Immunomodulatory Therapy for Neuropathic Pain

神经性疼痛的免疫调节疗法

• 批准号: 10684821
• 负责人: RIDONG CHEN
• 金额: $ 50.13万
• 依托单位: APT THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10684821
• 关键词: Address; Affect; Affinity; Aldesleukin; American; Analgesics; Animal Model; Anti-Inflammatory Agents; Anticonvulsants; Antidepressive Agents; Attenuated; Autoimmune; Autoimmune Diseases; Benefits and Risks; Binding; Binding Sites; Blood Glucose; Blood Vessels; CD8-Positive T-Lymphocytes; Cell Count; Cell physiology; Cells; Cessation of life; Chimeric Proteins; Clinical Research; Data; Development; Diabetic Neuropathies; Disease; Dose; Escherichia coli; FOXP3 gene; Functional disorder; GTP-Binding Proteins; Generations; Goals; Good Manufacturing Process; Half-Life; Homeostasis; Human; IL2 gene; IL2RA gene; Immune; In Vitro; Infection; Injections; Insulin-Dependent Diabetes Mellitus; Interferons; Interleukin-2; Kidney; Lesion; Lidocaine; Macrophage; Maintenance; Malignant Neoplasms; Mammalian Cell; Mechanics; Mediating; Memory; Modeling; Mononeuropathies; Mutation; NK Cell Activation; Natural Killer Cells; Nervous System; Neurons; Norepinephrine; Opioid; Pain; Pathogenicity; Pathway interactions; Patients; Peripheral nerve injury; Persons; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Polyneuropathy; Postherpetic neuralgia; Prevention strategy; Principal Investigator; Quality of life; Rattus; Reaction; Recombinant Proteins; Regulatory T-Lymphocyte; Renal carcinoma; Reporting; Safety; Self Tolerance; Sensory Ganglia; Serotonin; Serum Albumin; Severities; Site; Streptozocin; Symptoms; Syndrome; Th1 Cells; Therapeutic; Therapeutic Index; Thymus Gland; Toxic effect; Trigeminal Neuralgia; United States; Variant; Work; addiction; allodynia; analog; chronic constriction injury; chronic pain; cytokine; design; diabetic; diabetic rat; drug candidate; drug development; duloxetine; effector T cell; eosinophil; experience; functional status; gabapentin; immunomodulatory therapies; improved; inhibitor; innovation; large scale production; manufacture; manufacturing process; mechanical allodynia; melanoma; molecular size; neuroinflammation; neurotransmission; non-opioid analgesic; novel; novel strategies; novel therapeutics; opioid epidemic; opioid overdose; pain relief; painful neuropathy; pharmacologic; phase 1 study; post stroke pain; pregabalin; prevent; programs; receptor; response; restoration; reuptake; sciatic nerve; side effect; somatosensory; symptom management; symptom treatment; type I diabetic

