Development of DHES0815A; a novel HER2-directed antibody-drug conjugate comprised of a reduced potency mono-alkylating agent linked to a domain I binding HER2 antibody

Abstract Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a novel HER2 ADC, we selected an antibody that does not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents that alkylate and cross-link DNA. We modified the PBD dimer to alkylate, but not cross-link DNA. This HER2 ADC, DHES0815A, demonstrated in vivo efficacy in models of HER2-positive and HER2-low cancers and was well-tolerated in cynomolgus monkey safety studies. Mechanisms of action include induction of DNA damage and apoptosis, activity in non-dividing cells, and bystander activity. A dose-escalation study in patients with HER2-positive metastatic breast cancer showed early signs of anti-tumor activity with limited toxicity. However, delayed dermal, ocular and pulmonary toxicities developed. The delayed onset, as well as non-resolvable nature of the toxicities resulted in termination of the phase 1 trial.