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US 7,067,266 B2Granted
Modulators of leukocyte activation, Hck compositions and methods of use
AssigneeRigel Pharmaceuticals, Inc.
InventorsAnnabelle Friera, Brian R. Wong, Esteban Masuda, Mark Powell
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Abstract
The present invention provides compositions and methods for modulating leukocyte activation. Nucleic acids encoding proteins and proteins so encoded which are capable of modulating leukocyte activation are provided. Compositions and methods for the treatment of disorders related to leukocyte dysfunction or dysregulation are also provided. Prophylactics and methods for the prevention of such disorders are also provided. Also provided are compositions and methods for diagnostic and prognostic determination of such disorders. Further provided are assays for the identification of bioactive agents capable of modulating leukocyte activation.
Claims26
A method of screening for an immunosuppressant, comprising:
- a) combining a candidate bioactive agent, an HCK protein, and an HCK substrate protein, wherein said HCK protein comprises an amino acid sequence having at least about 95% identity to the amino acid sequence set forth in SEQ ID NO:2;
- b) detecting an inhibition of phosphorylation of said HCK substrate protein in the presence of said candidate bioactive agent;
- c) contacting said candidate bioactive agent to a lymphocyte;
- d) inducing activation of said lymphocyte;
- and
- e) determining the activation of said lymphocyte in the presence of said candidate bioactive agent;
- wherein said HCK protein will phosphorylate said HCK substrate protein in the absence of said candidate bioactive agent, and wherein a decrease in the activation of said lymphocyte in the presence of said candidate bioactive agent indicates that said candidate bioactive agent is an immunosuppressant.
4 more elements
A method of screening for an immunosuppressant, comprising:
- a) combining a candidate bioactive agent, an HCK protein, and an HCK binding partner, wherein said HCK protein comprises an amino acid sequence having at least about 95% identity to the amino acid sequence set forth in SEQ ID NO:2, and wherein said HCK binding partner is selected from the group consisting of Nef, gp130, WASP, WIP, CD44, CD4, IL-2R, Btk, Bcr-abl, Ras-GAP, hBRAG, Ig-α, Ig-β, and p120Cbl;
- b) detecting a decrease in the binding of said HCK protein to said HCK binding partner in the presence of said candidate bioactive agent;
- c) contacting said candidate bioactive agent to a lymphocyte;
- d) inducing activation of said lymphocyte;
- and
- e) determining the activation of said lymphocyte in the presence of said candidate bioactive agent;
- wherein said HCK protein will bind to said HCK binding partner in the absence of said candidate bioactive agent, and wherein a decrease in the activation of said lymphocyte in the presence of said candidate bioactive agent indicates that said candidate bioactive agent is an immunosuppressant.
4 more elements
A method of screening for an immunosuppressant, comprising:
- a) combining a candidate bioactive agent, and an HCK protein, wherein said HCK protein comprises an amino acid sequence having at least about 95% identity to the amino acid sequence set forth in SEQ ID NO:2;
- b) detecting binding of said HCK protein to said candidate bioactive agent;
- c) contacting said candidate bioactive agent to a lymphocyte;
- d) inducing activation of said lymphocyte;
- and
- e) determining the activation of said lymphocyte in the presence of said candidate bioactive agent;
- wherein a decrease in the activation of said lymphocyte in the presence of said
- candidate bioactive agent indicates that said candidate bioactive agent is an immunosuppressant.
5 more elements
A method of screening for an immunosuppressant, comprising:
- a) combining a candidate bioactive agent, an HCK protein, and an HCK substrate protein, wherein said HCK protein comprises an amino acid sequence having at least about 95% identity to the amino acid sequence set forth by residues 241–490, 24 1–505, or 230–505 in SEQ ID NO:2;
- b) detecting an inhibition of phosphorylation of said HCK substrate protein in the presence of said candidate bioactive agent;
- c) contacting said candidate bioactive agent to a lymphocyte;
- d) inducing activation of said lymphocyte;
- and
- e) determining the activation of said lymphocyte in the presence of said candidate bioactive agent;
- wherein said HCK protein will phosphorylate said HCK substrate protein in the absence of said candidate bioactive agent, and wherein a decrease in the activation of said lymphocyte in the presence of said candidate bioactive agent indicates that said candidate bioactive agent is an immunosuppressant.
4 more elements
A method of screening for an immunosuppressant, comprising:
- a) combining a candidate bioactive agent, an HCK protein, and an HCK binding partner, wherein said HCK protein comprises an amino acid sequence having at least about 95% identity to the amino acid sequences set forth by residues 1–211, 1–230, or 62–211 in SEQ ID NO:2, and wherein said HCK binding partner is selected from the group consisting of Nef, gp130, WASP, WIP, CD44, CD4, IL-2R, Btk, Bcr-abl, Ras-GAP, hBRAG, Ig-α, Ig-β, and p120Cbl;
- b) detecting a decrease in the binding of said HCK protein to said HCK binding partner in the presence of said candidate bioactive agent;
- c) contacting said candidate bioactive agent to a lymphocyte;
- d) inducing activation of said lymphocyte;
- and
- e) determining the activation of said lymphocyte in the presence of said candidate bioactive agent;
- wherein said HCK protein will bind to said HCK binding partner in the absence of said candidate bioactive agent, and wherein a decrease in the activation of said lymphocyte in the presence of said candidate bioactive agent indicates that said candidate bioactive agent is an immunosuppressant.
4 more elements
A method of screening for an immunosuppressant, comprising:
- a) combining a candidate bioactive agent, and an HCK protein, wherein said HCK protein comprises an amino acid sequence having at least about 95% identity to the amino acid sequences set forth by residues 1–211, 1–230, or 62–211 in SEQ ID NO:2;
- b) detecting binding of said HCK protein to said candidate bioactive agent;
- c) contacting said candidate bioactive agent to a lymphocyte;
- d) inducing activation of said lymphocyte;
- and
- e) determining the activation of said lymphocyte in the presence of said candidate bioactive agent;
- wherein a decrease in the activation of said lymphocyte in the presence of said
- candidate bioactive agent indicates that said candidate bioactive agent is an immunosuppressant.
5 more elements
Dependencies are inferred from the claim text.