Site-specific ligase-dependent conjugation with ring-opening linker improves safety and stability of HER2-targeting ADCs

Lei Huang, Gang Qin (), Chengcheng Gong, Yajun Sun, Hui Yang, Cao Lv, Chong Liu, Lu Jiang, Jinduo Yuan, Mingyu Hu, Xinju Gao, Jun Yang, Xuesong Li, Yu Si, Paul Song (), Yan Shi (), Lili Shi (), Bo Yang () and Biyun Wang ()
Additional contact information
Lei Huang: Naval Medical University
Gang Qin: Suzhou Industrial Park
Chengcheng Gong: Fudan University
Yajun Sun: Suzhou Industrial Park
Hui Yang: Suzhou Industrial Park
Cao Lv: Suzhou Industrial Park
Chong Liu: Suzhou Industrial Park
Lu Jiang: Suzhou Industrial Park
Jinduo Yuan: Suzhou Industrial Park
Mingyu Hu: Suzhou Industrial Park
Xinju Gao: Suzhou Industrial Park
Jun Yang: Suzhou Industrial Park
Xuesong Li: Suzhou Industrial Park
Yu Si: Suzhou Industrial Park
Paul Song: Suzhou Industrial Park
Yan Shi: Suzhou Industrial Park
Lili Shi: Suzhou Industrial Park
Bo Yang: The Fifth Medical Center of PLA General Hospital
Biyun Wang: Fudan University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Most of current ADCs have the problems of heterogeneity and payload-mediated off-target toxicities due to random conjugation and unstable linker. Herein we apply site-specific ligase-dependent conjugation (LDC) for GQ1001 and GQ1005, where humanized anti-HER2 antibody is linked to DM1 and DXd, respectively, via stable ring-opening linker. GQ1001 exhibits HER2 expression-dependent activity (contrary to T-DM1), indicating decreased off-target toxicity. The biostability of GQ1001 and GQ1005 in plasma is more favorable, and pharmacokinetics and safety profiles are improved in cynomolgus-monkeys with decreased circulating free-toxin levels. GQ1001 and GQ1005 are effective in animal models against pretreated HER2-positive cancers insensitive to HER2-targeting and/or chemotherapeutic drugs. The efficacy of GQ1001 is supra-additively enhanced by tyrosine-kinase inhibitors or chemotherapy, with manageable toxicity. GQ1001 is efficacious in cancers resistant to T-DXd due to high ABCG2 expression. Together, the LDC technology and ring-opening linker improve the stability and safety in GQ1001 and GQ1005 for treating refractory HER2-positive cancers.

Date: 2025
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DOI: 10.1038/s41467-025-64675-6

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