Synthetic development of a broadly neutralizing antibody against snake venom long-chain α-neurotoxins

Khalek, Irene S., Senji Laxme, R. R., Nguyen, Yen Thi Kim, Khochare, Suyog, Patel, Rohit, Woehl, Jordan, Smith, Jessica M., Saye-Francisco, Karen, Kim, Yoojin, Misson Mindrebo, Laetitia, Tran, Quoc, Kędzior, Mateusz, Boré, Evy, Limbo, Oliver, Verma, Megan, Stanfield, Robyn L., Menzies, Stefanie ORCID: https://orcid.org/0000-0002-9273-9296, Ainsworth, Stuart, Harrison, Robert, Burton, Dennis R., Sok, Devin, Wilson, Ian A., Casewell, Nicholas ORCID: https://orcid.org/0000-0002-8035-4719, Sunagar, Kartik and Jardine, Joseph G. (2024) 'Synthetic development of a broadly neutralizing antibody against snake venom long-chain α-neurotoxins'. Science Translational Medicine, Vol 16, Issue 735.

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Abstract

Snakebite envenoming is a major global public health concern for which improved therapies are urgently needed. The antigenic diversity present in snake venom toxins from various species presents a considerable challenge to the development of a universal antivenom. Here, we used a synthetic human antibody library to find and develop an antibody that neutralizes long-chain three-finger α-neurotoxins produced by numerous medically relevant snakes. Our antibody bound diverse toxin variants with high affinity, blocked toxin binding to the nicotinic acetylcholine receptor in vitro, and protected mice from lethal venom challenge. Structural analysis of the antibody-toxin complex revealed a binding mode that mimics the receptor-toxin interaction. The overall workflow presented is generalizable for the development of antibodies that target conserved epitopes among antigenically diverse targets, and it offers a promising framework for the creation of a monoclonal antibody–based universal antivenom to treat snakebite envenoming.

Item Type:	Article
Subjects:	WD Disorders of Systemic, Metabolic or Environmental Origin, etc > Animal Poisons > WD 410 Reptiles
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology Biological Sciences > Vector Biology Department
Digital Object Identifer (DOI):	https://doi.org/10.1126/scitranslmed.adk1867
SWORD Depositor:	JISC Pubrouter
Depositing User:	JISC Pubrouter
Date Deposited:	08 Mar 2024 09:59
Last Modified:	08 Mar 2024 09:59
URI:	https://archive.lstmed.ac.uk/id/eprint/24122

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