Claims
- 1. A method of inhibiting activation by CD40 ligand of smooth muscle cells bearing CD40 on the surface of the cells, comprising contacting the cells with an agent capable of inhibiting interaction between CD40 ligand and CD40 on the cells, the agent being present in an amount effective to inhibit activation of the cells.
- 2. The method of claim 1, wherein the smooth muscle cells are smooth muscle cells of the bladder, vascular smooth muscle cells, aortic smooth muscle cells, coronary smooth muscle cells, pulmonary smooth muscle cells, or gastrointestinal smooth muscle cells.
- 3. The method of claim 2, wherein the gastrointestinal smooth muscle cells are esophageal smooth muscle cells, stomachic smooth muscle cells, smooth muscle cells of the small intestine, or smooth muscle cells of the large intestine.
- 4. The method of claim 1, wherein the agent inhibits binding of CD40 ligand to CD40 on the cells.
- 5. The method of claim 1, wherein the agent is a protein.
- 6. The method of claim 5, wherein the protein comprises an antibody or portion thereof.
- 7. The method of claim 6, wherein the antibody is a monoclonal antibody.
- 8. The method of claim 7, wherein the monoclonal antibody specifically binds to the epitope to which monoclonal antibody 5c8 (ATCC Accession No. HB 10916) specifically binds.
- 9. The method of claim 8, wherein the monoclonal antibody is monoclonal antibody 5c8 (ATCC Accession No. HB 10916).
- 10. The method of claim 7, wherein the monoclonal antibody specifically binds to CD40.
- 11. The method of claim 10, wherein the antibody is humanized, chimeric, or primatized.
- 12. The method of claim 7, wherein the monoclonal antibody is a chimeric antibody.
- 13. The method of claim 7, wherein the monoclonal antibody is a humanized antibody.
- 14. The method of claim 6, wherein the portion of the antibody comprises a complementarity determining region or variable region of a light or heavy chain.
- 15. The method of claim 6, wherein the portion of the antibody comprises a complementarity determining region or a variable region.
- 16. The method of claim 15, wherein the portion of the antibody comprises a Fab or a single chain antibody.
- 17. The method of claim 5, wherein the protein comprises soluble extracellular region of CD40 ligand, or variant thereof including conservative substituents, or portion thereof; or soluble extracellular region of CD40, or variant thereof including conservative substituents, or portion thereof.
- 18. The method of claim 17, wherein the soluble extracellular region of CD40 ligand or CD40 is a monomer.
- 19. The method of claim 17, wherein the soluble extracellular region of CD40 is an oligomer.
- 20. The method of claim 17, wherein the protein comprising soluble extracellular region of CD40 or portion thereof or CD40 ligand or portion thereof further comprises an Fc region fused to the extracellular region of CD40 or portion thereof or CD40 ligand or portion thereof.
- 21. The method of claim 20, wherein the Fc region is capable of binding to protein A or protein G.
- 22. The method of claim 21, wherein the Fc region comprises IgG, IgA, IgM, IgD, or IgE, or subclasses thereof.
- 23. The method of claim 22, wherein:
the IgG is IgG1, IgG2, IgG3, or IgG4; or the IgA is IgA1 or IgA2.
- 24. The method of claim 1, wherein the agent is nonprotein.
- 25. The method of claim 1, wherein the agent is selected from a library of known agents.
- 26. The method of claim 1, wherein the agent is modified from a known agent.
- 27. The method of claim 26, wherein the modified agent is designed by structure optimization of a lead inhibitory agent based on a three-dimensional structure of a complex of soluble extracellular region of CD40 ligand or portion thereof with the lead inhibitory agent.
- 28. The method of claim 1, wherein the agent is selected by a screening method, which comprises:
isolating a sample of cells; culturing the sample under conditions permitting activation of CD40-bearing cells; contacting the sample with cells expressing a protein which is specifically recognized by monoclonal antibody 5c8 produced by the hybridoma having ATCC Accession No. HB 10916, or with a protein which is specifically recognized by monoclonal antibody 5c8 produced by the hybridoma having ATCC Accession No. HB 10916, effective to activate the CD40-bearing cells; contacting the sample with an amount of the agent effective to inhibit activation of the CD40-bearing cells if the agent is capable of inhibiting activation of the CD40-bearing cells; and determining whether the cells expressing the protein which is specifically recognized by monoclonal antibody 5c8 produced by the hybridoma having ATCC Accession No. HB 10916, or with the protein which is specifically recognized by monoclonal antibody 5c8 produced by the hybridoma having ATCC Accession No. HB 10916, activate the CD40-bearing cells in the presence of the agent.
- 29. The method of claim 28, wherein the agent is selected from a library of known agents.
- 30. The method of claim 29, wherein the known agents are nonprotein agents.
- 31. A method of inhibiting activation by CD40 ligand of smooth muscle cells bearing CD40 on the surface of the cells, in a subject, comprising administering to the subject an agent capable of inhibiting interaction between CD40 ligand and CD40 on the cells, the agent being present in an amount effective to inhibit activation of the cells in the subject.
- 32. The method of claim 31, wherein the smooth muscle cells are smooth muscle cells of the bladder, vascular smooth muscle cells, aortic smooth muscle cells, coronary smooth muscle cells, pulmonary smooth muscle cells, or gastrointestinal smooth muscle cells.
- 33. The method of claim 32, wherein the gastrointestinal smooth muscle cells are esophageal smooth muscle cells, stomachic smooth muscle cells, smooth muscle cells of the small intestine, or smooth muscle cells of the large intestine.
- 34. The method of claim 31, wherein the agent inhibits binding of CD40 ligand to CD40 on the cells.
- 35. The method of claim 31, wherein the agent is a protein.
