ID NO: 2) and humanized antibody AH (SEQ ID NO: 10 and SEQ ID NO: 11). [Figure 2A]Figures 2A-2B show alignments of the mouse VH and VL framework 1, CDR1, framework 2, CDR2, framework 3, CDR3, and framework 4 regions of antibody B source with their respective humanized sequences. Kabat CDRs are shown in bold, Chothia CDRs in italics, and combined CDRs in boxes. Backmutated framework positions are double underlined. Figure 2A shows the VH sequences of mouse antibody B (SEQ ID NO: 15) and humanized VH sequences BH.1A-BH.1C (SEQ ID NOs: 23-25). Figure 2B shows the VL sequences of mouse antibody B (SEQ ID NO: 16) and humanized VL sequences BH.1D-BH.1H (SEQ ID NOs: 26-30). [Figure 2B-1] FIG. 2B shows the VL sequences of mouse antibody B (SEQ ID NO: 16) and humanized VL sequences BH.1D to BH.1H (SEQ ID NOs: 26 to 30). [Figure 2B-2] FIG. 2B shows the VL sequences of mouse antibody B (SEQ ID NO: 16) and humanized VL sequences BH.1D to BH.1H (SEQ ID NOs: 26 to 30). [Figure 3]FIG. 1 shows a phylogenetic tree of TCRBV gene families and subfamilies to which the corresponding antibodies were mapped. The 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 entitled "TCR beta V (TCRβV)." [Figure 4A-1]Figures 4A-4C show human CD3+ T cells activated with anti-TCR Vβ13.1 antibody (AH.1) for 6 days. Human CD3+ T cells were isolated using magnetic bead separation (negative selection) and activated with immobilized (plate-coated) anti-TCR Vβ13.1 (AH.1) or anti-CD3ε (OKT3) antibodies at 100 nM for 6 days. Figure 4A shows two scatter plots (left: activated with OKT3; right: activated with AH.1) of expanded T cells assessed for TCR Vβ13.1 surface expression using anti-TCR Vβ13.1 (AH.1) followed by a secondary fluorochrome-conjugated antibody for flow cytometry analysis. Figure 4B shows the percentage (%) of TCR Vβ13.1-positive T cells activated by anti-TCR Vβ13.1 (AH.1) or anti-CD3e (OKT3) versus total T cells (CD3+). Figure 4C shows the relative cell count obtained by counting the number of events in each T cell subset gate (CD3 or TCR Vβ13.1) at a constant rate of 60 μl / min for 20 seconds. Data are shown as average values ​​from three donors. [Figure 4A-2] Figure 4A shows two scatter plots (left: activated with OKT3; right: activated with AH.1) of expanded T cells assessed for TCR Vβ13.1 surface expression using anti-TCR Vβ13.1 (AH.1) followed by a secondary fluorochrome-conjugated antibody for flow cytometry analysis. [Figure 4B] FIG. 4B is a plot of the percentage (%) of TCR Vβ13.1 positive T cells activated by anti-TCR Vβ13.1 (AH.1) or anti-CD3e (OKT3) versus total T cells (CD3+). [Figure 4C] Figure 4C shows relative cell counts obtained by counting the number of events in each T cell subset gate (CD3 or TCR Vβ13.1) for 20 seconds at a constant rate of 60 μl / min. Data are shown as average values ​​from three donors. [Figure 5A]Figures 5A-5B show the cytolytic activity of human CD3+ T cells activated with anti-TCR Vβ13.1 antibody (AH.1) against the transformed cell line RPMI8226. Figure 5A shows target cell lysis of human CD3+ T cells activated with AH.1 or OKT3. Human CD3+ T cells were isolated using magnetic bead separation (negative selection) and activated with immobilized (plate-coated) AH.1 or OKT3 at the indicated concentrations for 4 days before coculture with RPMI8226 cells at a 5:1 (E:T) ratio for 2 days. Samples were then analyzed for RPMI8226 cell lysis by FACS staining for CFSE / CD138-labeled and membrane-impermeable DNA dye (DRAQ7) using flow cytometry analysis. Figure 5B shows target cell lysis of human CD3+ T cells activated with AH.1 or OKT3 incubated with RPMI-8226 at a 5:1 (E:T) ratio for 6 days, followed by cytolysis analysis of RPMI8226 cells as described above. The percentage (%) of target cell lysis was determined by normalizing to basal target cell lysis (i.e., without antibody treatment) using the following formula: [(x - basal) / (100% - basal), where x is the cytolysis of the sample]. Data shown are representative of n = 1 donor. [Figure 5B] Figure 5B shows target cell lysis of human CD3+ T cells activated with AH.1 or OKT3 incubated with RPMI-8226 at a 5:1 (E:T) ratio for 6 days, followed by cytolysis analysis of RPMI8226 cells as described above. The percentage (%) of target cell lysis was determined by normalizing to basal target cell lysis (i.e., without antibody treatment) using the following formula: [(x - basal) / (100% - basal), where x is the cytolysis of the sample]. Data shown are representative of n = 1 donor. [Figure 6A]Figures 6A-6B show IFNg production by human PBMCs activated with the indicated antibodies. Human PBMCs were isolated from whole blood from the indicated number of donors, followed by solid-phase (plate-coated) stimulation with the indicated antibodies at 100 Nm. Supernatants were collected on days 1, 2, 3, 5, or 6. Figure 6A is a graph comparing IFNg production in human PBMCs activated with the indicated antibodies, activated with an anti-TCR Vβ13.1 antibody (AH.1 or AH.2) or an anti-CD3e antibody (OKT3 or SP34-2) on days 1, 2, 3, 5, or 6 after activation. Figure 6B shows IFNg production in human PBMCs activated with the indicated antibodies, activated with the indicated anti-TCR Vβ13.1 antibody or anti-CD3e antibody (OKT3) on days 1, 2, 3, 5, or 6 after activation. [Figure 6B] Figure 6B shows IFNg production in human PBMCs activated with the indicated anti-TCR Vβ13.1 antibodies or anti-CD3e antibody (OKT3) on days 1, 2, 3, 5, or 6 after activation. [Figure 7A] Figures 7A-7B show IL-2 production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described in Figures 6A-6B was used. [Figure 7B] Figures 7A-7B show IL-2 production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described in Figures 6A-6B was used. [Figure 8A] Figures 8A-8B show IL-6 production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described in Figures 6A-6B was used. [Figure 8B] Figures 8A-8B show IL-6 production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described in Figures 6A-6B was used. [Figure 9A]Figures 9A-9B show TNF-α production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described in Figures 6A-6B was used. [Figure 9B] Figures 9A-9B show TNF-α production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described in Figures 6A-6B was used. [Figure 10A] Figures 10A-10B show IL-1β production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described in Figures 6A-6B was used. [Figure 10B] Figures 10A-10B show IL-1β production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described in Figures 6A-6B was used. [Figure 11A] Figures 11A-11B are graphs showing the delayed kinetics of IFNg secretion in human PBMCs activated with the anti-TCR Vβ13.1 antibody AH.1 compared to PBMCs activated with the anti-CD3e antibody OKT3. Figure 11A shows IFNg secretion data from four donors. Figure 11B shows IFNg secretion data from an additional four donors. Data shown are representative of n=8 donors. [Figure 11B] Figure 11B shows IFNg secretion data from four additional donors. Data shown are representative of n=8 donors. [Figure 12] FIG. 1 shows an increase in CD8+ TSCM and Tempra T cell subsets in human PBMCs activated with anti-TCR Vβ13.1 antibodies (AH.1 or AH.2) compared to PBMCs activated with anti-CD3e antibodies (OKT3 or SP34-2). [Figure 13A]Figures 13A-13F show the characteristics of anti-TCRVb antibodies. Figure 13A is a graph showing the proliferation of T cells activated with anti-CD3 (OKT3) or anti-TCRVb antibodies. Figure 13B shows the selective expansion of CD45RA+ effector memory CD8+ and CD4+ T cells (TEMRA) using anti-TCRVb antibodies. Tn = naive T cells; Tscm = stem cell memory T cells; Tcm = central memory T cells; Tem = effector memory T cells; TEMRA = effector memory CD45RA+ T cells. Figure 13C is a graph showing IFN-γ secretion by PBMCs stimulated with anti-TCRVb or anti-CD3 antibodies. Figure 13D shows target cell lysis by T cells stimulated with anti-TCRVb or anti-CD3 antibodies. Cells were stimulated for 4 days, followed by 2 days of incubation with multiple myeloma target cells to assess cell killing. Figure 13E is a graph showing perforin secretion by T cells stimulated with anti-TCRVb antibody or anti-CD3 antibody. Perforin was analyzed by FACS staining in TCRVB-positive and TCRVB-negative T cells in PBMCs after stimulation with 100 ng / ml plate-bound antibody for 5 days. Figure 13F is a graph showing granzyme B secretion by T cells stimulated with anti-TCRVb antibody or anti-CD3 antibody. Granzyme B was analyzed by FACS staining in TCRVB-positive and TCRVB-negative T cells in PBMCs after stimulation with 100 ng / ml plate-bound antibody for 5 days. [Figure 13B] Figure 13B shows the selective expansion of CD45RA+ effector memory CD8+ and CD4+ T cells (TEMRA) cells using anti-TCRVb antibodies. Tn = naive T cells; Tscm = stem cell memory T cells; Tcm = central memory T cells; Tem = effector memory T cells; Temra = effector memory CD45RA+ T cells. [Figure 13C] Figure 13C is a graph showing IFN-g secretion by PBMCs stimulated with anti-TCRVb antibody or anti-CD3 antibody. [Figure 13D]Figure 13D shows target cell lysis by T cells stimulated with anti-TCRVb or anti-CD3 antibodies. Cells were stimulated for 4 days and then incubated with multiple myeloma target cells for 2 days to assess cell killing. [Figure 13E] Figure 13E is a graph showing perforin secretion by T cells stimulated with anti-TCRVb or anti-CD3 antibodies. Perforin was analyzed by FACS staining in TCRVb-positive and TCRVb-negative T cells in PBMCs after 5 days of stimulation with 100 ng / ml plate-bound antibody. [Figure 13F] Figure 13F is a graph showing granzyme B by T cells stimulated with anti-TCRVb or anti-CD3 antibodies. Granzyme B was analyzed by FACS staining in TCRVb-positive and TCRVb-negative T cells in PBMCs after stimulation with 100 ng / ml plate-bound antibody for 5 days. [Figure 14A] Figures 14A-14B show the production of IL-2 and IL-15 and the expansion of human NK cells following stimulation of PBMCs with anti-TCRVb antibody at a dose of 100 nM for 6 days. Figure 14A shows the secretion of IL-2 or IL-15 in T cells stimulated with anti-TCRVb antibody or anti-CD3 antibody. Figure 14B shows flow cytometry dot plots showing NKp46 staining versus CD56 antibody staining in cells stimulated with anti-TCRVb antibody or anti-CD3 antibody, or a control sample. [Figure 14B-1] Figure 14B shows flow cytometry dot plots showing NKp46 staining versus CD56 antibody staining in cells stimulated with anti-TCRVb or anti-CD3 antibodies, or control samples. [Figure 14B-2] Figure 14B shows flow cytometry dot plots showing NKp46 staining versus CD56 antibody staining in cells stimulated with anti-TCRVb or anti-CD3 antibodies, or control samples. [Figure 15A] 15A to 15C are diagrams showing cytokine secretion in PBMCs stimulated with anti-TCRVb antibody or anti-CD3 antibody. [Figure 15B] 15A to 15C are diagrams showing cytokine secretion in PBMCs stimulated with anti-TCRVb antibody or anti-CD3 antibody. [Figure 15C] 15A to 15C are diagrams showing cytokine secretion in PBMCs stimulated with anti-TCRVb antibody or anti-CD3 antibody. [Figure 16A] Figures 16A-16B show killing of MM cells by dual-targeting BCMA-TCRvb antibody molecules. Figure 16A shows in vitro killing by one of the following dual-targeting antibody molecules: BCMA-TCRVb (molecule I), BCMA-CD3, or control-TCRVb; or an isotype control. Figure 16B shows in vivo killing of MM cells by dual-targeting BCMA-TCRVb antibody (molecule I). [Figure 16B] Figure 16B shows in vivo killing of MM cells by the dual-targeted BCM-TCRVb antibody (molecule I). [Figure 17] Figure 1 shows lysis of MM target cells using a dual-targeting antibody (molecule E) that recognizes FcRH5 on one arm and TCRVb on the other arm. [Figure 18A] Figures 18A-18B show cytokine production from human PBMCs activated with anti-TCR Vβ8a antibody (BH.1) compared to those activated with anti-CD3ε antibody (OKT3 or SP34-2). Figure 18A shows that human PBMCs activated with anti-TCR Vβ8a antibody (BH.1) produce similar or reduced levels of IFNγ. Figure 18B shows that human PBMCs activated with anti-TCR Vβ8a antibody (BH.1) produce higher levels of IL-2 compared to those activated with anti-CD3ε antibody (OKT3 or SP34-2). Data shown are representative of n=6 donors. [Figure 18B]Figure 18B shows that human PBMCs activated with anti-TCR Vβ8a antibody (BH.1) produce higher levels of IL-2 when compared to those activated with anti-CD3ε antibodies (OKT3 or SP34-2). Data shown are representative of n=6 donors. [Figure 19A] Figures 19A-19C show cytokine production from human PBMCs activated with anti-TCR Vβ8a antibody (BH.1). Human PBMCs activated with anti-TCR Vβ8a antibody (BH.1) produced significantly less IL-6 (Figure 19A), IL1b (Figure 19B), and less TNFa (Figure 19C) compared to PBMCs activated with anti-CD3ε antibodies (OKT3 or SP34-2). Data shown are representative of n=6 donors. [Figure 19B] Figures 19A-19C show cytokine production from human PBMCs activated with anti-TCR Vβ8a antibody (BH.1). Human PBMCs activated with anti-TCR Vβ8a antibody (BH.1) produced significantly less IL-6 (Figure 19A), IL1b (Figure 19B), and less TNFa (Figure 19C) compared to PBMCs activated with anti-CD3ε antibodies (OKT3 or SP34-2). Data shown are representative of n=6 donors. [Figure 19C] Figures 19A-19C show cytokine production from human PBMCs activated with anti-TCR Vβ8a antibody (BH.1). Human PBMCs activated with anti-TCR Vβ8a antibody (BH.1) produced significantly less IL-6 (Figure 19A), IL1b (Figure 19B), and less TNFa (Figure 19C) compared to PBMCs activated with anti-CD3ε antibodies (OKT3 or SP34-2). Data shown are representative of n=6 donors. [Figure 20A]Figures 20A-20E show cytokine production from human PBMCs activated with anti-TCRβVD antibody compared to a control anti-CD3e antibody (OKT3). Figure 20A shows that human PBMCs activated with anti-TCRβVD antibody produce similar or reduced levels of IFNγ. Figure 20B shows that human PBMCs activated with anti-TCRβVD antibody produce higher levels of IL-2 compared to those activated with anti-CD3ε antibody (OKT3). Human PBMCs activated with anti-TCRβVD antibody do not significantly produce IL-1β (Figure 20C), IL-6 (Figure 20D), or TNF-alpha (Figure 20E). Data shown are representative of n=4 donors. [Figure 20B] Figures 20A-20E show cytokine production from human PBMCs activated with anti-TCRβVD antibody compared to a control anti-CD3e antibody (OKT3). Figure 20A shows that human PBMCs activated with anti-TCRβVD antibody produce similar or reduced levels of IFNγ. Figure 20B shows that human PBMCs activated with anti-TCRβVD antibody produce higher levels of IL-2 compared to those activated with anti-CD3ε antibody (OKT3). Human PBMCs activated with anti-TCRβVD antibody do not significantly produce IL-1β (Figure 20C), IL-6 (Figure 20D), or TNF-alpha (Figure 20E). Data shown are representative of n=4 donors. [Figure 20C]Figures 20A-20E show cytokine production from human PBMCs activated with anti-TCRβVD antibody compared to a control anti-CD3e antibody (OKT3). Figure 20A shows that human PBMCs activated with anti-TCRβVD antibody produce similar or reduced levels of IFNγ. Figure 20B shows that human PBMCs activated with anti-TCRβVD antibody produce higher levels of IL-2 compared to those activated with anti-CD3ε antibody (OKT3). Human PBMCs activated with anti-TCRβVD antibody do not significantly produce IL-1β (Figure 20C), IL-6 (Figure 20D), or TNF-alpha (Figure 20E). Data shown are representative of n=4 donors. [Figure 20D] Figures 20A-20E show cytokine production from human PBMCs activated with anti-TCRβVD antibody compared to a control anti-CD3e antibody (OKT3). Figure 20A shows that human PBMCs activated with anti-TCRβVD antibody produce similar or reduced levels of IFNγ. Figure 20B shows that human PBMCs activated with anti-TCRβVD antibody produce higher levels of IL-2 compared to those activated with anti-CD3ε antibody (OKT3). Human PBMCs activated with anti-TCRβVD antibody do not significantly produce IL-1β (Figure 20C), IL-6 (Figure 20D), or TNF-alpha (Figure 20E). Data shown are representative of n=4 donors. [Figure 20E]Figures 20A-20E show cytokine production from human PBMCs activated with anti-TCRβVD antibody compared to a control anti-CD3e antibody (OKT3). Figure 20A shows that human PBMCs activated with anti-TCRβVD antibody produce similar or reduced levels of IFNγ. Figure 20B shows that human PBMCs activated with anti-TCRβVD antibody produce higher levels of IL-2 compared to those activated with anti-CD3ε antibody (OKT3). Human PBMCs activated with anti-TCRβVD antibody do not significantly produce IL-1β (Figure 20C), IL-6 (Figure 20D), or TNF-alpha (Figure 20E). Data shown are representative of n=4 donors. [Figure 21A] Figures 21A-21B show cytokine production from human PBMCs activated with an anti-TCR Vβ5 antibody (Antibody E). Figure 21A shows that human PBMCs activated with an anti-TCR Vβ5 antibody produce similar or reduced levels of IFNγ compared to PBMCs activated with an anti-CD3ε antibody (OKT3 or SP34-2). Figure 21B shows that human PBMCs activated with an anti-TCR Vβ5 1 antibody produce higher levels of IL-2 when compared to those activated with an anti-CD3ε antibody (OKT3 or SP34-2). Data shown are representative of n=4 donors. [Figure 21B] Figure 21B shows that human PBMCs activated with anti-TCR Vβ5 1 antibodies produce higher levels of IL-2 when compared to those activated with anti-CD3ε antibodies (OKT3 or SP34-2). Data shown are representative of n=4 donors. [Figure 22A]Figures 22A-22D show cytokine production from human PBMCs activated with an anti-TCR Vβ5 antibody (Antibody E). Human PBMCs activated with anti-TCR Vβ5 antibodies produce significantly less IL-1β (Figure 22A), IL-6 (Figure 22B), TNF-alpha (Figure 22C), or IL-10 (Figure 22D) compared to PBMCs activated with anti-CD3ε antibodies (OKT3 or SP34-2). Data shown are representative of n=4 donors. [Figure 22B] Figures 22A-22D show cytokine production from human PBMCs activated with an anti-TCR Vβ5 antibody (Antibody E). Human PBMCs activated with anti-TCR Vβ5 antibodies produce significantly less IL-1β (Figure 22A), IL-6 (Figure 22B), TNF-alpha (Figure 22C), or IL-10 (Figure 22D) compared to PBMCs activated with anti-CD3ε antibodies (OKT3 or SP34-2). Data shown are representative of n=4 donors. [Figure 22C] Figures 22A-22D show cytokine production from human PBMCs activated with an anti-TCR Vβ5 antibody (Antibody E). Human PBMCs activated with anti-TCR Vβ5 antibodies produce significantly less IL-1β (Figure 22A), IL-6 (Figure 22B), TNF-alpha (Figure 22C), or IL-10 (Figure 22D) compared to PBMCs activated with anti-CD3ε antibodies (OKT3 or SP34-2). Data shown are representative of n=4 donors. [Figure 22D] Figures 22A-22D show cytokine production from human PBMCs activated with an anti-TCR Vβ5 antibody (Antibody E). Human PBMCs activated with anti-TCR Vβ5 antibodies produce significantly less IL-1β (Figure 22A), IL-6 (Figure 22B), TNF-alpha (Figure 22C), or IL-10 (Figure 22D) compared to PBMCs activated with anti-CD3ε antibodies (OKT3 or SP34-2). Data shown are representative of n=4 donors. [Figure 23A]Figures 23A-23E show cytokine production from human PBMCs activated by dual-targeting (bispecific molecules) containing an anti-TCRβV-binding moiety and a BCMA-binding moiety. Figure 23A shows that human PBMCs activated by the bispecific molecules produce similar or reduced levels of IFNγ as PBMCs activated with an anti-CD3ε antibody (OKT3). Figure 23B shows that human PBMCs activated by the bispecific molecules produce higher levels of IL-2 compared to PBMCs activated with an anti-CD3ε antibody (OKT3). Human PBMCs activated by the bispecific molecules do not significantly produce IL-1 beta (Figure 23C), IL-6 (Figure 23C), TNF alpha (Figure 23E), or IL-10 (Figure 23F). Data shown are representative of n=3 donors. [Figure 23B] Figure 23B shows that human PBMCs activated with the bispecific molecule produce higher levels of IL-2 when compared to PBMCs activated with an anti-CD3ε antibody (OKT3). Human PBMCs activated with the bispecific molecule do not significantly produce IL-1 beta (Figure 23C), IL-6 (Figure 23C), TNF alpha (Figure 23E), or IL-10 (Figure 23F). Data shown are representative of n=3 donors. [Figure 23C] Figure 23B shows that human PBMCs activated with the bispecific molecule produce higher levels of IL-2 when compared to PBMCs activated with an anti-CD3ε antibody (OKT3). Human PBMCs activated with the bispecific molecule do not significantly produce IL-1 beta (Figure 23C), IL-6 (Figure 23C), TNF alpha (Figure 23E), or IL-10 (Figure 23F). Data shown are representative of n=3 donors. [Figure 23D]Figure 23B shows that human PBMCs activated with the bispecific molecule produce higher levels of IL-2 when compared to PBMCs activated with an anti-CD3ε antibody (OKT3). Human PBMCs activated with the bispecific molecule do not significantly produce IL-1 beta (Figure 23C), IL-6 (Figure 23C), TNF alpha (Figure 23E), or IL-10 (Figure 23F). Data shown are representative of n=3 donors. [Figure 23E] Figure 23B shows that human PBMCs activated with the bispecific molecule produce higher levels of IL-2 when compared to PBMCs activated with an anti-CD3ε antibody (OKT3). Human PBMCs activated with the bispecific molecule do not significantly produce IL-1 beta (Figure 23C), IL-6 (Figure 23C), TNF alpha (Figure 23E), or IL-10 (Figure 23F). Data shown are representative of n=3 donors. [Figure 23F] Figure 23B shows that human PBMCs activated with the bispecific molecule produce higher levels of IL-2 when compared to PBMCs activated with an anti-CD3ε antibody (OKT3). Human PBMCs activated with the bispecific molecule do not significantly produce IL-1β (Figure 23C), IL-6 (Figure 23C), TNF-alpha (Figure 23E), or IL-10 (Figure 23F). Data shown are representative of n=3 donors. [Figure 24A]Figures 24A-24B show the structures and sequences of eight TCRβV proteins from seven different subfamilies: the TCRβV6 subfamily (showing TCRβV6-5 and TCRβV6-4), the TCRβV28 subfamily, the TCRβV19 subfamily, the TCRβV9 subfamily, the TCRβV5 subfamily, the TCRβV20 subfamily, and the TCRβV12 subfamily. Figure 24A shows a structural alignment of the different TCRβV proteins. The circled regions represent the outward-facing regions containing the proposed binding sites for the anti-TCRβV antibodies disclosed herein. Figure 24B shows an amino acid sequence alignment of the proteins shown in Figure 24A (SEQ ID NOS: 3449-3456, respectively, in order of appearance). The various TCRβV proteins (from the seven different TCRβV subfamilies) have diverse sequences but share conserved (similar) structure and function. [Figure 24B] Figure 24B shows an amino acid sequence alignment of the proteins shown in Figure 24A (SEQ ID NOS: 3449-3456, respectively, in order of appearance). The various TCRβV proteins (from seven different TCRβV subfamilies) have diverse sequences but share conserved (similar) structure and function. [Figure 25A] Figures 25A-25J show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 25B] Figures 25A-25J show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 25C]Figures 25A-25J show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 25D] Figures 25A-25J show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 25E] Figures 25A-25J show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 25F] Figures 25A-25J show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 25G] Figures 25A-25J show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 25H]Figures 25A-25J show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 25I] Figures 25A-25J show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 25J] Figures 25A-25J show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 26A] Figures 26A-26H show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing an anti-CD3e antibody (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 26B] Figures 26A-26H show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing an anti-CD3e antibody (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 26C]Figures 26A-26H show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing an anti-CD3e antibody (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 26D] Figures 26A-26H show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing an anti-CD3e antibody (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 26E] Figures 26A-26H show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing an anti-CD3e antibody (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 26F] Figures 26A-26H show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing an anti-CD3e antibody (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 26G] Figures 26A-26H show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing an anti-CD3e antibody (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 26H]Figures 26A-26H show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing an anti-CD3e antibody (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 27A] Figures 27A-27L show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 27B] Figures 27A-27L show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 27C] Figures 27A-27L show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 27D] Figures 27A-27L show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 27E]Figures 27A-27L show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 27F] Figures 27A-27L show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 27G] Figures 27A-27L show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 27H] Figures 27A-27L show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 27I] Figures 27A-27L show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 27J]Figures 27A-27L show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 27K] Figures 27A-27L show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 27L] Figures 27A-27L show cytokine or chemokine secretion in PBMCs activated with anti-TCRVb antibodies (molecule H), a control isotype (122), or bispecific anti-TCRVb antibodies (AH.1, BH.1) containing anti-CD3e antibodies (OKT3). Data shown are representative of n=2 donors and are representative of two independent experiments. [Figure 28] Graph showing mean tumor volume in NOD / SCID / IL-2Rγ null (NSG) mice implanted with Raji-luc cells on days 10-28. Stars indicate PBMC implantation. Open triangles indicate antibody treatment with the indicated antibodies. [Figure 29A]Figures 29A-B show the mean tumor burden (total flux) in NOD / SCID / IL-2Rγ null (NSG) mice implanted with cancer cells and treated with the indicated antibodies. NSG mice were implanted with PBMCs on day 1, followed by cancer cell injection on day 7 (Raji-luc in Figure 29A; K562-Luc control in Figure 29B). Antibody treatment with the indicated antibodies began on day 16. Figure 29A shows the mean tumor burden from days 16 to 37 in NOD / SCID / IL-2Rγ null (NSG) mice implanted with Raji-luc cells. Figure 29B shows the mean tumor burden from days 16 to 30 in animals implanted with K562-luc cells. [Figure 29B] Figures 29A-B show the mean tumor burden (total flux) in NOD / SCID / IL-2Rγ null (NSG) mice implanted with cancer cells and treated with the indicated antibodies. NSG mice were implanted with PBMCs on day 1, followed by cancer cell injection on day 7 (Raji-luc in Figure 29A; K562-Luc control in Figure 29B). Antibody treatment with the indicated antibodies began on day 16. Figure 29A shows the mean tumor burden from days 16 to 37 in NOD / SCID / IL-2Rγ null (NSG) mice implanted with Raji-luc cells. Figure 29B shows the mean tumor burden from days 16 to 30 in animals implanted with K562-luc cells. [Figure 30] 1 is a graph showing the mean tumor volume of mean tumor burden (total flux) in NOD / SCID / IL-2Rγ null (NSG) mice implanted with RPMI-8226 cells. RPMI-8226 cells were implanted on day 1. On day 11, PBMCs were implanted into the mice, and antibody treatment began on day 17. [Figure 31A] Figures 31A-31B are graphs showing % target cell lysis at different antibody concentrations. Figure 31A shows data generated using anti-TCR Vβ13.1 / anti-CD19 (molecule F), anti-CD3 / anti-CD19, and anti-TCR Vβ13.1 (AH.1). Figure 31B shows data generated using anti-TCR Vβ13.1 / anti-BCMA (molecule G), anti-CD3 / anti-BCMA, and anti-TCR Vβ13.1 (AH.1). [Figure 31B] Figure 31B shows data generated using anti-TCR Vβ13.1 / anti-BCMA (molecule G), anti-CD3 / anti-BCMA, and anti-TCR Vβ13.1 (AH.1). [Figure 32A] Figures 32A-32F are graphs showing cytokine secretion stimulated by anti-TCR Vβ / anti-BCMA (molecule H) or anti-CD3 (OKT3) on days 1, 2, 3, and 5. Cytokines examined include IFNγ, IL-2, IL-1β, IL-6, IL-10, and TNFα (Figures 32A-32F, respectively). [Figure 32B] Figures 32A-32F are graphs showing cytokine secretion stimulated by anti-TCR Vβ / anti-BCMA (molecule H) or anti-CD3 (OKT3) on days 1, 2, 3, and 5. Cytokines examined include IFNγ, IL-2, IL-1β, IL-6, IL-10, and TNFα (Figures 32A-32F, respectively). [Figure 32C] Figures 32A-32F are graphs showing cytokine secretion stimulated by anti-TCR Vβ / anti-BCMA (molecule H) or anti-CD3 (OKT3) on days 1, 2, 3, and 5. Cytokines examined include IFNγ, IL-2, IL-1β, IL-6, IL-10, and TNFα (Figures 32A-32F, respectively). [Figure 32D] Figures 32A-32F are graphs showing cytokine secretion stimulated by anti-TCR Vβ / anti-BCMA (molecule H) or anti-CD3 (OKT3) on days 1, 2, 3, and 5. Cytokines examined include IFNγ, IL-2, IL-1β, IL-6, IL-10, and TNFα (Figures 32A-32F, respectively). [Figure 32E]Figures 32A-32F are graphs showing cytokine secretion stimulated by anti-TCR Vβ / anti-BCMA (molecule H) or anti-CD3 (OKT3) on days 1, 2, 3, and 5. Cytokines examined include IFNγ, IL-2, IL-1β, IL-6, IL-10, and TNFα (Figures 32A-32F, respectively). [Figure 32F] Figures 32A-32F are graphs showing cytokine secretion stimulated by anti-TCR Vβ / anti-BCMA (molecule H) or anti-CD3 (OKT3) on days 1, 2, 3, and 5. Cytokines examined include IFNγ, IL-2, IL-1β, IL-6, IL-10, and TNFα (Figures 32A-32F, respectively). [Figure 33A] Figures 33A-33F are graphs showing cytokine secretion stimulated by anti-TRBC1 (antibody F) or anti-CD3 (OKT3) on days 2 and 5. Cytokines examined include IFNγ, IL-2, IL-1β, IL-6, IL-10, and TNFα (Figures 33A-33F, respectively). [Figure 33B] Figures 33A-33F are graphs showing cytokine secretion stimulated by anti-TRBC1 (antibody F) or anti-CD3 (OKT3) on days 2 and 5. Cytokines examined include IFNγ, IL-2, IL-1β, IL-6, IL-10, and TNFα (Figures 33A-33F, respectively). [Figure 33C] Figures 33A-33F are graphs showing cytokine secretion stimulated by anti-TRBC1 (antibody F) or anti-CD3 (OKT3) on days 2 and 5. Cytokines examined include IFNγ, IL-2, IL-1β, IL-6, IL-10, and TNFα (Figures 33A-33F, respectively). [Figure 33D]Figures 33A-33F are graphs showing cytokine secretion stimulated by anti-TRBC1 (antibody F) or anti-CD3 (OKT3) on days 2 and 5. Cytokines examined include IFNγ, IL-2, IL-1β, IL-6, IL-10, and TNFα (Figures 33A-33F, respectively). [Figure 33E] Figures 33A-33F are graphs showing cytokine secretion stimulated by anti-TRBC1 (antibody F) or anti-CD3 (OKT3) on days 2 and 5. Cytokines examined include IFNγ, IL-2, IL-1β, IL-6, IL-10, and TNFα (Figures 33A-33F, respectively). [Figure 33F] Figures 33A-33F are graphs showing cytokine secretion stimulated by anti-TRBC1 (antibody F) or anti-CD3 (OKT3) on days 2 and 5. Cytokines examined include IFNγ, IL-2, IL-1β, IL-6, IL-10, and TNFα (Figures 33A-33F, respectively). [Figure 34] Figure 34 is a FACS plot showing the expansion of TCRvb 6-5+ T cells over 8 days using anti-TCRvb 6-5 v1. [Figure 35] FIG. 35 is a bar graph showing the expansion of TCRvb 6-5+ CD4+ and TCRvb 6-5+ CD8+ T cells over 8 days using the anti-CD3ε antibody OKT3 (100 nM). [Figure 36] Figure 36 is a bar graph showing the expansion of TCRvb 6-5+ CD4+ and TCRvb 6-5+ CD8+ T cells over 8 days using anti-TCRvb 6-5 v1 antibody (100 nM). [Figure 37] Figure 37 is a FACS plot showing the expansion of TCRvb 6-5+ T cells over 8 days using anti-TCRvb 6-5 v1 or anti-CD3ε antibody OKT3. [Figure 38A]Figure 38A is a bar graph showing the percentage of TCRβV6-5+ T cells in PBMC cultures after 8 days of culture with the indicated antibodies. Data for 5 replicates are shown. [Figure 38B] Figure 38B is a bar graph showing the percentage of TCRβV6-5+ T cells in purified T cell cultures after 8 days of culture with the indicated antibodies. Data for 5 replicates are shown. [Figure 39A] FIG. 39A is a bar graph showing the relative numbers of TCRβV 6-5+ T cells in PBMC cultures after 8 days of culture with the indicated antibodies. [Figure 39B] FIG. 39B is a bar graph showing the relative numbers of TCRβV 6-5+ T cells in PBMC cultures after 8 days of culture with the indicated antibodies. [Figure 40A] FIG. 40A is a bar graph showing the relative numbers of TCRβV 6-5+ T cells in purified T cell cultures after 8 days of culture with the indicated antibodies. [Figure 40B] FIG. 40B is a bar graph showing the relative numbers of TCRβV 6-5+ T cells in purified T cell cultures after 8 days of culture with the indicated antibodies. [Figure 41] FIG. 41 is a line graph showing total CD3+ T cell numbers (fold increase) after 8 days of T cell culture with either anti-CD3ε antibody OKT3 or anti-TCRvb 6-5 v1 antibody. [Figure 42] Figure 42 is a series of line graphs showing target cell kinetics by TCRβV6-5 v1-activated T cells or anti-CD3ε (OKT3)-activated T cells. T cells from three different donors were utilized (donor 6769, donor 9880, donor 5411). [Figure 43A] Figure 43A is a scatter plot showing the percent of T cell-mediated target cell lysis by TCRβV6-5 v1-activated T cells or anti-CD3ε (OKT3)-activated T cells without T cell preactivation. Data are presented on day 6 of co-culture between target and effector T cells. [Figure 43B]Figure 43B is a scatter plot showing the percent of T cell-mediated target cell lysis by TCRβV6-5 v1-activated T cells or anti-CD3ε (OKT3)-activated T cells with 4 days of T cell preactivation. Data are presented on day 2 of co-culture between target and effector T cells (day 4 after T cell preactivation). [Figure 44] Figure 44 is a scatter plot showing the percent of T cell-mediated target cell lysis by TCRβV6-5 v1-activated T cells or anti-CD3ε (OKT3)-activated T cells with 4 days of T cell preactivation. Data are presented on day 2 of co-culture between target and effector T cells (day 4 after T cell preactivation). [Figure 45] Figure 45 is a bar graph showing T cell-mediated target cell lysis by TCRβV6-5 v1-activated T cells or anti-CD3ε (OKT3)-activated T cells (100 nM of each antibody). Data includes seven replicates for each experimental condition. [Figure 46] Figure 46 is a series of FACS plots showing cell surface expression of CD3ε on CD4+ TCRβV6-5− or CD4+ TCRβV6-5+ T cells activated with either SP34-2 (anti-CD3ε antibody) or anti-TCRβV6-5 v1 (anti-TCRβV6-5 antibody) on days 0, 1, 2, 4, 6, or 8 after antibody activation. [Figure 47] Figure 47 is a series of FACS plots showing cell surface expression of CD3ε on CD8+ TCRβV6-5− or CD8+ TCRβV6-5+ T cells activated with either SP34-2 (anti-CD3ε antibody) or anti-TCRβV6-5 v1 (anti-TCRβV6-5 antibody) on days 0, 1, 2, 4, 6, or 8 after antibody activation. [Figure 48] Figure 48 is a series of FACS plots showing cell surface expression of TCRβV on CD4+ TCRβV 6-5- or CD4+ TCRβV 6-5+ T cells activated with either SP34-2 (anti-CD3ε antibody) or anti-TCRβV 6-5 v1 (anti-TCRβV 6-5 antibody) on days 0, 1, 2, 4, 6, or 8 after antibody activation. [Figure 49] Figure 49 is a series of FACS plots showing cell surface expression of TCRβV on CD8+ TCRβV 6-5- or CD8+ TCRβV 6-5+ T cells activated with either SP34-2 (anti-CD3ε antibody) or anti-TCRβV 6-5 v1 (anti-TCRβV 6-5 antibody) on days 0, 1, 2, 4, 6, or 8 after antibody activation. [Figure 50A] Figure 50A shows FACS plots of TCRβV 6-5+ cynomolgus T cell expansion 7 days after activation of cynomolgus PBMCs, either unstimulated (left) or stimulated with anti-TCRβV 6-5 v1 (right). PBMCs from donor DW8N (fresh PBMC sample, male, 8 years old, weighing 7.9 kg) were used. [Figure 50B] Figure 50B shows FACS plots of TCRβV 6-5+ cynomolgus T cell expansion after 7 days of activation of cynomolgus PBMCs, either unstimulated (left) or stimulated with anti-TCRβV 6-5 v1 (right). PBMCs from donor G709 (cryopreserved sample, male, 6 years old, weighing 4.7 kg) were used. [Figure 51] Figure 51 shows FACS plots and corresponding microscopy images of TCRβV 6-5+ cynomolgus T cell expansion following activation of cryopreserved donor DW8N cynomolgus monkey PBMCs: unstimulated (left), stimulated with SP34-2 (anti-CD3ε antibody) (center), or stimulated with anti-TCRβV 6-5 v1 (right). The microscopy images show cell cluster formation (indicated by circles). [Figure 52] FIG. 52 shows a diagram of a FACS plot showing FACS gating / staining of PBMCs prior to γδ T cell purification. [Figure 53] FIG. 53 shows a diagram of a FACS plot showing FACS gating / staining of purified γδ T cell populations. [Figure 54] FIG. 54 shows activation of purified γδ T cell populations with anti-CD3ε antibody (SP34-2) (left) or anti-TCRβV antibody (anti-TCRβV 6-5 v1) (right). [Figure 55A]FIG. 55A shows IFNγ release from purified γδ T cell populations activated with anti-CD3ε antibody (SP34-2), anti-TCRβV antibody (anti-TCRβV 6-5 v1), or unstimulated. [Figure 55B] FIG. 55B shows the release of TNFα from purified γδ T cell populations activated with anti-CD3ε antibody (SP34-2), anti-TCRβV antibody (anti-TCRβV 6-5 v1), or unstimulated. [Figure 55C] FIG. 55C shows IL-2 release from purified γδ T cell populations activated with anti-CD3ε antibody (SP34-2), anti-TCRβV antibody (anti-TCRβV 6-5 v1), or unstimulated. [Figure 55D] FIG. 55D shows the release of IL-17A from purified γδ T cell populations activated with anti-CD3ε antibody (SP34-2), anti-TCRβV antibody (anti-TCRβV 6-5 v1), or unstimulated. [Figure 55E] FIG. 55E shows the release of IL-1α from purified γδ T cell populations activated with anti-CD3ε antibody (SP34-2), anti-TCRβV antibody (anti-TCRβV 6-5 v1), or unstimulated. [Figure 55F] FIG. 55F shows IL-1β release from purified γδ T cell populations activated with anti-CD3ε antibody (SP34-2), anti-TCRβV antibody (anti-TCRβV 6-5 v1), or unstimulated. [Figure 55G] FIG. 55G shows IL-6 release from purified γδ T cell populations activated with anti-CD3ε antibody (SP34-2), anti-TCRβV antibody (anti-TCRβV 6-5 v1), or unstimulated. [Figure 55H] FIG. 55H shows IL-10 release from purified γδ T cell populations activated with anti-CD3ε antibody (SP34-2), anti-TCRβV antibody (anti-TCRβV 6-5 v1), or unstimulated. [Figure 56]Figure 56 shows the relative representation of all TCR alpha V-segments (TRAV gene cluster) and their variants (top), all TCR beta V-segment 6-5 variants (TRBV6-5 gene) (bottom left), and all TCR beta V-segments and variants excluding 6-5 (bottom right). [Figure 57A] Figure 57A is a FACS plot showing phenotypic markers of CD4+ T cells expanded with an anti-TCRβV antibody (anti-TCRβV 6-5 v1). Defined phenotypes include TEMRA (top left), naive / TSCM (top right), TEM (bottom left), and TCM (bottom right). [Figure 57B] Figure 57B is a FACS plot showing phenotypic markers of CD4+ T cells expanded with anti-CD3ε antibody (OKT3). Defined phenotypes include TEMRA (top left), naive / TSCM (top right), TEM (bottom left), and TCM (bottom right). [Figure 58A] Figure 58A is a FACS plot showing phenotypic markers of CD8+ T cells expanded with an anti-TCRβV antibody (anti-TCRβV 6-5 v1). Defined phenotypes include TEMRA (top left), naive / TSCM (top right), TEM (bottom left), and TCM (bottom right). [Figure 58B] Figure 58B is a FACS plot showing phenotypic markers of CD8+ T cells expanded with anti-CD3ε antibody (OKT3). Defined phenotypes include TEMRA (top left), naive / TSCM (top right), TEM (bottom left), and TCM (bottom right). [Figure 59A] Figure 59A is a bar graph showing the percentage of PD1-expressing CD4+ T cells from T cell cultures activated with anti-TCRβV antibody (anti-TCRβV 6-5 v1), anti-CD3ε antibody (OKT3), or unstimulated. [Figure 59B] Figure 59B is a bar graph showing the percentage of PD1-expressing CD8+ T cells from T cell cultures activated with anti-TCRβV antibody (anti-TCRβV 6-5 v1), anti-CD3ε antibody (OKT3), or unstimulated. [Figure 60A] Figure 60A is a bar graph showing Ki-67 expression by CD4+ T cells from T cell cultures activated with anti-TCRβV antibody (anti-TCRβV 6-5 v1), anti-CD3ε antibody (OKT3), or unstimulated. [Figure 60B] Figure 60B is a bar graph showing Ki-67 expression by CD8+ T cells from T cell cultures activated with anti-TCRβV antibody (anti-TCRβV 6-5 v1), anti-CD3ε antibody (OKT3), or unstimulated. [Figure 61A] Figure 61A is a FACS plot showing the percentage of TEMRA-like CD8+ T cells activated using an anti-TCRβV antibody (anti-TCRβV 6-5 v1) that express CD57 (18.7%). [Figure 61B] Figure 61B is a FACS plot showing the percentage of TEM-like CD8+ T cells activated using anti-CD3ε antibody (OKT3) that express CD57 (46.8%) and the percentage of TCM-like CD8+ T cells activated using anti-CD3ε antibody (OKT3) that express CD57 (18.9%). [Figure 62] Figure 62 shows a series of FACS plots showing CD27 expression by CD4+ (top) or CD8+ (bottom) T cells from T cell cultures activated with an anti-TCRβV antibody (anti-TCRβV 6-5 v1), an anti-CD3ε antibody (OKT3), or unstimulated. [Figure 63] Figure 63 shows a series of FACS plots showing the expression of OX40, 41BB, and ICOS by CD4+ (top) or CD8+ (bottom) T cells from T cell cultures activated with an anti-TCRβV antibody (anti-TCRβV 6-5 v1), an anti-CD3ε antibody (OKT3), or unstimulated. [Figure 64-1] Figure 64 shows a series of FACS plots showing the percentage of CD3+ (CD4 gated) TCRβV6-5+ T cells 1, 2, 3, 4, 5, 6, and 8 days after activation with BCMA and an anti-TCR Vβ antibody, anti-TCR Vβ 6-5 v1. [Figure 64-2]Figure 64 shows a series of FACS plots showing the percentage of CD3+ (CD4 gated) TCRβV6-5+ T cells 1, 2, 3, 4, 5, 6, and 8 days after activation with BCMA and an anti-TCR Vβ antibody, anti-TCR Vβ 6-5 v1. [Figure 65A] Figure 65A shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgG1 N297A), anti-TCRβV (anti-TCR Vβ 6-5 v1), or anti-CD3ε (OKT3) antibodies at day 0 post activation. [Figure 65B] Figure 65B shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgG1 N297A), anti-TCRβV (anti-TCR Vβ 6-5 v1), or anti-CD3ε (OKT3) antibodies at day 1 post-activation. [Figure 65C] Figure 65C shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgG1 N297A), anti-TCRβV (anti-TCR Vβ 6-5 v1), or anti-CD3ε (OKT3) antibodies at day 2 post-activation. [Figure 65D] Figure 65D shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgG1 N297A), anti-TCRβV (anti-TCR Vβ 6-5 v1), or anti-CD3ε (OKT3) antibodies at day 3 post-activation. [Figure 65E] Figure 65E shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgG1 N297A), anti-TCRβV (anti-TCR Vβ 6-5 v1), or anti-CD3ε (OKT3) antibodies at day 4 post-activation. [Figure 65F] Figure 65F shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgG1 N297A), anti-TCRβV (anti-TCR Vβ 6-5 v1), or anti-CD3ε (OKT3) antibodies at day 5 post-activation. [Figure 65G] Figure 65G shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgG1 N297A), anti-TCRβV (anti-TCR Vβ 6-5 v1), or anti-CD3ε (OKT3) antibodies at day 6 post-activation. [Figure 65H] Figure 65H shows a series of FACS plots showing the percentage of CD4+ T cells expanded using isotype control (IgG1 N297A), anti-TCRβV (anti-TCR Vβ 6-5 v1), or anti-CD3ε (OKT3) antibodies at day 8 post-activation. [Figure 66A] Figure 66A is a bar graph showing ATP production from glycolysis of T cell cultures activated with the indicated antibodies. [Figure 66B] Figure 66B is a bar graph showing ATP production from oxidative phosphorylation of T cell cultures activated with the indicated antibodies. [Figure 67] Figure 67 is a line graph showing the oxygen consumption rate (OCR) of T cells activated with the indicated antibodies from about 0 to 75 minutes. [Figure 68A] Figure 68A shows the oxygen consumption rate (OCR) of T cells activated with the indicated antibodies during basal respiration. [Figure 68B] Figure 68B shows the oxygen consumption rate (OCR) of T cells activated with the indicated antibodies during maximal respiration. [Figure 68C] Figure 68C shows the oxygen consumption rate (OCR) of T cells activated with the indicated antibodies during spare respiratory capacity. [Figure 68D] FIG. 68D is a line graph showing the areas of basal and maximum respiration shown in FIGS. 68A and 68B, respectively. [Figure 69A] Figure 69A is a bar graph showing ATP production from glycolysis of T cell cultures activated with anti-TCRβV6-5 v1 and restimulated with the indicated antibodies. [Figure 69B]Figure 69B is a bar graph showing ATP production from oxidative phosphorylation of T cell cultures activated with anti-TCRβV6-5 v1 and restimulated with the indicated antibodies. [Figure 70A] Figures 70A-70G are graphs showing the expression of IFNg, TNFa, IL-1a, IL-1b, IL-6 (CRS and neurotoxicity-associated cytokines) using BHM1710 (anti-TCRVB), reduced affinity anti-CD3 antibody (TB), and SP34 anti-CD3e antibody. [Figure 70B] Figures 70A-70G are graphs showing the expression of IFNg, TNFa, IL-1a, IL-1b, IL-6 (CRS and neurotoxicity-associated cytokines) using BHM1710 (anti-TCRVB), reduced affinity anti-CD3 antibody (TB), and SP34 anti-CD3e antibody. [Figure 70C] Figures 70A-70G are graphs showing the expression of IFNg, TNFa, IL-1a, IL-1b, IL-6 (CRS and neurotoxicity-associated cytokines) using BHM1710 (anti-TCRVB), reduced affinity anti-CD3 antibody (TB), and SP34 anti-CD3e antibody. [Figure 70D] Figures 70A-70G are graphs showing the expression of IFNg, TNFa, IL-1a, IL-1b, IL-6 (CRS and neurotoxicity-associated cytokines) using BHM1710 (anti-TCRVB), reduced affinity anti-CD3 antibody (TB), and SP34 anti-CD3e antibody. [Figure 70E] Figures 70A-70G are graphs showing the expression of IFNg, TNFa, IL-1a, IL-1b, IL-6 (CRS and neurotoxicity-associated cytokines) using BHM1710 (anti-TCRVB), reduced affinity anti-CD3 antibody (TB), and SP34 anti-CD3e antibody. [Figure 70F] Figures 70A-70G are graphs showing the expression of IFNg, TNFa, IL-1a, IL-1b, IL-6 (CRS and neurotoxicity-associated cytokines) using BHM1710 (anti-TCRVB), reduced affinity anti-CD3 antibody (TB), and SP34 anti-CD3e antibody. [Figure 70G]Figures 70A-70G are graphs showing the expression of IFNg, TNFa, IL-1a, IL-1b, IL-6 (CRS and neurotoxicity-associated cytokines) using BHM1710 (anti-TCRVB), reduced affinity anti-CD3 antibody (TB), and SP34 anti-CD3e antibody. [Figure 71] Figure 71 is a FACS plot showing the percentage of NK cells expanded from T cell cultures activated with the indicated antibodies. [Figure 72] FIG. 72 is a bar graph showing the number of NK cells expanded from T cell cultures activated with the indicated antibodies. [Figure 73] Figure 73 shows a series of FACS plots demonstrating NK cell proliferation induced by T cell cultures activated with the indicated antibodies. [Figure 74] FIG. 74 is a diagram showing the assay described in the Examples for determining NK cell-mediated lysis of target K562 cells. [Figure 75] Figure 75 is a bar graph showing the percent target cell lysis mediated by NK cells activated by PBMCs activated with the indicated antibodies. [Figure 76] Figure 76 shows a series of FACS plots showing the proliferation of NK cells from PBMC cultures activated / expanded with the indicated antibodies (isotype control or OKT3). PBMCs from three donors (D1, D2, and D3) were analyzed. [Figure 77] Figure 77 shows a series of FACS plots showing proliferation of NK cells from PBMC cultures activated / expanded with the indicated antibodies (anti-TCRvβ 12-3 / 4 v1 or anti-TCRvβ 12-3 / 4 v2). PBMCs from three donors (D1, D2, and D3) were analyzed. [Figure 78] Figure 78 shows a series of FACS plots showing the proliferation of NK cells from PBMC cultures activated / expanded with the indicated antibodies (anti-TCRvβ 12-3 / 4 v3 or SP34-2). PBMCs from three donors (D1, D2, and D3) were analyzed. [Figure 79]Figure 79 is a bar graph showing the levels of IFNγ secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1, OKT3, or SP34) and cultured with the antibody for the indicated number of days (1, 3, or 5). [Figure 80] Figure 80 is a bar graph showing the levels of IL-2 secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1, OKT3, or SP34) and cultured with the antibody for the indicated number of days (1, 3, or 5). [Figure 81] Figure 81 is a bar graph showing the level of IL-15 secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1, OKT3, or SP34) and cultured with the antibody for the indicated number of days (1, 3, or 5). [Figure 82] Figure 82 is a bar graph showing the level of IL-1β secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1, OKT3, or SP34) and cultured with the antibody for the indicated number of days (1, 3, or 5). [Figure 83] Figure 83 is a bar graph showing the levels of IL-6 secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1, OKT3, or SP34) and cultured with the antibody for the indicated number of days (1, 3, or 5). [Figure 84] Figure 84 is a bar graph showing the level of IL-10 secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1, OKT3, or SP34) and cultured with the antibody for the indicated number of days (1, 3, or 5). [Figure 85] Figure 85 is a bar graph showing the levels of the indicated cytokines secreted by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1 or SP34). Data includes the use of 17 individual PBMC donors. [Figure 86A]Figure 86A is a bar graph showing the levels of IFNγ secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1 or OKT3) and cultured with the antibody for the indicated number of days (1, 2, 3, 5, or 6). [Figure 86B] Figure 86B is a bar graph showing the levels of IL-1β secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1 or OKT3) and cultured with the antibody for the indicated number of days (1, 2, 3, 5, or 6). [Figure 86C] Figure 86C is a bar graph showing the levels of IL-4 secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1 or OKT3) and cultured with the antibody for the indicated number of days (1, 2, 3, 5, or 6). [Figure 86D] Figure 86D is a bar graph showing the levels of IL-6 secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1 or OKT3) and cultured with the antibody for the indicated number of days (1, 2, 3, 5, or 6). [Figure 86E] Figure 86E is a bar graph showing the level of IL-10 secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1 or OKT3) and cultured with the antibody for the indicated number of days (1, 2, 3, 5, or 6). [Figure 86F] Figure 86F is a bar graph showing the levels of TNFα secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1 or OKT3) and cultured with the antibody for the indicated number of days (1, 2, 3, 5, or 6). [Figure 86G] Figure 86G is a bar graph showing the levels of IL-2 secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1 or OKT3) and cultured with the antibody for the indicated number of days (1, 2, 3, 5, or 6). [Figure 87A]Figure 87A is a bar graph showing the levels of IFNγ secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1, anti-TCRβV 6-5 v1, OKT3, SP34-2, or isotype control) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 87B] Figure 87B is a bar graph showing the levels of IL-1β secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1, anti-TCRβV 6-5 v1, OKT3, SP34-2, or isotype control) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 87C] Figure 87C is a bar graph showing the levels of IL-4 secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1, anti-TCRβV 6-5 v1, OKT3, SP34-2, or isotype control) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 87D] Figure 87D is a bar graph showing the levels of IL-6 secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1, anti-TCRβV 6-5 v1, OKT3, SP34-2, or isotype control) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 87E] Figure 87E is a bar graph showing the level of IL-10 secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1, anti-TCRβV 6-5 v1, OKT3, SP34-2, or isotype control) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 87F] Figure 87F is a bar graph showing the levels of TNFα secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1, anti-TCRβV 6-5 v1, OKT3, SP34-2, or isotype control) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 87G] Figure 87G is a bar graph showing the levels of IL-2 secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1, anti-TCRβV 6-5 v1, OKT3, SP34-2, or isotype control) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 88A] Figure 88A is a bar graph showing the levels of IFNγ secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1, anti-TCRβV 6-5 v1, OKT3, or SP34-2) and cultured with the antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 88B] Figure 88B is a bar graph showing the levels of IL-1β secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1, anti-TCRβV 6-5 v1, OKT3, or SP34-2) and cultured with the antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 88C] Figure 88C is a bar graph showing the levels of IL-4 secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1, anti-TCRβV 6-5 v1, OKT3, or SP34-2) and cultured with the antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 88D] Figure 88D is a bar graph showing the levels of IL-6 secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1, anti-TCRβV 6-5 v1, OKT3, or SP34-2) and cultured with the antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 88E] Figure 88E is a bar graph showing the level of IL-10 secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1, anti-TCRβV 6-5 v1, OKT3, or SP34-2) and cultured with the antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 88F]Figure 88F is a bar graph showing the levels of TNFα secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1, anti-TCRβV 6-5 v1, OKT3, or SP34-2) and cultured with the antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 88G] Figure 88G is a bar graph showing the level of IL-2 secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1, anti-TCRβV 6-5 v1, OKT3, or SP34-2) and cultured with the antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 89A] Figure 89A is a bar graph showing the levels of IL-17A secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1, OKT3, or SP34-2) and cultured with the antibody for the indicated number of days (2, 5, or 7). [Figure 89B] Figure 89B is a bar graph showing the levels of IL-17A secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1, OKT3, or SP34-2) and cultured with the antibody for the indicated number of days (2, 5, or 8). [Figure 89C] Figure 89C is a bar graph showing the levels of IL-17A secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1, OKT3, or SP34-2) and cultured with the antibody for the indicated number of days (2, 5, or 7). [Figure 89D] Figure 89D is a bar graph showing the levels of IL-17A secretion by T cells activated / expanded with the indicated antibody (anti-TCRβV 6-5 v1 or SP34-2) and cultured with the antibody for the indicated number of days (1, 3, 5, or 7). [Figure 90A]Figure 90A is a bar graph showing the levels of IFNγ secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90B] Figure 90B is a bar graph showing the levels of IL-1β secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90C] Figure 90C is a bar graph showing the levels of IL-4 secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90D] Figure 90D is a bar graph showing the levels of IL-6 secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90E] Figure 90E is a bar graph showing the level of IL-10 secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90F]Figure 90F is a bar graph showing the levels of TNFα secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90G] Figure 90G is a bar graph showing the level of IL-2 secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90H] Figure 90H is a bar graph showing the levels of IL-12p70 secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90I] Figure 90I is a bar graph showing the level of IL-13 secretion by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90J] Figure 90J is a bar graph showing the levels of IL-8 secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90K]Figure 90K is a bar graph showing the level of exotaxin secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90L] Figure 90L is a bar graph showing the levels of exotoxin-3 secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90M] Figure 90M is a bar graph showing the levels of IL-8 secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90N] Figure 90N is a bar graph showing the level of IP-10 secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90O] Figure 90O is a bar graph showing the levels of MCP-1 secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90P]Figure 90P is a bar graph showing the levels of MCP-4 secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90Q] Figure 90Q is a bar graph showing the level of MDC secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90R] Figure 90R is a bar graph showing the levels of MIP-1a secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90S] Figure 90S is a bar graph showing the levels of MIP-1b secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90T] Figure 90T is a bar graph showing the level of TARC secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90U]Figure 90U is a bar graph showing the levels of GMCSF secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90V] Figure 90V is a bar graph showing the levels of IL-12-23p40 secretion by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90W] Figure 90W is a bar graph showing the level of IL-15 secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90X] Figure 90X is a bar graph showing the level of IL-16 secretion by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90Y] Figure 90Y is a bar graph showing the levels of IL-17a secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90Z]Figure 90Z is a bar graph showing the level of IL-1a secretion by T cells activated / expanded with the indicated antibody (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibody for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90AA] Figure 90AA is a bar graph showing the levels of IL-5 secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90BB] Figure 90BB is a bar graph showing the levels of IL-7 secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90CC] Figure 90CC is a bar graph showing the levels of TNF-B secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 90DD] Figure 90DD is a bar graph showing the level of VEGF secretion by T cells activated / expanded with the indicated antibodies (isotype control; anti-TCRβV 6-5 v1 with anti-BCMA antibody; anti-TCRβV 6-5 v1; anti-TCRβV 123 / 4 v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 91]Figure 91 shows a graphical representation of the sequence relationships between different TCRVB clonotype subfamilies. [Figure 92A] Figure 92A is a bar graph showing the percentage of cytokine release from PBMCs activated / expanded for 8 days with the indicated antibodies (anti-TCRβV 12-3 / 4 v1 or SP34-2). [Figure 92B] Figure 92B is a bar graph showing the percentage of cytokine release from PBMCs activated / expanded for 8 days with the indicated antibodies (anti-TCRβV5 or SP34-2). [Figure 92C] Figure 92C is a bar graph showing the percentage of cytokine release from PBMCs activated / expanded for 8 days with the indicated antibodies (anti-TCRβV 10 or SP34-2). [Figure 93A] Figure 93A is a bar graph showing the level of IFNγ secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (3 or 6). [Figure 93B] Figure 93B is a bar graph showing the level of IL-10 secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (3 or 6). [Figure 93C] Figure 93C is a bar graph showing the level of IL-17A secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (3 or 6). [Figure 93D] Figure 93D is a bar graph showing the level of IL-1α secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (3 or 6). [Figure 93E] Figure 93E is a bar graph showing the level of IL-1β secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (3 or 6). [Figure 93F] Figure 93F is a bar graph showing the level of IL-6 secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (3 or 6). [Figure 93G]Figure 93G is a bar graph showing the level of TNFα secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (3 or 6). [Figure 93H] Figure 93H is a bar graph showing the level of IL-2 secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (3 or 6). [Figure 94] Figure 94 is a bar graph summarizing data from FACS analysis of PBMCs activated / expanded for 6 days using the indicated anti-TCRVβ antibodies. [Figure 95A] Figure 95A is a bar graph showing the level of IFNγ secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 95B] Figure 95B is a bar graph showing the level of IL-10 secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 95C] Figure 95C is a bar graph showing the level of IL-17A secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 95D] Figure 95D is a bar graph showing the level of IL-1α secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 95E] Figure 95E is a bar graph showing the level of IL-1β secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 95F] Figure 95F is a bar graph showing the level of IL-6 secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 95G] Figure 95G is a bar graph showing the level of IL-4 secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 95H]Figure 95H is a bar graph showing the level of IL-2 secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 96] Figure 96 is a bar graph summarizing data from FACS analysis of PBMCs activated / expanded for 7 days using the indicated anti-TCRVβ antibodies. [Figure 97A] Figure 97A is a bar graph showing the level of IFNγ secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (3 or 6). [Figure 97B] Figure 97B is a bar graph showing the level of IL-10 secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (3 or 6). [Figure 97C] Figure 97C is a bar graph showing the level of IL-17A secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (3 or 6). [Figure 97D] Figure 97D is a bar graph showing the level of IL-1α secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (3 or 6). [Figure 97E] Figure 97E is a bar graph showing the level of IL-1β secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (3 or 6). [Figure 97F] Figure 97F is a bar graph showing the level of IL-6 secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (3 or 6). [Figure 97G] Figure 97G is a bar graph showing the level of IL-4 secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (3 or 6). [Figure 97H] Figure 97H is a bar graph showing the level of TNFα secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (3 or 6). [Figure 97I]Figure 97I is a bar graph showing the level of IL-2 secretion by T cells activated / expanded with the indicated antibodies for the indicated number of days (3 or 6). [Figure 98A] Figure 98A is a bar graph showing the level of IFN-γ secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1 (plate coated), anti-CD3ε (plate coated), anti-TCRβV 6-5 v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 98B] Figure 98B is a bar graph showing the level of IFN-γ secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1 (plate coated), anti-CD3ε (plate coated), anti-TCRβV 6-5 v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 98C] Figure 98C is a bar graph showing the level of IL-1b secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1 (plate coated), anti-CD3ε (plate coated), anti-TCRβV 6-5 v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 98D] Figure 98D is a bar graph showing the level of IL-6 secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1 (plate coated), anti-CD3ε (plate coated), anti-TCRβV 6-5 v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 98E] Figure 98E is a bar graph showing the level of IL-10 secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1 (plate coated), anti-CD3ε (plate coated), anti-TCRβV 6-5 v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 98F] Figure 98F is a bar graph showing the level of IL-15 secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1 (plate coated), anti-CD3ε (plate coated), anti-TCRβV 6-5 v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 98G] Figure 98G is a bar graph showing the level of IL-17A secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1 (plate coated), anti-CD3ε (plate coated), anti-TCRβV 6-5 v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 98H] Figure 98H is a bar graph showing the level of IL-1a secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1 (plate coated), anti-CD3ε (plate coated), anti-TCRβV 6-5 v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 98I] Figure 98I is a bar graph showing the level of IL-1b secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1 (plate coated), anti-CD3ε (plate coated), anti-TCRβV 6-5 v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 98J] Figure 98J is a bar graph showing the level of IL-2 secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1 (plate coated), anti-CD3ε (plate coated), anti-TCRβV 6-5 v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 98K]Figure 98K is a bar graph showing the level of IL-4 secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1 (plate coated), anti-CD3ε (plate coated), anti-TCRβV 6-5 v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 98L] Figure 98L is a bar graph showing the levels of TNF-α secretion by T cells activated / expanded with the indicated antibodies (anti-TCRβV 6-5 v1 (plate coated), anti-CD3ε (plate coated), anti-TCRβV 6-5 v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 99] Figure 99 is a FACS plot showing the ability of MH3-2 to bind to PBMC from one of two donors when the PBMC were pre-incubated with TM23 or not (MH3-2 alone). [Figure 100] Figure 100 is a FACS plot showing the ability of MH3-2 to bind to PBMC from one of two donors when the PBMC were either pre-incubated with TM23 or not (MH3-2 alone). [Figure 101A] Figure 101A is a bar graph showing the polyfunctional strength index (PSI) of PBMC CD4+ T cells, CD4+ T cells expanded with anti-CD3 antibody (CD3-expanded T cells), and CD4+ T cells expanded with anti-TCRVβ 6-5 antibody (drug-expanded T cells). The effector mediators are granzyme B, IFNγ, MIP-1α, perforin, TNFα, and TNFβ. The stimulatory mediator is IL-5. The chemoattractant mediator is MIP-1b. [Figure 101B]Figure 101B is a bar graph showing the polyfunctional strength index (PSI) of PBMC CD8+ T cells, CD8+ T cells expanded with anti-CD3 antibody (CD3-expanded T cells), and CD8+ T cells expanded with anti-TCRVβ 6-5 antibody (drug-expanded T cells). Effector mediators are granzyme B, IFNγ, MIP-1α, perforin, and TNFβ. Chemoattractant mediators are MIP-1b and RANTES. [Figure 102A] Figures 102A-102C show binding of CD19xTCRvβ bispecific molecules to TCR molecules. Figure 102A is a diagram of the bispecific molecules used in this study. [Figure 102B] Figure 102B is a graph showing binding of CD19xTCRvβ bispecific molecules to soluble TCR. [Figure 102C] Figure 102C is a graph showing binding of CD19xTCRvβ bispecific molecules to TCR expressed on Jurkat cells. [Figure 103A] Figures 103A-103D show the characterization of the murine CD19xTCRvβ 13-2 / 3 (2x2) bispecific molecule. Figure 103A is a diagram of the bispecific molecule used in this study. [Figure 103B] Figure 103B is a graph showing the binding kinetics of mouse CD19xTCRvβ 13-2 / 3. [Figure 103C] FIG. 103C is a dot plot showing the expansion of TCRVB+ T cells after 6 days of incubation with murine CD19xTCRvβ 13-2 / 3. [Figure 103D] Figure 103D is a graph showing the relative number of splenic B cells after 6 days of in vitro incubation with murine CD19xTCRvβ 13-2 / 3 bispecific antibody. [Figure 104] FIG. 104 is a graph showing the levels of B cells in the blood or spleen of animals treated with 0.1 mg / kg or 1 mg / kg of murine CD19xTCRvβ 13-2 / 3 bispecific antibody. [Figure 105A]Figures 105A-105B are graphs showing the levels of NK cells (Figure 105A) or T cells (Figure 105B) in the blood or spleen of animals treated with 0.1 mg / kg or 1 mg / kg of murine CD19xTCRvβ 13-2 / 3 bispecific antibody. [Figure 105B] Figures 105A-105B are graphs showing the levels of NK cells (Figure 105A) or T cells (Figure 105B) in the blood or spleen of animals treated with 0.1 mg / kg or 1 mg / kg of murine CD19xTCRvβ 13-2 / 3 bispecific antibody. [Figure 106A] Figures 106A-106F show expansion of TCR VB+ T cells and lysis of target cells using CD19xTCRvβ bispecific molecules. Figure 106A is a diagram of the bispecific molecules used in this study. [Figure 106B] Figure 106B is a graph showing target cell lysis by pre-expanded TCRVB+ T cells or CD3+ expanded pan T cells. [Figure 106C] Figure 106C shows the depletion of purified B cells by purified T cells treated with the CD19xTCRvβ bispecific molecule. [Figure 106D] Figure 106D shows the depletion of purified B cells by purified T cells treated with CD19xCD3 bispecific molecules. [Figure 106E] Figure 106E shows the depletion of B cells in PBMC preparations treated with the CD19xTCRvβ bispecific molecule. [Figure 106F] Figure 106F shows the depletion of B cells in PBMC preparations treated with CD19xCD3 bispecific molecules. [Figure 107A] Figures 107A-107B are graphs showing the expression of various cytokines from PBMCs treated with the CD19 x CD3 bispecific molecule (Figure 107A) or the CD19xTCRVB 6-5 bispecific molecule (Figure 107B). [Figure 107B]Figures 107A-107B are graphs showing the expression of various cytokines from PBMCs treated with the CD19 x CD3 bispecific molecule (Figure 107A) or the CD19xTCRVB 6-5 bispecific molecule (Figure 107B). [Figure 108A] Figures 108A-108C show the CD19 x TCRvβ 6-5 (2x2) pharmacokinetic (PK) profile and dosing strategy. Figure 108A is a diagram of the experimental design. [Figure 108B] FIG. 108B is a graph showing the concentration of CD19×TCRvβ 6-5 at the indicated time points after treatment. [Figure 108C] FIG. 108C shows the detection reagents used to detect CD19×TCRvβ 6-5. DETAILED DESCRIPTION OF THE INVENTION

