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Updated: Jan 12, 2026

Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction
Published on: September 14, 2018
Site-specific ligase-dependent conjugation with ring-opening linker improves safety and stability of HER2-targeting
Lei Huang1, Gang Qin2,3, Chengcheng Gong4
1National Key Laboratory of Immunity and Inflammation, National Clinical Research Center for Digestive Diseases, Changhai Clinical Research Unit, Department of Gastroenterology, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, China.
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.
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