title: A humanized antibody that regulates the alternative pathway convertase: potential for therapy of renal disease associated with nephritic factors.
abstract: Dysregulation of the complement alternative pathway can cause disease in various organs that may be life-threatening. Severe alternative pathway dysregulation can be triggered by autoantibodies to the C3 convertase, termed nephritic factors, which cause pathological stabilization of the convertase enzyme and confer resistance to innate control mechanisms; unregulated complement consumption followed by deposition of C3 fragments in tissues ensues. The mAb, 3E7, and its humanized derivative, H17, have been shown previously to specifically bind activated C3 and prevent binding of both the activating protein, factor B, and the inhibitor, factor H, which are opposite effects that complicate its potential for therapy. Using ligand binding assays, functional assays, and electron microscopy, we show that these Abs bind C3b via a site that overlaps the binding site on C3 for the Ba domain within factor B, thereby blocking an interaction essential for convertase formation. Both Abs also bind the preformed convertase, C3bBb, and provide powerful inhibition of complement activation by preventing cleavage of C3. Critically, the Abs also bound and inhibited C3 cleavage by the nephritic factor-stabilized convertase. We suggest that by preventing enzyme formation and/or cleavage of C3 to its active downstream fragments, H17 may be an effective therapy for conditions caused by severe dysregulation of the C3 convertase and, in particular, those that involve nephritic factors, such as dense deposit disease.
authors.affiliation: Institute of Infection & Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom;
authors.forename: Danielle
authors.initials: D
authors.lastname: Paixão-Cavalcante
authors.forename: Eva
authors.initials: E
authors.lastname: Torreira
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Lindorfer
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodriguez de Cordoba
authors.forename: B Paul
authors.initials: BP
authors.lastname: Morgan
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Taylor
authors.forename: Oscar
authors.initials: O
authors.lastname: Llorca
authors.forename: Claire L
authors.initials: CL
authors.lastname: Harris
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology* / Q000627:therapeutic use; D051561:Complement C3 Convertase, Alternative Pathway / Q000037:antagonists & inhibitors / Q000276:immunology*; D050577:Complement C3-C5 Convertases / Q000276:immunology*; D011415:Complement Factor B / Q000276:immunology*; D003170:Complement Pathway, Alternative / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D050577:Complement C3-C5 Convertases; D051561:Complement C3 Convertase, Alternative Pathway; D011415:Complement Factor B
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