Anti-TCR antibody molecules and uses thereof

Abstract

To provide antibodies that avoid or reduce cytokine release syndrome and / or neurotoxicity in the application for redirecting T cells.SOLUTION: The present invention provides a multispecific molecule (e.g., a bispecific molecule), comprising a first moiety (e.g., a first immune cell engager) comprising an antibody molecule which binds (e.g., specifically binds) to a T cell receptor beta variable region (TCRβV) ("anti-TCRβV antibody molecule"). The present invention further provides a nucleic acid encoding the same, a method for producing the molecule, a pharmaceutical composition containing the molecule, and a method for treating cancer using the molecule.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 693,653, filed July 3, 2018, U.S. Provisional Application No. 62 / 737,829, filed September 27, 2018, U.S. Provisional Application No. 62 / 788,674, filed January 4, 2019, and U.S. Provisional Application No. 62 / 808,700, filed February 21, 2019, 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, 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 undesirable side effects of CRS and / or NT, e.g., CRS and / or NT associated with anti-CD3e targeting. do.

[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 10-12, 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., 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.

[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 determined by: (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) expansion of the memory T cell population, 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 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-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).

[0014] 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.

[0015] 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., at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, Hours, 8 hours, 9 hours, 10 hours delay, (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

[0016] 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.

[0017] 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) 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 SEQ ID NO: 10 or SEQ ID NO: 11; 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:

[0018] 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.

[0019] 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.

[0020] 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:

[0021] 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.

[0022] 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.

[0023] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) a VL comprising the LC CDR1 amino acid sequence of SEQ ID NO: 6 (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: 7 (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: 8 (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: 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:

[0024] 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; 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. The antigen-binding domain comprises:

[0025] In some embodiments, the anti-TCRβV antibody molecule comprises: (i) a VH amino acid sequence of SEQ ID NO: 9; (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; (iii) the VL amino acid sequence of SEQ ID NO: 10, 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 The antigen-binding domain comprises:

[0026] 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:

[0027] 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.

[0028] 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:

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[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 HC 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 HC of Table 2.

[0039] 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.

[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 a humanized BH HC in Table 2.

[0041] 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 inhibits the activation of memory T cells, e.g., effector memory T (T EM ) cells, e.g., T cells expressing CD45RA EM Cell (T EMRA ) cells, e.g., CD4+ or CD8+ T cells EMRA The expansion results in an expansion of the population of cells, 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). In some embodiments, the expansion is at least about 1.1-10-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).

[0042] In some embodiments, 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.

[0043] In some embodiments, the expanded effector memory T cell population comprises T cells, e.g., CD3+, CD8+, or CD4+ T cells. In some embodiments, the expanded effector memory T cell population comprises CD3+ and CD8+ T cells. In some embodiments, the expanded effector memory T cell population comprises CD3+ and CD4+ Contains T cells.

[0044] In some embodiments, the expanded effector memory T(T EM In some embodiments, the cell population includes T cells, e.g., CD3+, CD8+, or CD4+ T cells, that express or re-express CD45RA, e.g., are CD45RA+. In some embodiments, the population includes T cells that express CD45RA. EM Cells, e.g., T EMRA In 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.

[0045] In some embodiments, T EMRA The cells have low or no expression of CCR7, e.g., are CCR7- or CCR7 low. In some embodiments, the T EMRA Expression of CCR7 on cells cannot be detected by the methods disclosed herein, for example, flow cytometry.

[0046] In some embodiments, T EMRA The cells express CD95, e.g., are CD95+. In some embodiments, the T EMRA Expression of CD95 on cells can be detected by methods disclosed herein, for example, flow cytometry.

[0047] In some embodiments, T EMRA The cells express CD45RA, e.g., are CD45RA+, have low or no expression of CCR7, e.g., are CCR7- or CCR7 low, and express CD95, e.g., are CD95+. In some embodiments, the T EMRA The cells can be identified as CD45RA+, CCR7-, and CD95+ cells. In some embodiments, T EMRAThe cells include CD3+, CD4+, or CD8+ T cells (e.g., CD3+ T cells, CD3+ CD8+ T cells, or CD3+ CD4+ T cells).

[0048] 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. EMRA In 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 ... Marker expression 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 methods described in Examples 10 and 21. In some embodiments, the expansion is at least about 1.1- to 10-fold expansion (e.g., at least about 1.1-, 1.2-, 1.3-, 1.4-, 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 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.

[0049] 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

[0050] 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.

[0051] 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, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold lower, or at least 2- to 1000-fold lower (e.g., 5- to 900-fold, 10- to 800-fold, 20- to 700-fold, 50- to 600-fold, 100- to 500-fold, or This results in a reduction of emissions to 1 / 200 to 1 / 400.

[0052] 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 than 1 / 0, 1 / 700, 1 / 800, 1 / 900, 1 / 1000, or 1 / 2000, or at least 2-2000 fold reduction (e.g., 5-1000, 10-900, 20-800, 50-700, 100-600, 200-500, or 300-400 fold reduction).

[0053] 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.

[0054] 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.

[0055] 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 is 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 a 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-TCRβ antibody molecule is compared to expansion of an otherwise similar population not contacted with the anti-TCRβ antibody molecule.

[0056] 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.

[0057] In some embodiments of any of the compositions disclosed herein, an anti-TCRβV antibody Binding of the antibody molecule to the TCR βV 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 any of the activities described herein compared to the activity of the 16G8 or TM23 murine antibody, or a humanized version thereof, as described in U.S. Pat. No. 5,861,155. or a reduction of 2-fold or less, 5-fold or less, 10-fold or less, 20-fold or less, 50-fold or less, 100-fold or less, 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 less, or 2-2000-fold or less (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 less).

[0058] 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.

[0059] 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:

[0060] 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.

[0061] In some embodiments of any of the compositions disclosed herein, the anti-TCRβV antibody molecule is a member of the TCRBV family (e.g., gene family), such as, for example, the In some embodiments, the TCRBV gene family, e.g., the 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] In some embodiments of any of the compositions disclosed herein, the anti-TCRβ antibody molecule binds to a TCRβ region other than TCRβ V12 (e.g., a TCRβ V region described herein, e.g., TCRβ V6) 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. subfamily (e.g., TCRβ V6-5*01).

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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 that of the TM23 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155.

[0072] 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.

[0073] In some embodiments of any of the compositions 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.

[0074] 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.

[0075] In some embodiments of any of the compositions disclosed herein, the anti-TCRβ antibody molecule disclosed herein has 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. 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.

[0076] 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.

[0077] 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 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

[0078] 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

[0079] 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.

[0080] 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.

[0081] In one embodiment, a first moiety (e.g., a first antibody molecule) that binds (e.g., specifically binds) to a T cell receptor beta variable region (TCRβV) (an "anti-TCRβV antibody molecule") is provided. Provided herein are multispecific molecules (e.g., bispecific molecules) comprising an immune cell engager (e.g., an immune cell engager of the present invention).

[0082] 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.

[0083] 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").

[0084] 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.

[0085] 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:

[0086] 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.

[0087] 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.

[0088] In yet another aspect, the present disclosure provides a vector, e.g., an expression vector, 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.

[0089] 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.

[0090] In one aspect, the present disclosure provides a cell, e.g., a host cell, e.g., a cell population, comprising a nucleic acid molecule encoding an anti-TCRβ antibody molecule disclosed herein, or a nucleotide sequence having at least 75%, 80%, 85%, 90%, 95%, or 99% identity thereto. In some embodiments, the cell or cell population comprising a nucleic acid molecule encoding an anti-TCRβ antibody molecule comprises: (i) a variable region (VH), e.g., a VH listed in Table 1 or 2, or at least 75%, 80%, 85%, 90%, 95%, or 99% identity thereto; or 99% identity thereto, and a light chain comprising, for example, a light chain constant region 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 anti-TCRβ antibody molecule, e.g., the heavy and / or light chain of the anti-TCRβ 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 anti-TCRβ antibody molecule, e.g., the heavy and / or light chain of the anti-TCRβ antibody molecule.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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").

[0096] 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.

[0097] 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 a method of expanding, e.g., increasing the number of, a population of immune cells, 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"). The present invention provides a method for detecting a smeared image, the method comprising the steps of:

[0098] 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.

[0099] 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.

[0100] 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, CD8 T cells (e.g., 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).

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] In some embodiments, (i) and (ii) are conjugated, eg, linked. In some embodiments, (i) and (ii) are administered simultaneously or concurrently.

[0107] In some embodiments, the method further comprises (ii) reducing cytokine release syndrome compared to administration alone. In some embodiments, the method results in (ii) a reduction in neurotoxicity (NT) (e.g., a shorter duration or absence of NT) or a reduction in the severity of NT (e.g., the 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., a shorter duration or absence of NT) or a reduction in the severity of NT (e.g., the absence of severe NT) compared to administration alone.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] In another aspect, provided herein is a method of expanding, e.g., increasing the number of, an immune cell population, comprising contacting the immune cell population with an antibody molecule, e.g., a humanized antibody molecule (e.g., an anti-TCRβV antibody molecule described herein or a multispecific molecule comprising an anti-TCRβV antibody molecule described herein), that binds, e.g., specifically binds, to a T cell receptor beta variable chain (TCRβV) region, thereby expanding the immune cell population.

[0113] 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.

[0114] In another aspect, the disclosure provides a method of treating a subject having cancer, comprising the steps of: (i) obtaining a value of TCRβV molecule status for the subject, wherein said value comprises a measure of the presence, e.g., level or activity, of a TCRβV molecule in a sample obtained from the subject; and (ii) administering to the subject an effective amount of an anti-TCRβV antibody described herein in response to said value. and administering an RβV antibody molecule (e.g., a TCRβV agonist) to the patient, thereby treating the cancer.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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:

[0119] 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. A portion of any of the methods of treatment or compositions for use disclosed herein In embodiments, the status indicates responsiveness to a therapy, for example, a therapy comprising an anti-TCRβV antibody molecule, as described herein by way of example.

[0120] 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.

[0121] 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.

[0122] 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:

[0123] 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:

[0124] 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).

[0125] 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.

[0126] 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.

[0127] 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 the 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.

[0128] 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:

[0129] 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.

[0130] 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., 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.

[0131] 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.

[0132] 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.

[0133] Some embodiments of any of the compositions for the methods or uses disclosed herein In this state, 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.

[0134] 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.

[0135] 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.

[0136] In some embodiments, a 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 V molecule (e.g., an agonist anti-TCRβ V molecule described herein) that binds to one or more members of the TCRβ V3 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 V3 subfamily.

[0137] 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.

