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

治疗溃疡性结肠炎的新型口服酵母免疫疗法（快速通道）

• 批准号: 10610406
• 负责人: Zhiyong Yang
• 金额: $ 95.05万
• 依托单位: FZATA, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610406
• 关键词: Acute; Adoptive Transfer; Adult; Animal Disease Models; Animals; Antibodies; Antibody-mediated protection; Attention; Bacteria; Biochemical; Biological Assay; Biological Products; Bispecific Antibodies; Businesses; Chronic; Circulation; Clinic; Colitis; Colon; Crohn' s disease; Data; Development; Disease; Drug Kinetics; Ensure; Excretory function; Future; Genetic; Genetic Identity; Goals; Health; Hospitalization; Human; Immunoglobulin A; Immunoglobulin G; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestinal Diseases; Intestinal Secretions; Intestines; Lead; Microcapsules drug delivery system; Modeling; Morbidity - disease rate; Mucous Membrane; Mus; Operative Surgical Procedures; Oral; Oral Medicine; Outcome; Patients; Pharmaceutical Preparations; Phase; Phenotype; Probiotics; Process; Property; Quality of life; Regulation; Risk; Saccharomyces; Safety; Small Business Innovation Research Grant; Sodium Dextran Sulfate; System; T-Lymphocyte; TNF gene; Therapeutic; Tissues; Toxicology; Transgenic Mice; Treatment Cost; Treatment Efficacy; Ulcerative Colitis; Validation; Yeasts; analytical method; clinical development; design; dextran sulfate sodium induced colitis; dysbiosis; efficacy evaluation; efficacy study; fighting; gastrointestinal; genomic locus; gut inflammation; gut microbiota; immunogenicity; immunosuppressed; improved; intravenous administration; neutralizing antibody; novel; phase 1 study; phase 2 study; preclinical efficacy; product development; prototype; response; therapeutic protein

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.

抽象的 溃疡性结肠炎和克罗恩病是炎症性肠病 (IBD) 的主要形式， 其特征是慢性肠道炎症和肠道微生物群失调。 IBD 已与 生活质量差，并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。近十年来，抗肿瘤坏死因子α (TNF-a)已成为IBD治疗的基石，但长期全身使用这些药物 递送的生物制剂通常与效果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治疗药物，命名为 FZ006，通过利用 益生菌布拉酵母菌可提供针对人 TNF-a 的有效双特异性中和抗体 肠道以治疗溃疡性结肠炎。在我们的初步研究中，我们生成了 S 的原型。 分泌抗小鼠 TNF-a 抗体 (Sb-amTNF) 的 boulardii 菌株和概念验证数据证明 口服 Sb-amTNF 显着改善小鼠右旋糖酐硫酸钠和细菌性结肠炎。在这个快速- 跟踪 SBIR，我们将在第一阶段研究中追求具体目标 1，以进行生化和遗传研究 FZ006 的表征。在 II 期研究中，目标 2 将研究以下药物的药代动力学和安全性特征： FZ006和Aim 3将对FZ006在人TNF-a中进行IND支持的临床前疗效评估 转基因小鼠。所有拟议的活动将由杰出的咨询/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 临床开发。完成拟议的研究后，我们将进行 IIb 期发电 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 针对 UC 的酵母免疫疗法，UC 是一种导致巨大发病率和经济损失的慢性肠道疾病 美国和全球范围内的损失。