title: Complement is activated by IgG hexamers assembled at the cell surface.
abstract: Complement activation by antibodies bound to pathogens, tumors, and self antigens is a critical feature of natural immune defense, a number of disease processes, and immunotherapies. How antibodies activate the complement cascade, however, is poorly understood. We found that specific noncovalent interactions between Fc segments of immunoglobulin G (IgG) antibodies resulted in the formation of ordered antibody hexamers after antigen binding on cells. These hexamers recruited and activated C1, the first component of complement, thereby triggering the complement cascade. The interactions between neighboring Fc segments could be manipulated to block, reconstitute, and enhance complement activation and killing of target cells, using all four human IgG subclasses. We offer a general model for understanding antibody-mediated complement activation and the design of antibody therapeutics with enhanced efficacy.
authors.affiliation: Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, 3584 CH Utrecht, Netherlands.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Diebolder
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Beurskens
authors.forename: Rob N
authors.initials: RN
authors.lastname: de Jong
authors.forename: Roman I
authors.initials: RI
authors.lastname: Koning
authors.forename: Kristin
authors.initials: K
authors.lastname: Strumane
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Lindorfer
authors.forename: Marleen
authors.initials: M
authors.lastname: Voorhorst
authors.forename: Deniz
authors.initials: D
authors.lastname: Ugurlar
authors.forename: Sara
authors.initials: S
authors.lastname: Rosati
authors.forename: Albert J R
authors.initials: AJ
authors.lastname: Heck
authors.forename: Jan G J
authors.initials: JG
authors.lastname: van de Winkel
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.forename: Abraham J
authors.initials: AJ
authors.lastname: Koster
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Taylor
authors.forename: Erica Ollmann
authors.initials: EO
authors.lastname: Saphire
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Janine
authors.initials: J
authors.lastname: Schuurman
authors.forename: Piet
authors.initials: P
authors.lastname: Gros
authors.forename: Paul W H I
authors.initials: PW
authors.lastname: Parren
mesh_terms: D002462:Cell Membrane / Q000276:immunology*; D003167:Complement Activation; D003172:Complement C1 / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D007074:Immunoglobulin G / Q000737:chemistry* / Q000276:immunology; D008081:Liposomes; D011487:Protein Conformation; D055503:Protein Multimerization
chemical_list: D003172:Complement C1; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D008081:Liposomes