[0138] 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-TCRβ V molecule (e.g., an agonist anti-TCRβ V molecule described herein) that binds to one or more members of the TCRβ V19 subfamily. In some embodiments, the anti-TCRβ V molecule Administration of the vaccine results in the expansion of immune cells expressing one or more members of the TCRβ V19 subfamily.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] In some embodiments, a 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 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 V3 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 V3 subfamily.

[0143] 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.

[0144] 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 one or more TCRβV molecules, for example, (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*01, The level or activity of one or more TCRβV molecules, including (iv) the TCRβ V16 subfamily, or (v) the TCRβ V21 subfamily, is high, e.g., increased.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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:

[0151] 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:

[0152] 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.

[0153] 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.

[0154] 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: 6 (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: 7 (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: 8 (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: 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:

[0155] 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: 9, 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 a sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto. The antigen-binding domain comprises:

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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 V 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: 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, e.g., bound, 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.

[0164] 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:

[0165] 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.

[0166] 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.

[0167] 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) the HC CDR1 amino acid sequence of SEQ ID NO: 17 (or one, two, three or more thereof) a VH comprising an HC CDR2 amino acid sequence of SEQ ID NO: 18 (or an amino acid sequence having one, two, three, or four or fewer modifications, e.g., substitutions, additions, or deletions), an HC CDR3 amino acid sequence of SEQ ID NO: 19 (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:

[0168] 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 The 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:

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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: 26-28. 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] In some embodiments of any of the compositions or methods disclosed herein, the anti-TCRβ antibody molecule comprises a heavy chain constant region of IgGA1 or a fragment thereof, and optionally the IgGA1 heavy chain constant region has a sequence of SEQ ID NO: 74, or at least 85% thereto. , 90%, 95%, or 99% sequence identity.

[0180] 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.

[0181] 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").

[0182] In some embodiments, the cytokine profile, eg, cytokine secretion profile, comprises the level and / or activity of one or more cytokines and / or one or more chemokines (eg, as described herein).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).

[0183] 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.

[0184] 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.

[0185] In some embodiments, the binding of the anti-TCRBV antibody to the TCRβV region is determined by: (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) expansion of the memory T cell population, 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 one, two, three, or all of the For example, (ix) to (xii) are compared with non-TCRβV-binding T cell engagers.

[0186] 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).

[0187] 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).

[0188] 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.

[0189] 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.

[0190] 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 PP 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.

[0191] 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.

[0192] 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.

[0193] 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.

[0194] 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 chosen from the VHs of Table 1 or 2, 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 Table 1 or 2, 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.

[0195] In some embodiments of any of the methods 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 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

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] In some embodiments of any of the methods disclosed herein, the anti-TCRβV antibody 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.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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).

[0210] 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).

[0211] 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).

[0212] 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).

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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 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.

[0218] 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).

[0219] 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.

[0220] 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 antibodies, such as the antibodies described herein, do not induce CRS and / or NT when administered to a subject, e.g., a subject with a disease or condition described herein.

[0221] 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) the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof described in U.S. Patent No. 5,861,155. The TCRβV antibody molecule binds to a TCRβV region other than TCRβV12 (e.g., a TCRβV region described herein, e.g., the TCRβV6 subfamily (e.g., TCRβV6-5*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-TCRβV antibody molecule does not comprise the CDRs of the Antibody B murine antibody.

[0222] 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 that of the TM23 murine antibody or a humanized version thereof described in U.S. Patent No. 5,861,155. 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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, p5 3, 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, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RUI1, Binds to a cancer antigen selected from 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.

[0227] 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.

[0228] 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.

[0229] 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 on 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 due to, for example, one of limited tumor perfusion, vascular compression, or fibrous tumor stroma. In some embodiments, tumor targeting moieties, including BCMA targeting moieties, are disclosed in U.S. Patent 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, 9,426,241 ... 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.

[0230] 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)).

[0231] 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.

[0232] 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.

[0233] In some embodiments, the multispecific molecules disclosed herein are directed to cytokine molecules, e.g. For example, it further comprises 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 a 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., IL15R alpha dimerization domain) are not covalently linked, e.g., are non-covalently associated.

[0234] 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) tumor-targeting antibody molecules (e.g., antibody molecules described herein that bind to blood antigens selected from one or more of BCMA, FcRH5, CD19, CD22, CD33, CD123, FcRH5, CD179a, or CLEC12).

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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 regions) is altered, e.g., to increase or decrease dimerization compared to an unengineered interface. In some embodiments, the 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, 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.

[0239] 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 comprises 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.

[0240] 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.

[0241] In some embodiments, the multispecific molecule comprises a linker, e.g., 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 the second immune cell engager and a cytokine molecule ... cytokine molecule, between the antigen The tumor targeting moiety may further comprise a linker between one or more of: the tumor targeting moiety and the stromal-modifying moiety; the cytokine molecule and the stromal-modifying moiety; the antigen-binding domain of an anti-TCRβ antibody molecule disclosed herein and the dimerization module; the second immune cell engager and the dimerization module; the cytokine molecule and the dimerization module; the stromal-modifying moiety and the dimerization module; the tumor targeting moiety and the dimerization module; the tumor targeting moiety and the cytokine molecule; the tumor targeting moiety and the second immune cell engager; or the tumor targeting moiety and the antigen-binding domain of an 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.

[0242] In some embodiments of the methods or compositions for use disclosed herein, the disease is a cancer selected from a hematological cancer, a solid tumor, a metastatic cancer, a soft tissue tumor, a metastatic lesion, or a combination thereof.

[0243] 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.

[0244] 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.

[0245] 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).

[0246] 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.

[0247] Other features and advantages of the invention will be apparent from the following detailed description and claims. There will be. 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]

[0248] [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-2D 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. The various TCRβV proteins (from 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. 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 29]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). DETAILED DESCRIPTION OF THE INVENTION

[0249] 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 produce excessive amounts of pro-inflammatory cytokines, such as IL-1 beta, IL-6, IL-10, and TNF-α, resulting in 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, for example, to reduce CRS and / or neurotoxicity (NT), it is beneficial to bind and activate only a subset of effector T cells. There is a need to develop antibodies that can

[0250] 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.

[0251] 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 alpha and beta chains of highly diverse sequences show significant structural homology (Figures 24A and 24B) and similar functions, e.g., eliciting T cell activation.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] The present disclosure is directed, inter alia, to TCRs that bind to and, e.g., activate, a subset of T cells (T Antibody molecules directed to the variable chain of the beta subunit of TCRβV (TCRβV) are provided. 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 inhibit 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.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] In some embodiments, the anti-TCRβV antibody molecule does not comprise the CDRs of the TM23 murine antibody. Thus, provided herein are, inter alia, anti-TCRβ antibody molecules, multispecific or multifunctional molecules (e.g., multispecific or multifunctional antibody molecules) comprising anti-TCRβ antibody molecules, nucleic acids encoding the same, methods of producing the aforementioned molecules, pharmaceutical compositions comprising the aforementioned molecules, and methods of treating diseases or disorders, e.g., cancer, using the aforementioned molecules. The antibody molecules and pharmaceutical compositions disclosed herein can be used (alone or in combination with other agents or therapeutic modalities) to treat, prevent, and / or diagnose the diseases and conditions described herein, e.g., cancer. 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] 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 * 02. 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.

[0268] 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.

[0269] 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 chemokines. or the levels and / or activation of one or more chemokines (e.g., as described herein). In some embodiments, the cytokine profile comprises the levels and / or activation of naturally occurring cytokines, fragments or variants thereof. In some embodiments, the cytokine profile comprises 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); IL-8 (e.g., full length, a variant, or a fragment thereof); fragment); eotaxin (e.g., full length, variant, or fragment thereof); eotaxin-3 (e.g., full length, variant, or fragment thereof); IL-8 (HA) (e.g., full length, variant, or fragment thereof); IP-10 (e.g., full length, variant, or fragment thereof); MCP-1 (e.g., full length, variant, or fragment thereof); MCP-4 (e.g., full length, variant, or fragment thereof); MDC (e.g., full length, variant, or fragment thereof); MIP-1a (e.g., full length, variant, or fragment thereof); MIP-1b (e.g., full length, variant, or fragment thereof); TARC (e.g., full length, variant, or fragment thereof); GM-CSF (e.g., full length, variant, or fragment thereof); IL-12 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 secretion of one or more cytokines or chemokines.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] As used herein, a "multifunctional" or "multispecific" molecule refers to a molecule, e.g., a polypeptide, that has two or more functionalities, e.g., two or more binding specificities. In some embodiments, the functionalities 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 comprises an anti-TCRVb antibody molecule described herein.

[0274] 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.

[0275] In some embodiments, the multifunctional molecule comprises a cytokine molecule. As used herein, "cytokine molecule" refers to a full-length, fragment, or variant of a cytokine; a cytokine further comprising a receptor domain, e.g., a cytokine receptor dimerization domain; or an agonist of a cytokine receptor, e.g., an antibody molecule (e.g., an agonist antibody) against a cytokine receptor, 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.

[0276] 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.

[0277] 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. Certain terms are defined below.

[0278] 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."

[0279] 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.

[0280] As used herein, an "antibody molecule" refers to a protein, e.g., an immunoglobulin chain, or a fragment thereof, that contains 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., a Fab, Fab', F(ab')2, F(ab)2, variable fragment (Fv), domain antibody (dAb), or single-chain variable fragment (scFv). A functional antibody fragment binds to the same antigen 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 dAb (domain antibodies), single-chain, Fab, Fab', and F(ab')2 fragments, and single-chain variable fragments (scFv). In some embodiments, the antibody molecule is an antibody mimetic. In some embodiments, the antibody molecule is or includes an antibody-like framework or scaffold, such as fibronectin, ankyrin repeats (e.g., designed ankyrin repeat proteins (DARPins)), avimers, affibody affinity ligands, anticalins, or affilin molecules.

[0281] 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.

[0282] 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.

[0283] As used herein, "antigen" (Ag) refers to a substance that induces, for example, the activation and proliferation of certain immune cells. Antigens refer to molecules capable of eliciting an immune response, involving the production of antibodies and / or antibodies. Any macromolecule, including almost any protein or peptide, can be an antigen. Antigens can also be derived from genome 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, an antigen 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.

[0284] 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 participates in antigen binding. In embodiments, the antigen-binding site is formed by amino acid residues from 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 adjacent regions called "framework regions" (FR). FRs are amino acid sequences naturally found between and adjacent to the hypervariable regions in immunoglobulins. In embodiments, in an antibody molecule, the three hypervariable regions of the light chain and the three hypervariable regions of the heavy chain are positioned 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) typically consists 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.

[0285] 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.

