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

莱姆病(LD)是美国最流行的媒介传播疾病，多达30万人 一年的案子。该病是由几种伯氏疏螺旋体细菌引起的。 莱姆疏螺旋毛虫)，它们通过壁虱从啮齿动物水库传播给人类宿主。而短程的 抗生素通常能有效地消除细菌，相当数量的LD患者继续遭受长期的 长期、衰弱的后遗症，包括疼痛、疲劳、认知功能障碍和其他被称为后遗症的症状 治疗莱姆病(PTLD)。在美国，多达190万人患有PTLD。目前有 没有疫苗可以预防LD或PTLD。 我们正在开发一种针对LD和其他扁虱传播疾病(TBD)的免疫预防药物，其基础是 了解致病病原体用来逃避先天免疫的毒力机制。这些 病原体通过与人类结合来保护自己免受人类补体系统的消灭 补体抑制因子H(FH)，一种在血液中含量丰富的蛋白质。结合在细菌表面的FH可以阻断细菌表面的 激活替代补体途径，否则将摧毁细菌。我们已经制作了 重组蛋白是与莱姆疏螺旋体结合的FH结构域与恒定区 人IgG3(Fc3)，使用植物表达系统。在第一阶段，我们发现融合的Scr(6-7)/Fc3结合 对B.burgdorferi(BB)和B.afzelii(BA)，在人类补体存在的情况下，杀死细菌。我们有 还证明了Scr(6-7)/Fc3通过阻断细菌存活来预防小鼠的Bb和Ba感染 剂量低至2毫克/公斤，可用于喂食硬虱和硬虱对宿主的传播。 我们的总体目标是开发一种暴露前预防(PrEP)来预防LD和TBD。在此阶段 我们将优化Scr(6-7)/Fc3的体内药效和药代动力学。我们将进行 流程开发和开展初步的临床前安全性测试。 该项目是两个研究小组的合作，他们都是唯一有资格使其取得成功的 结论。行星生物技术公司(小型企业)将生产SCR(6，7)/FC3的新变种。 纽约州卫生局的林一品将评估这些蛋白质的中介能力 膜攻击复合体对莱姆氏和复发性热螺旋体的补体依赖性杀灭作用 人巨噬细胞吞噬巨噬细胞的吞噬功能及其在小鼠被蚤咬伤后阻断感染的能力 携带一种致命的莱姆疏螺旋体菌株。我们将选择一种主要的FH-FC免疫前预防药物候选药物， 扩大生产，对两种动物进行毒理学研究，并分析药代动力学和 人源化小鼠和非人灵长类动物的药效学。

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.