Site-specific ligase-dependent conjugation with ring-opening linker improves safety and stability of HER2-targeting ADCs
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.
Authors
- Yan Shi (ORCID: https://orcid.org/0000-0001-9777-8836)
- Biyun Wang (ORCID: https://orcid.org/0000-0002-7829-1544)
- Xinju Gao
- Lei Huang (ORCID: https://orcid.org/0000-0002-4225-9200)
- Gang Qin (ORCID: https://orcid.org/0000-0002-1365-1959)
- Bo Yang
- Chengcheng Gong (ORCID: https://orcid.org/0000-0002-5429-0248)
- Mingyu Hu (ORCID: https://orcid.org/0000-0002-2253-8624)
- Cao Lv (ORCID: https://orcid.org/0009-0008-2619-2836)
- Lu Jiang (ORCID: https://orcid.org/0000-0003-1105-8753)
- Paul H. Song (ORCID: https://orcid.org/0009-0000-4728-8476)
- Hui Yang (ORCID: https://orcid.org/0000-0003-0304-5098)
- H. J. Yang (ORCID: https://orcid.org/0009-0004-8274-9863)
- Chong Liu (ORCID: https://orcid.org/0000-0001-6578-5919)
- Xuesong Li (ORCID: https://orcid.org/0009-0008-8914-9907)
- Yajun Sun
- Jinduo Yuan
- Lili Shi (ORCID: https://orcid.org/0000-0001-6544-5084)
- Yu Si
Institutions
- Shanghai Medical College of Fudan University (CN)
- Second Military Medical University (CN)
- Chinese PLA General Hospital (CN)
- Fudan University Shanghai Cancer Center (CN)
- Wuzhou University (CN)
- Changhai Hospital (CN)
- ARTS Group (China) (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-03
- DOI
- https://doi.org/10.1038/s41467-025-64675-6
- Citations
- 2
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 2.09
Funders
- National Natural Science Foundation of China
- Changhai Hospital of Shanghai
- National Science and Technology Major Project
- National Health Commission of the People's Republic of China