[0286] 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 An important type of lymphocyte, derived from hematopoietic stem cells in the bone marrow. B cells are involved in humoral immune responses, while T cells are involved in cellular immune responses. The term "immune cell" includes immune effector cells.

[0287] 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.

[0288] 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.

[0289] 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, for example, a sequence at least 80%, 85%, 90%, 95% identical, or more identical to the specified sequence. In the context of amino acid sequences, the term "substantially identical" is used herein to refer to a first amino acid sequence containing a sufficient or minimal number of amino acid residues that are i) identical to a second amino acid sequence, or ii) are conservative substitutions for aligned amino acid residues in a second amino acid sequence, such that the first and second amino acid sequences may share a common structural domain and / or a common functional activity. For example, an amino acid sequence containing 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, such as a sequence provided herein.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] 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 10%, of the length of the reference sequence. Preferably, the amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are the same or different from each other. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein, amino acid or nucleic acid "identity" is equivalent to amino acid or nucleic acid "homology").

[0294] 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.

[0295] Comparison of sequences and determination of percent identity between two sequences can be achieved 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 incorporated into the GAP program of the GCG software package (available at http: / / www.gcg.com) using a Blossum62 matrix or a PAM250 matrix, 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 GAP program of the GCG software package (available at http: / / www.gcg.com) using a NWSgapdna.CMP matrix, a gap weight of 40, 50, 60, 70, or 80, and a length weight of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and which 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.

[0296] 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.

[0297] 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.

[0298] The molecules of the present invention may contain additional conservative or non-conservative modifications that do not substantially affect their function. It is understood that essential amino acid substitutions may be present. 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.

[0299] 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).

[0300] The terms "polypeptide," "peptide," and "protein" (when single-chain) are used interchangeably herein to refer to polymers of amino acids of any length. The polymers can be linear or branched, can contain modified amino acids, and can be interrupted by non-amino acids. These terms also encompass amino acid polymers that have been modified; 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, produced by recombinant techniques from eukaryotic or prokaryotic hosts, or can be the product of synthetic techniques.

[0301] 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.

[0302] 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 may be part of a composition, and such a vector or composition may still be isolated in that it is not part of the environment in which it is found in nature.

[0303] Various aspects of the invention are described in further detail below. Additional definitions are set forth throughout the specification. Human T cell receptor (TCR) complex T cell receptors (TCRs) can be found on the surface of T cells. TCRs recognize antigens, e.g., peptides, bound to major histocompatibility complex (MHC) molecules, presented on the surface of cells, e.g., antigen-presenting cells. TCRs are heterodimeric molecules and can include an alpha chain, a beta chain, a gamma chain, or a delta chain. TCRs containing an alpha chain and a beta chain are also called TCRαβ. The TCRβ chain consists of the following regions (also known as segments): variable (V), diverse (D), joining (J), and constant (C) (see Mayer G. and Nyland J. (2010) Chapter 10: Major Histocompatibility Complex and T-cell Receptors—Role in Immune Responses. In: Microbiology and Immunology online, University of South Carolina School of Medicine). The TCRα chain consists of the V, J, and C regions. Rearrangement of the T cell receptor (TCR) by somatic recombination of the V (variable), D (diverse), J (joining), and C (constant) regions is a critical event in the development and maturation of T cells. TCR gene rearrangement occurs in the thymus.

[0304] A TCR may comprise a receptor complex known as a TCR complex, which comprises a TCR heterodimer comprising an alpha chain and a beta chain, and a dimeric signaling molecule, e.g., a CD3 co-receptor, e.g., CD3δ / ε and / or CD3γ / ε. TCR beta V (TCRβV) Diversity in the immune system allows for defense against a vast array of pathogens. Because the size of the germline genome is limited, diversity is achieved not only through the process of V(D)J recombination, but also through deletion of nucleotide junctions (the junctions between the VD and DJ segments) and pseudorandom, non-templated addition of nucleotides. TCR beta genes undergo genetic rearrangement to generate diversity.

[0305] The TCR V beta repertoire varies between individuals and populations due to, for example, seven frequently occurring inactivating polymorphisms in functional gene segments and large insertion / deletion-associated polymorphisms encompassing two V beta gene segments. The present disclosure provides, inter alia, antibody molecules and fragments thereof that bind to, e.g., specifically bind to, e.g., human TCR beta V chains (TCRβV), e.g., TCRβV gene families (also referred to as groups), e.g., TCRβV subfamilies (also referred to as subgroups), e.g., as described herein. TCR beta V families and subfamilies are known in the art and are described, for example, in Yassai et al. (2009) Immunogenetics 61(7):493-502; Wei S. and Concannon P. (1994) Human Immunology 41(3) pp. 201-206. The antibodies described herein can be recombinant antibodies, e.g., recombinant non-murine antibodies, e.g., recombinant human or humanized antibodies.

[0306] In certain aspects, the present disclosure provides anti-TCRβ antibody molecules that bind to a human TCRβV, e.g., a TCRβV family, e.g., a gene family or variant thereof. In some embodiments, the TCRβV gene family includes one or more subfamilies, e.g., as described herein, e.g., as described in Figure 3, Table 8A or 8B. In some embodiments, the TCRβV gene family includes one or more subfamilies, e.g., a TCRβV V6 subfamily, a TCRβV V10 subfamily, a TCRβV V12 subfamily, a TCRβV V5 subfamily, a TCRβV V7 subfamily, a TCRβV V11 subfamily, a TCRβV V14 subfamily, a TCRβV V16 subfamily, a TCRβV V20 subfamily, a TCRβV V30 subfamily, a TCRβV V40 subfamily, a TCRβV V51 subfamily, a TCRβV V62 subfamily, a TCRβV V73 subfamily, a TCRβV V11 subfamily, a TCRβV V14 subfamily, a TCRβV V16 subfamily, a TCRβV V18 subfamily, a TCRβV V20 subfamily, a TCRβV V22 subfamily, a TCRβV V24 subfamily, a TCRβV V26 subfamily, a TCRβV V28 subfamily, a TCRβV V29 subfamily, a TCRβV V30 subfamily, a TCRβV V31 subfamily, a TCRβV V32 subfamily, a TCRβV V33 subfamily, a TCRβV V34 subfamily, a TCRβV V35 subfamily, a TCRβV V36 subfamily, a TCRβV V37 subfamily, a TCRβV V38 subfamily, a TCRβV V39 subfamily, a TCRβV V40 subfamily, a TCRβV 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 V17 subfamily, TCRβ V21 subfamily, TCRβ V23 subfamily, or TCRβ V26 subfamily.

[0307] In some embodiments, the TCRβ V6 subfamily is also known as TCRβ V13.1. In some embodiments, the TCRβ V6 subfamily is also known 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, or a variant thereof. In some embodiments, the TCRβ V6 comprises TCRβ V6-4 * 01, or a variant thereof. In some embodiments, the TCRβ V6 comprises TCRβ V6-4 * 02, or a variant thereof. In some embodiments, the TCRβ V6 comprises TCRβ V6-9 * 01, or a variant thereof. In some embodiments, the TCRβ V6 comprises TCRβ V6-8 * 01, or a variant thereof. In some embodiments, the TCRβ V6 comprises TCRβ V6-5 * 01, or a variant thereof. In some embodiments, the TCRβ V6 comprises TCRβ V6-6 * 02, or a variant thereof. In some embodiments, the TCRβ V6 comprises TCRβ V6-6* 01, or a variant thereof. In some embodiments, the TCRβ V6 comprises TCRβV6-2 * 01, or a variant thereof. In some embodiments, the TCRβ V6 comprises TCRβ V6-3 * 01, or a variant thereof. In some embodiments, the TCRβ V6 comprises TCRβ V6-1 * 01, or any variant thereof.

[0308] In some embodiments, TCRβ V6 is TCRβ V6-5 * 01, or a variant thereof. In some embodiments, TCRβ V6, e.g., TCRβ V6-5 * 01 is recognized, e.g., bound, by SEQ ID NO: 1 and / or SEQ ID NO: 2. In some embodiments, TCRβ V6, e.g., TCRβ V6-5 * 01 is recognized, e.g., bound by, SEQ ID NO: 9 and / or SEQ ID NO: 10. In some embodiments, TCRβ V6 is recognized, e.g., bound by, SEQ ID NO: 9 and / or SEQ ID NO: 11.

[0309] In some embodiments, the TCRβ V10 subfamily is also known as TCRβ V12. In some embodiments, the TCRβ V10 subfamily is also known as TCRβ V10-1 * 01. TCRβ V10-1 * 02. TCRβ V10-3 * 01 or TCRβ V10-2 * 01, or any variant thereof.

[0310] In some embodiments, the TCRβ V12 subfamily is also known as TCRβ V8.1. In some embodiments, the TCRβ V12 subfamily is also known as TCRβ V8.1. V12-4 * 01. TCRβ V12-3 * 01, or TCRβ V12-5 *01, or variants thereof. In some embodiments, TCR β V12 is recognized by, e.g., bound by, SEQ ID NO: 15 and / or SEQ ID NO: 16. In some embodiments, TCR β V12 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.

[0311] In some embodiments, the TCRβ V5 subfamily is TCRβ V5-5 * 01. TCRβ V5-6 * 01. TCRβ V5-4 * 01. TCRβ V5-8 * 01. TCRβ V5-1 * 01, or a variant thereof.

[0312] In some embodiments, the TCRβ V7 subfamily is TCRβ V7-7 * 01. TCRβ V7-6 * 01. TCRβ V7-8 * 02. TCRβ V7-4 * 01. TCRβ V7-2 * 02. TCRβ V7-2 * 03. TCRβ V7-2 * 01. TCRβ V7-3 * 01. TCRβ V7-9 * 03, or TCRβ V7-9 * 01, or any variant thereof.

[0313] In some embodiments, the TCRβ V11 subfamily is TCRβ V11-1 * 01. TCRβ V11-2 * 01 or TCRβ V11-3 * 01, or any variant thereof.

[0314] In some embodiments, the TCRβ V14 subfamily is TCRβ V14 * 01, or any variant thereof. In some embodiments, the TCRβ V16 subfamily is TCRβ V16 * 01, or any variant thereof.

[0315] In some embodiments, the TCRβ V18 subfamily is TCRβ V18 * 01, or any variant thereof. In some embodiments, the TCRβ V9 subfamily is TCRβ V9 * 01 or TCRβ V9 * 02, or any variant thereof.

[0316] In some embodiments, the TCRβ V13 subfamily is TCRβ V13 * 01, or any variant thereof. In some embodiments, the TCRβ V4 subfamily is TCRβ V4-2 * 01. TCRβ V4-3 * 01, or TCRβ V4-1 * 01, or any variant thereof.

