METHODS OF TREATING AND PREVENTING ACUTE MYOCARDIAL INFARCTION

• US 20090220564A1
• Filed: 08/18/2006
• Published: 09/03/2009
• Est. Priority Date: 08/19/2005
• Status: Abandoned Application

• Current Assignee: X-Cell Medical Incorporated
• Original Assignee: X-Cell Medical Incorporated
• Inventors: Baumbach, William R., Ben-Joseph, Oded, Shankar, Hariharan
• Application Number:
  US12/063,792
• Publication Number:
  US 20090220564A1
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/468 Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/626 Diabody or triabody

Abstract

The present disclosure provides methods and compositions for treating coronary tissue damaged as a result of a cardiac disorder such as ischemia, acute myocardial infarction, vulnerable plaques, or reperfusion injury. Specifically, the cardiac disorder is treated using a multivalent molecule that is specific for a marker located, in or near the damaged coronary tissue and a marker located on a target cell (e.g., a stem cell). The multivalent molecule may be administered by intravenous injection, intra-arterial catheter, intramyocardial injection, or implantable device (e.g, stent).

Claims

1. A method for treating a cardiac disorder in a patient, said method comprising administering to said patient a molecule, wherein said molecule is capable of binding (i) a coronary tissue marker and (ii) a target cell marker.

2. The method of claim 1, wherein said cardiac disorder is selected from the group consisting of acute myocardial infarction, a chronic ischemic condition, reperfusion injury, chronic heart disease, vulnerable plaques, and cardiac fibrosis.

3. The method of claim 1, wherein said cardiac disorder is acute myocardial infarction.

4. The method of claim 1, wherein said molecule is selected from the group consisting of a bispecific antibody, bispecific F(ab′

)₂ fragment, bispecific miniantibody, diabody, triabody, and tetrabody.

5. The method of claim 4, wherein said molecule is a diabody.

6. The method of claim 5, wherein said diabody is a human IgG.

7. The method of claim 1, wherein said coronary tissue marker is selected from the group consisting of matrix, metalloproteinase-1, matrix metalloproteinase-8, fibronectin, osteopontin, TLR4, IL1RL1-b, vascular cell adhesion molecule-1 (VCAM-1), Adam-like decysin-1 (ADAMDEC1), matrix metalloproteinase-9 (MMP-9), CD 163, chemokine (C—

X—

C motif) ligand-2 (CXCL2), retinoic acid responder-1 (RARRES1), LpPLA2;

colony-stimulating factor-2 receptor β

(CSF2RB), cathepsin S, chemokine (C—

C motif) ligand 18 (CCL

     18), spermidine/spermine N1 acetyltransferase, integrin β

2 (ITGB2), cystatin B (CSTB), legumain;

uncoupling protein 2 (UCP2), cathepsin B, RALGDS, F11 receptor (JAM-A), and ATPase plasma membrane 1 (ATP2B1).

8. The method of claim 1, wherein said target cell marker is present on a target cell is selected from the group consisting of a bone-marrow-derived stem cell, a circulating stem cell, a coronary stem cell, an endothelial progenitor cell, and a hormone/growth factor secreting cell.

9. The method of claim 1, wherein said target cell marker is selected from the group consisting of CD34, CD133, CD14, CXCR4, kinase insert domain receptor (KDR), Flk-1, VE-cadherin, c-Kit, and Sca-1.

10. The method of claim 1, wherein said target cell marker is CD34.

11. The method of claim 1, wherein said molecule is administered by intravenous, intra-arterial, or intramyocardial injection.

12. The method of claim 1, wherein said molecule is administered in the course of percutaneous transluminal coronary angioplasty.

13. The method of claim 1, wherein said molecule is administered using an implantable intra-arterial stent.

14. A molecule capable of binding (i) a coronary tissue marker and (ii) a target cell marker.

15. The molecule of claim 14, wherein said molecule is selected from the group consisting of a bispecific antibody, bispecific F(ab′

)₂ fragment, bispecific miniantibody, diabody, triabody, and tetrabody.

16. The molecule of claim 14, wherein said molecule is a diabody.

17. The molecule of claim 16, wherein said diabody is a human IgG.

18. The molecule of claim 14, wherein said coronary tissue marker is selected from the group consisting of matrix metalloproteinases-1, matrix metalloproteinase-8, fibronectin, osteopontin, TLR4, and IL1RL1-b.

