Compositions of pd-1 antagonists and methods of use

Abstract

Methods of treating cancer and infectious diseases utilizing a treatment regimen comprising administering a compound that reduces inhibitory signal transduction in T cells, in combination with a potentiating agent, such as cyclophosphamide, to produce potent T cell mediated responses, are described. Compositions comprising the PD-1 antagonists and potentiating agents useful in the methods of the invention are also disclosed.

What is claimed is: 
     
         1 . A therapeutic composition comprising a compound comprising a fusion protein comprising first and second peptide portions wherein said first peptide portion consists of an amino acid sequence selected from: wild type B7-DC, an amino acid sequence having at least 98% sequence identity to amino acids 20-221 or 20-121 of SEQ ID NO: 1 and which competes in vitro with wild-type B7-DC for binding to PD-1, a fragment of B7-DC which competes in vitro with wild-type B7-DC for binding to PD-1, and an extracellular domain of B7-DC and said second peptide portion comprises a portion of an immunoglobulin (Ig) and a potentiating agent selected from the group of: cyclophosphamide, an analog of cyclophosphamide, sunitinib, anti-TGNFβ, imatinib, anthracyclines, oxaliplatin, and doxorubicin. 
     
     
         2 . The composition of  claim 1  wherein said first peptide portion consists of a wild type B7-DC polypeptide. 
     
     
         3 . The composition of  claim 1 , wherein said B7-DC is a human B7-DC. 
     
     
         4 . The composition of  claim 1 , wherein said first peptide portion consists of a fragment of B7-DC which does not comprise any portion of the transmembrane portion of said B7-DC polypeptide. 
     
     
         5 . The composition of  claim 1 , wherein said first peptide portion consists of the soluble portion of said B7-DC polypeptide and said second peptide portion comprises the Fc region of an antibody but does not comprise any of the variable region of said antibody. 
     
     
         6 . The composition of  claim 1 , wherein said first peptide portion consists of the amino acid sequence of SEQ ID NO: 3 and said second polypeptide portion comprises the Fc region of an antibody but does not comprise any of the variable region of said antibody. 
     
     
         7 . The composition of  claim 1 , wherein said first peptide portion consists of an amino acid sequence having at least 98% sequence identity to amino acids 20-221 or 20-121 of SEQ ID NO: 1. 
     
     
         8 . The composition of  claim 1 , wherein said first peptide portion consists of the amino acid sequence of amino acids 20-221 or 20-121 of SEQ ID NO: 
     
     
         9 . The composition of  claim 1 , wherein said fusion protein comprises an amino acid sequence having at least 95% identity to the sequence of SEQ ID NO: 9, 10, 12 or 13. 
     
     
         10 . The composition of  claim 1 , wherein said fusion protein comprises the amino acid sequence of SEQ ID NO: 9, 10, 12, or 13. 
     
     
         11 . The composition of  claim 1 , wherein said fusion protein is a monomer. 
     
     
         12 . The composition of  claim 1 , wherein said fusion protein is part of a dimer. 
     
     
         13 . The composition of  claim 12 , wherein said dimer is a homodimer. 
     
     
         14 . The composition of  claim 12 , wherein said dimer is a heterodimer. 
     
     
         15 . The composition of  claim 1 , wherein said fusion protein comprises a first peptide portion which consists of 20-221 of SEQ ID NO: 1 and a second peptide portion which consists of the hinge, C H 2 and C H 3 regions of a human immunoglobulin Cγ1. 
     
     
         16 . The composition of  claim 1 , wherein said second peptide portion comprises amino acids 245-476 of human IgG1. 
     
     
         17 . The composition of  claim 1 , wherein said potentiating agent is cyclophosphamide or an analog of cyclophosphamide. 
     
     
         18 . The composition of  claim 1 , said compound and said potentiating agent are provided as separate medicaments. 
     
     
         19 . The composition of  claim 1 , wherein said first peptide portion consists of the extracellular domain of B7-DC or a polypeptide differing therefrom by only conservative amino acid substitutions. 
     
     
         20 . The composition of  claim 1 , further comprising at least one additional agent selected from the group consisting of an anti-PD-1 antibody, an anti-CTLA4 antibody, a mitosis inhibitor, an aromatase inhibitor, an A2AR antagonist, and an angiogenesis inhibitor. 
     
     
         21 . The therapeutic composition of  claim 1  further comprising a pharmaceutically acceptable carrier. 
     
     
         22 . A kit comprising
 (a) a dosage supply of a compound according to  claim 1 , and   (b) a supply of a potentiating agent.   
     
     
         23 . The kit of  claim 22  further comprising
 (c) a supply of pharmaceutically acceptable carrier; and 
 (d) printed instructions for administering said compound and said potentiating agent. 
 
     
     
         24 . The kit of  claim 22 , wherein said potentiating agent is cyclophosphamide or an analog of cyclophosphamide. 
     
     
         25 . The kit of  claim 24  wherein said cyclophosphamide or an analog of cyclophosphamide is provided in an amount of about 0.45 mg to about 4.5 mg. 
     
     
         26 . A composition comprising:
 a pharmaceutical composition comprising a fusion protein comprising a first and second peptide portion wherein said first peptide portion consists of amino acids 20-221 of SEQ ID NO: 1 and said second peptide portion comprises amino acids 245-476 of human IgG1 and a pharmaceutical carrier;   and cyclophosphamide.   
     
     
         27 . A method of treating cancer in a human comprising administering a therapeutically effective amount of a composition of  claim 26  to said human.