[0317] In some embodiments, the TCRβ V3 subfamily is TCRβ V3-1 * 01, or any variant thereof. In some embodiments, the TCRβ V2 subfamily is TCRβ V2 * 01, or any variant thereof.

[0318] In some embodiments, the TCRβ V15 subfamily is TCRβ V15 * 01, or any variant thereof. In some embodiments, the TCRβ V30 subfamily is TCRβ V30 * 01, or TCRβ V30 * 02, or any variant thereof In some embodiments, the TCRβ V19 subfamily is TCRβ V19 * 01, or TCRβ V19 *02, or any variant thereof.

[0319] In some embodiments, the TCRβ V27 subfamily is TCRβ V27 * 01, or any variant thereof. In some embodiments, the TCRβ V28 subfamily is TCRβ V28 * 01, or any variant thereof.

[0320] In some embodiments, the TCRβ V24 subfamily is TCRβ V24-1 * 01, or any variant thereof. In some embodiments, the TCRβ V20 subfamily is TCRβ V20-1 * 01, or TCRβ V20-1 * 02, or any variant thereof.

[0321] In some embodiments, the TCRβ V25 subfamily is TCRβ V25-1 * 0 1, or its variants. In some embodiments, the TCRβ V29 subfamily is TCRβ V29-1 * 01, or any variant thereof.

[0322] [Table 1]

[0323] [Table 2]

[0324] Exemplary amino acid sequences of TCRβV subfamily members can be found on the ImMunoGeneTics Information System website: http: / / www.imgt.org / , or similar resources.

[0325] [Table 3-1]

[0326] [Table 3-2]

[0327] [Table 3-3]

[0328] The alignment of TCRBV amino acid sequences in Table 9 highlights the diversity of TCR sequences. In particular, TRBV sequences from different subfamilies are quite different from each other. Anti-TCRβV antibody A novel class of antibodies, i.e., the anti-TCRβV antibody molecules disclosed herein, recognize structurally conserved regions, e.g., domains, on the TCRβV protein (e.g., as represented by the circled sections in Figure 24A) and have similar functions (e.g., similar cytokine profiles), despite having low sequence similarity (e.g., low sequence identity among different antibody molecules that recognize different TCRβV subfamilies). The discovery of these findings is disclosed herein, and therefore the anti-TCRβV antibody molecules disclosed herein share a structure-function relationship.

[0329] 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 in complex with the TCR alpha protein, for example, as depicted by the circled area in Figure 24 A. 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., as represented by the circled area in Figure 24A).

[0330] 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 Dec;11(6):701-13).

[0331] 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.

[0332] In some embodiments, the anti-TCRβV antibody molecules disclosed herein bind (e.g., specifically bind) to the TCRβV region. In some embodiments, binding of the anti-TCRβV antibody molecules disclosed herein 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"). In some embodiments, 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. In some embodiments, the non-TCRβV-binding T cell engager is an OKT3 antibody or an SP34-2 antibody.

[0333] In one aspect, the present disclosure provides an anti-TCRβV antibody molecule that binds to one or more human TCRβVs, e.g., TCRβV gene families, e.g., TCRβV subfamilies, e.g., as described herein, e.g., in Figure 3, Table 8A, or Table 8B. In some embodiments, the anti-TCRβV antibody molecule 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 V1 subfamily, TCRβ V1 subfamily, TCRβ V17 subfamily, TCRβ V21 subfamily, TCRβ It binds to one or more TCRβ V subfamilies selected from the V23 subfamily, or the TCRβ V26 subfamily, or variants thereof.

[0334] In some embodiments, the anti-TCRβ antibody molecule is TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01, or TCRβ V6-1*01, or a variant thereof. In some embodiments, the TCRβ V6 subfamily comprises TCRβ V6-5*01, or a variant thereof. In some embodiments, the TCRβ V6 comprises TCRβ V6-4*01, or a variant thereof. In some embodiments, the TCRβ V6 comprises TCRβ V6-4*02, or a variant thereof. In some embodiments, the TCRβ V6 comprises TCRβ V6-9*01, or a variant thereof. In some embodiments, the TCRβ V6 comprises TCRβ V6-8*01, or a variant thereof. In some embodiments, the TCRβ V6 comprises TCRβ V6-5*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-6*02, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-6*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-2*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-3*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-1*01, or a variant thereof.

[0335] In some embodiments, the anti-TCRβV antibody molecule binds to the TCRβ V10 subfamily, including TCRβ V10-1*01, TCRβ V10-1*02, TCRβ V10-3*01 or TCRβ V10-2*01, or variants thereof.

[0336] In some embodiments, the anti-TCRβV antibody molecule binds to the TCRβ V12 subfamily, including TCRβ V12-4*01, TCRβ V12-3*01 or TCRβ V12-5*01, or variants thereof.

[0337] In some embodiments, the anti-TCRβ antibody molecule is TCRβ V5-5*01, TCRβ It binds to the TCRβ V5 subfamily, including TCRβ V5-6*01, TCRβ V5-4*01, TCRβ V5-8*01, TCRβ V5-1*01, or variants thereof.

[0338] Exemplary anti-TCRβV antibody molecules and corresponding TCRβV subfamilies recognized by the anti-TCRβV antibody molecules are disclosed in Table 10A.

[0339] [Table 4-1]

[0340] [Table 4-2]

[0341] [Table 4-3]

[0342] [Table 4-4]

[0343] [Table 4-5]

[0344] 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 lower (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10-fold lower) 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.

[0345] In some embodiments, the anti-TCRβ antibody molecule binds to TCRβ V12 with an affinity and / or binding specificity that is higher (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2, 5, or 10 times higher) 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.

[0346] In some embodiments, the anti-TCRβV antibody molecule is a TCRβV antibody molecule described in U.S. Pat. No. 5,861,155. The 16G8 murine antibody or humanized version thereof binds to a TCRβ V 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 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 16G8 murine antibody or humanized version thereof described herein.

[0347] 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 lower (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10-fold lower) 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.

[0348] 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 is higher (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2, 5, or 10 times higher) than the affinity and / or binding specificity of the TM23 murine antibody or humanized version thereof described in U.S. Pat. No. 5,861,155.

[0349] In some embodiments, 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 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 described in U.S. Pat. No. 5,861,155. Anti-TCRβ V6 antibody Thus, in one aspect, the present disclosure provides anti-TCRβ V antibody molecules that bind to human TCRβ V6, e.g., a TCRβ V6 subfamily including 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 or a variant thereof. In some embodiments, the TCRβ V6 includes TCRβ V6-4*01 or a variant thereof. In some embodiments, the TCRβ V6 includes TCRβ V6-1*01 or a variant thereof. V6-4*02, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-9*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-8*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-5*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-6*02, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-6*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-2*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-3*01, or a variant thereof. In some embodiments, TCRβ V6 comprises TCRβ V6-1*01, or a variant thereof.

[0350] In some embodiments, TCRβ V6-5*01 is encoded by the nucleic acid sequence of SEQ ID NO: 43, or a sequence having 85%, 90%, 95%, 99% or higher identity thereto. SEQ ID NO: 43 ATGAGCATCGGCCTCCTGTGCTGTGCAGCCTTGTCTCTCCTGGGCAGGTCCAGTGAATGCTGGTGTCACTCAGACCCCAAAATTCCAGGTCCTGAAGACAGGACAGAGCATGACACTGCAGTGTGCCCAGGATATGAACCATGAATACATGTCCTGGTATCGACAAGACC CAGGCATGGGGCTGAGGCTGATTCATTACTCAGTTGGTGCTGGTATCACTGACCAAGGAGAAGTCCCCAATGGCTACAATGTCTCCAGATCAACCACAGAGGATTTCCCGCTCAGGCTGCTGTCGGCTGCTCCCTCCCAGACATCTGTGTACTTCTGTGCCAGCAGTTACTC In some embodiments, TCR β V6-5*01 comprises the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence having 85%, 90%, 95%, 99% or more identity thereto. SEQ ID NO: 44 MSIGLCCAALSLLWAGPVNAGVTQTPKFQVLKTGQSMTLQCAQDMNHEYMSWYRQDPGMGLRLIHYSVGAGITDQGEVPNGYNVSRSTTEDFPLRLLSAAPSQTSVYFCASSY In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a non-murine antibody molecule, e.g., a human or humanized antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a human antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a humanized antibody molecule.

[0351] In some embodiments, the anti-TCRβ V antibody molecule, eg, anti-TCRβ V6 (eg, anti-TCRβ V6-5*01) antibody molecule, is isolated or recombinant. In some embodiments, the anti-TCRβ antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one antigen-binding region, e.g., a variable region or antigen-binding fragment thereof, from an antibody described herein, e.g., an antibody selected from AH.1 or AH.2, or an antibody described in Table 1, or encoded by a nucleotide sequence in Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences.

[0352] In some embodiments, the anti-TCRβ antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one, two, three, or four variable regions from an antibody described herein, e.g., an antibody chosen from AH.1 or AH.2, or an antibody described in Table 1, or encoded by a nucleotide sequence in Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences.

[0353] In some embodiments, the anti-TCRβ antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one or two heavy chain variable regions from an antibody described herein, e.g., an antibody chosen from AH.1 or AH.2, or an antibody molecule described in Table 1, or encoded by a nucleotide sequence in Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences.

[0354] In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain variable region (VH) having the consensus sequence of SEQ ID NO: 231 or 3290. In some embodiments, the anti-TCRβ antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one or two light chain variable regions from an antibody described herein, e.g., an antibody chosen from AH.1 or AH.2, or an antibody described in Table 1, or encoded by a nucleotide sequence in Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences.

[0355] In some embodiments, the anti-TCRβV antibody molecule comprises a light chain variable region (VL) having the consensus sequence of SEQ ID NO: 230 or 3289. In some embodiments, the anti-TCRβ antibody molecule, e.g., the anti-TCRβ V6 (e.g., the anti-TCRβ V6-5*01) antibody molecule, comprises a heavy chain constant region of an IgG4, e.g., a human IgG4. In yet another embodiment, the anti-TCRβ antibody molecule, e.g., the anti-TCRβ V6 (e.g., the anti-TCRβ V6-5*01) antibody molecule, comprises a heavy chain constant region of an IgG1, e.g., a human IgG1. In one embodiment, the heavy chain constant region comprises an amino acid sequence set forth in Table 3, or a sequence substantially identical thereto (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical).

[0356] In some embodiments, the anti-TCRβ antibody molecule, e.g., the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a kappa light chain constant region, e.g., a human kappa light chain constant region. In one embodiment, the light chain constant region comprises an amino acid sequence set forth in Table 3, or a sequence substantially identical thereto (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical).

