Snake venom protection by a cocktail of varespladib and broadly neutralizing human antibodies

• Published in: Cell Vol. 188; no. 12; pp. 3117 - 3134.e11
• Main Authors: Glanville, Jacob, Bellin, Mark, Pletnev, Sergei, Zhang, Baoshan, Andrade, Joel Christian, Kim, Sangil, Tsao, David, Verardi, Raffaello, Bedi, Rishi, Liao, Sindy, Newland, Raymond, Bayless, Nicholas L., Youssef, Sawsan, Tully, Ena S., Bylund, Tatsiana, Kim, Sujeong, Hirou, Hannah, Liu, Tracy, Kwong, Peter D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.06.2025
• Subjects: 3FTX; Acetates; Animals; Antibodies, Neutralizing - immunology; Antivenins - immunology; Antivenins - therapeutic use; antivenom; broadly neutralizing antibody; elapid; Epitopes - immunology; Humans; Indoles; Keto Acids; LNX; Memory B Cells - immunology; Mice; monoclonal antibody; neurotoxin-protective antibody; PLA2; Receptors, Nicotinic - chemistry; Receptors, Nicotinic - immunology; Receptors, Nicotinic - metabolism; Snake Bites - drug therapy; Snake Bites - immunology; Snake Bites - prevention & control; Snake Venoms - immunology; SNX; neurotoxin-protective antibody; broadly neutralizing antibody; antivenom; LNX; elapid; PLA2; monoclonal antibody; SNX; 3FTX
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2025.03.050

Snake envenomation is a neglected tropical disease, with 600 species causing over 100,000 deaths and 300,000 permanent disabilities in humans annually. Broadly neutralizing antibodies and broad chemical inhibitors have been proposed as solutions, but how to develop a therapeutically effective cocktail and the number of required components have been unclear. To address this gap, we iteratively recovered two broadly neutralizing antivenom antibodies from the memory B cells of a hyperimmune human donor with extensive snake venom exposure. The antibodies recognized conserved neutralizing epitopes on prevalent long and short snake neurotoxins, with crystal structures revealing antibody mimicry of the interfaces between these neurotoxins and their host target, the nicotinic acetylcholine receptor. We combined and tested these antibodies and the phospholipase inhibitor varespladib. A 3-component cocktail rescued animals from whole-venom challenge of all species in a 19-member WHO Category 1 and Category 2 elapid diversity set, with complete protection against most snakes observed. [Display omitted] •We report a systematic method for the construction of a broad-spectrum snake antivenom•Broadly neutralizing antitoxin antibodies were identified from a venom-immune subject•Broad toxin neutralization involved recognition of conserved toxin-receptor interfaces•A 3-agent cocktail blocked envenomation by 19 diverse WHO Category 1 and Category 2 snakes To combat snake bites from diverse species, this work identifies broadly neutralizing antibodies from a donor hyperimmune to snake venom, and it demonstrates that a combination of two of the identified antibodies with an inhibitory drug can protect mice from envenomation by medically important snakes found around the world.