Selection and structural characterization of anti-TREM2 scFvs that reduce levels of shed ectodomain.

Epitopes / metabolism HEK293 Cells Humans Membrane Glycoproteins / metabolism Phagocytosis / physiology Receptors, Immunologic / metabolism Single-Chain Antibodies
Alzheimer's disease TREM2 X-ray crystallography microglia single-chain variable fragments

Journal

Structure (London, England : 1993)
ISSN: 1878-4186
Titre abrégé: Structure
Pays: United States
ID NLM: 101087697

Informations de publication

Date de publication:
04 11 2021
Historique:
received: 29 01 2021
revised: 11 05 2021
accepted: 09 06 2021
pubmed: 8 7 2021
medline: 17 3 2022
entrez: 7 7 2021
Statut: ppublish

Résumé

Mutations in TREM2, a receptor expressed by microglia in the brain, are associated with an increased risk of neurodegeneration, including Alzheimer's disease. Numerous studies support a role for TREM2 in sensing damaging stimuli and triggering signaling cascades necessary for neuroprotection. Despite its significant role, ligands and regulators of TREM2 activation, and the mechanisms governing TREM2-dependent responses and its cleavage from the membrane, remain poorly characterized. Here, we present phage display generated antibody single-chain variable fragments (scFvs) to human TREM2 immunoglobulin-like domain. Co-crystal structures revealed the binding of two scFvs to an epitope on the TREM2 domain distal to the putative ligand-binding site. Enhanced functional activity was observed for oligomeric scFv species, which inhibited the production of soluble TREM2 in a HEK293 cell model. We hope that detailed characterization of their epitopes and properties will facilitate the use of these renewable binders as structural and functional biology tools for TREM2 research.

Identifiants

DOI: 10.1016/j.str.2021.06.010 PMID: 34233201 PMC: PMC8575122
pubmed: 34233201
pii: S0969-2126(21)00214-8
doi: 10.1016/j.str.2021.06.010
pmc: PMC8575122
pii:
doi:

Substances chimiques

Epitopes 0
Membrane Glycoproteins 0
Receptors, Immunologic 0
Single-Chain Antibodies 0
TREM2 protein, human 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1241-1252.e5

Subventions

Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 106169/ZZ14/Z
Pays : United Kingdom

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests Y.C., S.J.N., P.J.A., and J.W. are employees of Eisai Ltd., and Eisai Inc.

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Auteurs

Aleksandra Szykowska (A)

Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.

Yu Chen (Y)

Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA.

Thomas B Smith (TB)

Alzheimer's Research UK Oxford Drug Discovery Institute, NDM Research Building, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7FZ, UK; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.

Charlotta Preger (C)

Structural Genomics Consortium (SGC), Karolinska Institutet, Karolinska University Hospital, Division of Rheumatology, Department of Medicine Solna, 171 76 Stockholm, Sweden.

Jingjing Yang (J)

Viva Biotech Ltd., 334 Aidisheng Road, Zhangjiang High-Tech Park, Shanghai 201203, China.

Dongming Qian (D)

Viva Biotech Ltd., 334 Aidisheng Road, Zhangjiang High-Tech Park, Shanghai 201203, China.

Shubhashish M Mukhopadhyay (SM)

Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.

Edvard Wigren (E)

Structural Genomics Consortium (SGC), Karolinska Institutet, Karolinska University Hospital, Division of Rheumatology, Department of Medicine Solna, 171 76 Stockholm, Sweden.

Stephen J Neame (SJ)

Eisai Ltd., Mosquito Way, Hatfield AL10 9SN, UK.

Susanne Gräslund (S)

Structural Genomics Consortium (SGC), Karolinska Institutet, Karolinska University Hospital, Division of Rheumatology, Department of Medicine Solna, 171 76 Stockholm, Sweden.

Helena Persson (H)

Science for Life Laboratory, Drug Discovery and Development & School of Engineering Sciences in Chemistry, Biotechnology and Health, Royal Institute of Technology (KTH), Stockholm, Sweden.

Peter J Atkinson (PJ)

Eisai Ltd., Mosquito Way, Hatfield AL10 9SN, UK.

Elena Di Daniel (E)

Alzheimer's Research UK Oxford Drug Discovery Institute, NDM Research Building, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7FZ, UK; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.

Emma Mead (E)

Alzheimer's Research UK Oxford Drug Discovery Institute, NDM Research Building, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7FZ, UK; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.

John Wang (J)

Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA.

John B Davis (JB)

Alzheimer's Research UK Oxford Drug Discovery Institute, NDM Research Building, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7FZ, UK; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK. Electronic address: john.davis@cmd.ox.ac.uk.

Nicola A Burgess-Brown (NA)

Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK. Electronic address: nicola.burgess-brown@cmd.ox.ac.uk.

Alex N Bullock (AN)

Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK. Electronic address: alex.bullock@cmd.ox.ac.uk.

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