Compositions and methods for detecting and treating diseases and conditions related to chemokine receptors

• US 20030124628A1
• Filed: 09/16/2002
• Published: 07/03/2003
• Est. Priority Date: 11/30/2001
• Status: Active Grant

• Current Assignee: ChemoCentryx, Inc. (Amgen Inc.)
• Original Assignee: ChemoCentryx, Inc. (Amgen Inc.)
• Inventors: Schall, Thomas J., Wei, Zheng, Burns, Jennifer M., Howard, Maureen C., Miao, Zhenhua, Premack, Brett A.
• Granted Patent: US 7,442,512 B2
• Time in Patent Office: Days
• US Class Current: 435/7.23
• 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: G01N 2500/10 involving cells
• CPC Class Codes: G01N 33/57407 Specifically defined cancers
• CPC Class Codes: G01N 33/57411 of cervix
• CPC Class Codes: G01N 33/57415 of breast
• CPC Class Codes: G01N 33/57449 of ovaries
• CPC Class Codes: G01N 33/6863 Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors

Abstract

The present invention provides methods for identifying an agent that specifically binds and/or modulates one topology of chemokine receptor but not a second topology of the receptor. Such agents are useful as therapeutics for diseases or conditions associated with a particular chemokine receptor topology. Moreover, the agents are useful for detecting a particular topology of a chemokine receptor, thereby diagnosing disease or predisposition for a disease. In addition, the agents are useful for identifying and isolating cells that express a particular topology of a chemokine receptor.

Claims

1. A method of identifying an agent that binds to a chemokine receptor having a first topology but does not bind to a chemokine receptor having a second topology, the method comprising,

i. providing a first cell comprising a chemokine receptor having a first topology and a second cell comprising the chemokine receptor having a second topology;

ii. contacting an agent of less than 1,500 daltons to the chemokine receptors; and

iii. selecting an agent that binds to the first topology of the chemokine receptor but does not bind to a chemokine receptor having a second topology.

2. The method of claim 1, wherein the agent is less than 600 daltons.

3. The method of claim 1, wherein the method further comprises selecting an agent that modulates intracellular signaling triggered by ligand binding to the first topology of the chemokine receptor, thereby identifying an agent that modulates intracellular signaling triggered by ligand binding to a chemokine receptor having a first topology but not the second topology.

4. The method of claim 3, wherein the agent modulates mobilization of intracellular calcium in response to binding of a ligand to the first topology of the chemokine receptor.

5. The method of claim 1, wherein the chemokine receptor is selected from the group consisting of CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CX3CR1, CXR1, CCXCKR (CCR11), US28, ECRF3, Kaposi'"'"'s Sarcoma-associated Herpesvirus GPCR, Poxvirus membrane-bound G Protein-coupled receptors, D6, and DARC.

6. The method of claim 1, wherein the first cell or the second cell is a cancer cell.

7. The method of claim 6, wherein the cancer cell is a breast cancer cell.

8. The method of claim 1, wherein the first cell or the second cell is a neutrophil, monocyte, macrophage, eosinophil, basophil, mast cell or B cell.

9. The method of claim 1, wherein the first cell or the second cell does not support an HIV infection.

10. The method of claim 1, wherein the first cell or the second cell is not a T-cell.

11. The method of claim 1, wherein the agent competes for binding with a natural ligand of the chemokine receptor.

12. The method of claim 1, the method further comprising selecting an agent that modulates a cell or tissue response in an animal, thereby identifying an agent that modulates a chemokine receptor-mediated tissue or cell response in an animal.

21. A method of identifying an antibody that binds to a chemokine receptor having a first topology but does not bind to a chemokine receptor having a second topology, the method comprising,

i. providing a first cell comprising a chemokine receptor having a first topology and a second cell comprising the chemokine receptor having a second topology;

ii. contacting an antibody to the chemokine receptors; and

iii. selecting an antibody that binds to the first topology of the chemokine receptor but does not bind to a chemokine receptor having a second topology.

