A Yeast-based Immunotherapy against Clostridioides difficile infection

摘要 在美国，耐抗生素的艰难梭菌每年造成29,000多人死亡， 该感染是对公共卫生的紧急威胁（如CDC所指定的）。C.菌感染 (CDI)近年来，由于高毒力和抗生素的出现， 耐药菌株CDI是由C.在结肠的艰难 主持人目前使用抗生素的标准治疗并不是最佳的，并且伴随着高复发率 这是由于破坏了宿主的定殖抗性。此外，没有批准预防 感染我们的目标是开发一种新的基于酵母的免疫预防/治疗剂， 经常性CDI。我们已经开发了一种治疗铅工程益生菌酵母，酵母菌 boulardii（Sb），分泌抗毒素ABAB（Sb-ABAB）。ABAB是4个VHH的融合蛋白，靶向2个不同的 TcdA中有2个中和表位，TcdB中有2个中和表位。ABAB在中和TcdA和TcdB方面是超强效的。 TcdB和广泛的活性，对毒素从64个临床分离。我们的初步数据显示，口服Sb- ABAB保护小鼠免受原发性和复发性CDI。这一快速通道SBIR的目标是：1） 表型和遗传表征Sb-ABAB以确保其身份和质量; 2）确定 3）开发临床相容的Sb-ABAB胶囊处方; 和4）在CDI的仔猪模型中进行IND使能功效研究。所有拟议的活动都将遵循 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。在完成建议的研究后，我们 将在未来进行Sb-ABAB的GMP生产、GLP毒理学和IND提交的IIb期。

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.