[0357] In some embodiments, the anti-TCRβ antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one, two, or three complementarity determining regions (CDRs) from the heavy chain variable region (VH) of an antibody described herein, e.g., an antibody chosen from AH.1 or AH.2, or described in Table 1, or encoded by a nucleotide sequence in Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences.

[0358] In some embodiments, an anti-TCRβ V antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising the amino acid sequence shown in Table 1 or encoded by the nucleotide sequence shown in Table 1. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six, or more changes, e.g., amino acid substitutions or deletions, compared to the amino acid sequence shown in Table 1 or encoded by the nucleotide sequence shown in Table 1.

[0359] In some embodiments, the anti-TCRβ antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one, two, or three complementarity determining regions (CDRs) from the light chain variable region of an antibody described herein, e.g., an antibody chosen from AH.1 or AH.2, or described in Table 1, or encoded by a nucleotide sequence in Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences.

[0360] In some embodiments, an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Table 1 or encoded by a nucleotide sequence shown in Table 1. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six, or more changes, e.g., amino acid substitutions or deletions, compared to the amino acid sequence shown in Table 1 or encoded by the nucleotide sequence shown in Table 1.

[0361] In some embodiments, an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one, two, three, four, five, or six CDRs (or collectively all of the CDRs) from heavy and light chain variable regions comprising the amino acid sequences shown in Table 1 or encoded by the nucleotide sequences shown in Table 1. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six, or more changes, e.g., amino acid substitutions or deletions, compared to the amino acid sequence shown in Table 1 or encoded by the nucleotide sequence shown in Table 1.

[0362] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises all six CDRs from an antibody described herein, e.g., an antibody selected from AH.1 or AH.2, or an antibody described in Table 1 or encoded by the nucleotide sequence in Table 1, or closely related CDRs, e.g., CDRs that are identical or have 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). In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, may comprise any CDR described herein.

[0363] In some embodiments, an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Table 1) from the heavy chain variable region of an antibody described herein, e.g., an antibody chosen from AH.1 or AH.2, or an antibody described in Table 1, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences, or has 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) compared to one, two, or three CDRs according to Kabat et al. as set out in Table 1.

[0364] In some embodiments, an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Table 1) from the light chain variable region of an antibody described herein, e.g., an antibody chosen from AH.1 or AH.2, or an antibody described in Table 1, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences, or has 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) compared to one, two, or three CDRs according to Kabat et al. as set out in Table 1.

[0365] In some embodiments, an anti-TCRβ V antibody molecule, such as anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises at least one, two, three, four, five, or six CDRs according to Kabat et al. (e.g., at least one, two, three, four, five, or six CDRs according to the Kabat definition as set out in Table 1) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from AH.1 or AH.2, or an antibody described in Table 1 or encoded by the nucleotide sequence in Table 1, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences, or has 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) compared to one, two, three, four, five, or six CDRs according to Kabat et al. as set out in Table 1.

[0366] In some embodiments, an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises all six CDRs according to Kabat et al. (e.g., all six CDRs according to the Kabat definition as set forth in Table 1) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from AH.1 or AH.2, or an antibody described in Table 1 or encoded by the nucleotide sequence in Table 1, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences, or has 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), compared to all six CDRs according to Kabat et al. as set forth in Table 1. In one embodiment, the anti-TCRβ V antibody molecule, eg, anti-TCRβ V6 (eg, anti-TCRβ V6-5*01) antibody molecule, may comprise any of the CDRs described herein.

[0367] In some embodiments, an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one, two, or three hypervariable loops that have the same canonical structure as the corresponding hypervariable loops of an antibody described herein, e.g., an antibody selected from AH.1 or AH.2, e.g., the same canonical structure as at least loop 1 and / or loop 2 of the heavy and / or light chain variable domain of an antibody described herein. See, e.g., Chothia et al. (1992) J. Mol. Biol. 227:799-817; Tomlinson et al. (1992) J. Mol. Biol. 227:776-798 for a description of the canonical structures of hypervariable loops. These structures can be determined by inspection of the tables provided in these references.

[0368] In some embodiments, an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one, two, or three CDRs according to Chothia et al. (e.g., at least one, two, or three CDRs according to the Chothia definition set out in Table 1) from the heavy chain variable region of an antibody described herein, e.g., AH.1 or AH.2, or an antibody described in Table 1, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences, or has 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) compared to one, two, or three CDRs according to Chothia et al. set out in Table 1.

[0369] In some embodiments, an anti-TCRβ V antibody molecule, such as anti-TCRβ V6 (e.g., anti The TCRβ V6-5*01) antibody molecule comprises at least one, two, or three CDRs according to Chothia et al. (e.g., at least one, two, or three CDRs according to the Chothia definition as set out in Table 1) from the light chain variable region of an antibody described herein, e.g., an antibody chosen from AH.1 or AH.2, or an antibody described in Table 1, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences, or has 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) compared to one, two, or three CDRs according to Chothia et al. as set out in Table 1.

[0370] In some embodiments, an anti-TCRβ V antibody molecule, such as anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule comprises at least one, two, three, four, five, or six CDRs according to Chothia et al. (e.g., at least one, two, three, four, five, or six CDRs according to the Chothia definition as set out in Table 1) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from AH.1 or AH.2, or an antibody described in Table 1 or encoded by the nucleotide sequence in Table 1, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences, or has 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) compared to one, two, three, four, five, or six CDRs according to Chothia et al. as set out in Table 1.

[0371] In some embodiments, an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises all six CDRs according to Chothia et al. (e.g., all six CDRs according to the Chothia definition as set forth in Table 1) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from AH.1 or AH.2, or an antibody described in Table 1 or encoded by the nucleotide sequence in Table 1, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences, or has 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) compared to all six CDRs according to Chothia et al. as set forth in Table 1. In one embodiment, the anti-TCRβ V antibody molecule, eg, anti-TCRβ V6 (eg, anti-TCRβ V6-5*01) antibody molecule, may comprise any of the CDRs described herein.

[0372] In some embodiments, the anti-TCRβ antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a combination of CDRs or hypervariable loops defined according to Kabat et al., Chothia et al., or described in Table 1.

[0373] In some embodiments, an anti-TCRβV antibody molecule, eg, an anti-TCRβ V6 (eg, anti-TCRβ V6-5*01) antibody molecule, may contain any combination of CDRs or hypervariable loops according to the definition of Kabat and Chothia.

[0374] In some embodiments, the combined CDRs shown in Table 1 are CDRs that include a Kabat CDR and a Chothia CDR. In some embodiments, an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a combination of CDRs or hypervariable loops identified as combined CDRs in Table 1. In some embodiments, an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a combination of CDRs or hypervariable loops identified as combined CDRs in Table 1. It may contain any combination of CDRs or hypervariable loops according to the described "combined" CDRs.

[0375] In one embodiment, e.g., an embodiment comprising a variable region, CDR (e.g., a combined CDR, Chothia CDR, or Kabat CDR), or other sequence referred to herein, e.g., in Table 1, the antibody molecule is a monospecific antibody molecule, a bispecific antibody molecule, a bivalent antibody molecule, a biparatopic antibody molecule, or an antibody molecule comprising an antigen-binding fragment of an antibody, e.g., a half antibody or an antigen-binding fragment of a half antibody. In certain embodiments, the antibody molecule comprises a multispecific molecule, e.g., a bispecific molecule, e.g., as described herein.

[0376] In one embodiment, the anti-TCRβ V antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule is (i) one, two or all 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: 2, SEQ ID NO: 10, or SEQ ID NO: 11; and / or (ii) one, two, or all 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 SEQ ID NO: 1 or SEQ ID NO: 9; Includes.

[0377] In some embodiments, the anti-TCRβ V antibody molecule, e.g., the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO:2, and HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO:1.

[0378] In some embodiments, an anti-TCRβV antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 10, and HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 9.

[0379] In some embodiments, an anti-TCRβV antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 11, and HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 9.

[0380] In one embodiment, the anti-TCRβ V antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule is (i) the LC CDR1 amino acid sequence of SEQ ID NO: 6, the LC CDR2 amino acid sequence of SEQ ID NO: 7, or the LC CDR3 amino acid sequence of SEQ ID NO: 8, and / or (ii) the HC CDR1 amino acid sequence of SEQ ID NO: 3, the HC CDR2 amino acid sequence of SEQ ID NO: 4, or the HC CDR3 amino acid sequence of SEQ ID NO: 5 Includes.

[0381] In some embodiments, the anti-TCRβ V antibody molecule, e.g., the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is (i) a light chain variable region (VL) comprising the LC CDR1 amino acid sequence of SEQ ID NO: 6, the LC CDR2 amino acid sequence of SEQ ID NO: 7, or the LC CDR3 amino acid sequence of SEQ ID NO: 8, and / or (ii) a heavy chain variable region (VH) comprising the HC CDR1 amino acid sequence of SEQ ID NO: 3, the HC CDR2 amino acid sequence of SEQ ID NO: 4, or the HC CDR3 amino acid sequence of SEQ ID NO: 5; Includes.

[0382] In one embodiment, the anti-TCRβ V antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule is (i) the LC CDR1 amino acid sequence of SEQ ID NO: 51, the LC CDR2 amino acid sequence of SEQ ID NO: 52, or the LC CDR3 amino acid sequence of SEQ ID NO: 53, and / or (ii) the HC CDR1 amino acid sequence of SEQ ID NO: 45, the HC CDR2 amino acid sequence of SEQ ID NO: 46, or the HC CDR3 amino acid sequence of SEQ ID NO: 47 Includes.

[0383] In some embodiments, the anti-TCRβ V antibody molecule, e.g., the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is (i) a light chain variable region (VL) comprising the LC CDR1 amino acid sequence of SEQ ID NO: 51, the LC CDR2 amino acid sequence of SEQ ID NO: 52, or the LC CDR3 amino acid sequence of SEQ ID NO: 53; and / or (ii) a heavy chain variable region (VH) comprising the HC CDR1 amino acid sequence of SEQ ID NO: 45, the HC CDR2 amino acid sequence of SEQ ID NO: 46, or the HC CDR3 amino acid sequence of SEQ ID NO: 47 Includes.

[0384] In one embodiment, the anti-TCRβ V antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule is (i) the LC CDR1 amino acid sequence of SEQ ID NO: 54, the LC CDR2 amino acid sequence of SEQ ID NO: 55, or the LC CDR3 amino acid sequence of SEQ ID NO: 56, and / or (ii) the HC CDR1 amino acid sequence of SEQ ID NO: 48, the HC CDR2 amino acid sequence of SEQ ID NO: 49, or the HC CDR3 amino acid sequence of SEQ ID NO: 50 Includes.

