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

• 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
• 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

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(申请人提供)：治疗特发性肺纤维化(IPF)需要新的抗纤维化药物。特发性肺间质纤维化是一种进行性、慢性衰弱的临床综合征，病因不明，结局不详。IPF症状包括持续咳嗽、进行性严重呼吸急促和运动能力下降。多达20万美国人患有这种疾病，预计存活时间仅为3-5年。目前还没有批准的美国药物，使肺移植成为延长生命的唯一选择。IPF以肺泡上皮细胞损伤、上皮-间充质转化(EMT)、成纤维细胞过度迁移、活化和增殖、细胞外基质沉积和组织重塑为主要特征。当足够比例的IPF肺形成疤痕时，就会发生呼吸衰竭和合并症。WNT1诱导信号蛋白-1(WISP1；又称CCN4)是EMT的一种自分泌和旁分泌细胞外刺激因子。研究表明：1.转化生长因子β可诱导人肺泡上皮细胞表达WISP1；2.肺间质纤维化时肺泡上皮细胞表面WISP1表达上调；3.WISP1蛋白在体外可促进EMT和成纤维细胞ECM的沉积；4.用中和抗体去除WISP1可减轻博莱霉素诱导的体内肺纤维化。目前，还没有针对WISP1或WNT途径的IPF药物在开发中。我们与我们的合作者一起概述了实验，这些实验将利用抗体发现、纤维化途径专业知识和气雾剂药物开发的强大组合，为发现、评估和开发用于IPF治疗的抗WISP1免疫疗法提供坚实的基础。