[0308] Current bispecific constructs designed to redirect T cells to promote tumor cell lysis for cancer immunotherapy typically utilize antibody fragments (e.g., Fab, scFv, VH) derived from monoclonal antibodies (mAbs) directed against the CD3e subunit of the T cell receptor (TCR). However, limitations of this approach may prevent the full realization of the therapeutic potential of such bispecific constructs. Previous studies have shown that even low "activating" doses of anti-CD3e mAbs can cause long-term T cell dysfunction and exert immunosuppressive effects. Furthermore, anti-CD3e mAbs are associated with side effects due to massive T cell activation. Large numbers of activated T cells secrete substantial amounts of cytokines, the most important of which is interferon gamma (IFNg). This excess amount of IFNg then activates macrophages, which then overproduce inflammatory cytokines such as IL-1beta, IL-6, IL-10, and TNF-α, causing a "cytokine storm" known as cytokine release syndrome (CRS) (Shimabukuro-Vornhagen et al., J Immunother Cancer. 2018 Jun. 15;6(1):56, incorporated herein by reference in its entirety). Thus, there is a need to develop antibodies that can bind to and activate only a subset of effector T cells, for example, to reduce CRS and / or neurotoxicity (NT).

[0309] The present invention features molecules and methods that target the TCRβV chain of the TCR. Without being bound by theory, such molecules can bind, activate, and / or expand only a subset of T cells, avoiding or reducing CRS and / or NT, and minimizing the potentially immunosuppressive effects of anti-CD3 mAbs.

