Anti-kir antibodies for the treatment of inflammatory and autoimmune disorders

Abstract

This invention relates to compounds that inhibit KIR2DL1, 2 and/or 3 polypeptide comprising compounds (e.g., anti-KIR2DL1, 2, and/or 3 antibodies) that neutralize NK cell inhibitory receptors and methods of using such compounds and compositions containing in the treatment and prevention of inflammatory or autoimmune disorders.

1 - 106 . (canceled) 
     
     
         107 . A method for treating an immune-complex mediated autoimmune disorder comprising administering to an individual in need thereof an effective amount of an antibody or antigen-binding fragment thereof that potentiates the cytotoxic activity of NK cells by blocking or neutralizing the inhibition of NK cell activity mediated by a KIR2DL1, KIR2DL2, and/or KIR2DL3 polypeptide. 
     
     
         108 . The method of  claim 107 , wherein said method reduces the number of T cells involved in said autoimmune disorder. 
     
     
         109 . The method of  claim 107 , wherein the KIR2DL1, KIR2DL2, and/or KIR2DL3 polypeptide is/are expressed on NK cells. 
     
     
         110 . The method of  claim 108 , wherein said T cells include one or more of pro-inflammatory, activated and/or proliferating T cells, CD4+ T cells, infiltrating T cells, and/or T cells which expresses express HLA-cw3 and/or HLA-cw4. 
     
     
         111 . The method of  claim 108 , wherein said T cells exhibit one or more of the following properties: are in circulation; are comprised in a diseased or inflamed tissue; are infiltrating T cells; are T cells that have infiltrated into disease tissues; are comprised in synovial joint tissues or synovial fluid; and are comprised in the central nervous system, colon, or dermal tissue. 
     
     
         112 . The method of  claim 111 , wherein said infiltrating T cells include one or more of the following: cells that have infiltrated into disease tissues; cells that have infiltrated into synovial joint tissues or synovial fluid; and cells that have infiltrated into the central nervous system, colon, or dermal tissue. 
     
     
         113 . The method of  claim 107 , which further comprises evaluating the presence, stage and/or evolution of the autoimmune disorder in the individual by analyzing at least one of levels of autoantibodies, C-reactive protein (CRP), proteolytic enzyme, inflammatory mediator(s), and marker(s) of ongoing inflammation. 
     
     
         114 . The method of  claim 107 , wherein the individual is experiencing an attack, crisis, exacerbation or flare of an autoimmune disorder. 
     
     
         115 . The method of  claim 114 , wherein said attack, crisis, exacerbation, or flare of an autoimmune disorder is detected in the individual using a compound that detects a marker of an autoimmune reaction. 
     
     
         116 . The method of  claim 107 , wherein the autoimmune disorder is selected from chronic inflammatory farmer's lung, Henoch-Schonlein purpura, IgA polyarteritis nodosa, sensory post-streptococcal nephritis, reactive arthritis, subacute bacterial endocarditis (SBE), subacute cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), systemic lupus erythematodes, or cutaneous SLE. 
     
     
         117 . The method of  claim 107 , wherein said antibody or antigen-binding fragment thereof is a human antibody, a chimeric antibody, a humanized antibody, a single-chain antibody, a bifunctional antibody, or an antigen-binding fragment thereof. 
     
