Novel Oral Yeast Immunotherapies for Ulcerative Colitis (Fast-track)

摘要 溃疡性结肠炎和克罗恩病是炎症性肠病(IBD)的主要形式，它是 以慢性肠道炎症和肠道微生物区系失调为特征。IBD已被认为与 生活质量差，经常导致需要住院和外科手术的并发症 在美国造成严重的发病率和经济损失。在过去的十年中，抗肿瘤坏死因子α (肿瘤坏死因子-a)已成为治疗IBD的基石，但长期使用这些药物对IBD 交付的生物制品往往与效果的丧失和全身性免疫抑制的风险有关。 为了克服这些障碍，我们开发了一种口服免疫治疗先导化合物，命名为FZ006，通过利用一种 益生菌布氏酵母菌将一种有效的抗人肿瘤坏死因子-a的双特异性中和抗体 用来治疗溃疡性结肠炎。在我们的初步研究中，我们生成了S。 分泌抗鼠肿瘤坏死因子-α抗体(SB-amTNF)的布氏杆菌株及概念验证数据 口服SB-amTNF可明显改善葡聚糖硫酸钠引起的小鼠细菌性结肠炎。在这一速度中- 跟踪SBIR，我们将在第一阶段研究中追求特定目标1，以进行生化和遗传 FZ006的表征。在第二阶段研究中，AIM 2将研究阿司匹林的药代动力学和安全性 FZ006和Aim 3将对FZ006在人肿瘤坏死因子-a中进行IND使能临床前疗效评估 转基因小鼠。所有拟议的活动将由一支特殊的咨询/顾问团队指导，该团队具有 在业务开发、生物制品监管、产品开发和规划方面的专业知识，以及 临床发展。待建议研究完成后，我们会进行第IIb阶段的发电工程。 FZ006的GMP产品，GLP毒理学和IND提交。我们的长期目标是开发一种新颖的口腔 酵母菌免疫疗法治疗UC，这是一种慢性肠道疾病，导致巨大的发病率和经济 在美国和全球的亏损。

Abstract Ulcerative colitis and Crohn’s disease are major forms of inflammatory bowel disease (IBD), which is characterized by chronic intestinal inflammation and gut microbiota dysbiosis. IBD has been associated with poor quality of life and often results in complications requiring hospitalizations and surgical procedures that causes significant morbidity and financial losses in the US. In past decade, anti-tumor necrosis factor alpha (TNF-a) have become the cornerstone of treatment for IBD, but the long-term use of these systemically delivered biologics is often associated with the loss of effects and the risks of generalized immunosuppression. To overcome the hurdles, we developed an oral immunotherapeutic lead, designated as FZ006, by utilizing a probiotic Saccharomyces boulardii to deliver a potent bi-specific neutralizing antibody against human TNF-a to the intestines in order to treat ulcerative colitis. In our preliminary studies, we generated a prototype of S. boulardii strain secreting an anti-mouse TNF-a antibody (Sb-amTNF) and proof-of-concept data demonstrating that oral Sb-amTNF significantly ameliorated dextran sodium sulfate and bacterial colitis in mice. In this Fast- track SBIR, we will pursue the Specific Aim 1 in Phase I study to perform biochemical and genetic characterization of FZ006. In Phase II studies, Aim 2 will investigate pharmacokinetic and safety profiles of FZ006, and Aim 3 will perform IND-enabling preclinical efficacy evaluation of FZ006 in human TNF-a transgenic mice. 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 generating GMP product of FZ006, GLP toxicology and IND submission. Our long-term goal is to develop a novel oral yeast immunotherapy against UC, a chronic intestinal disorder that causes tremendous morbidity and financial losses in the US and worldwide.