19. The molecule of claim 14, wherein said target cell marker is present on a target cell is selected from the group consisting of a bone-marrow-derived stem cell, a circulating stem cell, a coronary stem cell, an endothelial progenitor cell, and a hormone/growth factor secreting cell.

20. The molecule of claim 14, wherein said target cell marker is selected from the group consisting of CD34, CD 133, CD 14, CXCR4, kinase insert domain receptor (KDR), Flk-1, VE-cadherin, c-Kit, and Sea-1.

21. The molecule of claim 14, wherein said target cell marker is CD34.

22. The molecule of claim 14, wherein said molecule comprises a first VH and VL pair and a second VH and VL pair.

23. The molecule of claim 22, wherein said first VH and VL pair has a different binding specificity compared to said second VH and VL pair.

24. The molecule of claim 23, wherein at least one of said first VH and VL pair and said second VH and VL pair is derived from a hybridoma.

25. A pharmaceutical composition comprising the molecule of claim 14 and a pharmaceutically acceptable carrier.

26. The composition of claim 25, wherein said pharmaceutically acceptable carrier is a microparticle.

27. The pharmaceutical composition of claim 25, wherein said composition is suitable for intravenous, intra-arterial, or intramyocardial injection.

28. An implantable device comprising the molecule of claim 14.

29. The device of claim 28, wherein said molecule is coated on said device.

30. The device of claim 28, wherein said molecule is contained within a polymer coating on said device.

31. The device of claim 28, wherein said device is a stent.

32. A cardiovalent molecule for use in treating a cardiac disorder, wherein said cardiovalent molecule is capable of binding (i) a coronary tissue marker and (ii) a target cell marker.

33. The cardiovalent molecule of claim 32, wherein said cardiac disorder is selected from the group consisting of acute myocardial infarction, a chronic ischemic condition, reperfusion injury, chronic heart disease, vulnerable plaques, and cardiac fibrosis.

34. The cardiovalent molecule of claim 33, wherein said cardiac disorder is acute myocardial infarction.

35. The cardiovalent molecule of claim 32, wherein said cardiovalent molecule is selected from the group consisting of a bispecific antibody, bispecific F(ab′

)2 fragment, bispecific miniantibody, diabody, triabody, and tetrabody.

36. The cardiovalent molecule of claim 35, wherein said cardiovalent molecule is a diabody.

37. The cardiovalent molecule of claim 35, wherein said diabody is a human IgG.

38. The cardiovalent molecule of claim 32, wherein said coronary tissue marker is selected from the group consisting of matrix metalloproteinase-1, matrix metalloproteinase-8, fibronectin, osteopontin, TLR4, IL1RL1-b, vascular cell adhesion molecule-1 (VCAM-1), Adam-like decysin-1 (ADAMDEC1), matrix metalloproteinase-9 (MMP-9), CD163, chemokine (C—

X—

C motif) ligand-2 (CXCL2), retinoic acid responder-1 (RARRES1), LpPLA2;

colony-stimulating factor-2 receptor β

(CSF2RB), cathepsin S, chemokine (C—

C motif) ligand 18 (CCL1

     8), spermidine/spermine N1 acetyltransferase, integrin β

2 (ITGB2), cystatin B (CSTB), legumain;

uncoupling protein 2 (UCP2), cathepsin B, RALGDS, F11 receptor (JAM-A), and ATPase plasma membrane 1 (ATP2B1).

39. The cardiovalent molecule of claim 32, wherein said target cell marker is present on a target cell is selected from the group consisting of a bone-marrow-derived stem cell, a circulating stem cell, a coronary stem cell, an endothelial progenitor cell, and a hormone/growth factor secreting cell.

40. The cardiovalent molecule of claim 32, wherein said target cell marker is selected from the group consisting of CD34, CD133, CD14, CXCR4, kinase insert domain receptor (KDR), Flk-1, VE-cadherin, c-Kit, and Sea-1.

41. The cardiovalent molecule of claim 32, wherein said target cell marker is CD34.

42. The cardiovalent molecule of claim 32, wherein said cardiovalent molecule is administered by intravenous, intra-arterial, or intramyocardial injection.

43. The cardiovalent molecule of claim 32, wherein said cardiovalent molecule is administered in the course of percutaneous transluminal coronary angioplasty.

44. The cardiovalent molecule of any of claim 32, wherein said molecule is administered using an implantable intra-arterial stent.