Abstract B130: DUP9, a novel ecteinascidin derivative, as a payload for antibody drug conjugates, exhibits promising preclinical efficacy

Abstract Introduction: Deruxtecan (DXd)-based antibody drug conjugates (ADCs) have demonstrated remarkable efficacy across a range of cancers in preclinical and clinical studies. However, challenges remain, including intrinsic resistance arises from low or heterogeneous expression of target antigens, or acquired resistance develops after treatment with Dxd-based ADCs. Therefore, ADCs with novel mechanisms of action are needed to circumstance the clinical challenges. In the present study, a proprietary ecteinascidin derivative is developed as a payload named Duality Unique Payload 9 (DUP9). DUP9 is a DNA minor groove binder. It causes DNA adducts formation and inhibition of gene transcription by stalling RNA polymerase II, which ultimately leads to double-strand DNA breaks and cell death. DUP9 ADCs showed potent activity in preclinical models, both in vitro and in vivo. Methods: DUP9 was conjugated to a series of antibodies targeting various targets (EGFR, DLL3, etc) to generate ADCs with a cleavable liner. These ADCs were investigated in vitro in cell killing studies and in vivo in xenograft models, and compared with Dxd-based ADCs. Results: DUP9 ADCs showed potent activity against a broad range of cancer cell models, and displayed similar potency as Dxd-based ADCs. In vivo, DUP9 ADCs exhibited partial or complete tumor regression in various xenografts, including those with low antigen expression and those poorly responsive to Dxd-based ADCs. Bystander effect contributed to the strong antitumor activity of DUP9 ADC. Conclusions: DUP9 ADC exhibits promising therapeutic efficacy in preclinical models. With the novel mechanism of action, which is distinct from existing clinical ADC molecules, DUP9 ADC hold promise to address unmet medical needs in oncology. Citation Format: Shengchao Lin, Lei Yi, Yu Zhang, Jun Yao, Liwen Liang, Min Zhao, Rong Shi, Zhongyuan Zhu, Yang Qiu, Haiqing Hua. DUP9, a novel ecteinascidin derivative, 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 B130.