Anti-tcr antibody molecules and uses thereof
AssigneeElstar Therapeutics, Inc.
InventorsSeng-Lai TAN, Brian Edward VASH, Jonathan HSU, Dilini Charmain GUNASEKERA, Sangeetha Sagar PALAKURTHI, Andreas LOEW
Life of this patent
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Abstract
The disclosure provides antibody molecules that bind to TCR Vβ regions and multispecific molecules comprising said antibody molecules. Additionally, disclosed are nucleic acids encoding the same, methods of producing the aforesaid molecules, pharmaceutical compositions comprising aforesaid molecules, and methods of treating a cancer using the aforesaid molecules.
Claims183
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 multispecific molecule of any of the preceding claims, wherein binding of the first moiety to the TCRβV region results in reduced cytokine storm, e.g., reduced cytokine release syndrome (CRS), as measured by an assay of Example 3, e.g., relative to the cytokine storm induced by the non-TCRβV-binding T cell engager.
The multispecific molecule of any of the preceding claims, wherein binding of the first moiety to the TCRβV region results in one, two, three or all of:
- (ix) reduced T cell proliferation kinetics;
- (x) cell killing, e.g., target cell killing, e.g. cancer cell killing, e.g., as measured by an assay of Example 4;
- (xi) increased Natural Killer (NK) cell proliferation, e.g., expansion;
- or
- (xii) expansion, e.g., at least about 1.1-10 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), of a population of memory T cells,
- e.g., wherein (ix)-(xii) are relative to the non-TCRβV-binding T cell engager.
The multispecific molecule of any of the preceding claims, wherein the first moiety binds to one or more of a TCRβV subfamily chosen from:
- (i) TCRβV6 subfamily comprising, e.g., one or more of 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;
- (ii) TCRβV10 subfamily comprising, e.g., one or more of TCRβV10-1*01, TCRβV10-1*02, TCRβV10-3*01 or TCRβV10-2*01;
- (iii) TCRβV5 subfamily comprising, e.g., one or more of TCRβV5-6*01, TCRβV5-4*01, or TCRβV5-8*01;
- or
- (iv) TCRβV12 subfamily comprising, e.g., one or more of TCRβV12-4*01, TCRβV12-3*01, or TCRβV12-5*01.
The multispecific molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecule:
- (i) binds specifically to an epitope on TCRβV, e.g., the same or similar epitope as the epitope recognized by an anti-TCRβV antibody molecule as described herein, e.g., a second anti-TCRβV antibody molecule;
- (ii) shows the same or similar binding affinity or specificity, or both, as an anti-TCRβV antibody molecule as described herein, e.g., a second anti-TCRβV antibody molecule;
- (iii) inhibits, e.g., competitively inhibits, the binding of an anti-TCRβV antibody molecule as described herein, e.g., a second anti-TCRβV antibody molecule;
- (iv) binds the same or an overlapping epitope with an anti-TCRβV antibody molecule as described herein, e.g., a second anti-TCRβV antibody molecule;
- or
- (v) competes for binding, and/or binds the same epitope, with an anti-TCRβV antibody molecule as described herein, e.g., a second anti-TCRβV antibody molecule,
- wherein the second anti-TCRβV antibody molecule comprises an antigen binding domain comprising a heavy chain complementarity determining region 1 (HC CDR1), a heavy chain complementarity determining region 2 (HC CDR2) and/or a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO:
- 1 or SEQ ID NO:
- 9;
- and/or a light chain complementarity determining region 1 (LC CDR1), a light chain complementarity determining region 2 (LC CDR2), and/or a light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO:
- 2, SEQ ID NO:
- 10 or SEQ ID NO:
- 11.
The multispecific molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecule comprises an antigen binding domain comprising:
- (i) (a) a HC CDR1, a HC CDR2 and/or a HC CDR3 of SEQ ID NO:
- 15, SEQ ID NO:
- 23, SEQ ID NO:
- 24 or SEQ IC NO:
- 25;
- and/or (b) a LC CDR1, a LC CDR2, and/or a LC CDR3 of SEQ ID NO:
- 16, SEQ ID NO:
- 26, SEQ ID NO:
- 27, SEQ ID NO:
- 28, SEQ ID NO:
- 29 or SEQ ID NO:30;
- or
- (ii) (a) a LC CDR1, a LC CDR2 and/or a LC CDR3 of SEQ ID NO:
- 2, SEQ ID NO:
- 10 or SEQ ID NO:
- 11;
- and/or (b) a HC CDR1, a HC CDR2 and/or a HC CDR2 of SEQ ID NO:
- 1 or SEQ ID NO:
- 9.
