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

Joly, Sandrine; Augusto, Gilles; Mdzomba, Baya; Meli, Ivo; Vogel, Monique; Chan, Andrew; Pernet, Vincent (2024). Nogo-A neutralization in the central nervous system with a blood-brain barrier-penetrating antibody. Journal of controlled release, 366, pp. 52-64. Elsevier 10.1016/j.jconrel.2023.12.041

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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.

Item Type:

 Journal Article (Original Article)

Division/Institute:

 04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute for Immunology [discontinued]
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Rheumatology and Immunology
04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Neurology
04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Ophthalmology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Rheumatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Rheumatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Unit Sahli Building > Forschungsgruppe Neurologie

UniBE Contributor:

 Joly, Sandrine Marina Aline, Sousa Augusto, Gilles Anderson, Mdzomba, Julius Baya, Meli, Ivo Maurice, Vogel, Monique, Chan, Andrew Hao-Kuang, Pernet, Vincent

Subjects:

 600 Technology > 610 Medicine & health

ISSN:

 1873-4995

Publisher:

 Elsevier

Language:

 English

Submitter:

 Pubmed Import

Date Deposited:

 04 Jan 2024 08:01

Last Modified:

 04 Mar 2024 00:14

Publisher DOI:

 10.1016/j.jconrel.2023.12.041

PubMed ID:

 38154541

Uncontrolled Keywords:

 Blocking antibody Blood-brain barrier Brain-penetrating antibody Neuronal plasticity Nogo-A Transferrin receptor

BORIS DOI:

 10.48350/190970

URI:

 https://boris.unibe.ch/id/eprint/190970

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