PK/PD Evaluation of Antibody-Drug Conjugates with Enhanced Immune Effector Functions.

Abstract

Optimizing the interaction between antibody (mAb)-based therapeutics and immune effector functions (EFs) offers opportunities to improve the therapeutic window of these molecules. However, the role of EFs in antibody-drug conjugate (ADC) efficacy and toxicity remains unknown, with limited studies that have investigated how modulation of EF affects the pharmacology of ADCs. This study aimed to evaluate the effect of EF modulation on ADC efficacy using trastuzumab-vc-MMAE as a model ADC. A series of ADCs with enhanced or eradicated EF were synthesized through Fc engineering of the antibody. Cell-based assays confirmed that the alteration of EFs in ADCs did not change their in vitro potency, and the conjugation of vc-MMAE did not alter the trends in EFs modulation. Pharmacokinetic/pharmacodynamic (PK/PD) studies of Fc engineered ADCs were conducted in a syngeneic mouse system. The enhancement of EFs led to lower systemic exposure, faster clearance, and potentially enhanced tissue distribution and accumulation of ADCs. ADCs with enhanced EFs demonstrated improved efficacy in the syngeneic mouse tumor model, which was quantitatively confirmed by PK/PD modeling. The model indicated that EF enhancement was synergistic for ADC efficacy, whereas the complete removal of EF was less than additive. Our study suggests that developing ADCs with enhanced EF may improve the therapeutic effectiveness of ADCs, although the effect of this modification on ADC safety and extrapolation of our findings to other ADCs necessitates further investigation.