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Mitigation of T-cell dependent immunogenicity by reengineering factor VIIa analogue

Wojciech Jankowski, Joseph McGill, H. A. Daniel Lagassé, Stepan Surov, Gary Bembridge, Campbell Bunce, Edward Cloake, Mark H. Fogg, Katarzyna I. Jankowska, Abdul Khan, Joseph Marcotrigiano, Mikhail V. Ovanesov and Zuben E. Sauna

Key Points

  • An rFVIIa analog with increased procoagulant activity elicited anti-drug antibodies in some patients.

  • Redesigned rFVIIa analogs exhibit both desired functional activity and reduced immunogenicity risk.

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.

  • Submitted April 22, 2019.
  • Accepted July 3, 2019.
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