ArticleNature communications2025
Site-specific ligase-dependent conjugation with ring-opening linker improves safety and stability of HER2-targeting ADCs.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Formulation Matters: The Overlooked Engine of Stability and Success in Antibody-Drug Conjugates.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Recent advances in bispecific antibody-drug conjugates for breast cancer therapy.Cancer chemotherapy and pharmacology · 2026Review
- Plasma multi-omics reveals molecular remodeling and prognostic biomarkers in advanced breast cancer treated with trastuzumab deruxtecan.Frontiers in oncology · 2026Article
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Authors and funding
19 authors.
Funding
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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