A review of targeted drug delivery with antibody-drug complexes

Monoclonal antibodies are a versatile platform for targeted drug delivery. Their high specificity and favorable pharmacokinetics allow for selective drug delivery to targeted cells. A primary drug delivery application is antibody-drug conjugates (ADCs), which combine monoclonal antibodies with cytotoxic payloads via covalent linkers. While ADCs have shown remarkable clinical success, several limitations remain, including complex conjugation chemistries, heterogeneity in drug-to-antibody ratios, exposed hydrophobic patches, and off-target payload release, which can result in systemic toxicity. To complement existing ADC platforms and mitigate some of these issues, alternative formats referred to as antibody-drug complexes (ADCx) have been developed. ADCx are generated by forming reversible, high-affinity complexes between antibodies and drugs or preformed drug conjugates. This review discusses the ADCx formats reported to date, focusing on the unique advantages and potential limitations of each format. SIGNIFICANCE STATEMENT: Antibody-drug complexes offer a modular, noncovalent alternative to traditional antibody-drug conjugates. This review comprehensively evaluates antibody-drug complex formats, highlighting their potential to expand the utility of antibody-based drug delivery for next-generation therapeutics.