Post hoc assessment of the immunogenicity of bioengineered factor VIIa demonstrates the use of preclinical tools
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Post hoc assessment of the immunogenicity of bioengineered factor VIIa demonstrates the use of preclinical tools. / 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.
I: Science Translational Medicine, Bind 9, Nr. 372, eaag1286, 2017.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Post hoc assessment of the immunogenicity of bioengineered factor VIIa demonstrates the use of preclinical tools
AU - Lamberth, Kasper
AU - Reedtz-Runge, Stine Louise
AU - Simon, Jonathan
AU - Klementyeva, Ksenia
AU - Pandey, Gouri Shankar
AU - Padkjær, Søren Berg
AU - Pascal, Véronique
AU - León, Ileana R.
AU - Gudme, Charlotte Nini
AU - Buus, Søren
AU - Sauna, Zuben E.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
U2 - 10.1126/scitranslmed.aag1286
DO - 10.1126/scitranslmed.aag1286
M3 - Journal article
C2 - 28077675
AN - SCOPUS:85010685641
VL - 9
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 372
M1 - eaag1286
ER -
ID: 197962615