Antibody vaccine conjugates and uses therefor

Abstract

The present invention provides novel antibody vaccine conjugates and methods of using the same to induce a cytotoxic T cell (CTL) response. In a particular, embodiment, the vaccine conjugate includes a human chorionic gonadotropin beta subunit (βhCG) antigen linked to an anti-mannose receptor (MR) antibody.

1 . A method of inducing or enhancing a T cell mediated immune response against an antigen comprising contacting antigen presenting cells (APCs) with
 (a) a molecular conjugate comprising an antigen and a monoclonal antibody which binds to the human macrophage mannose receptor (MMR); and   (b) a toll receptor agonist or a combination of toll receptor agonists, such that the antigen is internalized, processed and presented to T cells in a manner which induces or enhances a T cell mediated immune response against an antigen.   
     
     
         2 . The method of  claim 1 , wherein the toll receptor agonist is selected from the group consisting of flagellin, MALP-2 (macrophage activating lipopeptide-2), LPS, R837, R848, polyI:C (inosine:cytosine polynucleotide), ssRNA, and dsRNA. 
     
     
         3 . The method of  claim 1 , wherein the combination of toll receptor agonists comprises R848 and polyI:C. 
     
     
         4 . The method of  claim 1 , wherein the antigen is a bacterial, viral or tumor antigen. 
     
     
         5 . The method of  claim 4 , wherein the antigen is a tumor-associated antigen selected from βhCG, gp100 or Pmel17, HER2/neu, CEA, gp100, MART1, TRP-2, melan-A, NY-ESO-1, MN (gp250), MAGE-1, MAGE-3, Tyrosinase, Telomerase, and MUC-1 antigens. 
     
     
         6 . The method of  claim 4 , wherein the antigen is a viral antigen selected from HIV-1 gag, HIV-1 env, HIV-1 nef, HBV core, FAS, HSV-1, HSV-2, p17, ORF2 and ORF3 antigens. 
     
     
         7 . The method of  claim 4 , wherein the antigen is a bacterial antigen selected from the group consisting from Toxoplasma gondii, Treponema pallidum, Anthrax, Botulism, Tetanus, Chlamydia, Cholera, Diptheria, Lyme Disease, Syphilis, and Tuberculosis antigens. 
     
     
         8 . The method of  claim 5 , wherein the antigen is a βhCG antigen. 
     
     
         9 . The method of  claim 1 , wherein the APCs are dendritic cells. 
     
     
         10 . The method of  claim 1 , wherein the T cell response is induced through both MHC Class I and MHC Class II pathways. 
     
     
         11 . The method of  claim 1 , wherein the T cell response is mediated by cytotoxic T cells and/or helper T cells. 
     
     
         12 . The method of  claim 1 , wherein the T cell response is induced by cross-presentation of the antigen to T cells through both MHC Class I and MHC Class II pathways. 
     
     
         13 . The method of  claim 1 , wherein the antibody is selected from the group consisting of human, humanized and chimeric antibodies. 
     
     
         14 . The method of  claim 1 , wherein the antibody is selected from the group consisting of a whole antibody, an Fab fragment and a single chain antibody. 
     
     
         15 . The method of  claim 1 , wherein the antibody comprises a heavy chain variable region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4 sequences and a light chain variable region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4 sequences, wherein:
 (a) the heavy chain variable region CDR3 sequence comprises SEQ ID NO: 15; and   (b) the light chain variable region CDR3 sequence comprises SEQ ID NO: 18;   (c) the heavy chain variable region CDR2 sequence comprises SEQ ID NO: 14;   (d) the light chain variable region CDR2 sequence comprises SEQ ID NO: 17;   (e) the heavy chain variable region CDR1 sequence comprises SEQ ID NO:13; and   (f) the light chain variable region CDR1 sequence comprises SEQ ID NO: 16.   
     
     
         16 . The method of  claim 1 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:4 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:8, or an antibody that competes for binding with the foregoing antibody. 
     
     
         17 . The method of  claim 1 , wherein the molecular conjugate and the toll receptor agonist or combination of toll receptor agonists, are linked. 
     
     
         18 . The method of  claim 17 , wherein the molecular conjugate and the toll-receptor agonist are expressed together as a single recombinant fusion protein. 
     
     
         19 . The method of  claim 1 , further comprising administration of a colony-stimulating factor. 
     
     
         20 . The method of  claim 1 , wherein the toll receptor agonist or combination of toll receptor agonists, is administered simultaneously with the molecular conjugate. 
     
     
         21 . The method of  claim 1 , wherein the toll receptor agonist or combination of toll receptor agonists, is administered prior to administration of the molecular conjugate. 
     
     
         22 . The method of  claim 1 , wherein the toll receptor agonist or combination of toll receptor agonists, is administered subsequent to administration of the molecular conjugate.