Enzymatic activities in chemokine-mediated inflammation

• US 7,572,600 B2
• Filed: 08/04/2005
• Issued: 08/11/2009
• Est. Priority Date: 08/04/2004
• Status: Active Grant

• Current Assignee: ChemoCentryx, Inc. (Amgen Inc.)
• Original Assignee: ChemoCentryx, Inc. (Amgen Inc.)
• Inventors: Berahovich, Robert D., Schall, Thomas J., Miao, Zhenhua, Premack, Brett
• Primary Examiner(s): Weber; Jon P
• Assistant Examiner(s): Srivastava; Kailash C
• Application Number:
  US11/198,935
• Publication Number:
  US 20060063223A1
• Time in Patent Office: 1,468 Days
• Field of Search: 435/4, 435/23
• US Class Current: 435/23
• 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: C07K 14/7158 for chemokines
• CPC Class Codes: C12Q 1/37 involving peptidase or proteinase
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• 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

Truncated chemokines lacking an N-terminal region that activate CCR1 and/or FPRL1 and compositions containing the truncated chemokines are provided. Methods of identifying agents that modulate CCR1 and/or FPRL1 activity either by modulating the production of the truncated chemokines or the ability of the truncated chemokines to activate CCR1 and/or FPRL1 are also disclosed. Methods using the truncated chemokines to inhibit or activate CCR1 and/or FPRL1 mediated biological activities are also disclosed.

Claims

1. A method for identifying an inhibitor of chemoattractant receptor activity, comprising:

(a) contacting protease with a chemoattractant substrate in the presence of a test compound;

(b) determining the activity of the protease in the presence of the test compound;

(c) comparing the activity of the protease in the presence of the test compound with the activity of the protease in the absence of the test compound;

(d) identifying the test compound as a potential inhibitor of chemoattractant receptor activity if the activity of the protease is inhibited in the presence of the test compound.

2. The method of claim 1, wherein the protease is selected from the group consisting of chymase, cathepsin G, and elastase.

3. The method of claim 1, further comprising conducting an assay of the chemoattractant receptor activity with the inhibitor identified in step (d) to determine whether the inhibitor inhibits the activity of the chemoattractant receptor.

4. The method of claim 1, wherein the chemoattractant receptor is

N-formyl peptide receptor Like1 (FPRL1).

5. The method of claim 1, wherein the chemoattractant receptor is C-C-chemokine receptor 1 (CCR1).

6. The method of claim 1, wherein the chemoattractant receptor activity is a biological activity selected from the group consisting of calcium mobilization, cell migration, and cell proliferation.

7. The method of claim 4, wherein the substrate is C-C-chemokine ligand 23β

(CCL23 β

).

8. The method of claim 5, wherein the chemoattractant substrate is selected from the group consisting of C-C-chemokine ligand 6 (CCL6), C-C-chemokine ligand 9 (CCL9), C-C-chemokine ligand 15 (CCL15) and C-C-chemokine ligand 23 (CCL23).

9. The method of claim 7, wherein the protease is selected from the group consisting of chymase, cathepsin G, and elastase.

10. The method of claim 9, further comprising conducting an assay of FPRL1 activity with the inhibitor identified in step (d) to determine whether the inhibitor inhibits the activity of FPRL1.