Nanobody therapy rescues behavioural deficits of NMDA receptor hypofunction

• 成果类型: Article
• 署名作者: Oosterlaken, Mathieu; Rogliardo, Angelina; Lipina, Tatiana; Lafon, Pierre-Andre; Tsitokana, Mireille Elodie; Keck, Mathilde; Cahuzac, Heloise; Prieu-Serandon, Pierre; Diem, Severine; Derieux, Cecile; Camberlin, Celia; Lafont, Chrystel; Meyer, Damien; Chames, Patrick; Vandermoere, Franck; Marin, Philippe; Prezeau, Laurent; Servent, Denis; Salahpour, Ali; Ramsey, Amy J.; Becamel, Carine; Pin, Jean-Philippe; Kniazeff, Julie; Rondard, Philippe
• 署名单位: Universite de Montpellier; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); University of Toronto; Universite Paris Saclay; CEA; Centre National de la Recherche Scientifique (CNRS); Aix-Marseille Universite; Institut National de la Sante et de la Recherche Medicale (Inserm); UNICANCER; Institut Paoli-Calmette (IPC); Universite de Montpellier; Ecole nationale superieure de chimie de Montpellier; Centre National de la Recherche Scientifique (CNRS); Universite de Montpellier; Institut National de la Sante et de la Recherche Medicale (Inserm)
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1319
• DOI: 10.1038/s41586-025-09265-8
• 发表日期: 2025-09-04
• 关键词: single-domain antibodies; blood-brain-barrier; allosteric modulators; DOUBLE-BLIND; mice; schizophrenia; activation; Mutation; phase-2; analyze

摘要

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.