RNA encoded nanobody-based immunotherapeutics targeting essential, host-interactive schistosome ectoenzymes

RNA 编码的基于纳米抗体的免疫疗法，靶向与宿主相互作用的重要血吸虫胞外酶

基本信息

批准号：
10571150
负责人：
Charles Bix Shoemaker
金额：
$ 24.75万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10571150
关键词：
Acetylcholinesterase Ache Adolescent Affinity Alpaca Binding Biochemical Chinese Hamster Ovary Cell Chronic Clinical Trials Country Data Development Disease Drug Kinetics Drug usage Ensure Enzymes Family Fc domain Genetic Transcription Goals Hand Helminths Human Immunize Immunotherapeutic agent In Vitro Infection Infection Control Infection prevention Intervention Laboratory Study Libraries Life Link Longevity Lymphocyte Messenger RNA Methods Molecular Molecular Target Mus Parasites Persons Phage Display Pharmaceutical Preparations Platyhelminths Praziquantel Praziquantel resistance Proteins Publishing RNA RNA Interference Reagent Recombinants Schistosoma Schistosoma mansoni Schistosomatidae Schistosomiasis Series Serum Surface Technology Testing Therapeutic Therapeutic Agents Therapeutic Intervention Tropical Disease Vaccines World Health Organization bone carbonate dehydratase dimer immunogenicity improved in vivo innovation nanobodies novel novel therapeutics phosphoric diester hydrolase prevent pyrophosphatase response success targeted treatment therapeutic RNA tool

项目摘要

Schistosomes are parasitic flatworms that cause a chronic, debilitating disease afflicting >200 million people in >70 countries. Since there are limited anti-schistosome drugs available and since these is no vaccine to prevent infection, we aim here to generate and test nanobody-based immunotherapeutics targeting essential surface-exposed parasite proteins as a novel intervention to control schistosomiasis. Nanobodies (camelid single- domain antibodies or VHHs) are small, versatile binding agents that can be multimerized for enhanced activities and delivered effectively by formulated mRNA. We have identified and characterized three S. mansoni tegumental ectoenzymes (SmNPP5, SmT-AChE, SmCA) that represent novel molecular targets for intervention to treat schistosomiasis. Each of the three enzymes is exposed at the host parasite interface and each is essential for the parasite to infect its vertebrate host. We aim to generate nanobodies that inhibit the function of these three target enzymes (each enzyme has been purified in functional form in CHO-S cells). The small size, stability to heat and pH extremes, low immunogenicity, and facility to express as multimers with enhanced activities, makes VHHs preferred therapeutic agents. We exploit advances in RNA therapeutics as our strategy to efficiently and economically deliver sustained levels of serum VHH-based therapeutics. Our overall goal is to generate a simple, practical, and potent anti-schistosome therapeutic that curtails disease at all stages of infection. In sum, we have identified new, well characterized, accessible and rational targets for anti-schistosome intervention, and we incorporate an innovative, novel, cutting-edge approach to control schistosomiasis. We have assembled a strong team and have on-hand all reagents and tools necessary to ensure the success of this project. Our data will act as a proof of principle supporting an approach that, in the longer term, could form the basis of a new therapeutic for human schistosomiasis, as well as for other debilitating helminth diseases.

血吸虫是一种寄生扁虫，会引起一种慢性、使人衰弱的疾病，使人痛苦不堪。超过 70 个国家/地区的超过 2 亿人口。由于抗血吸虫药物有限由于这些疫苗无法预防感染，因此我们的目标是生产和测试针对重要的表面暴露寄生虫的基于纳米抗体的免疫疗法蛋白质作为控制血吸虫病的新型干预措施。纳米抗体（骆驼单域抗体或 VHH）是小型、多功能的结合剂，可以多聚化增强活性并通过配制的 mRNA 有效传递。我们已经确定并表征了三种曼氏沙门氏菌外皮胞外酶（SmNPP5、SmT-AChE、 SmCA）代表了治疗血吸虫病的新分子靶标。三种酶中的每一种都暴露在宿主寄生虫界面，并且每种酶都是必需的让寄生虫感染其脊椎动物宿主。我们的目标是产生抑制这三种目标酶的功能（每种酶均已以功能形式纯化在 CHO-S 细胞中）。尺寸小，对热和极端 pH 值稳定，免疫原性低，以及表达为活性增强的多聚体的便利性，使 VHH 成为首选治疗剂。我们利用 RNA 疗法的进步作为我们的战略，以有效地并经济地提供持续水平的基于血清 VHH 的治疗。我们的整体目标是产生一种简单、实用且有效的抗血吸虫疗法减少感染各个阶段的疾病。总之，我们已经确定了新的、好的抗血吸虫干预的有特征的、可及的和合理的目标，以及我们采用创新、新颖、尖端的控制方法血吸虫病。我们组建了一支强大的团队并拥有所有试剂和确保该项目成功所必需的工具。我们的数据将作为证明支持一种方法的原则，从长远来看，该方法可以构成新的基础治疗人类血吸虫病以及其他使人衰弱的蠕虫疾病。