The multispecific molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecule binds the same or different TCRβV subfamily members.
The multispecific molecule of any of the preceding claims, which comprises an antibody molecule chosen from a bispecific antibody molecule, a bivalent antibody molecule, or a biparatopic antibody molecule.
The multispecific molecule of any of the preceding claims, which comprises a bispecific antibody molecule that binds to two different TCRβV subfamily members.
The multispecific molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecule binds:
- (i) one or more of a TCRβV6 subfamily member and one or more of a TCRβV10 subfamily member;
- (ii) one or more of a TCRβV6 subfamily member and one or more of a TCRβV5 subfamily member;
- (iii) one or more of a TCRβV6 subfamily member and one or more of a TCRβV12 subfamily member;
- (iv) one or more of a TCRβV10 subfamily member and one or more of a TCRβV5 subfamily member;
- (v) one or more of a TCRβV10 subfamily member and one or more of a TCRβV12 subfamily member;
- or
- (vi) one or more of a TCRβV5 subfamily member and one or more of a TCRβV12 subfamily member.
A multispecific molecule, e.g., a bispecific molecule, comprising the anti-TCRβV antibody molecule of any of claims 17-52.
An antibody molecule which binds, e.g., specifically binds, to a T cell receptor beta variable chain (TCRβV) region, wherein the anti-TCRβV antibody molecule comprises an antigen binding domain comprising:
- (a) a light chain variable region (VL) comprising:
- (i) one, two or all of (e.g., three) a light chain complementarity determining region 1 (LC CDR1), a light chain complementarity determining region 2 (LC CDR2), and a light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO:
- 10 or SEQ ID NO:
- 11;
- and
- (ii) a framework region (FR) having at least 95% identity with one, two, three, or all of (e.g., four) a non-murine germline framework 1 (FR1), a non-murine germline framework region 2 (FR2), a non-murine germline framework region 3 (FR3), and a non-murine germline framework region 4 (FR4);
- and/or
- (b) a heavy chain variable region (VH) comprising:
- (i) one, two or all of (e.g., three) a heavy chain complementarity determining region 1 (HC CDR1), a heavy chain complementarity determining region 2 (HC CDR2) and a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO:
- 9;
- and
- (ii) a framework region (FR) having at least 95% identity with one, two, three, or all of (e.g., four) a non-murine germline framework 1 (FR1), a non-murine germline framework region 2 (FR2), a non-murine germline framework region 3 (FR3), and a non-murine germline framework region 4 (FR4).
An antibody molecule which binds, e.g., specifically binds, to a T cell receptor beta variable chain (TCRβV) region, wherein the anti-TCRβV antibody molecule comprises an antigen binding domain comprising:
- (a) a light chain variable region (VL) comprising:
- (i) one, two or all of (e.g., three) a light chain complementarity determining region 1 (LC CDR1), a light chain complementarity determining region 2 (LC CDR2), and a light chain complementarity determining region 3 (LC CDR3) of a humanized B-H light chain (LC) of Table 2;
- and
- (ii) a framework region (FR) having at least 95% identity with one, two, three or all (e.g., four) of a framework region 1 (FR1), a framework region 2 (FR2), a framework region 3 (FR3), and a framework region 4 (FR4) of a humanized B-H LC of Table 2;
- and/or
- (b) a heavy chain variable region (VH) comprising:
- (i) one, two or all of (e.g., three) a heavy chain complementarity determining region 1 (HC CDR1), a heavy chain complementarity determining region 2 (HC CDR2) and a heavy chain complementarity determining region 3 (HC CDR3) of a humanized B-H heavy chain (HC) of Table 2;
- and
- (ii) a framework region (FR) having at least 95% identity with one, two, three or all (e.g., four) of a framework region 1 (FR1), a framework region 2 (FR2), a framework region 3 (FR3), and a framework region 4 (FR4) of a humanized B-H HC of Table 2.
The multispecific molecule or the anti-TCRβV antibody molecule of any of the preceding claims, wherein binding of the anti-TCRβV antibody molecule to a TCRβV region results in a reduction of at least 2, 5, 10, 20, 50, 100, or 200 fold, or at least 2-200 fold (e.g., 5-150, 10-100, 20-50 fold) in the expression level and or activity of IL-1(3 as measured by an assay of Example 3.
The multispecific molecule or the anti-TCRβV antibody molecule of any of the preceding claims, wherein binding of the anti-TCRβV antibody molecule to a TCRβV region results in a reduction of at least 2, 5, 10, 20, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 fold, or at least 2-1000 fold (e.g., 5-900, 10-800, 20-700, 50-600, 100-500, or 200-400 fold) in the expression level and or activity of IL-6 as measured by an assay of Example 3.
