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

摘要

By harnessing the payload DM1 and a monoclonalantibody LR004 through a noncleavable linker succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate, we designed andevaluated an antibody-drug conjugate LR-DM1 with anappropriate drug-antibody ratio of 3.6. LR-DM1, which wastargeted toward the epidermal growth factor receptor for pancreaticcancer, exhibited potent antiproliferation activityin vitrowith ahalf-maximal inhibitory concentration value of 7.03 nM for Capan-2 cells. Particularly, it displayed prominent tumor growth inhibitionin vivounder 20 mg/kg LR-DM1 dosage in a single administrationor multiple administrations without apparent abnormality ofpathological observation. Moreover, LR-DM1 possessed arelatively broad therapeutic index with a half-lethal dose above300 mg/kg, which was over 15-fold higher than the highest administration dosage of 20 mg/kg. This initial study on LR-DM1 holdspromise for further development of a new antibody drug conjugate that is transformative for treatment of patients concerned