Nanobody therapy rescues behavioural deficits of NMDA receptor hypofunction

Mathieu Oosterlaken, Angelina Rogliardo, Tatiana Lipina, Pierre-André Lafon, Mireille Elodie Tsitokana, Mathilde Keck, Héloïse Cahuzac, Pierre Prieu-Sérandon, Séverine Diem, Cécile Derieux, Célia Camberlin, Chrystel Lafont, Damien Meyer, Patrick Chames, Franck Vandermoere, Philippe Marin, Laurent Prézeau, Denis Servent, Ali Salahpour, Amy J. Ramsey, Carine Bécamel, Jean-Philippe Pin (), Julie Kniazeff () and Philippe Rondard ()
Additional contact information
Mathieu Oosterlaken: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM
Angelina Rogliardo: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM
Tatiana Lipina: University of Toronto
Pierre-André Lafon: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM
Mireille Elodie Tsitokana: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM
Mathilde Keck: CEA
Héloïse Cahuzac: CEA
Pierre Prieu-Sérandon: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM
Séverine Diem: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM
Cécile Derieux: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM
Célia Camberlin: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM
Chrystel Lafont: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM
Damien Meyer: Institute Paoli-Calmettes, CRCM, Aix Marseille University, CNRS, INSERM
Patrick Chames: Institute Paoli-Calmettes, CRCM, Aix Marseille University, CNRS, INSERM
Franck Vandermoere: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM
Philippe Marin: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM
Laurent Prézeau: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM
Denis Servent: CEA
Ali Salahpour: University of Toronto
Amy J. Ramsey: University of Toronto
Carine Bécamel: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM
Jean-Philippe Pin: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM
Julie Kniazeff: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM
Philippe Rondard: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM

Nature, 2025, vol. 645, issue 8079, 262-270

Abstract: Abstract There is an urgent need for efficient and innovative therapies to treat brain disorders such as psychiatric and neurodegenerative diseases. Immunotherapies have proved to be efficient in many medical areas, but have not been considered to treat brain diseases due to the poor brain penetration of immunoglobulins1,2. Here we developed a bivalent biparatopic antibody, made of two camelid heavy-chain antibodies (called nanobodies)3, one binding to, and the other potentiating the activity of, homodimeric metabotropic glutamate receptor 2. We show that this bivalent nanobody, given peripherally, reaches the brain and corrects cognitive deficits in two preclinical mouse models with endophenotypes resulting from NMDA receptor hypofunction. Notably, these in vivo effects last for at least 7 days after a single intraperitoneal injection and are maintained after subchronic treatment. Our results establish a proof of concept that nanobodies can target brain receptors, and pave the way for nanobody-based therapeutic strategies for the treatment of brain disorders.

Date: 2025
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DOI: 10.1038/s41586-025-09265-8

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