title: A Novel Factor H-Fc Chimeric Immunotherapeutic Molecule against Neisseria gonorrhoeae.
abstract: Neisseria gonorrhoeae, the causative agent of the sexually transmitted infection gonorrhea, has developed resistance to almost every conventional antibiotic. There is an urgent need to develop novel therapies against gonorrhea. Many pathogens, including N. gonorrhoeae, bind the complement inhibitor factor H (FH) to evade complement-dependent killing. Sialylation of gonococcal lipooligosaccharide, as occurs in vivo, augments binding of human FH through its domains 18-20 (FH18-20). We explored the use of fusing FH18-20 with IgG Fc (FH18-20/Fc) to create a novel anti-infective immunotherapeutic. FH18-20 also binds to select host glycosaminoglycans to limit unwanted complement activation on host cells. To identify mutation(s) in FH18-20 that eliminated complement activation on host cells, yet maintained binding to N. gonorrhoeae, we created four mutations in domains 19 or 20 described in atypical hemolytic uremic syndrome that prevented binding of mutated fH to human erythrocytes. One of the mutant proteins (D to G at position 1119 in domain 19; FHD1119G/Fc) facilitated complement-dependent killing of gonococci similar to unmodified FH18-20/Fc but, unlike FH18-20/Fc, did not lyse human erythrocytes. FHD1119G/Fc bound to all (100%) of 15 sialylated clinical N. gonorrhoeae isolates tested (including three contemporary ceftriaxone-resistant strains), mediated complement-dependent killing of 10 of 15 (67%) strains, and enhanced C3 deposition (≥10-fold above baseline levels) on each of the five isolates not directly killed by complement. FHD1119G/Fc facilitated opsonophagocytic killing of a serum-resistant strain by human polymorphonuclear neutrophils. FHD1119G/Fc administered intravaginally significantly reduced the duration and burden of gonococcal infection in the mouse vaginal colonization model. FHD1119G/Fc represents a novel immunotherapeutic against multidrug-resistant N. gonorrhoeae.
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester MA 01605;
authors.forename: Jutamas
authors.initials: J
authors.lastname: Shaughnessy
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester MA 01605;
authors.forename: Sunita
authors.initials: S
authors.lastname: Gulati
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester MA 01605;
authors.forename: Sarika
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: World Health Organization Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Department of Laboratory Medicine and Microbiology, Orebro University Hospital, SE-701 85 Orebro, Sweden;
authors.forename: Magnus
authors.initials: M
authors.lastname: Unemo
authors.affiliation: National Institute of Infectious Diseases, Tokyo 162-8640, Japan;
authors.forename: Makoto
authors.initials: M
authors.lastname: Ohnishi
authors.affiliation: Institute of Dermatology, Chinese Academy of Medical Sciences, Peking Union Medical College, Nanjing 210042, China;
authors.forename: Xia-Hong
authors.initials: XH
authors.lastname: Su
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester MA 01605; Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany;
authors.forename: Brian G
authors.initials: BG
authors.lastname: Monks
authors.affiliation: Centers for Therapeutic Innovation, Pfizer, Inc., Cambridge, MA 02139;
authors.forename: Alberto
authors.identifier: http://orcid.org/0000-0002-2869-5049
authors.initials: A
authors.lastname: Visintin
authors.affiliation: Section of Infectious Diseases, Boston Medical Center, Boston, MA 02118; and.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Madico
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester MA 01605;
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Lewis
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester MA 01605;
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.affiliation: Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester MA 01605.
authors.forename: George W
authors.initials: GW
authors.lastname: Reed
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester MA 01605;
authors.forename: Peter A
authors.initials: PA
authors.lastname: Rice
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester MA 01605; sanjay.ram@umassmed.edu.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Ram
mesh_terms: D000818:Animals; D017242:Complement Factor H / Q000276:immunology* / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006069:Gonorrhea / Q000276:immunology*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology* / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D009344:Neisseria gonorrhoeae / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology* / Q000494:pharmacology
chemical_list: D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D017242:Complement Factor H