New way in delivering immunomodulatory drugs in T1D

在 T1D 中提供免疫调节药物的新方法

• 批准号: 10576373
• 负责人: Reza Abdi
• 金额: $ 61.61万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-17 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576373
• 关键词: Address; Affinity; Antibodies; Antibody Therapy; Antidiabetic Drugs; Autoantigens; Autoimmune; Autoimmune Diabetes; Binding; Biodistribution; CD3 Antigens; Cell Communication; Clathrin; Data; Dendritic Cells; Diabetes Mellitus; Disease; Dose; Drug Delivery Systems; Encapsulated; Endocytosis; Endothelial Cells; Engineering; Epidemic; Equilibrium; Family; Formulation; Glycoproteins; Goals; Health; High Endothelial Venule; Home; Human; Immune; Immunosuppression; Immunotherapeutic agent; Inbred NOD Mice; Inflammation; Inflammatory; Injections; Insulin-Dependent Diabetes Mellitus; Lymphatic; Mediating; Methods; Monoclonal Antibodies; Morbidity - disease rate; Nanodelivery; Pancreas; Pathogenicity; Pathway interactions; Patients; Peripheral; Play; Process; Property; Public Health; Regulatory T-Lymphocyte; Research; Research Personnel; Role; Site; Specificity; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Toxic effect; Venous; autoreactive T cell; clinical application; clinical efficacy; collaborative approach; cytokine; density; design; diabetic; effective therapy; efficacy evaluation; experimental study; human data; immune modulating agents; improved; innovation; insulin dependent diabetes mellitus onset; insulitis; intravenous injection; lymph nodes; multidisciplinary; nanomedicine; nanoparticle; nanoparticle delivery; nanopolymer; novel; pre-clinical; preservation; prevent; side effect; surface coating; targeted delivery; trafficking; virtual

With no effective therapy to date, the ongoing Type 1 diabetes (T1D) epidemic continues to be a major health problem. While immune therapeutics hold great promise for the treatment of T1D, their inadequacy, serious toxicity, side effects, and morbidity have limited research efforts in the lifelong immunosuppression approach. This shortcoming has prompted investigators to search for alternative approaches. Targeted nanomedicine using polymeric nanoparticles (NPs) holds particular promise to enhance the delivery of immune therapeutics to treat T1D. This strategy can minimize the undesirable side effects of immune therapeutics by delivering them to diseased tissues, where they can undergo sustained release. In this multidisciplinary project, we aim to develop an innovative, targeted nanodelivery method for immune therapeutics for T1D. Although progress has been made in developing new formulations, a method of targeted delivery of NPs to specific tissue sites following systemic administration remains to be developed. The priming and activation of autoreactive T cells occurs in the pancreatic lymph nodes (PLNs), where naive T cells enter through lymph node (LN)-restricted vasculature known as high endothelial venules (HEVs) and encounter autoantigens from the pancreas presented by dendritic cells. Activated T cells traffic subsequently to the pancreas, causing insulitis and autoimmune diabetes. Notably, we have found that HEVs are also formed in the pancreas during the onset of diabetes in NOD mice. Here, for the first time, we have developed a nanodelivery of therapeutics to PLN and Pancreata of NOD mice targeting HEV with intra venous injection. We have generated a novel mAb and scFV against the peripheral node addressin (PNAd), a glycoprotein family expressed only by endothelial cells of the HEV. We also provide human data that supports the clinical applicability of our delivery platform. Moreover, our preliminary data shows that delivery of anti-CD3 antibody using our HEV targeted unprecedently increases the efficacy of anti CD3 in suppressing autoimmune diabetes in NOD mice. Our main hypothesis is that targeted delivery of anti-CD3 to the pancreatic lymph nodes (PLNs) and pancreata will increase its efficacy and decrease toxicity by reducing systemic dosing significantly. In Aim 1, we will examine and optimize the stability, binding efficacy, and biodistribution of anti HEV mAb-conjugated NPs in NOD mice. In Aim 2, we will assess the clinical efficacy and the mechanisms by which the delivery of anti-CD3 using anti HEV mAb- conjugated NPs reverse autoimmune diabetes in NOD mice. In Aim 3, we plan to test the binding capacity to the PLNs and pancreata of human T1D patients of our optimized anti HEV mAb-conjugated NPs. This multidisciplinary, collaborative approach will lay the groundwork for the introduction of an innovative, targeted delivery method of immune therapeutics for T1D.

迄今为止尚无有效的治疗，正在进行的1型糖尿病（T1D）流行仍然是一种主要健康状况 问题。虽然免疫治疗学对治疗T1D有很大的希望，但它们的不足，严重 毒性，副作用和发病率在终身免疫抑制方法中的研究工作有限。 这种缺点促使调查人员搜索替代方法。靶向纳米医学 使用聚合物纳米颗粒（NP）具有特别有望增强免疫疗法的递送 治疗T1D。这种策略可以通过提供免疫治疗剂的不良副作用来最大程度地减少 它们可以患病的组织，可以在那里持续释放。在这个多学科项目中，我们的目标是 开发一种用于T1D免疫疗法的创新的，有针对性的纳米传递方法。虽然进步有 是在开发新的制剂中制作的，一种将NP靶向特定组织位点的方法 遵循系统的管理仍有待开发。自动反应性T细胞的启动和激活 发生在胰腺淋巴结（PLN）中，幼稚的T细胞通过淋巴结（LN）限制 脉管系统被称为高内皮静脉（HEVS），并遇到胰腺的自动抗原 由树突状细胞提出。激活的T细胞随后流动到胰腺，导致胰岛炎和 自身免疫性糖尿病。值得注意的是，我们发现在胰腺中也形成了HEV 点头小鼠中的糖尿病。在这里，我们第一次为PLN开发了纳米疗法 点头小鼠靶向HEV的胰腺胰腺内注射。我们已经产生了一个新颖的mab和scfv 针对外围节点地址（PNAD），糖蛋白家族仅由内皮细胞表达 嘿。我们还提供了支持我们交付平台的临床适用性的人类数据。而且，我们的 初步数据表明，使用我们的HEV靶向抗CD3抗体的递送可毫不先前增加 抗CD3在抑制NOD小鼠自身免疫性糖尿病方面的功效。我们的主要假设是针对性的 将抗CD3递送至胰腺淋巴结（PLN）和胰腺，将提高其功效和 通过显着降低全身剂量来降低毒性。在AIM 1中，我们将检查并优化 NOD小鼠中抗HEV MAB偶联的NP的稳定性，结合功效和生物分布。在AIM 2中，我们将 评估使用抗HEV mab-抗CD3传递抗CD3的临床功效和机制 共轭的NP反向自身免疫性糖尿病。在AIM 3中，我们计划测试约束力 我们优化的抗HEV MAB偶联的NP的人类T1D患者的PLN和胰腺。这 多学科的协作方法将为引入创新的目标奠定基础 T1D免疫疗法的递送方法。