Human Anti-WISP1 Antibodies for Treatment of Idiopathic Pulmonary Fbrosis

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是一种进行性、慢性衰弱性临床综合征，病因不明，具有终末结局。IPF症状包括持续性咳嗽、进行性重度呼吸短促和运动能力下降。多达200，000美国人患有这种疾病，预期生存期仅为3-5年。目前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最初的特征是肺泡上皮细胞损伤，随后是上皮-间质转化（EMT）和过度的成纤维细胞迁移、活化和增殖，伴细胞外基质沉积和组织重塑。当足够比例的IPF肺出现瘢痕性呼吸衰竭和合并症时。WNT 1-诱导信号蛋白-1（WISP 1;也称为CCN 4）是EMT的自分泌和旁分泌细胞外刺激物。研究表明：1。WISP 1在人肺细胞中由TGF-β诱导; 2. WISP 1在IPF的肺泡上皮表面上调; 3. WISP 1蛋白在体外刺激EMT和成纤维细胞ECM沉积; 4.用中和抗体耗竭WISP 1在体内减弱博来霉素诱导的肺纤维化。目前，没有针对WISP 1或WNT通路的IPF药物正在开发中。 我们与合作者一起概述了将抗体发现、纤维化途径专业知识和气雾剂药物开发相结合的实验，为发现、评估和开发用于IPF治疗的抗WISP 1免疫疗法提供坚实的基础。

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.