Evaluation of Double Self-Immolative Linker-Based Antibody–Drug Conjugate FDA022-BB05 with Enhanced Therapeutic Potential
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, <b>FDA022-BB05</b> was successfully conjugated with the hydroxyl group-containing payload DXd using trastuzumab (FDA022) as the monoclonal antibody (mAb). <b>FDA022-BB05</b> 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 <b>FDA022-BB05</b>, 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.
Authors
- Xuefei Qiu
- Ke Shen (ORCID: https://orcid.org/0000-0003-4690-4040)
- Yinghan Wu (ORCID: https://orcid.org/0000-0003-1248-1123)
- Bei Gao (ORCID: https://orcid.org/0009-0002-5299-6690)
- Tong Yang (ORCID: https://orcid.org/0000-0001-7414-366X)
- Wei Lü (ORCID: https://orcid.org/0000-0003-3041-9200)
- Jun Xu (ORCID: https://orcid.org/0000-0003-1972-508X)
- Xuemei Cao (ORCID: https://orcid.org/0000-0001-5504-5554)
- Teng Zhao (ORCID: https://orcid.org/0009-0007-0899-5320)
- Qingsong Guo (ORCID: https://orcid.org/0009-0002-1605-6896)
- Shuangxi Liu (ORCID: https://orcid.org/0000-0002-1422-1096)
- Ruiwen Song (ORCID: https://orcid.org/0009-0009-0646-9313)
- Sicheng Yin
- Shulei Zhu (ORCID: https://orcid.org/0000-0002-9747-2105)
- Weinan Li (ORCID: https://orcid.org/0009-0008-0358-9742)
- Baoxia Wang
- Lei Wang (ORCID: https://orcid.org/0000-0001-7103-9402)
- Jingsong Wu
- Zhiyang Cheng (ORCID: https://orcid.org/0009-0001-7531-7016)
- Qian Xie (ORCID: https://orcid.org/0009-0008-2558-7916)
- Yifan Zhang (ORCID: https://orcid.org/0009-0001-0873-3853)
- Wenbo Zhang (ORCID: https://orcid.org/0000-0002-1886-0565)
Institutions
- East China Normal University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-10-24
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02243
- Citations
- 15
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 4.24
Funders
- National Natural Science Foundation of China