Fusion protein comprising factor H domains 6 and 7 and human IgG1 Fc as an antibacterial immunotherapeutic

Clin Vaccine Immunol. 2014 Oct;21(10):1452-9. doi: 10.1128/CVI.00444-14. Epub 2014 Aug 20.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / pharmacology*
  • Blood / microbiology
  • Colony Count, Microbial
  • Complement Factor H / administration & dosage
  • Complement Factor H / genetics
  • Complement Factor H / pharmacology*
  • Complement System Proteins / immunology
  • Complement System Proteins / metabolism
  • Disease Models, Animal
  • Immunoglobulin Fc Fragments / administration & dosage
  • Immunoglobulin Fc Fragments / genetics
  • Immunoglobulin Fc Fragments / pharmacology*
  • Immunoglobulin G / administration & dosage
  • Immunoglobulin G / genetics
  • Immunoglobulin G / pharmacology*
  • Immunotherapy / methods*
  • Meningococcal Infections / therapy*
  • Microbial Viability
  • Neisseria meningitidis, Serogroup C / drug effects*
  • Neisseria meningitidis, Serogroup C / physiology
  • Rats, Wistar
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / pharmacology
  • Treatment Outcome


  • Anti-Bacterial Agents
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Recombinant Fusion Proteins
  • Complement Factor H
  • Complement System Proteins