A - Human Necessities – 61 – K
Patent
A - Human Necessities
61
K
A61K 38/48 (2006.01) A61K 38/16 (2006.01) A61P 39/00 (2006.01) C12Q 1/02 (2006.01) C12Q 1/37 (2006.01) C12Q 1/56 (2006.01) C40B 30/00 (2006.01) C40B 30/06 (2006.01) C12N 9/64 (2006.01)
Patent
CA 2667841
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. Three examples of such recombinant APC mutants are KKK191-193AAA-APC, RR229/230AA-APC, and RR229/230AA plus KKK191-193AAA-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.
L'invention concerne des variantes (mutants) de la protéine C activée recombinante (APC) ou de la protéine C recombinante (promédicament, capable de se transformer en APC) qui présentent des réductions importantes de l'activité anticoagulante mais conservent des niveaux normaux d'activité anti-apoptotique. Trois exemples de tels mutants d'APC recombinants sont KKK191-193AAA-APC, RR229/230AA-APC et RR229/230AA plus KKK191-193AAA-APC. Les variantes d'APC et les promédicaments selon l'invention ont la propriété souhaitable d'être cytoprotectrices (effets anti-apoptotiques), tout en présentant un risque significativement réduit de saignement. L'invention concerne également un procédé d'utilisation des variantes d'APC ou des promédicaments selon l'invention pour traiter des sujets qui bénéficieront des activités cytoprotectrices de l'APC indépendamment de l'activité anticoagulante de l'APC. Ces sujets comprennent des patients à risque de dommages aux vaisseaux sanguins ou tissus dans divers organes causés, au moins en partie, par l'apoptose. Les patients à risque comprennent, par exemple, ceux souffrant de sepsie (grave), de lésions de reperfusion/ischémie, d'accident ischémique cérébral, d'infractus du myocarde aigu, de maladies neurodégénératives aiguës ou chroniques, ou de ceux subissant une transplantation d'organe ou une chimiothérapie, entre autres maladies. L'invention concerne également des procédés de criblage de variantes de protéine C recombinante ou d'APC qui sont utiles selon l'invention.
Gale Andrew J.
Griffin John H.
Mosnier Laurent O.
Macrae & Co.
The Scripps Research Institute
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