Modified annexin proteins and methods for their use in organ transplantation

• US 7,635,676 B2
• Filed: 11/03/2005
• Issued: 12/22/2009
• Est. Priority Date: 02/21/2001
• Status: Expired due to Fees

• Current Assignee: Alavita Pharmaceuticals, Inc. (Thermo Fisher Scientific Incorporated)
• Original Assignee: Alavita Pharmaceuticals, Inc. (Thermo Fisher Scientific Incorporated)
• Inventors: Allison, Anthony
• Primary Examiner(s): Robinson; Hope A
• Application Number:
  US11/267,837
• Publication Number:
  US 20060105952A1
• Time in Patent Office: 1,510 Days
• Field of Search: None
• US Class Current: 514/1.1
• CPC Class Codes: A01N 1/0226 Physiologically active agents, i.e. substances affecting physiological processes of cells and tissue to be preserved, e.g. anti-oxidants or nutrients
• CPC Class Codes: A61K 35/14 Blood; Artificial blood perfluorocarbons A61K31/02; umbilical cord blood A61K35/51; haemoglobin A61K38/42
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07K 14/4721 Lipocortins

Abstract

Modified annexin proteins, including a homodimer of human annexin V, are provided. Methods for their use, such as to prevent thrombosis without increasing hemorrhage and to attenuate ischemia-reperfusion injury (IPI), are also provided. The modified annexins bind phosphatidylserine (PS) on cell surfaces, thereby preventing the assembly of the prothromkinase complex. The modified annexin decreases the binding of leukocytes and platelets during post-ischemic reperfusion, thereby restoring microvascular blood flow and decreasing organ damage.

Claims

1. A method of protecting an organ or a tissue susceptible to ischemia reperfusion injury (IRI), comprising administering to a patient who is a recipient of an organ transplant a composition comprising an isolated annexin dimer at least 95% identical to a protein selected from the group consisting of SEQ ID NO:

6, SEQ ID NO;

26, SEQ ID NO;

27, SEQ ID NO;

19, SEQ ID NO;

23, SEQ ID NO;

3-linker-SEQ ID NO;

3, SEQ ID NO;

12-linker-SEQ ID NO;

12, and SEQ ID NO;

15-linker-SEQ ID NO;

15, SEQ ID NO;

3-linker-SEQ ID NO;

12, SEQ ID NO;

3-linker-SEQ ID NO;

15, SEQ ID NO;

12-linker-SEQ ID NO;

15, SEQ ID NO;

12-linker-SEQ ID NO;

3, SEQ ID NO;

15-linker-SEQ ID NO;

3 and SEQ ID NO;

15-linker-SEQ ID NO;

12, wherein the linker is at least one glycine-serine sequence, and whereby said administering protects said organ and tissue.

2. The method of claim 1, wherein said composition is administered in an intravascular dose of 10 to 1000 μ

g/kg.

3. The method of claim 2, wherein said composition is administered in an intravascular dose of 100 to 500 μ

g /kg.

4. The method of claim 1, wherein said composition is administered to the recipient patient during the transplantation.

5. The method of claim 1, wherein said annexin dimer is selected from the group consisting of SEQ ID NO:

6, SEQ ID NO;

19, SEQ ID NO;

27, SEQ ID NO;

23, SEQ ID NO;

3-linker-SEQ ID NO;

3, SEQ ID NO;

12-linker-SEQ ID NO;

12, and SEQ ID NO;

15-linker-SEQ ID NO;

15, SEQ ID NO;

3-linker-SEQ ID NO;

12, SEQ ID NO;

3-linker-SEQ ID NO;

15, SEQ ID NO;

12-linker-SEQ ID NO;

15, SEQ ID NO;

12-linker-SEQ ID NO;

3, SEQ ID NO;

15-linker-SEQ ID NO;

3, and SEQ ID NO;

15-linker-SEQ ID NO;

12.

6. A method of protecting an organ or a tissue susceptible to ischemia reperfusion injury (IRI), comprising administering to a patient who is a recipient of an organ transplant a composition comprising an isolated annexin dimer at least 95% identical to a protein selected from the group consisting of SEQ ID NO:

6, SEQ ID NO;

26, SEQ ID NO;

27, SEQ ID NO;

19, SEQ ID NO;

23, SEQ ID NO;

3-linker-SEQ ID NO;

12, SEQ ID NO;

3-linker-SEQ ID NO;

15, SEQ ID NO;

12 -linker-SEQ ID NO;

15, SEQ ID NO;

12 -linker-SEQ ID NO;

3, SEQ ID NO;

15-linker-SEQ ID NO;

3 and SEQ ID NO;

15-linker-SEQ ID NO;

12, wherein the linker is at least one glycine-serine sequence, and whereby said administering protects said organ and tissue.

7. A method of protecting organ or tissue transplants susceptible to ischemia reperfusion injury (IRI), comprising contacting said transplant with a preservation fluid for perfusion and storage, wherein said preservation fluid comprises an isolated annexin dimer at least 95% identical to a protein selected from the group consisting of SEQ ID NO:

6, SEQ ID NO;

19, SEQ ID NO;

27, SEQ ID NO;

23, SEQ ID NO;

3-linker-SEQ ID NO;

3, SEQ ID NO;

12 -linker-SEQ ID NO;

12, and SEQ ID NO;

15-linker-SEQ ID NO;

15, SEQ ID NO;

3-linker-SEQ ID NO;

12, SEQ ID NO;

3-linker -SEQ ID NO;

15, SEQ ID NO;

12-linker-SEQ ID NO;

15, SEQ ID NO;

12-linker-SEQ ID NO;

3, SEQ ID NO;

15-linker-SEQ ID NO;

3, and SEQ ID NO;

15-linker-SEQ ID NO;

12;

wherein the linker is at least one glycine-serine sequence, and whereby said contacting protects said organ and tissue transplants.

8. The method of claim 7, wherein said preservation fluid comprises an isolated annexin dimer in a concentration of 0.1 to 1 mg/l.