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2 results on '"Mark H. Fogg"'

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

Author

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

Subjects
Specialties of internal medicine, RC581-951
Abstract

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.

Published
2019
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2. Mitigation of T-cell dependent immunogenicity by reengineering factor VIIa analogue

Author

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

Subjects
0301 basic medicine, T-Lymphocytes, Population, Factor VIIa, 030204 cardiovascular system & hematology, Pharmacology, Hemophilia A, Protein Engineering, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Hemophilias, Medicine, Humans, Immunogenetic Phenomena, education, Deimmunization, Cells, Cultured, Factor IX, Blood coagulation test, education.field_of_study, Factor VII, business.industry, Immunogenicity, Thrombin, Hematology, Turoctocog alfa, Gene Therapy, Recombinant Proteins, 030104 developmental biology, chemistry, Blood Coagulation Tests, business, medicine.drug
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.

Published
2019

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