Compositions and Methods for Treating Cancer with Arginine Depletion and Immuno Oncology Agents

Abstract

Methods of treating tumors or cancer include administration of an arginine depleting enzyme and an immune-oncology agent.

1 . A method of inhibiting tumor growth in a subject, comprising administering a pharmaceutical composition comprising a therapeutic amount of a human Arginase I enzyme comprising a cobalt cofactor and a therapeutic amount of an immuno-oncology agent. 
     
     
         2 . The method of  claim 1 , wherein the tumor comprises arginine auxotrophic tumor cells. 
     
     
         3 . The method of  claim 1 , wherein the human Arginase I enzyme is stabilized by association with a stabilizing agent. 
     
     
         4 . The method of  claim 3 , wherein the stabilizing agent comprises polyethylene glycol, a synthetic protein polymer, an Fc fusion, or albumin. 
     
     
         5 . The method of  claim 1 , wherein the human Arginase I enzyme is pegylated. 
     
     
         6 . The method of  claim 1 , wherein the tumor exhibits a reduced or inhibited expression of argininosuccinate synthetase, ornithine transcarbamylase, argininosuccinate lyase, or a combination thereof. 
     
     
         7 . The method of  claim 1 , wherein the subject is an animal subject. 
     
     
         8 . The method of  claim 1 , wherein the subject is a human cancer patient. 
     
     
         9 . The method of  claim 1 , wherein the immuno-oncology agent enhances the subject's immune response. 
     
     
         10 . The method of  claim 9 , wherein the immuno-oncology agent inhibits an immune suppressor. 
     
     
         11 . The method of  claim 9 , wherein the immuno-oncology agent blocks a checkpoint inhibitor pathway. 
     
     
         12 . The method of  claim 9 , wherein the immuno-oncology agent comprises a PD-1, OX40 or other B7 pathway inhibitor. 
     
     
         13 . The method of  claim 11 , wherein the agent is an anti-PD-1 antibody or anti-PD-L1 antibody. 
     
     
         14 . The method of claim wherein the immune-oncology agent is an anti-OX40 or anti-OX40L antibody. 
     
     
         15 . The method of  claim 13 , wherein the agent comprises pembrolizumab, ipilimumab, atezolizumab or nivolumab. 
     
     
         16 . The method of  claim 13 , wherein the agent comprises ipilimumab. 
     
     
         17 . The method of  claim 1 , wherein the tumor comprises hepatocellular carcinoma, renal cell carcinoma, breast cancer, melanoma, prostate cancer, pancreatic cancer, bladder cancer, colon carcinoma, colorectal cancer, triple negative breast cancer, Hodgkin's lymphoma, gastric cancer, glioblastoma, Merkel cell carcinoma, lung carcinoma, small cell lung cancers or non-small cell lung cancers. 
     
     
         18 . The method of  claim 13 , wherein the administration of a combination of the human Arginase I enzyme and the anti-PD-1 antibody, anti-PDL-1 antibody, anti-OX40 antibody or anti-OX40L antibody exhibits an additive effect on tumor growth inhibition compared to the tumor growth inhibition exhibited by administering a therapeutic dose of the anti-PD-1 antibody alone or the anti-PDL-1 antibody alone, or the human Arginase I enzyme alone. 
     
     
         19 . The method of  claim 13 , wherein the administration of a combination of the human Arginase I enzyme and the anti-PD-1 antibody, the anti-PDL-1 antibody, the anti-OX40L antibody or the anti-OX40L antibody exhibits a synergistic effect on tumor growth inhibition compared to the tumor growth inhibition exhibited by administering a therapeutic dose of the anti-PD-1 antibody alone, the anti-PD-Li antibody, the anti-OX40 antibody or the anti-OX4OL antibody alone or the human Arginase I enzyme alone. 
     
     
         20 . The method of  claim 13 , wherein the human Arginase I enzyme and the anti-PD-1 antibody, the anti-PDL-1 antibody, the anti-OX40 antibody or the anti-OX4OL antibody are administered concurrently. 
     
     
         21 . The method of  claim 13 , wherein the human Arginase I enzyme and the anti-PD-1 antibody, the anti-PDL-1 antibody, the anti-OX40 antibody or the anti-OX4OL antibody are administered sequentially. 
     
     
         22 . The method of  claim 1 , wherein the human Arginase I enzyme displays a k cat /K M  for the hydrolysis of arginine between 400 mM −1  s −1  and 4,000 mM −1  s −1  at pH 7.4 and 37° C. 
     
     
         23 . The method of  claim 1 , wherein the human Arginase I enzyme comprises a ratio of cobalt to arginase of from 2 to 3 μgCo/mg arginase. 
     
