Combination therapy for cancer

Abstract

Methods of treating cancer with antibodies that bind colony stimulating factor 1 receptor (CSF1R) in combination with one or more immune stimulating agents are provided.

1 . A method of treating cancer in a subject comprising administering to the subject an anti-CSF1R antibody and at least one immune stimulating agent, chosen from agents falling within one or more of the following categories:
 a. an agonist of an immune stimulatory molecule, including a co-stimulatory molecule, such as an immune-stimulatory molecule found on a T cell or NK cell;   b. an antagonist of an immune inhibitory molecule, including a co-inhibitory molecule, such as an immune-stimulatory molecule found on a T cell or NK cell;   c. an antagonist of LAG-3, Galectin 1, Galectin 9, CEACAM-1, BTLA, CD25, CD69, TIGIT, CD113, GPR56, VISTA, B7-H3, B7-H4, 2B4, CD48, GARP, PD1H, LAIR1, TIM1, TIM3, TIM4, ILT4, IL-6, IL-10, TGFβ, VEGF, KIR, LAG-3, adenosine A2A receptor, PI3Kdelta, or IDO;   d. an agonist of B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD27, CD40, CD40L, DR3, CD28H, IL-2, IL-7, IL-12, IL-15, IL-21, IFNα, STING, or a Toll-like receptor agonist such as a TLR2/4 agonist;   e. an agent that binds to a member of the B7 family of membrane-bound proteins such as B7-1, B7-2, B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6;   f an agent that binds to a member of the TNF receptor family or a co-stimulatory or co-inhibitory molecule binding to a member of the TNF receptor family such as CD40, CD40L, OX40, OX40L, GITR, GITRL, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, EDA1, EDA2, TACI, APRIL, BCMA, LTβR, LIGHT, DeR3, HVEM, VEGL/TL1A, TRAMP/DR3, TNFR1, TNFβ, TNFR2, TNFα, 102, FAS, FASL, RELT, DR6, TROY, or NGFβ;   g. an agent that antagonizes or inhibits a cytokine that inhibits T cell activation such as IL-6, IL-10, TGFβ, VEGF;   h. an agonist of a cytokine that stimulates T cell activation such as IL-2, IL-7, IL-12, IL-15, IL-21, and IFNα; and   i. an antagonist of a chemokine, such as CXCR2, CXCR4, CCR2, or CCR4.   
     
     
         2 . The method of  claim 1 , wherein the at least one immune stimulating agent comprises a CD40 agonist, such as an anti-CD40 antibody, and optionally comprises at least one additional immune stimulating agent according to claim  1 (a)-(h). 
     
     
         3 . The method of  claim 2 , wherein the CD40 agonist comprises an anti-CD40 antibody comprising the CDRs of an antibody selected from CP-870,893; dacetuzumab; SEA-CD40; ADC-1013; RO7009789; and Chi Lob 7/4. 
     
     
         4 . The method of  claim 3 , wherein the anti-CD40 antibody comprises the heavy chain and light chain variable regions of an antibody selected from CP-870,893; dacetuzumab; SEA-CD40; ADC-1013; RO7009789; and Chi Lob 7/4. 
     
     
         5 . The method of  claim 4 , wherein the anti-CD40 antibody is an antibody selected from CP-870,893; dacetuzumab; SEA-CD40; ADC-1013; RO7009789; and Chi Lob 7/4. 
     
     
         6 . The method of  claim 2 , wherein the CD40 agonist comprises recombinant CD40L. 
     
     
         7 . The method of any one of the preceding claims, wherein the anti-CSF1R antibody and the at least one immune stimulating agent are administered concurrently or sequentially. 
     
     
         8 . The method of any one of the preceding claims, wherein the anti-CSF1R antibody and the at least one immune stimulating agent are administered concurrently. 
     
     
         9 . The method of  claim 7 , wherein one or more doses of at least one immune stimulating agent are administered prior to administering an anti-CSF1R antibody. 
     
     
         10 . The method of  claim 7 , wherein one or more doses of the anti-CSF1R antibody are administered prior to administering an immune stimulating agent. 
     
