Abstract 5820: An antibody drug conjugate platform based on novel camptothecin payloads with branch hydrophilic linkers and site-specific conjugation

Abstract

Abstract Antibody-drug conjugates (ADCs) have recently gained momentum as a therapeutic modality for the cell-specific delivery of small molecules beyond their originally-intended purpose of treating cancer. However, the selection of combinations of an optimum target, antibody, payload, linker as well conjugation, to achieve maximal therapeutic efficacy without excessive toxicity, still presents a significant challenge. Topoisomerase I (Topo I) inhibitors such as camptothecin (CPT) analogs represent the much success in ADC payload applications as two CPT analog-ADCs, trastuzumab deruxtecan (DS-8201a—Enhertu®) with Dxd payload and sacituzumab govitecan (TrodelvyTM) with SN38 payload have been approved and over 20 CPT analog-ADCs are in the clinical trials now. Topo I inhibitors trigger cell apoptosis through their specific binding at the DNA-topoisomerase interface, leading to the inhibition of DNA supercoiling and entanglement, resulting in DNA damage and cell death. This class of payloads in ADCs has demonstrated more wider therapeutic windows in clinical trials than regular antitubulin payloads, such as maytansine and MMAE, based ADCs. Here, we detail the discovery of CPT analogs, as payloads with a branch hydrophilic linker and site-specific conjugation for ADCs designed to have a widened therapeutic window compared with Dxd-GGFG linked ADCs. The CPT analogs based on the core structure of SN-38, wherein the hydrogen of C-11 was replaced with fluorine, and the hydroxyl group of C-10 was optionally replaced with an amino or a ether group. Many of the novel CPT analogs were at single to tens of pM of IC50 potency in vitro against several tested tumor cell lines, and some were more potent than Exatecan in the comparison tests. The ADCs constructed with branch hydrophilic linkers and the CrossConjuTM technology of chemically site-specific conjugation at Fab region of an antibody through C-10 position of the CPT payloads either with amide bond, either bond or carbamide bonds, or through C-20 position of the CPT payloads with carbamide or carbonate bonds, exhibited much better antitumor efficacy in vivo CDX tumor models, while having higher or similar MTDs in mice toxicity study in comparison with the ADC constructed with GGFG-Dxd, demonstrated wider therapeutic widows than that conjugated with GGFG-Dxd. Moreover, some of the constructed ADCs can overcomes in vitro- and in vivo-acquired resistance of commercial therapeutic drugs. Herein, we showcase our platform approach in CPT-ADC designs and constructions and can be thereby broadly applicable to construction of various CPT-ADCs for targeted treatment of cancers. Citation Format: Yuanyuan Huang, Hangbo Ye, Qingliang Yang, Lingli Zhang, Huihui Guo, Xiaolei Liu, Wenjun Li, Lu Bai, Junxiang Jia, Juan Wang, Xiangfei Kong, Jun Zheng, Yifang Xu, Gengxiang Zhao, Linyao Zhao, Xiang Cai, Ziyu Zhao, Hui Xia, Xia Zhou, You Zhou, Robert Y. Zhao. An antibody drug conjugate platform based on novel camptothecin payloads with branch hydrophilic linkers and site-specific conjugation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5820.