VISTA Antagonist and Methods of Use

Abstract

The present invention is directed to a peptide, multimer, conjugate, analog, derivative or mimetic thereof that inhibits the activity of VISTA. The invention further contemplates therapeutic use of the VISTA antagonist peptide, multimer, conjugate, derivative or mimetic thereof, including treating or preventing cancer, bacterial infections, viral infections, parasitic infections and fungal infections, as well as research uses of the antagonist.

1 . An isolated VISTA antagonist comprising a peptide which is identical to the amino acid sequence of SEQ ID NO:1 (Ser-Ser-Ala-Cys-Asp-Trp-Ile-Lys-Arg-Ser-Cys-His), or a multimer, conjugate, analog, derivative or mimetic thereof. 
     
     
         2 . An isolated VISTA antagonist according to  claim 1 , comprising a peptide which is identical to the amino acid sequence of SEQ ID NO:1 (Ser-Ser-Ala-Cys-Asp-Trp-Ile-Lys-Arg-Ser-Cys-His), or which comprises a peptide having an amino acid sequence that differs from SEQ ID NO:1 by at most 2 amino acid residues, or an multimer, conjugate, analog, derivative or mimetic thereof. 
     
     
         3 - 5 . (canceled) 
     
     
         6 . The isolated VISTA antagonist according to  claim 1 , wherein the cysteine residues at positions 4 and 11 of SEQ ID NO:1 (Ser-Ser-Ala-Cys-Asp-Trp-Ile-Lys-Arg-Ser-Cys-His), or their corresponding position in a variant of said peptide, form a disulfide bridge. 
     
     
         7 . An isolated VISTA antagonist according to  claim 1 , which has been modified to improve binding affinity and/or stability. 
     
     
         8 . The isolated VISTA antagonist of  claim 7 , wherein the modification is selected from the group consisting of PEG, acetylation, XTEN, albumin and multimerization. 
     
     
         9 . The isolated VISTA antagonist according to  claim 1 , which is directly or indirectly attached to an immunoglobulin polypeptide or a fragment thereof. 
     
     
         10 . The isolated antagonist of  claim 9 , wherein said immunoglobulin polypeptide comprises a human IgG1, IgG2, IgG3 or IgG4 constant region or fragment thereof. 
     
     
         11 - 12 . (canceled) 
     
     
         13 . An isolated VISTA antagonist according to  claim 1 , which comprises another moiety that targets said peptide to a target site. 
     
     
         14 - 20 . (canceled) 
     
     
         21 . A composition suitable for therapeutic, prophylactic or diagnostic use comprising a therapeutically, prophylactically or diagnostically effective amount of the isolated VISTA antagonist of  claim 1 . 
     
     
         23 . The composition of  claim 21 , further comprising another therapeutic agent. 
     
     
         24 . The composition of  claim 23 , wherein the other therapeutic agent is an anti-cancer agent, an anti-viral agent, a cytokine or an immune agonist. 
     
     
         25 . The composition of  claim 21 , wherein the other therapeutic agent is selected from CTLA-4-Ig, anti-PD-1, PD-L1 or PD-L2 fusion proteins, and EGFR antagonists. 
     
     
         26 - 32 . (canceled) 
     
     
         33 . A method for stimulating an immune response in a subject, comprising administering to the subject in need thereof an effective amount of an isolated VISTA antagonist according to  claim 1  optionally comprising another therapeutic agent selected from an anti-cancer agent, an anti-viral agent, a cytokine or an immune agonist. 
     
     
         34 . The method of  claim 33 , wherein the subject has an infection selected from the group consisting of bacterial, viral, parasitic and fungal infections. 
     
     
         35 - 39 . (canceled) 
     
     
         40 . The method of  claim 33 , for treating cancer in a subject. 
     
     
         41 . The method of  claim 33 , which is for enhancing anti-cancer or anti-tumor immunity, comprising administering to a subject in need thereof an effective amount of an isolated VISTA antagonist according to  claim 1  and optionally comprising another therapeutic agent selected from an anti-cancer agent, an anti-viral agent, a cytokine or an immune agonist. 
     
     
         42 . The method of  claim 33 , which is for treating or preventing cancer, inhibiting tumor invasion and/or cancer metastasis, comprising administering to a subject in need thereof an effective amount of said VISTA antagonist and optionally comprising another therapeutic agent selected from an anti-cancer agent, an anti-viral agent, a cytokine or an immune agonist. 
     
     
         44 . The method of  claim 33 , which is for treating or preventing a viral infection, comprising administering to a subject in need thereof an effective amount of said VISTA antagonist and optionally comprising another therapeutic agent selected from an anti-cancer agent, an anti-viral agent, a cytokine or an immune agonist. 
     
     
         45 - 50 . (canceled)