The Vedotin Antibody–Drug Conjugate Payload Drives Platform-Based Nonclinical Safety and Pharmacokinetic Profiles

Abstract Nonclinical safety and pharmacokinetic data for monomethyl auristatin E (MMAE) and 14 vedotin antibody–drug conjugates (ADC) were evaluated to determine patterns of toxicity, consistency of pharmacokinetic results, and species differences between rats and monkeys. Most nonclinical toxicities were antigen-independent, common across ADCs, and included hematologic, lymphoid, and reproductive toxicity related to MMAE pharmacology. Hematologic toxicity was the dose-limiting toxicity (DLT) or predominant toxicity for the majority of vedotin ADCs in both species. Tissue expression of the targeted antigen of an ADC rarely correlated with DLT; only two ADCs had antigen-dependent skin DLTs. For two additional ADCs, antigen-dependent delivery of MMAE in the bone marrow may have exacerbated the antigen-independent hematologic DLT. The highest tolerated doses and pharmacokinetics were similar within a given species, with rats tolerating higher doses than monkeys. Studies longer than 1 month in duration detected the same or fewer toxicities than 1-month studies and had no additional findings that affected the human risk assessment. These data support opportunities to streamline ADC toxicity assessments without compromising human starting dose selection or target organ identification.