[0310] TCRs are typically disulfide-linked, membrane-anchored heterodimeric proteins consisting of highly variable alpha (α) and beta (β) chains expressed as part of a complex with an invariant CD3 chain molecule. The 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 an immunoglobulin superfamily (IgSF) fold. TCRβ V chains can be further classified into 30 subfamilies (TRBV1-30). Despite their high structural and functional homology, amino acid sequence homology within TRBV genes is very low. Only four of the approximately 95 amino acids are identical, while 10 additional amino acids are conserved across all subfamilies (see Table 9 for an alignment of TCRβ amino acid sequences). Nevertheless, TCRs formed between highly divergent alpha and beta chains show significant structural homology (Figures 24A and 24B) and similar functions, e.g., eliciting T cell activation.

[0311] Disclosed herein is the discovery of a novel class of antibodies, namely, the anti-TCRβV antibody molecules disclosed herein, which, despite having low sequence similarity (e.g., low sequence identity between different antibody molecules that recognize different TCRβV subfamilies), recognize structurally conserved but sequence variable regions, e.g., domains, on the TCRβV protein (shown by the circled regions in Figure 24A) and have similar functions (e.g., T cell activation and similar cytokine profiles as described herein). Thus, the anti-TCRβV antibody molecules disclosed herein share a structure-function relationship.

[0312] Without being bound by theory, in some embodiments, the anti-TCRβV antibody molecules disclosed herein are believed to bind to an outward-facing epitope of the TCRβV protein when complexed with the TCRα protein, as shown, for example, by the circled region in Figure 24A. In some embodiments, the anti-TCRβV antibody molecules disclosed herein recognize (e.g., bind to) a domain (e.g., epitope) on the TCRβV protein that is (1) structurally conserved among different TCRβV subfamilies; and (2) has minimal sequence identity among different TCRβV subfamilies. As shown in Table 9, TCRβV proteins from different TCRβV subfamilies share minimal sequence similarity. However, as shown in Figures 24A-B, TCRβV proteins with minimal sequence similarity share similar 3D conformations and structures.

[0313] In some embodiments, the anti-TCRβV antibody molecules disclosed herein do not recognize, e.g., do not bind to, the interface of the TCRβV:TCRα complex. In some embodiments, the anti-TCRβV antibody molecules disclosed herein do not recognize, e.g., do not bind to, the constant region of the TCRβV protein.

[0314] In some embodiments, the anti-TCRβV antibody molecules disclosed herein do not recognize, e.g., do not bind to, one or more (e.g., all) of the complementarity determining regions (e.g., CDR1, CDR2 and / or CDR3) of the TCRβV protein.

[0315] The present disclosure provides, in particular, antibody molecules directed to the variable chain of the beta subunit of the TCR (TCRβV), which bind to and, e.g., activate, a subset of T cells. The anti-TCRβV antibody molecules disclosed herein result in reduced or no production of cytokines associated with CRS, e.g., IL-6, IL-1β, IL-10, and TNFα; and enhanced and / or delayed production of IL-2 and IFNg. In some embodiments, the anti-TCRβV antibodies disclosed herein have a cytokine profile, e.g., as described herein, that differs from the cytokine profile of T cell engagers that bind to receptors or molecules other than the TCRβV region ("non-TCRβV-binding T cell engagers"). In some embodiments, the anti-TCRβV antibodies disclosed herein target TCRβV+ T cells, e.g., T EMRA Without wishing to be bound by theory, in some embodiments, T EMRA It is believed that these cells can promote tumor cell lysis but not CRS. Accordingly, methods for producing the anti-TCRβV antibody molecules and uses thereof are provided herein. Also disclosed herein are multispecific, e.g., bispecific, molecules comprising the anti-TCRβV antibody molecules. In some embodiments, compositions comprising the anti-TCRβV antibody molecules of the present disclosure can be used, for example, to (1) activate and redirect T cells to promote tumor cell lysis for cancer immunotherapy; and / or (2) expand TCRβV+ T cells. In some embodiments, compositions comprising the anti-TCRβV antibody molecules disclosed herein limit the adverse side effects of CRS and / or NT, e.g., CRS and / or NT associated with anti-CD3e targeting.

[0316] In some embodiments, the anti-TCRβV antibody molecule does not bind to TCRβV12 or binds to TCRβV12 with an affinity and / or binding specificity that is lower (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2, 5, or 10 times less) than the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof, as described in U.S. Patent No. 5,861,155.

[0317] In some embodiments, the anti-TCRβV antibody molecule binds to TCRβV12 with an affinity and / or binding specificity that is greater (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2, 5, or 10 times greater) than the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof, as described in U.S. Patent No. 5,861,155.

[0318] In some embodiments, the anti-TCRβ antibody molecule is directed against a TCRβ V region other than the TCRβ V12 described herein (e.g., the TCRβ V6 subfamily (e.g., the TCRβ V6-5 * 01) with an affinity and / or binding specificity that is greater than (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10-fold greater than) the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof, as described in U.S. Pat. No. 5,861,155.

[0319] In some embodiments, the anti-TCRβV antibody molecule does not comprise the CDRs of the Antibody B murine antibody. In some embodiments, the anti-TCRβ antibody molecule is TCRβ V5-5 * 01 or TCRβ V5-1 * 01 or TCRβ V5-5 * 01 or TCRβ V5-1 *01 with an affinity and / or binding specificity that is lower (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10-fold less) than the affinity and / or binding specificity of the TM23 murine antibody or a humanized version thereof, as described in U.S. Pat. No. 5,861,155.

[0320] In some embodiments, the anti-TCRβ antibody molecule is TCRβ V5-5 * 01 or TCRβ V5-1 * 01 with an affinity and / or binding specificity that is greater (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10-fold greater) than the affinity and / or binding specificity of the TM23 murine antibody or a humanized version thereof, as described in U.S. Pat. No. 5,861,155.

[0321] In some embodiments, the anti-TCRβ antibody molecule is TCRβ V5-5 * 01 or TCRβ V5-1 * TCRβ V regions other than 01 (e.g., TCRβ V regions 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., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10-fold greater than) the affinity and / or binding specificity of the TM23 murine antibody or a humanized version thereof, as described in U.S. Pat. No. 5,861,155.

[0322] In some embodiments, the anti-TCRβV antibody molecule does not comprise the CDRs of the TM23 murine antibody. Thus, the present specification provides, inter alia, anti-TCRβ antibody molecules, multispecific or multifunctional molecules (e.g., multispecific molecules or multifunctional antibody molecules) comprising anti-TCRβ antibody molecules, nucleic acids encoding the same, methods for producing the aforementioned molecules, pharmaceutical compositions comprising the aforementioned molecules, and methods for producing the aforementioned molecules. Methods of treating diseases or disorders, e.g., cancer, using the described molecules are provided. The antibody molecules and pharmaceutical compositions disclosed herein can be used (alone or in combination with other drugs or therapeutic modalities) to treat, prevent, and / or diagnose the diseases and conditions described herein, e.g., cancer.

[0323] definition 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 invention belongs.

[0324] The words "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0325] When referring to a measurable value such as an amount, duration, or the like, the term "about" is meant to encompass a variation 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 particular value, where such variations are appropriate for practicing the disclosed methods.

[0326] The term "obtain" or "obtaining," as used herein, refers to gaining 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 obtaining" or "indirectly obtaining" the physical entity or value. "Directly obtaining" means performing a process (e.g., performing a synthetic or analytical method) to obtain the physical entity or value. "Indirectly obtaining" refers to receiving the physical entity or value from another party or source (e.g., a third party that directly obtained the physical entity or value). Directly obtaining a physical entity includes performing a process that involves a physical change of a physical substance, e.g., a starting material. Directly obtaining a value includes performing a process that involves a physical change of a sample or another substance, e.g., performing an analytical process that involves a physical change of a substance, e.g., a sample.

[0327] As used herein, the term "T cell receptor beta variable chain" or "TCRβV" refers to the extracellular region of the T cell receptor beta chain that contains the antigen recognition domain of the T cell receptor. The term TCRβV includes isoforms, mammalian, e.g., human TCRβV, human species homologs, and analogs that share at least one epitope with the TCRβV. Human TCRβVs include, but are not limited to, TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, TCRβ V29 subfamily, TCRβ V1 subfamily, TCRβ V1 subfamily, TCRβ V17 subfamily, TCRβ V21 subfamily, TCRβ In some embodiments, the TCRβ V6 subfamily includes gene families including the TCRβ V6-4 subfamily, the TCRβ V23 subfamily, or the TCRβ V26 subfamily, as well as subfamilies including members of said subfamilies and variants thereof (e.g., structural or functional variants thereof). * 01. TCRβ V6-4 * 02. TCRβ V6-9 * 01. TCRβ V6-8 * 01. TCRβ V6-5 * 01. TCRβ V6-6 * 0 2. TCRβ V6-6 * 01. TCRβ V6-2 * 01. TCRβ V6-3 * 01 or TCRβ V6-1 *In some embodiments, the TCRβV comprises TCRβV6-5. * 01, or variants thereof, e.g., variants having 85%, 90%, 95%, 99% or more identity to the naturally occurring sequence. * 01 is also known as TRBV65; TCRBV6S5; TCRBV13S1, or TCRβ V13.1. * 01, for example, human TCRβV6-5 * The amino acid sequence of 01 is known in the art and is available, for example, from IMGT ID In some embodiments, TCRβV6-5 * 01 is encoded by the nucleic acid sequence of SEQ ID NO: 43, or a sequence having 85%, 90%, 95%, 99% or more identity thereto. * 01 comprises the amino acid sequence of SEQ ID NO: 44, or a sequence having 85%, 90%, 95%, 99% or more identity thereto.

[0328] The term "human-like antibody molecule," as used herein, refers to a humanized antibody molecule, a human antibody molecule, or an antibody molecule having at least 95% identity with non-murine germline framework regions, e.g., FR1, FR2, FR3, and / or FR4. In some embodiments, a human-like antibody molecule comprises a framework region having at least 95% identity with a human germline framework region, e.g., FR1, FR2, FR3, and / or FR4 of a human germline framework region. In some embodiments, a human-like antibody molecule is a recombinant antibody. In some embodiments, a human-like antibody molecule is a humanized antibody molecule. In some embodiments, a human-like antibody molecule is a human antibody molecule. In some embodiments, a human-like antibody molecule is a phage-displayed or yeast-displayed antibody molecule. In some embodiments, a human-like antibody molecule is a chimeric antibody molecule. In some embodiments, a human-like antibody molecule is a CDR-grafted antibody molecule.

