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

Animals Antibodies, Monoclonal / classification Bleeding Time Cell Membrane Permeability / drug effects Cells, Cultured Crystallography, X-Ray Hemophilia A / blood Hemorrhage / prevention & control Human Umbilical Vein Endothelial Cells / drug effects Humans Immunoglobulin Fab Fragments / immunology Macaca fascicularis Male Protein C / antagonists & inhibitors Protein C Inhibitor / blood

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
12 06 2020

Historique:

received: 23 08 2019

accepted: 15 05 2020

entrez: 14 6 2020

pubmed: 14 6 2020

medline: 25 8 2020

Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-020-16720-9 PMID: 32532974 PMC: PMC7293249

pubmed: 32532974

doi: 10.1038/s41467-020-16720-9

pii: 10.1038/s41467-020-16720-9

pmc: PMC7293249

doi:

Substances chimiques

Antibodies, Monoclonal 0

Immunoglobulin Fab Fragments 0

Protein C 0

Protein C Inhibitor 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

2992

Subventions

Organisme : NHLBI NIH HHS

ID : R01 HL142975

Pays : United States

Organisme : NHLBI NIH HHS

ID : R01 HL148096

Pays : United States

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