ArticleFrontiers in immunology2025
Targeting CD16A on NK cells and GPC3 in hepatocellular carcinoma: development and functional validation of a therapeutic bispecific antibody.
Article in Frontiers in immunology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Natural killer cell-based therapy for hepatocellular carcinoma (HCC): A literature review.Medical oncology (Northwood, London, England) · 2026Review
- Emerging Immune-Based Therapeutic Strategies in Hepatocellular Carcinoma.Liver international : official journal of the International Association for the Study of the Liver · 2026Review
- Bispecific antibodies in gastrointestinal cancers: current applications and future perspectives.Frontiers in oncology · 2026Review
- Nanotechnology-Enabled Diagnosis and Treatment of Hepatocellular Carcinoma: Theranostics, Combination Regimens, and Translation.International journal of nanomedicine · 2026Review
- Glypican-3-Specific CAR NK Cells Co-Secreting IL-15 and IFN-α Have Increased Anti-Tumor Function Versus Hepatocellular Carcinoma In Vitro.International journal of molecular sciences · 2025Article
- Dual T/NK cell engagement via B7-H6-targeted bispecific antibodies and IL-15 eradicates chemo-resistant solid tumors.Frontiers in immunology · 2025Article
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Authors and funding
6 authors.
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Abstract
Introduction: Advanced hepatocellular carcinoma (HCC) poses significant therapeutic challenges due to chemotherapy resistance and limited efficacy of current targeted therapies. To address this unmet need, we developed a bispecific antibody (BsAb) platform targeting CD16A on natural killer (NK) cells and glypican-3 (GPC3), a tumor-specific antigen overexpressed in 70% of HCC cases. Methods: High-affinity anti-CD16A single-chain variable fragments (scFvs) were selected via phage display, followed by engineering of Fc-stabilized BsAbs (MA4-hFc(N297A)-CD16A series) to minimize FcγR-mediated toxicity. Functional validation included binding kinetics (ELISA, flow cytometry, and fluorescence co-localization analysis), Results: The lead candidate, MA4-hFc-CD16AM19, exhibited nanomolar affinity (EC50 < 10 nM for human CD16A) with no murine cross-reactivity. It demonstrated potent, dose-dependent cytotoxicity against GPC3+ HCC lines (HepG2/Huh7/Hep3B, IC50 = 15-35 ng/mL) via NK cell activation, surpassing conventional antibody-dependent cellular cytotoxicity (ADCC). Combined with sorafenib, MA4-hFc-CD16AM19 achieved synergistic tumor suppression (CI=0.41). Conclusion: This study introduces three innovations: (1) a species-specific CD16A binder overcoming polymorphism limitations, (2) Fc domain engineering (N297A) to optimize stability and safety, and (3) a synergistic combination strategy with sorafenib. The results provide a translatable framework for GPC3+ solid tumor immunotherapy.
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