Human Anti-WISP1 Antibodies for Treatment of Idiopathic Pulmonary Fbrosis

用于治疗特发性肺纤维化的人抗 WISP1 抗体

基本信息

批准号：
8785946
负责人：
Gunnar Joerg Floris Kaufmann
金额：
$ 22.48万
依托单位：
SORRENTO THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-18 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8785946
关键词：
Address Aerosols Affect Alveolar American Antibodies Attenuated Back Bleomycin Cells Cicatrix Clinical Collaborations Comorbidity Coughing Data Deposition Development Disease Drug Delivery Systems Drug Kinetics Epithelial Epithelial Cells Etiology Evaluation Event Exercise Extracellular Matrix FDA approved Fatal Outcome Fibroblasts Fibrosis Future Growth Factor Hamman-Rich syndrome Human Hyperplasia Immunotherapy In Vitro Intravenous Kinetics Left lung Libraries Life Life Expectancy Lung Lung Transplantation Matrix Metalloproteinases Mediating Mesenchymal Modeling Monoclonal Antibodies Outcome Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Phase Process Production Pulmonary Fibrosis Pulmonology Regulation Respiratory Failure Risk Route Safety Shortness of Breath Signal Transduction Signaling Protein Solid Stimulus Structure of parenchyma of lung Surface Symptoms Syndrome Therapeutic Tissues Universities WISP1 gene WNT1 gene analytical method autocrine base biophysical properties candidate identification cell injury design drug development extracellular human WISP1 protein in vivo method development migration neutralizing antibody novel paracrine pre-clinical public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): New anti-fibrotic drugs are needed to treat Idiopathic Pulmonary Fibrosis (IPF). IPF is a progressive, chronically debilitating clinical syndrome with unknown etiology and a terminal outcome. IPF symptoms include persistent cough, progressive severe shortness of breath and decreased exercise capacity. Up to 200,000 Americans suffer from this disease with expected survival limited to 3-5 years. There are currently no approved US drugs leaving lung transplantation as the only option to extend life. IPF is initially characterized by alveolar epithelial cell injury followed by epithelial-mesenchymal transition (EMT) and exaggerated fibroblast migration, activation and proliferation with extracellular matrix deposition and tissue remodeling. When a sufficient proportion of the IPF lung becomes scarred respiratory failure and comorbidities occur. WNT1- Inducible Signaling Protein-1 (WISP1; also known as CCN4) is an autocrine and paracrine extracellular stimulus for EMT. Studies have shown that: 1. WISP1 is induced in human lung cells by TGF-¿; 2. WISP1 is upregulated at the alveolar epithelial surface in IPF; 3. WISP1 protein stimulates EMT and fibroblast ECM deposition in vitro; 4. depletion of WISP1 with neutralizing antibodies attenuates bleomycin-induced pulmonary fibrosis in vivo. Currently, no IPF drugs are in development that target WISP1 or the WNT pathway. Together with our collaborators we have outlined experiments that will harness a powerful combination of antibody discovery, fibrotic pathway expertise and aerosol drug development to provide a solid basis for the discovery, evaluation and development of an anti-WISP1 immunotherapy for IPF treatment.

描述（由申请人提供）：需要新的抗纤维化药物来治疗特发性肺纤维化（IPF），IPF 是一种病因不明的进行性慢性衰弱性临床综合征，其最终症状包括持续性咳嗽、进行性严重呼吸困难。多达 200,000 名美国人患有这种疾病，预计生存期仅限于 3-5 年。目前美国还没有批准肺移植作为治疗方法的药物。 IPF 最初的特征是肺泡上皮细胞损伤，然后是上皮间质转化 (EMT) 和过度的成纤维细胞迁移、活化和增殖，并伴有细胞外基质沉积和重塑组织，当足够比例的 IPF 肺部出现疤痕时。 WNT1-诱导信号蛋白-1（WISP1；也称为 CCN4）是一种自分泌和旁分泌的细胞外信号。研究表明： 1. WISP1 在人肺细胞中被 TGF-¿ 2. WISP1 在 IPF 中肺泡上皮表面上调；3. WISP1 蛋白在体外刺激 EMT 和成纤维细胞 ECM 沉积；4. 用中和抗体消除 WISP1 可减轻体内的 IPF 药物。我们与我们的合作者一起概述了针对 WISP1 或 WNT 通路的开发，这些实验将利用抗体发现的强大组合，纤维化途径专业知识和气雾剂药物开发为发现、评估和开发用于 IPF 治疗的抗 WISP1 免疫疗法提供了坚实的基础。