Abstract 5733: Design and synthesis of the novel camptothecin analog MF-6 for application into site-specific antibody-drug conjugate

Abstract Introduction: Antibody-drug conjugates (ADCs) have emerged as a revolutionary breakthrough in cancer treatment by precisely targeting tumor cells with high-potency payloads attached to specific antibodies. However, the efficacy and safety of ADCs largely depend on the design and optimization of their payloads. This study leverages the advanced MtoxinTm platform to develop a novel ADC payload, MF6, aiming to enhance the antitumor activity of ADCs through precise drug design. Methods: Supported by the MtoxinTm platform, we first modified camptothecin-based compounds by preparing a series of camptothecin analogs with different substituents at the core position. Through in vitro efficacy testing, we screened out a series of compounds with significant antitumor activity and further optimized their attached dipeptide linkers. Subsequently, we conjugated the optimized drug-linker conjugates with anti-Trop2 and anti-B7H3 monoclonal antibodies to form novel ADCs. To comprehensively evaluate the potential of these ADCs, we conducted multiple experiments in vitro and in vivo, including pharmacodynamics, pharmacokinetics, safety, and antitumor activity studies. Results: The experimental results showed that MF6, as a free molecule, exhibited good drug-killing activity and maintained significant efficacy in multidrug-resistant models resistant to DXd. ADCs constructed using the clinically validated site-specific conjugation technology IDDC™ and our novel payload MF6 demonstrated good uniformity and stability, and exhibited significant antitumor efficacy in multiple CDX models. Additionally, these ADCs showed good bystander killing activity, meaning they could kill nearby tumor cells, thereby further enhancing their antitumor effect. We also found that ADCs synthesized with MF6 had excellent serum and plasma stability and pharmacokinetic properties, providing strong support for their future clinical application. Conclusions: This study successfully developed a novel ADC payload MF6 based on the MtoxinTm platform and initially validated its antitumor activity and safety in multiple in vitro and in vivo models. These results provide a solid experimental foundation for the further development of MF6-based ADCs for the treatment of various cancers. In the future, we will continue to explore the potential of MF6 and anticipate that MF6-based ADCs will undergo further clinical validation and application, bringing more precise, effective, and safe treatment options to cancer patients. Citation Format: Xiaowei Cen, Hui Xu, Huikai Zhu, Hua Deng, Zhenzhen Wang, Junwei Xu, Xueying Li, Zhiheng Wu, Yiyan Zhang, Yuhang Chen, Xiaolin Chen, Li Chen, Wei Zhou, Hai Wu. Design and synthesis of the novel camptothecin analog MF-6 for application into site-specific antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5733.