Facile generation of biepitopic antibodies with intrinsic agonism for activating tumor necrosis factor receptors.

4-1BB CD137 FcγR OX40 TNF TNFR agonist antibody biparatopic mAb receptor clustering

Journal

Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030

Informations de publication

Date de publication:
17 Apr 2024
Historique:
received: 11 12 2023
revised: 28 02 2024
accepted: 29 03 2024
medline: 24 4 2024
pubmed: 24 4 2024
entrez: 23 4 2024
Statut: aheadofprint

Résumé

Agonist antibodies are being pursued for therapeutic applications ranging from neurodegenerative diseases to cancer. For the tumor necrosis factor (TNF) receptor superfamily, higher-order clustering of three or more receptors is key to their activation, which can be achieved using antibodies that recognize two unique epitopes. However, the generation of biepitopic (i.e., biparatopic) antibodies typically requires animal immunization and is laborious and unpredictable. Here, we report a simple method for identifying biepitopic antibodies that potently activate TNF receptors without the need for additional animal immunization. Our approach uses existing, receptor-specific IgGs, which lack intrinsic agonist activity, to block their corresponding epitopes, then selects single-chain antibodies that bind accessible epitopes. The selected antibodies are fused to the light chains of IgGs to generate human tetravalent antibodies. We highlight the broad utility of this approach by converting several clinical-stage antibodies against OX40 and CD137 (4-1BB) into biepitopic antibodies with potent agonist activity.

Identifiants

DOI: 10.1016/j.chembiol.2024.03.010 PMID: 38653243
pubmed: 38653243
pii: S2451-9456(24)00126-0
doi: 10.1016/j.chembiol.2024.03.010
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests P.T. is a member of the scientific advisory boards for Nabla Bio, Adimab, Aureka Biotechnologies, and Dualitas Therapeutics.

Auteurs

Harkamal S Jhajj (HS)

Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.

John S Schardt (JS)

Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.

Namir Khalasawi (N)

Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.

Emily L Yao (EL)

Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.

Timon S Lwo (TS)

Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.

Na-Young Kwon (NY)

Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.

Ryen L O'Meara (RL)

Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.

Alec A Desai (AA)

Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.

Peter M Tessier (PM)

Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: ptessier@umich.edu.

Classifications MeSH