     
         24 . The method of  claim 1 , wherein the human Arginase I enzyme is produced by contacting an arginase apoenzyme with cobalt or a cobalt ion at a temperature of from 30° C. to 55° C. for a period of from 15 minutes to 60 minutes. 
     
     
         25 . A method of treating cancer in a cancer patient comprising administering to said patient a therapeutic amount of a pharmaceutical composition comprising a pegylated human Arginase I enzyme comprising a cobalt cofactor and an immune system modulating therapy comprising administering a pharmaceutical composition comprising an immuno-oncology agent. 
     
     
         26 . The method of  claim 25 , wherein the pharmaceutical composition comprising a pegylated human Arginase I enzyme comprising a cobalt cofactor and a pharmaceutical composition comprising an immuno-oncology agent are administered concurrently. 
     
     
         27 . The method of  claim 25 , wherein the pharmaceutical composition comprising a human Arginase I enzyme comprising a cobalt cofactor and a pharmaceutical composition comprising an immuno-oncology agent are administered sequentially. 
     
     
         28 . The method of  claim 25 , wherein a therapeutic amount of the pegylated human Arginase I enzyme comprising a cobalt cofactor is from about 0.01 mg/kg to about 7.5 mg/kg. 
     
     
         29 . The method of  claim 25 , wherein a therapeutic amount of the pegylated human Arginase I enzyme comprising a cobalt cofactor is from about 0.05 mg/kg to about 5 mg/kg. 
     
     
         30 . The method of  claim 25 , wherein a therapeutic amount of the pegylated human Arginase I enzyme comprising a cobalt cofactor is from about 0.1 mg/kg to about 5 mg/kg. 
     
     
         31 . The method of  claim 25 , wherein the immuno-oncology agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-OX40 antibody or an anti-OX40L antibody. 
     
     
         32 . The method of  claim 31 , wherein the immuno-oncology agent is selected from pembrolizumab, ipilimumab, atezolizumab and nivolumab. 
     
     
         33 . The method of  claim 31 , wherein the cancer patient is treated for hepatocellular carcinoma, renal cell carcinoma, breast cancer, melanoma, prostate cancer, pancreatic cancer, bladder cancer, colon carcinoma, colorectal cancer, triple negative breast cancer, Hodgkin's lymphoma, gastric cancer, glioblastoma, Merkel cell carcinoma, lung carcinoma, small cell lung cancer or non-small cell lung cancer. 
     
     
         34 . The method of  claim 25 , wherein the pharmaceutical composition comprising a pegylated human Arginase I enzyme comprising a cobalt cofactor is administered parenterally. 
     
     
         36 . The method of  claim 25 , wherein the pharmaceutical composition comprising a pegylated human Arginase I enzyme comprising a cobalt cofactor is administered topically, intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intratracheally, intraocularly, intranasally, intravitreally, intravaginally, intrarectally, intramuscularly, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, orally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, via a catheter, or via a lavage. 
     
     
         37 . The method of  claim 25  wherein the pharmaceutical composition is administered intravenously. 
     
     
         38 . A method of treating cancer in a cancer patient comprising administering to said patient an arginine depleting agent and a checkpoint pathway inhibitor. 
     
     
         39 . The method of  claim 38 , wherein the therapeutic effect of treatment with said arginine depleting agent and a checkpoint pathway inhibitor is additive as compared to treatment the arginine depleting agent alone or said checkpoint pathway inhibitor alone. 
     
     
         40 . The method of  claim 38 , wherein the therapeutic effect of treatment with said arginine depleting agent and a checkpoint pathway inhibitor is synergistic as compared to treatment the arginine depleting agent alone or said checkpoint pathway inhibitor alone. 
     
     
         41 . The method of  claim 38 , wherein the treatment results in from 50% to 99% reduction in serum arginine in the patient. 
     
     
         42 . The method of  claim 38 , wherein the treatment results in from 90% to 99% reduction of serum arginine in the patient. 
     
     
         43 . The method of  claim 38 , wherein the treatment results in reduction of serum arginine in the patient to an undetectable level. 
     
     
         44 . The method of  claim 38 , wherein the arginine depleting agent comprises an arginase enzyme, an arginine deiminase enzyme or a combination thereof. 
     
     
         45 . The method of  claim 38 , wherein the enzyme is a human enzyme. 
     
     
         46 . The method of  claim 38 , wherein said enzyme is an engineered human arginase. 
     
     
         47 . The method of  claim 38 , in which said enzyme is stabilized by conjugation or association with an Fc fragment, pegylation, albumin or a synthetic protein polymer. 
     
     
         48 . A method of inhibiting tumor growth in a subject, comprising administering a pharmaceutical composition comprising a therapeutic amount of a human arginase I enzyme or a mycoplasma arginine deiminase enzyme and a therapeutic amount of an immuno-oncology agent.