FH-Fc as a Pre-Exposure Prophylactic for Tickborne Disease

FH-Fc 作为蜱传疾病的暴露前预防剂

• 批准号: 10477657
• 负责人: Yi-Pin Lin
• 金额: $ 100万
• 依托单位: PLANET BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-17 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477657
• 关键词: Acute; Aftercare; Alternative Complement Pathway; Amino Acid Sequence; Animals; Antibiotic Therapy; Antibiotics; Bacteria; Binding; Biological Assay; Biotechnology; Black-legged Tick; Blood; Borrelia; Borrelia afzelii; Borrelia burgdorferi; Borrelia burgdorferi Group; Businesses; Clinical Trials; Collaborations; Complement; Complement Factor H; Complement Inactivators; Complement Membrane Attack Complex; Development; Disease; Dose; Drug Kinetics; Early Diagnosis; Europe; Fatigue; Formulation; Future; Goals; Half-Life; Health; Healthcare Systems; Heart; Human; IgG3; Immune; Immunoglobulin Constant Region; Impaired cognition; In Vitro; Individual; Infection; Invaded; Ixodes; Lead; Lyme Disease; Lyme disease diagnosis; Macaca fascicularis; Measures; Mediating; Modeling; Modification; Morbidity - disease rate; Mus; Mutation; N-terminal; Natural Immunity; Nervous system structure; New York; North America; Nymph; Order Spirochaetales; Pain; Patients; Persons; Pharmaceutical Preparations; Phase; Planets; Plants; Process; Production; Prophylactic treatment; Proteins; Rattus; Recombinant Fusion Proteins; Recombinant Proteins; Relapsing Fever; Research; Research Personnel; Ricinus plant; Rodent; Small Business Technology Transfer Research; Surface; Sushi Domain; Symptoms; Syndrome; System; Testing; Tick-Borne Diseases; Ticks; Time; Toxicokinetics; Toxicology; Transgenic Organisms; United States; Vaccines; Variant; Vector-transmitted infectious disease; Virulence; Virulent; Work; animal safety; arm; base; complement system; cost; cross reactivity; design; drug candidate; drug development; feeding; high risk; human tissue; humanized mouse; improved; in vivo; infection risk; lead candidate; macrophage; neonatal Fc receptor; nonhuman primate; novel; pathogen; pharmacokinetics and pharmacodynamics; pre-exposure prophylaxis; preclinical safety; prevent; prophylactic; safety testing; scale up; stability testing; tick feeding; tick transmission; transmission process

Lyme disease (LD) is the most prevalent vector-borne disease in the United States, with up to 300,000 cases a year. LD is caused by several species of the spirochete bacteria Borrelia burgdorferi sensu lato (the Lyme borreliae), which are transmitted by ticks from rodent reservoirs to human hosts. While a short course of antibiotics is usually effective in eliminating the bacteria a sizeable number of LD patients continue to suffer long- term, debilitating sequelae, including pain, fatigue, cognitive dysfunction and other symptoms known as post- treatment Lyme disease (PTLD). As many as 1.9 million people in the US suffer from PTLD. There is currently no vaccine that can prevent LD or PTLD. We are developing an immunoprophylactic for LD and other tick-borne diseases (TBD) based on an understanding of the virulence mechanisms that the causal pathogens use to evade innate immunity. These pathogens protect themselves from elimination by the human complement system by binding to the human complement inhibitor Factor H (FH), a protein abundant in blood. FH bound to bacterial surfaces blocks the activation of the alternative complement pathway that would otherwise destroy the bacteria. We have produced recombinant proteins that are fusions of the FH domains that bind to Lyme borreliae with the constant region of human IgG3 (Fc3), using a plant expression system. In Phase I we showed that the fusion SCR(6-7)/Fc3 binds to B. burgdorferi (Bb) and B. afzelii (Ba) and, in the presence of human complement, kills the bacteria. We have also demonstrated that SCR(6-7)/Fc3 prevents Bb and Ba infection in mice by blocking bacterial survival in fed ticks and tick-to-host transmission at a dose as low as 2 mg/kg. Our overall goal is to develop a pre-exposure prophylactic (PrEP) to prevent LD and TBDs. In this Phase II STTR project we will optimize the in vivo efficacy and pharmacokinetics of SCR(6-7)/Fc3. We will conduct process development and carry out preliminary preclinical safety testing. The project is a collaboration of two research groups that are uniquely qualified to bring it to a successful conclusion. Planet Biotechnology Inc (the small business concern) will produce novel variants of SCR(6,7)/Fc3. Yi-Pin Lin at the New York State Department of Health will evaluate the ability of the proteins to mediate complement-dependent killing of Lyme and relapsing fever spirochetes by membrane attack complex and opsonophagocytosis by human macrophages and their ability to block infection when mice are bitten by ticks carrying a virulent Lyme borreliae strain. We will select a lead FH-Fc pre-immune prophylaxis drug candidate, scale up production, conduct toxicology studies in two animal species and analyze pharmacokinetics and pharmacodynamics in humanized mice and non-human primates.

莱姆病（LD）是美国最流行的病媒传播疾病， 案件一年。LD是由螺旋体细菌Borrelia burgdorferi sensu lato（广义伯氏疏螺旋体）的几个物种引起的。 莱姆病螺旋体），由蜱虫从啮齿动物宿主传播给人类宿主。虽然短期课程 抗生素通常能有效地消除细菌，相当多的LD患者继续遭受长期- 长期的，使人衰弱的后遗症，包括疼痛，疲劳，认知功能障碍和其他症状，被称为后， 莱姆病（Lyme Disease，PTLD）美国有190万人患有PTLD。目前 没有疫苗可以预防LD或PTLD。 我们正在开发一种免疫预防LD和其他蜱传疾病（TBD）的基础上， 了解致病病原体用来逃避先天免疫的毒力机制。这些 病原体通过与人补体系统结合来保护自身不被人补体系统消除 补体抑制因子H（FH），一种血液中丰富的蛋白质。结合到细菌表面的FH阻断了 激活替代补体途径，否则会破坏细菌。我们已经生产 重组蛋白，其是结合莱姆病疏螺旋体的FH结构域与 人IgG 3（Fc 3），使用植物表达系统。在第一阶段，我们发现融合SCR（6-7）/Fc 3结合 到B。burgdorferi（Bb）和B. afzelii（Ba），并且在人补体存在下杀死细菌。我们有 还证明SCR（6-7）/Fc 3通过阻断细菌存活来预防小鼠中的Bb和Ba感染 在进食蜱虫和蜱虫到宿主传播中，剂量低至2 mg/kg。 我们的总体目标是开发一种暴露前预防剂（PrEP）来预防LD和TBD。在这个阶段 II STTR项目中，我们将优化SCR（6-7）/Fc 3的体内功效和药代动力学。我们会进行 工艺开发并进行初步临床前安全性测试。 该项目是两个研究小组的合作，这两个研究小组具有独特的资格，能够成功地将其 结论Planet Biotechnology Inc（小型企业）将生产SCR（6，7）/Fc 3的新变体。 纽约州卫生部的Yi-Pin Lin将评估蛋白质介导 补体依赖性杀死莱姆病和回归热螺旋体的膜攻击复合物， 人类巨噬细胞的调理吞噬作用及其在小鼠被蜱叮咬时阻断感染的能力 携带莱姆病螺旋体病毒我们将选择一种主要的FH-Fc免疫前预防药物候选物， 扩大生产规模，在两种动物物种中进行毒理学研究，并分析药代动力学， 在人源化小鼠和非人灵长类动物中的药效学。