     
         11 . The method of any one of the preceding claims, wherein the cancer is selected from non-small cell lung cancer, melanoma, squamous cell carcinoma of the head and neck, ovarian cancer, pancreatic cancer, renal cell carcinoma, hepatocellular carcinoma, bladder cancer, endometrial cancer, Hodgkin's lymphoma, lung cancer, glioma, gioblastoma multiforme, colon cancer, breast cancer, bone cancer, skin cancer, uterince cancer, gastric cancer, stomach cancer, lymphoma, lymphocytic leukemia, multiple myeloma, prostate cancer, mesothelioma, and kidney cancer. 
     
     
         12 . The method of any one of the preceding claims, wherein the cancer is recurrent or progressive after a therapy selected from surgery, chemotherapy, radiation therapy, or a combination thereof. 
     
     
         13 . The method of any one of the preceding claims, wherein the anti-CSF1R antibody blocks binding of CSF1 and/or IL-34 to CSF1R. 
     
     
         14 . The method of any one of the preceding claims, wherein the anti-CSF1R antibody inhibits ligand-induced CSF1R phosphorylation in vitro. 
     
     
         15 . The method of any one of the preceding claims, wherein the antibody is selected from:
 a) an antibody comprising a heavy chain comprising the sequence of SEQ ID NO: 39 and a light chain comprising the sequence of SEQ ID NO: 46;   b) an antibody comprising a heavy chain comprising a heavy chain (HC) CDR1 having the sequence of SEQ ID NO: 15, an HC CDR2 having the sequence of SEQ ID NO: 16, and an HC CDR3 having the sequence of SEQ ID NO: 17, and a light chain comprising a light chain (LC) CDR1 having the sequence of SEQ ID NO: 18, a LC CDR2 having the sequence of SEQ ID NO: 19, and a LC CDR3 having the sequence of SEQ ID NO: 20; and   c) an antibody comprising a heavy chain comprising the sequence of SEQ ID NO: 53 and a light chain comprising the sequence of SEQ ID NO: 60.   
     
     
         16 . The method of  claim 15 , wherein the antibody is a humanized antibody. 
     
     
         17 . The method of  claim 15  or  claim 16 , wherein the antibody is selected from a Fab, an Fv, an scFv, a Fab′, and a (Fab′) 2 . 
     
     
         18 . A composition comprising an anti-CSF1R antibody and at least one immune stimulating agent, chosen from agents falling within one or more of the following categories:
 a. an agonist of an immune stimulatory molecule, including a co-stimulatory molecule, such as an immune-stimulatory molecule found on a T cell or NK cell;   b. an antagonist of an immune inhibitory molecule, including a co-inhibitory molecule, such as an immune-stimulatory molecule found on a T cell or NK cell;   c. an antagonist of LAG-3, Galectin 1, Galectin 9, CEACAM-1, BTLA, CD25, CD69, TIGIT, CD113, GPR56, VISTA, B7-H3, B7-H4, 2B4, CD48, GARP, PD1H, LAIR1, TIM1, TIM3, TIM4, ILT4, IL-6, IL-10, TGFβ, VEGF, KIR, LAG-3, adenosine A2A receptor, PI3Kdelta, or IDO;   d. an agonist of B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD27, CD40, CD40L, DR3, CD28H, IL-2, IL-7, IL-12, IL-15, IL-21, IFNα, STING, or a Toll-like receptor agonist such as a TLR2/4 agonist;   e. an agent that binds to a member of the B7 family of membrane-bound proteins such as B7-1, B7-2, B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6;   f. an agent that binds to a member of the TNF receptor family or a co-stimulatory or co-inhibitory molecule binding to a member of the TNF receptor family such as CD40, CD40L, OX40, OX40L, GITR, GITRL, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, EDA1, EDA2, TACI, APRIL, BCMA, LTβR, LIGHT, DeR3, HVEM, VEGL/TL1A, TRAMP/DR3, TNFR1, TNFβ, TNFR2, TNFα, 1β2, FAS, FASL, RELT, DR6, TROY, or NGFβ;   g. an agent that antagonizes or inhibits a cytokine that inhibits T cell activation such as IL-6, IL-10, TGFβ, VEGF;   h. an agonist of a cytokine that stimulates T cell activation such as IL-2, IL-7, IL-12, IL-15, IL-21, and IFNα; and   i. an antagonist of a chemokine, such as CXCR2, CXCR4, CCR2, or CCR4.   
     
