A Yeast-based Immunotherapy against Clostridioides difficile infection

摘要 耐药艰难梭菌每年在美国造成超过2.9万人死亡， 这种感染是对公共卫生的紧急威胁(由疾控中心指定)。艰难梭菌感染的发生率 (CDI)和疾病严重程度近年来由于超强毒力和抗生素的出现- 耐药菌株。CDI是由艰难梭菌在肠道分泌的外毒素TcdA和TcdB引起的。 主持人。目前标准的抗生素治疗并不理想，而且复发率很高。 由于寄主侵染抗性的破坏。此外，目前还没有批准的预防措施 感染。我们的目标是开发一种新的基于酵母的免疫预防/治疗方法，以预防和治疗原发和 复发性CDI。我们通过设计一种名为酵母的益生菌开发出一种治疗用的铅。 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中的中和表位和TcdB中的2个中和表位。ABAB对TcdA和TcdA均有超强中和作用 对临床分离株的毒素具有广泛的抗菌活性。我们的初步数据显示，口服SB- ABAB可保护小鼠免受原发和复发的CDI。此快速通道SBIR的目标是：1) 对SB-ABAB进行表型和遗传特征鉴定，以确保其身份和质量；2)确定 SB-ABAB的药代动力学和安全性研究：3)建立SB-ABAB胶囊的临床配伍处方； 4)在CDI仔猪模型上进行IND使能效能研究。所有拟议的活动都将由 卓越的顾问/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 今后将继续进行Sb-ABAB的GMP制造、GLP毒理学和IND提交的第二阶段b。

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.