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: 10219129
• 负责人: KEITH WYCOFF
• 金额: $ 18.17万
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219129
• 关键词: Acute; Aftercare; Alternative Complement Pathway; Amino Acids; Animals; Antibiotic Therapy; Antibiotics; Antibodies; Antigens; Bacteria; Binding; Biological Assay; Biotechnology; Birds; Blood; Borrelia; Borrelia Infections; Borrelia burgdorferi Group; Businesses; Chimeric Proteins; Collaborations; Complement; Complement Activation; Complement Factor H; Complement Inactivators; Complement Membrane Attack Complex; Disease; Dose; Early Diagnosis; Europe; Fatigue; Foundations; Goals; Half-Life; Health; Healthcare Systems; Heart; Human; IgG1; IgG3; Immune response; Immunoglobulin Constant Region; Impaired cognition; In Vitro; Individual; Infection; Invaded; Lyme Disease; Mediating; Modification; Monoclonal Antibodies; Morbidity - disease rate; Mouse Strains; Mus; N-terminal; Natural Immunity; Neisseria gonorrhoeae; Nervous system structure; New York; North America; North Dakota; Order Spirochaetales; OspA protein; Pain; Patients; Phase; Planets; Plants; Protein Engineering; Proteins; Recombinant Fusion Proteins; Recombinants; Relapsing Fever; Research; Research Personnel; Rodent; Serum; Small Business Innovation Research Grant; Surface; Sushi Domain; Symptoms; Syndrome; System; Testing; Tick-Borne Diseases; Ticks; Time; United States; Universities; Vaccines; Variant; Vector-transmitted infectious disease; Virulence; Virulent; arm; bactericide; base; complement system; cost; design; disease diagnosis; disorder prevention; experimental study; high risk; improved; in vivo; infection risk; macrophage; mouse model; novel; pathogen; potency testing; pre-exposure prophylaxis; prevent; prophylactic; relapsing fever borrelia; tick transmission; tick-borne pathogen; vector tick

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 animal (bird, 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 IgG1 (Fc), using a plant expression system. These fusion proteins (SCR6,7/Fc and SCR(18-20)/Fc) bind to Lyme borreliae and, in the presence of human complement, kill the bacteria. The Fc gives the proteins a long half-life, which may allow them to be used as a pre-exposure prophylactic (PrEP) to prevent LD and TBDs. The overall goal of this Phase I SBIR is to demonstrate the efficacy of SCR6,7/Fc and SCR(18-20)/Fc in preventing Lyme borreliae infection in a mouse model of LD and determine a minimal effective dose. The project is a collaboration of three research groups that are uniquely qualified to bring it to a successful conclusion. Planet Biotechnology (the small business concern) will produce SCR6,7/Fc and SCR(18-20)/Fc and two novel Fc variants of both proteins designed to enhance complement activation. Catherine Brissette at the University of North Dakota 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. Yi- Pin Lin at the New York State Department of Health will evaluate the ability of the proteins to block infection when mice are bitten by ticks carrying a virulent Lyme borreliae strain. The mouse experiments are designed to both identify the most potent SCR6,7/Fc and SCR(18-20)/Fc variant and identify the minimal dose that is 100% effective in blocking infection when injected 1 day prior to tick challenge. If successful, we will have demonstrated the commercial potential of an FH/Fc fusion as a PrEP for LD and potentially other TBD.

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（Lyme borreliae），由蜱从动物（鸟类、啮齿动物）宿主传播给人类宿主。而 短疗程的抗生素通常能有效地消除相当数量的LD患者的细菌 继续遭受长期的，使人衰弱的后遗症，包括疼痛，疲劳，认知功能障碍和其他 症状称为治疗后莱姆病（PTLD）。在美国，多达190万人患有 PTLD。目前还没有疫苗可以预防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 1（Fc），使用植物表达系统。这些融合蛋白（SCR 6，7/Fc和SCR（18-20）/Fc）结合 莱姆病疏螺旋体，并在人类补体存在的情况下杀死细菌。Fc给蛋白质一个长的 半衰期，这可能允许它们用作暴露前预防剂（PrEP），以预防LD和TBD。 本I期SBIR的总体目标是证明SCR 6，7/Fc和SCR（18-20）/Fc在以下方面的疗效： 在LD小鼠模型中预防莱姆病螺旋体感染，并确定最小有效剂量。项目 是三个研究小组的合作，这三个研究小组具有独特的资格，能够成功地完成这项工作。星球 生物技术（小企业关注）将产生SCR 6，7/Fc和SCR（18-20）/Fc以及两种新的Fc 这两种蛋白质的变体被设计为增强补体激活。凯瑟琳·梅塞塞特在牛津大学 北达科他州将评估蛋白质介导补体依赖性杀死莱姆病的能力， 回归热螺旋体通过膜攻击复合物和调理吞噬作用通过人巨噬细胞。咦-- 纽约州卫生部的PinLin将评估这些蛋白质阻止感染的能力 当老鼠被带有莱姆病螺旋体的蜱叮咬时。小鼠实验的目的是 两者都鉴定了最有效的SCR 6，7/Fc和SCR（18-20）/Fc变体，并鉴定了100%的最小剂量 在蜱攻击前1天注射时有效阻断感染。如果成功，我们将证明 FH/Fc融合物作为LD和潜在其他TBD的PrEP的商业潜力。