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 molecular conjugate comprising a monoclonal antibody that binds to human antigen presenting cells (APCs) linked to β human chorionic gonadotropin (βhCG) and to an immunostimulatory agent. 
     
     
         2 . The molecular conjugate of  claim 1 , wherein the βhCG and the immunostimulatory agent are linked to the antibody covalently, non-covalently, recombinantly or using a combination thereof. 
     
     
         3 .- 6 . (canceled) 
     
     
         7 . The molecular conjugate of  claim 1 , wherein the antibody, the βhCG and the immunostimulatory agent are expressed together as a single recombinant fusion protein. 
     
     
         8 . The molecular conjugate of  claim 1 , wherein the immunostimulatory agent is selected from the group consisting of a CD40 ligand, a cytokine, a colony-stimulating factor, an anti-CTLA-4 antibody, a toll receptor agonist, LPS (endotoxin), R837, R848, polyl:C (inosine:cytosine polynucleotide), ssRNA, dsRNA, Bacille Calmette-Guerin (BCG), Levamisole hydrochloride, and an intravenous immune globulin. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The molecular conjugate of  claim 1 , wherein the antibody binds to a C-type lectin expressed on human dendritic cells. 
     
     
         12 . The molecular conjugate of  claim 1 , wherein the antibody binds to the human mannose receptor. 
     
     
         13 . The molecular conjugate of  claim 1 , wherein the antibody is selected from the group consisting of human, humanized and chimeric antibodies. 
     
     
         14 . The molecular conjugate 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 molecular conjugate of  claim 1 , wherein the conjugate is a recombinant fusion protein. 
     
     
         16 . The molecular conjugate of  claim 1 , wherein the antibody comprises a human heavy chain variable region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4 sequences and a human light chain variable region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4 sequences, wherein:
 (a) the human heavy chain variable region CDR3 sequence comprises SEQ ID NO: 15, and conservative modifications thereof; and   (b) the human light chain variable region CDR3 sequence comprises SEQ ID NO: 18, and conservative modifications thereof.   
     
     
         17 . The molecular conjugate of  claim 16 , wherein the human heavy 30 chain variable region CDR2 sequence comprises SEQ ID NO: 14, and conservative modifications thereof; and the human light chain variable region CDR2 sequence comprises SEQ ID NO:17, and conservative modifications thereof. 
     
     
         18 . The molecular conjugate of  claim 16 , wherein the human heavy chain variable region CDR1 sequence comprises SEQ ID NO:13, and conservative modifications thereof; and
 the human light chain variable region CDR1 sequence comprises SEQ ID NO: 16, and conservative modifications thereof.   
     
     
         19 . (canceled) 
     
     
         20 . The molecular conjugate of  claim 1 , wherein the antibody comprises human heavy chain and human light chain variable regions comprising the amino acid sequences shown in SEQ ID NO: 4 and SEQ ID NO: 8, respectively, or an amino acid sequence that is sufficiently homologous to SEQ ID NO: 4 or SEQ ID NO: 8 such that the antibody retains the ability to bind to human dendritic cells. 
     
     
         21 .- 26 . (canceled) 
     
     
         27 . The molecular conjugate of  claim 1  which is internalized and processed by APCs, such that a T cell-mediated immune response is generated against the antigen. 
     
     
         28 . The molecular conjugate of  claim 27 , wherein the T cell response is mediated by cytotoxic T cells. 
     
     
         29 . The molecular conjugate of  claim 27 , wherein the T cell response is mediated by both CD4+ and CD8+ T cells. 
     
     
         30 . The molecular conjugate of  claim 27 , wherein the T cell response is induced through both MHC class I and MHC class II pathways. 
     
     
         31 . A composition comprising an immunostimulatory agent and a molecular conjugate of an antibody that binds to APCs linked to βhCG. 
     
     
         32 . The composition of  claim 31 , wherein the immunostimulatory agent is linked to the molecular conjugate. 
     
     
         33 . (canceled) 
     
     
         34 . The composition of  claim 31 , wherein the antibody is a human antibody. 
     
     
         35 . The composition of  claim 31 , further comprising a pharmaceutically acceptable carrier or an adjuvant. 
     
     
         36 . (canceled) 
     
     
         37 . The composition of  claim 31 , wherein the immunostimulatory agent is selected from the group consisting of a CD40 ligand, a cytokine, a colonystimulating factor, an anti-CTLA-4 antibody, a toll receptor agonist, LPS (endotoxin), R837, R848, polyI-C (inosine:cytosine polynucleotide), ssRNA, dsRNA, Bacille Calmette-Guerin (BCG), Levamisole hydrochloride, and an intravenous immune globulin. 
     
     
         38 .- 40 . (canceled) 
     
     
         41 . A method of immunizing a subject comprising administering a composition of  claim 31  such that a T cell-mediated immune response is generated against βhCG. 
     
     
         42 . The method of  claim 41 , wherein the immunostimulatory agent is linked to the molecular conjugate. 
     
     
         43 . The method of  claim 41 , further comprising the step of administering an adjuvant. 
     
     
         44 . The method of  claim 41 , wherein the immunostimulatory agent is selected from the group consisting of a CD40 ligand, a cytokine, a colony-stimulating factor, an anti-CTLA-4 antibody, a toll receptor agonist, LPS (endotoxin), R837, R848, polyI-C (inosine:cytosine polynucleotide), ssRNA, dsRNA, Bacille Calmette-Guerin (BCG), Levamisole hydrochloride, and an intravenous immune globulin. 
     
     
         45 . (canceled)