Method of detecting tim-3 using antibody molecules to tim-3

Abstract

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 .- 58 . (canceled) 
     
     
         59 . A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof an antibody molecule capable of binding to human TIM-3 in an amount effective to stimulate the immune response, 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.   
     
     
         60 .- 64 . (canceled) 
     
     
         65 . The method of  claim 59 , wherein the antibody molecule is administered in combination with a second therapeutic agent or procedure, wherein the second therapeutic agent or procedure is chosen from one or more of chemotherapy, a targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, an immune-based therapy, a cytokine, surgical procedure, a radiation procedure, an activator of a costimulatory molecule, an inhibitor of an inhibitory molecule, a vaccine, or a cellular immunotherapy. 
     
     
         66 . The method of  claim 65 , wherein the antibody molecule is administered in combination with:
 (a) an agonist of a costimulatory molecule chosen from one or more of 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   (b) an inhibitor of an immune checkpoint molecule chosen from one or more of PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, CEACAM-1, CEACAM-5, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR.   
     
     
         67 .- 79 . (canceled) 
     
     
         80 . The method of  claim 66 , wherein the antibody molecule is administered in combination with one or more of the following:
 (a) an inhibitor of PD-1;   (b) an inhibitor of PD-L1;   (c) an inhibitor of LAG-3;   (d) an agonist of GITR;   (e) a chemotherapy to treat a lung cancer;   (f) an indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor to treat a lung cancer;   (g) an inhibitor of CTLA-4 to treat a lung cancer or a melanoma;   (h) a MEK inhibitor to treat a lung cancer, a melanoma, or a renal cancer;   (i) a cancer vaccine;   (j) one or more of:
 (i) an immune-based therapy; 
 (ii) a targeting agent; 
 (iii) a VEGF tyrosine kinase inhibitor; 
 (iv) an RNAi inhibitor; or 
 (v) an inhibitor of a downstream mediator of VEGF signaling to treat a renal cancer; 
   (k) one, two or all of oxaliplatin, leucovorin or 5-FU, to treat a lung cancer, a melanoma, or a renal cancer; or   (l) a tyrosine kinase inhibitor to treat a renal cancer.   
     
     
         81 . The method of  claim 80 , wherein:
 (a) the inhibitor of PD-1 is an anti-PD-1 antibody molecule or a fusion protein;   (b) the inhibitor of PD-L1 is an anti-PD-L1 antibody molecule or a fusion protein;   (c) the inhibitor of LAG-3 is an anti-LAG-3 antibody molecule or a fusion protein;   (d) the agonist of GITR is an anti-GITR antibody molecule or a fusion protein;   (e) the chemotherapy to treat a lung cancer is a platinum doublet therapy;   (f) the indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor to treat a lung cancer is INCB24360;   (g) the inhibitor of CTLA-4 to treat a lung cancer or a melanoma is an anti-CTLA-4 antibody or a soluble ligand of CTLA-4;   (h) the inhibitor of CTLA-4 to treat a lung cancer or a melanoma is an anti-CTLA-4 antibody, wherein the antibody molecule is for use further in combination with a BRAF inhibitor;   (i) the cancer vaccine is a dendritic cell renal carcinoma (DC-RCC) vaccine;   (j) the immune-based therapy comprises interleukin-2 or interferon-α;   (k) the targeting agent is a VEGF inhibitor;   (l) the VEGF tyrosine kinase inhibitor is sunitinib, sorafenib, axitinib, or pazopanib;   (m) the inhibitor of a downstream mediator of VEGF signaling to treat a renal cancer is an inhibitor of the mammalian target of rapamycin (mTOR); or   (n) the tyrosine kinase inhibitor to treat a renal cancer is axitinib.   
     
     
         82 . The method of  claim 80 , wherein:
 (a) the inhibitor of PD-1 is MDX-1106, Merck 3475, AMP-224, or AMP-514;   (b) the inhibitor of PD-L1 is YW243.55.S70, MPDL3280A, MEDI-4736, or MSB-0010718C;   (c) the anti-CTLA-4 antibody is ipilimumab;   (d) the BRAF inhibitor is vemurafenib or dabrafenib;   (e) the VEGF inhibitor is an anti-VEGF antibody; or   (f) the inhibitor of mTOR is everolimus or temsirolimus.   
     
