Evaluation of Double Self-Immolative Linker-Based Antibody–Drug Conjugate FDA022-BB05 with Enhanced Therapeutic Potential
Yifan Zhang, Lei Wang, Xuemei Cao, Ruiwen Song, Sicheng Yin, Zhiyang Cheng, Weinan Li, Keyu Shen, Teng Zhao, Jun Xu, Shuangxi Liu, Qian Xie, Yinghan Wu, Bei Gao, Qingsong Guo, Jingsong Wu, Xuefei Qiu, Baoxia Wang, Wenbo Zhang, Tong Yang, Wei Lü, Shulei Zhu
Abstract
Typical antibody–drug conjugates (ADCs) with valine–alanine linkage, often conjugated with the amino group in payloads, face challenges when interacting with hydroxyl group-containing payloads. Herein, we introduced a transformative Val–Ala-based double self-immolative linker-payload platform, reshaping ADCs by optimizing hydroxyl group-containing payload integration. Utilizing this platform, FDA022-BB05 was successfully conjugated with the hydroxyl group-containing payload DXd using trastuzumab (FDA022) as the monoclonal antibody (mAb). FDA022-BB05 demonstrated enhanced stability, effective cathepsin B sensitivity, reduced cell proliferation, increased bystander killing, and targeted delivery. Notably, acute toxicity evaluations in diverse preclinical models indicated favorable safety profiles and tolerability, with a broad therapeutic index in HER2-positive and -negative xenografts. Overall, these compelling findings support the promising therapeutic potential of FDA022-BB05, emphasizing the significance of diverse linker-payload platform strategies. This ADC is a valuable addition to targeted cancer therapy development, currently advancing through phase I clinical trials.