Evaluation of Double Self-Immolative Linker-Based Antibody-Drug Conjugate FDA022-BB05 with Enhanced Therapeutic Potential

  • J Med Chem. 2024 Nov 14;67(21):19852-19873. doi: 10.1021/acs.jmedchem.4c02243.
Yifan Zhang  1 ,  Lei Wang  2 ,  Xuemei Cao  1 ,  Ruiwen Song  1 ,  Sicheng Yin  1 ,  Zhiyang Cheng  2 ,  Weinan Li  1 ,  Keyu Shen  1 ,  Teng Zhao  1 ,  Jun Xu  1 ,  Shuangxi Liu  1 ,  Qian Xie  1 ,  Yinghan Wu  1 ,  Bei Gao  1 ,  Qingsong Guo  1 ,  Jingsong Wu  1 ,  Xuefei Qiu  1 ,  Baoxia Wang  1 ,  Wenbo Zhang  1 ,  Tong Yang  1 ,  Wei Lu  2 ,  Shulei Zhu  3  2
Affiliations
  • 1. R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd., Shanghai 201210, P. R. China.
  • 2. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, P. R. China.
  • 3. Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, P. R. China.
PMID: 39444220 DOI: 10.1021/acs.jmedchem.4c02243
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.

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