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

American Association for the Advancement of Science (AAAS) - Tập 16 Số 735 - 2024
Irene S. Khalek1,2,3, R. R. Senji Laxme4,2, Yen Thi Kim Nguyen5, Suyog Khochare4, Rohit N. Patel6, Jordan L. Woehl1,2,3, Jessica Smith1,2,3, Karen L. Saye-Francisco1,2, Y.T. Kim1,2,3, Laetitia Misson Mindrebo1,2,3, Quoc Tran1,2,3, Mateusz Kędzior1,2,3, Evy Boré6, Oliver Limbo1,2,3, Mohit Verma1,2,3, Robyn L. Stanfield5, Stefanie K. Menzies6, Stuart Ainsworth6, Robert A. Harrison6, Dennis R. Burton7,1,2,8, Devin Sok7,1,2,3, Ian A. Wilson5,9, Nicholas R. Casewell6, Kartik Sunagar4, Joseph G. Jardine1,2,3
1Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA 92037, USA.
2IAVI Neutralizing Antibody Center, Scripps Research Institute, La Jolla, CA 92037, USA.
3IAVI, New York, NY 10004, USA
4Evolutionary Venomics Lab, Centre for Ecological Sciences, Indian Institute of Science, Bangalore 560012, Karnataka, India.
5Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA
6Centre for Snakebite Research & Interventions, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK.
7Consortium for HIV/AIDS Vaccine Development (CHAVD), Scripps Research Institute, La Jolla, CA 92037, USA.
8Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139, USA
9Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, CA 92037, USA.

Tóm tắt

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.

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American Association for the Advancement of Science (AAAS)

Tập 16 Số 735

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