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

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

Author information

1
Global Research, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. zuben.sauna@fda.hhs.gov kplm@novonordisk.com.
2
Global Research, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
3
Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapeutics, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
4
Laboratory of Experimental Immunology, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
5
Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapeutics, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA. zuben.sauna@fda.hhs.gov kplm@novonordisk.com.

Abstract

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.

PMID:
28077675
DOI:
10.1126/scitranslmed.aag1286
[Indexed for MEDLINE]

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