Site-specific ligase-dependent conjugation with ring-opening linker improves safety and stability of HER2-targeting ADCs
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Le résumé fourni par la source
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. Toxicity of antibody drug conjugates (ADCs) is often caused by off-target shedding of therapeutic payloads due to linker instability. Here, the authors demonstrate that site-specific ligase-dependent conjugation of therapeutic payloads to engineered trastuzumab via a ring-opening linker improves stability compared to conventional HER2- targeting ADCs.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Site-specific ligase-dependent conjugation with ring-opening linker improves safety and stability of HER2-targeting ADCs
- Date Crossref
- 03/11/2025
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Second Military Medical University pays non établi dans la noticeUniversité ou école supérieure
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Changhai Hospital National Key Laboratory of Immunity and Inflammation pays non établi dans la noticeÉtablissement de santé
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Shanghai Medical College of Fudan University Department of Oncology pays non établi dans la noticeUniversité ou école supérieure
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Fudan University Shanghai Cancer Center Department of Breast and Urological Medical Oncology pays non établi dans la noticeÉtablissement de santé
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Chinese PLA General Hospital pays non établi dans la noticeÉtablissement de santé
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Ltd. GeneQuantum Healthcare (Suzhou) Co. pays non établi dans la noticeEntreprise
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The Fifth Medical Center of PLA General Hospital Department of Medical Oncology pays non établi dans la noticeÉtablissement de santé
Second Military Medical University, National Key Laboratory of Immunity and Inflammation — Changhai Hospital et Department of Oncology — Shanghai Medical College of Fudan University, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.