Nebulized 'muco-trapping' antibodies for treating respiratory syncytial virus (RSV) infections

Project Summary Respiratory Syncytial VirusRSVis the leading cause of viral death in infants and young childrenand a major cause of respiratory illness in immune compromised adults and the elderlyUnfortunatelythere is currently no effective therapy for RSVSynagispalivizumaba monoclonal antibodymAbthat binds RSVis given by intramuscular injection to a small subset of high risk infants as immunoprophylaxisHoweverit is not effective at treating RSVand both pediatric and geriatric RSV patients are simply placed on supportive therapyWe believe a pathogen specificsafeeffective and topically delivered antiviral would provide a powerful option addressing the current gap in pharmacological interventionsHuman mAb delivered locally to mucosal surfaces offer exceptional promise combining safetyeffectiveness and unparalleled specificityAdding further to the promise of mAbthe Lai Lab recently discovered a novel antibody function in mucustrapping individual pathogens in mucusand have pioneered a technology enhancing the use of mAb in mucosal secretions based on carefully tuned affinity between IgG Fc and mucinswhich has been exclusively licensed to MucommuneWe have shown that engineered mAb can trap a variety of pathogens in different human mucus secretions at sub neutralizing concentrationsIn turnthis prevents pathogens from accessing the underlying epitheliumfacilitates rapid eliminationand enables effective protection in vivounderscoring the broad applicability of the Mucommune technologyInterestinglyRSV sheds exclusively from the apical surface of infected cellsindicating that RSV must traverse airway mucusAMbefore spreading to neighboring cellsThereforewe seek to harness our mAb technology and develop amuco trappingvariant of the palivizumab mAb that can be delivered directly to the airways by nebulizationthereby reducing the spread of RSV in the lung and facilitating rapid elimination of the virusWe will build upon pilot studies that demonstrate mAb can potently trap RSV in human AMfacilitate rapid elimination of viral particles from the mouse lung airwaysand remain stable when nebulized using a vibrating mesh nebulizerIn Aimworking together with Tony Hickey at RTIwe will verify that nebulization of mAb for delivery into the small airways will maintain the structural stability and native antigen binding affinity of the mAband estimate the dose that can be delivered to the pediatric lungIn Aimwe will validate that nebulizedmuco trappingpalivizumab can retain its muco trapping function in fresh human AMand effectively reduce RSV titers when delivered via nebulization to cotton rats following RSV challengeSuccessful completion of these Phase I SBIR studies will lead to a Phase II proposal focused on developing a shelf stable formulation that could be nebulized and administered to pediatric patients with diagnosed RSV infectionBy enabling enhanced mAb function in mucus secretionswe expect Mucommune will help pave the way for improvedmolecularly targeted therapies and prophylaxis against a broad spectrum of pathogens and microbes across all major mucosal surfaces Narrative The lack of effective vaccines and treatments for many common respiratory infections has resulted in tremendous health and cost burden in the United States and worldwidethusthere is an urgent need for alternative methods to treat respiratory infectionsTowards this goalMucommune is developing antibodies engineered to trap pathogens in mucusthereby facilitating their rapid elimination via natural mucociliary clearanceThis SBIR will establish the feasibility of nebulizing muco trapping antibodies that retain their structural stability as well as muco trapping and protective functions against Respiratory Syncytial Virusa leading cause of viral death in children in the U S