Immunomodulatory Therapy for Neuropathic Pain

神经性疼痛的免疫调节疗法

• 批准号: 10490450
• 负责人: RIDONG CHEN
• 金额: $ 92.25万
• 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/10490450
• 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; Cyclic GMP; Data; Development; Diabetic Neuropathies; Disease; Dose; Escherichia coli; FOXP3 gene; Functional disorder; GTP-Binding Proteins; Generations; Goals; Half-Life; Homeostasis; Human; IL2 gene; IL2RA gene; Immune; In Vitro; Infection; Injections; Insulin-Dependent Diabetes Mellitus; Interferons; Interleukin-2; Kidney; Lesion; Lidocaine; Maintenance; Malignant Neoplasms; Mammalian Cell; Mechanics; Mediating; Memory; Modeling; Mononeuropathies; Mutation; NK Cell Activation; Natural Killer Cells; Nervous system structure; Neurons; Norepinephrine; Opioid; Pain; Pathogenicity; Pathway interactions; Patients; Peripheral nerve injury; Persons; Pharmaceutical Preparations; Pharmacology; 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; base; 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; macrophage; 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; 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.

首席研究员/计划主任（最后，第一，中间：Ridong Chen 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，已经存在 对阿片类药物的过度依赖，导致阿片类药物过量成瘾和死亡的令人震惊的流​​行。 ne Ropathic疼痛很难治疗，只有30-40％的患者可以缓解有意义的疼痛（> 40-50％）。当前的 疗法（例如Duloxeline和Gabapentin）主要通过关注神经递质 - 疼痛途径中的sion有效性有限，严重的副作用和狭窄的治疗指数。因此，新颖 迫切需要非阿片类药物疗法来安全地管理症状，还针对潜在的病理律师 生物学机制将改善受影响患者的功能状况和生活质量。 最近已经显示，CD4+ TH1是神经性疼痛发育的主要参与者。白介素2 （IL-2）是通过直接结合其生成，生存和功能的关键细胞因子 高亲和力受体。低剂量RIL-2的治疗增加了抗炎调节性T细胞和M2类型 巨噬细胞和抑制致病性干扰素 - 分泌T辅助1型细胞。这种RIL-2治疗是 在人类临床研究中有效的自身免疫性疾病而没有并发症或感染。因此，resto- 使用低剂量IL2的调节性T细胞的定量或增强可能为预防和 神经性疼痛的治疗。但是，当前的低剂量RIL2治疗存在几个缺点，包括 半衰期短，在体外聚集的承诺会导致注射部位不良局部反应，并且有潜力 狭窄的治疗窗口。我们设计了专有IL2的变体，可以实现选择性刺激 一群treg，带有延长的半衰期和一个宽阔的治疗窗口。在第一阶段的研究中，我们成功地 确定了称为APT603的变体，该变体可有选择地刺激调节性T细胞并提供可靠的 在大鼠的慢性收缩损伤模型中，大鼠的镇痛效率极佳 轮廓。通过经验丰富的药物开发团队，我们建议确定两个井中的剂量反应 具有不同病理生理学的神经性疼痛模型，并进行至关重要的活动 启用IND申请APT603。 具体目的1：确定APT603的治疗指数，用于废除Ste-的神经性疼痛 在坐骨神经慢性损伤（CCI）的大鼠模型中，诱导的（T1D）糖尿病大鼠（CCI）。 具体目标2：制造CGMP（当前的良好制造实践）APT603。 具体目标3：评估APT603的非临床安全性。 长期目标是将候选药物作为一种安全和疾病改良的镇痛治疗。 每周或每两周给药将为患者提供持续的神经性疼痛缓解，而没有诱发的明显 副作用，耐受性或成瘾。