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

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 developme...

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Bibliographic Details
Published in:Science translational medicine 2017-01, Vol.9 (372)
Main Authors: Lamberth, Kasper, Reedtz-Runge, Stine Louise, Simon, Jonathan, Klementyeva, Ksenia, Pandey, Gouri Shankar, Padkjær, Søren Berg, Pascal, Véronique, León, Ileana R, Gudme, Charlotte Nini, Buus, Søren, Sauna, Zuben E
Format: Article
Language:English
Subjects:
Adolescent
Adult
Antibodies, Neutralizing - immunology
Cell Proliferation
Child
Cross-Over Studies
Data Interpretation, Statistical
Double-Blind Method
Epitopes - immunology
Factor VIIa - immunology
Factor VIII - immunology
Hemophilia A - blood
Hemophilia A - therapy
Histocompatibility Antigens Class II - immunology
HLA Antigens - immunology
Humans
Male
Mutation
Protein Engineering - methods
Recombinant Proteins - immunology
Software
Treatment Outcome
Young Adult
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Summary: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.
ISSN:1946-6234
1946-6242
DOI:10.1126/scitranslmed.aag1286