Antibody molecules to TIM-3 and uses thereof
Antibody molecules that specifically bind to TIM-3 are disclosed. The anti-TIM-3 antibody molecules can be used to treat, prevent and/or diagnose immune, cancerous, or infectious conditions and/or disorders.
1. A method of treating a hematological cancer, comprising administering to a subject in need thereof an antibody molecule capable of binding to human TIM-3 in an amount effective to treat the hematological cancer, wherein the antibody molecule comprises:
(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 10; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14;
(b) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 4; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 6, a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8;
(c) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 25; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14;
(d) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 24; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 6, a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8;
(e) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 31; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14; or
(f) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 30; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 6, a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8.
2. The method of claim 1 , wherein the hematological cancer is a leukemia, a lymphoma, or a myeloma, or a metastatic lesion thereof.
3. The method of claim 1 , wherein the hematological cancer is a B-cell acute lymphoid leukemia (BALL), a T-cell acute lymphoid leukemia (TALL), an acute myeloid leukemia (AML), an acute lymphoid leukemia (ALL), a chronic myelogenous leukemia (CML), a chronic lymphocytic leukemia (CLL), a B cell prolymphocytic leukemia, a blastic plasmacytoid dendritic cell neoplasm, a Burkitt's lymphoma, a diffuse large B cell lymphoma, a Follicular lymphoma, a hairy cell leukemia, a small cell- or a large cell-follicular lymphoma, a malignant lymphoproliferative condition, a MALT lymphoma, a mantle cell lymphoma, a Marginal zone lymphoma, a multiple myeloma, a myelodysplasia and myelodysplastic syndrome, a non-Hodgkin's lymphoma, a plasmablastic lymphoma, a plasmacytoid dendritic cell neoplasm, a Waldenstrom macroglobulinemia, a preleukemia, or a metastatic lesion thereof.
4. The method of claim 1 , wherein the antibody molecule is administered in combination with a second therapeutic agent or procedure.
5. The method of claim 4 , wherein the antibody molecule is administered concurrently with, prior to, or subsequent to the second therapeutic agent or procedure.
6. The method of claim 4 , wherein the second therapeutic agent or procedure is one or more of a chemotherapy, a targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, an immune-based therapy, a cytokine, a surgical procedure, a radiation procedure, an activator of a costimulatory molecule, an inhibitor of an inhibitory molecule, a vaccine, or a cellular immunotherapy.
7. The method of claim 1 , wherein the antibody molecule is administered in combination with an agonist of a costimulatory molecule or an inhibitor of an immune checkpoint molecule,
wherein the costimulatory molecule is OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand; or
wherein the antibody molecule is administered in combination with an inhibitor of an immune checkpoint molecule, wherein the immune checkpoint molecule is PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, CEACAM-1, CEACAM-5, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR.
8. The method of claim 1 , wherein the antibody molecule is administered in combination with an inhibitor of PD-1.
9. The method of claim 8 , wherein the inhibitor of PD-1 is an anti-PD-1 antibody molecule or a fusion protein, or is MDX-1106, Merck 3475, AMP-224, or AMP-514.
10. The method of claim 1 , wherein the antibody molecule is administered in combination with an inhibitor of PD-L1.
11. The method of claim 1 , wherein the inhibitor of PD-L1 is an anti-PD-L1 antibody molecule or a fusion protein, or is YW243.55.570, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105.
12. The method of claim 1 , wherein the antibody molecule is administered in combination with a chemotherapeutic agent.
13. The method of claim 1 , wherein the chemotherapeutic agent comprises cytarabine, daunorubicin, idarubicin, clofarabine, decitabine, vosaroxin, azacitidine, clofarabine, ribavirin, CPX-351, treosulfan, or elacytarabine.
