IL-10NanoCap® for Therapy of Familial Adenomatous Polyposis

IL-10NanoCap® 用于治疗家族性腺瘤性息肉病

• 批准号: 10115707
• 负责人: DOMINICK AUCI
• 金额: $ 84.75万
• 依托单位: THERAPYX, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-07 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115707
• 关键词: Adenocarcinoma; American; ApcMin/+ mice; Area; Bacteroides fragilis; Biological Sciences; Cancer Model; Chemistry; Chemoprevention; Clinical; Clinical Data; Clinical Trials; Colectomy; Collaborations; Colon; Colon Carcinoma; Colorectal Cancer; Data; Development; Disease; Dominant Genetic Conditions; Dose; Dose-Limiting; Drug Kinetics; Excision; Familial Adenomatous Polyposis Syndrome; Formulation; Future; Gastrointestinal tract structure; Genetic; Genetic Diseases; Human; Immune; Immune signaling; Immunooncology; Incentives; Interleukin-10; Intestinal Polyposis; Intestines; Laboratories; Life; Long-Term Effects; Malignant Neoplasms; Medical; Modeling; Monitor; Mus; Oral; Oral Administration; Particulate; Phase; Polyps; Preparation; Prevention; Preventive; Primates; Process; Production; Protocols documentation; Publishing; Rare Diseases; Rattus; Recombinants; Rectum; Regimen; Research Personnel; Risk; Rodent; Schedule; Science; Serum; Small Business Innovation Research Grant; Structure; Therapeutic; Toxic effect; Toxicology; Treatment Efficacy; Treatment Protocols; Universities; Validation; Work; adenoma; anticancer research; base; clinically relevant; colon carcinogenesis; comparative; cytokine; design; human model; in vivo; manufacturing process; meetings; mouse model; nonhuman primate; novel therapeutics; particle; pharmacokinetics and pharmacodynamics; polyposis; pre-clinical; response biomarker; scale up; treatment optimization; tumor progression; tumorigenesis

Project Summary/Abstract Familial adenomatous polyposis (FAP) is an autosomal dominant genetic disease that leads to the development of hundreds to thousands of adenomas in the rectum and the colon. Current medical management involves endoscopic monitoring, resection of advanced polyps and ultimately colectomy in the second decade of life. The risk of developing colorectal cancer is 100% and chemoprevention has not been successful. We have demonstrated that oral administration of our proprietary sustained-release particulate formulation of Interleukin- 10 (IL-10NanoCap) suppresses: a) intestinal polyposis in the APCmin/+ mouse model; b) intestinal/colon carcinogenesis in the APCmin/+ mouse / Bacteroides fragilis compound model; and c) sporadic adenocarcinoma in the CDX2P-NLS Cre;APC+/loxP genetic colon cancer model. These findings, which were published in Cancer Research and Oncoimmunology provide the requisite milestones and the underpinning rationale for this Fast- track application. In Phase I segment, Aim 1 we will establish final proof-of-principle for in vivo therapeutic efficacy of our recently-developed scaled-up commercial batch IL-10NanoCap in the APCmin/+ / Bacteroides fragilis murine FAP model. In Phase II segment, Aim 2 we will optimize the treatment protocol; determine long- term efficacy in early (preventive) and established (treatment) disease settings using the new regimen; delineate the effect of long-term treatment on gut/systemic immune activity; identify serum response markers; and obtain preliminary PK/PD data in the above model. In Aim 3 we will produce multiple large-batches of bulk human IL- 10NanoCap, demonstrate lot-to-lot consistency and determine long-term stability prior to use in standard GLP rat toxicology studies (Aim 4). The pre-clinical data from Aims 1-4 will constitute the basis of the written questions and the briefing package that will be submitted to the FDA for a type C pre-pre-IND meeting (Aim 5). Successful completion of these studies will inform and incentivize future SBIR Phase IIb-supported non-human primate toxicology and an open IND in preparation for clinical trials.

项目总结/摘要 家族性腺瘤性息肉病（FAP）是一种常染色体显性遗传疾病， 直肠和结肠中有数百至数千个腺瘤。目前的医疗管理包括 内窥镜监测，切除晚期息肉，并最终在生命的第二个十年进行结肠切除术。的 患结肠直肠癌的风险是100%，化学预防尚未成功。我们有 表明口服我们专有的白细胞介素缓释颗粒制剂， 10（IL-10 NanoCap）抑制：a）APC min/+小鼠模型中的肠息肉病; B）肠/结肠 APC min/+小鼠/脆弱拟杆菌复合模型中的致癌作用;和 在CDX 2 P-NLS Cre;APC+/loxP遗传结肠癌模型中。这些研究结果发表在《癌症》杂志上， 研究和肿瘤免疫学提供了必要的里程碑和基本原理，这一快速- 跟踪应用程序。在第一阶段，目标1，我们将建立体内治疗的最终原理验证 我们最近开发的按比例放大的商业批次IL-10 NanoCap在APCmin/+ /拟杆菌中的功效 fragilis鼠FAP模型。在第二阶段，目标2，我们将优化治疗方案;确定长期- 使用新方案在早期（预防性）和确定（治疗性）疾病环境中的长期疗效;描述 长期治疗对肠道/全身免疫活性的影响;鉴定血清应答标志物;并获得 上述模型中的初步PK/PD数据。在目标3中，我们将生产多个大批次的散装人IL-1。 10 NanoCap，证明批间一致性，并在用于标准GLP前确定长期稳定性 大鼠毒理学研究（目标4）。目的1-4的临床前数据将构成书面问题的基础 以及将提交给FDA的C类IND前会议简报包（目标5）。成功 这些研究的完成将为未来SBIR IIb期支持的非人灵长类动物提供信息和激励 毒理学和开放的IND，为临床试验做准备。