Post hoc assessment of the immunogenicity of bioengineered factor VIIa demonstrates the use of preclinical tools

Sci Transl Med. 2017 Jan 11;9(372):eaag1286. doi: 10.1126/scitranslmed.aag1286.


Immunogenicity is an important consideration in the licensure of a therapeutic protein because the development of neutralizing anti-drug antibodies (ADAs) can affect both safety and efficacy. Neoantigens introduced by bioengineering of a protein drug are a particular cause for concern. The development of a bioengineered recombinant factor VIIa (rFVIIa) analog was discontinued after phase 3 trials because of the development of ADAs. The unmodified parent molecule (rFVIIa), on the other hand, has been successfully used as a drug for more than two decades with no reports of immunogenicity in congenital hemophilia patients with inhibitors. We used computational and experimental methods to demonstrate that the observed ADAs could have been elicited by neoepitopes in the engineered protein. The human leukocyte antigen type of the patients who developed ADAs is consistent with this hypothesis of a neoepitope-driven immune response, a finding that might have implications for the preclinical screening of therapeutic protein analogs.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Antibodies, Neutralizing / immunology
  • Cell Proliferation
  • Child
  • Cross-Over Studies
  • Data Interpretation, Statistical
  • Double-Blind Method
  • Epitopes / immunology
  • Factor VIII / immunology*
  • Factor VIIa / immunology
  • HLA Antigens / immunology
  • Hemophilia A / blood*
  • Hemophilia A / therapy*
  • Histocompatibility Antigens Class II / immunology
  • Humans
  • Male
  • Mutation
  • Protein Engineering / methods*
  • Recombinant Proteins / immunology
  • Software
  • Treatment Outcome
  • Young Adult


  • Antibodies, Neutralizing
  • Epitopes
  • HLA Antigens
  • Histocompatibility Antigens Class II
  • Recombinant Proteins
  • vatreptacog alfa
  • F8 protein, human
  • Factor VIII
  • Factor VIIa

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