14. The method of claim 1 , wherein the antibody molecule is administered in combination with a chemotherapeutic, a tyrosine kinase inhibitor, an immunotoxin, a DT3881L3 fusion protein, interferon alfa, a steroid, an apoptotic agent, an immunotherapy, a CD52 targeting agent, an HSP90 inhibitor, an mTOR inhibitor, a SMO antagonist, a ribonucleotide reductase inhibitor, a JAK-2 inhibitor, hydroxychloroquine, a retinoid, a cyclin-dependent kinase inhibitor, an HDAC inhibitor, a PARP inhibitor, an MDM2 antagonist, an aurora B kinase inhibitor, a radioimmunotherapy, a hedgehog inhibitor, a STATS inhibitor, KB004, a cancer vaccine, a bone marrow transplantation, a stem cell transplantation, a radiation therapy, a SRC inhibitor, a polo-like kinase inhibitor, cenersen, a CD45 targeting agent, a cyclin-dependent kinase inhibitor, LY573636-sodium, ZRx-101, MLN4924, lenalidomide, histamine dihydrochloride, or a combination thereof.
15. The method of claim 1 , wherein the subject has, or is identified as having, a hematological cancer that:
(a) expresses TIM-3;
(b) is positive for one, two, or all of PD-L1, CD8, or IFN-γ; or
(c) is tumor infiltrating lymphocyte (TIL) positive.
16. The method of claim 1 , wherein the antibody molecule is administered:
(a) at a dose of about 0.1 to 30 mg/kg;
(b) at a dose of about 1 to 5 mg/kg;
(c) once a week to once every 2, 3, or 4 weeks; or
(d) once a week to once every 2, 3, or 4 weeks.
17. The method of claim 1 , wherein said antibody molecule is a humanized antibody molecule, and/or comprises an antigen binding fragment of an antibody, a half antibody or antigen binding fragment of a half antibody, or a Fab, F(ab′)2, Fv, or a single chain Fv fragment (scFv).
18. The method of claim 1 , wherein said antibody molecule comprises:
(a) a VH comprising the amino acid sequence of SEQ ID NO: 1, 16, 26, 32, 36, 44, 48, 52, 60, 68, 72, 76, 80, 84, 92, or 100, or an amino acid sequence at least 85% identical to any of the amino acid sequence of SEQ ID NOs: 1, 16, 26, 32, 36, 44, 48, 52, 60, 68, 72, 76, 80, 84, 92, or 100;
(b) a VL comprising the amino acid sequence of SEQ ID NO: 2, 20, 40, 56, 64, 88, 96, or 104, or an amino acid sequence at least 85% identical to any of SEQ ID NOs: 2, 20, 40, 56, 64, 88, 96, or 104; or
(c) both (a) and (b).
19. The method of claim 1 , wherein said antibody molecule comprises:
(a) a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2;
(b) a VH comprising the amino acid sequence of SEQ ID NO: 16 and a VL comprising the amino acid sequence of SEQ ID NO: 20;
(c) a VH comprising the amino acid sequence of SEQ ID NO: 26 and a VL comprising the amino acid sequence of SEQ ID NO: 20,
(d) a VH comprising the amino acid sequence of SEQ ID NO: 32 and a VL comprising the amino acid sequence of SEQ ID NO: 20;
(e) a VH comprising the amino acid sequence of SEQ ID NO: 36 and a VL comprising the amino acid sequence of SEQ ID NO: 40;
(f) a VH comprising the amino acid sequence of SEQ ID NO: 44 and a VL comprising the amino acid sequence of SEQ ID NO: 40;
(g) a VH comprising the amino acid sequence of SEQ ID NO: 48 and a VL comprising the amino acid sequence of SEQ ID NO: 40;
(h) a VH comprising the amino acid sequence of SEQ ID NO: 36 and a VL comprising the amino acid sequence of SEQ ID NO: 20;
(i) a VH comprising the amino acid sequence of SEQ ID NO: 16 and a VL comprising the amino acid sequence of SEQ ID NO: 40;
(j) a VH comprising the amino acid sequence of SEQ ID NO: 52 and a VL comprising the amino acid sequence of SEQ ID NO: 56;
(k) a VH comprising the amino acid sequence of SEQ ID NO: 60 and a VL comprising the amino acid sequence of SEQ ID NO: 56;
(l) a VH comprising the amino acid sequence of SEQ ID NO: 52 and a VL comprising the amino acid sequence of SEQ ID NO: 64;
(m) a VH comprising the amino acid sequence of SEQ ID NO: 60 and a VL comprising the amino acid sequence of SEQ ID NO: 64;
(n) a VH comprising the amino acid sequence of SEQ ID NO: 68 and a VL comprising the amino acid sequence of SEQ ID NO: 64;
(o) a VH comprising the amino acid sequence of SEQ ID NO: 72 and a VL comprising the amino acid sequence of SEQ ID NO: 64;
