Pharmacology and pharmacokinetics of antibody-drug conjugates, where do we stand?
Cet article passe en revue les données évaluant les caractéristiques pharmacocinétiques et pharmacodynamiques des conjugués anticorps-médicaments et fait le point sur les stratégies thérapeutiques les utilisant seuls ou en combinaison avec d'autres anticancéreux (agents cytotoxiques, inhibiteurs de point de contrôle immunitaire, thérapies ciblées, etc.)
Antibody-drug conjugates (ADCs) are a rising therapeutic class in oncology and hematology, with eleven drugs approved by the US Food and Drug Administration as of January 2025. These “magic bullets” have a complex structure, including a monoclonal antibody, a linker, attachment sites, and a payload usually disrupting microtubules, targeting DNA, or inhibiting topoisomerase 1. By targeting specific tumor antigens, they are expected to be exquisitely effective in releasing “supertoxic” payloads inside tumor cells after intracellular trafficking. Additionally, they may exert a bystander effect, wherein the released payloads act on neighboring cells, amplifying their therapeutic impact regardless of target expression. ADCs have been game-changing drugs to treat tumors with once dismal prognoses or with previously considered unactionable targets, such as HER2-low or triple-negative breast cancer. To what extent there is room for personalized medicine to improve the toxicity/efficacy ratio remains unknown. However, there are inherent issues related to the complexity of the pharmacokinetics of ADCs and their assessments: efficacy or toxicity may be influenced by the clearance of the intact ADC, the circulating payload, or the payload-linker complex. Deciphering these multifaceted exposure-outcomes relationships for both efficacy and safety endpoints, is critical for advancing precision medicine and enabling personalized dosing strategies. To improve future developments and broaden their therapeutic scope, several strategies can be developed, including developing adequate combinations with other treatment classes (cytotoxic agents, immune-checkpoint inhibitors, oral molecular-targeted therapies). In this review, we will discuss the PK/PD aspects of ADCs and their dosing to improve their use in current and future indications.