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 monoclonal antibody or antigen-binding fragment thereof that binds to human Killer Immunoglobulin-Like Receptor (KIR) 2DL1, human KIR2DL2, and human KIR2DL3, but does not bind to human KIR2DS4.
52 . The monoclonal antibody or antigen-binding fragment of claim 51 , wherein the antibody or antigen-binding fragment does not bind to KIR2DS3.
53 . The monoclonal antibody or antigen-binding fragment of claim 51 , wherein the antibody or antigen-binding fragment reduces, neutralizes or reverses inhibition of NK cell cytotoxicity mediated by human KIR2DL1, human KIR2DL2, and human KIR2DL3.
54 . The monoclonal antibody or antigen-binding fragment of claim 51 , wherein the antibody or antigen-binding fragment blocks the binding of at least one of human KIR2DL1, human KIR2DL2 and human KIR2DL3 to a human leukocyte antigen (HLA)-C class I molecule.
55 . The monoclonal antibody or antigen-binding fragment of claim 51 , wherein the antibody or antigen-binding fragment blocks (i) the binding of an HLA-Cw4 molecule to human KIR2DL1, and (ii) the binding of an HLA-Cw3 molecule to at least one of human KIR2DL2 and human KIR2DL3.
56 . The monoclonal antibody or antigen-binding fragment of claim 51 , wherein the antibody or antigen-binding fragment potentiates the lytic activity of an NK cell against a human target cell expressing an HLA-C class I molecule.
57 . The monoclonal antibody or antigen-binding fragment of claim 51 , wherein the antibody or antigen-binding fragment competes for binding to human KIR2DL1, human KIR2DL2 and/or human KIR2DL3 with an antibody comprising a light chain variable (VL) region having the amino acid sequence set forth in SEQ ID NO: 15 and a heavy chain variable (VH) region having the amino acid sequence set forth in SEQ ID NO: 17.
58 . The monoclonal antibody or antigen-binding fragment of claim 51 , wherein the antibody or antigen-binding fragment comprises a light chain variable (VL) region having the amino acid sequence set forth in SEQ ID NO: 15 and/or a heavy chain variable (VH) region having the amino acid sequence set forth in SEQ ID NO: 17.
59 . The monoclonal antibody or antigen-binding fragment of claim 51 , wherein the 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.
60 . The monoclonal antibody or antigen-binding fragment of claim 51 , wherein the antibody or antigen-binding fragment is an IgG1, IgG2, IgG3, or IgG4 antibody.
61 . The monoclonal antibody or antigen-binding fragment of claim 51 , wherein the antibody or antigen-binding fragment is a human antibody, a humanized antibody, a chimeric antibody, or an antigen-binding fragment thereof.
62 . The monoclonal antibody or antigen-binding fragment of claim 51 , wherein the antibody or antigen-binding fragment binds to a human KIR2DL1 epitope that comprises the amino acid residues L38, R41, M44, F45, N46, D47, T48, L49, R50, I52, F64, D72, Y80, P87, and Y88 in the extracellular region of KIR2DL1 having the sequence shown as SEQ ID NO:23.
63 . The monoclonal antibody or antigen-binding fragment of claim 51 , wherein the antibody or antigen-binding fragment binds to a human KIR2DL1 epitope that comprises the amino acid residues M44, F45, and D72 in the extracellular region of KIR2DL1 having the sequence shown as SEQ ID NO:23 and blocks the binding of an HLA-Cw4 molecule to human KIR2DL1.
64 . A nucleic acid encoding the monoclonal antibody or antigen-binding fragment of claim 51 .
65 . A vector comprising the nucleic acid of claim 64 .
66 . A cell comprising the vector of claim 65 .
67 . A method of producing a monoclonal antibody or antigen-binding fragment thereof that binds to human KIR2DL1, human KIR2DL2, and human KIR2DL3, but does not bind to human KIR2DS4, comprising culturing the cell of claim 66 under conditions suitable for expression of the antibody or antigen-binding fragment.
68 . A pharmaceutical composition comprising the monoclonal antibody or antigen-binding fragment of claim 51 in an amount effective to detectably potentiate NK cell cytotoxicity in a patient and a pharmaceutically effective carrier or excipient.
69 . A method of potentiating natural killer (NK) cell activity in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the monoclonal antibody or antigen-binding fragment of claim 51 .
70 . A method of treating cancer, infectious disease, or immune disease in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the monoclonal antibody or antigen-binding fragment of claim 51 .