Recombinant human CC10 protein for treatment and prevention of chronic lung allograft dysfunction

摘要 每年在美国进行超过5，000例肺移植（LTx）以挽救患者的生命 在由COPD、特发性肺纤维化、囊性纤维化、肺 高血压和其他晚期肺病。绝大多数LTx患者的长期生存率 严重受限于慢性肺移植物功能障碍（CLAD），中位生存期为6年 移植后迫切需要新的疗法来改善LTx的临床结局， CLAD。天然CC 10/SCGB 1A 1是一种重要的宿主防御、免疫调节和免疫调节因子， 肺中的稳态蛋白，这是已知的缺乏CLAD。重组人 CC 10蛋白（rhCC 10）在体内可增加天然CC 10水平，是生物学候选物 可能治疗和预防CLAD。它已显示出减少肺组织病理学的功效， 小鼠模型：1）CLAD原位肺移植模型，2）闭塞性细支气管炎 由于原位骨髓移植引起的，除了减少肺部炎症， 在其他几种急性肺损伤和肺纤维化的动物模型中，RhCC 10是 在3项人体研究中也显示出安全性， 呼吸窘迫的严重早产儿的肺部。在CLAD患者中， 最佳的给药途径是吸入，然而，吸入是一种固有的低效给药途径。 交付方式高达70%的每种药物剂量可能被浪费，因此，有利的是， 优化药物效力，以便能够生产和输送足够数量的药物， 端点。我们的团队已经开发出了增强rhCC 10效力的方法， 拟议的研究将扩大这些方法，表征所得产品，并优化 他们最大的抗炎活性奠定了基础，在体内研究的制剂 具有增强的效力。

Abstract Over 5,000 lung transplants (LTx) are performed in the US each year to save the lives of patients in respiratory failure due to COPD, idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary hypertension, and other terminal lung conditions. The vast majority of LTx, long-term survival is significantly limited by chronic lung allograft dysfunction (CLAD) with a median survival of 6 years post-transplant. New therapies are urgently needed to improve clinical outcomes in LTx and CLAD. Native CC10/SCGB1A1 is an important host defense, immunomodulatory, and homeostatic protein in the lungs, which is known to be deficient in CLAD. Recombinant human CC10 protein (rhCC10) can augment native CC10 levels in vivo and is a biologic candidate potentially to treat and prevent CLAD. It has shown efficacy in decreasing lung histopathology in a murine models of; 1) orthotopic lung transplant model of CLAD, 2) bronchiolitis obliterans caused by orthotopic bone marrow transplant, in addition to reducing pulmonary inflammation and fibrosis in several other animal models of acute lung injury and pulmonary fibrosis. RhCC10 was also shown to be safe in 3 human studies and showed potent anti-inflammatory effects in the lungs of severely premature infants experiencing respiratory distress. In CLAD patients, the optimal route of administration is by inhalation, however, inhalation is an inherently inefficient delivery method. Up to 70% of each drug dose may be wasted, therefore, it is advantageous to optimize drug potency to enable production and delivery of sufficient quantities to impact clinical endpoints. Our group has developed methods to enhance the potency of rhCC10 and the proposed studies will scale-up these methods, characterize the resulting products, and optimize them for maximal anti-inflammatory activity to lay groundwork for in vivo studies of preparations with enhanced potency.