A Yeast-based Immunotherapy against Clostridioides difficile infection

基于酵母的针对艰难梭菌感染的免疫疗法

基本信息

批准号：
10380184
负责人：
Zhiyong Yang
金额：
$ 93.27万
依托单位：
FZATA, 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：
2020-08-01 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380184
关键词：
Animals Antibiotic Resistance Antibiotics Attention Biochemical Genetics Biological Products Blood Circulation Businesses Centers for Disease Control and Prevention (U.S.)Cessation of life Chemicals Chimeric Proteins Clinic Clinical Clinical Course of Disease Clostridium difficile Colon DNA cassette Data Databases Development Development Plans Diarrhea Dose Drug Kinetics Encapsulated Engineering Ensure Enteral Epitopes Excipients Exotoxins Family suidae Formulation Freezing Future Genetic Identity Gnotobiotic Goals Human Immunoglobulin A Immunoglobulin G Immunotherapy In Vitro Incidence Infection Inflammation Intestines Lead Life Modeling Mus Oral Pharmaceutical Preparations Phase Phenotype Physiology Powder dose form Prevention Probiotics Production Property Pseudomembranous Colitis Public Health Recurrence Regulation Saccharomyces Safety Severity of illness Site Small Business Innovation Research Grant System Technology Testing Therapeutic Tissues Toxicology Toxin Treatment Efficacy Validation Virulence Factors Yeasts analytical method antibiotic-associated diarrhea antitoxin base capsule clinical development colonization resistance efficacy evaluation efficacy study experimental study gastrointestinal genomic locus host colonization immunosuppressed microbiota novel phase 2 study pill porcine model preclinical efficacy prevent product development reconstitution resistant strain response screening standard care

项目摘要

Abstract Antibiotic-resistant Clostridioides difficile is responsible for more than 29,000 deaths in the US each year and the infection is an urgent threat (as designated by CDC) to public health. The incidence of C. difficile infection (CDI) and disease severity is increasing in recent years due to the emergence of hypervirulent and antibiotic- resistant strains. CDI is caused by the exotoxins TcdA and TcdB secreted by C. difficile in the colon of the host. Current standard treatment with antibiotics is not optimal and is accompanied by a high recurrence rate due to the disruption of host colonization resistance. Moreover, there is no approved prevention against the infection. Our goal is to develop a novel yeast-based immunoprophylactic/therapeutic against both primary and recurrent CDI. We have developed a therapeutic lead by engineering a probiotic yeast, Saccharomyces boulardii (Sb), to secrete an antitoxin ABAB (Sb-ABAB). ABAB is a fusion protein of 4 VHHs targeting 2 distinct neutralizing epitopes in TcdA and 2 in TcdB respectively. ABAB is ultrapotent in neutralizing both TcdA and TcdB and broadly active against toxins from 64 clinical isolates. Our preliminary data showed that oral Sb- ABAB protected mice from both primary and recurrent CDI. The objectives of this Fast-track SBIR are to: 1) phenotypically and genetically characterize Sb-ABAB to ensure its identity and quality; 2) determine pharmacokinetic and safety profiles of Sb-ABAB; 3) develop clinic-compatible formula of Sb-ABAB capsules; and 4) perform IND-enabling efficacy study in a piglet model of CDI. All proposed activities will be guided by an exceptional advisory/consultant team with specialized expertise in business development, biologics regulation, product development and planning, and clinical development. Upon the completion of the proposed studies, we will pursue Phase IIb for GMP manufacturing of Sb-ABAB, GLP toxicology and IND submission in the future.

抽象的具有抗生素耐药性的艰难梭菌每年导致美国超过 29,000 人死亡，该感染是对公共健康的紧急威胁（由疾病预防控制中心指定）。艰难梭菌感染的发生率近年来，由于高毒力和抗生素的出现，（CDI）和疾病严重程度不断增加耐药菌株。 CDI是由结肠中艰难梭菌分泌的外毒素TcdA和TcdB引起的主持人。目前的抗生素标准治疗并不是最佳的，并且复发率很高由于宿主定植抵抗力的破坏。此外，目前还没有经过批准的预防措施感染。我们的目标是开发一种新型的基于酵母的免疫预防/治疗剂，针对原发性和复发性 CDI。我们通过改造益生菌酵母（Saccharomyces）开发了一种治疗先导药物 boulardii (Sb)，分泌抗毒素 ABAB (Sb-ABAB)。 ABAB 是 4 个 VHH 的融合蛋白，针对 2 个不同的分别是 TcdA 中的中和表位和 TcdB 中的 2 个中和表位。 ABAB 具有超强中和 TcdA 和 TcdB 对 64 种临床分离株的毒素具有广泛活性。我们的初步数据表明口服 Sb- ABAB 保护小鼠免受原发性和复发性 CDI 的侵害。该快速通道 SBIR 的目标是：1) 对 Sb-ABAB 进行表型和遗传表征，以确保其特性和质量； 2）确定 Sb-ABAB 的药代动力学和安全性特征； 3）开发临床相容的Sb-ABAB胶囊配方； 4) 在 CDI 仔猪模型中进行 IND 有效性研究。所有拟议的活动都将由卓越的咨询/顾问团队，在业务开发、生物制品监管、产品开发和规划以及临床开发。完成拟议的研究后，我们未来将进行 Sb-ABAB GMP 生产、GLP 毒理学和 IND 提交的 IIb 期。