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.

抽象的蛇咬伤为人类健康带来了全球风险。超过125年，抗蛇毒包括动物衍生的多克隆血清免疫球蛋白G（IgG）。近几十年来，IgG消化为抗原结合碎片（2）被发现可减少非人类抗蛇毒的一些最严重的副作用。这些抗蛇毒是通过用单个蛇毒物免疫马或绵羊来获得的，以生产仅对那些特定蛇种有效的产品。目前有40多个抗毒剂针对单个蛇种的产品，这些治疗都提出了一些挑战，包括早期对动物等离子体衍生的抗蛇毒的不良反应，缩短半衰期，需要重复静脉注射（iv）医务人员输注，并正确识别特定的蛇。相反，人类重组的广泛中和抗体（BNAB）能够识别所有蛇的共享毒素毒液将使单一广谱产品的生产能够治疗所有蛇咬。人IgG bnabs 将避免非人类抗蛇毒固有的血清疾病和过敏反应的风险使用肌肉内（IM）输送和现场部署，具有3周半衰期的完整IgG产品。我们将扩展我们从第一阶段的工作，从独特的抗体库中鉴定出的完全人类的BNAB是特征和验证是具有广泛的体内功效。现在，Centivax将完成BNABS的发现与所有蛇毒共有的剩下的关键毒素，以开发venpen，宽阔的光谱，恒温，冻干，完全衍生的人类抗毒剂，对制冷或训练的需求减少，能够输送可登台的双室注射器。独特地，这些抗体是从A中分离出来的独特的超级免疫主题，其免疫系统已经发展出广泛中和，高度份化抗蛇毒液抗体通过17+以上的剂量自我免疫的历史多年的蛇毒。 Centivax正在开发Venpen Universal Antinom的途径，一种已经开发的长神经毒素的体内保护抗体，一种广泛的中和化抗体，bnabs 在开发的各个阶段，其他四个最危险的毒素。目标1：完成通过识别bnabs对抗Elapidae Snake家族中其余占主导地位的毒素的鸡尾酒和在体内显示保护整个毒液的整个毒液的医疗后果属。目标2：完成识别viperidae家族中主要毒素的bnabs的发展，特征体内防止医疗后果的毒性属属的保护。目标3：组合并制定最终的Venpen BNAB鸡尾酒，用于冻干，用于静脉输液和快速IM递送双室自动注射器。恒温的，广泛中和的潜在优势和应用反势已经达到了遥远的范围，包括最大程度地保护所有暴露于美国军方蛇咬伤的美国人人事在全国范围内部署了全球和农村社区。