[0385] In some embodiments, the anti-TCRβ V antibody molecule, e.g., the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is (i) a light chain variable region (VL) comprising the LC CDR1 amino acid sequence of SEQ ID NO: 54, the LC CDR2 amino acid sequence of SEQ ID NO: 55, or the LC CDR3 amino acid sequence of SEQ ID NO: 56, and / or (ii) a heavy chain variable region (VH) comprising the HC CDR1 amino acid sequence of SEQ ID NO: 48, the HC CDR2 amino acid sequence of SEQ ID NO: 49, or the HC CDR3 amino acid sequence of SEQ ID NO: 50 Includes.

[0386] In one embodiment, the light or heavy chain variable framework (e.g., a region encompassing at least FR1, FR2, FR3, and optionally FR4) of an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, contains (a) at least 80%, 85%, 87% of the amino acid residues from a human light or heavy chain variable framework, e.g., from a human mature antibody, a human germline sequence, or a human consensus sequence. (b) a light or heavy chain variable framework that comprises 90%, 92%, 93%, 95%, 97%, 98%, or 100% of amino acid residues from a human light or heavy chain variable framework, e.g., 20% to 80%, 40% to 60%, 60% to 90%, or 70% to 95% of the light or heavy chain variable framework residues from a human mature antibody, a human germline sequence, or a human consensus sequence; (c) a non-human framework (e.g., a rodent framework); or (d) a non-human framework that comprises, e.g., an antigenic or cytotoxic determinant. The framework can be selected from non-human frameworks that have been modified, e.g., deimmunized or partially humanized, to remove nucleotides. In one embodiment, the light or heavy chain variable framework region (particularly FR1, FR2 and / or FR3) comprises a light or heavy chain variable framework sequence that is at least 70, 75, 80, 85, 87, 88, 90, 92, 94, 95, 96, 97, 98, 99% identical or identical to the framework of the VL or VH segment of a human germline gene.

[0387] In some embodiments, an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a heavy chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more changes, e.g., amino acid substitutions or deletions, from the amino acid sequence of an AH.1 or AH.2, e.g., from the amino acid sequence of the FR region throughout the variable region, e.g., as shown in FIG. 1A, or SEQ ID NO:9.

[0388] Alternatively, or in combination with the heavy chain substitutions described herein, an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more amino acid changes, e.g., amino acid substitutions or deletions, from the amino acid sequence of the FR region in the entire variable region, e.g., as shown in Figure 1B, or SEQ ID NO: 10 or SEQ ID NO: 11, from the amino acid sequence of AH.1 or AH.2.

[0389] In some embodiments, the anti-TCRβ antibody molecule, e.g., the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises one, two, three, or four heavy chain framework regions shown in Figure 1A, or a sequence substantially identical thereto.

[0390] In some embodiments, the anti-TCRβ antibody molecule, e.g., the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises one, two, three, or four light chain framework regions shown in Figure 1B, or a sequence substantially identical thereto.

[0391] In some embodiments, the anti-TCRβ V antibody molecule, eg, the anti-TCRβ V6 (eg, anti-TCRβ V6-5*01) antibody molecule, comprises a light chain framework region 1 of AH.1 or AH.2, eg, as shown in FIG. 1B.

[0392] In some embodiments, the anti-TCRβ V antibody molecule, eg, the anti-TCRβ V6 (eg, anti-TCRβ V6-5*01) antibody molecule, comprises light chain framework region 2 of AH.1 or AH.2, eg, as shown in FIG. 1B.

[0393] In some embodiments, the anti-TCRβ V antibody molecule, eg, the anti-TCRβ V6 (eg, anti-TCRβ V6-5*01) antibody molecule, comprises light chain framework region 3 of AH.1 or AH.2, eg, as shown in FIG. 1B.

[0394] In some embodiments, the anti-TCRβ V antibody molecule, eg, the anti-TCRβ V6 (eg, anti-TCRβ V6-5*01) antibody molecule, comprises light chain framework region 4 of AH.1 or AH.2, eg, as shown in FIG. 1B.

[0395] In some embodiments, the anti-TCRβ V antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain comprising a framework region, e.g., framework region 1 (FR1), that comprises an alteration, e.g., a substitution (e.g., a conservative substitution), e.g., at position 10 according to Kabat numbering. FR1 comprises a phenylalanine at position 10, e.g., a serine to phenylalanine substitution. In some embodiments, the substitution is relative to the human germline light chain framework region sequence.

[0396] In some embodiments, an anti-TCRβ V antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain comprising a framework region, e.g., framework region 2 (FR2), that comprises an alteration, e.g., a substitution (e.g., a conservative substitution), at a position disclosed herein according to Kabat numbering. In some embodiments, FR2 comprises a histidine at position 36 according to Kabat numbering, e.g., a substitution at position 36, e.g., a tyrosine to histidine substitution. In some embodiments, FR2 comprises an alanine at position 46 according to Kabat numbering, e.g., a substitution at position 46, e.g., an arginine to alanine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0397] In some embodiments, an anti-TCRβ V antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain comprising a framework region, e.g., framework region 3 (FR3), that comprises an alteration, e.g., a substitution (e.g., a conservative substitution), at a position disclosed herein according to Kabat numbering. In some embodiments, FR3 comprises a phenylalanine at position 87 according to Kabat numbering, e.g., a substitution at position 87, e.g., a tyrosine to phenylalanine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0398] In some embodiments, an anti-TCRβ V antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain comprising: (a) framework region 1 (FR1) comprising a phenylalanine at position 10 according to Kabat numbering, e.g., a substitution at position 10, e.g., a serine to phenylalanine substitution; (b) framework region 2 (FR2) comprising a histidine at position 36 according to Kabat numbering, e.g., a substitution at position 36, e.g., a tyrosine to histidine substitution, and an alanine at position 46 according to Kabat numbering, e.g., a substitution at position 46, e.g., an arginine to alanine substitution; and (c) framework region 3 (FR3) comprising a phenylalanine at position 87 according to Kabat numbering, e.g., a substitution at position 87, e.g., a tyrosine to phenylalanine substitution, e.g., as set forth in the amino acid sequence of SEQ ID NO: 10. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0399] In some embodiments, an anti-TCRβ V antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a light chain variable domain comprising: (a) framework region 2 (FR2) comprising a histidine at position 36 according to Kabat numbering, e.g., a substitution at position 36, e.g., a tyrosine to histidine substitution, and an alanine at position 46 according to Kabat numbering, e.g., a substitution at position 46, e.g., an arginine to alanine substitution, and (b) framework region 3 (FR3) comprising a phenylalanine at position 87 according to Kabat numbering, e.g., a substitution at position 87, e.g., a tyrosine to phenylalanine substitution, e.g., as set forth in the amino acid sequence of SEQ ID NO: 11. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0400] In some embodiments, an anti-TCRβ V antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises (a) an alteration, e.g., a substitution (e.g., (b) framework region 1 (FR1) comprising an alteration, e.g., a substitution (e.g., a conservative substitution), at one or more (e.g., all) positions disclosed herein according to Kabat numbering; and (c) framework region 3 (FR3) comprising an alteration, e.g., a substitution (e.g., a conservative substitution), at one or more (e.g., all) positions disclosed herein according to Kabat numbering. In some embodiments, the substitutions are relative to a human germline light chain framework region sequence.

[0401] In some embodiments, the anti-TCRβ V antibody molecule, e.g., the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises heavy chain framework region 1 of AH.1 or AH.2, e.g., as shown in Figure 1A.

[0402] In some embodiments, the anti-TCRβ V antibody molecule, e.g., the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises heavy chain framework region 2 of AH.1 or AH.2, e.g., as shown in Figure 1A.

[0403] In some embodiments, the anti-TCRβ V antibody molecule, e.g., the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises heavy chain framework region 3 of AH.1 or AH.2, e.g., as shown in Figure 1A.

[0404] In some embodiments, the anti-TCRβ V antibody molecule, eg, the anti-TCRβ V6 (eg, anti-TCRβ V6-5*01) antibody molecule, comprises heavy chain framework region 4 of AH.1 or AH.2, eg, as shown in FIG. 1A.

[0405] In some embodiments, an anti-TCRβ V antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a heavy chain variable domain comprising a framework region, e.g., framework region 3 (FR3), comprising an alteration, e.g., a substitution (e.g., a conservative substitution), at a position disclosed herein according to Kabat numbering. In some embodiments, FR3 comprises a threonine at position 73 according to Kabat numbering, e.g., a substitution at position 73, e.g., a glutamic acid to threonine substitution. In some embodiments, FR3 comprises a glycine at position 94 according to Kabat numbering, e.g., a substitution at position 94, e.g., an arginine to glycine substitution. In some embodiments, the substitution is relative to a human germline heavy chain framework region sequence.

[0406] In some embodiments, an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises a heavy chain variable domain comprising framework region 3 (FR3) comprising a threonine at position 73 according to Kabat numbering, e.g., a substitution at position 73, e.g., a glutamic acid to threonine substitution, and a glycine at position 94 according to Kabat numbering, e.g., a substitution at position 94, e.g., an arginine to glycine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 10.

[0407] In some embodiments, an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises heavy chain framework regions 1-4 of AH.1 or AH.2, e.g., SEQ ID NO: 9, or those shown in Figures 1A and 1B.

[0408] In some embodiments, an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises light chain framework regions 1-4 of AH.1, e.g., that of SEQ ID NO: 10, or that shown in Figures 1A and 1B.

[0409] In some embodiments, the anti-TCRβ antibody molecule, e.g., the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises light chain framework regions 1-4 of AH.2, e.g., SEQ ID NO: 11, or those shown in Figures 1A and 1B.

[0410] In some embodiments, the anti-TCRβ antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises heavy chain framework regions 1-4 of AH.1, e.g., SEQ ID NO: 9, and light chain framework regions 1-4 of AH.1, e.g., SEQ ID NO: 10, or those depicted in Figures 1A and 1B.

[0411] In some embodiments, the anti-TCRβ antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises heavy chain framework regions 1-4 of AH.2, e.g., SEQ ID NO: 9, and light chain framework regions 1-4 of AH.2, e.g., SEQ ID NO: 11, or those depicted in Figures 1A and 1B.

[0412] In some embodiments, the heavy or light chain variable domain, or both, of an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises an amino acid sequence that is substantially identical to an amino acid disclosed herein, e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical to a variable region of an antibody selected from an antibody described herein, e.g., AH.1 or AH.2, or described in Table 1, or encoded by a nucleotide sequence in Table 1, or that differs by at least 1 or 5 residues and fewer than 40, 30, 20, or 10 residues from a variable region of an antibody described herein.

