Abstract B129: DUP5, a novel mRNA translation inhibitor as a payload for antibody drug conjugates, exhibits promising preclinical efficacy

Abstract Introduction: Currently majority of clinical stage antibody-drug conjugates (ADCs) are based on payloads with either tubulin inhibitors or topoisomerase I inhibitors. There is unmet medical need for ADCs with novel mechanisms of action to treat patients with primary or acquired resistance to existing ADC molecules. Duality Unique Payload 5 (DUP5) is a proprietary inhibitor of mRNA translation by selectively inhibiting eukaryotic initiation factor-4A (eIF4A). eIF4A is an ATP-dependent RNA helicase, and is critical for regulating cap-dependent protein synthesis. The DUP5 payload displayed potent activity in vitro against a panel of solid tumor cell lines. DUP5 ADCs showed promising anti-tumor activity in various preclinical models. Methods: Proprietary eIF4A inhibitor was conjugated to a series of antibodies targeting various targets (Her2, EGFR, GPC3, BCMA, etc) to generate ADCs (with DAR of 8). These ADCs were tested in vitro in cell killing studies and in vivo in xenograft models, and compared with ADCs conjugated with deruxtecan (Dxd). Results: DUP5 ADCs exhibited partial or complete tumor regression in vivo in xenograft models of solid tumors, including those poorly responsive to Dxd ADCs. Mechanism studies showed that DUP5 payload suppressed the translation of oncogenic proteins. DUP5 ADCs showed bystander effect, which also contributed to the potent antitumor activity of DUP5 ADCs. Conclusions: DUP5 payload demonstrated unique anti-cancer activity through inhibition of onco-protein translation. Based on the novel mechanism, DUP5 ADCs exhibit promising therapeutic efficacy in preclinical models. Citation Format: Shengchao Lin, Bing Li, Yu Zhang, Jun Yao, Liwen Liang, Yang Xu, Rong Shi, Zhongyuan Zhu, Yang Qiu, Haiqing Hua. DUP5, a novel mRNA translation inhibitor as a payload for antibody drug conjugates, exhibits promising preclinical efficacy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B129.