Exploring a Novel Approach to Senolysis Using a Urokinase Plasminogen Activator Receptor-targeting Antibody-Drug Conjugate

A multitude of highly deleterious age-related diseases are strongly associated with cellular senescence and the accumulation of senescent cells. Senescent cells are defined by a permanent growth arrest and exhibit increasing amounts of harmful characteristics as people age. Removing senescent cells through senolysis reduces the likelihood of developing senescence-associated pathologies. Through antibody-drug conjugates (ADCs), targeted senolysis that ablates senescent cells while causing minimal damage to healthy tissues can be achieved. Urokinase plasminogen activator receptor (uPAR) is an abundant protein in the surfaceome of diverse types of senescent cells and an established biomarker for cellular senescence. This study proposes a novel ADC-based senolytic strategy by designing an ADC tailored for senolysis that targets uPAR. By leveraging both uPAR overexpression as well as the upregulation of an internalization mediator plasminogen activator inhibitor-1 (PAI-1) in senescent cells. The design seeks to maximize therapeutic efficacy for preventing various age-related diseases while bearing minimal off-target risks.