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 means to reduce on-target skin toxicity observed with enfortumab vedotin, an anti-nectin-4-MMAE ADC approved for patients with advanced urothelial cancer, 15A7.5, an anti-nectin-4 monoclonal antibody that exhibited differential nectin-4 binding between tumor 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 MonoMethyl Auristatin-E resistant xenograft model. ETx-22 has a highest non severely toxic dose of over 20 mg/kg in non-human primates without signs of important skin toxicity. ETx-22 represents a valuable therapy, for the treatment of patients with nectin-4 expressing tumors including those that have become resistant to enfortumab vedotin treatment.