Design and Development of Immunotolerant S. aureus Biotherapies

The increasing incidence of multi drug resistance in Staphylococcus aureus and other bacteria represents a public health crisisTwo thirds of hospital associated Saureus infections andof those acquired in the community are now methicillin resistantMRSAMRSA causes rtinfections in the US each yearand it is responsible for half of all US deaths caused by drug resistant bacteriaThis threat to public health is creating demand for new therapeutic agentsbut traditional antibiotic development pipelines are not keeping pace with the escalating problemMoreoverantibacterial chemotherapies have proven widely susceptible to rapid evolution of bacterial resistanceBacteriolytic enzymessuch as Staphylococcus simulans lysostaphinare an innovative new class of antibiotics that catalytically dismantle cell wall peptidoglycan causing bacterial lysis and deathDue to peptidoglycan s conserved nature and complex biosynthesissuch enzymes have proven less susceptible to emergent resistanceUnfortunatelylysostaphin elicits anti drug antibodies in vivoand this immunogenicity and associated toxicity are barriers to clinical translationSupported by a successful Phase I STTR grantStealth Biologics has re engineered lysostaphin for reduced immunogenicity in humansThe pivotal outcomes of the Phase I STTR project weredesign and construction of Fa globally deimmunized variant of lysostaphinin vitro validation of Fs anti MRSA potencypreliminary quantification of Fsynergy with FDA approved antibioticsdemonstration of reduced immunogenicity in human cellular immunoassaysandconfirmation of reduced in vivo immunogenicity and consequent enhanced therapeutic efficacy in humanized HLA transgenic miceCollectivelythese data suggest that Fis a promising therapeutic for drug resistant Saureus infectionsIn the proposed Phase II STTRwe have designed a systematic and focused strategy for constructing an Ftarget product profileTPPIn AimFmanufacturing and purification will be optimized and scaled upIn Aiman initial clinical indication will be selected based on Fs in vivo efficacy in two well established modelsrabbit bacteremia endocarditis and murine skin infectionEfficacy studies will be supported by rigorous experimental analyses of in vitro potencyin vitro resistance susceptibilityin vivo maximum tolerated doseand in vivo pharmacokineticsAimwill yield a preliminary toxicity and immunogenicity profile in rabbits and humanized mice that have received escalating single or repeated doses of FThe resulting data package will enable construction of a TPP that will guide design and execution of comprehensive IND enabling studiesWe anticipate that Fbased antibacterial therapies will prove to be potentsafeand amenable to repeated dosingAs suchFwill benefit from competitive advantages relative to more immunogenic phage endolysinsand ultimately it may represent a breakthrough drug for life threatening MRSA infections