- 36. The method of claim 35, wherein the protein comprises an antibody or portion thereof.
- 37. The method of claim 36, wherein the antibody is a monoclonal antibody.
- 38. The method of claim 37, wherein the monoclonal antibody specifically binds to the epitope to which monoclonal antibody 5c8 (ATCC Accession No. HB 10916) specifically binds.
- 39. The method of claim 38, wherein the agent is monoclonal antibody 5c8 (ATCC Accession No. HB 10916).
- 40. The method of claim 37, wherein the monoclonal antibody specifically binds to CD40.
- 41. The method of claim 40, wherein the antibody is humanized, chimeric, or primatized.
- 42. The method of claim 37, wherein the monoclonal antibody is a chimeric antibody.
- 43. The method of claim 37, wherein the monoclonal antibody is a humanized antibody.
- 44. The method of claim 36, wherein the portion of the antibody comprises a complementarity determining region or variable region of a light or heavy chain.
- 45. The method of claim 36, wherein the portion of the antibody comprises a complementarity determining region or a variable region.
- 46. The method of claim 45, wherein the portion of the antibody comprises a Fab or a single chain antibody.
- 47. The method of claim 31, wherein the subject is a mammal.
- 48. The method of claim 47, wherein the mammal is a rodent.
- 49. The method of claim 47, wherein the mammal is a human.
- 50. The method of claim 31, wherein the protein comprises soluble extracellular region of CD40 ligand, or variant thereof including conservative substituents, or portion thereof; or soluble extracellular region of CD40, or variant thereof including conservative substituents, or portion thereof.
- 51. The method of claim 50, wherein the soluble extracellular region of CD40 ligand or CD40 is a monomer.
- 52. The method of claim 50, wherein the soluble extracellular region of CD40 is an oligomer.
- 53. The method of claim 50, wherein the protein comprising soluble extracellular region of CD40 or portion thereof or CD40 ligand or portion thereof further comprises an Fc region fused to the extracellular region of CD40 or portion thereof or CD40 ligand or portion thereof.
- 54. The method of claim 53, wherein the Fc region is capable of binding to protein A or protein G.
- 55. The method of claim 53, wherein the Fc region comprises IgG, IgA, IgM, IgD, or IgE, or subclasses thereof.
- 56. The method of claim 55, wherein:
the IgG is IgG1, IgG2, IgG3, or IgG4; or the IgA is IgA1 or IgA2.
- 57. The method of claim 31, wherein the agent is nonprotein.
- 58. The method of claim 57, wherein the agent is a small molecule.
- 59. The method of claim 31, wherein the agent is selected from a library of known agents.
- 60. The method of claim 31, wherein the agent is modified from a known agent.
- 61. The method of claim 60, wherein the modified agent is designed by structure optimization of a lead inhibitor based on a three-dimensional structure of a complex of soluble extracellular region of CD40 ligand or portion thereof with the lead inhibitor.
- 62. The method of claim 31, wherein the agent is selected by a screening method, which comprises:
isolating a sample of cells; culturing the sample under conditions permitting activation of CD40-bearing cells; contacting the sample with cells expressing a protein which is specifically recognized by monoclonal antibody 5c8 produced by the hybridoma having ATCC Accession No. HB 10916, or with a protein which is specifically recognized by monoclonal antibody 5c8 produced by the hybridoma having ATCC Accession No. HB 10916, effective to activate the CD40-bearing cells; contacting the sample with an amount of the agent effective to inhibit activation of the CD40-bearing cells if the agent is capable of inhibiting activation of the CD40-bearing cells; and determining whether the cells expressing the protein which is specifically recognized by monoclonal antibody 5c8 produced by the hybridoma having ATCC Accession No. HB 10916, or with the protein which is specifically recognized by monoclonal antibody 5c8 produced by the hybridoma having ATCC Accession No. HB 10916,activate the CD40-bearing cells in the presence of the agent.
- 63. The method of claim 62, wherein the agent is selected from a library of known agents.
- 64. The method of claim 63, wherein the known agents are nonprotein agents.
- 65. A method of treating, in a subject, a smooth muscle cell-dependent disease, comprising inhibiting activation by CD40 ligand of smooth muscle cells bearing CD40 on the surface of the cells according to the method of claim 31.
- 66. The method of claim 65, wherein the smooth muscle cell-dependent disease is a vascular disease.
- 67. The method of claim 66, wherein the vascular disease is atherosclerosis.
- 68. The method of claim 65, wherein the smooth muscle cell-dependent disease is a gastrointestinal disease.
- 69. The method of claim 68, wherein the gastrointestinal disease is selected from the group consisting of: esophageal dysmotility, inflammatory bowel disease, and scleroderma.
- 70. The method of claim 65, wherein the smooth muscle cell-dependent disease is a bladder disease.
Parent Case Info
[0001] This application claims the priority of U.S. patent application Ser. No. 08/677,730, filed Jul. 8, 1996 the contents of which is hereby incorporated by reference into the present application.
Government Interests
[0002] The invention disclosed herein was made with Government support under NIH Grant Nos. K08-AR-01904, RO1-CA55713, RO1-AI-28367, RO1-AI-14969, HL21006, HL42833, HL50629, and RO1-AI-14969 from the Department of Health and Human Services. Accordingly, the U.S. Government has certain rights in this invention.
Continuations (3)
|
Number |
Date |
Country |
Parent |
09218523 |
Dec 1998 |
US |
Child |
10298508 |
Nov 2002 |
US |
Parent |
PCT/US97/12925 |
Jul 1997 |
US |
Child |
09218523 |
Dec 1998 |
US |
Parent |
08677730 |
Jul 1996 |
US |
Child |
PCT/US97/12925 |
Jul 1997 |
US |