Antibody-Biocide Fusions to Control Cryptosporidium

描述（由申请人提供）：隐孢子虫病是世界范围内腹泻疾病的主要原因，是B类生物威胁剂。人类隐孢子虫和细小隐孢子虫这两种主要的隐孢子虫导致了人类90%以上的病例。小锥虫是人畜共患的，在牛中有宿主，是一种经济上重要的致病原因。目前还没有针对隐孢子虫病的特效药。该项目的目标是准备好向外许可定向生物杀灭剂治疗方法，这些治疗方法针对影响人和牲畜的隐孢子虫物种，并且在口服治疗隐孢子虫病方面有效。Directed BiocideTM方法创建了一种重组融合蛋白，其中针对隐孢子虫孢子体表面表位的抗体将含有天然抗菌肽或酶的抗隐孢子虫杀菌剂递送到孢子体表面。通过这种方法，Directed BiocideTM产品在比单独作用的孢子子中和抗体低得多的浓度下有效。将开发更多的定向生物杀灭剂，以针对人类隐孢子虫病的所有致病物种，包括人隐孢子虫，并将在体外和多种动物模型中进行测试。这些新的融合蛋白产品将建立适合人类使用产品的纯化策略。该项目还在继续研究在转基因牛的奶中生产抗隐孢子虫定向杀菌剂，用于牲畜或大量种群的口服治疗。公共卫生相关性：隐孢子虫病是世界范围内腹泻疾病的最重要原因之一，影响免疫功能低下和免疫功能正常的个体，有时引起大规模暴发。隐孢子虫是B类生物威胁剂。目前尚无治疗隐孢子虫病的有效药物。该项目开发了一种新的重组蛋白药物来中和两种隐孢子虫，这两种隐孢子虫导致90%以上的人类感染病例。

DESCRIPTION (provided by applicant): Cryptosporidiosis is a leading cause of diarrheal disease worldwide and is a category B biothreat agent. Two major species, Cryptosporidium hominis and Cryptosporidium parvum are responsible for over ninety percent of cases in man. C. parvum is zoonotic, with a reservoir in cattle, where it is an economically important cause of disease. There is currently no specific drug for cryptosporidiosis. The goal of this project is to bring to the point of readiness for out-licensing Directed BiocideTM therapeutics which target Cryptosporidium species affecting man and livestock and which are effective in oral treatment of cryptosporidiosis. The Directed BiocideTM approach creates a recombinant fusion protein in which an antibody targeting a surface epitope on Cryptosporidium sporozoites delivers an anticryptosporidial biocide comprising a natural antimicrobial peptide or enzyme to the surface of the sporozoite. With this approach Directed BiocideTM products are effective at far lower concentrations than a sporozoite-neutralizing antibody acting alone. Additional Directed BiocidesTM will be developed to target all causal species of human cryptosporidiosis, including C. hominis, and will be tested in vitro and in multiple animal models. Purification strategies will be established for these novel fusion protein products which will be suitable for human use products. The project also continues research to produce anticryptosporidial Directed BiocidesTM in milk of transgenic cattle for oral treatment of livestock or large populations. PUBLIC HEALTH RELEVANCE: Cryptosporidiosis is one of the most important causes of diarrheal disease worldwide, affecting both immunocompromised and immunocompetent individuals and sometimes causing mass outbreaks. Cryptosporidium is a Category B biothreat agent. Currently there is no effective drug available for cryptosporidiosis. This project develops a novel recombinant protein drug to neutralize the two species of Cryptosporidium that are responsible for over 90% of cases affecting humans.