Methods of treating by administering anti-kit antibodies
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. A method for treating or managing a KIT-mediated disorder, wherein the KIT-mediated disorder is associated with KIT expression and/or activity, the method comprising administering to a subject in need thereof a therapeutically effective amount of an antibody or an antigen-binding fragment thereof, which immunospecifically binds to human KIT and comprises:
(i) a variable light (“VL”) chain region comprising a VL CDR1, VL CDR2, and VL CDR3 comprising 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 comprising the amino acid sequences of SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25, respectively.
2. A method for treating or managing a KIT-mediated disorder, wherein the KIT-mediated disorder is associated with KIT expression and/or activity, the method comprising administering to a subject in need thereof a therapeutically effective amount of a conjugate comprising an antibody or an antigen-binding fragment thereof, which immunospecifically binds to human KIT and comprises:
(i) a VL chain region comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22, respectively; and
(ii) a VH chain region comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25, respectively,
which antibody or antigen-binding fragment thereof is linked to a therapeutic agent.
3. The method of claim 1 , wherein the KIT-mediated disorder is cancer, an inflammatory condition, or fibrosis.
4. A method for inhibiting KIT activity in a cell expressing KIT comprising contacting the cell with an effective amount of an antibody or an antigen-binding fragment thereof, which immunospecifically binds to human KIT and comprises:
(i) a VL chain region comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22, respectively; and
(ii) a VH chain region comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25, respectively.
5. A method for inducing or enhancing apoptosis in a cell expressing KIT comprising contacting the cell with an effective amount of an antibody or an antigen-binding fragment thereof, which immunospecifically binds to human KIT and comprises:
(i) a VL chain region comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22, respectively; and
(ii) a VH chain region comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25, respectively.
6. A method for inducing cell differentiation comprising contacting a cell expressing KIT with an effective amount of an antibody or an antigen-binding fragment thereof, which immunospecifically binds to human KIT and comprises:
(i) a VL chain region comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22, respectively; and
(ii) a VH chain region comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25, respectively.
7. The method of claim 2 , wherein the KIT-mediated disorder is cancer, an inflammatory condition, or fibrosis.
8. The method of claim 3 , wherein the cancer is leukemia, chronic myelogenous leukemia, lung cancer, small cell lung cancer, or gastrointestinal stromal tumors.
9. The method of claim 7 , wherein the cancer is leukemia, chronic myelogenous leukemia, lung cancer, small cell lung cancer, or gastrointestinal stromal tumors.
10. The method of claim 3 , wherein the cancer is refractory to treatment by a tyrosine kinase inhibitor.
11. The method of claim 7 , wherein the cancer is refractory to treatment by a tyrosine kinase inhibitor.
12. The method of claim 10 , wherein the tyrosine kinase inhibitor is imatinib mesylate or SU11248.
13. The method of claim 11 , wherein the tyrosine kinase inhibitor is imatinib mesylate or SU11248.
14. The method of claim 1 , wherein the method further comprises administering a second therapeutic agent.
15. The method of claim 2 , wherein the method further comprises administering a second therapeutic agent.
16. The method of claim 14 , wherein the second therapeutic agent is a chemotherapeutic agent, tyrosine kinase inhibitor, an antibody, or a cytokine.
17. The method of claim 15 , wherein the second therapeutic agent is a chemotherapeutic agent, tyrosine kinase inhibitor, an antibody, or a cytokine.
18. The method of claim 16 , wherein the tyrosine kinase inhibitor is imatinib mesylate or SU11248.
19. The method of claim 17 , wherein the tyrosine kinase inhibitor is imatinib mesylate or SU11248.
20. The method of claim 6 , wherein the cell is a stem cell.
21. The method of claim 1 , wherein the KIT-mediated disorder is systemic mast cell disorder.
22. The method of claim 2 , wherein the KIT-mediated disorder is systemic mast cell disorder.