ACTIVATED PROTEIN C VARIANTS WITH NORMAL CYTOPROTECTIVE ACTIVITY BUT REDUCED ANTICOAGULANT ACTIVITY

摘要

Variants (mutants) of recombinant activated protein C (APC) or recombinan t protein C (prodrug, capable of being converted to APC) that have substanti al reductions in anticoagulant activity but that retain normal levels of ant i-apoptotic activity are provided. Three examples of such recombinant APC mu tants are KKK191-193AAA-APC, RR229/230AA-APC, and RR229/230AA plus KKK191-19 3AAA-APC. APC variants and prodrugs of the invention have the desirable prop erty of being cytoprotective (anti-apoptotic effects), while having signific antly reduced risk of bleeding. The invention also provides a method of usin g the APC variants or prodrugs of the invention to treat subjects who will b enefit from APC's cytoprotective activities that are independent of APC's an ticoagulant activity. These subjects include patients at risk of damage to b lood vessels or tissue in various organs caused, at least in part, by apopto sis. 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 trans plantation 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.