Compositions and methods for enhancing immune responses mediated by antigen-presenting cells

Abstract

Molecular adjuvants are disclosed comprising an antigen presenting cell-targeting ligand linked to an immunogen, e.g. tumor associated antigens, bacterial or viral antigens. The ligand and the immunogen are linked via a cleavable linker such as a protease-sensitive oligopeptide, to facilitate processing of the adjuvant by the antigen presenting cell. Methods are disclosed for delivery of these molecular adjuvants to patients, resulting in the transduction of activating signals to the targeted antigen presenting cell, thereby enhancing the immune response to the co-delivered immunogen.

1 . A molecular adjuvant for enhancing an immune response to an immunogen comprising: 
 a targeting ligand having binding affinity for a characteristic determinant of an antigen presenting cell, the targeting ligand being linked to the immunogen by a cleavable linker, whereby binding of the molecular adjuvant to the antigen presenting cell determinant activates the antigen presenting cell, effecting delivery of said immunogen to an antigen presenting pathway of the antigen presenting cell.    
     
     
         2 . The molecular adjuvant of  claim 1 , wherein the targeting ligand binds specifically to a determinant comprising an immunomodulatory receptor of the antigen presenting cell.  
     
     
         3 . The molecular adjuvant of  claim 2 , wherein the targeting ligand binds specifically to a receptor selected from the group consisting of C5a receptor, IFN-gamma receptor, CD21 (C3d) receptor, CD64 (FcgRI) receptor, and CD23 (FceRII) receptor.  
     
     
         4 . The molecular adjuvant of  claim 3 , wherein the targeting ligand binds specifically to a C5a receptor and is selected from the group consisting of C5a and a peptide agonist analog of C5a comprising the C-terminal ten residues of C5a.  
     
     
         5 . The molecular adjuvant of  claim 4 , wherein the targeting ligand is a peptide comprising the sequence YSFKPMPLaR, which is SEQ ID NO:1.  
     
     
         6 . The molecular adjuvant of  claim 3 , wherein the targeting ligand binds specifically to an IFN-gamma receptor and is selected from the group consisting of IFN-gamma and a peptide analog of IFN-gamma comprising the N-terminal 39 residues of INF-gamma.  
     
     
         7 . The molecular adjuvant of  claim 6 , wherein the targeting ligand is a peptide comprising a sequence selected from the group consisting of 
 HGTVIESLESLNNYFNFFGIDVEEKSLFLDIWRNWQKDG, which is SEQ ID NO:3; and    QDPYVKEAENLKKYFNAGHSDVADNGTLFLGILKNWKEE, which is SEQ ID NO:4.    
     
     
         8 . The molecular adjuvant of  claim 1 , wherein the immunogen comprises at least one substance selected from the group consisting of peptides, glycopeptides, phosphopeptides, lipopeptides, proteins, glycoproteins, phosphoproteins, lipoproteins, carbohydrates, nucleic acids and lipids.  
     
     
         9 . The molecular adjuvant of  claim 8 , wherein the immunogen comprises a peptide.  
     
     
         10 . The molecular adjuvant of  claim 9 , wherein the peptide is an epitope of human mucin-1.  
     
     
         11 . The molecular adjuvant of  claim 9 , wherein the peptide is an epitope of hepatitis B surface antigen.  
     
     
         12 . The molecular adjuvant of  claim 8 , wherein the immunogen comprises a protein.  
     
     
         13 . The molecular adjuvant of  claim 12 , wherein the protein is serum amyloid A (SAA).  
     
     
         14 . The molecular adjuvant of  claim 13  having the formula SAA-K-Ahx-YSFKPMPLaR (SAA-SEQ ID NO: 8).  
     
     
         15 . The molecular adjuvant of  claim 1 , wherein the immunogen comprises a tumor-specific antigen.  
     
     
         16 . The molecular adjuvant of  claim 1 , wherein the cleavable linker comprises an oligopeptide that is cleavable by a protease.  
     
     
         17 . The molecular adjuvant of  claim 16 , wherein the cleavable linker is sensitive to cleavage by a protease of the trypsin family of proteases.  
     
     
         18 . The molecular adjuvant of  claim 16 , wherein the cleavable linker comprises a dibasic dipeptide sequence.  
     
     
         19 . The molecular adjuvant of  claim 18 , wherein the cleavable linker comprises an Arg-Arg dipeptide sequence.  
     
     
         20 . The molecular adjuvant of  claim 18 , wherein the cleavable linker comprises Arg-Val-Arg-Arg (SEQ ID NO:19).  
     
     
         21 - 28 . (canceled)