[0413] In some embodiments, the anti-TCRβ antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises at least one, two, three, or four antigen-binding regions, e.g., variable regions, having an amino acid sequence set forth in Table 1, or a sequence substantially identical thereto (e.g., at least about 85%, 90%, 95%, 99% or more identical thereto, or a sequence that differs by 1, 2, 5, 10, or 15 or fewer amino acid residues from a sequence set forth in Table 1). In another embodiment, the anti-TCRβ antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecules comprise a VH and / or VL domain encoded by a nucleic acid having a nucleotide sequence set forth in Table 1, or a sequence substantially identical thereto (e.g., at least about 85%, 90%, 95%, 99% or more identical thereto, or a sequence that differs by no more than 3, 6, 15, 30, or 45 nucleotides from a sequence set forth in Table 1).

[0414] In some embodiments, the anti-TCRβ V antibody molecule, e.g., the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a VH domain comprising the amino acid sequence of SEQ ID NO:9, an amino acid sequence that is at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO:9, or an amino acid sequence that differs from the amino acid sequence of SEQ ID NO:9 by 1, 2, 5, 10, or 15 or fewer amino acid residues; and / or a VL domain comprising the amino acid sequence of SEQ ID NO:10, an amino acid sequence that is at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO:10, or an amino acid sequence that differs from the amino acid sequence of SEQ ID NO:10 by 1, 2, 5, 10, or 15 or fewer amino acid residues. Includes.

[0415] In some embodiments, the anti-TCRβ V antibody molecule, e.g., the anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a VH domain comprising the amino acid sequence of SEQ ID NO:9, an amino acid sequence that is at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO:9, or an amino acid sequence that differs from the amino acid sequence of SEQ ID NO:9 by 1, 2, 5, 10, or 15 or fewer amino acid residues; and / or a VL domain comprising the amino acid sequence of SEQ ID NO:11, an amino acid sequence that is at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO:11, or an amino acid sequence that differs from the amino acid sequence of SEQ ID NO:11 by 1, 2, 5, 10, or 15 or fewer amino acid residues. Includes.

[0416] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a full-length antibody or a fragment thereof (e.g., Fab, F(ab')2, Fv, or single-chain Fv fragment (scFv)). In embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a monoclonal antibody or an antibody having a single specificity. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, may also be a humanized, chimeric, camelid, shark, or in vitro-generated antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is a humanized antibody molecule. The heavy and light chains of an anti-TCRβ antibody molecule, e.g., an anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, can be full length (e.g., the antibody can comprise at least one, and preferably two, complete heavy chains, and at least one, and preferably two, complete light chains), or can comprise 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, or a camelid antibody).

[0417] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, is in the form of a multispecific molecule, e.g., a bispecific molecule, e.g., as described herein.

[0418] In some embodiments, the anti-TCRβ antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, has a heavy chain constant region (Fc) selected from, e.g., IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE heavy chain constant regions. In some embodiments, the Fc region is selected from IgG1, IgG2, IgG3, and IgG4 heavy chain constant regions. In some embodiments, the Fc region is selected from the heavy chain constant region of IgG1 or IgG2 (e.g., human IgG1 or IgG2). In some embodiments, the heavy chain constant region is human IgG1.

[0419] In some embodiments, the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, has a light chain constant region selected from, e.g., kappa or lambda, preferably kappa (e.g., human kappa) light chain constant regions. In one embodiment, the constant region is altered, e.g., mutated, to modify the properties of the anti-TCRβV antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule (e.g., to increase or decrease one or more of Fc receptor binding, antibody glycosylation, number of cysteine ​​residues, effector cell function, or complement function). For example, the constant region may be altered, e.g., mutated, to modify Fc receptor binding, e.g., to increase or decrease one or more of Fc receptor binding, ... and 478 (N to F) (e.g., the mutated positions correspond to positions 132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K), and 314 (N to F) of SEQ ID NO: 212 or 214, or positions 135 (M to Y), 137 (S to T), 139 (T to E), 316 (H to K), and 317 (N to F) of SEQ ID NO: 215, 216, 217, or 218).

[0420] Antibody AH.1 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 3278 and a light chain comprising the amino acid sequence of SEQ ID NO: 72. Antibody AH.2 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 3278 and a light chain comprising the amino acid sequence of SEQ ID NO: 3279.

[0421] [Table 5-1]

[0422] [Table 5-2]

[0423] [Table 5-3]

[0424] [Table 5-4]

[0425] [Table 5-5]

[0426] [Table 5-6]

[0427]

Table 5-7

[0428]

Table 5-8

[0429]

Table 5-9

[0430]

Table 5-10

[0431]

Table 5-11

[0432]

Table 5-12

[0433]

Table 5-13

[0434]

Table 5-14

[0435]

Table 5-15

[0436]

Table 5-16

[0437]

Table 5-17

[0438]

Table 5-18

[0439]

Table 5-19

[0440]

Table 5-20

[0441]

Table 5-21

[0442]

Table 5-22

[0443]

Table 5-23

[0444]

Table 5-24

[0445]

Table 5-25

[0446]

Table 5-26

[0447]

Table 5-27

[0448] In some embodiments, the anti-TCRβ antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the VH and / or VL of an antibody set forth in Table 1, or a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0449] In some embodiments, the anti-TCRβ antibody molecule, e.g., anti-TCRβ V6 (e.g., anti-TCRβ V6-5*01) antibody molecule, comprises the VH and VL of an antibody set forth in Table 1, or a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto. Alignment of affinity-matured humanized antibody AH VL sequences

[0450] [ka]

[0451] [ka]

[0452] Consensus VL: SEQ ID NO: 230 DIQMTQSPSFLSASVGDRVTITCKASQNV G / E / A / DN / DR / K VAW Y / H QQKPGKAPKALIYSSSHRY K / S GVPSRFSGSGSGTEFTLTISSLQPEDFATYFCQQFKSYPLTFGQGTKLEIK Consensus VL: SEQ ID NO: 3289 DIQMTQSPSFLSASVGDRVTITCKASQNVX1X2X3VAWX4QQKPGKAPKALIYSSSHRYX5GVPSRFSGSGSGTEFTLTISSLQPEDFATYFCQQFKSYPLTFGQGTKLEIK (X1 is G, E, A, or D, X2 is N or D, X3 is R or K, X4 is Y or H, and X5 is K or S) Alignment of affinity-matured humanized antibody AH VH sequences

[0453] [ka]

[0454] [ka]

[0455] [ka]

[0456] Consensus VH: SEQ ID NO: 231 QVQLVQSGAEVKKPGSSVKVSCKASG H / T / G / YD / T / S FH / R / D / K / TL / D / K / T / NW / F / T / I / Y / G YIHWVRQAPGQGLEWMG R / WV / I / FF / S / YA / P GSG N / ST / V / Y / IK / R YNEKFKGRVTITADTSTSTAYMELSSLRSEDTAVYYCA G / VSY / I YS Y / AD / G VLDYWGQGTTVTVSS Consensus VH: SEQ ID NO: 3290 QVQLVQSGAEVKKPGSSVKVSCKASGX1X2FX3X4X5YIHWVRQAPGQGLEWMGX6X7X8X9GSGX 10 X 11 X 12 YNEKFKGRVTITADTSTSTAYMELSSLRSEDTAVYYCAX 13 SX14 YSX 15 X 16 VLDYWGQGTTVTVSS (X1 is H or T or G or Y, X2 is D or T or S, X3 is H or R or D or K or T, X4 is L or D or K or T or N, X5 is W or F or T or I or Y or G, X6 is R or W, X7 is V or I or F, X8 is F or S or Y, X9 is A or P, and X10 is N or S wherein X11 is T or V or Y or I, X12 is K or R, X13 is G or V, X14 is Y or I, X15 is Y or A, and X16 is D or G. In some embodiments, the anti-TCRVb antibodies disclosed herein have an antigen-binding domain having a VL with the consensus sequence of SEQ ID NO: 230 (position 30 is G, E, A or D, position 31 is N or D, position 32 is R or K, position 36 is Y or H, and / or position 56 is K or S).

[0457] In some embodiments, the anti-TCRVb antibodies disclosed herein have an antigen-binding domain having a VH with the consensus sequence of SEQ ID NO: 231 (position 27 is H or T or G or Y, position 28 is D or T or S, position 30 is H or R or D or K or T, position 31 is L or D or K or T or N, position 32 is W or F or T or I or Y or G, position 49 is R or W, position 50 is V or I or F, position 51 is F or S or Y, position 52 is A or P, position 56 is N or S, position 57 is T or V or Y or I, position 58 is K or R, position 97 is G or V, position 99 is Y or I, position 102 is Y or A, and / or position 103 is D or G). Anti-TCRβ V12 antibody Thus, in one aspect, the present disclosure provides anti-TCRβ antibody molecules that bind to a TCRβ V12 subfamily that includes human TCRβ V12, e.g., TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01. In some embodiments, the TCRβ V12 subfamily includes TCRβ V12-4*01. In some embodiments, the TCRβ V12 subfamily includes TCRβ V12-3*01.

[0458] In some embodiments, the anti-TCRβV antibody molecule, e.g., the anti-TCRβ V12 antibody molecule, is a non-murine antibody molecule, e.g., a human or humanized antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., the anti-TCRβ V12 antibody molecule, is a human antibody molecule. In some embodiments, the anti-TCRβV antibody molecule, e.g., the anti-TCRβ V12 antibody molecule, is a humanized antibody molecule.

[0459] In some embodiments, the anti-TCRβV antibody molecule, eg, the anti-TCRβ V12 antibody molecule, is isolated or recombinant. In some embodiments, the anti-TCRβ antibody molecule, e.g., the anti-TCRβ V12 antibody molecule, comprises at least one antigen-binding region, e.g., a variable region or antigen-binding fragment thereof, from an antibody described herein, e.g., an antibody described in Table 2 or encoded by a nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences.

[0460] In some embodiments, the anti-TCRβ antibody molecule, e.g., the anti-TCRβ V12 antibody molecule, comprises at least one, two, three, or four variable regions from an antibody described herein, e.g., an antibody described in Table 2 or encoded by a nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences.

[0461] In some embodiments, the anti-TCRβ antibody molecule, e.g., the anti-TCRβ V12 antibody molecule, comprises at least one or two heavy chain variable regions from an antibody described herein, e.g., an antibody described in Table 2 or encoded by a nucleotide sequence in Table 2; includes sequences that are substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences.

