title: A human monoclonal antibody targeting the stem cell factor receptor (c-Kit) blocks tumor cell signaling and inhibits tumor growth.
abstract: Stem cell factor receptor (c-Kit) exerts multiple biological effects on target cells upon binding its ligand stem cell factor (SCF). Aberrant activation of c-Kit results in dysregulated signaling and is implicated in the pathogenesis of numerous cancers. The development of more specific and effective c-Kit therapies is warranted given its essential role in tumorigenesis. In this study, we describe the biological properties of CK6, a fully human IgG1 monoclonal antibody against the extracellular region of human c-Kit. CK6 specifically binds c-Kit receptor with high affinity (EC 50 = 0.06 nM) and strongly blocks its interaction with SCF (IC 50 = 0.41 nM) in solid phase assays. Flow cytometry shows CK6 binding to c-Kit on the cell surface of human small cell lung carcinoma (SCLC), melanoma, and leukemia tumor cell lines. Furthermore, exposure to CK6 inhibits SCF stimulation of c-Kit tyrosine kinase activity and downstream signaling pathways such as mitogen-activated protein kinase (MAPK) and protein kinase B (AKT), in addition to reducing tumor cell line growth in vitro. CK6 treatment significantly decreases human xenograft tumor growth in NCI-H526 SCLC (T/C% = 57) and Malme-3M melanoma (T/C% = 58) models in vivo. The combination of CK6 with standard of care chemotherapy agents, cisplatin and etoposide for SCLC or dacarbazine for melanoma, more potently reduces tumor growth (SCLC T/C% = 24, melanoma T/C% = 38) compared with CK6 or chemotherapy alone. In summary, our results demonstrate that CK6 is a c-Kit antagonist antibody with tumor growth neutralizing properties and are highly suggestive of potential therapeutic application in treating human malignancies harboring c-Kit receptor.
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Lebron
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Brennan
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Damoci
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: Marie C
authors.initials: MC
authors.lastname: Prewett
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: Marguerita
authors.initials: M
authors.lastname: O'Mahony
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: Inga J
authors.initials: IJ
authors.lastname: Duignan
authors.affiliation: Eli Lilly and Company; Indianapolis, IN USA.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Credille
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: James T
authors.initials: JT
authors.lastname: DeLigio
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Starodubtseva
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Amatulli
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: Kaben D
authors.initials: KD
authors.lastname: Schwartz
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Burtrum
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Balderes
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: Kris
authors.initials: K
authors.lastname: Persaud
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: David
authors.initials: D
authors.lastname: Surguladze
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Loizos
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: Keren
authors.initials: K
authors.lastname: Paz
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company; New York, NY USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Kotanides
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D003606:Dacarbazine / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D064593:Heterografts; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D005047:Etoposide; D003606:Dacarbazine; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D002945:Cisplatin
keywords: c-Kit; monoclonal antibody; targeted therapy; tumor cell signaling; tumor growth