[0329] The term "cytokine profile," as used herein, refers to the levels and / or activation of one or more cytokines or chemokines, such as those described herein. In some embodiments, the cytokine profile includes the levels and / or activation of naturally occurring cytokines, fragments, or variants thereof. In certain embodiments, the cytokine profile includes the levels and / or activation of one or more cytokines and / or one or more chemokines (e.g., as described herein). In some embodiments, the cytokine profile includes the levels and / or activation of naturally occurring cytokines, fragments, or variants thereof. In some embodiments, the cytokine profile includes the levels and / or activation of naturally occurring chemokines, fragments, or variants thereof. In certain embodiments, the cytokine profile is selected from the group consisting of IL-2 (e.g., full length, a variant, or a fragment thereof); IL-1β (e.g., full length, a variant, or a fragment thereof); IL-6 (e.g., full length, a variant, or a fragment thereof); TNFα (e.g., full length, a variant, or a fragment thereof); IFNg (e.g., full length, a variant, or a fragment thereof); IL-10 (e.g., full length, a variant, or a fragment thereof); IL-4 (e.g., full length, a variant, or a fragment thereof); TNFα (e.g., full length, a variant, or a fragment thereof); IL-12p70 (e.g., full length, a variant, or a fragment thereof); IL-13 (e.g., full length, a variant, or a fragment thereof fragment); IL-8 (e.g., full length, variants, or fragments thereof); eotaxin (e.g., full length, variants, or fragments thereof); eotaxin-3 (e.g., full length, variants, or fragments thereof); IL-8(HA) (e.g., full length, variants, or fragments thereof); IP-10 (e.g., full length, variants, or fragments thereof); MCP-1 (e.g., full length, variants, or fragments thereof); MCP-4 (e.g., full length, variants, or fragments thereof); MDC (e.g., full length, variants, or fragments thereof); MIP-1a (e.g., full length, variants, or fragments thereof); MIP-1b (e.g., full length, variants, or fragments thereof); TARC (e.g., In some embodiments, the cytokine profile comprises the levels and / or activation of one or more of: GM-CSF (e.g., full length, variant, or fragment); IL-12 23p40 (e.g., full length, variant, or fragment); IL-15 (e.g., full length, variant, or fragment); IL-16 (e.g., full length, variant, or fragment); IL-17a (e.g., full length, variant, or fragment); IL-1a (e.g., full length, variant, or fragment); IL-5 (e.g., full length, variant, or fragment); IL-7 (e.g., full length, variant, or fragment); TNF-β (e.g., full length, variant, or fragment); or VEGF (e.g., full length, variant, or fragment). In some embodiments, the cytokine profile comprises the secretion of one or more cytokines or chemokines.

[0330] In certain embodiments, cytokines in a cytokine profile can be modulated, e.g., increased or decreased, by the anti-TCRBV antibody molecules described herein. In one embodiment, the cytokine profile includes cytokines associated with cytokine storm or cytokine release syndrome (CRS), e.g., IL-6, IL-1β, TNFα, and IL-10.

[0331] The term "variant" refers to a polypeptide having substantially the same amino acid sequence as, or encoded by a substantially identical nucleotide sequence as, a naturally occurring sequence. In some embodiments, the variant is a functional variant. In some embodiments, a TCRβV variant can bind to TCRα and form a TCRα:β complex.

[0332] The term "functional variant" refers to a polypeptide that has substantially the same amino acid sequence as a naturally occurring sequence, or is encoded by substantially the same nucleotide sequence, and may have one or more activations of the naturally occurring sequence.

[0333] As used herein, a "multifunctional" or "multispecific" molecule refers to a molecule, e.g., a polypeptide, having two or more functionalities, e.g., two or more binding specificities. In some embodiments, the functionalities can include one or more immune cell engagers, one or more tumor-binding molecules, one or more cytokine molecules, one or more stromal-modifying agents, and other moieties described herein. In some embodiments, the multispecific molecule is a multispecific antibody molecule, e.g., a bispecific antibody molecule. In some embodiments, the multispecific molecule includes an anti-TCRVb antibody molecule described herein.

[0334] In some embodiments, the multifunctional molecule comprises an immune cell engager. "Immune cell engager" refers to one or more binding specificities that bind to and / or activate immune cells, e.g., cells involved in an immune response. In embodiments, the immune cells are selected from T cells, NK cells, B cells, dendritic cells, and / or macrophage cells. The immune cell engager can be an antibody molecule, a receptor molecule (e.g., a full-length receptor, a receptor fragment, or a fusion thereof (e.g., a receptor-Fc fusion)), or a ligand molecule (e.g., a full-length ligand, a ligand fragment, or a fusion thereof (e.g., a ligand-Fc fusion)) that binds to an immune cell antigen (e.g., a T cell, NK cell antigen, B cell antigen, dendritic cell antigen, and / or macrophage cell antigen). In embodiments, the immune cell engager specifically binds to a target immune cell, e.g., preferentially binds to a target immune cell. For example, if the immune cell engager is an antibody molecule, it binds to an immune cell antigen (e.g., a T cell antigen, an NK cell antigen, a B cell antigen, a dendritic cell antigen, and / or a macrophage cell antigen) with a dissociation constant of less than about 10 nM.

[0335] In some embodiments, the multifunctional molecule comprises a cytokine molecule. As used herein, a "cytokine molecule" refers to a full-length, fragment, or variant of a cytokine; The term "cytokine" refers to a cytokine comprising a receptor domain, e.g., a cytokine receptor dimerization domain; or an agonist of a cytokine receptor, e.g., an antibody molecule against a cytokine receptor (e.g., an agonist antibody), which induces activation of at least one naturally occurring cytokine. In some embodiments, the cytokine molecule is selected from interleukin-2 (IL-2), interleukin-7 (IL-7), interleukin-12 (IL-12), interleukin-10 (IL-10), interleukin-15 (IL-15), interleukin-18 (IL-18), interleukin-21 (IL-21), or interferon gamma, or a fragment or variant thereof, or a combination of any of the aforementioned cytokines. The cytokine molecule may be a monomer or a dimer. In embodiments, the cytokine molecule may further comprise a cytokine receptor dimerization domain. In other embodiments, the cytokine molecule is an agonist of a cytokine receptor, for example, an antibody molecule (eg, an agonist antibody) against a cytokine receptor selected from IL-15Ra or IL-21R.

[0336] As used herein, the term "molecule," as used in, e.g., antibody molecules, cytokine molecules, receptor molecules, includes full-length naturally occurring molecules as well as variants, e.g., functional variants (e.g., truncations, fragments, mutations (e.g., substantially similar sequences) or derivatized forms thereof), so long as at least one function and / or activity of the unmodified (e.g., naturally occurring) molecule remains.

[0337] In some embodiments, the multifunctional molecule comprises a stromal-modifying moiety. As used herein, "stromal-modifying moiety" refers to an agent, e.g., a protein (e.g., an enzyme), that can modify, e.g., degrade, a component of the stroma. In embodiments, the stromal component is selected from, for example, an ECM component, e.g., a glycosaminoglycan, such as hyaluronic acid (also known as hyaluronic acid or HA), chondroitin sulfate, chondroitin, dermatan sulfate, heparin sulfate, heparin, entactin, tenascin, aggrecan, and keratin sulfate; or an extracellular protein, e.g., collagen, laminin, elastin, fibrinogen, fibronectin, and vitronectin.

[0338] Certain terms are defined below. As used herein, the articles "a" and "an" refer to one or to more than one, e.g., at least one, of the grammatical object of the article. The use of the terms "a" or "an," when used with the term "comprising" herein, can mean "one," but is also consistent with the meaning of "one or more," "at least one," and "one or more than one."

[0339] As used herein, "about" and "approximately" generally refer to an acceptable degree of error for the quantity measured given the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given range of values.

[0340] As used herein, "antibody molecule" refers to a protein, e.g., an immunoglobulin chain, or fragment thereof, that comprises at least one immunoglobulin variable domain structure and / or sequence. Antibody molecules encompass antibodies (e.g., full-length antibodies) and antibody fragments. In certain embodiments, an antibody molecule comprises an antigen-binding or functional fragment of a full-length antibody, or a full-length immunoglobulin chain. For example, a full-length antibody is an immunoglobulin (Ig) molecule (e.g., an IgG antibody) that occurs naturally or is formed by the recombinant process of normal immunoglobulin gene fragments. In embodiments, an antibody molecule refers to an immunologically active antigen-binding portion of an immunoglobulin molecule, e.g., an antibody fragment. An antibody fragment, e.g., a functional fragment, is a portion of an antibody, e.g., Fab, Fab', F(ab'), F(ab), variable fragment (Fv), domain fragment (Fv), or fragment (Fv). A functional antibody fragment binds to the same antigen as that recognized by an intact (e.g., full-length) antibody. The term "antibody fragment" or "functional fragment" also includes isolated fragments consisting of the variable regions, such as an "Fv" fragment consisting of the variable regions of the heavy and light chains, or a recombinant single-chain polypeptide molecule in which the variable regions of the light and heavy chains are linked by a peptide linker ("scFv protein"). In some embodiments, an antibody fragment does not include a portion of an antibody that does not have antigen-binding activity, such as an Fc fragment or a single amino acid residue. Exemplary antibody molecules include full-length antibodies and antibody fragments, such as dAbs (domain antibodies), single-chain, Fab, Fab', and F(ab')2 fragments, and single-chain variable fragments (scFv). In some embodiments, an antibody molecule is an antibody mimetic. In some embodiments, the antibody molecule is or comprises an antibody-like framework or scaffold, such as a fibronectin, ankyrin repeat (e.g., designed ankyrin repeat proteins (DARPins)), avimer, affibody affinity ligand, anticalin, or affilin molecule.

[0341] As used herein, "immunoglobulin variable domain sequence" refers to an amino acid sequence capable of forming 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-terminal or C-terminal amino acids, or may include other modifications compatible with forming a protein structure.

[0342] In embodiments, the antibody molecule is monospecific, e.g., comprises binding specificity for a single epitope. In some embodiments, the antibody molecule is multispecific, e.g., comprises multiple immunoglobulin variable domain sequences, wherein 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, the antibody molecule is a bispecific antibody molecule. As used herein, a "bispecific antibody molecule" refers to an antibody molecule that has specificity for more than one (e.g., two, three, four, or more) epitopes and / or antigens.

[0343] As used herein, "antigen" (Ag) refers to a molecule capable of eliciting an immune response, e.g., involving activation of certain immune cells and / or antibody production. Any macromolecule, including almost any protein or peptide, can be an antigen. Antigens can also be derived from genomic recombinants or DNA. For example, any DNA containing a nucleotide sequence or partial nucleotide sequence encoding a protein capable of eliciting an immune response encodes an "antigen." In embodiments, an antigen need not be encoded solely by the full-length nucleotide sequence of a gene, nor need it be encoded by a gene at all. In embodiments, antigens can be synthesized or derived from a biological sample, e.g., a tissue sample, a tumor sample, cells, or a fluid containing other biological components. As used herein, "tumor antigen" or, synonymously, "cancer antigen" includes any molecule present on or associated with a cancer, e.g., a cancer cell, or the tumor microenvironment, capable of eliciting an immune response. As used herein, "immune cell antigen" includes any molecule present on or associated with an immune cell, capable of eliciting an immune response.

[0344] The "antigen-binding site" or "binding site" of an antibody molecule refers to the portion of an antibody molecule, e.g., an immunoglobulin (Ig) molecule, that is involved in antigen binding. In embodiments, the antigen-binding site is formed by amino acid residues of the variable regions (V) of the heavy (H) and light (L) chains. Three highly divergent stretches within the variable regions of the heavy and light chains, called hypervariable regions, are located between more conserved flanking regions called "framework regions" (FR). FRs are amino acid residues naturally found between and adjacent to the hypervariable regions in immunoglobulins. The framework regions are sequences of amino acids. In embodiments, in an antibody molecule, the three hypervariable regions of the light chain and the three hypervariable regions of the heavy chain are arranged relative to each other in three-dimensional space to form an antigen-binding surface 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." Framework regions and CDRs are defined and described, for example, in Kabat, E. A. et al. (1991) Sequences of Proteins of Immunological Interest, 5th ed., USDapartment 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 composed of three CDRs and four FRs, arranged from amino terminus to carboxy terminus in the following amino acid order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0345] As used herein, "cancer" can encompass all types of oncogenic processes and / or cancerous growths. In embodiments, cancer includes primary tumors as well as metastatic tissues, or malignantly transformed cells, tissues, or organs. In embodiments, cancer encompasses all histopathologies and stages of cancer, e.g., invasive / severe stages. In embodiments, cancer includes recurrent and / or resistant cancers. The terms "cancer" and "tumor" can be used interchangeably. For example, both terms encompass solid tumors and liquid tumors. As used herein, the term "cancer" or "tumor" includes precancers, as well as malignant cancers and tumors.

[0346] As used herein, "immune cell" refers to any of a variety of cells that function in the immune system, e.g., defend against infection and foreign agents. In embodiments, the 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 by attacking larger pathogens through contact or by engulfing and killing microorganisms, and are mediators of the activation of the adaptive immune response. Cells of the adaptive immune system are a specialized type of leukocyte called lymphocytes. B cells and T cells are important types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, and T cells are involved in the cellular immune response. The term "immune cell" includes immune effector cells.

[0347] The term "immune effector cell," as used herein, refers to a cell that is involved in an immune response, e.g., promoting 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 cells, and mast cells.

[0348] The term "effector function" or "effector response" refers to a specialized function of a cell. The effector function of a T cell can be, for example, cytolytic activity or helper activity, including secretion of cytokines.

[0349] The compositions and methods of the present invention encompass polypeptides and nucleic acids having a specified sequence or a sequence substantially identical or similar thereto, e.g., a sequence that is at least 80%, 85%, 90%, 95% identical, or more identical to a specified sequence. In the context of amino acid sequences, the term "substantially identical" is used herein to mean either i) identical to a second amino acid sequence, or ii) a variation in a second amino acid sequence, such that the first and second amino acid sequences may have common structural domains and / or common functional activity. A first amino acid sequence refers to a sequence that contains a sufficient or minimum number of amino acid residues that are conservative substitutions for the aligned amino acid residues. For example, an amino acid sequence that contains a common structural domain has at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a reference sequence, e.g., a sequence provided herein.

[0350] The term "substantially identical" as used herein in the context of nucleotide sequences refers to a first nucleic acid sequence that contains a sufficient number or a 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 polypeptides having a common functional activity, or encode a common polypeptide structural domain or common polypeptide functional activity. For example, a nucleotide sequence that has at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a reference sequence, such as a sequence provided herein.

[0351] The term "variant" refers to a polypeptide having substantially the same amino acid sequence as a reference amino acid sequence or encoded by substantially the same nucleotide sequence. In some embodiments, the variant is a functional variant.

[0352] The term "functional variant" refers to a polypeptide having an amino acid sequence substantially identical to a reference amino acid sequence, or a polypeptide encoded by a substantially identical nucleotide sequence, which may have one or more activations of the reference amino acid sequence.

[0353] 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 two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., for optimal alignment, gaps can be introduced into one or both of the first and second amino acid or nucleic acid sequences, and non-homologous sequences can be ignored for comparison purposes). In a preferred embodiment, the length of the 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%, or 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, 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").

[0354] The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, and takes into account the number of gaps and the length of each gap that need to be introduced for optimal alignment of the two sequences.

[0355] Comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453) algorithm as incorporated into the GAP program of the GCG software package (available at http: / / www.gcg.com), using either a Blossum62 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, percent identity between two nucleotide sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453) algorithm as incorporated into the GAP program of the GCG software package (available at http: / / www.gcg.com). The score is determined using the GAP program on the GCG page (available at http: / / www.gcg.com), using the NWSgapdna.CMP matrix and gap weights of 40, 50, 60, 70, or 80 and length weights of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and those that should be used unless otherwise specified) is a Blossum62 scoring matrix with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5.

[0356] 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) incorporated into the ALIGN program (version 2.0), using a PAM120 residue weight table, a gap length penalty of 12, and a gap penalty of 4.

[0357] The nucleic acid and protein sequences described herein can be used as "query sequences" to conduct searches against public databases, for example, to 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 using the NBLAST program, score=100, word length=12, to obtain nucleotide sequences homologous to the nucleic acid molecules of the invention. BLAST protein searches can be performed using the XBLAST program, score=50, word length=3, to obtain amino acid sequences homologous to the 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 (eg, XBLAST and NBLAST) can be used.

[0358] It is understood that the molecules of the present invention may have additional conservative or non-essential amino acid substitutions which do not substantially affect their function. The term "amino acid" is intended to encompass all molecules, whether natural or synthetic, that contain both amino and acid functionalities and can be included in naturally occurring amino acid polymers. Exemplary amino acids include naturally occurring amino acids; their analogs, derivatives and homologs; amino acid analogs with variant side chains; and all stereoisomers of any of the foregoing. As used herein, the term "amino acid" includes both D or L optical isomers and peptidomimetics.

[0359] A "conservative amino acid substitution" is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues with similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0360] The terms "polypeptide," "peptide," and "protein" (when single chain) are used interchangeably herein to refer to polymers of amino acids of any length. It can be linear or branched, can contain modified amino acids, and can be interrupted by non-amino acids. These terms also include modified amino acid polymers; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. Polypeptides can be isolated from natural sources, can be produced by recombinant technology from eukaryotic or prokaryotic hosts, or can be the product of synthetic techniques.

[0361] 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 their analogs. A polynucleotide can be either single-stranded or double-stranded, and if single-stranded, can be the coding strand or the non-coding (antisense) strand. A polynucleotide can comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides can be interrupted by non-nucleotide components. A polynucleotide can be further modified after polymerization, for example, by conjugation with a labeling component. A nucleic acid can be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semi-synthetic, or synthetic origin that does not occur in nature or is linked to another polynucleotide in a non-naturally occurring sequence.

[0362] The term "isolated" as used herein refers to a material that is removed from its original or natural environment (e.g., the natural environment if it occurs in nature). For example, a naturally occurring polynucleotide or polypeptide present in a living animal is not isolated, but an identical polynucleotide or polypeptide that has been separated by human intervention from some or all of the coexisting materials in the natural system is isolated. Such a polynucleotide may be part of a vector, and / or such a polynucleotide or polypeptide m...

Claims

1. A multispecific molecule (e.g., a bispecific molecule) comprising a first portion (e.g., a first immune cell engager) comprising an antibody molecule (an "anti-TCRβV antibody molecule") that binds to (e.g., specifically binds to) a T cell receptor beta variable region (TCRβV), wherein binding of the first portion to the TCRβV region results in a cytokine profile that differs from the cytokine profile of a T cell engager that binds to a receptor or molecule other than the TCRβV region (a "non-TCRβV-binding T cell engager").

2. 10. The multispecific molecule of claim 1, comprising a second portion comprising one or more of a tumor-targeting moiety, a cytokine molecule, a stromal-modifying moiety, or an anti-TCRβV antibody molecule other than the first portion.

3. 3. The multispecific molecule of claim 1 or 2, wherein the first portion comprising the anti-TCRβV antibody molecule comprises an Fc region comprising a variant, such as an Fc variant described in Table 21, such as an Asn297Ala (N297A) mutation or a Leu234Ala / Leu235Ala (LALA) mutation.

4. The multispecific molecule of claim 3 , wherein the non-TCRβV-binding T cell engager comprises an antibody that binds to a CD3 molecule (e.g., a CD3 epsilon (CD3e) molecule) or a TCR alpha (TCRα) molecule.

5. The cytokine profile of the first portion is: (i) an increase in the level, e.g., expression level, and / or activity, of IL-2; (ii) a reduction in the level, e.g., expression level, and / or activity of IL-1β; (iii) a reduction in the level, e.g., expression level, and / or activity of IL-6; (iv) a reduction in the level, e.g., expression level, and / or activity of TNFα; (v) reducing the level, e.g., expression level, and / or activity, of IL-10; (vi) a delay in the increase in the level, e.g., expression level, and / or activity of IL-2, e.g., a delay of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or more; (vii) a delay in the increase in the level, e.g., expression level, and / or activity of IFNg, e.g., a delay of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or (viii) an increase in the level, e.g., expression level, and / or activity of IL-15 including one, two, three, four, five, six, seven, or all of the following: For example, the multispecific molecule of claim 3 or 4, wherein (i) to (viii) are compared with the cytokine profile of a non-TCRβV-binding T cell engager.

6. 10. The multispecific molecule of any of the preceding claims, wherein binding of the first portion to the TCRβV region results in a reduced cytokine storm, e.g. a reduced cytokine release syndrome (CRS), as measured by the assay of Example 3, e.g. compared to the cytokine storm induced by a non-TCRβV-binding T cell engager.

