Antibody-drug conjugates (ADCs) are consisted of antibodies, linker 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 the 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 summarized 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 the design strategies for multi-specific drugs aimed at combating drug resistance. Our discussion offers insights into the progress made in refining ADC technologies, with a focus on enhancing therapeutic outcomes.
Keywords: antibody-drug conjugates * homogeneous DAR * drug resistance * multi-specific ADC.
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