ArticleActa pharmacologica Sinica2026
Novel anti-HER2 nanobody-drug conjugates with enhanced penetration of solid tumor and BBB, reduced systemic exposure and superior antitumor efficacy.
Article in Acta pharmacologica Sinica, 2026. 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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3 citing papers in PubMed.
- Antibody-drug conjugates in breast cancer brain and leptomeningeal metastases: mechanistic insights and therapeutic progress.Cancer metastasis reviews · 2026Review
- Theranostic vNAR-Based Immunoconjugates Achieve Selective Intracellular Cisplatin Delivery in Embedded 3D HER2-Positive Breast Cancer In Vitro Model.Pharmaceuticals (Basel, Switzerland) · 2026Article
- De Novo Design of High-Affinity HER2-Targeting Protein Minibinders.Biomolecules · 2025Article
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4 authors.
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Abstract
Antibody-drug conjugate (ADC) represents a promising paradigm for tumor-targeted delivery of chemotherapy. Trastuzumab deruxtecan (T-Dxd/DS-8201), a second-generation HER2-ADC, has significantly improved treatment outcomes for breast cancer patients. But due to the large molecular weight, the performance of ADC is still limited by lower tumor penetration, insufficient BBB permeability, and prolonged systemic exposure to normal tissues. In this study, we generated novel anti-HER2 nanobodies (VHH2, VHH3) that exhibited outstanding target affinity and tumor inhibition. After i.v. injection, VHH3-Fc fusion distributed 4 to 5-fold higher in subcutaneous tumor and intracranial tumor compared with trastuzumab. VHH3-Fc and VHH3-ABD were also more penetrant in an in vitro BBB permeability assay. Site-specific conjugation of VHH3-Fc or VHH3-ABD fusions with anti-microtubule MMAE or anti-topoisomerase-1 Dxd payload produced nanobody-drug conjugates (NDCs) with highly potent and durable antitumor efficacy. When evaluated on the same linker-payload (GGFG-Dxd) dosages, VHH3-Fc-Dxd (DAR3.9) outperformed T-Dxd (DAR8) in both the subcutaneous and intracranial tumor models. Moreover, IHC staining and RNA-seq analysis of the treated tumor tissues revealed the involvement of the cGAS-STING-IFNs pathway in mediating the drug activity. Gene expression and protein function were more profoundly modulated by VHH3-Fc-Dxd than T-Dxd. Unlike the higher tumor distribution, the mouse serum PK study revealed a faster clearance (T
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