7. the binding of the first portion to the TCRβ V region (ix) reducing T cell proliferation kinetics; (x) cell killing, e.g., target cell killing, e.g., cancer cell killing, e.g., as measured by the assay of Example 4; (xi) natural killer (NK) cell proliferation, e.g., increased expansion, or (xii) expansion of a population of T cells with a memory-like phenotype, e.g., at least about 1.1 to 10x magnification (e.g., at least about 1.1x, 1.2x, 1.3x, 1.4x, 1.5x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, or 10x magnification) resulting in one, two, three or all of the following: For example, the multispecific molecule of any preceding claim, wherein (ix) to (xii) are compared to a non-TCRβV binding T cell engager.

8. The multispecific molecule of claim 7 , wherein the T cell population with a memory-like phenotype comprises CD45RA+ CCR7− T cells, such as CD4+ and / or CD8+ T cells.

9. The first part is (i) the TCRβ V6 subfamily, including, for example, one or more of 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; (ii) For example, TCRβ V10-1*01, TCRβ V10-1*02, TCRβ the TCRβ V10 subfamily, including one or more of TCRβ V10-3*01 or TCRβ V10-2*01; (iii) the TCRβ V5 subfamily, including, for example, one or more of TCRβ V5-6*01, TCRβ V5-4*01, TCRβ V5-1*01, or TCRβ V5-8*01; (iv) the TCRβ V12 subfamily, including, for example, one or more of TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01; (v) TCRβ V27 subfamily; (vi) TCRβ V28 subfamily; (vii) the TCRβ V4 subfamily, including, for example, one or more of TCRβ V4-1, TCRβ V4-2, or TCRβ V4-3; (viii) TCRβ V19 subfamily; (ix) TCRβ V9 subfamily, or (x) TCRβ V11 subfamily, including, for example, TCRβ V11-2 10. The multispecific molecule of any preceding claim, which binds to one or more of the TCRβV subfamilies selected from:

10. The anti-TCRβV antibody molecule is (i) specifically binds to an epitope on TCRβV, e.g., an epitope that is the same as or similar to an epitope recognized by an anti-TCRβV antibody molecule described herein, e.g., a second anti-TCRβV antibody molecule; (ii) exhibits the same or similar binding affinity or specificity, or both, as an anti-TCRβV antibody molecule described herein, e.g., a second anti-TCRβV antibody molecule; (iii) inhibits, e.g., competitively inhibits, binding of an anti-TCRβV antibody molecule described herein, e.g., a second anti-TCRβV antibody molecule; (iv) binds to the same or overlapping epitope as an anti-TCRβV antibody molecule described herein, e.g., a second anti-TCRβV antibody molecule; or (v) competes for binding with and / or binds to the same epitope as an anti-TCRβV antibody molecule described herein, e.g., a second anti-TCRβV antibody molecule; the second anti-TCRβV antibody molecule comprises heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and / or heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 1 or SEQ ID NO: 9, and / or light chain complementarity determining region 1 (LC CDR1), light chain complementarity determining region 2 (LC CDR3) of SEQ ID NO: 2, SEQ ID NO: 10, or SEQ ID NO: 11; 10. The multispecific molecule of any of the preceding claims, comprising an antigen-binding domain comprising light chain complementarity determining region 1 (LC CDR2), and / or light chain complementarity determining region 2 (LC CDR3).

11. The anti-TCRβV antibody molecule is (i) (a) the HC of SEQ ID NO: 15, SEQ ID NO: 23, SEQ ID NO: 24, or SEQ ID NO: 25 (b) a HC CDR1, a HC CDR2, and / or a HC CDR3, and / or a LC CDR1, a LC CDR2, and / or a 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, or (ii) (a) an LC CDR1, an LC CDR2, and / or an LC CDR3 of SEQ ID NO:2, SEQ ID NO:10, or SEQ ID NO:11, and / or (b) an HC CDR1, an HC CDR2, and / or an HC CDR2 of SEQ ID NO:1 or SEQ ID NO:

9.

10. The multispecific molecule of any preceding claim, comprising an antigen-binding domain comprising:

12. 10. The multispecific molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecules bind to the same or different TCRβV subfamily members.

13. 10. The multispecific molecule of any preceding claim, comprising an antibody molecule selected from a bispecific antibody molecule, a bivalent antibody molecule, or a biparatopic antibody molecule.

14. 10. The multispecific molecule of any preceding claim, comprising a bispecific antibody molecule that binds to two different TCRβV subfamily members.

15. The anti-TCRβV antibody molecule is (i) one or more TCRβ V6 subfamily members and TCRβ one or more of the V10 subfamily members, (ii) one or more TCRβ V6 subfamily members and one or more TCRβ V5 subfamily members; (iii) one or more TCRβ V6 subfamily members and one or more TCRβ V12 subfamily members; (iv) one or more TCRβ V10 subfamily members and one or more TCRβ V5 subfamily members; (v) one or more TCRβ V10 subfamily members and one or more TCRβ V12 subfamily members; or (vi) one or more TCRβ V5 subfamily members and one or more TCRβ V12 subfamily members 10. A multispecific molecule according to any preceding claim, which binds to

16. A multispecific, e.g., bispecific, molecule comprising an anti-TCRβV antibody molecule according to any one of claims 1 to 15.

17. An antibody molecule that binds to, e.g., specifically binds to, a T cell receptor beta variable chain (TCRβV) region, wherein the anti-TCRβV antibody molecule is (a) a light chain variable region (VL), (i) one, two, or all (e.g., three) of light chain complementarity determining region 1 (LC CDR1), light chain complementarity determining region 2 (LC CDR2), and light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO: 10 or SEQ ID NO: 11; and (ii) one, two, three, or more of (e.g., four) non-mouse germline framework region 1 (FR1), non-mouse germline framework region 2 (FR2), non-mouse germline framework region 3 (FR3), and non-mouse germline framework region 4 (FR4); a light chain variable region (VL) comprising framework regions (FR) having at least 95% identity to one or all of the (b) a heavy chain variable region (VH), (i) one, two, or all of (e.g., three) heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 9; and (ii) a heavy chain variable region (VH) comprising a framework region (FR) having at least 95% identity to one, two, three, or all of (e.g., four) non-mouse germline framework region 1 (FR1), non-mouse germline framework region 2 (FR2), non-mouse germline framework region 3 (FR3), and non-mouse germline framework region 4 (FR4); An antibody molecule comprising an antigen-binding domain comprising:

18. The anti-TCRβV antibody molecule of claim 17, wherein the VL comprises an amino acid sequence having the consensus sequence of SEQ ID NO:

230.

19. The anti-TCRβV antibody molecule of claim 17 or 18, wherein VH comprises an amino acid sequence having the consensus sequence of SEQ ID NO:

231.

20. 20. The anti-TCRβV antibody molecule of any of claims 17 to 19, which binds to TCRβ V6, such as one or more of 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.

21. (i) HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 1 or SEQ ID NO: 9, or the amino acid sequences listed in Table 1; or (ii) LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO:2, SEQ ID NO:10, or SEQ ID NO:11, or the amino acid sequences listed in Table 1 21. An anti-TCRβV antibody molecule according to any one of claims 17 to 20, comprising an antigen-binding domain comprising:

22. 22. An anti-TCRβV antibody molecule according to any of claims 17 to 21, comprising an antigen-binding domain comprising a light chain variable region (VL) comprising one, two, or all (e.g., three) of LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 2, SEQ ID NO: 10, or SEQ ID NO: 11, or the amino acid sequence listed in Table 1.

23. 23. The anti-TCRβV antibody molecule of any of claims 17 to 22, comprising an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two, or all (e.g., three) of HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 1 or SEQ ID NO: 9, or the amino acid sequence listed in Table 1.

24. (i) a VL comprising the LC CDR1 amino acid sequence of SEQ ID NO: 6 (or an amino acid sequence having no more than one, two, three, or four modifications, e.g., substitutions, additions, or deletions), the LC CDR2 amino acid sequence of SEQ ID NO: 7 (or an amino acid sequence having no more than one, two, three, or four modifications, e.g., substitutions, additions, or deletions), and / or the LC CDR3 amino acid sequence of SEQ ID NO: 8 (or an amino acid sequence having no more than one, two, three, or four modifications, e.g., substitutions, additions, or deletions), and / or (ii) a VH comprising the HC CDR1 amino acid sequence of SEQ ID NO: 3 (or an amino acid sequence having one, two, three, or four or fewer modifications, e.g., substitutions, additions, or deletions), the HC CDR2 amino acid sequence of SEQ ID NO: 4 (or an amino acid sequence having one, two, three, or four or fewer modifications, e.g., substitutions, additions, or deletions), and / or the HC CDR3 amino acid sequence of SEQ ID NO: 5 (or an amino acid sequence having one, two, three, or four or fewer modifications, e.g., substitutions, additions, or deletions).

24. An anti-TCRβV antibody molecule according to any one of claims 17 to 23, comprising an antigen-binding domain comprising:

25. a variable heavy chain (VH) of an amino acid sequence listed in Table 1, e.g., SEQ ID NO:9 or SEQ ID NO:1312, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to an amino acid sequence listed in Table 1, e.g., SEQ ID NO:9 or SEQ ID NO:1312; and / or A variable light chain (VL) of an amino acid sequence listed in Table 1, e.g., SEQ ID NO: 10 or SEQ ID NO: 11 or SEQ ID NO: 1314, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to an amino acid sequence listed in Table 1, e.g., SEQ ID NO: 10 or SEQ ID NO: 11 or SEQ ID NO: 1314.

25. An anti-TCRβV antibody molecule according to any one of claims 17 to 24, comprising an antigen-binding domain comprising:

26. (i) the VH amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 1312; (ii) an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:1312; (iii) the VL amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 1314, and / or (iv) an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 1314.

26. An anti-TCRβV antibody molecule according to any one of claims 17 to 25, comprising an antigen-binding domain comprising:

27. (i) the VH amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 1312; (ii) an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:1312; (iii) the VL amino acid sequence of SEQ ID NO: 11 or SEQ ID NO: 1314, and / or (iv) an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 11 or SEQ ID NO: 1314.

27. An anti-TCRβV antibody molecule according to any one of claims 17 to 26, comprising an antigen-binding domain comprising:

28. (i) a threonine at position 73, e.g., a substitution at position 73 according to Kabat numbering, e.g., a glutamic acid to threonine substitution, or (ii) a glycine at position 94, e.g., a substitution at position 94 according to Kabat numbering, e.g., an arginine to glycine substitution. and a heavy chain comprising a framework region, e.g., framework region 3 (FR3), comprising one or both of:

28. The anti-TCRβV antibody molecule of any of claims 17 to 27, wherein the substitution is relative to a human germline heavy chain framework region sequence.

29. Phenyalanine at position 10, e.g., a substitution at position 10 according to Kabat numbering, e.g., a serine to phenylalanine substitution.

29. The anti-TCRβV antibody molecule of any of claims 17 to 28, wherein the substitution is relative to a human germline light chain framework region sequence.

30. (i) a histidine at position 36, e.g., a substitution at position 36 according to Kabat numbering, e.g., a tyrosine to histidine substitution, or (ii) an alanine at position 46, e.g., a substitution at position 46 according to Kabat numbering, e.g., an arginine to alanine substitution and a light chain comprising a framework region, e.g., framework region 2 (FR2), comprising one or both of: the substitution is relative to a human germline light chain framework region sequence; An anti-TCRβV antibody molecule according to any one of claims 17 to 29.

31. 31. An anti-TCRβV antibody molecule according to any one of claims 17 to 30, comprising a light chain comprising a framework region, e.g., 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, wherein the substitution is relative to a human germline light chain framework region sequence.

32. An antibody molecule that binds to, e.g., specifically binds to, a T cell receptor beta variable chain (TCRβV) region, wherein the anti-TCRβV antibody molecule is (a) a light chain variable region (VL), (i) one, two, or all of (e.g., three) light chain complementarity determining region 1 (LC CDR1), light chain complementarity determining region 2 (LC CDR2), and light chain complementarity determining region 3 (LC CDR3) of a humanized B-H light chain (LC) of Table 2; and (ii) a light chain variable region (VL) comprising a framework region (FR) having at least 95% identity to one, two, three, or all (e.g., four) of framework region 1 (FR1), framework region 2 (FR2), framework region 3 (FR3), and framework region 4 (FR4) of humanized B-H LC of Table 2; and / or (b) a heavy chain variable region (VH), (i) one, two, or all of (e.g., three) heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3) of a humanized B-H heavy chain (HC) of Table 2; and (ii) a heavy chain variable region (VH) comprising a framework region (FR) having at least 95% identity to one, two, three, or all (e.g., four) of framework region 1 (FR1), framework region 2 (FR2), framework region 3 (FR3), and framework region 4 (FR4) of the humanized B-H HC of Table 2; An antibody molecule comprising an antigen-binding domain comprising:

33. 33. The anti-TCRβV antibody molecule of claim 32, which binds to TCRβ V12, such as TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01, or a variant thereof.

34. (i) the HC CDR1, HC CDR2, and HC CDR3 of antibody BH listed in Table 2, or (ii) LC CDR1, LC CDR2, and LC CDR3 of antibodies BH listed in Table 2 34. The anti-TCRβV antibody molecule of claim 32 or 33, comprising an antigen-binding domain comprising:

35. 35. The anti-TCRβV antibody molecule of any of claims 32 to 34, comprising an antigen-binding domain comprising a light chain variable region (VL) comprising one, two, or all (e.g., three) of LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 2, SEQ ID NO: 10, or SEQ ID NO: 11, or the amino acid sequence listed in Table 1.

36. An anti-TCRβV antibody molecule according to any one of claims 32 to 35, comprising an antigen-binding domain comprising a heavy chain variable region (VH) comprising one, two, or all (e.g., three) of HC CDR1, HC CDR2, and HC CDR3 of humanized antibody B-H listed in Table 2.

37. An anti-TCRβV antibody molecule according to any of claims 32 to 36, comprising an antigen-binding domain comprising a light chain variable region (VL) comprising one, two, or all (e.g., three) of LC CDR1, LC CDR2, and LC CDR3 of humanized antibody B-H listed in Table 2.

38. a VH sequence of humanized antibody B-H listed in Table 2, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to a VH of humanized antibody B-H listed in Table 2, and / or A VL sequence of humanized antibody BH listed in Table 2, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to the VL of humanized antibody BH listed in Table 2.

38. An anti-TCRβV antibody molecule according to any one of claims 32 to 37, comprising:

39. 39. An anti-TCRβV antibody molecule according to any one of claims 32 to 38, comprising a framework region (FR) having at least 95% identity with one of FR1, FR2, FR3, and FR4 of the humanized BH LC of Table 2.

40. 40. An anti-TCRβV antibody molecule according to any one of claims 32 to 39, comprising a framework region (FR) having at least 95% identity with any two of FR1, FR2, FR3, and FR4 of the humanized B-H LC of Table 2.

41. An anti-TCRβV antibody molecule according to any one of claims 32 to 40, comprising a framework region (FR) having at least 95% identity with any three of FR1, FR2, FR3, and FR4 of the humanized B-H LC of Table 2.

42. 42. An anti-TCRβV antibody molecule according to any one of claims 32 to 41, comprising a framework region (FR) having at least 95% identity with all of FR1, FR2, FR3, and FR4 of the humanized B-H LC of Table 2.

43. 43. An anti-TCRβV antibody molecule according to any one of claims 32 to 42, comprising a framework region (FR) having at least 95% identity with one of FR1, FR2, FR3, and FR4 of the humanized BH HC of Table 2.

44. 43. An anti-TCRβV antibody molecule according to any one of claims 32 to 42, comprising a framework region (FR) having at least 95% identity with any two of FR1, FR2, FR3, and FR4 of the humanized BH HC of Table 2.

45. 43. An anti-TCRβV antibody molecule according to any one of claims 32 to 42, comprising a framework region (FR) having at least 95% identity with any three of FR1, FR2, FR3, and FR4 of the humanized BH HC of Table 2.

46. 43. An anti-TCRβV antibody molecule according to any one of claims 32 to 42, comprising a framework region (FR) having at least 95% identity with all of FR1, FR2, FR3, and FR4 of the humanized BH HC of Table 2.

47. An anti-TCRβV antibody molecule described in any of claims 17 to 46, wherein binding of the anti-TCRβV antibody molecule to the TCRβV region results in a cytokine profile that is different from the cytokine profile of a T cell engager that binds to a receptor or molecule other than the TCRβV region (a "non-TCRβV-binding T cell engager").

48. The anti-TCRβV antibody molecule of claim 47, wherein the non-TCRβV-binding T cell engager comprises an antibody that binds to a CD3 molecule (e.g., a CD3 epsilon (CD3e) molecule) or a TCR alpha (TCRα) molecule.

49. The cytokine profile of the first portion is: (i) an increase in the level, e.g., expression level, and / or activity, of IL-2; (ii) a reduction in the level, e.g., expression level, and / or activity of IL-1β; (iii) a reduction in the level, e.g., expression level, and / or activity of IL-6; (iv) a reduction in the level, e.g., expression level, and / or activity of TNFα; (v) reducing the level, e.g., expression level, and / or activity, of IL-10; (vi) a delay in the increase in the level, e.g., expression level, and / or activity of IL-2, e.g., a delay of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or more; (vii) a delay in the increase in the level, e.g., expression level, and / or activity of IFNg, e.g., a delay of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or (viii) an increase in the level, e.g., expression level, and / or activity of IL-15 including one, two, three, four, five, six, seven, or all of the following: For example, the anti-TCRβV antibody molecule of claim 47 or 48, wherein (i) to (vii) are compared with the cytokine profile of a non-TCRβV-binding T cell engager.

50. An anti-TCRβV antibody molecule described in any of claims 17 to 49, wherein binding of the anti-TCRβV antibody molecule to the TCRβV region results in a reduced cytokine storm, e.g., a reduced cytokine release syndrome (CRS), as measured by the assay of Example 3, compared to the cytokine storm induced by a non-TCRβV-binding T cell engager.

51. Binding of the anti-TCRβV antibody molecule to the TCRβV region For example, compared to non-TCRβV binding T cell engagers, (ix) reducing T cell proliferation kinetics; (x) cell killing, e.g., target cell killing, e.g., cancer cell killing, e.g., as measured by the assay of Example 4; (xi) natural killer (NK) cell proliferation, e.g., increased expansion, or (xii) expansion of a population of T cells having a memory-like phenotype, e.g., at least about a 1.1- to 10-fold expansion (e.g., at least about a 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold expansion).

51. An anti-TCRβV antibody molecule according to any one of claims 17 to 50, which provides one, two, three or all of the following:

52. The anti-TCRβV antibody molecule of claim 51, wherein the T cell population with a memory-like phenotype comprises CD45RA+ CCR7- T cells, such as CD4+ and / or CD8+ T cells.

53. 10. The multispecific molecule or anti-TCRβV antibody molecule of any of the preceding claims, wherein binding of the anti-TCRβV antibody molecule to the TCRβV region results in at least a 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or 200-fold, or 2- to 200-fold (e.g., 5- to 150-fold, 10- to 100-fold, 20- to 50-fold) reduction in IL-1β expression levels and / or activity as measured by the assay of Example 3.

54. 10. The multispecific molecule or anti-TCRβV antibody molecule of any of the preceding claims, wherein binding of the anti-TCRβV antibody molecule to the TCRβV region results in at least a 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold, or 2-1000-fold (e.g., 5-900-fold, 10-800-fold, 20-700-fold, 50-600-fold, 100-500-fold, or 200-400-fold) reduction in IL-6 expression levels and / or activity as measured by the assay of Example 3.

55. The binding of the anti-TCRβV antibody molecule to the TCRβV region, when measured by the assay of Example 3, is at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 300-fold, at least 400-fold, at least 500-fold, at least 600-fold, at least 700-fold, at least 800-fold, or at least 900-fold lower than the expression level and / or activity of TNFα.

3. The multispecific molecule or anti-TCRβV antibody molecule of any preceding claim, which results in a reduction in TCRβV activity of at least 1000-fold, or at least 2000-fold, or at least 2-2000-fold (e.g. at least 5-1000-fold, at least 10-900-fold, at least 20-800-fold, at least 50-700-fold, at least 100-600-fold, at least 200-500-fold, or at least 300-400-fold).

56. 10. The multispecific molecule or anti-TCRβV antibody molecule of any of the preceding claims, wherein binding of the anti-TCRβV antibody molecule to the TCRβV region results in an increase in IL-2 expression levels and / or activity of at least 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1000-fold, or 2000-fold, or at least 2-2000-fold (e.g., 5-1000-fold, 10-900-fold, 20-800-fold, 50-700-fold, 100-600-fold, 200-500-fold, or 300-400-fold), as measured by the assay of Example 3.

