Novel anti-fibrotic therapy for IPF

特发性肺纤维化的新型抗纤维化治疗 摘要 特发性肺纤维化(IPF)的特点是肌成纤维细胞积聚、细胞外沉积 基质(ECM)(包括胶原和纤维连接蛋白)和进行性弥漫性肺间质纤维化。 间充质祖细胞向肌成纤维细胞的不适当增殖和转化 (MPC)在疾病病理中起着关键作用。尽管这种特发性疾病背后的分子机制 疾病一直不清楚，最近的研究表明S100A4是MPC的关键自分泌-旁分泌介质 自我更新。S100A4是MPC恶化纤维化的必要条件和充分条件，使这个成员成为 小的EF-手基序钙离子结合蛋白是一个有希望的疾病修改目标(夏，2017)。近期工作 证实了这一论点(Li，2018)。基于这些研究，在这个第一阶段项目中，我们将生成一个面板 高亲和力的人类单抗(HumAbbs)可以阻断S100A4信号。评审团的排名将是- 使用新的体外试验进行排序，然后使用新的人评估最佳候选HumAb MPC基因增强的博莱霉素致小鼠肺间质纤维化模型。我们乐观地认为，这种方法将产生一流的 对这种毁灭性疾病的治疗。

Novel anti-fibrotic therapy for IPF Abstract Idiopathic pulmonary fibrosis (IPF) is characterized by myofibroblast accumulation, deposition of extracellular matrix (ECM) (including collagen and fibronectin), and progressive diffuse fibrosis in the lung interstitium. Inappropriate proliferation of fibroblasts and transformation to myofibroblasts from mesenchymal progenitor cells (MPC) play key roles in disease pathology. Although the molecular mechanisms that underlie this idiopathic disease have been obscure, recent studies implicate S100A4 as a critical autocrine-paracrine mediator of MPC self-renewal. S100A4 is both necessary and sufficient for MPCs to worsen fibrosis, making this member of the small EF-hand motif Ca2+-binding proteins a promising disease-modifying target (Xia, 2017). Recent work confirms this contention (Li, 2018). Based on these studies, during this Phase 1 project, we will generate a panel of high-affinity human monoclonal antibodies (humAbs) that block S100A4 signaling. The panel will be rank- ordered using novel in vitro assays followed by evaluation of the top candidate humAb using a novel human MPC-augmented bleomycin murine model of IPF. We are optimistic that this approach will yield a best-in-class therapy for this devastating disease.