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

基本信息

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
项目类别：
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

项目摘要

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) 是美国最流行的媒介传播疾病，高达 300,000 每年病例数。 LD 是由几种螺旋体细菌伯氏疏螺旋体 (Borrelia burgdorferi sensu lato)（伯氏疏螺旋体）引起的。莱姆疏螺旋体），通过蜱从动物（鸟类、啮齿动物）宿主传播至人类宿主。虽然一个短期抗生素疗程通常可以有效消除相当多的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)。美国有多达 190 万人患有此病 PTLD。目前尚无疫苗可以预防 LD 或 PTLD。我们正在开发一种针对 LD 和其他蜱传疾病 (TBD) 的免疫预防药物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补体系统结合来保护自己不被人类补体系统消除。补体抑制剂 H 因子 (FH)，一种血液中丰富的蛋白质。 FH 与细菌表面结合可阻断激活替代补体途径，否则会破坏细菌。我们已经生产了重组蛋白是结合莱姆疏螺旋体的 FH 结构域与恒定区的融合体人 IgG1 (Fc)，使用植物表达系统。这些融合蛋白（SCR6,7/Fc 和 SCR(18-20)/Fc）结合莱姆疏螺旋体，在人类补体存在的情况下，杀死细菌。 Fc 赋予蛋白质长半衰期，这可能使它们可以用作暴露前预防剂 (PrEP)，以预防 LD 和 TBD。 I 期 SBIR 的总体目标是证明 SCR6,7/Fc 和 SCR(18-20)/Fc 在在 LD 小鼠模型中预防莱姆疏螺旋体感染并确定最低有效剂量。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质，能够取得成功。行星生物技术（小型企业）将生产 SCR6,7/Fc 和 SCR(18-20)/Fc 以及两种新型 Fc 两种蛋白质的变体旨在增强补体激活。凯瑟琳·布里塞特 (Catherine Brissette) 大学北达科他州将评估这些蛋白质介导补体依赖性杀死莱姆病和回归热螺旋体通过膜攻击复合物和人类巨噬细胞的调理吞噬作用。伊- 纽约州卫生部的 Pin Lin 将评估这些蛋白质阻止感染的能力当老鼠被携带有毒莱姆疏螺旋体菌株的蜱虫叮咬时。小鼠实验的目的是两者都确定了最有效的 SCR6,7/Fc 和 SCR(18-20)/Fc 变体，并确定了 100% 的最小剂量在蜱攻击前 1 天注射可有效阻止感染。如果成功的话，我们将证明 FH/Fc 融合作为 LD 和其他潜在 TBD 的 PrEP 的商业潜力。