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.

项目摘要/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，导致发展 直肠和结肠中的数百至数千个腺瘤。当前的医疗管理涉及 内窥镜监测，晚期息肉的切除以及最终在生命的第二个十年中。这 结直肠癌的风险为100％，化学预防尚未成功。我们有 证明我们的专有持续释放酶颗粒颗粒的口服介绍了白介素 - 10（IL-10NANOCAP）抑制：a）APCMIN/+小鼠模型中的肠道息肉； b）肠/结肠 APCMIN /+小鼠 /杀菌剂Fragilis化合物模型中的致癌作用；和c）零星腺癌 在CDX2P-NLS CRE中； APC+/LOXP遗传结肠癌模型。这些发现，发表在癌症中 研究和OncoMumumanology提供了必要的里程碑以及这一快速的基本原理 跟踪应用。在第一阶段细分市场中，目标1我们将建立体内治疗的最终原理证明 我们最近开发的规模扩展的商业批次IL-10NANOCAP的功效 Fragilis鼠FAP模型。在第二阶段段，目标2我们将优化治疗方案；确定长期 使用新方案的早期（预防）和建立（治疗）疾病环境的术语疗效；描绘 长期治疗对肠道/全身免疫活性的影响；识别血清反应标记；并获得 上述模型中的初步PK/PD数据。在AIM 3中，我们将产生多个大批量的人类IL- 10NANOCAP，表现出批次对路的一致性，并在使用标准GLP之前确定长期稳定性 大鼠毒理学研究（AIM 4）。 AIM 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的简报包进行C型C型预告片会议（AIM 5）。成功的 这些研究的完成将告知并激励未来的SBIR阶段IIB支持的非人类灵长类动物 毒理学和开放式IND，以准备临床试验。