A Dual-Payload Bispecific ADC Improved Potency and Efficacy over Single-Payload Bispecific ADCs

Background/Objectives: All current FDA-approved antibody–drug conjugates (ADCs) are single-target and single-payload molecules that have limited efficacy in patients due to drug resistance. Therefore, our goal was to generate a novel ADC that was less susceptible to single points of resistance to reduce the likelihood of patient relapse. Methods: We developed a dual-targeting, dual-payload ADC by conjugating a bispecific EGFR x cMET antibody to two payloads (MMAF and SN38) that had separate mechanisms of action using a novel tri-functional linker. This dual-payload ADC was tested for potency and efficacy in dividing and nondividing in vitro cell models using multiple tumor cell types. Efficacy of the dual-payload ADC was confirmed using in vivo models. Results: Our ADC with dual MMAF and SN38 payloads was more efficacious in inhibiting cell proliferation than single-payload ADCs across multiple cancer cell lines. In addition, the dual-payload molecule inhibited nondividing cells, which were more resistant to traditional ADC payloads. The dual-payload ADC also exhibited more potent tumor growth inhibition in vivo compared to that of single-payload ADCs. Conclusions: Overall, the bispecific antibody conjugated with both the MMAF and SN38 payloads inhibited tumor growth more strongly than ADCs conjugated with MMAF or SN38 alone. Developing dual-payload ADCs could limit the impact of acquired resistance in patients as well as lower the effective dose of each payload.