CD80 EXTRACELLULAR DOMAIN POLYPEPTIDES AND THEIR USE IN CANCER TREATMENT
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.
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.