Novel hydrophilic linker to improve stability and in vitro activity of antibody-drug conjugates

ADC development is often limited by hydrophobic payload-driven issues such as poor manufacturability, reduced stability, and suboptimal pharmacokinetics, which constrain the therapeutic index of highly potent cytotoxics. A novel hydrophilic solubilizing linker (SoluFlex Link) was therefore developed and evaluated in tumor-targeting ADCs with different antibodies and multiple payload classes, including topoisomerase I inhibitors, and attenuated DNA alkylators. These linkers increased ADC hydrophilicity beyond that of payloads, improved thermal stability under stress, and consistently shifted in vitro potency of matched ADCs from micromolar to low-nanomolar IC50 values while maintaining strict target dependence. The hydrophilic linker attenuated excessive cytotoxicity into a more optimal range, suggesting a broader therapeutic window without loss of antitumor effect. Exatecan ADCs incorporating the hydrophilic linker achieved significant tumor growth inhibition with high tumor regression rates at tolerated doses, outperforming T-DXd, thereby demonstrating that this hydrophilic linker platform can enhance stability, fine-tune cytotoxicity, and improve overall ADC efficacy.