     
         83 . The method of  claim 59 , wherein the antibody molecule is used in combination with one or more of: 1) a protein kinase C (PKC) inhibitor; 2) a heat shock protein 90 (HSP90) inhibitor; 3) an inhibitor of a phosphoinositide 3-kinase (PI3K) and/or target of rapamycin (mTOR); 4) an inhibitor of cytochrome P450 (e.g., a CYP17 inhibitor or a 17alpha-Hydroxylase/C17-20 Lyase inhibitor); 5) an iron chelating agent; 6) an aromatase inhibitor; 7) an inhibitor of p53, e.g., an inhibitor of a p53/Mdm2 interaction; 8) an apoptosis inducer; 9) an angiogenesis inhibitor; 10) an aldosterone synthase inhibitor; 11) a smoothened (SMO) receptor inhibitor; 12) a prolactin receptor (PRLR) inhibitor; 13) a Wnt signaling inhibitor; 14) a CDK4/6 inhibitor; 15) a fibroblast growth factor receptor 2 (FGFR2)/fibroblast growth factor receptor 4 (FGFR4) inhibitor; 16) an inhibitor of macrophage colony-stimulating factor (M-CSF); 17) an inhibitor of one or more of c-KIT, histamine release, Flt3 (e.g., FLK2/STK1) or PKC; 18) an inhibitor of one or more of VEGFR-2 (e.g., FLK-1/KDR), PDGFRbeta, c-KIT or Raf kinase C; 19) a somatostatin agonist and/or a growth hormone release inhibitor; 20) an anaplastic lymphoma kinase (ALK) inhibitor; 21) an insulin-like growth factor 1 receptor (IGF-1R) inhibitor; 22) a P-Glycoprotein 1 inhibitor; 23) a vascular endothelial growth factor receptor (VEGFR) inhibitor; 24) a BCR-ABL kinase inhibitor; 25) an FGFR inhibitor; 26) an inhibitor of CYP11B2; 27) a HDM2 inhibitor, e.g., an inhibitor of the HDM2-p53 interaction; 28) an inhibitor of a tyrosine kinase; 29) an inhibitor of c-MET; 30) an inhibitor of JAK; 31) an inhibitor of DAC; 32) an inhibitor of 11(3-hydroxylase; 33) an inhibitor of IAP; 34) an inhibitor of PIM kinase; 35) an inhibitor of Porcupine; 36) an inhibitor of BRAF, e.g., BRAF V600E or wild-type BRAF; 37) an inhibitor of HER3; 38) an inhibitor of MEK; 39) an inhibitor of a lipid kinase; or 40) a BCL-2 inhibitor (e.g., oblimersen sodium or ABT-263). 
     
     
         84 . The method of  claim 59 , wherein the antibody molecule is used in combination with one or more of Compounds A1 to A51 as described in Table 6. 
     
     
         85 . The method of  claim 59 , wherein the antibody molecule is administered in combination with azacitidine, decitabine, or both for treating an acute myeloid leukemia (AML) or a myelodysplastic syndrome. 
     
     
         86 . The method of  claim 59 , wherein the antibody molecule is administered:
 (a) at a dose of about 1 to 30 mg/kg;   (b) at a dose of about 1 to 5 mg/kg; or   (c) once a week to once every 2, 3, or 4 weeks.   
     
     
         87 . The method of  claim 86 , wherein the antibody molecule is administered at a dose from about 10 to 20 mg/kg every other week. 
     
     
         88 . The method of  claim 59 , wherein the 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). 
     
     
         89 . The method of  claim 59 , 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).   
     
     
         90 . The method of  claim 59 , 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.   
     
     
         91 . The method of  claim 59 , 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.   
     
     
         92 . The method of  claim 59 , 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).   
     
     
         93 . The method of  claim 59 , 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;   (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.   
     
     
         94 . The method of  claim 59 , wherein said antibody molecule binds an IgV domain of TIM-3. 
     
     
         95 . The method of  claim 59 , wherein said antibody molecule is capable of binding to human TIM-3 with a dissociation constant (K D ) of less than about 0.5 nM. 
     
     
         96 . The method of  claim 59 , wherein said antibody molecule is capable of reducing one or more of the following:
 (i) binding of TIM-3 to phosphatidylserine (PtdSer);   (ii) binding of TIM-3 to HMGB1;   (iii) binding of TIM-3 to CEACAM-1;   (iv) binding of TIM-3 to Semaphorin-4 Å; or   (vi) PtdSer-mediated membrane penetration of TIM-3.   
     
     
         97 . The method of  claim 59 , wherein said antibody molecule is capable of enhancing an antigen-specific T cell response. 
     
     
         98 . The method of  claim 59 , wherein said antibody molecule modulates one or more activities of TIM-3 chosen from:
 (i) enhancing IFN-gamma and/or TNF-alpha secretion in T cells;   (ii) enhancing proliferation in T cells;   (iii) enhancing an NK cell cytotoxic activity;   (iv) reducing suppressor activity of regulatory T cells (Tregs); or   (v) increasing an immune stimulation property of macrophages and/or antigen presenting cells.   
     
     
         99 . A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof an antibody molecule capable of binding to human TIM-3 in an amount effective to stimulate the immune response, 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. 
     
     
         100 . A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof an antibody molecule capable of binding to human TIM-3 in an amount effective to stimulate the immune response, wherein the antibody molecule comprises 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. 
     
     
         101 . A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof an antibody molecule capable of binding to human TIM-3 in an amount effective to stimulate the immune response, 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. 
     
     
         102 . A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof an antibody molecule capable of binding to human TIM-3 in an amount effective to stimulate the immune response, wherein the antibody molecule comprises 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.