The multispecific molecule or the anti-TCRβV antibody molecule of any of the preceding claims, binding of the anti-TCRβV antibody molecule to a TCRβV region results in a reduction of at least 2, 5, 10, 20, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or 2000 fold, or at least 2-2000 fold (e.g., 5-1000, 10-900, 20-800, 50-700, 100-600, 200-500, or 300-400 fold) in the expression level and or activity of TNFα as measured by an assay of Example 3.
The multispecific molecule or the anti-TCRβV antibody molecule of any of the preceding claims, wherein binding of the anti-TCRβV antibody molecule to a TCRβV region results in an increase of at least 2, 5, 10, 20, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or 2000 fold, or at least 2-2000 fold (e.g., 5-1000, 10-900, 20-800, 50-700, 100-600, 200-500, or 300-400 fold) in the expression level and or activity of IL-2 as measured by an assay of Example 3.
The multispecific molecule or the anti-TCRβV antibody molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecule comprises an antigen binding domain comprising a single chain Fv (scFv) or a Fab.
The multispecific molecule or the anti-TCRβV antibody molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecule binds to a conformational or a linear epitope on the T cell.
The multispecific molecule or the anti-TCRβV antibody molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecule is a full antibody (e.g., an antibody that includes 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′)2, Fv, a single chain Fv fragment, a single domain antibody, a diabody (dAb), a bivalent antibody, or bispecific antibody or fragment thereof, a single domain variant thereof, or a camelid antibody).
The multispecific molecule or the anti-TCRβV antibody molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecule comprises one or more heavy chain constant regions chosen from IgG1, IgG2, IgG3, IgGA1, IgGA2, IgG4, IgJ, IgM, IgD, or IgE, or a fragment thereof, e.g., as described in Table 3.
The multispecific molecule or the anti-TCRβV antibody molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecule comprises a heavy chain constant region of an IgM or a fragment thereof, optionally wherein the IgM heavy chain constant region comprises the sequence of SEQ ID NO:
- 73, or a sequence with at least 85%, 90%, 95%, or 99% sequence identity thereto.
The multispecific molecule or the anti-TCRβV antibody molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecule comprises a heavy chain constant region of an IgJ or a fragment thereof, optionally wherein the IgJ heavy chain constant region comprises the sequence of SEQ ID NO:
- 76 or a sequence with at least 85%, 90%, 95%, or 99% sequence identity thereto.
The multispecific molecule or the anti-TCRβV antibody molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecule comprises a heavy chain constant region of an IgGA1, or a fragment thereof, optionally wherein the IgGA1 heavy chain constant region comprises the sequence of SEQ ID NO:
- 74, or a sequence with at least 85%, 90%, 95%, or 99% sequence identity thereto.
The multispecific molecule or the anti-TCRβV antibody molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecule comprises a heavy chain constant region of an IgGA2, or a fragment thereof, optionally wherein the IgGA2 heavy chain constant region comprises a sequence listed in Table 3, e.g., SEQ ID NO:
- 75, or a sequence with at least 85%, 90%, 95%, or 99% sequence identity thereto.
The multispecific molecule or the anti-TCRβV antibody molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecule comprises a light chain constant region chosen from the light chain constant regions of kappa or lambda, or a fragment thereof, e.g., as described in Table 3.
The multispecific molecule or the anti-TCRβV antibody molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecule comprises a light chain constant region of a kappa chain, or a fragment thereof, optionally wherein the kappa chain constant region comprises the sequence of SEQ ID NO:
- 39, or a sequence with at least 85%, 90%, 95%, or 99% sequence identity thereto.
The multispecific molecule or the anti-TCRβV antibody molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecule comprises:
- (i) one or more heavy chain constant regions comprising a heavy chain constant region chosen from IgG1, IgG2, IgG3, IgGA1, IgGA2, IgG4, IgJ, IgM, IgD, or IgE, or a fragment thereof, e.g., as described in Table 3;
- and
- (ii) a light chain constant region comprising a light chain constant region chosen from the light chain constant regions of kappa or lambda, or a fragment thereof, e.g., as described in Table 3.