[0462] In some embodiments, the anti-TCRβ antibody molecule, e.g., the anti-TCRβ V12 antibody molecule, comprises at least one or two light chain variable regions from an antibody described herein, e.g., an antibody described in Table 2 or encoded by a nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences.

[0463] In some embodiments, the anti-TCRβ antibody molecule, e.g., the anti-TCRβ V12 antibody molecule, comprises a heavy chain constant region of an IgG4, e.g., human IgG4. In yet another embodiment, the anti-TCRβ antibody molecule, e.g., the anti-TCRβ V12 antibody molecule, comprises a heavy chain constant region of an IgG1, e.g., human IgG1. In one embodiment, the heavy chain constant region comprises an amino acid sequence set forth in Table 3, or a sequence substantially identical thereto (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical).

[0464] In some embodiments, the anti-TCRβ antibody molecule, e.g., the anti-TCRβ V12 antibody molecule, comprises a kappa light chain constant region, e.g., a human kappa light chain constant region. In one embodiment, the light chain constant region comprises an amino acid sequence set forth in Table 3, or a sequence substantially identical thereto (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical).

[0465] In some embodiments, the anti-TCRβ antibody molecule, e.g., the anti-TCRβ V12 antibody molecule, comprises at least one, two, or three complementarity determining regions (CDRs) from the heavy chain variable region of an antibody described herein, e.g., an antibody described in Table 2 or encoded by a nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences.

[0466] In some embodiments, the anti-TCRβ antibody molecule, e.g., the anti-TCRβ V12 antibody molecule, comprises at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising the amino acid sequence shown in Table 2 or encoded by the nucleotide sequence shown in Table 2. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six, or more changes, e.g., amino acid substitutions or deletions, compared to the amino acid sequence shown in Table 2 or encoded by the nucleotide sequence shown in Table 2.

[0467] In some embodiments, the anti-TCRβ antibody molecule, e.g., the anti-TCRβ V12 antibody molecule, comprises at least one, two, or three complementarity determining regions (CDRs) from the light chain variable region of an antibody described herein, e.g., an antibody described in Table 2 or encoded by a nucleotide sequence in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences.

[0468] In some embodiments, the anti-TCRβ V antibody molecule, e.g., the anti-TCRβ V12 antibody molecule, comprises at least one, two, or three CDRs (or CDRs) from a light chain variable region comprising an amino acid sequence shown in Table 2 or encoded by a nucleotide sequence shown in Table 2. In one embodiment, one or more of the CDRs (or all of the CDRs collectively) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, compared to the amino acid sequence shown in Table 2 or encoded by the nucleotide sequence shown in Table 2.

[0469] In some embodiments, the anti-TCRβV antibody molecule, e.g., the anti-TCRβ V12 antibody molecule, comprises at least one, two, three, four, five, or six CDRs (or collectively all of the CDRs) from heavy and light chain variable regions comprising the amino acid sequences shown in Table 2 or encoded by the nucleotide sequences shown in Table 2. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six, or more changes, e.g., amino acid substitutions or deletions, compared to the amino acid sequence shown in Table 2 or encoded by the nucleotide sequence shown in Table 2.

[0470] In some embodiments, the anti-TCRβV antibody molecule, e.g., the anti-TCRβ V12 antibody molecule, comprises all six CDRs from an antibody described herein, e.g., an antibody described in Table 2 or encoded by a nucleotide sequence in Table 2, or closely related CDRs, e.g., CDRs that are identical or have at least one amino acid change but no more than two, ...

Claims

1. 1. A composition comprising a multispecific molecule for use in the selective expansion of a subset of T cells expressing a T cell receptor in a T cell population, the multispecific molecule comprising: (i) an antibody molecule that binds to a T cell receptor beta variable region (TCRβV); and (ii) cytokine molecules Including, the antibody molecule that binds to TCRβV binds to TCRβV of the T cell receptor beta chain (TCRβ) of a TCR expressed on a T cell subset of the T cell population; A composition that selectively expands a subset of T cells in a T cell population when an effective amount of the multispecific molecule is contacted with the T cell population.

2. the multispecific molecule comprises a first polypeptide chain and a second polypeptide chain; the first polypeptide chain comprises a first member of a dimerization module, and the second polypeptide chain comprises a second member of said dimerization module, and the first polypeptide chain and the second polypeptide chain form a complex through association of the first member of the dimerization module and the second member of the dimerization module; The composition of claim 1 , wherein the dimerization module comprises an immunoglobulin constant region.

3. 3. The composition of claim 2, wherein the first member of the dimerization module is a first Fc region and the second member of the dimerization module is a second Fc region.

4. 4. The composition of claim 3, wherein the first Fc region is a modified Fc region comprising a knob and the second Fc region is a modified Fc region comprising a hole, or the first Fc region is a modified Fc region comprising a hole and the second Fc region is a modified Fc region comprising a knob.

5. The composition of claim 3 or 4, wherein the first Fc region and / or the second Fc region comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 41 or the sequence of SEQ ID NO:

42.

6. The composition of any one of claims 3 to 5, wherein the first Fc region and / or the second Fc region comprises a mutation that reduces Fc receptor binding compared to an Fc region that does not have the mutation.

7. The composition of any one of claims 3 to 6, wherein the first Fc region and / or the second Fc region comprises an N297A mutation according to EU numbering.

8. The composition of any one of claims 3 to 7, wherein the first polypeptide chain comprises an antibody molecule that binds to a TCRβV linked to a first Fc region, and the second polypeptide chain comprises a cytokine molecule linked to a second Fc region.

9. (A)(i) a first Fc region: (a) Cys at position 349 in the heavy chain constant region according to EU numbering; (b) Ser at position 366 in the heavy chain constant region according to EU numbering; (c) Ala at position 368 in the heavy chain constant region according to EU numbering, and (d) Val at position 407 in the heavy chain constant region according to EU numbering and (ii) the second Fc region comprises: (a) Cys at position 354 in the heavy chain constant region according to EU numbering, and (b) Trp at position 366 in the heavy chain constant region according to EU numbering; Contains; or (B)(i) the first Fc region: (a) Cys at position 354 in the heavy chain constant region according to EU numbering, and (b) Trp at position 366 in the heavy chain constant region according to EU numbering; and (ii) the second Fc region comprises: (a) Cys at position 349 in the heavy chain constant region according to EU numbering; (b) Se at position 366 in the heavy chain constant region according to EU numbering r, (c) Ala at position 368 in the heavy chain constant region according to EU numbering, and (d) Val at position 407 in the heavy chain constant region according to EU numbering; The composition according to any one of claims 3 to 8, comprising:

10. The multispecific molecule comprises: A, B-[dimerization module]-C, -D Including, (i) the dimerization module comprises an immunoglobulin constant domain, and (ii) A, B, C, and D are, independently, (a) absent, (b) an antibody molecule that binds to said TCRβV, or (c) a cytokine molecule; The composition of any one of claims 1 to 9, wherein at least one of A, B, C, and D is an antibody molecule that binds to the TCRβV region, and at least one of A, B, C, and D is a cytokine molecule.

11. The multispecific molecule of any one of claims 1 to 10, wherein the antibody molecule that binds to the TCRβ V region is an scFv, a single domain antibody, a camelid antibody, or a Fab.

12. The composition of any one of claims 1 to 11, wherein the antibody molecule that binds to TCRβV binds to TCRβV1, TCRβV2, TCRβV3, TCRβV4, TCRβV5, TCRβV6, TCRβV7, TCRβV8, TCRβV9, TCRβV10, TCRβV11, TCRβV12, TCRβV19, TCRβV20, TCRβV21, TCRβV23, TCRβV24, TCRβV25, TCRβV26, TCRβV27, TCRβV28, TCRβV29, or TCRβV30.

13. The antibody molecule that binds to TCRβV is selected from the group consisting of TCRβV2, TCRβV4-1, TCRβV4-2, TCRβV5-1, TCRβV5-5, TCRβV5-6, TCRβV6, TCRβV6-5, TCRβV6-6, TCRβV6-9, TCRβV7-2, TCRβV7-3, TCRβV7-8, TCRβV7-9, TCRβV9, TCR The composition of any one of claims 1 to 12, which binds to TCRβV10-1, TCRβV10-2, TCRβV10-3, TCRβV11-2, TCRβV12-3, TCRβV12-4, TCRβV12-5, TCRβV19, TCRβV20-1, TCRβV21, TCRβV24-1, TCRβV25-1 or TCRβV28.

14. The composition according to any one of claims 1 to 12, wherein the antibody molecule that binds to TCRβV binds to TCRβV2, TCRβV3-1, TCRβV4-1, TCRβV4-2, TCRβV5-1, TCRβV5-4, TCRβV5-5, TCRβV5-6, TCRβV6-1, TCRβV6-5, TCRβV6-6, TCRβV7-3, TCRβV7-6, TCRβV7-8, TCRβV9, TCRβV11-2, TCRβV19, TCRβV20-1, TCRβV24-1, TCRβV27, TCRβV28, TCRβV29-1 or TCRβV30.

15. The composition according to any one of claims 1 to 12, wherein the antibody molecule that binds to TCRβV binds to TCRβV5, TCRβV6, TCRβV10, TCRβV12, or TCRβV20.

16. 16. The composition of any one of claims 1 to 15, wherein the cytokine molecule is selected from the group consisting of interleukin-2 (IL-2), interleukin-7 (IL-7), interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-18 (IL-18), interleukin-21 (IL-21), and interferon gamma.

17. The composition of any one of claims 1 to 16, wherein the cytokine molecule is IL-2, IL-15, or IL-21.

18. Cytokine molecules (i) IL-2 comprising a sequence having at least 90% sequence identity with the sequence of SEQ ID NO: 2191, the sequence of SEQ ID NO: 2270 or the sequence of SEQ ID NO: 2280; (ii) IL-15 comprising a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 2170, or the sequence of SEQ ID NO: 2320; or (iii) The composition according to any one of claims 1 to 17, which is an IL-21 comprising a sequence having at least 90% sequence identity with the sequence of SEQ ID NO: 2193.

19. Cytokine molecules (i) IL-2 comprising the sequence of SEQ ID NO: 2191, the sequence of SEQ ID NO: 2270 or the sequence of SEQ ID NO: 2280; (ii) IL-15 comprising the sequence of SEQ ID NO: 2170 or the sequence of SEQ ID NO: 2320; or (iii) The composition according to any one of claims 1 to 18, which is an IL-21 comprising the sequence of SEQ ID NO: 2193.

20. The composition of any one of claims 1 to 19, wherein the expansion of T cells occurs in vivo.

21. The composition of any one of claims 1 to 19, wherein the expansion of T cells occurs ex vivo.

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