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

TY - JOUR

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

SN - 1946-6234

VL - 9

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 372

M1 - eaag1286

ER -