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， 其特征在于慢性肠道炎症和肠道微生物群失调。IBD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 （TNF-α）已成为治疗IBD的基石，但长期使用这些系统性 递送的生物制剂通常与作用的丧失和全身免疫抑制的风险相关。 为了克服这些障碍，我们开发了一种口服免疫先导物，命名为FZ 006， 益生菌布拉酵母（Saccharomycesboulardii）递送针对人TNF-α的有效双特异性中和抗体， 治疗溃疡性结肠炎在我们的初步研究中，我们产生了一个原型的S。 分泌抗小鼠TNF-α抗体（Sb-amTNF）的布拉氏菌菌株，并且概念验证数据表明 口服Sb-amTNF显著改善了小鼠的葡聚糖硫酸钠和细菌性结肠炎。在这个快速- 跟踪SBIR，我们将在I期研究中追求特定目标1，以进行生化和遗传学研究， FZ 006的特征。在II期研究中，Aim 2将研究 FZ 006和Aim 3将进行FZ 006在人TNF-α中的IND使能临床前疗效评价 转基因小鼠所有拟议的活动将由一个特殊的咨询/顾问团队指导， 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。待建议的研究完成后，我们会进行第IIb期研究， FZ 006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型的口腔 酵母免疫疗法对UC，慢性肠道疾病，造成巨大的发病率和财政 在美国和世界范围内的损失。

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.