Mitigation of T-cell dependent immunogenicity by reengineering factor VIIa analogue.
Blood Adv
; 3(17): 2668-2678, 2019 09 10.
Article
en En
| MEDLINE
| ID: mdl-31506285
ABSTRACT
Vatreptacog alfa (VA), a recombinant activated human factor VII (rFVIIa) variant with 3 amino acid substitutions, was developed to provide increased procoagulant activity in hemophilia patients with inhibitors to factor VIII or factor IX. In phase 3 clinical trials, changes introduced during the bioengineering of VA resulted in the development of undesired anti-drug antibodies in some patients, leading to the termination of a potentially promising therapeutic protein product. Here, we use preclinical biomarkers associated with clinical immunogenicity to validate our deimmunization strategy applied to this bioengineered rFVIIa analog. The reengineered rFVIIa analog variants retained increased intrinsic thrombin generation activity but did not elicit T-cell responses in peripheral blood mononuclear cells isolated from 50 HLA typed subjects representing the human population. Our algorithm, rational immunogenicity determination, offers a broadly applicable deimmunizing strategy for bioengineered proteins.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Linfocitos T
/
Ingeniería de Proteínas
/
Factor VIIa
Límite:
Humans
Idioma:
En
Revista:
Blood Adv
Año:
2019
Tipo del documento:
Article
País de afiliación:
Moldova