title: Combinatorial peptides directed to inhibitory antibodies against human blood clotting factor VIII.
abstract: The development of antibodies against blood clotting factor VIII is a major complication affecting 20-30% of hemophilia A patients receiving replacement with FVIII concentrates. This study investigated generating peptides acting as broadly neutralizing agents to block factor VIII antibodies. These peptides were selected from dual positional scanning decapeptide libraries on cellulose membranes. From this library comprising 6.8 x 10(12) peptides we selected 468 peptides for further screening rounds. Finally we identified two decapeptides with the ability to block 8 out of 10 inhibitory antibodies from sera of patients with FVIII inhibitors demonstrated by competition assays. Sequence alignment of the peptides showed similarity with several domains in the FVIII molecule demonstrating the mimotope nature of the selected peptides. Our results show the efficiency of the combinatorial library approach and show the potential of combinatorial peptides to compete out polyclonal inhibitor IgG from a broad range of patients' sera. Combinatorial peptides could be novel and highly effective drug candidates for alternative treatment in patients with factor VIII inhibitors.
authors.affiliation: Department of Biotechnology, University of Natural Resources and Applied Life Sciences, Vienna, Austria.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Kopecky
authors.forename: Sabine
authors.initials: S
authors.lastname: Greinstetter
authors.forename: Ingrid
authors.initials: I
authors.lastname: Pabinger
authors.forename: Andrea
authors.initials: A
authors.lastname: Buchacher
authors.forename: Jürgen
authors.initials: J
authors.lastname: Römisch
authors.forename: Alois
authors.initials: A
authors.lastname: Jungbauer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001323:Autoantibodies / Q000276:immunology*; D001667:Binding, Competitive / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D020650:Combinatorial Chemistry Techniques; D000939:Epitopes; D005169:Factor VIII / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D018716:Molecular Mimicry / Q000276:immunology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology* / Q000627:therapeutic use; D019151:Peptide Library; D017434:Protein Structure, Tertiary
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D010446:Peptide Fragments; D019151:Peptide Library; D005169:Factor VIII