The multispecific molecule or the anti-TCRβV antibody molecule of any of the preceding claims, wherein the anti-TCRβV antibody molecule comprises:
- (i) a heavy chain constant region comprising:
- (a) an IgM heavy chain constant region or a fragment thereof, comprising the sequence of SEQ ID NO:
- 73, or a sequence with 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 with at least 85%, 90%, 95%, or 99% sequence identity thereto;
- or
- (c) an IgGA2 heavy chain constant region or a fragment thereof, comprising the sequence of SEQ ID NO:
- 75, or a sequence with at least 85%, 90%, 95%, or 99% sequence identity thereto;
- and
- (ii) a light chain constant region comprising a kappa chain constant region comprising the sequence of SEQ ID NO:
- 39, or a sequence with at least 85%, 90%, 95%, or 99% sequence identity thereto,
- optionally wherein, 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 with at least 85%, 90%, 95%, or 99% sequence identity thereto.
A method of modulating, e.g., enhancing, an immune response in a subject comprising administering to the subject an effective amount of an antibody molecule which binds (e.g., specifically binds) to a T cell receptor beta variable region (TCRβV) (“anti-TCRβV antibody molecule”).
A method of expanding, e.g., increasing the number of, an immune cell population comprising, contacting the immune cell population with an effective amount of an antibody molecule which binds (e.g., specifically binds) to a T cell receptor beta variable region (TCRβV) (“anti-TCRβV antibody molecule”).
A method of treating a disease, e.g., cancer, in a subject comprising administering to the subject an effective amount of an antibody molecule which binds (e.g., specifically binds) to a T cell receptor beta variable region (TCRβV) (“anti-TCRβV antibody molecule”), thereby treating the cancer.
A composition comprising an antibody molecule which binds (e.g., specifically binds) to a T cell receptor beta variable region (TCRβV) (“anti-TCRβV antibody molecule”), for use in treating a disease, e.g., cancer, in a subject.
A composition comprising an antibody molecule which binds (e.g., specifically binds) to a T cell receptor beta variable region (TCRβV) (“anti-TCRβV antibody molecule”), for use in the manufacture of a medicament for treating a disease, e.g., cancer, in a subject.
A method of treating, e.g., preventing or reducing, cytokine release syndrome (CRS) and/or neurotoxicity (NT) in a subject, e.g., CRS and/or NT associated with a treatment, e.g., a previously administered treatment, comprising administering to the subject an effective amount of an antibody molecule which binds (e.g., specifically binds) to a T cell receptor beta variable region (TCRβV) (“anti-TCRβV antibody molecule”), thereby preventing CRS and/or NT in the subject.
A method of targeting a therapy, e.g., treatment, to a T cell in a subject having a disease, e.g., cancer, comprising administering an effective amount of:
- (i) an antibody molecule which binds (e.g., specifically binds) to a T cell receptor beta variable region (TCRβV) (“anti-TCRβV antibody molecule”);
- and
- (ii) the therapy, e.g., a tumor targeting therapy (e.g., an antibody that binds to a cancer antigen), e.g., as described herein,
- thereby targeting the therapy to the T cell in the subject.
A method of treating a subject having a cancer, the method comprising:
- acquiring a value of the status of a TCRβV subfamily for the subject, wherein said value comprises a measure of the presence of, e.g., level or activity of, a TCRβV molecule in a sample from the subject, and
- administering an effective amount of an antibody molecule which binds (e.g., specifically binds) to a T cell receptor beta variable region (TCRβV) (“anti-TCRβV antibody molecule”);
- to the subject,
- thereby treating the subject.
A method of treating a subject having a cancer, the method comprising administering an effective amount of an antibody molecule which binds (e.g., specifically binds) to a T cell receptor beta variable region (TCRβV) (“anti-TCRβV antibody molecule”) to the subject, wherein the subject has a higher, e.g., increased, level or activity of one or more TCRβV subfamilies, e.g., as described herein, compared to a reference level or activity of one or more TCRβV subfamilies, e.g., in a healthy subject, e.g., a subject not having a cancer.
A method of expanding a population of immune effector cells from a subject having a cancer, the method comprising:
- (i) isolating a biological sample comprising a population of immune effector cells from the subject;
- e.g., a peripheral blood sample, biopsy sample, or bone marrow sample;
- (ii) acquiring a value of the status of one or more TCRβV subfamilies for the subject, e.g., in the biological sample from the subject, wherein said value comprises a measure of the presence of, e.g., level or activity of, a TCRβV subfamily in a sample from the subject compared to a reference value, e.g., a sample from a health subject, wherein a value that is higher, e.g., increased, in the subject relative to the reference, e.g., healthy subject, is indicative of the presence of cancer in the subject, and
- (iii) contacting the biological sample comprising a population of immune effector cells with an anti-TCRβV antibody molecule, e.g., as described herein.
The method, or composition for use of any one of claims 98-178, wherein the anti-TCRβV antibody molecule binds to an outward facing region (e.g., epitope) on a TCRβV protein, e.g., as depicted by the circled area in FIG. 24A.
Dependencies are inferred from the claim text.