HUMAN ANTI-KIR ANTIBODIES
Compositions and methods for regulating an immune response in a subject are described. More particularly, described are human antibodies that regulate the activity of NK cells and allow a potentiation of NK cell cytotoxicity in mammalian subjects, and antibodies having antigen-binding properties similar to those of human monoclonal antibody 1-7F9 or 1-4F1. Described also are also fragments and derivatives of such antibodies, as well as pharmaceutical compositions comprising the same and their uses, particularly for use in therapy, to increase NK cell activity or cytotoxicity in subjects.
1 - 50 . (canceled)
51 . A method of potentiating natural killer (NK) cell activity in a subject comprising administering to the subject a therapeutically effective amount of an isolated antibody that binds to a Killer Immunoglobulin-Like Receptor (KIR), or an antigen-binding fragment thereof, said antibody comprising: (i) a heavy chain CDR1 having the amino acid sequence corresponding to residues 31-35 of SEQ ID NO:17; (ii) a heavy chain CDR2 having the amino acid sequence corresponding to residues 50-65 of SEQ ID NO:17; (iii) a heavy chain CDR3 having the amino acid sequence corresponding to residues 99-112 of SEQ ID NO:17; (iv) a light chain CDR1 having the amino acid sequence corresponding to residues 24-34 of SEQ ID NO:15; (v) a light chain CDR2 having the amino acid sequence corresponding to residues 50-56 of SEQ ID NO:15; and (vi) a light chain CDR3 having the amino acid sequence corresponding to residues 89-97 or SEQ ID NO:15.
52 . The method of claim 51 , wherein the antibody or antigen-binding fragment comprises a light chain variable (V L ) region having the amino acid sequence set forth in SEQ ID NO: 15 and a heavy chain variable (V H ) region having the amino acid sequence set forth in SEQ ID NO: 17.
53 . The method of claim 52 , wherein the isolated antibody or antigen-binding fragment binds to each one of human KIR2DL1, human KIR2DL2, and human KIR2DL3, but does not bind to human KIR2DS4.
54 . The method of claim 52 , wherein the isolated antibody or antigen-binding fragment further does not bind to human KIR2DS3.
55 . The method of claim 51 , wherein the isolated antibody or antigen-binding fragment has a dissociation constant (Kd) for human KIR2DL3 of no more than about 0.025 nM and/or a dissociation constant (Kd) for human KIR2DL1 of no more than about 0.45 nM.
56 . The method of claim 51 , wherein the isolated antibody or antigen-binding fragment reduces, neutralizes or reverses inhibition of NK cell cytotoxicity mediated by human KIR2DL1, human KIR2DL2, and/or human KIR2DL3.
57 . The method of claim 51 , wherein the isolated antibody or antigen-binding fragment reduces, neutralizes or reverses inhibition of NK cell cytotoxicity mediated by human KIR2DL1, human KIR2DL2, and human KIR2DL3.
58 . The method of claim 51 , wherein the isolated antibody or antigen-binding fragment blocks the binding of at least one of human KIR2DL1, human KIR2DL2, and human KIR2DL3 to a human HLA-C class I molecule.
59 . The method of claim 56 , wherein the isolated antibody or antigen binding fragment blocks (i) the binding of a human HLA-Cw4 molecule to human KIR2DL1 and (ii) the binding of a human HLA-Cw3 molecule to at least one of human KIR2DL2 and human KIR2DL3.
60 . The method of claim 51 , wherein the isolated antibody or antigen-binding fragment thereof is an IgG4 antibody, a monoclonal antibody and/or a human antibody, a humanized antibody or a chimeric antibody or antigen-binding fragment thereof.
61 . A method of treating cancer, infectious disease or immune disease in a subject comprising administering to the subject a therapeutically effective amount of an isolated antibody that binds to a Killer Immunoglobulin-Like Receptor (KIR), or an antigen-binding fragment thereof, said antibody comprising: (i) a heavy chain CDR1 having the amino acid sequence corresponding to residues 31-35 of SEQ ID NO:17; (ii) a heavy chain CDR2 having the amino acid sequence corresponding to residues 50-65 of SEQ ID NO:17; (iii) a heavy chain CDR3 having the amino acid sequence corresponding to residues 99-112 of SEQ ID NO:17; (iv) a light chain CDR1 having the amino acid sequence corresponding to residues 24-34 of SEQ ID NO:15; (v) a light chain CDR2 having the amino acid sequence corresponding to residues 50-56 of SEQ ID NO:15; and (vi) a light chain CDR3 having the amino acid sequence corresponding to residues 89-97 or SEQ ID NO:15.
62 . The method of claim 61 , wherein the antibody or antigen-binding fragment comprises a light chain variable (V L ) region having the amino acid sequence set forth in SEQ ID NO: 15 and a heavy chain variable (V H ) region having the amino acid sequence set forth in SEQ ID NO: 17.
63 . The method of claim 62 , wherein the isolated antibody or antigen-binding fragment binds to each one of human KIR2DL1, human KIR2DL2, and human KIR2DL3, but which does not bind to human KIR2DS4.
64 . The method of claim 63 , wherein the isolated antibody or antigen binding fragment further does not bind to human KIR2DS3.
65 . The method of claim 61 , wherein the isolated antibody or antigen-binding fragment has a dissociation constant (Kd) for human KIR2DL3 of no more than about 0.025 nM and/or a dissociation constant (Kd) for human KIR2DL1 of no more than about 0.45 nM.
66 . The method of claim 61 , wherein the isolated antibody or antigen-binding fragment reduces, neutralizes or reverses inhibition of NK cell cytotoxicity mediated by human KIR2DL1, human KIR2DL2, and/or human KIR2DL3.
67 . The method of claim 61 , wherein the isolated antibody or antigen-binding fragment reduces, neutralizes or reverses inhibition of NK cell cytotoxicity mediated by human KIR2DL1, human KIR2DL2, and human KIR2DL3.
68 . The method of claim 61 , wherein the isolated antibody or antigen-binding fragment blocks the binding of at least one of human KIR2DL1, human KIR2DL2, and human KIR2DL3 to a human HLA-C class I molecule.
69 . The method of claim 61 , wherein the isolated antibody or antigen-binding fragment thereof is an IgG4 antibody, a monoclonal antibody and/or a human antibody, a humanized antibody or a chimeric antibody or antigen-binding fragment thereof.
70 . An isolated antibody or an antigen-binding fragment thereof that binds to each one of human Killer Immunoglobulin-Like Receptor (KIR)2DL1, human KIR2DL2, and human KIR2DL3, but which does not bind human KIR2DS4 or human KIR2DS3.