Principal Investigator/Program Director (Last, First, Middle: Ridong Chen Project Summary More than 25 million Americans suffer from chronic pain. Due to the lack of other treatments, there has been an overreliance on opioids, contributing to an alarming epidemic of opioid overdose addictions and deaths. Neu- ropathic pain is difficult to treat, with only 30-40% of patients achieving meaningful (>40-50%) pain relief. Current therapies (e.g., duloxeline and gabapentin) mainly address symptoms by focusing on blocking neurotransmis- sion in the pain pathway with limited efficacy, severe side effects, and narrow therapeutic indices. Hence, novel non-opioid therapies are urgently needed to safely manage symptoms and also target the underlying pathophys- iological mechanisms that will improve the functional status and quality of life of affected patients. It has been recently shown that CD4+ Th1 is a major player for neuropathic pain development. Interleukin-2 (IL-2) is the key cytokine for the generation, survival, and function of regulatory T cells by direct binding to its high affinity receptor. Treatment with low-dose rIL-2 increased anti-inflammatory regulatory T cells and M2 type macrophages and inhibited pathogenic interferon- secreting T helper type 1 cells. This rIL-2 treatment was efficacious in human clinical studies for autoimmune diseases without complications or infections. Hence, resto- ration or enhancement of regulatory T cells with low-dose IL2 may offer a novel strategy for prevention and treatment of neuropathic pain. However, several drawbacks exist for current low-dose rIL2 therapy, including a short half-life, propensity for in vitro aggregation causing adverse local reaction at injection sites, and a potential narrow therapeutic window. We have designed proprietary IL2-based variants that will enable selective stimu- lation of Tregs with an extended half-life and a broad therapeutic window. In the Phase I study, we successfully identified the variant, designated APT603, which selectively stimulates regulatory T cells and provides robust analgesic efficacy in the chronic constriction injury model of mononeuropathy in rats with an excellent safety profile. With an experienced drug development team, we propose to determine dose responses in two well es- tablished models of neuropathic pain with distinct pathophysiology and to conduct critical activities necessary to enable IND filing for APT603.  Specific Aim 1: Determine the therapeutic index of APT603 for abrogating neuropathic pain in STE- induced (T1D) diabetic rats and in a rat model of sciatic nerve chronic constriction injury (CCI).  Specific Aim 2: Manufacture cGMP (Current Good Manufacturing Practice) grade APT603.  Specific Aim 3: Evaluate the nonclinical safety of APT603. The long-term goal is to develop the drug candidate as a safe and disease-modifying analgesic therapy. Weekly or bi-weekly dosing will provide sustained neuropathic pain relief for patients without inducing significant side effects, tolerance, or addiction.

首席调查员/项目主任(最后、第一、中间：陈日东 项目摘要 超过2500万美国人患有慢性疼痛。由于缺乏其他治疗方法，一直有 对阿片类药物的过度依赖，助长了阿片类药物过量成瘾和死亡的令人震惊的流行。新大学- 迷走神经疼痛很难治疗，只有30-40%的患者获得有意义的疼痛缓解(&gt；40%-50%)。当前 治疗方法(如度洛辛和加巴喷丁)主要通过阻断神经传递来治疗症状。 Sion在疼痛通路中疗效有限，副作用严重，治疗指标狭窄。因此，小说 迫切需要非阿片类药物来安全地管理症状，并针对潜在的病理物理- 将改善受影响患者的功能状态和生活质量的生物学机制。 最近的研究表明，CD4+Th1在神经病理性疼痛的发生中起着重要作用。白介素2 (IL-2)是调节性T细胞生成、存活和功能的关键细胞因子，通过与其直接结合 高亲和力受体。小剂量rIL-2治疗可增加抗炎调节性T细胞和M2型 并抑制致病的干扰素-分泌T辅助1型细胞。这种rIL-2治疗是 在人体自身免疫性疾病的临床研究中有效，无并发症或感染。因此，恢复- 低剂量IL2配给或增强调节性T细胞可能为预防和治疗慢性前列腺癌提供一种新的策略。 神经性疼痛的治疗。然而，目前的低剂量rIL2治疗存在几个缺点，包括 半衰期短，在注射部位引起不良局部反应的体外聚集倾向，以及潜在的 治疗窗口狭窄。我们已经设计了基于IL2的专有变种，将使选择性激发- Tregs具有延长的半衰期和广阔的治疗窗口。在第一阶段的研究中，我们成功地 确定了该变体，命名为APT603，它选择性地刺激调节性T细胞，并提供强大的 安全性极好的单神经病大鼠慢性压迫性损伤模型的镇痛效果 侧写。与经验丰富的药物开发团队一起，我们建议在两个井中确定剂量反应- 建立具有不同病理生理学的神经病理性疼痛模型，并进行必要的关键活动 启用APT603的IND备案。 特异性目标1：确定APT603消除短暂性脑梗塞神经病理性疼痛的治疗指数 诱导(T1D)糖尿病大鼠和坐骨神经慢性压迫损伤(CCI)大鼠模型。 具体目标2：制造CGMP(现行良好制造规范)级APT603。 特定目标3：评价APT603的非临床安全性。 长期目标是将该候选药物开发为一种安全和改善疾病的止痛疗法。 每周或每两周给药将为患者提供持续的神经病理性疼痛缓解，而不会导致明显的 副作用、耐受性或成瘾。