     
         19 . The composition of  claim 18 , wherein the at least one immune stimulating agent comprises a CD40 agonist, such as an anti-CD40 antibody, and optionally further comprises at least one additional immune stimulating agent according to claim  18 (a)-(h). 
     
     
         20 . The composition of  claim 19 , wherein the CD40 agonist comprises an anti-CD40 antibody comprising the CDRs of an antibody selected from CP-870,893; dacetuzumab; SEA-CD40; ADC-1013; RO7009789; and Chi Lob 7/4. 
     
     
         21 . The composition of  claim 20 , wherein the CD40 agonist comprises an anti-CD40 antibody comprising the heavy chain and light chain variable regions of an antibody selected from CP-870,893; dacetuzumab; SEA-CD40; ADC-1013; RO7009789; and Chi Lob 7/4. 
     
     
         22 . The composition of  claim 21 , wherein the anti-CD40 antibody is an antibody selected from CP-870,893; dacetuzumab; SEA-CD40; ADC-1013; RO7009789; and Chi Lob 7/4. 
     
     
         23 . The composition of  claim 19 , wherein the CD40 agonist comprises recombinant CD40L. 
     
     
         24 . The composition of any one of  claims 18  to  23 , wherein the anti-CSF1R antibody is selected from:
 a) an antibody comprising a heavy chain comprising the sequence of SEQ ID NO: 39 and a light chain comprising the sequence of SEQ ID NO: 46; 
 b) an antibody comprising a heavy chain comprising a heavy chain (HC) CDR1 having the sequence of SEQ ID NO: 15, an HC CDR2 having the sequence of SEQ ID NO: 16, and an HC CDR3 having the sequence of SEQ ID NO: 17, and a light chain comprising a light chain (LC) CDR1 having the sequence of SEQ ID NO: 18, a LC CDR2 having the sequence of SEQ ID NO: 19, and a LC CDR3 having the sequence of SEQ ID NO: 20; and 
 c) an antibody comprising a heavy chain comprising the sequence of SEQ ID NO: 53 and a light chain comprising the sequence of SEQ ID NO: 60. 
 
     
     
         25 . The composition of  claim 24 , wherein the anti-CSF1R antibody is a humanized antibody. 
     
     
         26 . The composition of  claim 24  or  claim 25 , wherein the anti-CSF1R antibody is selected from a Fab, an Fv, an scFv, a Fab′, and a (Fab′) 2 . 
     
     
         27 . The composition of any one of  claims 18  to  26 , wherein each of the anti-CSF1R antibody and the at least one immune stimulating agent are each present in separate compartments or containers. 
     
     
         28 . The composition of any one of  claims 18 - 26 , wherein the anti-CSF1R antibody and at least one immune stimulating agent are mixed or formulated together. 
     
     
         29 . The composition of any one of  claims 18 - 28  for use in treating cancer. 
     
     
         30 . Use of the composition of any one of  claims 18 - 28  for preparation of a medicament for treatment of cancer. 
     
     
         31 . The composition or use of  claim 29  or  30 , wherein the cancer is selected from non-small cell lung cancer, melanoma, squamous cell carcinoma of the head and neck, ovarian cancer, pancreatic cancer, renal cell carcinoma, hepatocellular carcinoma, bladder cancer, endometrial cancer, Hodgkin's lymphoma, lung cancer, glioma, gioblastoma multiforme, colon cancer, breast cancer, bone cancer, skin cancer, uterince cancer, gastric cancer, stomach cancer, lymphoma, lymphocytic leukemia, multiple myeloma, prostate cancer, mesothelioma, and kidney cancer.