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（由申请人提供）：需要新的抗纤维化药物治疗特发性肺纤维化（IPF）。IPF是一种进行性，慢性衰弱的临床综合征，病因不明，终末结果。IPF症状包括持续咳嗽，进行性严重呼吸短促和运动能力下降。多达20万美国人患有这种疾病，预计生存期为3-5年。目前还没有批准的美国药物将肺移植作为延长生命的唯一选择。IPF的最初特征是肺泡上皮细胞损伤，随后是上皮-间质转化（EMT），成纤维细胞迁移、活化和增殖过度，伴有细胞外基质沉积和组织重塑。当足够比例的IPF肺变成疤痕时，就会出现呼吸衰竭和合并症。WNT1-诱导信号蛋白-1 （WISP1，也称为CCN4）是EMT的自分泌和旁分泌细胞外刺激。研究表明：1。TGF-¿在人肺细胞中诱导WISP1；2. IPF中肺泡上皮表面WISP1表达上调；3. WISP1蛋白在体外刺激EMT和成纤维细胞ECM沉积；4. 在体内用中和抗体去除WISP1可减轻博莱霉素诱导的肺纤维化。目前，还没有针对WISP1或WNT通路的IPF药物正在开发中。与我们的合作者一起，我们概述了实验，将利用抗体发现，纤维化途径专业知识和气溶胶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。