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Mitigation of T-cell dependent immunogenicity by reengineering factor VIIa analogue.
Blood Adv 2019; 3(17):2668-2678BA

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.

Authors+Show Affiliations

Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD. Center for Theoretical Problems of Physicochemical Pharmacology, Moscow, Russia.Abzena, Babraham Research Campus, Cambridge, United Kingdom.Abzena, Babraham Research Campus, Cambridge, United Kingdom.Abzena, Babraham Research Campus, Cambridge, United Kingdom.Abzena, Babraham Research Campus, Cambridge, United Kingdom.Laboratory of Cellular Hematology, Division of Blood Components and Devices, Office of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD; and.Department of Chemistry and Chemical Biology, Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ.Department of Chemistry and Chemical Biology, Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ.Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31506285

Citation

Jankowski, Wojciech, et al. "Mitigation of T-cell Dependent Immunogenicity By Reengineering Factor VIIa Analogue." Blood Advances, vol. 3, no. 17, 2019, pp. 2668-2678.
Jankowski W, McGill J, Lagassé HAD, et al. Mitigation of T-cell dependent immunogenicity by reengineering factor VIIa analogue. Blood Adv. 2019;3(17):2668-2678.
Jankowski, W., McGill, J., Lagassé, H. A. D., Surov, S., Bembridge, G., Bunce, C., ... Sauna, Z. E. (2019). Mitigation of T-cell dependent immunogenicity by reengineering factor VIIa analogue. Blood Advances, 3(17), pp. 2668-2678. doi:10.1182/bloodadvances.2019000338.
Jankowski W, et al. Mitigation of T-cell Dependent Immunogenicity By Reengineering Factor VIIa Analogue. Blood Adv. 2019 Sep 10;3(17):2668-2678. PubMed PMID: 31506285.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitigation of T-cell dependent immunogenicity by reengineering factor VIIa analogue. AU - Jankowski,Wojciech, AU - McGill,Joseph, AU - Lagassé,H A Daniel, AU - Surov,Stepan, AU - Bembridge,Gary, AU - Bunce,Campbell, AU - Cloake,Edward, AU - Fogg,Mark H, AU - Jankowska,Katarzyna I, AU - Khan,Abdul, AU - Marcotrigiano,Joseph, AU - Ovanesov,Mikhail V, AU - Sauna,Zuben E, PY - 2019/04/22/received PY - 2019/07/03/accepted PY - 2019/9/12/entrez PY - 2019/9/12/pubmed PY - 2019/9/12/medline SP - 2668 EP - 2678 JF - Blood advances JO - Blood Adv VL - 3 IS - 17 N2 - 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. SN - 2473-9537 UR - https://www.unboundmedicine.com/medline/citation/31506285/Mitigation_of_T-cell_dependent_immunogenicity_by_reengineering_factor_VIIa_analogue L2 - https://ashpublications.org/bloodadvances/article-lookup/doi/10.1182/bloodadvances.2019000338 DB - PRIME DP - Unbound Medicine ER -