(p) a VH comprising the amino acid sequence of SEQ ID NO: 76 and a VL comprising the amino acid sequence of SEQ ID NO: 56;
(q) a VH comprising the amino acid sequence of SEQ ID NO: 80 and a VL comprising the amino acid sequence of SEQ ID NO: 56;
(r) a VH comprising the amino acid sequence of SEQ ID NO: 68 and a VL comprising the amino acid sequence of SEQ ID NO: 56;
(s) a VH comprising the amino acid sequence of SEQ ID NO: 72 and a VL comprising the amino acid sequence of SEQ ID NO: 56;
(t) a VH comprising the amino acid sequence of SEQ ID NO: 76 and a VL comprising the amino acid sequence of SEQ ID NO: 64;
(u) a VH comprising the amino acid sequence of SEQ ID NO: 80 and a VL comprising the amino acid sequence of SEQ ID NO: 64;
(v) a VH comprising the amino acid sequence of SEQ ID NO: 84 and a VL comprising the amino acid sequence of SEQ ID NO: 88;
(w) a VH comprising the amino acid sequence of SEQ ID NO: 92 and a VL comprising the amino acid sequence of SEQ ID NO: 96; or
(x) a VH comprising the amino acid sequence of SEQ ID NO: 100 and a VL comprising the amino acid sequence of SEQ ID NO: 104.
20. The method of claim 1 , wherein said antibody molecule comprises:
(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 22;
(b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 28 and a light chain comprising the amino acid sequence of SEQ ID NO: 22;
(c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 34 and a light chain comprising the amino acid sequence of SEQ ID NO: 22;
(d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain comprising the amino acid sequence of SEQ ID NO: 42;
(e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 46 and a light chain comprising the amino acid sequence of SEQ ID NO: 42;
(f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 50 and a light chain comprising the amino acid sequence of SEQ ID NO: 42;
(g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 116 and a light chain comprising the amino acid sequence of SEQ ID NO: 22;
(h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 121 and a light chain comprising the amino acid sequence of SEQ ID NO: 42;
(i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 54 and a light chain comprising the amino acid sequence of SEQ ID NO: 58;
(j) a heavy chain comprising the amino acid sequence of SEQ ID NO: 62 and a light chain comprising the amino acid sequence of SEQ ID NO: 58;
(k) a heavy chain comprising the amino acid sequence of SEQ ID NO: 54 and a light chain comprising the amino acid sequence of SEQ ID NO: 66;
(l) a heavy chain comprising the amino acid sequence of SEQ ID NO: 62 and a light chain comprising the amino acid sequence of SEQ ID NO: 66;
(m) a heavy chain comprising the amino acid sequence of SEQ ID NO: 70 and a light chain comprising the amino acid sequence of SEQ ID NO: 66;
(n) a heavy chain comprising the amino acid sequence of SEQ ID NO: 74 and a light chain comprising the amino acid sequence of SEQ ID NO: 66;
(o) a heavy chain comprising the amino acid sequence of SEQ ID NO: 78 and a light chain comprising the amino acid sequence of SEQ ID NO: 58;
(p) a heavy chain comprising the amino acid sequence of SEQ ID NO: 82 and a light chain comprising the amino acid sequence of SEQ ID NO: 58;
(r) a heavy chain comprising the amino acid sequence of SEQ ID NO: 70 and a light chain comprising the amino acid sequence of SEQ ID NO: 58;
(s) a heavy chain comprising the amino acid sequence of SEQ ID NO: 74 and a light chain comprising the amino acid sequence of SEQ ID NO: 58;
(t) a heavy chain comprising the amino acid sequence of SEQ ID NO: 78 and a light chain comprising the amino acid sequence of SEQ ID NO: 66;
(u) a heavy chain comprising the amino acid sequence of SEQ ID NO: 82 and a light chain comprising the amino acid sequence of SEQ ID NO: 66;
(v) a heavy chain comprising the amino acid sequence of SEQ ID NO: 86 and a light chain comprising the amino acid sequence of SEQ ID NO: 90;
(w) a heavy chain comprising the amino acid sequence of SEQ ID NO: 94 and a light chain comprising the amino acid sequence of SEQ ID NO: 98; or
(x) a heavy chain comprising the amino acid sequence of SEQ ID NO: 102 and a light chain comprising the amino acid sequence of SEQ ID NO: 106.
