Conditionally active antibody‒drug conjugates

Conditionally active antibody‒drug conjugates (ADCs) can be achieved through antibody engineering and/or linker-payload design to achieve context-dependent activation, addressing the limitations of conventional ADCs such as premature payload release, inefficient tumor penetration, and on-target, off-tumor toxicities. Antibody surfaces can be modified with steric shields, site-specific conjugation, or reversible masking groups to further limit off-target binding. Linker-payloads are masked in circulation through prodrug strategies, such as multi-step or logic-gated linkers, releasable caps, or bioorthogonal chemistries. These strategies confine cytotoxic drugs to the tumor microenvironment (TME), enhancing intratumoral drug concentration, expanding the therapeutic window, and reducing systemic toxicity. Early clinical studies of conditionally active ADCs targeting ROR2, AXL, and CD71 have demonstrated promising safety and efficacy. This review discusses the underlying mechanisms, antibody engineering and linker-payload design strategies, and clinical progress of conditionally active ADCs, and considers future avenues to improve tumor selectivity and therapeutic performance.