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

重组人 CC10 蛋白用于治疗和预防慢性同种异体肺移植功能障碍

基本信息

批准号：
10602077
负责人：
APRILE L PILON
金额：
$ 26.07万
依托单位：
APCBIO INNOVATIONS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-05 至 2024-08-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10602077
关键词：
Acute Acute Lung Injury Airway Fibrosis Allografting Animal Model Animals Anti-Inflammatory Agents Antiinflammatory Effect Antioxidants Biochemical Biological Biological Assay Biological Response Modifier Therapy Bone Marrow Transplantation Bronchiolitis Obliterans Cells Chronic Chronic Obstructive Pulmonary Disease Chronic lung disease Clinical Clinical Management Clinical Trials Cystic Fibrosis Data Development Dose Epithelial Cells Event Fibrosis Functional disorder Future Goals Health Histopathology Host Defense Human IL8 gene Immune In Vitro Individual Infection Inflammation Inflammatory Inhalation Inhalation Exposure Injury Life Longevity Lung Lung Transplantation Lung diseases Mediating Mediator Methods Modeling Mus Neutrophilia Outcome Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phase Phenotype Phosphorylation Physiology Play Premature Infant Preparation Prevention Procedures Process Production Protein Isoforms Proteins Pulmonary Fibrosis Pulmonary Hypertension Pulmonary Inflammation Reactive Oxygen Species Recombinants Research Respiratory Failure Respiratory Mucosa Respiratory distress Role Route Secretory Cell Signal Transduction Small Business Innovation Research Grant Structure of parenchyma of lung Supplementation T cell response TNF gene Testing Therapeutic Transgenic Organisms Transplant Recipients Work adaptive immune response airway epithelium airway remodeling cell injury cell regeneration cell type clinical development design donor-specific antibody epithelial repair epithelium regeneration experience gain of function idiopathic pulmonary fibrosis immunogenicity immunoregulation improved in vitro Assay in vivo injured airway lung allograft mouse model neutrophil novel novel therapeutic intervention novel therapeutics oxidation p65 post-transplant prevent recruit response scale up secretory protein therapeutically effective transplant model wasting

项目摘要

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.

抽象的美国每年进行超过 5,000 例肺移植 (LTx) 以挽救患者的生命慢性阻塞性肺病（COPD）、特发性肺纤维化、囊性纤维化、肺纤维化等引起的呼吸衰竭高血压和其他晚期肺部疾病。绝大多数 LTx 的长期生存是受到慢性同种异体肺移植功能障碍 (CLAD) 的显着限制，中位生存期为 6 年移植后。迫切需要新疗法来改善 LTx 和 CLAD。天然 CC10/SCGB1A1 是一种重要的宿主防御、免疫调节和肺部的稳态蛋白，已知 CLAD 缺乏该蛋白。重组人 CC10 蛋白 (rhCC10) 可以提高体内天然 CC10 水平，是一种生物候选药物可能治疗和预防 CLAD。它已显示出在减少肺组织病理学方面的功效小鼠模型； 1）CLAD原位肺移植模型，2）闭塞性细支气管炎由原位骨髓移植引起，除了减少肺部炎症和其他几种急性肺损伤和肺纤维化动物模型中的纤维化。 RhCC10 是 3 项人体研究也显示出安全性，并显示出有效的抗炎作用患有呼吸窘迫的严重早产儿的肺部。在 CLAD 患者中，最佳给药途径是吸入，但吸入本质上是低效的交货方式。每个药物剂量的 70% 可能被浪费，因此，有利的是优化药物效力，以便生产和交付足够数量的药物以影响临床端点。我们的小组开发了增强 rhCC10 和拟议的研究将扩大这些方法的规模，表征所得产品，并优化它们具有最大的抗炎活性，为制剂的体内研究奠定基础具有增强的效力。