Alpha-subunit of the Mac-1 leukocyte adhesion receptor

• US 20030013850A1
• Filed: 05/20/2002
• Published: 01/16/2003
• Est. Priority Date: 08/23/1988
• Status: Active Grant

• Current Assignee: Angel Corbi, Timothy A. Springer
• Original Assignee: Angel Corbi, Timothy A. Springer
• Inventors: Springer, Timothy A., Corbi, Angel
• Granted Patent: US 6,683,158 B2
• Time in Patent Office: Days
• US Class Current: 530/350
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/12 Antivirals
• 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
• CPC Class Codes: C07K 14/70525 ICAM molecules, e.g. CD50, CD54, CD102
• CPC Class Codes: C07K 14/70553 Integrin beta2-subunit-containing molecules, e.g. CD11, CD18
• CPC Class Codes: C07K 16/2845 against integrin beta2-subunit-containing molecules, e.g. CD11, CD18

Abstract

The present invention relates to Mac-1 alpha-subunit which is involved in the process through which cells recognize and migrate to sites of inflammation as well as attach to cellular substrates during inflammation. The invention is directed toward such molecules, the functional derivatives of such molecules, screening assays for identifying such molecules and therapeutic and diagnostic uses for such molecules.

Claims

1. Mac-1 alpha-subunit, or a functional derivative thereof, substantially free of natural contaminants.

2. The Mac-1 alpha-subunit or said functional derivative thereof of claim 1, wherein said Mac-1 alpha-subunit is additionally capable of binding to a molecule present on the surface of a cell.

3. The Mac-1 alpha-subunit of claim 2, wherein said molecule present on the surface of a cell is iC3b or another natural ligand of Mac-1.

4. The Mac-1 alpha-subunit of claim 1, wherein said molecule is capable of associating with a Mac-1 beta subunit to form a Mac-1 heterodimer.

5. The Mac-1 alpha-subunit of claim 4, wherein said heterodimer is capable of binding iC3b or another natural ligand of Mac-1.

6. The Mac-1 alpha-subunit molecule of claim 2, wherein said molecule additionally contains at least one polypeptide selected from the group consisting of:

7. The functional derivative of the Mac-1 alpha-subunit of claim 2 wherein said functional derivative is a fragment of the Mac-1 alpha-subunit.

8. The functional derivative of the Mac-1 alpha-subunit of claim 2 wherein said functional derivative is a variant of Mac-1 alpha-subunit.

9. The functional derivative of the Mac-1 alpha-subunit of claim 2 wherein said functional derivative is an analog of Mac-1 alpha-subunit.

10. The functional derivative of the Mac-1 alpha-subunit of claim 2 wherein said functional derivative is a chemical derivative of Mac-1 alpha-subunit.

11. A recombinant DNA molecule capable of expressing Mac-1 alpha-subunit or a functional derivative thereof.

12. The DNA molecule of claim 11, wherein said Mac-1 alpha-subunit or said functional derivative thereof contains at least one polypeptide selected from the group consisting of:

13. The Mac-1 alpha molecule or functional derivative thereof produced by expression of the recombinant molecule of claim 11.

15. The method of claim 14 wherein said anti-inflammatory agent is the Mac-1 alpha-subunit.

16. The method of claim 14 wherein said anti-inflammatory agent is a functional derivative of the Mac-1 alpha-subunit.

17. The method of claim 14 which additionally comprises the administration of the Mac-1 beta-subunit or a functional derivative of the Mac-1 beta-subunit.

18. The method of claim 17 wherein said Mac-1 alpha subunit is produced by the expression of recombinant nucleic acid molecule and wherein said Mac-1 alpha subunit is associated with said beta subunit to thereby form a Mac-1 heterodimer.

19. The method of claim 14 wherein said anti-inflammatory agent is provided to said subject prior to the initiation of said inflammation.

20. The method of claim 14 wherein said anti-inflammatory agent is administered by means selected from the group consisting of enteral means and parenteral means.

21. The method of claim 20 wherein said parenteral means are selected from the group consisting of:

intramuscular, intravenous, and subcutaneous means.

22. The method of claim 14 wherein said inflammation is associated with a condition selected from the group consisting of:

asthma;

adult respiratory distress syndrome;

atherosclerosis;

multiple organ injury syndrome secondary to septicemia;

multiple organ injury syndrome secondary to trauma;

reperfusion injury of tissue;

acute glomerulonephritis;

reactive arthritis;

dermatosis with acute inflammatory components;

a central nervous system inflammatory disorder;

thermal injury;

hemodialysis;

leukapheresis;

ulcerative colitis;

Crohn'"'"'s disease;

necrotizing enterocolitis;

granulocyte transfusion associated syndrome;

cytokine-induced toxicity; and

atherosclerosis.

23. The method of claim 22 wherein said condition is adult respiratory distress syndrome.

24. The method of claim 22 wherein said condition is multiple organ injury syndrome secondary to septicemia.

25. The method of claim 22 wherein said condition is multiple organ injury syndrome secondary to trauma.

26. The method of claim 22 wherein said condition is reperfusion injury of tissue.

27. The method of claim 26 wherein said reperfusion injury is reperfusion injury of myocardial tissue.

28. The method of claim 22 wherein said condition is acute glomerulonephritis.

29. The method of claim 22 wherein said condition is reactive arthritis.

30. The method of claim 22 wherein said condition is dermatosis with acute inflammatory components.

31. The method of claim 22 wherein said condition is a central nervous system inflammatory disorder.

32. The method of claim 31 wherein said central nervous system inflammatory disorder is acute purulent meningitis.

33. The method of claim 22 wherein said condition is thermal injury.

34. The method of claim 22 wherein said condition is hemodialysis.

35. The method of claim 22 wherein said condition is leukapheresis.

36. The method of claim 22 wherein said condition is ulcerative colitis.

37. The method of claim 22 wherein said condition is Crohn'"'"'s disease.

38. The method of claim 22 wherein said condition is necrotizing enterocolitis.

39. The method of claim 22 wherein said condition is granulocyte transfusion associated syndrome.

40. The method of claim 22 wherein said condition is cytokine-induced toxicity.

41. The method of claim 22 wherein said condition is atherosclerosis.

14. A method for treating inflammation resulting from a response of the non-specific defense system in a mammalian subject which comprises providing to a subject in need of such treatment an anti-inflammatory agent, in an amount sufficient to suppress said inflammation;

wherein said anti-inflammatory agent is selected from the group consisting of;

the Mac-1 alpha-subunit; and

a functional derivative of the Mac-1 alpha-subunit.

42. A method of treating viral infection which comprises providing to a subject in need of such treatment, an effective amount of a composition comprising the alpha-subunit of MAC-1, or a functional derivative thereof.

43. The method of claim 42 wherein said MAC-1 alpha-subunit is provided in association with a beta chain of the CD-18 family.

44. The method of claim 42 wherein said viral infection is a rhinoviral infection.

45. The method of claim 43 wherein said viral infection is a rhinoviral infection.