Targeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia.

Nature Communications
Xiao-Yan ZhaoVolker Laux

Abstract

Activated protein C (APC) is a plasma serine protease with antithrombotic and cytoprotective functions. Based on the hypothesis that specific inhibition of APC's anticoagulant but not its cytoprotective activity can be beneficial for hemophilia therapy, 2 types of inhibitory monoclonal antibodies (mAbs) are tested: A type I active-site binding mAb and a type II mAb binding to an exosite on APC (required for anticoagulant activity) as shown by X-ray crystallography. Both mAbs increase thrombin generation and promote plasma clotting. Type I blocks all APC activities, whereas type II preserves APC's cytoprotective function. In normal monkeys, type I causes many adverse effects including animal death. In contrast, type II is well-tolerated in normal monkeys and shows both acute and prophylactic dose-dependent efficacy in hemophilic monkeys. Our data show that the type II mAb can specifically inhibit APC's anticoagulant function without compromising its cytoprotective function and offers superior therapeutic opportunities for hemophilia.

References

Nov 1, 1981·The Journal of Clinical Investigation·J H GriffinC Wideman
Aug 5, 2000·Seminars in Thrombosis and Hemostasis·J M Lusher
Sep 14, 2001·Haemophilia : the Official Journal of the World Federation of Hemophilia·F VianelloA Girolami
Jan 30, 2003·Trends in Cardiovascular Medicine·Alireza R Rezaie
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
Apr 26, 2005·Methods : a Companion to Methods in Enzymology·William Ying Khee HwangJefferson Foote
Oct 31, 2006·Nature Medicine·Tong ChengBerislav V Zlokovic
Feb 27, 2009·Blood·Laurent O MosnierJohn H Griffin
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Jun 6, 2009·American Journal of Health-system Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists·Henry J MannDouglas E Schlichting
Oct 27, 2009·Nature Medicine·Jun XuCharles T Esmon
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Aug 9, 2011·Seminars in Immunopathology·Charles T Esmon
Mar 31, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·Max WarnckeChristoph Heusser
Apr 1, 2015·Blood·John H GriffinLaurent O Mosnier
Aug 27, 2016·American Journal of Hematology·Jan Hartmann, Stacy E Croteau
Oct 30, 2016·Blood·Stéphanie G I PolderdijkJames A Huntington
Jun 21, 2017·Current Opinion in Hematology·Stéphanie G I PolderdijkJames A Huntington
Jan 11, 2018·Blood·Raja PrinceAnne Angelillo-Scherrer
Jun 6, 2018·Blood·John H GriffinLaurent O Mosnier

❮ Previous
Next ❯

Citations

Feb 13, 2021·Pediatric Blood & Cancer·Yakun ZhaoJordan A Shavit
Feb 26, 2021·TheScientificWorldJournal·José F Santos-NetoBruna A S Machado
Nov 7, 2021·Proceedings of the National Academy of Sciences of the United States of America·Wariya SanrattanaSteven de Maat
Dec 2, 2021·Pediatrics in Review·Omar Matuk-VillazonFernando F Corrales-Medina
Feb 2, 2022·Biomolecular Concepts·José Manuel Pérez de la LastraAntonio Morales-delaNuez

❮ Previous
Next ❯

Methods Mentioned

BETA
phage-display
ELISA
X-ray
PCR
glycosylation
electrophoresis
size-
exclusion chromatography
transfection
size-exclusion chromatography

Software Mentioned

PHASER
PyMOL
Schrodinger suite
HKL2000
COOT
Image Studio
PHENIX
CCP4 suite
PyMOL Molecular Graphics System
Graphpad Prism

Related Concepts

Related Feeds

Blood Clotting Disorders

Thrombophilia includes conditions with increased tendency for excessive blood clotting. Blood clotting occurs when the body has insufficient amounts of specialized proteins that make blood clot and stop bleeding. Here is the latest research on blood clotting disorders.

Related Papers

Journal of Thrombosis and Haemostasis : JTH
John H GriffinLaurent O Mosnier
Blood
Laurent O MosnierJohn H Griffin
Current Opinion in Hematology
Stéphanie G I PolderdijkJames A Huntington
© 2022 Meta ULC. All rights reserved