Methods and compositions for treating cancer and infectious diseases

Abstract

The invention relates to compositions comprising a CD4 lymphocyte depleting agent; and methods of using the compositions to treat, prevent, reduce the severity of and/or slow the progression of a condition in a subject. The invention also relates to use of combinations of a CD4 lymphocyte depleting agent and at least one additional agent to treat, prevent, reduce the severity of and/or slow the progression of a condition in a subject. The additional agent may be an immune check point inhibitor, an adoptive immune therapeutic, an immune adjuvant, or an immune modulating agent, or their combinations.

What is claimed is: 
     
         1 . A method of treating, preventing, reducing the severity of and/or slowing the progression of a condition in a subject in need thereof, comprising:
 administering a therapeutically effective amount of an anti-CD4 antibody to deplete CD4+ regulatory T cells (Tregs) in the subject; and   administering a therapeutically effective amount of an immune checkpoint inhibitor to the subject, thereby treating, reducing the severity of and/or slowing the progression of the cancer in the subject, wherein the immune checkpoint inhibitor is selected from the group consisting of an antibody against PD-1, an antibody against PD-L1, or a combination thereof,   wherein the subject has had the cancer for an amount of time long enough to prime the immune system prior to administration of the anti-CD4 antibody.   
     
     
         2 . The method of  claim 1 , wherein the cancer is kidney cancer, melanoma, prostate cancer, breast cancer, cervical cancer, liver cancer, ovarian cancer, glioblastoma, renal cancer, lung cancer, pancreatic cancer, gastric cancer, head and neck cancer, brain cancer, colon cancer, or bladder cancer. 
     
     
         3 . The method of  claim 1 , wherein the subject is a human. 
     
     
         4 . The method of  claim 1 , wherein the anti-CD4 antibody is a monoclonal antibody or a fragment thereof, a polyclonal antibody or a fragment thereof, a chimeric antibody, a humanized antibody, a human antibody or a fragment thereof, or a single chain antibody. 
     
     
         5 . The method of  claim 1 , wherein the anti-CD4 antibody depleting agent is a humanized anti-CD4 antibody. 
     
     
         6 . The method of  claim 1 , wherein the anti-CD4 antibody is zanolimumab, keliximab or OKT4. 
     
     
         7 . The method of  claim 1 , wherein the anti-CD4 antibody is administered at 100-200 mg/day, 200-300 mg/day, 300-400 mg/day, 400-500 mg/day, 500-600 mg/day, 600-700 mg/day, 700-800 mg/day, 800-900 mg/day, 900-1000 mg/day, 1000-1100 mg/day, 1100-1200 mg/day, 1200-1300 mg/day, 1300-1400 mg/day, 1400-1500 mg/day, 1500-1600 mg/day, 1600-1700 mg/day, 1700-1800 mg/day, 1800-1900 mg/day or 1900-2000 mg/day. 
     
     
         8 . The method of  claim 1 , wherein the anti-CD4 antibody is administered intravenously, intramuscularly, subcutaneously, or intraperitoneally. 
     
     
         9 . The method of  claim 1 , wherein the immune checkpoint inhibitor is an antibody against PD-1 selected from Lambrolizumab, Nivolumab and Pidilizumab. 
     
     
         10 . The method of  claim 1 , wherein the immune checkpoint inhibitor is an antibody against PD-L1 selected from MPDL3280A, MEDI4736 and BMS-936559. 
     
     
         11 . The method of  claim 1 , wherein the immune checkpoint inhibitor is administered at 0.1-0.5 mg/day, 0.5-1.0 mg/day, 1.0-1.5 mg/day, 1.5-2.0 mg/day, 2.0-2.5 mg/day, 2.5-5 mg/day, 5-10 mg/day, 10-15 mg/day, 15-20 mg/day, 20-25 mg/day, 25-30 mg/day, 30-35 mg/day, 35-40 mg/day, 40-45 mg/day, 45-50 mg/day, 50-55 mg/day, 55-60 mg/day, 60-65 mg/day, 65-70 mg/day, 70-75 mg/day, 75-80 mg/day, 80-85 mg/day, 85-90 mg/day, 90-95 mg/day or 95-100 mg/day. 
     
     
         12 . The method of  claim 1 , wherein the immune checkpoint inhibitor is administered intravenously, intramuscularly, subcutaneously, or intraperitoneally. 
     
     
         13 . The method of  claim 1 , wherein the anti-CD4 antibody and the immune checkpoint inhibitor are administered concurrently. 
     
     
         14 . The method of  claim 1 , wherein the anti-CD4 antibody is administered before or after administering the immune checkpoint inhibitor. 
     
     
         15 . The method of  claim 1 , wherein the administration of the anti-CD4 antibody induces interferon-gamma (IFN-γ) response in the subject. 
     
     
         16 . The method of  claim 1 , further comprising administering a therapeutically effective amount of an immune modulating agent to the subject. 
     
     
         17 . The method of  claim 16 , wherein the immune modulating agent is selected from an mTOR inhibitor, a STAT inhibitor, a TGFβ receptor inhibitor, and a tyrosine kinase inhibitor. 
     
     
         18 . The method of  claim 17 , wherein the mTOR inhibitor is temsirolimus, evirolimus, or sirolimus. 
     
     
         19 . The method of  claim 17 , wherein the tyrosine kinase inhibitor is selected from sunitinib, erlotinib, vandetanib, cediranib, brivanib, foretinib, and dovitinib. 
     
     
         20 . The method of  claim 1 , further comprising administering a therapeutically effective amount of a chemotherapeutic agent to the subject.