A chimeric protein for the selective expansion of regulatory T cells

用于选择性扩增调节性 T 细胞的嵌合蛋白

• 批准号: 9141489
• 负责人: Bellur S Prabhakar
• 金额: $ 26.07万
• 依托单位: SAHANE BIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9141489
• 关键词: Address; Adult; Affect; Asia; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Beta Cell; Biological Availability; Biotechnology; Cells; Chimeric Proteins; Chronic Disease; Clinical; Data; Data Reporting; Development; Diabetes Mellitus; Diabetic Nephropathy; Diagnosis; Ensure; Europe; Excretory function; Extracellular Domain; Face; Family member; Future; Goals; Half-Life; Human; Hyperglycemia; IgG1; Immune; Immune system; Inbred NOD Mice; Insulin; Insulin-Dependent Diabetes Mellitus; Leukocytes; Life; Ligands; Mammalian Cell; Marketing; Medical; Metabolism; Methods; Mus; Neuropathy; Normalcy; Outcome; Pancreas; Patients; Phase; Play; Production; Proteins; Recombinants; Regulation; Regulatory T-Lymphocyte; Renal clearance function; Retinal Diseases; Role; Safety; Serum; Signal Transduction; Structure of beta Cell of islet; T-Lymphocyte; TCR Activation; TNF gene; TNFSF4 gene; Testing; Therapeutic; Therapeutic Effect; TimeLine; Toxic effect; Treatment Efficacy; absorption; base; cell type; diabetes mellitus therapy; diabetic; effective therapy; in vivo; innovation; insulin dependent diabetes mellitus onset; jagged1 protein; medical complication; notch protein; novel therapeutics; phase 1 study; prevent; public health relevance; receptor; reconstitution; restoration; standard of care; therapeutic protein

 DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is a chronic disease caused by the autoimmune destruction of the insulin producing beta cells in the pancreas. Current treatment options for T1D are severely limited. All patients diagnosed with T1DM are placed on life-long insulin therapy and the current standard of care for adult patients with T1DM is intensive diabetes therapy to avoid long-term medical complications such as diabetic nephropathy, neuropathy, and retinopathy, among other complications (1, 2). T cells are believed to play a major role in the autoimmune destruction of pancreatic β cells in T1D (3, 4). Many aspects of immune regulation including regulatory T cell (Treg) function has been found to be defective in T1D (4-10). Hence, restoration of Treg numbers and function to normalcy can be an effective strategy in preventing and/or treating T1D (11-14). Several TCR activation dependent methods have been developed for Treg expansion but they cannot be used in vivo, because such methods can activate Teff as well as Tregs, thus limiting the therapeutic efficacy. Methods for TCR-dependent ex vivo Treg expansion have been developed, but is impractical as the Tregs will have to be patient specific and requires repeated ex vivo expansion. Our recent studies have shown that soluble OX40L and Jagged-1 (Jag1) can cause a significant expansion of Tregs in vivo and suppress T1D in NOD mice. However, developing a clinically acceptable therapeutic consisting of two soluble ligands may face regulatory hurdles. We have developed mouse (m) and human (h) OX40L-Jag1- Fc fusion proteins that can be used to expand Tregs ex vivo. In our Phase-1 studies we will establish their therapeutic potential by testing their abilityto induce Tregs in vivo through the following aims: In aim-1, we will test if mOX40L-Jag1-Fc fusion protein can expand Tregs and delay/prevent the onset of hyperglycemia in NOD mice. In aim-2, we will test if hOX40L-Jag1-Fc is able to expand human Tregs in immunodeficient NSG mice reconstituted with human immune cells. Successful outcome of our studies would illustrate the potential clinical utility of our novel therapeutic. Subsequently, Absorption, Distribution, Metabolism, Excretion and Toxicity studies can be carried out to establish the safety of OX40L-Jag1-Fc required for IND filing to FDA. This novel therapeutic can be potentially used to effectively treat T1D and other autoimmune diseases with Treg insufficiency.

 描述(申请人提供)：1型糖尿病(T1D)是一种慢性疾病，由胰腺中产生胰岛素的β细胞的自身免疫破坏引起。目前对T1D的治疗选择严重有限。所有被诊断为T1 DM的患者都接受终身胰岛素治疗，目前T1 DM成人患者的护理标准是强化糖尿病治疗，以避免长期的医学并发症，如糖尿病肾病、神经病变和视网膜病变，以及其他并发症(1，2)。T细胞被认为在T1D(3，4)胰腺β细胞的自身免疫破坏中起主要作用。免疫调节的许多方面，包括调节性T细胞(Treg)功能，在T1D(4-10)被发现是有缺陷的。因此，将Treg数目和功能恢复到正常可能是预防和/或治疗T1D(11-14)的有效策略。几种依赖TCR激活的方法已被开发用于Treg的扩增，但它们不能在体内使用，因为这些方法既可以激活Teffs，也可以激活Tregs，从而限制了治疗效果。依赖TCR的Treg体外扩增的方法已经开发出来，但由于Treg必须针对患者而进行，并且需要重复体外扩增，因此方法是不切实际的。我们最近的研究表明，可溶性OX40L和Jagge-1(Jag1)可以在体内引起Tregs的显著扩张，并抑制NOD小鼠的T1D。然而，开发一种由两种可溶性配体组成的临床可接受的治疗药物可能面临调控障碍。我们已经开发出小鼠(M)和人(H)OX40L-Jag1-Fc融合蛋白，可用于体外扩增Tregs。在我们的第一阶段研究中，我们将通过测试它们在体内诱导Tregs的能力来确定它们的治疗潜力，目的如下：在Aim-1中，我们将测试mOX40L-Jag1-Fc融合蛋白是否能够扩大Tregs并延迟/预防NOD小鼠高血糖的发生。在AIM-2中，我们将测试hOX40L-Jag1-Fc是否能够在由人免疫细胞重组的免疫缺陷NSG小鼠中扩增人Tregs。我们研究的成功结果将说明我们新的治疗方法的潜在临床应用。随后，可以进行吸收、分布、代谢、排泄和毒性研究，以确定向FDA提交IND文件所需的OX40L-Jag1-FC的安全性。这种新的治疗方法可能被有效地用于治疗T1D和其他伴有Treg功能不全的自身免疫性疾病。