Development of low-cost, field-ready nanobodies against snake venom

开发低成本、可现场使用的抗蛇毒纳米抗体

• 批准号: 10255596
• 负责人: GEOFFREY A CHANG
• 金额: $ 25.59万
• 依托单位: VENOMYX, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10255596
• 关键词: Address; Affect; Affinity; Africa; Animals; Antibodies; Antigens; Antivenins; Asia; Binding; Biodistribution; Biological; Biological Assay; Biological Response Modifier Therapy; Categories; Cessation of life; Characteristics; Clinical; Clinical Trials; Cold Chains; Collaborations; Complementarity Determining Regions; Complex; Consequentialism; Developing Countries; Development; Diversity Library; Dose; Drug Kinetics; Drug usage; Economics; Epitopes; Equus caballus; Exposure to; Flow Cytometry; Future; Genetic Recombination; Geographic Locations; Goals; Health; Health Professional; Human; Immunization; Immunoglobulin Fragments; Immunohistochemistry; In Vitro; Incidence; Individual; Interferometry; International; Label; Latin America; Leadership; Left; Life; Mainstreaming; Mammals; Medical Economics; Metalloproteases; Military Personnel; Modernization; Molecular Weight; Oceania; Participant; Pathology; Patients; Penetration; Phospholipase A2; Populations at Risk; Preclinical Testing; Production; Property; Proteins; Public Health; Recombinants; Risk; Safety; Sampling; Serine Protease; Shark; Sheep; Snake Venoms; Snakes; Specificity; System; Techniques; Technology; Temperature; Testing; Therapeutic; Therapeutic antibodies; Time; Tissues; Toxicology; Toxin; United States; Validation; Variant; Venoms; Work; World Health Organization; Yeasts; base; cost; drug discovery; efficacy study; experience; flexibility; health training; hyperimmunization; immunogenic; immunogenicity; improved; in vivo; interest; member; nanobodies; neglect; neglected tropical diseases; patient population; pet animal; physically handicapped; pre-clinical; preclinical trial; remote location; response; socioeconomics; thermostability

PROJECT SUMMARY Snakebite constitutes one of the largest and most tenacious public health issues on a global scale. Every year, up to 5 million people will suffer snakebite envenomation, causing approximately 125,000 deaths and 400,000 left with permanent physical disability. Nearly 8,000 snakebites occur in the United States each year. The regions most affected are in Asia, Africa, Latin America, and Oceania where snakebite has a high socioeconomic impact on both the local and global economies. As of 2017, the WHO has labeled snakebite as a Category A Neglected Tropical Disease. Therapies for snakebite victims are animal-based antivenoms, which for over a century have consisted of the whole sera or purified antibodies of large mammals (horses and sheep) that have been hyperimmunized with snake venoms. These antivenoms contain a relatively small fraction of effective venom- specific antibodies, requiring multiple doses that can cause adverse immunogenic effects in patients. Antivenom also has relatively high batch-to-batch variation and its efficacies are largely species-specific, requiring a match between the species used in immunization and the venom in need of neutralization. The economics of antivenom manufacture are challenging to scale to profitability, leading to scarce and unreliable supplies. Further complicating the issue is the reliance on cold chain storage and distribution and consequential lack of availability to snakebite victims in remote locations where the bulk of envenomations occur. Despite these issues, antivenom is one of the few biological therapies that has yet to enter the modern era of mainstream biologics, despite the presence of an overwhelmingly large patient population. In order to address the complex medical and economic requirements of snakebite, we propose the use of an oligoclonal mixture of single-domain antibodies, also known as nanobodies (Nbs). These antibody fragments (15 kDa in molecular weight) are the variable heavy chain regions (VHH) of camelid or shark antibodies with several attractive properties for the space, including low immunogenicity, high biodistribution and tissue penetration, low cost of scaled production, and tunable pharmacokinetics. Nbs are also often highly thermostable, allowing for accessibility in much-needed developing countries. Nbs have long, flexible complementarity-determining regions (CDRs) which can increase the likelihood of binding conserved or cryptic epitopes on these toxins, allowing for broad species coverage critical to pan-specificities. Towards this end, Venomyx Therapeutics, Inc. is working in collaboration with the Chang lab at UCSD to exploit a powerful platform to discover Synthetically Evolved Nbs (SENs) for high affinity and efficacy against venom targets of interest. Together with the snake venom expertise at Venomyx, we will generate low-cost, thermostable, broadly-effective Nbs against snake venom toxin as leads for future development, preclinical testing, and eventual human trials to neutralize venom from snakebite.

项目摘要 在全球范围内，Snakebite构成了最大，最顽强的公共卫生问题之一。每年， 多达500万人将遭受蛇咬的侵害，造成约125,000人死亡和40万人 留有永久性的身体残疾。每年在美国发生近8,000蛇。地区 受蛇咬伤具有很高的社会经济影响的亚洲，非洲，拉丁美洲和大洋洲的影响最大 在地方和全球经济体上。截至2017年，世卫组织已将Snakebite标记为忽视的类别 热带疾病。蛇咬受害者的疗法是基于动物的抗蛇毒物，一个多世纪以来 由大型哺乳动物（马和绵羊）的整个血清或纯化的抗体组成 用蛇毒液过度免疫。这些抗蛇云含有相对较小的有效毒液 - 特定的抗体，需要多种剂量，这可能会对患者产生不良的免疫原性作用。抗蛇毒 还具有相对较高的批处理变化，其功效在很大程度上是特定于物种的，需要匹配 在免疫中使用的物种与需要中和的毒液之间。抗蛇毒的经济学 制造业在扩展盈利能力方面具有挑战性，导致稀缺和不可靠的供应。更远 使问题复杂化的是依赖冷链存储和分配以及缺乏可用性 在发生大部分毒化的偏远地区的蛇咬伤。尽管存在这些问题，但 是尚未进入现代生物制剂的少数几种生物疗法之一，尽管 存在绝大多数的患者人群。 为了满足蛇咬的复杂医疗和经济要求，我们建议使用 单域抗体的寡克隆混合物，也称为纳米剂（NBS）。这些抗体片段（15 分子量中的KDA是骆驼或鲨鱼抗体的可变重链区域（VHH） 该空间的有吸引力的特性，包括低免疫原性，高生物分布和组织渗透，低 扩展生产和可调药代动力学的成本。 NBS通常也很高温，可以 急需的发展中国家的可及性。 NB具有长而灵活的互补性区域 （CDR）可以增加这些毒素上结合或神秘表位的可能性，从而允许 广泛的物种覆盖范围至关重要。为此，Venomyx Therapeutics，Inc。正在工作 与UCSD的Chang Lab合作，利用一个强大的平台来发现合成发展的NBS （Sens）针对感兴趣的毒液靶标的高亲和力和功效。与蛇毒专业知识一起 在Venomyx，我们将针对蛇毒毒素产生低成本，可热稳定的，广泛有效的NB 为了将来开发，临床前测试和最终的人类试验，以中和蛇咬的毒液。