Compositions and methods for preventing and treating allograft rejection

• US 5,883,082 A
• Filed: 11/23/1994
• Issued: 03/16/1999
• Est. Priority Date: 08/14/1990
• Status: Expired due to Term

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.), Board of Regents of the University of Texas System (University of Texas System), University of Texas System
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.), Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Bennett, C. Frank, Stepkowski, Stanislaw M.
• Primary Examiner(s): Feisee, Lila
• Assistant Examiner(s): Bansal, Geetha P.
• Application Number:
  US08/344,155
• Time in Patent Office: 1,574 Days
• Field of Search: 536/23.1, 536/24.5, 514/44, 424/152.1
• US Class Current: 514/44.00A
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/711 Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
• 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: A61K 39/39533 against materials from animals
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 14/70525 ICAM molecules, e.g. CD50, CD54, CD102
• CPC Class Codes: C07K 14/70542 CD106
• CPC Class Codes: C07K 14/70564 Selectins, e.g. CD62
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/352 linked to the nucleic acid via a carbon atom
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2310/3531 Hydrogen
• CPC Class Codes: C12N 2310/3533 Halogen

Abstract

Compositions and methods are provided for the prevention and treatment of allograft rejection. Compositions are provided which comprise an antisense oligonucleotide targeted to a nucleic acid sequence encoding intercellular adhesion molecule-1, vascular cell adhesion molecule-1, or endothelial leukocyte adhesion molecule-1 in combination with an immunosuppressive agent. Methods of preventing or treating allograft rejection by treating an allograft recipient with such a composition are provided. Methods for preventing allograft rejection comprising perfusion of the graft are also provided.

Claims

1. A composition for treating allograft rejection comprising an oligonucleotide targeted to a nucleic acid sequence encoding intercellular adhesion molecule-1, endothelial leukocyte adhesion molecule-1 or vascular cell adhesion molecule-1 in combination with an immunosuppressive agent, said oligonucleotide consisting of SEQ ID NO:

1, 7, 8, 13, 14, 15, 22, 23, 24, 25, 26, 84, 31, 32, 33, 35, 36, 52, 53, 54, 56, 57, 58, 50, 51, 60, 63, 65, 67, 68, 70, 71 or 72.

2. The composition of claim 1 wherein the oligonucleotide comprises SEQ ID NO:

22.

3. The composition of claim 1 wherein the immunosuppressive agent is a monoclonal antibody directed against lymphocyte function associated antigen-1.

4. The composition of claim 1 wherein the immunosuppressive agent is brequinar, rapamycin or anti-lymphocyte serum.

5. The composition of claim 1 wherein the immunosuppressive agent is an antisense oligonucleotide targeted to B7-2 or LFA-1.

6. A method of treating allograft rejection in an allograft recipient comprising treating the allograft recipient with a composition of claim 1.

13. A method of preventing allograft rejection in an allograft recipient comprising treating the allograft recipient with a composition of claim 1.

14. A method of preventing rejection of an allograft by an allograft recipient comprising perfusing the allograft with a composition of claim 1.

15. The method of claim 14 wherein the perfusion is performed ex vivo.

7. A method of preventing allograft rejection in an allograft recipient comprising treating the allograft recipient with an oligonucleotide targeted to a nucleic acid sequence encoding intercellular adhesion molecule-1, endothelial leukocyte adhesion molecule-1 or vascular cell adhesion molecule-1, in combination with an immunosuppressive agent, said oligonucleotide consisting of SEQ ID NO:

1, 7, 8, 13, 14, 15, 22, 23, 24, 25, 26, 84, 31, 32, 33, 35, 36, 52, 53, 54, 56, 57, 58, 50, 51, 60, 63, 65, 67, 68, 70, 71 or 72.

8. The method of claim 7 wherein the immunosuppressive agent is a monoclonal antibody directed against lymphocyte function associated antigen-1.

9. The method of claim 7 wherein the immunosuppressive agent is brequinar, rapamycin or anti-lymphocyte serum.

10. The method of claim 7 wherein the immunosuppressive agent is an antisense oligonucleotide targeted to B7-2 or LFA-1.

11. The method of claim 7 wherein the allograft is a cardiac allograft.

12. The method of claim 7 wherein the allograft is a renal allograft.

16. A method of preventing rejection of an allograft comprising perfusing the allograft with an oligonucleotide targeted to a nucleic acid sequence encoding intercellular adhesion molecule-1, endothelial leukocyte adhesion molecule-1 or vascular cell adhesion molecule-1, said oligonucleotide consisting of SEQ ID NO:

1, 7, 8, 13, 14, 15, 22, 23, 24, 25, 26, 84, 31, 32, 33, 35, 36, 52, 53, 54, 56, 57, 58, 50, 51, 60, 63, 65, 67, 68, 70, 71 or 72.

17. The method of claim 16 wherein the oligonucleotide comprises SEQ ID NO:

22.

18. A method of treating allograft rejection in an allograft recipient comprising treating the allograft recipient with an oligonucleotide targeted to a nucleic acid sequence encoding intercellular adhesion molecule-1, endothelial leukocyte adhesion molecule-1 or vascular cell adhesion molecule-1 in combination with an immunosuppressive agent, said oligonucleotide consisting of SEQ ID NO:

1, 7, 8, 13, 14, 15, 22, 23, 24, 25, 26, 84, 31, 32, 33, 35, 36, 52, 53, 54, 56, 57, 58, 50, 51, 60, 63, 65, 67, 68, 70, 71 or 72.

19. The method of claim 18 wherein the immunosuppressive agent is a monoclonal antibody directed against lymphocyte function associated antigen-1.

20. The method of claim 18 wherein the immunosuppressive agent is brequinar, rapamycin or anti-lymphocyte serum.

21. The method of claim 18 wherein the immunosuppressive agent is an antisense oligonucleotide targeted to B7-2 or LFA-1.

22. The method of claim 18 wherein the allograft is a cardiac allograft.

23. The method of claim 18 wherein the allograft is a renal allograft.