A novel anti-c-Kit antibody-drug conjugate to treat wild-type and activating-mutant c-Kit-positive tumors.

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c‐Kit overexpression and activating mutations, which are reported in various cancers, including gastrointestinal stromal tumor (GIST), small‐cell lung cancer (SCLC), acute myeloid leukemia, acral melanoma, and systemic mastocytosis (SM), confer resistance to tyrosine kinase inhibitors (TKIs). To overcome TKI resistance, an anti‐c‐Kit antibody–drug conjugate was developed in this study to treat wild‐type and mutant c‐Kit‐positive cancers. NN2101, a fully human IgG1, was conjugated to DM1, a microtubule inhibitor, through N‐succinimidyl‐4‐(N‐maleimidomethyl) cyclohexane‐1‐carboxylate (SMCC) (to give NN2101‐DM1). The antitumor activity of NN2101‐DM1 was evaluated in vitro and in vivo using various cancer cell lines. NN2101‐DM1 exhibited potent growth‐inhibitory activities against c‐Kit‐positive cancer cell lines. In a mouse xenograft model, NN2101‐DM1 exhibited potent growth‐inhibitory activities against imatinib‐resistant GIST and SM cells. In addition, NN2101‐DM1 exhibited a significantly higher anti‐cancer effect than carboplatin/etoposide against SCLC cells where c‐Kit does not mediate cancer pathogenesis. Furthermore, the combination of NN2101‐DM1 with imatinib in imatinib‐sensitive GIST cells induced complete remission compared with treatment with NN2101‐DM1 or imatinib alone in mouse xenograft models. These results suggest that NN2101‐DM1 is a potential therapeutic agent for wild‐type and mutant c‐Kit‐positive cancers.