| Autor: |
Tuan-Minh Do, Cécile Capdevila, Laurent Pradier, Véronique Blanchard, Mati Lopez-Grancha, Nathalie Schussler, Anke Steinmetz, Jochen Beninga, Denis Boulay, Philippe Dugay, Patrick Verdier, Nadine Aubin, Gihad Dargazanli, Catarina Chaves, Elisabeth Genet, Yves Lossouarn, Christophe Loux, François Michoux, Nicolas Moindrot, Franck Chanut, Thierry Gury, Stéphanie Eyquem, Delphine Valente, Olivier Bergis, Ercole Rao, Dominique Lesuisse |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
|
| Zdroj: |
Molecular Therapy: Methods & Clinical Development, Vol 19, Iss , Pp 58-77 (2020) |
| Druh dokumentu: |
article |
| ISSN: |
2329-0501 |
| DOI: |
10.1016/j.omtm.2020.08.014 |
| Popis: |
Most antibodies display very low brain exposure due to the blood-brain barrier (BBB) preventing their entry into brain parenchyma. Transferrin receptor (TfR) has been used previously to ferry antibodies to the brain by using different formats of bispecific constructs. Tetravalent bispecific tandem immunoglobulin Gs (IgGs) (TBTIs) containing two paratopes for both TfR and protofibrillar forms of amyloid-beta (Aβ) peptide were constructed and shown to display higher brain penetration than the parent anti-Aβ antibody. Additional structure-based mutations on the TfR paratopes further increased brain exposure, with maximal enhancement up to 13-fold in wild-type mice and an additional 4–5-fold in transgenic (Tg) mice harboring amyloid plaques, the main target of our amyloid antibody. Parenchymal target engagement of extracellular amyloid plaques was demonstrated using in vivo and ex vivo fluorescence imaging as well as histological methods. The best candidates were selected for a chronic study in an amyloid precursor protein (APP) Tg mouse model showing efficacy at reducing brain amyloid load at a lower dose than the corresponding monospecific antibody. TBTIs represent a promising format for enhancing IgG brain penetration using a symmetrical construct and keeping bivalency of the payload antibody. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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