     
         118 . The method of  claim 107 , wherein said antibody or antigen-binding fragment thereof comprises:
 (a) a light chain variable (V L ) region comprising (i) a CDR1 having an amino acid sequence corresponding to residues 24-34 of SEQ ID NO: 1; a CDR2 amino acid sequence corresponding to residues 50-56 of SEQ ID NO: 1; and a CDR3 amino acid sequence corresponding to residues 89-97 of SEQ ID NO: 1; or (ii) a CDR1 having an amino acid sequence corresponding to residues 24-34 of SEQ ID NO: 3; a CDR2 amino acid sequence corresponding to residues 50-56 of SEQ ID NO: 3; and a CDR3 amino acid sequence corresponding to residues 89-97 of SEQ ID NO: 3; and/or   (b) a heavy chain variable (V H ) region comprising (i) a CDR1 having the amino acid sequence corresponding to residues 31-35 of SEQ ID NO: 2, a CDR2 having the amino acid sequence corresponding to residues 50-65 of SEQ ID NO: 2, and a CDR3 having the amino acid sequence corresponding to residues 99-112 of SEQ ID NO: 2, or (ii) a CDR1 having the amino acid sequence corresponding to residues 31-35 of SEQ ID NO: 4, a CDR2 having the amino acid sequence corresponding to residues 50-65 of SEQ ID NO: 4, and a CDR3 having the amino acid sequence corresponding to residues 99-112 of SEQ ID NO: 4; or   (c) a V L  region comprising amino acids having the sequence set forth in SEQ ID NO:1, 3, or 5 and/or a V H  region comprising amino acids having the sequence set forth in SEQ ID NO:2, 4, or 6; or   (d) a V L  region and a V H  region comprising (i) amino acids having the sequences set forth in SEQ ID NO:1 and SEQ ID NO:2, respectively, or (ii) amino acids having the sequences set forth in SEQ ID NO:3 and SEQ ID NO:4, respectively; or   (e) a light chain and a heavy chain comprising amino acids having the sequences set forth in SEQ ID NO:5 and SEQ ID NO:6, respectively.   
     
     
         119 . The method of  claim 107 , wherein said antibody or antigen-binding fragment thereof
 (a) binds to an epitope within a region of KIR2DL1, KIR2DL2 and KIR2DL3 having the amino acid sequence set forth in SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, or SEQ ID NO: 24;   (b) results in at least about 20% increase in NK cell-mediated specific lysis of NK target cells;   (c) competes with (i) an antibody comprising a light chain variable region having the amino acid sequence set forth in SEQ ID NO:1 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2, or (ii) an antibody deposited as CNCM I-3224, for binding to the same antigenic determinant region of human KIR2DL1, KIR2DL2 and/or KIR2DL3;   (d) cross-reacts with (i) KIR2DL1 and KIR2DL2/3, (ii) KIR3DL1 and KIR3DL2, (iii) KIR2DL1 and KIR2DL2/3 and KIR2DS4, or (iv) KIR2DL1 and KIR2DL2/3 but not KIR2DS4;   (e) binds to at least two different inhibitory KIR receptors expressed on the surface of NK cells;   (f) binds to a common antigenic determinant region of human KIR2DL receptors;   (g) binds to at least one of KIR2DL1 and/or KIR2DL2/3 and neutralizes KIR2DL1 and/or KIR2DL2/3-mediated inhibition of NK cell cytotoxicity; and/or   (h) is an IgG2 or IgG4 antibody.   
     
     
         120 . The method of  claim 107 , wherein said antibody or antigen-binding fragment thereof is an antibody deposited as CNCM I-3224. 
     
     
         121 . The method of  claim 107 , wherein the antibody or antigen-binding fragment thereof is administered as a monotherapy. 
     
     
         122 . The method of  claim 107 , wherein the antibody or antigen-binding fragment thereof is administered as a pharmaceutically acceptable composition comprising an effective amount of the antibody. 
     
     
         123 . The method of  claim 107 , wherein the antibody or antigen-binding fragment thereof is administered in an amount resulting in substantially complete saturation of the KIR2DL1, KIR2DL2 and/or KIR2DL3 polypeptide on NK cells for a period of at least about 1 week, 2 weeks, or 1 month. 
     
     
         124 . The method of  claim 107 , wherein the antibody or antigen-binding fragment thereof is administered several times at a dosing frequency selected from once about every 2 weeks, once about every 1 month, once about every 2 months, or once every period of more than 2 months.