57. 10. A multispecific molecule or anti-TCRβV antibody molecule according to any of the preceding claims, wherein the anti-TCRβV antibody molecule comprises an antigen-binding domain comprising a single chain Fv (scFv) or a Fab.

58. 10. A multispecific molecule or anti-TCRβV antibody molecule according to any of the preceding claims, wherein the anti-TCRβV antibody molecule binds to a conformational epitope or a linear epitope on a T cell.

59. The anti-TCRβV antibody molecule may be a full-length antibody (e.g., an antibody comprising at least one, preferably two, complete heavy chains and at least one, preferably two, complete light chains), or an antigen-binding fragment (e.g., Fab, F(ab')2, Fv, single-chain Fv fragment, single-domain antibody, dasAb, dasBb, dasCb, dasD ...

10. A multispecific molecule or anti-TCRβV antibody molecule according to any preceding claim, which is a diabody (dAb), a bivalent antibody, or a bispecific antibody or fragment thereof, a single domain variant thereof, or a camelid antibody.

60. 10. The multispecific molecule or anti-TCRβ antibody molecule of any of the preceding claims, wherein the anti-TCRβ antibody molecule comprises one or more heavy chain constant regions selected from IgG1, IgG2, IgG3, IgGA1, IgGA2, IgG4, IgJ, IgM, IgD, or IgE, e.g., as described in Table 3, or fragments thereof.

61. 10. A multispecific molecule or anti-TCRβV antibody molecule according to any of the preceding claims, wherein the anti-TCRβV antibody molecule comprises an IgM heavy chain constant region or a fragment thereof, optionally wherein the IgM heavy chain constant region comprises the sequence of SEQ ID NO: 73 or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto.

62. 10. A multispecific molecule or an anti-TCRβ antibody molecule according to any of the preceding claims, wherein the anti-TCRβ antibody molecule comprises the heavy chain constant region of IgJ or a fragment thereof, optionally wherein the IgJ heavy chain constant region comprises the sequence of SEQ ID NO: 76 or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto.

63. 10. A multispecific molecule or anti-TCRβ antibody molecule according to any of the preceding claims, wherein the anti-TCRβ antibody molecule comprises the heavy chain constant region of IgGA1 or a fragment thereof, optionally wherein the IgGA1 heavy chain constant region comprises the sequence of SEQ ID NO: 74 or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto.

64. 10. The multispecific molecule or anti-TCRβ antibody molecule of any of the preceding claims, wherein the anti-TCRβ antibody molecule comprises an IgG2 heavy chain constant region or a fragment thereof, optionally wherein the IgG2 heavy chain constant region comprises a sequence listed in Table 3, such as the sequence of SEQ ID NO: 75, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto.

65. 10. The multispecific molecule or anti-TCRβV antibody molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecule comprises a light chain constant region selected from the kappa or lambda light chain constant regions, e.g., as set forth in Table 3, or a fragment thereof.

66. 3. A multispecific molecule or anti-TCRβV antibody molecule according to any of the preceding claims, wherein the anti-TCRβV antibody molecule comprises a light chain constant region of a kappa chain or a fragment thereof, and optionally the kappa chain constant region comprises the sequence of SEQ ID NO: 39 or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto.

67. The anti-TCRβV antibody molecule is (i) one or more heavy chain constant regions, including a heavy chain constant region selected from IgG1, IgG2, IgG3, IgGA1, IgGA2, IgG4, IgJ, IgM, IgD, or IgE, e.g., as set forth in Table 3, or a fragment thereof; and (ii) a light chain constant region comprising a light chain constant region selected from the kappa or lambda light chain constant regions, e.g., as set forth in Table 3, or a fragment thereof.

10. The multispecific molecule or anti-TCRβV antibody molecule of any of the preceding claims, comprising:

68. The anti-TCRβV antibody molecule is (i) a heavy chain constant region, (a) the sequence of SEQ ID NO: 73, or at least 85%, 90%, 95%, or or a fragment thereof, comprising a sequence having 99% sequence identity thereto; (b) an IgGA1 heavy chain constant region or fragment thereof comprising the sequence of SEQ ID NO: 74, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto; or (c) a heavy chain constant region comprising an IgG2 heavy chain constant region or a fragment thereof comprising the sequence of SEQ ID NO: 75, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto; and (ii) a light chain constant region, including a kappa chain constant region, comprising the sequence of SEQ ID NO: 39, or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto. Including, Optionally, the anti-TCRβV antibody molecule further comprises an IgJ heavy chain constant region or a fragment thereof, wherein the IgJ heavy chain constant region comprises the sequence of SEQ ID NO: 76 or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto.

69. 69. The multispecific molecule of any one of claims 1 to 16 or 53 to 68, wherein the second moiety is a tumor-targeting moiety.

70. 69. The multispecific molecule of any one of claims 1 to 16 or 53 to 68, wherein the second moiety is a cytokine molecule.

71. 69. The multispecific molecule of any one of claims 1 to 16 or 53 to 68, wherein the second moiety is a stroma-modifying moiety.

72. 69. The multispecific molecule of any one of claims 1 to 16 or 53 to 68, wherein the second portion is an anti-TCRβV antibody molecule other than the first portion.

73. 73. The multispecific molecule of any one of claims 1 to 16 or 53 to 72, wherein the first and / or second portion binds to and activates an immune cell, e.g., an effector cell.

74. 73. The multispecific molecule of any one of claims 1 to 16 or 53 to 72, wherein the first and / or second portion binds to but does not activate an immune cell, e.g., an effector cell.

75. 75. The multispecific molecule of any one of claims 1 to 16 or 53 to 74, wherein the second moiety is selected from an NK cell engager, a T cell engager other than an anti-TCRβV antibody molecule, a B cell engager, a dendritic cell engager, or a macrophage cell engager, or a combination thereof.

76. 70. The multispecific molecule of any one of claims 1 to 16 or 53 to 69, wherein the tumor targeting moiety comprises an antibody molecule (e.g., Fab or scFv), receptor molecule (e.g., receptor, receptor fragment, or functional variant thereof), or ligand molecule (e.g., ligand, ligand fragment, or functional variant thereof) that binds to a cancer antigen, or a combination thereof.

77. 80. The multispecific molecule of any one of claims 1 to 16, 53 to 69, or 76, wherein the tumor targeting moiety binds to a cancer antigen present on a cancer, e.g., a hematological cancer, a solid tumor, a metastatic cancer, a soft tissue tumor, a metastatic lesion, or a combination thereof.

78. 78. The multispecific molecule of claim 77, wherein the cancer antigen is a tumor or stromal antigen, or a blood antigen.

79. Cancer antigens include BCMA, CD19, CD20, CD22, FcRH5, PDL1, CD47, gangloside 2 (GD2), prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PMSA), prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), Ron kinase, c-Met, immature laminin receptor, TAG-72, BING-4, calcium-activated chloride channel 2, cyclin-B1, 9D7, Ep-CAM, and E phA3, Her2 / neu, telomerase, SAP-1, survivin, NY-ESO-1 / LAG-1, PRAME, SSX-2, Melan-A / MART-1, Gp100 / pmel17, tyrosinase, TRP-1 / -2, MC1R, β-catenin, BRCA1 / 2, CDK4, CML66, fibronectin, p53, Ras, TGF-B receptor, AFP, ETA, MAGE, MUC-1, CA-125, BAGE, GAGE, NY-E SO-1, β-catenin, CDK4, CDC27, α-actinin-4, TRP1 / gp75, TRP2, gp100, melan-A / MART1, ganglioside, WT1, EphA3, epidermal growth factor receptor (EGFR), MART-2, MART-1, MUC1, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RUI1, RUI2, SAGE, TRG, TRP1, TSTA, folate receptor alpha, 79. The multispecific molecule of claim 77 or 78, selected from L1-CAM, CAIX, gpA33, GD3, GM2, VEGFR, integrins (integrin alpha V beta 3, integrin alpha 5 beta 1), carbohydrate (Le), IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, (FAP), TGF-beta, hyaluronic acid, collagen, such as type IV collagen, tenascin C, or tenascin W.

80. 80. The multispecific molecule of any one of claims 1 to 16, 53 to 69, or 76 to 79, wherein the tumor-targeting moiety is a BCMA-targeting moiety or an FcRH5-targeting moiety.

81. 81. The multispecific molecule of any one of claims 77 to 80, wherein the cancer is a solid tumor, including but not limited to pancreatic cancer (e.g., pancreatic adenocarcinoma), breast cancer, colorectal cancer, lung cancer (e.g., small cell or non-small cell lung cancer), skin cancer, ovarian cancer, or liver cancer.

82. 81. The multispecific molecule of any one of claims 77 to 80, wherein the cancer is a B-cell or T-cell malignancy, e.g., a hematological cancer, including but not limited to Hodgkin's lymphoma, non-Hodgkin's lymphoma (e.g., B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia), acute myeloid leukemia (AML), chronic myelogenous leukemia, myelodysplastic syndrome, multiple myeloma, and acute lymphocytic leukemia.

83. 71. The multispecific molecule of any one of claims 1 to 16, 53 to 68, or 70, wherein the cytokine molecule is selected from interleukin-2 (IL-2), interleukin-7 (IL-7), interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-18 (IL-18), interleukin-21 (IL-21), or interferon gamma, or a fragment, variant, or combination thereof.

84. 68. The cytokine molecule of claim 1, wherein the cytokine molecule is a monomer or a dimer. 70 or 83. A multispecific molecule according to any one of claims 70 or 83.

85. 85. The multispecific molecule of any one of claims 1 to 16, 53 to 68, 70, or 83 to 84, wherein the cytokine molecule further comprises a receptor dimerization domain, e.g., an IL15Ralpha dimerization domain.

86. 86. The multispecific molecule of any one of claims 1 to 16, 53 to 68, 70, or 83 to 85, wherein the cytokine molecule (e.g., IL-15) and the receptor dimerization domain (e.g., IL15Ralpha dimerization domain) are not covalently linked, e.g., are non-covalently associated.

87. 87. The multispecific molecule of any one of claims 1 to 16 or 53 to 86, further comprising an immunoglobulin constant region (e.g., an Fc region) selected from the heavy chain constant region of IgG1, IgG2, IgG3, IgGAl, IgG2, IgG4, IgJ, IgM, IgD, or IgE, or a fragment thereof, optionally wherein the heavy chain constant region comprises a human IgG1, IgG2, or IgG4 heavy chain constant region.

88. 88. The multispecific molecule of claim 87, wherein the immunoglobulin constant region (e.g., Fc region) is linked, e.g., covalently linked, to one or more of a tumor targeting moiety, a cytokine molecule, or a stroma-modifying moiety.

89. 89. The multispecific molecule of claim 87 or 88, wherein the interface of the first and second immunoglobulin chain constant regions (e.g., Fc regions) has been altered, e.g., mutated, to increase or decrease dimerization, e.g., compared to an unengineered interface.

90. 90. The multispecific molecule of claim 89, wherein dimerization of the immunoglobulin chain constant regions (e.g., Fc regions) provides one or more of paired holes and protrusions ("knobs-in-holes"), electrostatic interactions, or strand exchange at the Fc interface of the first and second Fc regions, thereby forming a higher ratio of heteromultimers:homomultimers, e.g., compared to an interface that is not engineered.

91. 90. The multispecific molecule of any of claims 1 to 16 or 53 to 90, further comprising a linker, e.g., a linker described herein, optionally wherein the linker is selected from a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, or a non-helical linker.

92. An isolated nucleic acid molecule comprising a nucleotide sequence encoding an anti-TCRβV antibody molecule described in any one of claims 17 to 53, or a nucleotide sequence having at least 75%, 80%, 85%, 90%, 95%, or 99% identity thereto.

93. An isolated nucleic acid molecule comprising a nucleotide sequence encoding a multispecific molecule of any of claims 1 to 16 or 53 to 91, or a nucleotide sequence having at least 75%, 80%, 85%, 90%, 95%, or 99% identity thereto.

94. 94. A vector, e.g., an expression vector, comprising one or more of the nucleic acid molecules of any of claims 92 or 93.

95. 95. A cell, e.g., a host cell, comprising a nucleic acid molecule according to any of claims 92 or 93, or a vector according to claim 94.

96. A method for making, e.g., producing or manufacturing, an anti-TCRβV antibody molecule described in any one of claims 17 to 53, or a multispecific molecule described in any one of claims 1 to 16 or 53 to 91, the method comprising a step of culturing a host cell described in claim 95 under suitable conditions, e.g., conditions suitable for expression of the anti-TCRβV antibody molecule or multispecific molecule.

97. A pharmaceutical composition comprising an anti-TCRβV antibody molecule described in any one of claims 17 to 53 or a multispecific molecule described in any one of claims 1 to 16 or 53 to 91, and a pharmaceutically acceptable carrier, excipient, or stabilizer.

98. A method for modulating, e.g., enhancing, an immune response in a subject, the method comprising administering to the subject an effective amount of an antibody molecule that binds (e.g., specifically binds) to a T-cell receptor beta variable region (TCRβV) (an "anti-TCRβV antibody molecule").

99. A method of modulating, e.g., enhancing, an immune response in a subject, comprising administering to the subject an effective amount of a multispecific molecule described in any of claims 1-16 or 53-91.

100. 100. The method of claim 98 or 99, comprising expanding a population of immune cells, e.g., increasing their number, in the subject.

101. 1. A method for expanding, e.g., increasing the number of, a population of immune cells, the method comprising contacting the population of immune cells with an effective amount of an antibody molecule that binds (e.g., specifically binds) to a T-cell receptor beta variable region (TCRβV) (an "anti-TCRβV antibody molecule").

102. A method for expanding, e.g., increasing the number of, an immune cell population, comprising contacting the immune cell population with an effective amount of a multispecific molecule described in any of claims 1 to 16 or 53 to 91.

103. 103. A method according to any of claims 100 to 102, wherein the expansion occurs in vivo or ex vivo (e.g. in vitro).

104. 104. The method of any of claims 100 to 103, wherein the immune cell population comprises cells that express TCRβV, e.g., TCRβV+ cells.

105. The method of claim 104, wherein the TCRβV-expressing cell is a T cell, e.g., a CD8+ T cell, a CD3+ T cell, or a CD4+ T cell.

106. 106. The method of any of claims 100-105, wherein the immune cell population comprises T cells (e.g., CD4 T cells, CD8 T cells (e.g., effector T cells, T cells with a memory-like phenotype or memory T cells (e.g., memory effector T cells (e.g., TEM cells, e.g., TEMRA cells)), or tumor-infiltrating lymphocytes (TILs).

107. 107. The method of any of claims 100-106, wherein the immune cell population comprises T cells, natural killer cells, B cells, or myeloid cells.

108. 108. The method of any of claims 100 to 107, wherein the immune cell population is obtained from a healthy subject.

109. 109. The method of any of claims 100 to 108, wherein the immune cell population is obtained from a subject (e.g., from an apheresis sample derived from the subject), e.g., having a disease described herein, e.g., cancer, and optionally the immune cell population comprises tumor infiltrating lymphocytes (TILs).

110. 110. The method of any of claims 100 to 109, which results in at least 1.1 to 10 fold expansion (e.g. at least 1.1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold expansion).

111. 111. The method of any of claims 100 to 110, further comprising contacting the cell population with an agent that promotes, e.g., increases, the expansion of immune cells.

112. 112. The method of any of claims 100 to 111, further comprising contacting the cell population with an immune checkpoint inhibitor, for example a PD-1 inhibitor.

113. 113. The method of any of claims 100 to 112, further comprising contacting the cell population with a 4-1BB (CD127) agonist, for example an anti-4-1BB antibody.

114. 114. The method of any of claims 100 to 113, further comprising contacting the cell population with a population of non-dividing cells, e.g., feeder cells, e.g., irradiated allogeneic human PBMCs.

115. 115. The method of any of claims 100 to 114, wherein the cell population is expanded in an appropriate medium (e.g., a medium described herein) comprising one or more cytokines, e.g., IL-2, IL-7, IL-15, or combinations thereof.

116. 116. The method of any of claims 100-115, wherein the cell population is expanded for a period of at least about 4 hours, 6 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 22 hours, or at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 1,6 days, 17 days, 18 days, 19 days, 20 days, or 21 days, or at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks.

117. 117. The method of any one of claims 100 to 116, wherein the expansion of the immune cell population is compared to the expansion of a similar cell population using an antibody that binds to a CD3 molecule, e.g., a CD3 epsilon (CD3e) molecule, or a TCR alpha (TCRα) molecule.

118. 118. The method of any of claims 100 to 117, wherein the expansion of the immune cell population is compared to the expansion of a similar cell population that has not been contacted with an anti-TCRβV antibody molecule or a multispecific molecule comprising an anti-TCRβV antibody molecule.

119. 119. The method of any of claims 100 to 118, wherein the expansion of a population of T cells with a memory-like phenotype, e.g., CD45RA+ CCR7- cells (e.g., memory effector T cells, e.g., TEM cells, e.g., TEMRA cells), is compared to the expansion of a similar cell population using an antibody that binds to a CD3 molecule, e.g., a CD3 epsilon (CD3e) molecule, or a TCR alpha (TCRα) molecule.

120. Expanded T cells with a memory-like phenotype, e.g., effector memory cell populations, are (i) cells that have detectable levels of CD45RA, e.g., express or re-express CD45RA; (ii) cells with low or no expression of CCR7, and / or (iii) cells that have detectable levels of CD95, e.g., express CD95; 120. The method of claim 119, for example, comprising a CD45RA+, CCR7-, CD95+ T cell population, and optionally, wherein the T cells comprise CD3+, CD4+ or CD8+ T cells.

121. 121. The method of any of claims 100 to 120, which results in the expansion, e.g., selective or preferential expansion, of T cells expressing a TCR comprising a T cell receptor (TCR) alpha and / or TCR beta molecule, e.g., TCR alpha-beta T cells (αβ T cells).

122. 122. The method of claim 121, which results in the expansion of αβ T cells in excess of the expansion of T cells expressing a TCR comprising a TCR gamma and / or TCR delta molecule, e.g., TCR gamma-delta T cells (γδ T cells).

123. A method of treating a disease, e.g., cancer, in a subject, comprising administering to the subject an effective amount of an antibody molecule that binds (e.g., specifically binds) to a T-cell receptor beta variable region (TCRβV) (an "anti-TCRβV antibody molecule"), thereby treating the cancer.

124. A composition comprising an antibody molecule that binds (e.g., specifically binds) to a T-cell receptor beta variable region (TCRβV) (an "anti-TCRβV antibody molecule") for use in treating a disease, e.g., cancer, in a subject.

125. A composition comprising an antibody molecule that binds (e.g., specifically binds) to a T-cell receptor beta variable region (TCRβV) (an "anti-TCRβV antibody molecule") for use in the manufacture of a medicament for treating a disease, e.g., cancer, in a subject.

126. 100. A method of treating a disease, e.g., cancer, in a subject, comprising administering to the subject an effective amount of a multispecific molecule of any of claims 1-16 or 53-91, thereby treating the cancer.

127. 100. A composition comprising a multispecific molecule according to any of claims 1 to 16 or 53 to 91 for use in treating a disease, e.g., cancer, in a subject.

128. 100. A composition comprising a multispecific molecule according to any of claims 1 to 16 or 53 to 91 for use in the manufacture of a medicament for treating a disease, e.g., cancer, in a subject.

129. A method of treating, e.g., preventing or reducing, cytokine release syndrome (CRS) and / or neurotoxicity (NT) in a subject, e.g., CRS and / or NT associated with a treatment, e.g., a previously administered treatment, comprising administering to the subject an effective amount of an antibody molecule that binds (e.g., specifically binds) to a T-cell receptor beta variable region (TCRβV) (an "anti-TCRβV antibody molecule"), thereby preventing CRS and / or NT in the subject.

130. Treating cytokine release syndrome (CRS) and / or neurotoxicity (NT) in a subject, e.g., CRS and / or NT associated with a treatment, e.g., a previously administered treatment. A method for preventing, e.g., reducing, CRS and / or NT in a subject, comprising administering to a subject an effective amount of a multispecific molecule of any of claims 1-16 or 53-91, thereby preventing CRS and / or NT in the subject.

131. 1. A method of targeting therapy, e.g., treatment, to T cells in a subject having a disease, e.g., cancer, comprising administering an effective amount of: (i) an antibody molecule that binds to (e.g., specifically binds to) the T cell receptor beta variable region (TCRβV) (an "anti-TCRβV antibody molecule"); and (ii) a therapy, e.g., a tumor-targeted therapy (e.g., an antibody that binds to a cancer antigen), e.g., as described herein thereby targeting the therapy to T cells in the subject.

