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

• 批准号: 10337793
• 负责人: Zhiyong Yang
• 金额: $ 55.44万
• 依托单位: FZATA, INC.
• 依托单位国家: 美国
• 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/10337793
• 关键词: Animals; Antibiotic Resistance; Antibiotics; Attention; Biochemical Genetics; Biological; 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

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 抗生素耐药梭菌艰难梭菌每年在美国造成29,000多人死亡， 感染是对公共卫生的紧急威胁（由CDC指定）。艰难梭菌感染的发生率 （CDI）和疾病的严重程度近年来由于高呼吸和抗生素的出现而增加 抗性菌株。 CDI是由Exotoxins TCDA和TCDB引起的，由艰难梭菌在结肠中分泌 主持人。当前使用抗生素的标准治疗不是最佳的，并且伴随着高复发率 由于宿主定植抗性的破坏。此外，没有批准的预防 感染。我们的目标是开发一种基于酵母的新型免疫原性/针对原发性和 经常性CDI。我们通过设计益生菌酵母，糖疗法的铅开发了治疗铅 Boulardii（SB），分泌抗毒素ABAB（SB-ABAB）。 ABAB是4个靶向2个不同的融合蛋白 TCDA中和tCDB中的2个中和表位。 ABAB在中和TCDA和 TCDB和对64个临床分离株的毒素广泛活跃。我们的初步数据表明口服SB- ABAB保护的小鼠免受原发性和复发性CDI的影响。此快速轨道SBIR的目标是：1） 表型和遗传学的特征是SB-ABAB，以确保其身份和质量； 2）确定 SB-ABAB的药代动力学和安全概况； 3）开发SB-ABAB胶囊的临床兼容公式； 4）在CDI的仔猪模型中执行辅助功效研究。所有拟议的活动将由 具有专业专业知识，生物制剂监管专业知识的卓越咨询/顾问团队， 产品开发和计划以及临床开发。拟议的研究完成后，我们 将来将攻读IIB阶段，用于SB-ABAB，GLP毒理学和IND提交的GMP制造。