Emphysema is a prevalent chronic obstructive pulmonary disease (COPD) induced predominantly by cigarette smoking through a complex mechanism that includes excessive apoptotic cell death of alveolar lung structural cells and chronic inflammation and for which there are scarce therapeutic options. We have made the novel discovery that pro-apoptotic and monocyte stimulating cytokine endothelial monocyte activating protein (EMAP II) is upregulated in the human bronchoalveolar lavage of current-smokers and of COPD patients who were ex-smokers. Enhanced levels of EMAP II in the murine lung can be experimentally induced by exposing mice to cigarette smoke (CS); furthermore, lung-specific transgenic overexpression of EMAP II causes emphysematous pathology in mouse lung. The strong correlation between disease pathology and EMAP II levels suggested modulating levels of this cytokine might be a useful therapeutic intervention in emphysema. To this end, we developed an EMAP II specific neutralizing rat monoclonal antibody (mAB), which abrogated functional and morphometric manifestations of CS-induced emphysema in mice when administered either concomitantly or after prolonged CS exposure. Based on these encouraging early results, we are now pursuing development of a fully humanized mAB EMAP II neutralizing antibody as a potentially new therapeutic for COPD/emphysema in current and former smokers. Here we propose to perform initial critical activities of developing a fully humanized monoclonal antibody. The studies proposed here will be the basis for future development goals of establishing a highly specific fully humanized EMAP II mAB for use in human COPD patients.
Public Health Relevance: There is an urgent need for effective treatments to address emphysema and chronic obstructive pulmonary disease (COPD). We have shown that the protein endothelial monocyte activating protein (EMAP II) is induced in human and mouse lungs upon cigarette smoke exposure and causes lung emphysema in mice. We have developed a monoclonal antibody to EMAP II that blocks lung emphysema formation and progression in animal disease models. Based on these encouraging results, we are establishing the tools for humanizing and improving this antibody, which will allow us to develop this novel disease treatment for human COPD patients.
Public Health Relevance Statement: There is an urgent need for effective treatments to address emphysema and chronic obstructive pulmonary disease (COPD). We have shown that the protein endothelial monocyte activating protein (EMAP II) is induced in human and mouse lungs upon cigarette smoke exposure and causes lung emphysema in mice. We have developed a monoclonal antibody to EMAP II that blocks lung emphysema formation and progression in animal disease models. Based on these encouraging results, we are establishing the tools for humanizing and improving this antibody, which will allow us to develop this novel disease treatment for human COPD patients.
NIH Spending Category: Biotechnology; Chronic Obstructive Pulmonary Disease; Emphysema; Immunization; Lung; Smoking and Health; Tobacco
Project Terms: Address; Adrenal Cortex Hormones; Affect; Affinity; Alveolar; Animal Disease Models; Antibodies; antigen antibody binding; antigen binding; Apoptotic; base; Binding (Molecular Function); Biological; Biological Assay; Blocking Antibodies; Bronchoalveolar Lavage; Bronchodilator Agents; cDNA Library; Cell Death; Cell Line; Cells; Chimera organism; chimeric antibody; Chinese Hamster Ovary Cell; Chronic; Chronic Obstructive Airway Disease; Cigarette; cigarette smoke; Cigarette smoke-induced emphysema; cigarette smoking; Complementarity Determining Regions; Complex; Controlled Clinical Trials; cytokine; Development; Digestion; Disease; effective therapy; Endothelial Cells; endothelial monocyte-activating polypeptide II; Epidemic; Epitope Mapping; Epitopes; Evolution; Excision; Exhibits; Future; Genes; Goals; Human; humanized antibody; humanized monoclonal antibodies; Hybridomas; IgG1; IgG2; Immunoglobulin G; Immunoglobulin Variable Region; Immunoprecipitation; improved; in vitro testing; Individual; Inflammation; Inflammatory; Length; Lung; Lung diseases; Maps; Methods; Monoclonal Antibodies; monocyte; Mortality Vital Statistics; Mus; Mutation; neutralizing antibody; neutralizing monoclonal antibodies; new therapeutic target; novel; novel therapeutics; overexpression; Oxygen; Parents; Pathology; Patients; Phase; Prevalence; Process; Production; Property; protein aminoacid sequence; Proteins; Pulmonary Emphysema; Rattus; Recombinants; respiratory; Respiratory Failure; Respiratory physiology; Role; Small Business Innovation Research Grant; Smoker; socioeconomics; Supplementation; Symptoms; synthetic peptide; System; Therapeutic; Therapeutic Intervention; Tissues; tool; Toxic effect; Transgenic Organisms; vector; Western Blotting
