Immunomodulatory Therapy for Neuropathic Pain
神经性疼痛的免疫调节疗法
基本信息
- 批准号:10684821
- 负责人:
- 金额:$ 50.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAffectAffinityAldesleukinAmericanAnalgesicsAnimal ModelAnti-Inflammatory AgentsAnticonvulsantsAntidepressive AgentsAttenuatedAutoimmuneAutoimmune DiseasesBenefits and RisksBindingBinding SitesBlood GlucoseBlood VesselsCD8-Positive T-LymphocytesCell CountCell physiologyCellsCessation of lifeChimeric ProteinsClinical ResearchDataDevelopmentDiabetic NeuropathiesDiseaseDoseEscherichia coliFOXP3 geneFunctional disorderGTP-Binding ProteinsGenerationsGoalsGood Manufacturing ProcessHalf-LifeHomeostasisHumanIL2 geneIL2RA geneImmuneIn VitroInfectionInjectionsInsulin-Dependent Diabetes MellitusInterferonsInterleukin-2KidneyLesionLidocaineMacrophageMaintenanceMalignant NeoplasmsMammalian CellMechanicsMediatingMemoryModelingMononeuropathiesMutationNK Cell ActivationNatural Killer CellsNervous SystemNeuronsNorepinephrineOpioidPainPathogenicityPathway interactionsPatientsPeripheral nerve injuryPersonsPharmaceutical PreparationsPhasePhenotypePlasmaPolyneuropathyPostherpetic neuralgiaPrevention strategyPrincipal InvestigatorQuality of lifeRattusReactionRecombinant ProteinsRegulatory T-LymphocyteRenal carcinomaReportingSafetySelf ToleranceSensory GangliaSerotoninSerum AlbuminSeveritiesSiteStreptozocinSymptomsSyndromeTh1 CellsTherapeuticTherapeutic IndexThymus GlandToxic effectTrigeminal NeuralgiaUnited StatesVariantWorkaddictionallodyniaanalogchronic constriction injurychronic paincytokinedesigndiabeticdiabetic ratdrug candidatedrug developmentduloxetineeffector T celleosinophilexperiencefunctional statusgabapentinimmunomodulatory therapiesimprovedinhibitorinnovationlarge scale productionmanufacturemanufacturing processmechanical allodyniamelanomamolecular sizeneuroinflammationneurotransmissionnon-opioid analgesicnovelnovel strategiesnovel therapeuticsopioid epidemicopioid overdosepain reliefpainful neuropathypharmacologicphase 1 studypost stroke painpregabalinpreventprogramsreceptorresponserestorationreuptakesciatic nerveside effectsomatosensorysymptom managementsymptom treatmenttype I diabetic
项目摘要
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/项目主任(后、一、中:陈日东
项目概要
超过 2500 万美国人患有慢性疼痛。由于缺乏其他治疗方法,
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惊人流行。新-
神经性疼痛很难治疗,只有 30-40% 的患者 (>40-50%) 能够有效缓解疼痛。当前的
治疗(例如度洛西林和加巴喷丁)主要通过阻断神经传递来解决症状
疼痛通路中的药物治疗效果有限、副作用严重且治疗指数狭窄。因此,小说
迫切需要非阿片类药物疗法来安全地控制症状并针对潜在的病理学
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 是神经性疼痛发展的主要参与者。白介素-2
(IL-2) 是调节性 T 细胞的生成、存活和功能的关键细胞因子,通过直接与其结合
高亲和力受体。低剂量rIL-2治疗增加抗炎调节T细胞和M2型
巨噬细胞和抑制致病性干扰素-γ分泌T辅助1型细胞。该 rIL-2 治疗是
在自身免疫性疾病的人体临床研究中有效,无并发症或感染。因此,恢复
用低剂量 IL2 定量或增强调节性 T 细胞可能会提供一种新的预防和治疗策略。
治疗神经性疼痛。然而,目前的低剂量 rIL2 疗法存在一些缺点,包括
半衰期短,体外聚集的倾向导致注射部位局部不良反应,以及潜在的
治疗窗窄。我们设计了基于 IL2 的专有变体,可以实现选择性刺激
Tregs 的作用具有延长的半衰期和广泛的治疗窗口。在第一阶段研究中,我们成功
鉴定出该变体,命名为 APT603,它选择性地刺激调节性 T 细胞并提供强大的
在大鼠单神经病慢性压迫性损伤模型中的镇痛效果具有良好的安全性
轮廓。凭借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-
建立了具有独特病理生理学的神经性疼痛模型,并进行必要的关键活动
启用 APT603 的 IND 备案。
具体目标 1:确定 APT603 消除 STE 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缩窄损伤(CCI)大鼠模型。
具体目标 2:生产 cGMP(现行良好生产规范)等级 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开发为安全且缓解疾病的镇痛疗法。
每周或每两周一次给药将为患者提供持续的神经性疼痛缓解,而不会引起明显的疼痛。
副作用、耐受性或成瘾性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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RIDONG CHEN其他文献
RIDONG CHEN的其他文献
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