title: A novel bifunctional chimeric complement inhibitor that regulates C3 convertase and formation of the membrane attack complex.
abstract: Human cells express cell surface complement regulatory molecules that inhibit the activity of the C3/C5 convertases (DAF, MCP, CR1) or inhibit the membrane attack complex (CD59). A single molecule that inhibits both the convertase activity and formation of the membrane attack complex has never been characterized. To this end, we have developed two reciprocal chimeric complement inhibitors (CD, NH2-CD59-DAF-GPI; and DC, NH2-DAF-CD59-GPI) that contain the functional domains of decay accelerating factor (DAF; CD55) and CD59. Cell surface expression of the CD and DC chimeric proteins was detected with DAF- and CD59-specific antisera. Cell surface C3d deposition was inhibited on cells expressing the chimeric molecules, thereby indicating that the DAF moiety was functional in both molecules. Conversely, Ab-blocking experiments demonstrated that only the DC molecule retained CD59 function. Therefore, the DC molecule represents a novel potent chimeric bifunctional complement inhibitor that retains the functional domains of two distinct complement regulatory molecules.
authors.affiliation: Department of Molecular Development, Alexion Pharmaceuticals, Inc., New Haven, CT 06511, USA.
authors.forename: W L
authors.initials: WL
authors.lastname: Fodor
authors.forename: S A
authors.initials: SA
authors.lastname: Rollins
authors.forename: E R
authors.initials: ER
authors.lastname: Guilmette
authors.forename: E
authors.initials: E
authors.lastname: Setter
authors.forename: S P
authors.initials: SP
authors.lastname: Squinto
mesh_terms: D000818:Animals; D001483:Base Sequence; D018958:CD55 Antigens / Q000235:genetics / Q000502:physiology*; D018957:CD59 Antigens / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D050577:Complement C3-C5 Convertases / Q000037:antagonists & inhibitors* / Q000235:genetics; D003169:Complement Inactivator Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015938:Complement Membrane Attack Complex / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D018958:CD55 Antigens; D018957:CD59 Antigens; D003169:Complement Inactivator Proteins; D015938:Complement Membrane Attack Complex; D011993:Recombinant Fusion Proteins; D050577:Complement C3-C5 Convertases