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

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2025-05-02 DOI:10.1016/j.cell.2025.03.050

Jacob Glanville, Mark Bellin, Sergei Pletnev, Baoshan Zhang, Joel Christian Andrade, Sangil Kim, David Tsao, Raffaello Verardi, Rishi Bedi, Sindy Liao, Raymond Newland, Nicholas L. Bayless, Sawsan Youssef, Ena S. Tully, Tatsiana Bylund, Sujeong Kim, Hannah Hirou, Tracy Liu, Peter D. Kwong

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Abstract

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.

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由varespladib和广泛中和的人类抗体混合而成的蛇毒保护

蛇中毒是一种被忽视的热带疾病，每年有600种蛇导致10万多人死亡，30万人永久残疾。广泛中和抗体和广泛的化学抑制剂已被提出作为解决方案，但如何开发一种治疗有效的鸡尾酒和所需成分的数量尚不清楚。为了解决这一差距，我们从大量暴露于蛇毒的超免疫人类供体的记忆B细胞中反复恢复了两种广泛中和的抗蛇毒抗体。这些抗体识别了流行的长和短蛇神经毒素的保守中和表位，其晶体结构揭示了这些神经毒素与其宿主靶点烟碱乙酰胆碱受体之间界面的抗体模拟。我们结合并测试了这些抗体和磷脂酶抑制剂varespladib。一种由三种成分组成的鸡尾酒拯救了19个成员组成的世卫组织第一类和第二类蛇类多样性集合中所有物种的动物，使它们免受全毒液的攻击，并完全保护它们免受大多数观察到的蛇的攻击。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.