Use of C1 inhibitor for the prevention of ischemia-reperfusion injury

• US 8,071,532 B2
• Filed: 12/19/2006
• Issued: 12/06/2011
• Est. Priority Date: 12/21/2005
• Status: Active Grant

• Current Assignee: Pharming Intellectual Property B.V. (Pharming Group N.V.)
• Original Assignee: Pharming Intellectual Property B.V. (Pharming Group N.V.)
• Inventors: Mannesse, Maurice, Nuijens, Johannes Henricus, Pieper, Frank, De Simoni, Maria Grazia, Ziere, Gijsbertus Johannes
• Primary Examiner(s): CARLSON, KAREN C
• Application Number:
  US12/158,987
• Publication Number:
  US 20080305993A1
• Time in Patent Office: 1,813 Days
• Field of Search: 514/1, 530/350
• US Class Current: 514/1
• CPC Class Codes: A61K 38/57 from animals; from humans A61K38/553, A61K38/556 take precedence
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention relates to the therapeutic and prophylactic use of C1 inhibitor for preventing, reducing and treating ischemia and reperfusion injury. The C1 inhibitor of the present invention is still therapeutically effective when administered after an ischemic period and reperfusion and therefore particularly useful for unforeseen occurrences of ischemic reperfusion such as e.g. a stroke.

Claims

1. A method for preventing, reducing or treating ischemia and/or reperfusion injury, said method comprising administering to a subject in need thereof a pharmaceutical composition comprising a C 1 inhibitor recombinantly expressed in eukarvotic cell culture or in a transgenic nonhuman animal to have a reduced level of terminal sialic acid residues compared to plasma derived human C 1 inhibitor and a plasma half life shorter than 6 hours, wherein the administration of the C1 inhibitor occurs before 6 hours after the onset of ischemia or after reperfusion.

2. The method of claim 1, wherein the C1 inhibitor is administered at least one hour after the start of reperfusion.

3. The method of claim 1, wherein the C1 inhibitor comprises a glycan that has a terminal saccharide residue selected from galactose, N -acetylgalactosamine, N-acetylglucosamine, mannose and fucose.

4. The method of claim 1, wherein the C1 inhibitor is obtained from a transgenic nonhuman animal.

5. The method of claim 4, wherein the animal is a mammal and the C1 inhibitor is obtained from milk of the mammal.

6. The method of claim 4, wherein the transgenic non-human animal is a bovine or a lagomorph.

7. The method of claim 6, wherein the lagomorph is a rabbit.

8. The method of claim 1, wherein the C 1 inhibitor is administered at a dose range of 50 to 2000 units per kilogram body weight.

9. The method of claim 1, wherein the pharmaceutical composition is administered to said subject after, or in combination with, a thrombolytic agent.

10. The method of claim 1, wherein the pharmaceutical composition further comprises a thrombolytic agent.

11. The method of claim 1, wherein said administering of the pharmaceutical composition prevents, reduces or treats an unforeseen, sudden or acute incident of ischemia and/or reperfusion injury.

12. The method of claim 1, wherein said administering is after the subject has suffered a stroke.

13. The method of claim 12, wherein the C1 inhibitor exerts a neuroprotective effect.

14. The method of claim 13 wherein the neuroprotective effect of the C1 inhibitor is in hippocampus and/or cerebral cortex.

15. The method of claim 1, wherein said administering is after the subject has undergone an organ transplant.

16. The method of claim 1 wherein the subject is undergoing an organ transplant.

17. The method of claim 1, wherein the ischemia and/or reperfusion injury occurs in myocardium, kidney, gastrointestinal tract, or brain.

18. The method of claim 1, wherein the C1 inhibitor reduces size of a lesion resulting from the ischemia and/or reperfusion.

19. The method of claim 1, wherein the pharmaceutical composition is administered at least 30 minutes after the start of reperfusion.

20. The method of claim 1, wherein the pharmaceutical composition is administered 10 minutes after the start of reperfusion.

21. The method of claim 1, wherein the C1 inhibitor is administered at least 1 hour after onset of ischemia.

22. The method of claim 1, wherein the pharmaceutical composition is administered no more than 4 hours after onset of ischemia.