SBIR/STTR Award attributes
Antimicrobial resistance is a major public health problem worldwideNeisseria gonorrhoeaeNgthe causative agent of the sexually transmitted infection gonorrheahas become multidrug resistant and has achievedsuperbugstatusIn additionbetweenandof women successfully treated for gonorrhea are re infected within three monthsNovel therapeutics against Ng are urgently neededComplementCis a key arm of innate immune defensesA mechanism used by several pathogensincluding Ngto escape Cis to bind to a host Cinhibitor called factor HFHFH comprisesdomainsarranged in an extended head to tail fashionOnly the four N terminal domainsdomainspossess Cinhibiting activitythe remainder of the molecule is important for recognition of host surfacesMany pathogensincluding Nghave evolved to bind FH through domainsand orA recombinant fusion of FH domainswith a point mutation in domainto abrogate binding to host cellsto IgG FcFHFcbinds to and promotes Cdependent killing of NgTopically administered FHFc attenuates Ng infection in the mouse vaginal colonization modelWe have producedin our plant expression systemvariant FHFc molecules with different Fc or different linkers between FH and FcWe demonstrated the functional superiority of plant made FHFc variants incorporating flexible linkersGGGGSorGGGGSboth in vitro and in a mouse vaginal infection prophylactic modelWe have also shown that the functionality of these molecules depends on the ability of the Fc to activate complement on the Ng surfaceWe envision using FHGS hFc to prevent re infection in women treated for uncomplicated gonorrheaIn this Fast Track project we seek to further preclinical development of this promising immunotherapeutic against drug resistant NgIn Phase I we will produce and test in vitro five new FHGS hFc variants where the Fc is modified to improve Cmediated killing of Ng and identify two lead variants with the greatest potencyIn Phase II we will compare the potency of these FHGS hFc lead variants in vivo against four divergent Ng isolatesdetermining the minimum effective doseWe will test their in vitro potency againstdiverse Ng clinical isolatesWe will scale up purification and evaluate the ability of the two lead variants to undergo spray drying and retain in vitro potencyBased on the sum of all the above experimentswe will select one variant as a lead for commercializationWe will formulate the lead FHGS hFc variant in an intravaginal ring designed for sustainedcontrolled release over several weeksand evaluate its PK and safety in rhesus macaquesWe will perform a six month drug substance stability study in anticipation of a future Phaseclinical trialWith the help of a large contract manufacturer of plant made proteinswe will conduct a technoeconomic analysis to determine the commercial viability of plant made FHGS hFcand seek the guidance of the FDA on future FHGS hFc nonclinical and clinical development Gonorrheaa sexually transmitted infection that adversely affects the reproductive health of women worldwidehas become resistant to almost every conventional antibioticWe have producedin a plant expression systema chimeric Fc fusion protein that activates complement on and kills gonococciIn this proposalwe will test variants of this protein for enhanced activity in vivo and in vivo and will conduct additional nonclinical studies designed to progress the product toward a Phaseclinical trial and commercial development as an immunoprophylactic or as an adjunctive treatment against multidrug resistant gonorrhea
