Development of World's First Fully Human Broad Spectrum Anti-Snake Venom

摘要 毒蛇咬伤对人类健康构成全球性风险。125年来，抗蛇毒血清包括 动物源性多克隆血清免疫球蛋白G（IgG）。近几十年来，IgG被消化成抗原结合蛋白， 已发现Fab（2）片段可减少非人抗蛇毒血清的一些最严重的副作用。 这些抗蛇毒血清是通过用个别蛇毒免疫马或羊而获得的， 一种只对特定种类的蛇有效的产品。目前有超过40种抗蛇毒血清 针对个别蛇类的产品，这些治疗都存在几个挑战，包括早期- 对动物血浆衍生的抗蛇毒血清发生不良反应，半衰期缩短，需要重复静脉注射 (IV)由医务人员进行输液，并正确识别特定的蛇。相反，人类 重组广泛中和抗体（bnAbs）能够识别所有蛇中发现的共享毒素， 毒液将使生产单一的广谱产品，以治疗所有蛇咬伤。人IgG bnAb 将避免非人抗蛇毒血清固有的血清病和过敏反应风险， 使用肌内（IM）递送和现场部署具有3周半衰期的完整IgG产品。我们将扩展 我们的工作从第一阶段，其中完全人类，从一个独特的抗体库中鉴定的bnAb是 经表征和验证具有广泛的体内功效。现在，森蒂瓦克斯将完成bnAbs的发现， 针对所有蛇毒共有的其余关键毒素，用于开发VenPen，一种广谱， 热稳定，冻干，完全人源性抗蛇毒血清，减少了对冷藏或培训的需求， 能够IM递送可现场部署的双室注射器。独特的是，这些抗体分离自 独特的超免疫主体，其免疫系统已经发展出广泛中和，高度专业化， 抗蛇毒抗体通过记录的剂量递增的自我免疫史超过17+ 多年来，各种各样的蛇毒液。Centivax正在开发VenPen通用抗蛇毒血清， 已经开发了一种针对长神经毒素的广泛中和的体内保护性抗体， 其他四种最危险的毒素在不同的发展阶段。目标1：完成 通过鉴定针对Elapidae蛇科中剩余的主要毒素的bnAb， 证明了对具有医学后果的各种眼镜蛇属的全毒液的体内保护。 目标2：完成针对蝰蛇科主要毒素的bnAb鉴定的开发， 描述了在体内对不同种类的具有医学后果的蝰蛇的保护作用。目标3：联合收割机 并配制用于冻干的最终VenPen bnAb混合物，用于IV小瓶和快速IM递送 双室自动注射器。热稳定的、广泛中和的 抗蛇毒血清的影响深远，包括最大限度地保护所有美国人暴露于蛇咬伤，美国军方 工作人员部署在国内和国外以及世界各地的农村社区。

ABSTRACT Snakebite envenoming poses a global risk to human health. For over 125 years, antivenoms have consisted of animal-derived polyclonal serum immunoglobulin G (IgG). In recent decades, IgG digested into antigen-binding fragments Fab(2) has been found to reduce some of the most severe side-effects of non-human antivenom. These antivenoms are obtained by immunizing horses or sheep with individual snake venom, in order to produce a product that is effective only against those specific snake species. There are currently over 40 antivenom products against individual snake species, and these treatments all present several challenges, including early- onset adverse reactions to animal plasma derived antivenoms, shortened half-life, need for repeated intravenous (IV) infusion by medical personnel, and correct identification of the specific snake. In contrast, human recombinant broadly neutralizing antibodies (bnAbs) capable of recognizing shared toxins found across all snake venoms would enable the production of a single broad-spectrum product to treat all snakebite. Human IgG bnAbs would avoid the serum sickness and anaphylaxis risk inherent to non-human antivenom, making possible safe use of intramuscular (IM) delivery and field deployment of a full IgG product with a 3-week half-life. We will extend our work from the Phase I, where fully-human, bnAbs identified from a unique antibody repertoire were characterized and validated to have broad in vivo efficacy. Now, Centivax will complete the discovery of bnAbs against the remaining key toxins common to all snake venom, for the development of VenPen, a broad-spectrum, thermostabilized, lyophilized, fully human-derived antivenom, with reduced need for refrigeration or training and capable of IM delivery a field-deployable dual-chamber injector. Uniquely, these antibodies were isolated from a unique hyper-immune subject whose immune system has developed broadly neutralizing, highly-specialized anti-snake venom antibodies through a history of documented escalating dose self-immunizations over 17+ years with diverse snake venoms. Centivax is well on the way to developing VenPen universal antivenom, with one broadly-neutralizing in vivo protective antibody to long-neurotoxins already developed and bnAbs to the other four most dangerous toxins in various stages of development. Aim 1: Complete the development of the elapid cocktail by identifying bnAbs against the remaining dominant toxins in the Elapidae snake family and demonstrate protection in vivo against whole venom of diverse elapid snake genera of medical consequence. Aim 2: Complete the development of identifying bnAbs against dominant toxins in the Viperidae family, and characterize the protection in vivo against diverse genera of viperids of medical consequence. Aim 3: Combine and formulate the final VenPen bnAb cocktail for lyophilization for use in both IV vials as well as rapid IM delivery dual chamber auto-injector. The potential benefits and applications of a thermostabilized, broadly neutralizing anti-venom are far reaching including maximizing protection of all Americans exposed to snakebite, U.S. military personnel deployed both nationally and abroad, and rural communities worldwide.