132. 1. A method of targeting therapy, e.g., treatment, to T cells in a subject having a disease, e.g., cancer, comprising administering an effective amount of: (i) a multispecific molecule according to any one of claims 1 to 16 or 53 to 91, and (ii) a therapy, e.g., a tumor-targeted therapy (e.g., an antibody that binds to a cancer antigen), e.g., as described herein thereby targeting the therapy to T cells in the subject.

133. (ii) The method of claim 131 or 132, which results in a reduction in cytokine release syndrome (CRS) (e.g., shorter duration or absence of CRS) or a reduction in severity of CRS (e.g., absence of severe CRS, e.g., CRS grade 4 or 5) compared to administration alone.

134. 134. The method of any one of claims 131 to 133, wherein the anti-TCRβV antibody or multispecific molecule is administered concurrently with or following administration of a treatment associated with CRS.

135. 1. A method of treating a subject having cancer, comprising: obtaining a value of TCRβV subfamily status for a subject, said value comprising a measure of the presence, e.g., level or activity, of a TCRβV molecule in a sample from the subject; administering to the subject an effective amount of an antibody molecule that binds to (e.g., specifically binds to) a T cell receptor beta variable region (TCRβV) (an "anti-TCRβV antibody molecule"); thereby treating a subject.

136. 1. A method of treating a subject having cancer, comprising: obtaining a value of TCRβV subfamily status for a subject, said value comprising a measure of the presence, e.g., level or activity, of a TCRβV molecule in a sample from the subject; administering to the subject an effective amount of a multispecific molecule of any of claims 1-16 or 53-91; thereby treating a subject.

137. A method of treating a subject having cancer, comprising administering to the subject an effective amount of an antibody molecule that binds to (e.g., specifically binds to) a T-cell receptor beta variable region (TCRβV) (an "anti-TCRβV antibody molecule"), wherein the subject has, e.g., a level or activity of one or more TCRβV subfamilies described herein that is higher than, e.g., a reference level of one or more TCRβV subfamilies in a healthy subject, e.g., a subject without cancer. The method further comprises a method in which the activity is high, e.g., increased, compared to the normal or normal activity.

138. A method of treating a subject having cancer, comprising administering to the subject an effective amount of a multispecific molecule of any of claims 1-16 or 53-91, wherein the subject has a high, e.g., increased, level or activity of one or more TCRβV subfamilies, e.g., as described herein, compared to a reference level or activity of one or more TCRβV subfamilies in a healthy subject, e.g., a subject without cancer.

139. 1. A method of expanding a population of immune effector cells from a subject with cancer, comprising: (i) isolating a biological sample, e.g., a peripheral blood sample, a biopsy sample, or a bone marrow sample, from a subject, comprising an immune effector cell population; (ii) obtaining for a subject, e.g., in a biological sample from the subject, a value of the status of one or more TCRβV subfamilies, wherein the value comprises a measure of the presence, e.g., level or activity, of a TCRβV subfamily in a sample from the subject compared to a reference value, e.g., a sample from a healthy subject, wherein a high, e.g., increased value in the subject compared to the reference, e.g., healthy subject, indicates the presence of cancer in the subject; (iii) contacting the biological sample containing the immune effector cell population with, for example, an anti-TCRβV antibody molecule described herein; A method comprising:

140. 140. The method of claim 139, further comprising administering to the subject a population of immune effector cells contacted with an anti-TCRβV antibody molecule.

141. 1. A method of expanding a population of immune effector cells from a subject with cancer, comprising: (i) isolating a biological sample, e.g., a peripheral blood sample, a biopsy sample, or a bone marrow sample, from a subject, comprising an immune effector cell population; (ii) obtaining for a subject, e.g., in a biological sample from the subject, a value of the status of one or more TCRβV subfamilies, wherein the value comprises a measure of the presence, e.g., level or activity, of a TCRβV subfamily in a sample from the subject compared to a reference value, e.g., a sample from a healthy subject, wherein a high, e.g., increased value in the subject compared to the reference, e.g., healthy subject, indicates the presence of cancer in the subject; (iii) contacting a biological sample containing an immune effector cell population with a multispecific molecule of any of claims 1 to 16 or 53 to 91; A method comprising:

142. 142. The method of claim 141, further comprising administering to the subject the population of immune effector cells contacted with the multispecific molecule.

143. 143. The method of any one of claims 139 to 142, comprising measuring T cell function (e.g., cytotoxic activity, cytokine secretion, or degranulation) in the immune effector cell population, e.g., compared to a reference population, e.g., an otherwise similar population not contacted with the anti-TCRβV antibody molecule, or an immune effector cell population obtained from a healthy subject (e.g., a subject without cancer).

144. The biological sample containing the immune effector cell population is contacted with an anti-TCRβV antibody molecule or multispecific molecule that binds to one or more TCRβV subfamilies (e.g., the same TCRβV subfamily) identified as being high, e.g., increased, in the biological sample.

144. The method of any one of claims 139 to 143.

145. 145. The method of any one of claims 139 to 144, wherein a biological sample containing an immune effector cell population is contacted with an anti-TCRβV antibody molecule or multispecific molecule that does not bind to one or more TCRβV subfamilies (e.g., different TCRβV subfamilies) identified as being high, e.g., increased, in the biological sample.

146. 146. The method of any one of claims 139 to 145, wherein the cancer is a solid tumor, including but not limited to melanoma, pancreatic cancer (e.g., pancreatic adenocarcinoma), breast cancer, colorectal cancer (CRC), lung cancer (e.g., small cell or non-small cell lung cancer), skin cancer, ovarian cancer, or liver cancer.

147. 146. The method of any one of claims 139 to 145, wherein the cancer is a B-cell or T-cell malignancy, e.g., a hematological cancer, including but not limited to Hodgkin's lymphoma, non-Hodgkin's lymphoma (e.g., 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's lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia), acute myeloid leukemia (AML), chronic myelogenous leukemia, myelodysplastic syndrome, multiple myeloma, and acute lymphocytic leukemia.

148. The cancer is B-CLL, and the TCRβV molecule is (i) the TCRβ V6 subfamily, including, for example, 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; (ii) the TCRβ V5 subfamily, including TCRβ V5-6*01, TCRβ V5-4*01, or TCRβ V5-8*01; (iii) the TCRβ V3 subfamily, including TCRβ V3-1*01; (iv) the TCRβ V2 subfamily, including TCRβ V2*01; or (v) TCRβ V19 subfamily, including TCRβ V19*01 or TCRβ V19*02 148. The method of any one of claims 139 to 147, comprising:

149. The cancer is melanoma, and the TCRβV molecule is, for example, 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 148. The method of any one of claims 139 to 147, comprising a TCRβ V6 subfamily, including TCRβ V6-2*01, TCRβ V6-3*01, or TCRβ V6-1*01.

150. The cancer is DLBCL, and the TCRβV molecule is (i) the TCRβ V13 subfamily, including TCRβ V13*01; (ii) the TCRβ V3 subfamily, including TCRβ V3-1*01; or (iii) TCRβ V23 subfamily 148. The method of any one of claims 139 to 147, comprising:

151. The cancer is CRC, and the TCRβV molecule is (i) the TCRβ V19 subfamily, including TCRβ V19*01 or TCRβ V19*02; (ii) TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ TCRβ V12 subfamily, including V12-5*01; (iii) the TCRβ V16 subfamily, including TCRβ V16*01; or (iv) TCRβ V21 subfamily 148. The method of any one of claims 139 to 147, comprising:

152. the tumor comprises an antigen, e.g., a tumor antigen, e.g., a tumor-associated antigen or a neoantigen; and / or one or more TCRβV subfamilies recognize, e.g., bind to, a tumor antigen; 152. The method of any one of claims 139 to 151.

153. 153. The method of any one of claims 139 to 152, wherein the sample comprises a blood sample, e.g., a peripheral blood sample, a biopsy, e.g., a tumor biopsy, or a bone marrow sample.

154. 153. The method of any one of claims 139 to 152, wherein the sample comprises a biological sample containing immune cells, e.g., cells expressing TCRBV (e.g., TCRBV+ cells), T cells, or NK cells.

155. The T cells may be CD4 T cells, CD8 T cells (e.g., effector T cells, or memory T cells (e.g., memory effector T cells (e.g., T ＥＭ Cells, e.g., T ＥＭＲＡ 155. The method of claim 154, comprising a leukocyte, a leukocyte (L1), a leukocyte (L2), a leukocyte (L3), a leukocyte (L4), a leukocyte (L5), a leukocyte (L6), a leukocyte (L7), a leukocyte (L8), a leukocyte (L9 ...1), a leukocyte (L

156. 156. The method of any of claims 139 to 155, which results in an expansion, e.g., in vivo or ex vivo expansion, of an immune effector cell population comprising TCRVB-expressing immune effector cells, e.g., T cells, of at least 1.1 to 1000 fold, e.g., 1.1 to 10 fold, 10 to 100 fold, 100 to 200 fold, 200 to 300 fold, 300 to 400 fold, 400 to 500 fold, 500 to 600 fold, 600 to 700 fold, 700 to 800 fold, 800 to 900 fold, or 900 to 1000 fold expansion.

157. 157. The method of any of claims 139 to 156, wherein the cell population is expanded in an appropriate medium (e.g., a medium described herein) comprising one or more cytokines, e.g., IL-2, IL-7, IL-15, or combinations thereof.

158. 158. The method of any of claims 139-157, wherein the cell population is expanded for a period of at least about 4 hours, 6 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 22 hours, or at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 1,6 days, 17 days, 18 days, 19 days, 20 days, or 21 days, or at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks.

159. 159. The method of any of claims 139 to 158, wherein the expansion of the immune cell population is compared to the expansion of a similar cell population using an antibody that binds to a CD3 molecule, e.g., a CD3 epsilon (CD3e) molecule, or a TCR alpha (TCRα) molecule.

160. 160. The method of any of claims 139 to 159, wherein the expansion of the immune cell population is compared to the expansion of a similar cell population that has not been contacted with the anti-TCRβV antibody molecule.

161. T cells with a memory-like phenotype, e.g., memory effector T cells, e.g., T 161. The method of any of claims 139 to 160, wherein the expansion of an EM cell, e.g., TEMRA cell, population is compared to the expansion of a similar cell population using an antibody that binds to a CD3 molecule, e.g., a CD3 epsilon (CD3e) molecule, or a TCR alpha (TCRα) molecule.

162. Expanded T cells with a memory-like phenotype, e.g., effector memory cell populations, are (i) cells that have detectable levels of CD45RA, e.g., express or re-express CD45RA; (ii) cells with low or no expression of CCR7, and / or (iii) cells that have detectable levels of CD95, e.g., express CD95; 162. The method of any of claims 133 to 161, for example comprising a CD45RA+, CCR7-, CD95+ T cell population, and optionally wherein the T cells comprise CD3+, CD4+ or CD8+ T cells.

163. 163. The method of any of claims 139 to 162, which results in the expansion, e.g., selective or preferential expansion, of T cells expressing a TCR comprising a T cell receptor (TCR) alpha and / or TCR beta molecule, e.g., TCR alpha-beta T cells (αβ T cells).

164. 164. The method of claim 163, which results in the expansion of αβ T cells in excess of the expansion of T cells expressing a TCR comprising a TCR gamma and / or TCR delta molecule, e.g., TCR gamma-delta T cells (γδ T cells).

165. 165. The method or composition for use of any one of claims 98 to 164, wherein the anti-TCRβV antibody molecule comprises a light chain variable region (VL) comprising one, two or all of LC CDR1, LC CDR2 and LC CDR3 of the VL disclosed in Table 1, Table 2, Table 10, Table 11, Table 12 or Table 13, e.g., an antigen-binding domain comprising SEQ ID NO: 1314, SEQ ID NO: 2, SEQ ID NO: 10, SEQ ID NO: 11, 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.

166. 166. The method or composition for use of any one of claims 98 to 165, wherein the anti-TCRβV antibody molecule comprises a heavy chain variable region (VH) comprising one, two or all of HC CDR1, HC CDR2 and HC CDR3 of the VH disclosed in Table 1, Table 2, Table 10, Table 11, Table 12 or Table 13, e.g., an antigen-binding domain comprising SEQ ID NO: 1312, SEQ ID NO: 1, SEQ ID NO: 9, SEQ ID NO: 15, SEQ ID NO: 23, SEQ ID NO: 24 or SEQ ID NO:

25.

167. The anti-TCRβV antibody molecule is (i) a VL comprising the LC CDR1 amino acid sequence of SEQ ID NO: 20 (or an amino acid sequence having no more than one, two, three, or four modifications, e.g., substitutions, additions, or deletions), the LC CDR2 amino acid sequence of SEQ ID NO: 21 (or an amino acid sequence having no more than one, two, three, or four modifications, e.g., substitutions, additions, or deletions), and / or the LC CDR3 amino acid sequence of SEQ ID NO: 22 (or an amino acid sequence having no more than one, two, three, or four modifications, e.g., substitutions, additions, or deletions), and / or (ii) the HC CDR1 amino acid sequence of SEQ ID NO: 17 (or an amino acid sequence having no more than one, two, three, or four modifications thereof, e.g., substitutions, additions, or deletions), the HC CDR2 amino acid sequence of SEQ ID NO: 18 (or an amino acid sequence having no more than one, two, three, or four modifications thereof, e.g., substitutions, additions, or deletions), and / or 167. The method or composition for use of any one of claims 98 to 166, wherein said VH comprises an antigen-binding domain comprising a VH comprising the HC CDR3 amino acid sequence of SEQ ID NO: 19 (or an amino acid sequence having no more than one, two, three, or four alterations, e.g., substitutions, additions, or deletions).

168. The anti-TCRβV antibody molecule is a variable heavy chain (VH) of SEQ ID NO:23, SEQ ID NO:24, or SEQ ID NO:25, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto; and / or A variable light chain (VL) of SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, or SEQ ID NO:30, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto.

168. A composition for the method or use of any one of claims 98 to 167, comprising an antigen-binding domain comprising:

169. The anti-TCRβV antibody molecule is (i) a VL comprising the LC CDR1 amino acid sequence of SEQ ID NO: 6 (or an amino acid sequence having no more than one, two, three, or four modifications, e.g., substitutions, additions, or deletions), the LC CDR2 amino acid sequence of SEQ ID NO: 7 (or an amino acid sequence having no more than one, two, three, or four modifications, e.g., substitutions, additions, or deletions), and / or the LC CDR3 amino acid sequence of SEQ ID NO: 8 (or an amino acid sequence having no more than one, two, three, or four modifications, e.g., substitutions, additions, or deletions), and / or (ii) a VH comprising the HC CDR1 amino acid sequence of SEQ ID NO: 3 (or an amino acid sequence having one, two, three, or four or fewer modifications, e.g., substitutions, additions, or deletions), the HC CDR2 amino acid sequence of SEQ ID NO: 4 (or an amino acid sequence having one, two, three, or four or fewer modifications, e.g., substitutions, additions, or deletions), and / or the HC CDR3 amino acid sequence of SEQ ID NO: 5 (or an amino acid sequence having one, two, three, or four or fewer modifications, e.g., substitutions, additions, or deletions).

169. A composition for the method or use of any one of claims 98 to 168, comprising an antigen-binding domain comprising:

170. The anti-TCRβV antibody molecule is a variable heavy chain (VH) of SEQ ID NO: 1 or SEQ ID NO: 9 or SEQ ID NO: 1312, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto; and / or A variable light chain (VL) of SEQ ID NO:2, SEQ ID NO:10, or SEQ ID NO:11, or SEQ ID NO:1314, or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto.

170. A composition for the method or use of any one of claims 98 to 169, comprising an antigen-binding domain comprising:

171. The anti-TCRβV antibody molecule is (i) 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, or (ii) an asparagine at position 2, e.g., a substitution at position 2 according to Kabat numbering, e.g., an isoleucine to asparagine, serine to asparagine, or tyrosine to asparagine, or (iii) a leucine at position 4, e.g., a substitution at position 4 according to Kabat numbering, e.g., a methionine to leucine substitution. a light chain comprising a framework region, e.g., framework region 1 (FR1), comprising one, two, or all (e.g., three) of: the substitution is relative to a human germline light chain framework region sequence; 171. A composition for the method or use of any one of claims 98 to 170.

172. The anti-TCRβV antibody molecule is (i) a glycine at position 66, e.g., a substitution at position 66 according to Kabat numbering, e.g., a lysine to glycine or a serine to glycine substitution, or (ii) an asparagine at position 69, e.g., a substitution at position 69 according to Kabat numbering, e.g., a threonine to asparagine substitution, or (iii) a tyrosine at position 71, e.g., a substitution at position 71 according to Kabat numbering, e.g., a phenylalanine to tyrosine or an alanine to tyrosine substitution. a light chain comprising a framework region, e.g., framework region 3 (FR3), comprising one, two, or all (e.g., three) of: the substitution is relative to a human germline light chain framework region sequence; 172. A composition for the method or use of any one of claims 98 to 171.

173. A method or composition for use according to any one of claims 98 to 171, wherein binding of an anti-TCRβV antibody molecule to the TCRβV region results in a cytokine profile that differs from the cytokine profile of a T cell engager that binds to a receptor or molecule other than the TCRβV region (a "non-TCRβV-binding T cell engager").

174. 174. The method or composition for use of claim 173, wherein the non-TCRβV-binding T cell engager comprises an antibody that binds to a CD3 molecule (e.g., a CD3 epsilon (CD3e) molecule), or a TCR alpha (TCRα) molecule.

175. The cytokine profile of the first portion is: (i) an increase in the level, e.g., expression level, and / or activity, of IL-2; (ii) a reduction in the level, e.g., expression level, and / or activity of IL-1β; (iii) a reduction in the level, e.g., expression level, and / or activity of IL-6; (iv) a reduction in the level, e.g., expression level, and / or activity of TNFα; (v) reducing the level, e.g., expression level, and / or activity, of IL-10; (vi) a delay in the increase in the level, e.g., expression level, and / or activity of IL-2, e.g., a delay of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or more; (vii) a delay in the increase in the level, e.g., expression level, and / or activity of IFNg, e.g., a delay of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or (viii) an increase in the level, e.g., expression level, and / or activity of IL-15 including one, two, three, four, five, six, seven, or all of the following: For example, a composition for use according to claim 173 or 174, wherein (i) to (vii) are compared with the cytokine profile of a non-TCRβV-binding T cell engager.

176. A composition for use according to any one of claims 173 to 175, wherein binding of the anti-TCRβV antibody molecule to the TCRβV region results in a reduction in cytokine storm, e.g., a reduction in cytokine release syndrome (CRS), as measured by the assay of Example 3, e.g., compared to the cytokine storm induced by a non-TCRβV-binding T cell engager.

177. Binding of the anti-TCRβV antibody molecule to the TCRβV region For example, compared to non-TCRβV binding T cell engagers, (ix) reducing T cell proliferation kinetics; (x) cell killing, e.g., target cell killing, e.g., cancer cell killing, e.g., as measured by the assay of Example 4; (xi) natural killer (NK) cell proliferation, e.g., increased expansion, or (xii) expansion of a population of T cells having a memory-like phenotype, e.g., at least about a 1.1- to 10-fold expansion (e.g., at least about a 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold expansion); 177. A composition for the method or use of any one of claims 173 to 176, which results in one, two, three or all of:

178. A method or composition for use according to any one of claims 98 to 177, wherein the anti-TCRβV antibody molecule binds to an outward-facing region (e.g., epitope) on the TCRβV protein, e.g., as indicated by the circled region in Figure 24A.

179. The method or composition for use of claim 178, wherein the externally facing region on the TCRβV protein comprises a structurally conserved region of TCRβV, e.g., a region of TCRβV that has a similar structure across one or more TCRβV subfamilies.

180. 179. The method or composition for use of any one of claims 98 to 179, wherein the method further comprises the step of administering (e.g., sequentially, simultaneously, or concurrently) a second agent, e.g., a therapeutic agent, e.g., as described herein.

181. 181. The method or composition for use of claim 180, wherein the second agent, e.g., therapeutic agent, comprises a chemotherapeutic agent, a biological agent, a hormone therapy), radiation, or surgery.

182. 135. A method or composition for use according to any one of claims 98 to 134, wherein the disease is cancer, such as a solid tumor or a blood cancer, or a metastatic lesion.

183. The method of claim 175, wherein the cancer antigen is BCMA or FcRH5.

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