Nogo-A neutralization in the central nervous system with a blood-brain barrier-penetrating antibody

Sandrine Joly; Gilles Augusto; Baya Mdzomba; Ivo Meli; Monique Vogel; Andrew Chan; Vincent Pernet

doi:10.1016/j.jconrel.2023.12.041

Nogo-A neutralization in the central nervous system with a blood-brain barrier-penetrating antibody

J Control Release. 2024 Feb:366:52-64. doi: 10.1016/j.jconrel.2023.12.041. Epub 2023 Dec 29.

Authors

Sandrine Joly¹, Gilles Augusto², Baya Mdzomba³, Ivo Meli³, Monique Vogel⁴, Andrew Chan³, Vincent Pernet⁵

Affiliations

¹ Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Switzerland; Center for experimental neurology (ZEN), Bern University Hospital, University of Bern, Switzerland; Centre de recherche du CHU de Québec-Université Laval and Department of Molecular Medicine, Faculté de médecine, Université Laval, Québec, Québec, Canada; Department of Ophthalmology, Bern University Hospital, University of Bern, Switzerland; Department of Biomedical Research, University of Bern, Bern, Switzerland.
² Department of Biomedical Research, University of Bern, Bern, Switzerland; Department of Immunology, Inselspital, Bern University Hospital, University of Bern, Switzerland; Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
³ Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Switzerland; Center for experimental neurology (ZEN), Bern University Hospital, University of Bern, Switzerland; Department of Biomedical Research, University of Bern, Bern, Switzerland.
⁴ Department of Biomedical Research, University of Bern, Bern, Switzerland; Department of Immunology, Inselspital, Bern University Hospital, University of Bern, Switzerland.
⁵ Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Switzerland; Center for experimental neurology (ZEN), Bern University Hospital, University of Bern, Switzerland; Centre de recherche du CHU de Québec-Université Laval and Department of Molecular Medicine, Faculté de médecine, Université Laval, Québec, Québec, Canada; Department of Biomedical Research, University of Bern, Bern, Switzerland. Electronic address: vincent.pernet@insel.ch.

PMID: 38154541
DOI: 10.1016/j.jconrel.2023.12.041

Abstract

The poor penetration of monoclonal antibodies (mAb) across the blood-brain barrier (BBB) impedes the development of regenerative therapies for neurological diseases. For example, Nogo-A is a myelin-associated protein highly expressed in the central nervous system (CNS) whose inhibitory effects on neuronal plasticity can be neutralized with direct administration of 11C7 mAb in CNS tissues/fluids, but not with peripheral administrations such as intravenous injections. Therefore, in the present study, we engineered a CNS-penetrating antibody against Nogo-A by combining 11C7 mAb and the single-chain variable fragment (scFv) of 8D3, a rat antibody binding transferrin receptor 1 (TfR) and mediating BBB transcytosis (11C7-scFv8D3). The binding of 11C7-scFv8D3 to Nogo-A and to TfR/CD71 was validated by capture ELISA and Biolayer Interferometry. After intravenous injection in mice, capture ELISA measurements revealed fast plasma clearance of 11C7-scFv8D3 concomitantly with brain and spinal cord accumulation at levels up to 19 fold as high as those of original 11C7 mAb. 11C7-scFv8D3 detection in the parenchyma indicated effective blood-to-CNS transfer. A single dose of 11C7-scFv8D3 induced stronger activation of the growth-promoting AkT/mTOR/S6 signaling pathway than 11C7 mAb or control antibody. Taken together, our results show that BBB-crossing 11C7-scFv8D3 engages Nogo-A in the mouse CNS and stimulates neuronal growth mechanisms.

Keywords: Blocking antibody; Blood-brain barrier; Brain-penetrating antibody; Neuronal plasticity; Nogo-A; Transferrin receptor.

MeSH terms

Animals
Antibodies, Monoclonal* / metabolism
Blood-Brain Barrier* / metabolism
Brain / metabolism
Mice
Myelin Proteins / metabolism
Nogo Proteins
Rats

Substances

Nogo Proteins
Antibodies, Monoclonal
Myelin Proteins