title: Development of Autologous C5 Vaccine Nanoparticles to Reduce Intravascular Hemolysis in Vivo.
abstract: The complement system is emerging as a new target for treating many diseases. For example, Eculizumab, a humanized monoclonal antibody against complement component 5 (C5), has been approved for paroxysmal nocturnal hemoglobinuria (PNH) in which patient erythrocytes are lysed by complement. In this study, we developed vaccines to elicit autologous anti-C5 antibody production in mice for complement inhibition. Immunization of mice with a conservative C5 xenoprotein raised high titers of IgG's against the xenogenous C5, but these antibodies did not reduce C5 activity in the blood. In contrast, an autologous mouse C5 vaccine containing multiple predicted epitopes together with a tolerance-breaking peptide was found to induce anti-C5 autoantibody production in vivo, resulting in decreased hemolytic activity in the blood. We further validated a peptide epitope within this C5 vaccine and created recombinant virus-like particles (VLPs) displaying this epitope fused with the tolerance breaking peptide. Immunizing mice with these novel nanoparticles elicited strong humoral responses against recombinant mouse C5, reduced hemolytic activity, and protected the mice from complement-mediated intravascular hemolysis in a model of PNH. This proof-of-concept study demonstrated that autologous C5-based vaccines could be an effective alternative or supplement for treating complement-mediated diseases such as PNH.
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic , Cleveland, Ohio, United States.
authors.forename: Lingjun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic , Cleveland, Ohio, United States.
authors.forename: Wen
authors.initials: W
authors.lastname: Qiu
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology , Atlanta, Georgia, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Crooke
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic , Cleveland, Ohio, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology , Atlanta, Georgia, United States.
authors.forename: Areeba
authors.initials: A
authors.lastname: Abid
authors.affiliation: Department of Biochemistry, Virginia Polytechnic Institute & State University , Blacksburg, Virginia, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology , Atlanta, Georgia, United States.
authors.forename: M G
authors.identifier: 0000-0001-8247-3108
authors.initials: MG
authors.lastname: Finn
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic , Cleveland, Ohio, United States.
authors.forename: Feng
authors.identifier: 0000-0002-7202-1447
authors.initials: F
authors.lastname: Lin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003182:Complement C5 / Q000502:physiology; D006461:Hemolysis; D051379:Mice; D053758:Nanoparticles; D014612:Vaccines / Q000276:immunology
chemical_list: D003182:Complement C5; D014612:Vaccines