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

世界上第一个全人类广谱抗蛇毒的开发

基本信息

批准号：
10699564
负责人：
Jacob Glanville
金额：
$ 99.56万
依托单位：
CENTIVAX INC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-14 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10699564
关键词：
Adverse event Adverse reactions American Anaphylaxis Animal Sources Animals Antibodies Antibody Repertoire Antivenins Bite Cell Line Cells Cessation of life Clinical Trials Dangerousness Development Disabled Persons Dose Elapidae Equus caballus Exposure to Fab Immunoglobulins Family Formulation Freeze Drying Funding Future Generations Goals Grant Half-Life Health Health Personnel Homologous Gene Human Immune Immune system Immunity Immunization Immunize Immunoglobulin G Individual Infusion procedures Injury Intramuscular Intravenous Intravenous infusion procedures Left Legal patent Libraries Life Medical Methodology Military Personnel Monitor Mus Neurotoxins Patients Persons Phase Phenotype Phylogenetic Analysis Plasma Population Production Protocols documentation Recombinants Recording of previous events Refrigeration Reporting Research Proposals Risk Robotics Route Rural Community Serotherapies Serum Serum Sickness Sheep Small Business Innovation Research Grant Snake Bites Snake Venoms Snakes Source Syringes Technology Temperature Time Toxin Training United States National Institutes of Health Vaccines Venoms Vial device Viperidae Work commercialization cost early experience early onset experimental study global health human monoclonal antibodies humanized antibody immunogenicity in vivo innovation lead candidate lead optimization male manufacture melting member middle age monomer neutralizing antibody neutralizing monoclonal antibodies scale up side effect single cell sequencing thermostability

项目摘要

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.

抽象的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被消化成抗原结合研究发现片段 Fab(2) 可以减少非人类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单独的蛇毒对马或羊进行免疫而获得的，以产生一种仅对那些特定蛇种有效的产品。目前有40多种抗蛇毒血清针对个别蛇种的产品，这些治疗方法都带来了一些挑战，包括早期- 动物血浆来源的抗蛇毒血清会出现不良反应，半衰期缩短，需要反复静脉注射（四）由医务人员输液，并正确识别具体蛇。相比之下，人类重组广泛中和抗体 (bnAb) 能够识别所有蛇中发现的共有毒素毒液将使单一广谱产品的生产能够治疗所有蛇咬伤。人 IgG bnAb 将避免非人类抗蛇毒血清固有的血清病和过敏反应风险，从而使安全成为可能使用半衰期为 3 周的完整 IgG 产品进行肌内 (IM) 递送和现场部署。我们将延长我们的工作从第一阶段开始，从独特的抗体库中鉴定出全人 bnAb 经表征和验证具有广泛的体内功效。现在，Centivax将完成bnAb的发现对抗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、完全源自人类的抗蛇毒血清，减少了冷藏或培训的需要，能够通过 IM 输送可现场部署的双室注射器。独特的是，这些抗体是从独特的超免疫受试者，其免疫系统已发展出广泛的中和性、高度专业化通过 17 岁以上有记录的递增剂量自我免疫史获得抗蛇毒抗体多年与各种蛇毒。 Centivax 正在开发 VenPen 通用抗蛇毒血清，一种针对已开发的长神经毒素的体内广泛中和性保护性抗体和针对其他四种最危险的毒素处于不同的发展阶段。目标1：完成开发通过识别针对 Elapidae 蛇科中剩余主要毒素的 bnAbs 和证明了体内对多种蛇属蛇毒的保护作用具有医学意义。目标 2：完成针对蝰蛇科主要毒素的 bnAb 鉴定开发，以及描述了对具有医疗后果的不同属蝰蛇的体内保护作用。目标 3：结合并配制最终的 VenPen bnAb 冻干混合物，用于静脉注射和快速肌内注射双室自动注射器。热稳定、广泛中和的潜在好处和应用抗蛇毒血清影响深远，包括最大限度地保护所有遭受蛇咬伤的美国人，美国军方部署在国内外以及世界各地农村社区的人员。