Development of an engineered CCL20 protein as a lead therapeutic molecule for psoriasis

开发工程化 CCL20 蛋白作为银屑病的主要治疗分子

• 批准号: 10263914
• 负责人: Chad Allen Koplinski
• 金额: $ 82.91万
• 依托单位: XLOCK BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263914
• 关键词: Affect; Alkaline Phosphatase; Alternative Therapies; Animal Model; Animals; Antibodies; Autoimmune Diseases; Award; Biochemical; Biological; Biological Assay; Biological Markers; Biological Response Modifier Therapy; CCL20 gene; CCR6 gene; Candidiasis; Cells; Clinical; Clinical Trials; Creatinine; Cyclic GMP; Dermatitis; Dermis; Development; Diagnosis; Disease; Disease model; Dose; Engineering; Formulation; Functional disorder; G-Protein-Coupled Receptors; Generations; Goals; Gold; Grant; Half-Life; Hepatic; Homeostasis; Human; Humira; Immune; Immune response; Immunosuppression; In Vitro; Industrialization; Inflammation; Inflammatory; Injections; Interleukin-17; Intraperitoneal Injections; Kidney; Lead; Life; Ligands; Link; Liver; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Mediating; Methods; Modeling; Mucous Membrane; Mycoses; Pathology; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Population; Preparation; Production; Proteins; Protocols documentation; Psoriasis; Publishing; Quality Control; Quality of life; Recombinant Proteins; Reproducibility; Risk; Rodent; Safety; Schedule; Serology; Signal Transduction; Signs and Symptoms; Site; Skin; Small Business Innovation Research Grant; Symptoms; Testing; Therapeutic; Time; Tissues; Topical application; Toxicology; Treatment Protocols; Tuberculosis; Urea; Variant; Wisconsin; Work; autoinflammatory; base; chemokine; clinically relevant; cytokine release syndrome; dimer; drug candidate; drug development; experimental study; first-in-human; high risk; human disease; human model; immunogenicity; in vivo; infection rate; infliximab; inhibitor/antagonist; innovation; interleukin-23; lead candidate; lead optimization; man; medical schools; migration; milligram; mouse model; next generation; nonhuman primate; novel therapeutics; pre-clinical; preclinical development; prevent; prototype; receptor; recruit; research and development; safety study; side effect; skin disorder; success; therapeutic candidate; therapeutic lead compound; tissue biomarkers; tumor necrosis factor-alpha inhibitor

Project Summary/Abstract The goal of this project is to develop and validate a novel therapeutic lead compound for the treatment of psoriasis. 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 psoriasis through the initiation and continuous recruitment of inflammatory Th17-expressing cells into the dermis. Our recently 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. This lead compound (CCL20LD), invented by the PI at the Medical College of Wisconsin, prevented the development and progression of psoriatic dermatitis (PsD) in a preclinical mouse model that faithfully recapitulates human psoriasis. During PF’s SBIR Phase I grant award period, we successfully completed all three milestones focused on the preclinical development of CCL20LD as a psoriatic therapy. First, using a new systemic, IL-23 minicircle model, Protein Foundry showed that CCL20LD alleviated signs of skin inflammation after disease establishment, demonstrating that CCL20LD is efficacious as a therapeutic treatment in a clinically relevant model of human psoriasis. Second, CCL20LD was shown in preliminary serological analyses to be relatively safe, with no accumulation of hepatic or nephrotic biomarkers of tissue damage. Third, PF validated a reproducible manufacturing and quality control protocol for the CCL20LD protein. Given the successful completion of the phase I work and the notable efficacy in animals, we propose to develop CCL20LD as a next-generation treatment for psoriasis. To perform the R/R&D necessary for an IND, this phase II application proposes to develop an optimized dosing schedule using clinically relevant animal models, and validate the safety profile in rodents to guide IND-enabling GLP toxicology studies in non-human primates. In Aim 1 of this application, Protein Foundry and its academic collaborators at UC Davis will establish the therapeutic dose and schedule which produces the strongest anti- psoriatic effect in the shortest time period. In Aim 2, Protein Foundry will use cytokine storm and anti-drug antibody assays to test immunogenicity and establish a toxicology profile in rodents to guide GLP toxicology studies in non-human primates. Lastly, in Aim 3, Protein Foundry will explore topical formulations for testing in animal models as a first key step in differentiating CCL20LD from current market therapeutics and fully establish CCL20LD’s targeted product profile. 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 psoriasis 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.

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。趋化因子在正常免疫反应中协调炎症细胞的迁移 是免疫组织发育和动态平衡所必需的。当趋化因子功能发生异常时， 免疫细胞的不当募集可导致多种具有破坏性影响的炎性病理。 病人的生活质量。趋化因子CCL20及其G蛋白偶联受体CCR6驱动 炎性Th17表达在银屑病发病中的启动和持续募集 细胞进入真皮。我们最近发表的生化、基于细胞和体内的研究证明， 完全模拟天然CCL20分子二聚体的工程重组蛋白 逆转其正常的促炎功能。这种先导化合物(CCL20LD)是由PI在 威斯康星医学院预防牛皮癣(PSD)的发展和进展 一个临床前的小鼠模型，忠实地概括了人类牛皮癣。在PF的SBIR第一阶段授予奖期间 期间，我们成功地完成了CCL20LD AS临床前开发的所有三个里程碑 牛皮癣疗法。首先，使用一种新的系统性IL-23微循环模型，Protein Foundry显示CCL20LD 减轻疾病建立后的皮肤炎症迹象，证明CCL20LD是有效的 作为临床相关的人类牛皮癣模型的治疗方法。其次，CCL20LD是 初步血清学分析显示相对安全，没有肝或肾病积聚 组织损伤的生物标志物。第三，PF验证了可重复制造和质量控制协议 CCL20LD蛋白。鉴于第一阶段工作的成功完成和在动物身上的显著效果， 我们建议开发CCL20LD作为治疗牛皮癣的下一代药物。进行研发工作 对于IND来说是必要的，这个第二阶段的应用程序建议开发一个优化的剂量计划，使用 临床相关的动物模型，并验证啮齿类动物的安全性，以指导启用IND的GLP 非人灵长类动物的毒理学研究。在这项应用的目标1中，蛋白质铸造及其学术 加州大学戴维斯分校的合作者将确定产生最强抗病毒药物的治疗剂量和时间表 在最短的时间内起到牛皮癣的作用。在目标2中，蛋白质制造公司将使用细胞因子风暴和抗药性 用抗体检测鼠类的免疫原性并建立毒理学图谱以指导GLP毒理学 对非人类灵长类动物的研究。最后，在目标3中，Protein Foundry将探索用于测试的局部配方 动物模型是将CCL20LD与当前市场治疗方法区分开来的第一个关键步骤 建立CCL20LD的目标产品简介。通过对其本机进行工程来更改CCR6信令 Ligand是治疗自身炎症性疾病的临床方法的创新范式转变。 将CCL20工程变体作为生物疗法的开发将产生重大的积极影响 对于牛皮癣患者，通过减少副作用和提供一种延长治疗寿命的药物。 此外，这种方法还具有治疗其他由Th17介导的疾病的潜力。