The Evolution of Antibody‐Drug Conjugates: Toward Accurate DAR and Multi‐specificity

Abstract Antibody‐drug conjugates (ADCs) consist of antibodies, linkers and payloads. They offer targeted delivery of potent cytotoxic drugs to tumor cells, minimizing off‐target effects. However, the therapeutic efficacy of ADCs is compromised by heterogeneity in the drug‐to‐antibody ratio (DAR), which impacts both cytotoxicity and pharmacokinetics (PK). Additionally, the emergence of drug resistance poses significant challenges to the clinical advancement of ADCs. To overcome these limitations, a variety of strategies have been developed, including the design of multi‐specific drugs with accurate DAR. This review critically summarizes the current challenges faced by ADCs, categorizing key issues and evaluating various innovative solutions. We provide an in‐depth analysis of the latest methodologies for achieving homogeneous DAR and explore design strategies for multi‐specific drugs aimed at combating drug resistance. Our discussion offers a current perspective on the advancements made in refining ADC technologies, with an emphasis on enhancing therapeutic outcomes.