Biological Evaluation of Cleavable Linkers in Exatecan-Based Antibody-Drug Conjugates: A Comparative Study of DXd and Exo-Linker Platforms

Antibody-drug conjugates (ADCs) represent a transformative class of cancer therapies that combine the specificity of monoclonal antibodies with the cytotoxicity of potent drug payloads. This study presents the development and evaluation of a novel exolinker designed to enhance ADC stability and pharmacokinetics by addressing the limitations associated with traditional cleavable linkers. Using trastuzumab conjugated with a payload linker consisting of an exo-linker and exo-EVC-Exatecan (APL-1082), we examined key parameters, including in vivo efficacy and pharmacokinetic profiles in rat models, to directly compare it with the clinically validated trastuzumab-deruxtecan (T-DXd, Enhertu). Our Exo-linker ADC demonstrated superior stability and maintained drug-to-antibody ratios (DAR) with reduced aggregation and hydrophobicity compared to T-DXd, suggesting an improved pharmacokinetic profile. Additionally, combining the Exo-linker with AJICAP site-specific conjugation technology enabled the production of high-DAR ADCs, achieving a DAR of 10 with promising homogeneity and physicochemical properties. Collectively, these findings underscore the potential of the exo-linker as a versatile platform for next-generation ADCs, offering enhanced stability, efficacy, and expanded therapeutic possibilities.