Ilt3 binding molecules and uses therefor

Abstract

The present invention provides binding molecules that specifically bind to ILT3, e.g., human ILT3 (hILT3), on antigen presenting cells, such as for example, monocytes, macrophages and dendritic cells (DC), e.g., monocyte-derived dendritic cells (MDDC). The binding molecules of the invention are characterized by binding to hILT3 with high affinity and downmodulating immune responses in vitro, e.g., downmodulating alloimmune responses; the production of inflammatory cytokines by dendritic cells, e.g., monocyte-derived dendritic cells (MDDC); the upregulation of costimulatory molecules by DC, e.g., MDDC; and/or calcium flux in monocytes. In addition, the binding molecules upregulate the expression of inhibitory receptors on dendritic cells, e.g., immature dendritic cells. Surprisingly, these same binding molecules which downmodulate immune responses in vitro, are immunostimulatory in vivo. Various aspects of the invention relate to binding molecules, and pharmaceutical compositions thereof. Methods of using the binding molecules of the invention to detect human ILT3 or to modulate human ILT3 activity, either in vitro or in vivo, are also encompassed by the invention.

1 - 26 . (canceled) 
     
     
         27 . A method for upmodulating an immune response in a subject, comprising contacting a cell from the subject with an anti-ILT3 antibody or an antigen binding fragment thereof that inhibits immune cell activation in vitro. 
     
     
         28 . (canceled) 
     
     
         29 . A method for treating cancer in a subject, comprising contacting a cell with an anti-ILT3 antibody, such that cancer is treated in a subject. 
     
     
         30 . The method of  claim 29 , wherein the type of cancer is selected from the group consisting of: pancreatic cancer, melanomas, breast cancer, lung cancer, bronchus cancer, colorectal cancer, prostate cancer, pancreas cancer, stomach cancer, ovarian cancer, urinary bladder cancer, brain or central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, uterine or endometrial cancer, cancer of the oral cavity or pharynx, liver cancer, kidney cancer, testicular cancer, biliary tract cancer, small bowel or appendix cancer, salivary gland cancer, thyroid gland cancer, adrenal gland cancer, osteosarcoma, chondrosarcoma, and cancer of hematological tissues. 
     
     
         31 - 43 . (canceled) 
     
     
         44 . The method of  claim 27  or  29 , wherein the anti-ILT-3 antibody comprises:
 a. a heavy chain variable region (VH) complementarity determining region 1 (VH CDR1) comprising the amino acid sequence shown in SEQ ID NO: 3; 
 b. a heavy chain variable region (VH) complementarity determining region 2 (VH CDR2) comprising the amino acid sequence shown in SEQ ID NO: 4; 
 c. a heavy chain variable region (VH) complementarity determining region 3 (VH CDR3) comprising the amino acid sequence shown in SEQ ID NO: 5; 
 d. a light chain variable region (VL) complementarity determining region 1 (VL CDR1) comprising the amino acid sequence shown in SEQ ID NO: 6; 
 e. a light chain variable region (VL) complementarity determining region 2 (VL CDR2) comprising the amino acid sequence shown in SEQ ID NO: 7; and 
 f. a light chain variable region (VL) complementarity determining region 3 (VL CDR3) comprising the amino acid sequence shown in SEQ ID NO: 8. 
 
     
     
         45 . The method of  claim 44 , wherein the anti-ILT-3 antibody comprises: a heavy chain variable region comprising amino acids 20-135 of SEQ ID NO: 1 and a light chain variable region comprising amino acids 21-127 of SEQ ID NO: 2, wherein said antibody or antigen-binding fragment specifically binds a polypeptide consisting of the amino acid sequence of SEQ ID NO: 18. 
     
     
         46 . The method of  claim 44 , wherein the antibody comprises a heavy chain constant region. 
     
     
         47 . The method of  claim 46 , wherein the heavy chain constant region is a IgG1 heavy chain constant region. 
     
     
         48 . The method of  claim 44 , wherein the antibody comprises a human heavy chain constant region. 
     
     
         49 . The method of  claim 48 , wherein the antibody further comprises a human light chain constant region. 
     
     
         50 . The method of  claim 48 , wherein the heavy chain constant region is a human IgG1 heavy chain constant region. 
     
     
         51 . The method of  claim 50 , wherein the human heavy chain constant region comprises the amino acid sequence shown in one of SEQ ID NOs: 28-29. 
     
     
         51 . The method of  claim 44 , wherein the antibody comprises: the VH CDR1 of SEQ ID NO: 3; the VH CDR2 of SEQ ID NO: 4, the VH CDR3 of SEQ ID NO: 5; the VL CDR1 of SEQ ID NO: 6, the VL CDR2 of SEQ ID NO: 7 and the VL CDR3 of SEQ ID NO: 8, wherein framework regions of the VH are human VH framework regions, and wherein framework regions of the VL are human VL framework regions. 
     
     
         52 . The method of  claim 44 , wherein the antibody or antigen-binding fragment is selected from the group consisting of a single chain antibody, an scFv fragment, a Fab fragment, a F(ab)2 fragment, a humanized antibody, and a chimeric antibody.