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

项目摘要/摘要 该项目的目标是开发和验证一种新的治疗糖尿病的先导化合物。 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 这是免疫组织发育和动态平衡所必需的。当异常趋化因子 功能发生时，免疫细胞的不当募集可导致多种炎性病理 对病人的生活质量产生毁灭性的影响。趋化因子CCL20及其G蛋白偶联受体 CCR6通过启动和持续招募的方式推动银屑病的发展 皮肤和结缔组织中表达Th17的炎性细胞。我们出版的生物化学，基于细胞和 体内研究证明，一种模仿天然二聚体的工程化重组蛋白 CCL20分子完全逆转其正常的促炎功能。在第一阶段SBIR项目中， 先导化合物(CCL20LD)减少了临床前已建立的银屑病皮炎(PSD)的迹象 真实再现人类牛皮癣的小鼠模型。出乎意料的是，CCL20LD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显示疗效 关节炎。同一项目也产生了良好的初步安全概况，没有肝脏或 肾脏毒性和有效的制造和质量控制方案。有很大需求需要新的 银屑病关节炎的治疗，因为目前的选择带有免疫抑制和丧失 随着时间的推移而产生效果。这个直接到第二阶段的提案建立在完成的第一阶段里程碑的基础上 CCL20LD的临床前测试和优化，并组装必要的有效性、安全性和 IND应用程序和牛皮癣关节炎临床试验的制造数据。XLock Biosciences，LLC(XL) 将生产CCL20LD蛋白，并指导提出的三个特定目标的研究。在目标1中，XLock 将通过已知的扩展修饰来提高第一代CCL20LD分子的体内稳定性 生物药物的循环半衰期。在Aim 2 XL和它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效果的治疗剂量和方案 最短的时间段。最后，在Aim 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对共生真菌感染易感性的影响 通过改造天然配体改变CCR6信号是临床上的一种创新范式转变 治疗自发性炎症性疾病的方法。工程化CCL20生物突变体的研究进展 治疗将通过减少副作用和治疗对银屑病关节炎患者产生显著的积极影响 提供一种延长治疗寿命的药物。此外，所得到的方法具有潜在的 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.