EGFR is an attractive target for the treatment of a variety of solid tumors because of its role as a driver oncogene and high level of expression. Four EGFR-targeting agents, including two antibodies (Abs), have been approved for clinical use. Despite anti-tumor benefits, inhibition of EGFR pathway is associated with significant dermatologic toxicities; resistance to EGFR antagonists also develops.
To enhance potency with comparable or better tolerability, we developed IMGN289, an EGFR-targeting antibody-“drug” conjugate (ADC) that disrupts tumor growth both by inhibiting EGFR signaling and through direct anti-mitotic activity. To reduce potential dermatologic toxicities associated with EGFR pathway inhibition, a unique Ab discovery approach was employed. Hybridomas from mice immunized with EGFR-expressing tumor cells were screened for EGFR binding and selective inhibitory activity against EGFR-dependent tumor cells. This approach revealed a novel class of Ab with selective EGFR antagonistic activity. A humanized lead Ab was identified, J2898A, which was comparable in potency to cetuximab in vitro against a panel of EGFR-dependent tumor cell lines and in vivo against two head and neck tumor xenograft models. Notably, in cultures of human primary keratinocytes, this Ab was markedly less cytotoxic than cetuximab and did not affect TNFα-induced cytokine production, which has been implicated in chronic dermatologic toxicities induced by other anti-EGFR agents. To further enhance cytotoxic activity and to potentially overcome resistance to EGFR-targeting therapies, J2898A was conjugated to the maytansinoid DM1, a potent anti-tubulin agent, via a non-cleavable linker, SMCC. IMGN289 was not only more potent than J2898A against EGFR-dependent tumors, but also was effective against EGFR-positive tumor cells that grow independently of signaling via the EGFR pathway or have acquired resistance to EGFR inhibitors, including lung adenocarcinoma cell lines harboring the T790M EGFR mutation or MET gene amplification. Despite having potent activity against EGFR-expressing tumor cells, IMGN289 was less toxic to cultured keratinocytes than cetuximab. Moreover, a toxicology study in cynomolgus monkeys demonstrated that IMGN289 was well tolerated and exhibited a similar toxicity profile to that published for trastuzumab emtansine (T-DM1), another ADC which utilizes SMCC-DM1 as the selected linker-payload format.
In summary, IMGN289 combines EGFR inhibition mediated by its J2898A Ab component with the potent cytotoxicity provided by its DM1 payload, and is highly active against EGFR-positive tumors regardless of their dependency on the EGFR pathway. IMGN289 thus represents a promising novel candidate for treatment of EGFR-expressing solid tumors.
Citation Format: Yulius Y. Setiady, Peter U. Park, Jose F. Ponte, Ling Dong, Anna Skaletskaya, Jennifer A. Coccia, Erica Hong, Lauren Clancy, Lingyun Rui, Jan Pinkas, Robert J. Lutz, John M. Lambert, Thomas D. Chittenden. Development of a novel antibody-maytansinoid conjugate, IMGN289, for the treatment of EGFR-expressing solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5463. doi:10.1158/1538-7445.AM2013-5463