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.
Public Health Relevance Statement: The proposed research will contribute to our fundamental understanding of the impact of reactive oxygen species on CC10 activity, as well as of the processes underlying the development of CLAD/bronchiolitis obliterans and immune-mediated airway injury. It could also lead to not only development of novel biologic therapeutics to prevent and/or treat CLAD with improved clinical management of CLAD patients but also may reveal new therapeutic approaches that could enhance the health and lifespan of lung and other transplant recipients.
Project Terms: Animals; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Anti-Inflammatory Agents; Antioxidants; anti-oxidant; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Response Modifier Therapy; Biological Therapy; biological therapeutic; biological treatment; biologically based therapeutics; biotherapeutics; biotherapy; Bone Marrow Transplantation; Bone Marrow Grafting; Bone Marrow Transplant; Marrow Transplantation; Bronchiolitis Obliterans; Exudative Bronchiolitis; Proliferative Bronchiolitis; Cells; Cell Body; Clinical Trials; Cystic Fibrosis; Mucoviscidosis; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Epithelial Cells; Fibrosis; Future; Goals; Health; Human; Modern Man; Pulmonary Hypertension; In Vitro; Premature Infant; infants born premature; infants born prematurely; premature baby; premature infant human; preterm baby; preterm infant; preterm infant human; Infection; Inflammation; Longevity; Length of Life; life span; lifespan; Lung; Lung Respiratory System; pulmonary; Lung diseases; Pulmonary Diseases; Pulmonary Disorder; disease of the lung; disorder of the lung; lung disorder; Lung Transplantation; Lung Grafting; Pulmonary Graft; Pulmonary Transplant; Pulmonary Transplantation; lung transplant; Methods; Mus; Mice; Mice Mammals; Murine; neutrophil; Blood Neutrophil; Blood Polymorphonuclear Neutrophil; Marrow Neutrophil; Neutrophilic Granulocyte; Neutrophilic Leukocyte; Polymorphonuclear Cell; Polymorphonuclear Leukocytes; Polymorphonuclear Neutrophils; oxidation; Patients; Phenotype; Phosphorylation; Protein Phosphorylation; Physiology; Play; Production; Proteins; Pulmonary Fibrosis; Lung Tissue Fibrosis; fibrosis in the lung; lung fibrosis; Research; Role; social role; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Testing; Work; Mediating; Neutrophilia; Active Oxygen; Oxygen Radicals; Pro-Oxidants; Reactive Oxygen Species; injuries; Injury; improved; Procedures; Acute; Chronic; Clinical; Phase; biologic; Biological; Biochemical; wasting; Individual; Acute Pulmonary Injury; Acute Lung Injury; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Therapeutic; Inflammatory; Transplant Recipients; transplant patient; Life; Immune; Immunes; Event; Route; cell type; Respiratory distress; Host Defense; Allografting; Inhalation Exposure; experience; Protein Isoforms; Isoforms; secretory protein; cell injury; Cellular injury; cell damage; cellular damage; damage to cells; injury to cells; Animal Model; Animal Models and Related Studies; model of animal; p65; Transgenic Organisms; transgenic; Histopathology; immunoregulation; Immunomodulation; immune modulation; immune regulation; immunologic reactivity control; immunomodulatory; immunoregulatory; novel; Prevention; Pathogenesis; Chronic lung disease; chronic pulmonary disease; Respiratory Mucosa; Airway mucosa; TNF gene; (TNF)-a; Cachectin; Macrophage-Derived TNF; Monocyte-Derived TNF; TNF; TNF A; TNF Alpha; TNF-a; TNFA; TNFa; Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; Structure of parenchyma of lung; Lung Parenchyma; Lung Tissue; Modeling; response; Airway failure; Respiratory Failure; preventing; prevent; IL8 gene; 3-10C; AMCF-I; CXCL8; GCP1; IL-8; IL8; K60; SCYB8; TSG-1; b-ENAP; Dose; Data; Recombinants; Supplementation; in vitro Assay; in vivo; Antiinflammatory Effect; anti-inflammatory effect; Clinical Management; Secretory Cell; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Preparation; preparations; Process; Development; developmental; Pathway interactions; pathway; immunogenicity; designing; design; airway remodeling; lung allograft; Outcome; scale up; Respiratory Epithelium; Structure of respiratory epithelium; respiratory tract epithelium; airway epithelium; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; gain of function; airway injury; impaired airway; respiratory injury; respiratory tract injury; injured airway; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; new treatment approach; new treatment strategy; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; novel therapeutic intervention; T cell response; Lung Inflammation; Pneumonitis; Pulmonary Inflammation; adaptive immune response; clinical development; recruit; Inhaling; Inhalation; transplant model; Fibrosing Alveolitis; diffuse interstitial pulmonary fibrosis; idiopathic pulmonary fibrosis; post-transplantation; posttransplant; posttransplantation; post-transplant; regenerate epithelium; epithelium regeneration; cellular regeneration; cell regeneration; epithelial repair; therapeutically effective; donor antibodies; donor-specific antibody; Airway Fibrosis; Airway scar; Respiratory fibrosis; Chronic Obstructive Pulmonary Disease; COPD; Chronic Obstruction Pulmonary Disease; Chronic Obstructive Lung Disease; Mediator
