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型治疗先导化合物，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症细胞的迁移 反应，并且是免疫组织发育和体内平衡所必需的。当趋化因子异常时 功能发生时，免疫细胞的不当募集可导致多种炎症病理 对患者的生活质量造成毁灭性影响。趋化因子 CCL20 及其 G 蛋白偶联受体 CCR6 通过启动和持续招募 CCR6 来驱动银屑病的发展 表达 Th17 的炎症细胞进入皮肤和结缔组织。我们发表的生物化学、细胞和 体内研究证明，一种工程重组蛋白可以模仿天然蛋白质的二聚体版本 CCL20 分子完全逆转其正常的促炎功能。在第一阶段 SBIR 项目中， 在临床前研究中，先导化合物 (CCL20LD) 减少了已确定的银屑病皮炎 (PsD) 的症状 忠实再现人类牛皮癣的小鼠模型。没想到，CCL20LD治疗也缓解了 关节和肌腱炎症，在人类银屑病临床相关模型中证明了疗效 关节炎。同一项目还产生了良好的初步安全性，没有任何肝脏或肝脏损害的迹象。 肾毒性以及经过验证的生产和质量控制方案。迫切需要新的 银屑病关节炎的治疗方法，因为目前的选择存在免疫抑制和丧失免疫功能的风险 随着时间的推移疗效。该直接进入第二阶段的提案建立在已完成的第一阶段里程碑的基础上 CCL20LD 的临床前测试和优化，并收集必要的功效、安全性和 银屑病关节炎 IND 申请和临床试验的生产数据。 XLock 生物科学有限责任公司 (XL) 将制造 CCL20LD 蛋白并指导针对三个具体目标提出的研究。在目标 1 中，XLock 将通过已知可延长的修饰提高第一代 CCL20LD 分子的体内稳定性 生物药物的循环半衰期。 In Aim 2 XL 及其在加州大学戴维斯分校的学术合作者将建立 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 最短的时间段。最后，在目标 3 中，XL 在威斯康星医学院的合作者将测量 CCL20LD 的免疫调节活性及其对啮齿动物共生真菌感染易感性的影响。 通过对其天然配体进行改造来改变 CCR6 信号传导是临床领域的创新范式转变 治疗自身炎症性疾病的方法。开发工程 CCL20 变体作为生物 治疗方法将通过减少副作用和对银屑病关节炎患者产生显着的积极影响 提供具有延长治疗寿命的药物。此外，所得方法有可能 治疗其他 Th17 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.