Development of a Fully Humanized Antibody for Treating Lung Emphysema

DESCRIPTION provided by applicant Emphysema is a prevalent chronic obstructive pulmonary disease COPD induced predominantly by cigarette smoking is defined as the combination of chronic bronchitis in the airways and emphysema which characterized by excessive cell apoptotic cell death of alveolar lung structural cells and chronic inflammation Because alveolar structures are essential for gas exchange in the lungs loss of this tissue component in emphysema affects life quality and health dramatically Current COPD therapy targets mainly the airways and no treatment is available for halting loss of parenchymal lung tissue The founders of EmphyMAb have made the discovery that pro apoptotic and monocyte stimulating cytokine endothelial monocyte activating protein EMAPPI is upregulated in the human bronchoalveolar lavage of current smokers and of COPD patients who were ex smokers Enhanced levels of EMAPII in the murine lung can be experimentally induced by exposing mice to cigarette smoke CS furthermore lung specific transgenic overexpression of EMAPII causes emphysematous pathology in mouse lung The strong correlation between disease pathology and EMAPII levels suggested modulating levels of this cytokine might be a useful therapeutic intervention in emphysema To this end the EmphMAb team developed an EMAPII 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 The team succeeded in generation of a partially humanized chimeric antibody with only slightly less affinity and activity in comparison to the parental one In this Phase I application EmphyMAb and its partners at Indiana University plan to fully humanize and increase affinity of the MAb and determine that the bioactivity and affinity of this recombinant antibody are better or at least equivalent to the original MAb The studies proposed here will be the basis for future goals of establishing a highly specific fully humanized EMAP II mAB for use in human COPD patients as a first treatment for halting the progressive loss of gas exchange permitting lung tissue PUBLIC HEALTH RELEVANCE There is an urgent need for effective treatments to address the progressive tissue loss in emphysema as the most fatal component of chronic obstructive pulmonary disease COPD Current treatment mostly targets the airway and cannot halt lung tissue destruction which when progressive finally leads to the need of oxygen treatment and or prolonged hospitalization EmphyMAb and its research partners at Indiana University 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 The team has developed a monoclonal antibody to EMAP II that blocks lung emphysema formation and progression in animal disease models Based on these encouraging results EmphyMAb are finalizing the humanization and increasing the potency of this antibody in preparation for studies to examine safety in animals which will allow us to proceed to testing in human subjects and ultimately COPD patients