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）是美国最普遍的媒介传播疾病，高达30万一年。 LD是由多种螺旋体细菌引起的，borrelia burgdorferi sensu lato（莱姆·伯雷利亚（Lyme Borreliae），由动物（鸟类，啮齿动物）水库传播到人类宿主。而a 简短的抗生素过程通常有效消除细菌数量相当多的LD患者继续遭受长期，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）。美国多达190万人遭受 PTLD。目前没有疫苗可以防止LD或PTLD。我们正在开发一种基于LD和其他tick传播疾病（TBD）的免疫原性了解因果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的结合来保护自己免受人类补体系统的消除补体抑制剂H（FH），一种丰富的血液蛋白质。 FH结合到细菌表面会阻塞替代补体途径的激活，否则会破坏细菌。我们已经生产了重组蛋白是与lyme borreliae结合的FH结构域的融合的蛋白质使用植物表达系统的人IgG1（FC）。这些融合蛋白（SCR6,7/FC和SCR（18-20）/FC）结合到莱姆伯氏菌，在人类补体的情况下，杀死细菌。 FC使蛋白质很长半衰期，这可以使它们被用作预防前的预防（PREP），以防止LD和TBD。 I阶段I SBIR的总体目标是证明SCR6,7/FC和SCR（18-20）/FC的功效防止LD小鼠模型中的莱姆疏螺旋体感染，并确定最小的有效剂量。项目是三个研究小组的合作，它们具有独特的资格，可以使其成功得出结论。行星生物技术（小型企业问题）将产生SCR6,7/FC和SCR（18-20）/FC和两个新颖的FC 两种蛋白质的变体旨在增强补体激活。大学的凯瑟琳·布里斯特（Catherine Brissette）北达科他州将评估蛋白质介导lyme和膜攻击复合物和人类巨噬细胞的肿瘤吞噬作用。 yi- 纽约州卫生部的PIN LIN将评估蛋白质阻断感染的能力当小鼠被带有强大的莱姆硼菌菌株的壁虱咬伤时。鼠标实验设计为同时识别最有效的SCR6,7/FC和SCR（18-20）/FC变体，并确定最小剂量为100％在tick挑战赛前1天注射时，有效阻止感染。如果成功，我们将证明 FH/FC融合的商业潜力作为LD的准备和其他TBD。