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.

由于迄今为止尚无有效的治疗方法，持续流行的 1 型糖尿病 (T1D) 仍然是一个主要的健康问题 问题。虽然免疫疗法对于治疗 T1D 有很大希望，但其不足之处、严重的 毒性、副作用和发病率限制了终身免疫抑制方法的研究工作。 这一缺点促使研究人员寻找替代方法。靶向纳米医学 使用聚合物纳米粒子 (NP) 特别有希望增强免疫治疗的传递 治疗 T1D。该策略可以通过提供免疫疗法来最大限度地减少不良副作用 它们到达患病组织，在那里它们可以持续释放。在这个多学科项目中，我们的目标是 开发一种创新的、有针对性的纳米递送方法，用于 T1D 的免疫治疗。尽管取得了进展 开发新配方，一种将纳米颗粒靶向递送至特定组织部位的方法 后续的系统给药仍有待开发。自身反应性 T 细胞的启动和激活 发生在胰腺淋巴结 (PLN) 中，幼稚 T 细胞通过淋巴结 (LN) 限制进入此处 被称为高内皮微静脉 (HEV) 的脉管系统会遇到来自胰腺的自身抗原 由树突状细胞呈现。激活的 T 细胞随后流入胰腺，引起胰岛炎和 自身免疫性糖尿病。值得注意的是，我们发现 HEV 也在胰腺中形成。 NOD 小鼠患有糖尿病。在这里，我们首次开发了一种纳米递送疗法至 PLN 和 通过静脉注射靶向 HEV 的 NOD 小鼠的胰腺。我们生成了一种新型 mAb 和 scFV 对抗外周结寻址蛋白 (PNAd)，这是一种仅由结节内皮细胞表达的糖蛋白家族 混合动力汽车。我们还提供支持我们的交付平台的临床适用性的人体数据。此外，我们的 初步数据表明，使用我们的 HEV 靶向递送抗 CD3 抗体前所未有地增加了 抗 CD3 在抑制 NOD 小鼠自身免疫糖尿病中的功效。我们的主要假设是有针对性的 将抗 CD3 递送至胰腺淋巴结 (PLN) 和胰腺将提高其功效 通过显着减少全身剂量来降低毒性。在目标 1 中，我们将检查并优化 抗 HEV mAb 缀合的 NP 在 NOD 小鼠中的稳定性、结合功效和生物分布。在目标 2 中，我们将 评估使用抗 HEV mAb 递送抗 CD3 的临床疗效和机制 共轭纳米颗粒可逆转 NOD 小鼠的自身免疫性糖尿病。在目标 3 中，我们计划测试结合能力 我们优化的抗 HEV mAb 缀合的 NP 的人类 T1D 患者的 PLN 和胰腺。这 多学科、协作的方法将为引入创新的、有针对性的方法奠定基础 T1D 免疫治疗的递送方法。