Preclinical Antitumor Activity of a Novel Anti–c-KIT Antibody–Drug Conjugate against Mutant and Wild-type c-KIT–Positive Solid Tumors

Purpose: c-KIT overexpression is well-recognized in cancers such as GIST, SCLC, melanoma, NSCLC and AML. Treatment with the small molecule inhibitors imatinib, sunitinib and regorafenib result in resistance (c-KIT mutant tumors) or limited activity (c-KIT wildtype tumors). We selected an anti-c-KIT ADC approach to evaluate the anti-cancer activity in multiple disease models. Experimental Design: A humanized anti-c-KIT antibody LMJ729 was conjugated to the microtubule destabilizing maytansinoid, DM1, via a non-cleavable linker (SMCC). The activity of the resulting ADC, LOP628, was evaluated in vitro against GIST, SCLC and AML models and in vivo against GIST and SCLC models. Results: LOP628 exhibited potent anti-proliferative activity on c-KIT positive cell lines whereas LMJ729 displayed little to no effect. At exposures predicted to be clinically achievable, LOP628 demonstrated single administration regressions or stasis in GIST and SCLC xenograft models in mice. LOP628 also displayed superior efficacy in an imatinib-resistant GIST model. Further, LOP628 was well-tolerated in monkeys with an adequate therapeutic index several fold above efficacious exposures. Safety findings were consistent with the pharmacodynamic effect of neutropenia due to c-KIT-directed targeting. Additional toxicities were considered off-target and were consistent with DM1, such as effects in the liver and hematopoietic/lymphatic system. Conclusions:The preclinical findings suggest that the c-KIT directed ADC may be a promising therapeutic for the treatment of mutant and wildtype c-KIT positive cancers and supported the clinical evaluation of LOP628 in GIST, AML and SCLC patients.