Abstract C159: A human monoclonal antibody targeting the stem cell factor receptor (c-Kit) blocks tumor cell signaling and inhibits tumor growth.

Abstract

Abstract Stem cell factor receptor also known as c-Kit is a receptor tyrosine kinase that mediates cell growth, survival, and differentiation signals in response to its ligand stem cell factor (SCF). Aberrant c-Kit expression and/or activation through mutations or autocrine/paracrine signaling mechanisms occur in various malignancies and promote tumor development. Specific therapeutic targeting of c-Kit in cancer is warranted given its cancer role. In this study, we characterize the biological properties of CK6, a fully human IgG1 monoclonal antibody against the extracellular region of human c-Kit. CK6 specifically binds human c-Kit receptor with high affinity (EC50= 0.06nM) and strongly blocks its interaction with SCF (IC50= 0.41nM) in solid phase assays. Flow cytometry shows CK6 binding to the cell surface of small cell lung carcinoma (SCLC), melanoma, leukemia, and other human c-Kit expressing tumor cell lines. Furthermore, exposure to CK6 inhibits SCF stimulation of c-Kit tyrosine kinase activity and downstream signaling pathways in these tumor cell lines. Reduced levels of phosphorylated c-Kit, mitogen-activated protein kinase (MAPK) and protein kinase B/Akt were observed. Given these findings, we evaluated the antitumor growth efficacy of CK6 in several human xenograft tumor models in vivo. CK6 monotherapy treatment significantly suppressed tumor growth of NCI-H526 SCLC (T/C%= 50) and Malme-3M Melanoma (T/C%= 58) xenograft models. The combination of CK6 with standard of care (SOC) chemotherapy agents, cisplatin and etoposide for SCLC or dacarbazine for melanoma, led to enhanced tumor growth inhibition (SCLC T/C%= 12; melanoma T/C%= 38) compared to CK6 monotherapy or SOC 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 cancers harboring c-Kit receptor. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C159. Citation Format: Maria Lebron, Laura Brennan, Chris Damoci, Marie Prewett, Marina Starodubtseva, Michael Amatulli, Yiwei Zhang, Douglas Burtrum, Paul Balderes, Kris Persaud, David Surguladze, Nick Loizos, Keren Paz, Helen Kotanides. A human monoclonal antibody targeting the stem cell factor receptor (c-Kit) blocks tumor cell signaling and inhibits tumor growth. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C159.