ANTI-KIT ANTIBODIES AND USES THEREOF
Provided herein, in one aspect, are antibodies that immunospecifically bind to a human KIT antigen comprising the fourth and/or fifth extracellular Ig-like domains (that is, D4 and/or D5 domains), polynucleotides comprising nucleotide sequences encoding such antibodies, and expression vectors and host cells for producing such antibodies. The antibodies can inhibit KIT activity, such as ligand-induced receptor phosphorylation. Also provided herein are kits and pharmaceutical compositions comprising antibodies that specifically bind to a KIT antigen, as well as methods of treating or managing a KIT-mediated disorder or disease and methods of diagnosing a KIT-mediated disorder or disease using the antibodies described herein.
1 . An antibody, which immunospecifically binds to a D4/D5 region of human KIT (SEQ ID NO: 15), comprising:
(i) a variable light (“VL”) chain region comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22, respectively; and
(ii) a variable heavy (“VH”) chain region comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25, respectively.
2 . The antibody of claim 1 , which comprises:
a VL chain region comprising the amino acid sequence of SEQ ID NO: 2, and a VH chain region comprising the amino acid sequence of SEQ ID NO: 3 or 5.
3 . The antibody of claim 1 , which comprises:
(i) a VL chain region comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22, respectively; and a VH chain region comprising the amino acid sequence of SEQ ID NO: 3 or 5; or
(ii) a VL chain region comprising the amino acid sequence of SEQ ID NO: 2; and a VH chain region comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25, respectively.
4 . An antibody, which immunospecifically binds to a D4/D5 region of human KIT (SEQ ID NO: 15), wherein said antibody competes for binding to the D4/D5 region of human KIT with, or binds to the same epitope as the epitope of, an antibody comprising a VL chain region comprising the amino acid sequence of SEQ ID NO: 2, and a VH chain region comprising the amino acid sequence of SEQ ID NO: 3 or 5.
5 . The antibody of 1, wherein the antibody further comprises a human light chain constant region and a human heavy chain constant region.
6 . The antibody of claim 1 , wherein the antibody is a humanized monoclonal antibody.
7 . The antibody of claim 1 , wherein the antibody is a monoclonal antibody.
8 . The antibody of claim 1 , wherein the antibody is an isolated antibody.
9 . The antibody of claim 1 , wherein the antibody has one or more of the following properties:
(i) inhibits KIT receptor phosphorylation;
(ii) does not block KIT ligand binding to KIT; and
(iii) is internalized by a cell expressing the KIT to which said antibody binds.
10 . A conjugate comprising the antibody of claim 1 linked to an agent.
11 . The conjugate of claim 10 , wherein the agent is a toxin.
12 . A pharmaceutical composition comprising the conjugate of claim 10 and a pharmaceutically acceptable carrier.
13 . A pharmaceutical composition comprising the antibody of claim 1 .
14 . An polynucleotide comprising nucleotide sequences encoding a VH chain region, a VL chain region, or both a VL chain region and a VH chain region, of an antibody of claim 1 .
15 . The polynucleotide of claim 14 , wherein the polynucleotide comprises nucleotide sequences encoding a VH chain region, a VL chain region, or both a VL chain region and a VH chain region, of an antibody which immunospecifically binds to a D4/D5 region of human KIT (SEQ ID NO: 15), wherein said polynucleotide comprises the nucleotide sequences of SEQ ID NO: 8 or 9, or SEQ ID NOs: 8 and 9.
16 . An expression vector comprising the polynucleotide of claim 14 .
17 . A host cell comprising one or more polynucleotides of claim 14 .
18 . A hybridoma cell producing the antibody of claim 1 .
19 . A method for treating or managing a KIT-mediated disorder or a symptom thereof, comprising administering to a subject in need thereof an effective amount of the antibody of claim 1 .
20 . A method for treating or managing a KIT-mediated disorder or a symptom thereof, comprising administering to a subject in need thereof an effective amount of the conjugate of claim 10 .
21 . The method of claim 19 or 20 , wherein the KIT-mediated disorder is cancer, an inflammatory condition, or fibrosis.
22 . The method of claim 21 , wherein the cancer is leukemia, chronic myelogenous leukemia, lung cancer, small cell lung cancer, sarcoma, or gastrointestinal stromal tumors.
23 . The method of claim 22 , wherein the method further comprises administering to the subject a second agent.
24 . The method of claim 23 , wherein the second agent is a chemotherapeutic agent, tyrosine kinase inhibitor, an antibody, or a cytokine.
25 . The method of claim 24 , wherein the tyrosine kinase inhibitor is imatinib mesylate or SU11248.
26 . The method of claim 23 , wherein the second agent is a histone deacetylase inhibitor.
27 . A method for diagnosing a subject with a KIT-mediated disorder comprising contacting cells or a sample obtained from the subject with the antibody of claim 1 , detecting binding of the antibody to KIT present on the cells or sample, and correlating the binding of the antibody to KIT with the expression level of KIT polypeptide of the cells or the sample.
28 . The method of claim 27 , wherein the KIT-mediated disorder is cancer, an inflammatory condition, or fibrosis.
29 . A method for inhibiting KIT activity of a cell expressing KIT comprising contacting the cell with an effective amount of the antibody of claim 1 .
30 . A method for inducing or enhancing apoptosis, or for inhibiting cell proliferation, in a cell expressing KIT comprising contacting the cell with the antibody of claim 1 .
31 . A method of making an antibody which immunospecifically binds to a D4/D5 region of human KIT (SEQ ID NO: 15) comprising culturing the cell of claim 17 .
32 . A method of making an antibody which immunospecifically binds to a D4/D5 region of human KIT (SEQ ID NO: 15) comprising culturing the cell of claim 18 .
33 . The method claim 32 further comprising the step of obtaining the antibody from said cell.