Title:
ACTIVATED PROTEIN C VARIANTS WITH NORMAL CYTOPROTECTIVE ACTIVITY BUT REDUCED ANTICOAGULANT ACTIVITY
Document Type and Number:
WIPO Patent Application WO2005007820
Kind Code:
A3
Abstract:
Variants (mutants) of recombinant activated protein C (APC) or recombinant protein C (prodrug, capable of being converted to APC) that have substantial reductions in anticoagulant activity but that retain normal levels of anti-apoptotic activity are provided. Two examples of such recombinant APC mutants are 3K3A-APC and 229/230-APC. APC variants and prodrugs of the invention have the desirable property of being cytoprotective (anti-apoptotic effects), while having significantly reduced risk of bleeding. The invention also provides a method of using the APC variants or prodrugs of the invention to treat subjects who will benefit from APC's cytoprotective activities that are independent of APC's anticoagulant activity. These subjects include patients at risk of damage to blood vessels or tissue in various organs caused, at least in part, by apoptosis. At risk patients include, for example, those suffering (severe) sepsis, ischemia/reperfusion injury, ischemic stroke, acute myocardial infarction, acute or chronic neurodegenerative diseases, or those undergoing organ transplantation or chemotherapy, among other conditions. Methods of screening for variants of recombinant protein C or APC that are useful in accordance with the invention are also provided.
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Inventors:
GRIFFIN JOHN H (US)
MOSNIER LAURENT O (US)
GALE ANDREW J (US)
MOSNIER LAURENT O (US)
GALE ANDREW J (US)
Application Number:
PCT/US2004/021797
Publication Date:
September 29, 2005
Filing Date:
July 08, 2004
Export Citation:
Assignee:
SCRIPPS RESEARCH INST (US)
GRIFFIN JOHN H (US)
MOSNIER LAURENT O (US)
GALE ANDREW J (US)
GRIFFIN JOHN H (US)
MOSNIER LAURENT O (US)
GALE ANDREW J (US)
International Classes:
A01N1/02; A61K38/36; C12N9/64; C12P21/02; C12N; (IPC1-7): A61K38/36; C12P21/02; A01N1/02
Foreign References:
| US6037322A | 2000-03-14 | |||
| US6130201A | 2000-10-10 |
Other References:
GERLITZ B. ANDGRINNELL B.W. ET AL: "Mutation of protease domain residues Lys37-39 in human protein C inhibits activation by the thrombomodulin-thrombin complex without affecting activation by free thrombin.", J.BIOL.CHEM., vol. 271, no. 37, 13 September 1996 (1996-09-13), pages 22285 - 22288, XP002989622
RIEWALD M. ET AL: "Activation of endothelial cell protease activated receptor 1 by the protein C pathway.", SCIENCE., vol. 296, 7 June 2002 (2002-06-07), pages 1880 - 1882, XP002989623
RIEWALD M. ET AL: "Activation of endothelial cell protease activated receptor 1 by the protein C pathway.", SCIENCE., vol. 296, 7 June 2002 (2002-06-07), pages 1880 - 1882, XP002989623
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