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Nanobody therapy rescues behavioural deficits of NMDA receptor hypofunction

Author

Listed:
  • Mathieu Oosterlaken

    (Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM)

  • Angelina Rogliardo

    (Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM
    Institut des Neurosciences de Montpellier)

  • 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
    Institute Paoli-Calmettes, CRCM, Aix Marseille University, 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
    Institut des Biomolécules Max Mousseron, Université de Montpellier, CNRS, ENSCM)

  • Philippe Rondard

    (Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM)

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.

Suggested Citation

  • Mathieu Oosterlaken & Angelina Rogliardo & Tatiana Lipina & Pierre-André Lafon & Mireille Elodie Tsitokana & Mathilde Keck & Héloïse Cahuzac & Pierre Prieu-Sérandon & Séverine Diem & Cécile Derieux & , 2025. "Nanobody therapy rescues behavioural deficits of NMDA receptor hypofunction," Nature, Nature, vol. 645(8079), pages 262-270, September.
    • Handle: RePEc:nat:nature:v:645:y:2025:i:8079:d:10.1038_s41586-025-09265-8
    DOI: 10.1038/s41586-025-09265-8
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