ETx-22, a Novel Nectin-4–Directed Antibody–Drug Conjugate, Demonstrates Safety and Potent Antitumor Activity in Low-Nectin-4–Expressing Tumors

Abstract

Nectin-4 is a cell adhesion molecule expressed at various levels in many solid tumors, including urothelial cancer. As a means to reduce on-target skin toxicity observed with enfortumab vedotin (EV), an anti–nectin-4–monomethyl auristatin E (MMAE) antibody–drug conjugate (ADC) approved for patients with advanced urothelial cancer, 15A7.5, an anti–nectin-4 mAb that exhibited differential nectin-4–binding between tumors and primary keratinocytes, was selected for the development of ETx-22. Exatecan, a topoisomerase I inhibitor, was chosen as payload. ETx-22 ADC induced rapid and long-lasting tumor regression in various patient-derived xenograft models expressing low to high levels of nectin-4 and also in a monomethyl auristatin E–resistant xenograft model. ETx-22 has a highest nonseverely toxic dose of more than 20 mg/kg in nonhuman primates (NHP) without signs of significant skin toxicity. ETx-22 represents a valuable therapy for the treatment of patients with nectin-4–expressing tumors, including those that are resistant to EV treatment.