Development of highly potent human monoclonals for RSV immunoprophylaxis

PROJECT SUMMARY Respiratory syncytial virusRSVis a leading cause of infant hospitalizations in the U Sand the disease burden among the elderly is similar to non pandemic influenza ATraditional strategies have failed to generate an effective RSV vaccineand in some instances vaccination resulted in enhanced diseaseunderscoring the complexity of the human immune response to RSVAlthough a prophylactic antibody is availablepalivizumaba humanized mouse mAb marketed by MedImmune as Synagisits high cost and modest efficacy have restricted its use to high risk infantsMoreoverdue to this high costpalivizumab is inaccessible to children in developing nations and is unavailable inof themost populous countriesmore than half the worldandapos s population does not have access to this type of treatmentThe public health benefit and the worldwide accessibility would undoubtedly be improved by lowering the cost of RSV immunoprophylaxisIn this PhaseproposalDartmouth CollegeHanoverNHAdimabLebanonNHand Mapp BiopharmaceuticalIncSan DiegoCAare teaming to develop a fully human mAb with the following propertiesandgtfold neutralization potency versus palivizumab and at leastfold more potent in vitro and in vivo than Medimmune and Regeneronandapos s current clinical candidatesMEDIREGNbinds a different epitope than palivizumab and neutralizes palivizumab resistant strainsandIncreased serum half life so injections can be administered once per RSV season rather than monthly as required for palivizumabWith a more potent mAbi elower dosethat can be dosed less frequentlythe teamandapos s objective is to dramatically lower the price for RSV immunoprophylaxisIn additioncompetition in the marketplace would also help to reduce costs since palivizumab currently has a monopoly on the RSV marketWe propose the following Specific Aims to accomplish our objectiveEngineer and produce the best in vitro neutralizing mAbs with and without fucosylation of N glycansSelect lead candidates for advancement to in vivo testing using neutralization potency and manufacturability criteriaDetermine the in vivo potency of the neutralizing mAbs produced with or without fucosylation PROJECT NARRATIVE Respiratory Syncytial VirusRSVinfects nearly all children byyears of ageIn the U SRSV is the leading cause of lower respiratory tract disease in young children and a major cause of asthma and wheezing throughout childhoodRSV has a disease burden similar to that of non pandemic influenza A for elderlyandgtyears of ageand high risk adultscongestive heart failure or chronic pulmonary diseaseOur long term goal is to develop a safe and effective immunoprophylaxis product for RSVIn addition to infant populationsuse of the product in elderly populations may provide protection in nursing homes and rehabilitation hospitals during the RSV season