Screening and Functional Analysis of TEK Mutations in Chinese Children With Primary Congenital Glaucoma.

Overexpression and gain-of-function mutations of c-Kit have been implicated in cancers including gastrointestinal stromal tumors, small cell lung cancer, acute myeloid leukemia, and systemic mastocytosis. In clinics, small-molecule c-Kit inhibitors often result in secondary c-Kit mutations or are ineffective despite c-Kit overexpression. We developed NN3201, a novel c-Kit-targeting antibody-drug conjugate, via rational design to evaluate its anticancer activity in c-Kit-positive tumors and preclinical pharmacologic profiles. A fully human c-Kit antibody NN2101 was conjugated to monomethyl auristatin E with a Drug-to-Antibody Ratio (DAR) of 4 utilizing a ThioBridge linker to generate NN3201. Antitumor efficacies of NN3201 were evaluated in c-Kit-positive cancer cell lines, cell line-derived xenografts, and patient-derived xenografts. NN3201 selectively binds to c-Kit and is rapidly internalized. By its design, NN3201 exhibits no antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity and possessed decreased binding to FcγRs. Inhibition of stem cell factor/c-Kit downstream signaling pathways, cell-cycle arrest, and bystander effect were demonstrated as mechanisms of action for NN3201. In xenograft models, NN3201 showed superior efficacy regardless of c-Kit mutations. Repeated intravenous administration of NN3201 was well tolerated in cynomolgus monkeys, confirming the no observed adverse effect level of NN3201 to be 2 mg/kg and the highest nonseverely toxic dose to be >2 mg/kg. NN3201 exhibited significant c-Kit-dependent antitumor efficacies in various tumor models, followed by favorable pharmacokinetic and toxicity profiles in cynomolgus monkeys. These data suggest that NN3201 is a promising therapeutic in small cell lung cancer and gastrointestinal stromal tumors and warrant evaluation in a phase I clinical study.