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: 10457732
• 负责人: Reza Abdi
• 金额: $ 63.59万
• 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/10457732
• 关键词: Address; Affinity; Antibodies; Antibody Therapy; Antidiabetic Drugs; Attenuated; Autoantigens; Autoimmune; Autoimmune Diabetes; Binding; Biodistribution; CD3 Antigens; 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; Immunomodulators; Immunosuppression; Immunotherapeutic agent; Inbred NOD Mice; Inflammation; Inflammatory; Injections; Insulin-Dependent Diabetes Mellitus; Lymphatic; Mediating; Methods; Monoclonal Antibodies; Morbidity - disease rate; Nano delivery; Pancreas; Pathogenicity; Pathway interactions; Patients; Peripheral; Play; Polymers; Process; Property; Public Health; Regulatory T-Lymphocyte; Research; Research Personnel; Role; Site; Specificity; Surface; 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; improved; innovation; insulin dependent diabetes mellitus onset; insulitis; intravenous injection; lymph nodes; multidisciplinary; nanomedicine; nanoparticle; novel; pre-clinical; preservation; prevent; response; side effect; 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.

由于到目前为止还没有有效的治疗方法，正在进行的1型糖尿病(T1D)流行仍然是一个主要的健康问题 有问题。虽然免疫疗法在治疗T1D方面大有可为，但它们的不足、严重 毒性、副作用和发病率限制了终身免疫抑制方法的研究努力。 这一缺陷促使调查人员寻找替代方法。靶向纳米医学 使用聚合物纳米颗粒(Nps)尤其有望增强免疫疗法的传递。 治疗T1D。这一策略可以将免疫疗法的不良副作用降至最低 它们被转移到病变组织，在那里它们可以进行持续释放。在这个多学科的项目中，我们的目标是 开发一种创新的、靶向的纳米递送方法，用于治疗T1D的免疫疗法。尽管取得了进展， 在开发新配方方面取得了进展，这是一种将NPs靶向输送到特定组织部位的方法 之后的系统管理仍有待发展。自身反应性T细胞的启动和激活 发生在胰腺淋巴结(PLN)，幼稚T细胞通过LN限制进入 称为高内皮微静脉(HEV)的血管系统与来自胰腺的自身抗原相遇 由树突状细胞呈递。激活的T细胞随后进入胰腺，导致胰腺炎和 自身免疫性糖尿病。值得注意的是，我们发现在肝炎发作期间，胰腺中也形成了HEV。 NOD小鼠的糖尿病。在这里，我们第一次开发了一种纳米疗法给PLN和 静脉注射HEV靶向NOD小鼠胰腺的实验研究我们已经产生了一种新型的单抗和单链抗体 针对外周节点寻址蛋白(PNAD)，一个仅由血管内皮细胞表达的糖蛋白家族。 混合动力车。我们还提供人体数据，以支持我们的交付平台的临床适用性。而且，我们的 初步数据显示，使用我们的靶向HEV交付抗CD3抗体前所未有地增加了 抗CD3对NOD小鼠自身免疫性糖尿病的抑制作用。我们的主要假设是有针对性的 将抗CD3抗体输送到胰腺淋巴结(PLN)和胰腺将增加其疗效和 通过显著减少全身用药来降低毒性。在目标1中，我们将研究和优化 抗HEV单抗偶联纳米粒在NOD小鼠体内的稳定性、结合效率和生物分布。在目标2中，我们将 评价抗-HEV单抗介导抗-CD3的临床疗效及机制 结合的NPs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以 我们优化的抗HEV单抗标记纳米粒在人T1D患者的PLN和胰腺组织中的表达。这 多学科协作方法将为引入创新的、有针对性的 T1D免疫治疗药物的给药方式。