Development of a pan-tau multivalent nanobody that binds tau aggregation motifs and recognizes pathological tau aggregates.

Autor:	McArthur N; School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA., Kang B; School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA., Rivera Moctezuma FG; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA., Shaikh AT; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA., Loeffler K; School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA., Bhatt NN; Mitchell Center for Neurodegenerative Disease, University of Texas Medical Branch, Galveston, Texas, USA.; Department of Neurology, University of Texas Medical Branch, Galveston, Texas, USA., Kidd M; Mitchell Center for Neurodegenerative Disease, University of Texas Medical Branch, Galveston, Texas, USA.; Department of Neurology, University of Texas Medical Branch, Galveston, Texas, USA., Zupancic JM; Department of Chemical Engineering, University of Michigan, North Campus Research Complex, Ann Arbor, Michigan, USA.; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA., Desai AA; Department of Chemical Engineering, University of Michigan, North Campus Research Complex, Ann Arbor, Michigan, USA.; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA., Djeddar N; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA., Bryksin A; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA., Tessier PM; Department of Chemical Engineering, University of Michigan, North Campus Research Complex, Ann Arbor, Michigan, USA.; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA.; Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan, USA.; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA., Kayed R; Mitchell Center for Neurodegenerative Disease, University of Texas Medical Branch, Galveston, Texas, USA.; Department of Neurology, University of Texas Medical Branch, Galveston, Texas, USA., Wood LB; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA.; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA.; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA., Kane RS; School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA.; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA.; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA.
Jazyk:	angličtina
Zdroj:	Biotechnology progress [Biotechnol Prog] 2024 Sep-Oct; Vol. 40 (5), pp. e3463. Date of Electronic Publication: 2024 Apr 03.
DOI:	10.1002/btpr.3463
Abstrakt:	Alzheimer's disease and other tauopathies are characterized by the misfolding and aggregation of the tau protein into oligomeric and fibrillar structures. Antibodies against tau play an increasingly important role in studying these neurodegenerative diseases and the generation of tools to diagnose and treat them. The development of antibodies that recognize tau protein aggregates, however, is hindered by complex immunization and antibody selection strategies and limitations to antigen presentation. Here, we have taken a facile approach to identify single-domain antibodies, or nanobodies, that bind to many forms of tau by screening a synthetic yeast surface display nanobody library against monomeric tau and creating multivalent versions of our lead nanobody, MT3.1, to increase its avidity for tau aggregates. We demonstrate that MT3.1 binds to tau monomer, oligomers, and fibrils, as well as pathogenic tau from a tauopathy mouse model, despite being identified through screens against monomeric tau. Through epitope mapping, we discovered binding epitopes of MT3.1 contain the key motif VQIXXK which drives tau aggregation. We show that our bivalent and tetravalent versions of MT3.1 have greatly improved binding ability to tau oligomers and fibrils compared to monovalent MT3.1. Our results demonstrate the utility of our nanobody screening and multivalent design approach in developing nanobodies that bind amyloidogenic protein aggregates. This approach can be extended to the generation of multivalent nanobodies that target other amyloid proteins and has the potential to advance the research and treatment of neurodegenerative diseases. (© 2024 The Authors. Biotechnology Progress published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.)
Databáze:	MEDLINE
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