Cuypers, Marie-Lynn;
Jaspers, Tom;
Clerckx, Jarne;
Leekens, Simon;
Cawthorne, Christopher;
Bormans, Guy;
Cleeren, Frederik;
... Dewilde, Maarten; + view all
(2025)
Increasing brain half-life of antibodies by additional binding to myelin oligodendrocyte glycoprotein, a CNS specific protein.
Fluids and Barriers of the CNS
, 22
(1)
, Article 11. 10.1186/s12987-025-00624-1.
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Abstract
Background: Therapeutic antibodies for the treatment of neurological disease show great potential, but their applications are rather limited due to limited brain exposure. The most well-studied approach to enhance brain influx of protein therapeutics, is receptor-mediated transcytosis (RMT) by targeting nutrient receptors to shuttle protein therapeutics over the blood–brain barrier (BBB) along with their endogenous cargos. While higher brain exposure is achieved with RMT, the timeframe is short due to rather fast brain clearance. Therefore, we aim to increase the brain half-life of antibodies by binding to myelin oligodendrocyte glycoprotein (MOG), a CNS specific protein. Methods: Alpaca immunization with mouse/human MOG, and subsequent phage selections and screenings for MOG binding single variable domain antibodies (VHHs) were performed to find mouse/human cross-reactive VHHs. Their ability to increase the brain half-life of antibodies was evaluated in healthy wild-type mice by coupling two different MOG VHHs (low/high affinity) in a mono- and bivalent format to a β-secretase 1 (BACE1) inhibiting antibody or a control (anti-SARS-CoV-2) antibody, fused to an anti-transferrin receptor (TfR) VHH for active transport over the BBB. Brain pharmacokinetics and pharmacodynamics, CNS and peripheral biodistribution, and brain toxicity were evaluated after intravenous administration to balb/c mice. Results: Additional binding to MOG increases the Cmax and brain half-life of antibodies that are actively shuttled over the BBB. Anti-SARS-CoV-2 antibodies coupled with an anti-TfR VHH and two low affinity anti-MOG VHHs could be detected in brain 49 days after a single intravenous injection, which is a major improvement compared to an anti-SARS-CoV-2 antibody fused to an anti-TfR VHH which cannot be detected in brain anymore one week post treatment. Additional MOG binding of antibodies does not affect peripheral biodistribution but alters brain distribution to white matter localization and less neuronal internalization. Conclusions: We have discovered mouse/human/cynomolgus cross-reactive anti-MOG VHHs which have the ability to drastically increase brain exposure of antibodies. Combining MOG and TfR binding leads to distinct PK, biodistribution, and brain exposure, differentiating it from the highly investigated TfR-shuttling. It is the first time such long brain antibody exposure has been demonstrated after one single dose. This new approach of adding a binding moiety for brain specific targets to RMT shuttling antibodies is a huge advancement for the field and paves the way for further research into brain half-life extension.
| Type: | Article |
|---|---|
| Title: | Increasing brain half-life of antibodies by additional binding to myelin oligodendrocyte glycoprotein, a CNS specific protein |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s12987-025-00624-1 |
| Publisher version: | https://doi.org/10.1186/s12987-025-00624-1 |
| Language: | English |
| Additional information: | © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modifed the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, Blood-brain barrier, VHH, Myelin oligodendrocyte glycoprotein, Transferrin receptor, Brain half-life extension, beta-secretase 1, TRANSFERRIN RECEPTOR, PABINAFUSP ALPHA |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10207806 |
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