A novel anti gonorrhea immunotherapeutic

Antimicrobial resistance is a major public health problem worldwide Neisseria gonorrhoeae Ng the causative agent of the sexually transmitted infection gonorrhea has become multidrug resistant and has achieved superbug status Novel therapeutics against Ng are urgently needed Complement C is a key arm of innate immune defenses A mechanism used by several pathogens including Ng to escape C is to bind to a host C inhibitor called factor H FH FH comprises domains arranged in an extended head to tail fashion Only the four N terminal domains domains possess C inhibiting activity the remainder of the molecule is important for recognition of host surfaces Many pathogens including Ng bind FH through domains and or A recombinant fusion of FH domains to IgG Fc FH Fc promotes C dependent killing of Ng Domains and in the context of full length FH bind to host cells and protect them from damage by C Introducing a D G amino acid mutation in domain of FH Fc to yield FH Fc retained anti Ng efficacy but abrogated C mediated lysis of host cells Topically administered FH Fc attenuated Ng infection in the mouse vaginal colonization model Planet Biotechnology Inc PBI has pioneered the production of functional antibodies and Fc fusion proteins in tobacco plants Nicotiana benthamiana Production of large quantities of functional FH Fc in plants at relatively low costs compared to traditional mammalian cell culture systems constitutes an ideal platform for developing anti infective immunotherapeutics In Aim PBI will produce four FH Fc molecules differing in their Fc three with human Fc hFc for studies in vitro and one with mouse Fc mFc for studies in mice The three different hFcandapos s fused to FH will be i Fc from IgG equivalent to what has been produced in CHO cells ii a linear chimera comprising IgG Fc plus CH and CH from IgA and iii Fc from IgA We expect human IgA Fc to increase ADCC by engaging Fc RI on human neutrophils In Aim UMass will examine the ability of the three FH hFcandapos s described above to i bind to ii deposit C on iii effect C dependent killing of and iv support opsonophagocytosis of drug resistant Ng The efficacy of FH mFc against Ng will be tested in the mouse vaginal colonization model using human FH transgenic BALB c mice The use of these novel mice will evaluate the therapeutic in the context of human FH as would occur in humans We also speculate that FH Fc may guide bacteria to Fc receptors on antigen presenting cells and elicit an immune response that may protect mice against reinfection This possibility will be addressed by re infecting the mice following FH Fc or control treatment We envision the use of FH Fc either as a topical prophylactic in women at high risk for gonorrhea or as a parenteral adjunctive anti infective While this proposal focuses on Ng we believe FH Fc will be useful against several medically important drug resistant pathogens that bind to human FH Gonorrhea a sexually transmitted infection that adversely affects the reproductive health of women worldwide has become resistant to almost every conventional antibiotic In an effort to develop new therapies against gonorrhea we have created a chimeric Fc fusion protein that activates complement on and kills gonococci In this proposal we will develop additional chimeric molecules with novel Fc modifications and produce these fusion proteins in tobacco plants which will provide an economical alternative to develop adjunctive treatments against multidrug resistant gonorrhea