title: Fusion protein comprising factor H domains 6 and 7 and human IgG1 Fc as an antibacterial immunotherapeutic.
abstract: The emergence of antimicrobial resistance among several medically important pathogens represents a serious threat to human health globally and necessitates the development of novel therapeutics. Complement forms a key arm of innate immune defenses against invading pathogens. A mechanism of complement evasion employed by many pathogens is binding of complement inhibitors, including factor H (FH), a key downregulator of the alternative pathway. Most FH-binding bacteria engage FH through regions in FH spanned by domains 6 and 7 and/or 18 through 20. We created a chimeric protein that comprised human FH domains 6 and 7 fused to human IgG1 Fc (FH6,7/HuFc) and tested its activity as an immunotherapeutic against Neisseria meningitidis, which binds FH through domains 6 and 7. FH6,7/HuFc bound to meningococci and effectively blocked FH binding to bacteria. FH6,7/HuFc enhanced human C3 and C4 deposition and facilitated complement-mediated killing in a dose-responsive manner; complement activation and killing were classical pathway dependent. To investigate in vivo efficacy, infant Wistar rats were treated intraperitoneally (IP) with different doses of FH6,7/HuFc and challenged 2 h later with serogroup C strain 4243 given IP. At 8 to 9 h after the challenge, the FH6,7/HuFc-treated rats had >100-fold fewer CFU per ml of blood than control animals pretreated with phosphate-buffered saline (PBS) or FH18-20/HuFc, which does not bind to meningococci (P < 0.0001). These data provide proof of concept of the utility of FH/Fc fusion proteins as anti-infective immunotherapeutics. Because many microbes share a common binding region(s) in FH, FH/Fc chimeric proteins may be a promising candidate for adjunctive therapy against drug-resistant pathogens.
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Jutamas
authors.initials: J
authors.lastname: Shaughnessy
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, California, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Vu
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Rahi
authors.initials: R
authors.lastname: Punjabi
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Judit
authors.initials: J
authors.lastname: Serra-Pladevall
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Rosane B
authors.initials: RB
authors.lastname: DeOliveira
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, California, USA.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Granoff
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA sanjay.ram@umassmed.edu.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Ram
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001769:Blood / Q000382:microbiology; D015169:Colony Count, Microbial; D017242:Complement Factor H / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D003165:Complement System Proteins / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D007167:Immunotherapy / Q000379:methods*; D008589:Meningococcal Infections / Q000628:therapy*; D050296:Microbial Viability; D038542:Neisseria meningitidis, Serogroup C / Q000187:drug effects* / Q000502:physiology; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D017242:Complement Factor H; D003165:Complement System Proteins