21. The method of claim 1 , wherein said antibody molecule comprises:
(a) a heavy chain constant region of IgG1, IgG2, IgG3, or IgG4;
(b) a light chain constant region of kappa or lambda; or
(c) both (a) and (b).
22. The method of claim 1 , wherein said antibody molecule comprises:
(a) a human IgG4 heavy chain constant region with a mutation at position 228 according to EU numbering or position 108 of SEQ ID NO: 108 or 110 and a kappa light chain constant region;
(b) a human IgG4 heavy chain constant region with a Serine to Proline mutation at position 228 according to EU numbering or position 108 of SEQ ID NO: 108 or 110 and a kappa light chain constant region;
(c) a human IgG1 heavy chain constant region with an Asparagine to Alanine mutation at position 297 according to EU numbering or position 180 of SEQ ID NO: 112 and a kappa light chain constant region; or
(d) a human IgG1 heavy chain constant region with an Aspartate to Alanine mutation at position 265 according to EU numbering or position 148 of SEQ ID NO: 113 and Proline to Alanine mutation at position 329 according to EU numbering or position 212 of SEQ ID NO: 113, and a kappa light chain constant region; or
(e) a human IgG1 heavy chain constant region with a Leucine to Alanine mutation at position 234 according to EU numbering or position 117 of SEQ ID NO: 114 and Leucine to Alanine mutation at position 235 according to EU numbering or position 118 of SEQ ID NO: 114, and a kappa light chain constant region.
23. A method of treating a hematological cancer, comprising administering to a subject in need thereof an antibody molecule capable of binding to human TIM-3 in an amount effective to treat the hematological cancer, wherein the antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 52 and a VL comprising the amino acid sequence of SEQ ID NO: 64.
24. The method of claim 23 , wherein the antibody molecule is administered in combination with azacitidine, decitabine, or both for treating an acute myeloid leukemia (AML) or a myelodysplastic syndrome.
25. A method of treating a hematological cancer, comprising administering to a subject in need thereof an antibody molecule capable of binding to human TIM-3 in an amount effective to treat the hematological cancer, wherein the antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 54 and a light chain comprising the amino acid sequence of SEQ ID NO: 66.
26. The method of claim 25 , wherein the antibody molecule is administered in combination with azacitidine, decitabine, or both for treating an acute myeloid leukemia (AML) or a myelodysplastic syndrome.
27. A method of treating a hematological cancer, comprising administering to a subject in need thereof an antibody molecule capable of binding to human TIM-3, in combination with azacytidine, decitabine, or both, in an amount effective to treat the hematological cancer, wherein the antibody molecule comprises:
(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 10; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14;
(b) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 4; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 6, a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8;
(c) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 25; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14;
(d) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 24; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 6, a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8;
(e) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 31; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14; or
(f) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 30; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 6, a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8, wherein the hematological cancer is an acute myeloid leukemia (AML), a myelodysplastic syndrome, or a metastatic lesion thereof.
28. The method of claim 1 , wherein the hematological cancer is an acute myeloid leukemia (AML), a myelodysplastic syndrome, or a metastatic lesion thereof.
29. The method of claim 27 , wherein the hematological cancer is an acute myeloid leukemia (AML).
30. The method of claim 27 , wherein the hematological cancer is a myelodysplastic syndrome.