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

Author

Listed:
  • Lei Huang

    (Naval Medical University)

  • Gang Qin

    (Suzhou Industrial Park
    Fumin III Plant)

  • Chengcheng Gong

    (Fudan University)

  • Yajun Sun

    (Suzhou Industrial Park
    Fumin III Plant)

  • Hui Yang

    (Suzhou Industrial Park
    Fumin III Plant)

  • Cao Lv

    (Suzhou Industrial Park
    Fumin III Plant)

  • Chong Liu

    (Suzhou Industrial Park
    Fumin III Plant)

  • Lu Jiang

    (Suzhou Industrial Park
    Fumin III Plant)

  • Jinduo Yuan

    (Suzhou Industrial Park
    Fumin III Plant)

  • Mingyu Hu

    (Suzhou Industrial Park
    Fumin III Plant)

  • Xinju Gao

    (Suzhou Industrial Park
    Fumin III Plant)

  • Jun Yang

    (Suzhou Industrial Park
    Fumin III Plant)

  • Xuesong Li

    (Suzhou Industrial Park
    Fumin III Plant)

  • Yu Si

    (Suzhou Industrial Park
    Fumin III Plant)

  • Paul Song

    (Suzhou Industrial Park
    Fumin III Plant)

  • Yan Shi

    (Suzhou Industrial Park
    Fumin III Plant)

  • Lili Shi

    (Suzhou Industrial Park
    Fumin III Plant)

  • Bo Yang

    (The Fifth Medical Center of PLA General Hospital)

  • Biyun Wang

    (Fudan University)

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.

Suggested Citation

  • 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 & B, 2025. "Site-specific ligase-dependent conjugation with ring-opening linker improves safety and stability of HER2-targeting ADCs," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64675-6
    DOI: 10.1038/s41467-025-64675-6
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    References listed on IDEAS

    as
    1. Guolan Lu & Naoki Nishio & Nynke S. Berg & Brock A. Martin & Shayan Fakurnejad & Stan Keulen & Alexander D. Colevas & Greg M. Thurber & Eben L. Rosenthal, 2020. "Co-administered antibody improves penetration of antibody–dye conjugate into human cancers with implications for antibody–drug conjugates," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
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