Conditionally active antibody‒drug conjugates
- 1Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health; State Key Laboratory of Respiratory Health and Multimorbidity; West China Hospital, Sichuan University, Chengdu 610041, China
- 2State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China
Abstract
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.
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BibTeX
@article{guo2026conditionally,
title = {{Conditionally active antibody‒drug conjugates}},
author = {Cuiyu Guo and Yaqin He and Ying Lu and Qilin Dun and Jinliang Yang and Yuxi Wang},
journal = {Acta pharmaceutica Sinica. B},
year = {2026},
month = aug,
doi = {10.1016/j.apsb.2026.08.023},
url = {https://europepmc.org/article/PMC/PMC13729715},
note = {CC BY},
}
RIS
TY - JOUR
TI - Conditionally active antibody‒drug conjugates
AU - Cuiyu Guo
AU - Yaqin He
AU - Ying Lu
AU - Qilin Dun
AU - Jinliang Yang
AU - Yuxi Wang
PY - 2026
DA - 2026/08/31
JO - Acta pharmaceutica Sinica. B
DO - 10.1016/j.apsb.2026.08.023
UR - https://europepmc.org/article/PMC/PMC13729715
AB - 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.
SN - 2211-3835
SN - 2211-3843
ER -