Nanobody-based recombinant antivenom for cobra, mamba and rinkhals bites

Ahmadi, Shirin and Burlet, Nick J. and Benard-Valle, Melisa and Guadarrama-Martínez, Alid and Kerwin, Samuel and Cardoso, Iara A. and Marriott, Amy E. and Edge, Rebecca J. and Crittenden, Edouard and Neri-Castro, Edgar and Fernandez-Quintero, Monica L. and Nguyen, Giang T. T. and O’Brien, Carol and Wouters, Yessica and Kalogeropoulos, Konstantinos and Thumtecho, Suthimon and Ebersole, Tasja Wainani and Dahl, Camilla Holst and Glegg-Sørensen, Emily U. and Jansen, Tom and Boddum, Kim and Manousaki, Evangelia and Rivera-de-Torre, Esperanza and Ward, Andrew B. and Morth, J. Preben and Alagón, Alejandro and Mackessy, Stephen P. and Ainsworth, Stuart and Menzies, Stefanie K. and Casewell, Nicholas R. and Jenkins, Timothy P. and Ljungars, Anne and Laustsen, Andreas H. (2025) Nanobody-based recombinant antivenom for cobra, mamba and rinkhals bites. Nature, 647. pp. 716-725. ISSN 0028-0836

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Abstract

Each year, snakebite envenoming claims thousands of lives and causes severe injury to victims across sub-Saharan Africa, many of whom depend on antivenoms derived from animal plasma as their sole treatment option1. Traditional antivenoms are expensive, can cause adverse immunological reactions, offer limited efficacy against local tissue damage and are often ineffective against all medically relevant snake species2. There is thus an urgent unmet medical need for innovation in snakebite envenoming therapy. However, developing broad-spectrum treatments is highly challenging owing to the vast diversity of venomous snakes and the complex and variable composition of their venoms3. Here we addressed this challenge by immunizing an alpaca and a llama with the venoms of 18 different snakes, including mambas, cobras and a rinkhals, constructing phage display libraries, and identifying high-affinity broadly neutralizing nanobodies. We combined eight of these nanobodies into a defined oligoclonal mixture, resulting in an experimental polyvalent recombinant antivenom that was capable of neutralizing seven toxin families or subfamilies. This antivenom effectively prevented venom-induced lethality in vivo across 17 African elapid snake species and markedly reduced venom-induced dermonecrosis for all tested cytotoxic venoms. The recombinant antivenom performed better than a currently used plasma-derived antivenom and therefore shows considerable promise for comprehensive, continent-wide protection against snakebites by all medically relevant African elapids.