Peptide decoys selected by phage display block in vitro and in vivo activity of a human anti-FVIII inhibitor.
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.
Villard
Sylvie
S
Unité Mixte de Recherche 5094 of the Centre National de la Recherche Scientifique Institut National de la Recherche Médicale, Faculté de Pharmacie, Montpellier, France.
Lacroix-Desmazes
Sebastien
S
Kieber-Emmons
Thomas
T
Piquer
Dominique
D
Grailly
Sabrina
S
Benhida
Abdellah
A
Kaveri
Srini V
SV
Saint-Remy
Jean-Marie
JM
Granier
Claude
C
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
D000939:Epitopes; D007518:Isoantibodies; D019151:Peptide Library; D010455:Peptides; D005169:Factor VIII