13. The method of claim 31, wherein the cell or tissue response comprises chemotaxis of cells.

14. The method of claim 32, wherein the chemotactic cells are leukocytes.

15. The method of claim 33, wherein leukocyte chemotaxis is decreased.

16. The method of claim 33, wherein leukocyte chemotaxis is increased.

17. The method of claim 31, wherein the cell or tissue response comprises the development of cancer.

18. The method of claim 36, wherein the cell or tissue comprises metastatic cancer cells.

19. The method of claim 31, wherein the cell or tissue response comprises inflammation.

20. The method of claim 37, wherein the agent decreases metastasis when a therapeutically sufficient amount of the agent is administered to an animal having metastatic cancer.

22. The method of claim 21, wherein the method further comprises selecting an antibody that modulates intracellular signaling triggered by ligand binding to the first topology of the chemokine receptor, thereby identifying an antibody that modulates intracellular signaling triggered by ligand binding to a chemokine receptor having a first topology but not the second topology.

23. The method of claim 22, wherein the antibody modulates mobilization of intracellular calcium in response to binding of a ligand to the first topology of the chemokine receptor.

24. The method of claim 21, wherein the chemokine receptor is selected from the group consisting of CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CX3CR1, CXR1, CCXCKR (CCR11), US28, ECRF3, Kaposi'"'"'s Sarcoma-associated Herpesvirus GPCR, Poxvirus membrane-bound G Protein-coupled receptors, D6, and DARC.

25. The method of claim 21, wherein the first cell or the second cell is a cancer cell.

26. The method of claim 25, wherein the cancer cell is a breast cancer cell.

27. The method of claim 21, wherein the first cell or the second cell is a neutrophil, monocyte, macrophage, eosinophil, basophil, mast cell or B cell.

28. The method of claim 21, wherein the first cell or the second cell does not support an HIV infection.

29. The method of claim 21, wherein the first cell or the second cell is not a T-cell.

30. The method of claim 21, wherein the antibody competes for binding with a natural ligand of the chemokine receptor.

31. The method of claim 21, the method further comprising selecting an antibody that modulates a cell or tissue response in an animal, thereby identifying an antibody that modulates a chemokine receptor-mediated tissue or cell response in an animal.

32. The method of claim 31, wherein the cell or tissue response comprises chemotaxis of cells.

33. The method of claim 32, wherein the chemotactic cells are leukocytes.

34. The method of claim 33, wherein leukocyte chemotaxis is decreased.

35. The method of claim 33, wherein leukocyte chemotaxis is increased.

36. The method of claim 31, wherein the cell or tissue response comprises the development of cancer.

37. The method of claim 36, wherein the cell or tissue comprises metastatic cancer cells.

38. The method of claim 31, wherein the cell or tissue response comprises inflammation.

39. The method of claim 37, wherein the antibody decreases metastasis when a therapeutically sufficient amount of the agent is administered to an animal having metastatic cancer.

40. A method of identifying novel topologies of a chemokine receptor, the method comprising,

providing at least two cell types, each cell type expressing the chemokine receptor;

testing a plurality of different chemokines for the ability to bind to the chemokine receptor on the two cell types; and

identifying a chemokine that binds to the chemokine receptor on a first cell type but does not bind to the chemokine receptor on a second cell type, thereby identifying novel topologies of a chemokine receptor.

41. The method of claim 40, wherein the chemokine receptor is selected from the group consisting of CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CX3CR1, CXR1, CCXCKR (CCR11), US28, ECRF3, Kaposi'"'"'s Sarcoma-associated Herpesvirus GPCR, Poxvirus membrane-bound G Protein-coupled receptors, D6, and DARC.

42. The method of claim 40, wherein at least 3 cell types are tested.

43. The method of claim 40, wherein at least 10 chemokines are tested.

44. The method of claim 40, wherein the chemokines are selected from the group consisting of CL1, XCL2, CX3CL1, CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL10, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, and CCL28.

45. The method of claim 40, wherein the chemokines are tethered to a solid support.

46. The method of claim 40, wherein the testing step comprises determining the ability of the chemokines to compete with a ligand that binds to the chemokine receptor in each cell type.

47. The method of claim 46, wherein the ligand is labeled.

48. The method of claim 40, wherein at least one cell type expresses an endogenous chemokine receptor.

49. The method of claim 40, wherein at least one cell type expresses a recombinantly expressed chemokine receptor.

50. The method of claim 40, wherein the cell types tested comprise a cancer cell and a non-cancer cell.