The role of hydrophilic linkers in next-generation antibody-drug conjugates

Chemical linkers in antibody-drug conjugates (ADCs) play crucial roles in delivery of cytotoxic payloads into targets to ensure target-responsive release of active therapeutic format, without premature release of toxins in the circulatory system. However, hydrophobic payloads often induce ADC aggregation especially for those with high drug antibody ratio, leading to rapid in vivo clearance and compromised therapeutic effects. Consequently, developing ADCs with hydrophilic moieties on existing or emerging linkers have proven highly fruitful. In this perspective, we recapitulate the hydrophilic linkers of ADCs that exert significant impacts on ADC druggability by shielding the lipophilicity of payloads. Linkers functionalized with hydrophilic groups such as PEG, PSAR, saccharides or ionizable groups serve to augment aqueous solubility, ameliorate aggregation and improve safety of ADCs, thereby enhancing the pharmacokinetic and pharmacodynamic performance.