Antibodies Against Human NKG2D and Uses Thereof

Abstract

The present invention provides isolated anti-human NKG2D monoclonal antibodies useful for therapeutic applications in humans. Typically, the antibodies are fully human or humanized to minimize the risk for immune responses against the antibodies when administered to a patient. Preferred antibodies include human monoclonal antibodies MS and 21F2. As described herein, other antigen-binding molecules such as, e.g., antigen-binding antibody fragments, antibody derivatives, and multi-specific molecules, can be designed or derived from such antibodies.

1 . An isolated human monoclonal antibody, or an antigen-binding fragment thereof, which binds human NKG2D (hNKG2D) and has one or more properties selected from
 (a) reducing hNKG2D-mediated activation of an hNKG2D-expressing NK or T cell;   (b) competing with MICA in binding to hNKG2D;   (c) reducing the amount of NKG2D on the surface of an NKG2D-expressing NK or T cell;   (d) when immobilized, does not significantly co-stimulate CD3-triggered proliferation of peripheral blood mononuclear cells (PBMCs);   (e) binding to cynomolgous and rhesus NKG2D; and   (f) binding to hNKG2D with a KD of 1 nM or less.   
     
     
         2 . The antibody or antigen-binding fragment of  claim 1 , which has properties (a) to (d), and, optionally, (e) and/or (f). 
     
     
         3 . An isolated monoclonal antibody, or an antigen-binding fragment thereof, which binds hNKG2D and cross-links no more than two hNKG2D dimers when added to NKG2D-expressing NK or T cells. 
     
     
         4 . The antibody or antigen-binding fragment of  claim 3 , which, when bound to a first hNKG2D monomer in an hNKG2D dimer, blocks binding of the antibody or antigen-binding fragment to the second hNKG2D monomer. 
     
     
         5 . The antibody or antigen-binding fragment of  claim 4 , for which the ratio of the solvent-exclusion areas on the first and second hNKG2D monomers in an hNKG2D dimer is about 2:1 or more. 
     
     
         6 . The antibody or antigen-binding fragment of  claim 1 , which is human or humanized. 
     
     
         7 . The antibody or antigen-binding fragment of  claim 1 , which competes with a reference antibody in binding to hNKG2D, wherein the reference antibody comprises:
 (a) a heavy-chain variable region comprising the sequence of SEQ ID NO:44 and a light-chain variable region comprising the sequence of SEQ ID NO:45; or   (b) a heavy-chain variable region comprising the sequence of SEQ ID NO:46 and a light-chain variable region comprising the sequence of SEQ ID NO:47.   
     
     
         8 . The antibody or antigen-binding fragment of  claim 1 , which binds to an epitope comprising Lys 150, Ser 151, Tyr 152, Thr 180, Ile 181, Ile 182, Glu 183, Met 184, Gln 185, Leu 191, Lys 197, Tyr 199, Glu 201, Thr 205, Pro 206, Asn 207, or Thr 208 of SEQ ID NO:2, or any combination thereof. 
     
     
         9 . The antibody or antigen-binding fragment of  claim 1 , comprising a paratope comprising a residue corresponding to Gln 1, Asp 26, Asp 27, Ser 30, Ser 31, Tyr 32, Tyr 33, His 50, Ser 52, Tyr 53, Ser 54, Ser 56, Ala 57, Asn 58, Trp 98 or Asp 99 of SEQ ID NO: 44 or Tyr 33 or Trp 97 of SEQ ID NO:45, or any combination thereof. 
     
     
         10 . The antibody or antigen-binding fragment of any of  claim 1 , comprising:
 (a) a heavy-chain variable region CDR1 comprising the sequence of SEQ ID NO:48;   (b) a heavy-chain variable region CDR2 comprising the sequence of SEQ ID NO:49; and   (c) a heavy-chain variable region CDR3 comprising the sequence of SEQ ID NO:50; and, optionally,   (d) a light-chain variable region CDR1 comprising the sequence of SEQ ID NO:51;   (e) a light-chain variable region CDR2 comprising the sequence of SEQ ID NO:52; and   (f) a light-chain variable region CDR3 comprising the sequence of SEQ ID NO:53.   
     
     
         11 . The antibody or antigen-binding fragment of  claim 1 , comprising:
 (a) a heavy-chain variable region CDR1 comprising the sequence of SEQ ID NO:54;   (b) a heavy-chain variable region CDR2 comprising the sequence of SEQ ID NO:55; and   (c) a heavy-chain variable region CDR3 comprising the sequence of SEQ ID NO:56; and, optionally,   (d) a light-chain variable region CDR1 comprising the sequence of SEQ ID NO:57;   (e) a light-chain variable region CDR2 comprising the sequence of SEQ ID NO:58; and   (f) a light-chain variable region CDR3 comprising the sequence of SEQ ID NO:59.   
     
     
         12 . The antibody or antigen-binding fragment of  claim 1 , which comprises:
 (a) a heavy-chain variable region comprising the sequence of SEQ ID NO:44 and a light-chain variable region comprising the sequence of SEQ ID NO:45; or   (b) a heavy-chain variable region comprising the sequence of SEQ ID NO:46 and a light-chain variable region comprising the sequence of SEQ ID NO:47.   
     
     
         13 . A method of producing an anti-NKG2D antibody, or an antigen-binding fragment thereof, comprising culturing a host cell comprising a nucleic acid encoding an antibody or antigen-binding fragment of  claim 1  under suitable conditions and recovering said antibody or antigen-binding fragment thereof. 
     
     
         14 . A method for treating an inflammatory or autoimmune disorder, comprising administering the antibody or antigen-binding fragment of  claim 1  to a human subject suffering from or at risk for an inflammatory or autoimmune disorder. 
     
     
         15 . The method of  claim 14 , wherein the inflammatory or autoimmune disorder is rheumatoid arthritis, multiple sclerosis, systemic lupus erythomatosus (SLE), psoriasis, celiac disease, ulcerative colitis, Crohn's disease, transplant rejection, or graft-versus-host disease.