Targeting the CCR6-CCL20 pathway for treatment of psoriatic joint and entheseal inflammation

项目概要/摘要 该项目的目标是开发和验证一种新的治疗先导化合物，用于治疗 银屑病关节炎（PsA）。趋化因子在正常免疫过程中协调炎性细胞的迁移 免疫系统是免疫系统的重要组成部分，是免疫系统的反应，是免疫组织发育和体内平衡所必需的。当异常的趋化因子 当功能发生时，免疫细胞的不适当募集可导致各种炎症病理， 对病人的生活质量造成毁灭性的影响。趋化因子CCL 20及其G蛋白偶联受体 CCR 6通过启动和持续募集 炎症性Th 17表达细胞进入皮肤和结缔组织。我们发表的生物化学，细胞为基础的， 体内研究证明，模拟天然蛋白的二聚体形式的工程化重组蛋白， CCL 20分子完全逆转其正常的促炎功能概况。在第一阶段SBIR项目中， 先导化合物（CCL 20 LD）在临床前试验中减少了已建立的银屑病皮炎（PsD）的体征， 小鼠模型忠实地再现了人类银屑病。出乎意料的是，CCL 20 LD治疗也缓解了 关节和肌腱炎症，在临床相关的人类银屑病模型中证明有效性 关节炎同一项目还产生了有利的初步安全性特征，没有肝脏或 肾毒性和经验证的生产和质量控制方案。有一个新的重大需求 治疗银屑病关节炎，因为目前的选择进行免疫抑制和损失的风险， 随着时间的推移，功效。本直接进入第二阶段的建议书建立在已完成的第一阶段里程碑的基础上， CCL 20 LD的临床前测试和优化，并组装必要的有效性，安全性， 用于IND申请和银屑病关节炎临床试验的生产数据。XLock Biosciences，LLC（XL） 将生产CCL 20 LD蛋白，并指导三个具体目标的研究。在Aim 1中，XLock 将改善第一代CCL 20 LD分子的体内稳定性， 生物药物的循环半衰期。在目标2 XL和它的学术合作者在加州大学戴维斯分校将建立 在关节组织中产生最强抗银屑病作用的治疗剂量和时间表 最短的时间。最后，在目标3中，XL在威斯康星州医学院的合作者将测量 CCL 20 LD的免疫调节活性及其对啮齿动物真菌感染易感性的影响 通过其天然配体的工程改造改变CCR 6信号传导是临床治疗的创新范式转变。 治疗自身炎症性疾病的方法。开发工程化的CCL 20变体作为生物学 治疗方法将通过减少副作用和减少副作用对银屑病关节炎患者产生显着的积极影响， 提供具有延长的治疗寿命的药物。此外，所得到的方法具有用于 治疗其他Th 17介导的疾病。

Project Summary/Abstract The goal of this project is to develop and validate a novel therapeutic lead compound for the treatment of psoriatic arthritis (PsA). Chemokines orchestrate the migration of inflammatory cells during normal immune responses and are required for immune tissue development and homeostasis. When aberrant chemokine function occurs, improper recruitment of immune cells can lead to a variety of inflammatory pathologies with devastating effects on a patient’s quality of life. The chemokine CCL20 and its G protein-coupled receptor CCR6 drive the development of psoriatic disease through the initiation and continuous recruitment of inflammatory Th17-expressing cells into skin and connective tissue. Our published biochemical, cell-based and in vivo studies prove that an engineered recombinant protein that mimics the dimeric version of the natural CCL20 molecule completely reverses its normal pro-inflammatory functional profile. In a Phase I SBIR project, the lead compound (CCL20LD) reduced the signs of established psoriatic dermatitis (PsD) in a preclinical mouse model that faithfully recapitulates human psoriasis. Unexpectedly, CCL20LD treatment also alleviated joint and tendon inflammation, demonstrating efficacy in a clinically relevant model of human psoriatic arthritis. The same project also yielded a favorable preliminary safety profile with no indication of liver or kidney toxicity and a validated manufacturing and quality control protocol. There is a significant need for new treatments for psoriatic arthritis because current options carry the risk of immunosuppression and loss of efficacy over time. This Direct-to-Phase II proposal builds on the completed Phase I milestones to complete preclinical testing and optimization of CCL20LD and assemble the necessary efficacy, safety, and manufacturing data for an IND application and clinical trials for psoriatic arthritis. XLock Biosciences, LLC (XL) will manufacture the CCL20LD protein and direct the studies proposed in three specific aims. In Aim 1, XLock will improve the in vivo stability of the first generation CCL20LD molecule with modifications known to extend the circulating half-life of biologic drugs. In Aim 2 XL and its academic collaborators at UC Davis will establish the therapeutic dose and schedule which produces the strongest anti-psoriatic effect in joint tissues in the shortest time period. Lastly, in Aim 3, XL’s collaborators at the Medical College of Wisconsin will measure CCL20LD’s immunomodulatory activity and its effect on rodent susceptibility to commensal fungal infection. Altering CCR6 signaling through the engineering of its native ligand is an innovative paradigm shift in clinical approaches for treating auto-inflammatory diseases. Development of engineered CCL20 variants as biological therapeutics will have significant positive impact for psoriatic arthritis patients by reducing side effects and providing a drug with extended therapeutic lifetimes. Moreover, the resultant method has the potential for treating other Th17–mediated diseases.