Article Dans Une Revue Biomaterials Année : 2025

Functional targeting of Glypican-4 by a conformation-specific single-domain antibody

Résumé

The heparan sulphate proteoglycan, Glypican-4 (GPC-4), is an integral component of cell surfaces that fulfils key functions as a modulator of cell communication. Over time, human GPC-4 (hGPC4) has gained recognition as a valuable target for enhancing the therapeutic potential of human pluripotent stem cells (hPSCs). hGPC-4 is also a promising diagnostic and therapeutic target for a range of developmental and neurological disorders, as well as cancer. Its involvement in multiple biological processes and its impact on cellular signaling pathways make it a compelling candidate for future research and clinical applications. Here, we report RB1 and RB3 as the first hGPC-4-specific nanobodies, exhibiting high affinity for both recombinant and cell surface-associated hGPC-4 molecules. Notably, the bivalent nanobody Fc-fusion form of RB1, termed RB1-Fc, demonstrates a significant ~14-fold increase in apparent binding affinity on cells when compared to the monovalent RB1. Furthermore, binding of RB1-Fc to hGPC-4 is dependent on the native conformation of hGPC-4, demonstrating that RB1-Fc is a conformational nanobody. Notably, RB1-Fc neutralizes the activity of GPC-4, as shown by our functional studies in hPSCs. These studies demonstrate the potent efficacy of the lead hGPC4 nanobodies, RB1-Fc and RB3. They also provide a solid rationale for using these nanobodies in the detection and characterization of physiologically and clinically relevant hGPC-4. Additionally, their potential as agents for therapeutic targeting of hGPC-4 opens new avenues for treating disorders associated with dysregulated hGPC-4 activity.

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hal-05409215 , version 1 (10-12-2025)

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Remi Bonjean, Rossana Cuciniello, Brigitte Kerfelec, Patrick Chames, Rosanna Dono. Functional targeting of Glypican-4 by a conformation-specific single-domain antibody. Biomaterials, 2025, 328, pp.123864. ⟨10.1016/j.biomaterials.2025.123864⟩. ⟨hal-05409215⟩
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