IL-10NanoCap® for Therapy of Familial Adenomatous Polyposis

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病。 在直肠和结肠有成百上千的腺瘤。目前的医疗管理包括 内窥镜监测，晚期息肉切除，并最终在生命的第二个十年切除结肠。这个 罹患结直肠癌的风险是100%，而化学预防并不成功。我们有 证明口服我们专有的白细胞介素2缓释微粒制剂 10(IL-10NanoCap)抑制：a)APCmin/+小鼠模型的肠息肉；b)肠/结肠 APCmin/+小鼠/脆弱类杆菌复合模型的致癌作用；c)散发性腺癌 在CDX2P-NLS Cre；APC+/loxP遗传性结肠癌模型中。这些发现发表在《癌症》杂志上 研究和肿瘤免疫学提供了必要的里程碑和支持这种快速- 跟踪应用程序。在第一阶段，目标1，我们将建立活体治疗的最终原则证明 我们最近开发的规模化商业批次IL-10NanoCap对APCmin/+/类杆菌的疗效 Fragilis小鼠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)和确定(治疗)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；确定血清反应标志物；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量的人IL- 10NanoCap，在用于标准GLP之前，证明批次到批次的一致性并确定长期稳定性 老鼠毒理学研究(目标4)。来自目标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Pre-Pre-IND会议的简报包(AIM 5)。成功 这些研究的完成将为未来SBIR IIb期支持的非人类灵长类提供信息和激励 毒理学和一个开放的IND为临床试验做准备。

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.