Antibody-Biocide Fusions to Control Cryptosporidium

描述(由申请人提供)：隐孢子虫病是全球腹泻疾病的主要原因，是一种B类生物制剂。人类隐孢子虫和微小隐孢子虫这两个主要物种造成了90%以上的人类病例。微小隐孢子虫是一种人畜共患病，在牛中有一个宿主，在那里它是一种重要的经济致病原因。目前还没有治疗隐孢子虫病的特效药。该项目的目标是使获得许可的定向BiocideTM疗法达到准备就绪的地步，这种疗法针对影响人和牲畜的隐孢子虫物种，并在口服治疗隐孢子虫病方面有效。定向BiocideTM方法创建了一种重组融合蛋白，其中针对隐孢子虫子孢子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输送到子孢子表面。通过这种方法，定向的BiocideTM产品在比单独作用的子孢子中和抗体低得多的浓度下有效。额外的定向BiocidesTM将被开发成针对所有人类隐孢子虫病的致病物种，包括人隐孢子虫，并将在体外和多种动物模型中进行测试。将为这些适合人类使用的新型融合蛋白产品制定纯化策略。该项目还在继续研究，在转基因牛的牛奶中生产抗隐孢子虫导向的BiocidesTM，用于牲畜或大量人口的口服治疗。公共卫生相关性：隐孢子虫病是全世界腹泻疾病的最重要原因之一，影响免疫受损和免疫能力正常的个人，有时还会造成大规模暴发。隐孢子虫是一种B类生物制剂。目前还没有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了90%以上影响人类的病例。

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.