Abstract 1695: Development of a novel antibody-drug conjugate for the treatment of c-Kit expressing solid tumors and AML
Authors: Abrams Tinya J. , Niu Xiaohong , Embry Millicent , Kline Janine , Patawaran Montesa , Fanton Christie , Ison-Dugenny Marjorie , Schneider Tracy , Miller Kathy , Wang Zhen , Ghoddusi Majid , Cohen Steven , Hong E. Erica , Lees Emma , Schleyer Siew 
Published: August 2015

c-Kit is an attractive target for the treatment of a variety of solid tumors [gastrointestinal tumors (GIST), small cell lung cancer (SCLC), melanoma] and acute myelogenous leukemia (AML) due to its role as an oncogenic driver and high level of expression. Several targeted therapies, such as imatinib, sunitinib and regorafenib, bind to c-Kit and are approved for clinical use. However, due to their insufficient activity on cancers expressing wildtype c-Kit or insensitive forms of mutant c-Kit, the clinical response has been quite varied. Moreover, despite initial anti-cancer benefits in c-Kit mutant settings (such as in GIST), resistance to c-Kit inhibitor therapies emerges due primarily to the development of additional mutations in c-Kit.

In an attempt to broaden the treatment of patients whose cancers express c-Kit (wildtype and mutant) and to enhance potency with comparable or better tolerability than the current therapeutics, we developed a c-Kit-targeting antibody-drug conjugate (ADC) that disrupts tumor growth through anti-mitotic activity. Hybridomas from mice immunized with the c-Kit extracellular domain (ECD) were screened for selective c-Kit binding and degradation. A humanized lead antibody (Ab) was identified, which rapidly internalized upon binding cell-surface c-Kit, but did not block binding to the c-Kit ligand (SCF). The Ab exhibited minimal-to-no cytotoxicity against c-Kit+ cell lines in vitro. To generate cytotoxic activity and to potentially overcome resistance to current c-Kit-targeting therapies, the Ab was conjugated to the maytansinoid DM1, a powerful anti-tubulin agent, via a non-cleavable linker, SMCC (technology licensed from ImmunoGen, Inc.). The ADC demonstrated robust anti-proliferative activity against cell lines expressing mutant c-Kit (GIST) and wildtype c-Kit (SCLC, AML) in vitro. The ADC also demonstrated potent anti-cancer activity in GIST and SCLC tumor xenograft models in vivo.

In summary, the anti-c-Kit ADC is highly selective and active against cancers with elevated c-Kit expression regardless of their mutational status, thus representing a promising novel therapeutic approach for the treatment of c-Kit+ solid tumors, such as GIST and SCLC, as well as hematological malignancies such as AML and aggressive systemic mastocytosis (ASM).

Citation Format: Tinya J. Abrams, Xiaohong Niu, Millicent Embry, Janine Kline, Montesa Patawaran, Christie Fanton, Marjorie Ison-Dugenny, Tracy Schneider, Kathy Miller, Zhen Wang, Majid Ghoddusi, Steven Cohen, E. Erica Hong, Emma Lees, Siew Schleyer. Development of a novel antibody-drug conjugate for the treatment of c-Kit expressing solid tumors and AML. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1695. doi:10.1158/1538-7445.AM2015-1695