Rational Design and Systemic Appraisal of an EGFR-Targeting Antibody–Drug Conjugate LR-DM1 for Pancreatic Cancer

作者：Mei Zhu, Lei Zhou, Shangjiu Hu, Qingfang Miao, Jianhua Gong, Na Zhang, Guoning Zhang, Minghua Wang, Juxian Wang, Hongwei He, Yucheng Wang · 发表于：Journal of Medicinal Chemistry · 年份：2022 · DOI：10.1021/acs.jmedchem.1c01920 · 被引用次数：10 · 研究领域：Lung Cancer Treatments and Mutations、HER2/EGFR in Cancer Research、Pancreatic and Hepatic Oncology Research

By harnessing the payload DM1 and a monoclonal antibody LR004 through a noncleavable linker succinimidyl-4-( N -maleimidomethyl)-cyclohexane-1-carboxylate, we designed and evaluated an antibody–drug conjugate LR-DM1 with an appropriate drug–antibody ratio of 3.6. LR-DM1, which was targeted toward the epidermal growth factor receptor for pancreatic cancer, exhibited potent antiproliferation activity in vitro with a half-maximal inhibitory concentration value of 7.03 nM for Capan-2 cells. Particularly, it displayed prominent tumor growth inhibition in vivo under 20 mg/kg LR-DM1 dosage in a single administration or multiple administrations without apparent abnormality of pathological observation. Moreover, LR-DM1 possessed a relatively broad therapeutic index with a half-lethal dose above 300 mg/kg, which was over 15-fold higher than the highest administration dosage of 20 mg/kg. This initial study on LR-DM1 holds promise for further development of a new antibody drug conjugate that is transformative for treatment of patients concerned.