title: Peptide decoys selected by phage display block in vitro and in vivo activity of a human anti-FVIII inhibitor.
abstract: Hemophilia A is a life-threatening, hemorrhagic, X-linked recessive disorder resulting in deficient factor VIII (FVIII) activity. After the infusion of therapeutic FVIII, 25% of patients develop anti-FVIII antibodies that inhibit FVIII procoagulant activity, thus precluding further administration of FVIII. Here we report a novel approach aimed at neutralizing the activity of FVIII inhibitors by peptide epitope surrogates. To illustrate our concept, we chose the human anti-FVIII monoclonal antibody, Bo2C11, as a representative of anti-FVIII antibodies and a phage-displayed peptide library approach to obtain surrogate peptides. We selected a series of constrained dodecapeptides with the core sequence W-NR, which specifically interacts with the combining site of Bo2C11. The peptides mimic the epitope recognized by Bo2C11 and are able to inhibit specifically and in a dose-dependent manner the binding of Bo2C11 to FVIII. Peptide 107, in particular, neutralized the activity of Bo2C11 in vitro and restored normal hemostasis in hemophilic mice. Thus, the use of peptide decoys may be a promising new approach for the neutralization of pathologic antibodies.
authors.affiliation: Unité Mixte de Recherche 5094 of the Centre National de la Recherche Scientifique Institut National de la Recherche Médicale, Faculté de Pharmacie, Montpellier, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Villard
authors.forename: Sebastien
authors.initials: S
authors.lastname: Lacroix-Desmazes
authors.forename: Thomas
authors.initials: T
authors.lastname: Kieber-Emmons
authors.forename: Dominique
authors.initials: D
authors.lastname: Piquer
authors.forename: Sabrina
authors.initials: S
authors.lastname: Grailly
authors.forename: Abdellah
authors.initials: A
authors.lastname: Benhida
authors.forename: Srini V
authors.initials: SV
authors.lastname: Kaveri
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Saint-Remy
authors.forename: Claude
authors.initials: C
authors.lastname: Granier
mesh_terms: D000595:Amino Acid Sequence; D000915:Antibody Affinity; D000939:Epitopes; D005169:Factor VIII / Q000276:immunology* / Q000627:therapeutic use; D006467:Hemophilia A / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007518:Isoantibodies / Q000187:drug effects*; D019151:Peptide Library; D010455:Peptides / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000939:Epitopes; D007518:Isoantibodies; D019151:Peptide Library; D010455:Peptides; D005169:Factor VIII