Cd80 extracellular domain polypeptides and their use in cancer treatment

Abstract

This application relates to CD80 (B7-1) extracellular domain (ECD) polypeptides and CD80-ECD fusion molecules and their use in treatment of cancer, both alone and in combination with other therapeutic agents, such as immune stimulating agents such as PD-1/PD-L1 inhibitors.

What is claimed is: 
     
         1 . A method of treating cancer in a subject comprising administering to the subject an effective amount of a composition comprising (i) CD80 extracellular domain (ECD) fusion molecules comprising the amino acid sequence of SEQ ID NO:20 and (ii) at least one pharmaceutically acceptable carrier, wherein the CD80 ECD fusion molecules comprise at least 15 moles of sialic acid (SA) per mole of CD80 ECD fusion protein. 
     
     
         2 . The method of  claim 1 , wherein the CD80 ECD fusion molecules comprise 15-60 moles of SA per mole of CD80 ECD fusion protein. 
     
     
         3 . The method of  claim 2 , wherein the CD80 ECD fusion molecules comprise 15-40 moles of SA per mole of CD80 ECD fusion protein. 
     
     
         4 . The method of  claim 2 , wherein the CD80 ECD fusion molecules comprise 15-30 moles of SA per mole of CD80 ECD fusion protein. 
     
     
         5 . The method of  claim 2 , wherein the CD80 ECD fusion molecules comprise 20-30 moles of SA per mole of CD80 ECD fusion protein. 
     
     
         6 . The method of  claim 1 , wherein the CD80 ECD fusion molecules comprise at least 20 moles of SA per mole of CD80 ECD fusion protein. 
     
     
         7 . The method of  claim 1 , wherein the composition alone does not cause significant release of interferon gamma or TNF alpha from T-cells in vitro. 
     
     
         8 . The method of  claim 1 , wherein the composition alone causes less release of interferon gamma or TNF alpha from T-cells in vitro than TGN1412 alone. 
     
     
         9 . The method of  claim 8 , wherein the composition alone is at least 1000-fold less potent at inducing interferon gamma or TNF alpha release compared to TGN1412 alone. 
     
     
         10 . The method of  claim 2 , wherein the composition alone does not cause significant release of interferon gamma or TNF alpha from T-cells in vitro. 
     
     
         11 . The method of  claim 2 , wherein the composition alone causes less release of interferon gamma or TNF alpha from T-cells in vitro than TGN1412 alone. 
     
     
         12 . The method of  claim 11 , wherein the composition alone is at least 1000-fold less potent at inducing interferon gamma or TNF alpha release compared to TGN1412 alone. 
     
     
         13 . The method of  claim 1 , wherein the composition is capable of at least 90% tumor growth inhibition in at least one mouse syngeneic cancer model over a period of at least 1 week, 10 days, two weeks, or three weeks following administration of a single dose of the fusion molecule at 0.3 to 0.6 mg/kg. 
     
     
         14 . The method of  claim 13 , wherein the mouse syngeneic cancer model is a CT26 tumor model. 
     
     
         15 . The method of  claim 1 , wherein the cancer is a solid tumor. 
     
     
         16 . The method of  claim 15 , wherein the cancer is selected from colorectal cancer, breast cancer, gastric cancer, 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, and endometrial cancer. 
     
     
         17 . The method of  claim 15 , wherein the cancer is recurrent or progressive after a therapy selected from surgery, chemotherapy, radiation, or a combination thereof. 
     
     
         18 . The method of  claim 2 , wherein the cancer is a solid tumor. 
     
     
         19 . The method of  claim 1 , wherein the composition is administered in combination with at least one additional therapeutic agent. 
     
     
         20 . The method of  claim 19 , wherein the additional therapeutic agent is a programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitor. 
     
     
         21 . The method of  claim 20 , wherein the PD-1/PD-L1 inhibitor is an anti-PD-1 antibody. 
     
     
         22 . The method of  claim 20 , wherein the PD-1/PD-L1 inhibitor is an anti-PD-L1 antibody. 
     
     
         23 . The method of  claim 20 , wherein the composition and the PD-1/PD-L1 inhibitor are administered concurrently. 
     
     
         24 . The method of  claim 20 , wherein the composition and the PD-1/PD-L1 inhibitor are administered sequentially. 
     
     
         25 . The method of  claim 20 , wherein the subject previously received PD-1/PD-L1 inhibitor therapy and is resistant to treatment with a PD-1/PD-L1 inhibitor. 
     
     
         26 . The method of  claim 2 , wherein the composition is administered in combination with at least one additional therapeutic agent. 
     
     
         27 . The method of  claim 26 , wherein the additional therapeutic agent is a programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitor. 
     
     
         28 . The method of  claim 18 , wherein the composition is administered in combination with at least one additional therapeutic agent. 
     
     
         29 . The method of  claim 28 , wherein the additional therapeutic agent is a programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitor. 
     
     
         30 . A method of treating cancer in a subject comprising administering to the subject an effective amount of a composition comprising (i) CD80 ECD fusion molecules comprising the amino acid sequence of SEQ ID NO:20, and (ii) at least one pharmaceutically acceptable carrier. 
     
     
         31 . The method of  claim 30 , wherein the composition alone does not cause significant release of interferon gamma or TNF alpha from T-cells in vitro. 
     
     
         32 . The method of  claim 30 , wherein the composition alone causes less release of interferon gamma or TNF alpha from T-cells in vitro than TGN1412 alone. 
     
     
         33 . The method of  claim 32 , wherein the composition alone is at least 1000-fold less potent at inducing interferon gamma or TNF alpha release compared to TGN1412 alone. 
     
     
         34 . The method of  claim 30 , wherein the composition is capable of at least 90% tumor growth inhibition in at least one mouse syngeneic cancer model over a period of at least 1 week, 10 days, two weeks, or three weeks following administration of a single dose of the fusion molecule at 0.3 to 0.6 mg/kg. 
     
     
         35 . The method of  claim 34 , wherein the mouse syngeneic cancer model is a CT26 tumor model. 
     
     
         36 . The method of  claim 30 , where in the cancer is a solid tumor. 
     
     
         37 . The method of  claim 36 , wherein the cancer is selected from colorectal cancer, breast cancer, gastric cancer, 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, and endometrial cancer. 
     
     
         38 . The method of  claim 36 , wherein the cancer is recurrent or progressive after a therapy selected from surgery, chemotherapy, radiation, or a combination thereof. 
     
     
         39 . The method of  claim 30 , wherein the composition is administered in combination with at least one additional therapeutic agent. 
     
     
         40 . The method of  claim 39 , wherein the additional therapeutic agent is a PD-1/PD-L1 inhibitor. 
     
     
         41 . The method of  claim 40 , wherein the PD-1/PD-L1 inhibitor is an anti-PD-1 antibody. 
     
     
         42 . The method of  claim 40 , wherein the PD-1/PD-L1 inhibitor is an anti-PD-L1 antibody. 
     
     
         43 . The method of  claim 40 , wherein the composition and the PD-1/PD-L1 inhibitor are administered concurrently. 
     
     
         44 . The method of  claim 40 , wherein the composition and the PD-1/PD-L1 inhibitor are administered sequentially. 
     
     
         45 . The method of  claim 40 , wherein the subject previously received PD-1/PD-L1 inhibitor therapy and is resistant to treatment with a PD-1/PD-L1 inhibitor.