Exposure-Response Relationships of Antibody Drug Conjugates in Solid Tumours

Abstract

Over the last decade, there has been an increase in development of antibody drug conjugates (ADCs), a drug class designed to bring chemotherapeutic agents to tumour sites. The pharmacokinetics of ADCs are complex, due to their multifaceted structure consisting of an antibody linked to a (chemotherapeutic) payload. This review provides an overview of the pharmacokinetics of approved ADCs for patients with solid tumours in relation to toxicity and/or efficacy outcomes. Due to the complex nature and in vivo modifications of an ADC, the pharmacokinetic exposure is measured partially or with surrogate entities. These entities include the calculated drug-to-antibody ratio (DAR)-corrected ADC, measured conjugated antibody, total antibody and/or free payload concentration. A clear exposure-efficacy and exposure-toxicity relation was evident for the majority of ADCs. A higher exposure of almost all ADCs approved for patients with solid tumours, specifically the conjugated antibody entity, was related to higher objective response rates. A higher exposure of the free circulating cytotoxic payload and of the surrogate entities of ADC exposure, of ADCs with cleavable linkers, was related to toxicity. This is unsurprising as a higher circulating payload may induce toxicities associated with the related chemotherapeutic compound. Non-cleavable linkers increase the plasma stability compared to cleavable linkers, resulting in the absence of an (systemic) exposure-toxicity relation. The exposure-response relations for efficacy and toxicity seem apparent based on current literature, but quantification of all ADC components should be considered to fully elucidate the exposure-response relations. This is a crucial next step for dose optimisation and development of a new generation of this important new therapeutic class.