AUTHOR=Ai Zhijuan , Wang Bing , Song Yunlong , Cheng Panpan , Liu Xinlin , Sun Peng 

TITLE=Prodrug-based bispecific antibodies for cancer therapy: advances and future directions

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1523693

DOI=10.3389/fimmu.2025.1523693

ISSN=1664-3224

ABSTRACT=Bispecific antibodies represent an innovative paradigm in cancer therapy, offering broader therapeutic potential compared to conventional monoclonal antibodies. To increase tumor selectivity while mitigating off-target effects in normal tissues, the concept of prodrug-based bispecific antibodies has emerged. This review delineates the various mechanisms underlying the action of prodrug-based bispecific antibodies, including protease-mediated activation, steric hindrance release via proteolytic processing, activation by soluble factors, conditional assembly, and chain exchange-mediated activation. We also address the critical challenges that must be overcome to optimize the development and clinical application of these sophisticated therapeutic agents.