Hematopoietic progenitor kinase 1 for modulation of an immune response
First Claim
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1. A method of identifying a candidate compound for modulating hematopoietic progenitor kinase 1 (HPK1) activity, the method comprising:
- a. contacting an HPK1 or a fragment thereof comprising ser171 with a test compound; and
b. determining whether the test compound binds to the HPK1 or fragment thereof at a site that modulates protein kinase A (PKA) binding or phosphorylation of the ser171, wherein a compound that binds to the HPK1 or fragment thereof at a site that modulates the PKA binding or phosphorylation of the ser171 is a candidate compound for modulating HPK1 activity.
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Abstract
Methods of regulating hematopoietic progenitor kinase 1 (HPK1) are described as are methods of identifying compounds that can regulate HPK1.
40 Citations
78 Claims
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1. A method of identifying a candidate compound for modulating hematopoietic progenitor kinase 1 (HPK1) activity, the method comprising:
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a. contacting an HPK1 or a fragment thereof comprising ser171 with a test compound; and
b. determining whether the test compound binds to the HPK1 or fragment thereof at a site that modulates protein kinase A (PKA) binding or phosphorylation of the ser171, wherein a compound that binds to the HPK1 or fragment thereof at a site that modulates the PKA binding or phosphorylation of the ser171 is a candidate compound for modulating HPK1 activity. - View Dependent Claims (2, 3, 4, 5, 6)
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7. A method of identifying a candidate compound for enhancing dendritic cell maturation or migration, the method comprising:
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a. contacting a cell with a test compound; and
b. determining whether the test compound decreases HPK1 expression or activity compared to a control cell that is not contacted with the test compound, wherein a compound that decreases HPK1 expression or activity is a candidate compound for enhancing dendritic cell maturation or migration. - View Dependent Claims (8, 9, 10)
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11. A method of enhancing maturation or migration of dendritic cells, the method comprising
contacting a cell with a compound that decreases the level of HPK1 expression or HPK1 activity in a dendritic cell compared to the level of expression in a dendritic cell that is not contacted with the compound, wherein the decrease in the HPK1 expression or activity indicates at least one of increased maturation of dendritic cells or migration of dendritic cells.
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18. A method of identifying a candidate compound for modulating HPK1 activity, the method comprising:
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a) contacting a cell that expresses HPK1 with a test compound; and
b) determining whether the test compound modulates Cbl-b expression or activity in the contacted cell;
wherein the ability of the test compound to modulate Cbl-1 is indicative of the ability of the compound to modulate HPK1 activity. - View Dependent Claims (19, 20, 21, 22)
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23. A method of identifying a candidate compound for modulating an immune response, the method comprising:
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a. contacting a cell that expresses HPK1 with a test compound;
b. determining whether the test compound modulates Cbl-b expression or activity in the contacted cell; and
c. determining whether the test compound modulates HPK1 activity in the contacted cell, wherein the test compound that modulates Cbl-1 and HPK1 activity is a candidate compound for modulating an immune response. - View Dependent Claims (24, 25)
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26. A method of identifying a candidate compound for modulating a T cell response in an animal, the method comprising:
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a. administering a test compound to an animal, the compound having the ability to decrease Cbl-b expression or activity in a cell that expresses HPK1; and
b. determining whether the animal has an increased T cell response to T cell receptor (TCR) stimulation compared to a wild type animal to which the test compound was not administered, wherein an increased or decreased T cell response in the animal is indicative of the ability of the test compound to modulate T cell activity, and the test compound is a candidate compound for modulating HPK1 activity. - View Dependent Claims (27)
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28. A method of identifying a compound that enhances an immune response, the method comprising:
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a. administering a compound to a hematopoietic cell; and
b. assaying the hematopoietic cell for at least one indication of HPK1 inhibition, wherein HPK1 inhibition is indicative of an enhanced immune response. - View Dependent Claims (29, 30, 31, 32, 33, 34, 35, 36, 37, 77, 78)
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- 38. A method of modulating an immune response, the method comprising contacting an immune system cell with a compound that modulates HPK1 expression or activity.
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48. A method of identifying a subject at risk for, or having, an immune disorder or immune system cancer, the method comprising:
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a) determining the level of HPK1 activity in a cell obtained from the subject; and
b) comparing the level of HPK1 activity in the cell to a non-immune disorder reference level of HPK1 or immune system cancer reference level of HPK1, wherein a decreased level of HPK1 in the cell compared to the reference indicates that the subject is at risk for, or has, an immune disorder or an immune system cancer. - View Dependent Claims (49, 50, 51)
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52. A method of identifying a subject at risk for or having a cancer, the method comprising:
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a) determining the level of HPK1 activity in a cell obtained from the subject; and
b) comparing the level of HPK1 activity in the cell to a non-cancer reference level of HPK1, wherein an increased level of HPK1 compared to the reference indicates that the subject is at risk for or has a cancer. - View Dependent Claims (53, 54, 55)
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- 56. A method of treating a subject at risk for, or having, an immune disorder, the method comprising providing to a subject a pharmaceutically effective amount of a compound that inhibits HPK1 expression or activity, thereby decreasing the risk for having the immune disorder or treating the immune disorder.
- 59. A method of treating a subject at risk for, or having, a cancer, the method comprising providing to a subject a pharmaceutically effective amount of a compound that inhibits HPK1 expression or activity, thereby decreasing the risk for having the cancer or treating the cancer.
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62. A method of altering at least one HPK1-mediated effect, the effect comprising increasing IL-2 production, increasing TNF secretion, increasing IFN-γ
- production increasing T cell proliferation, increasing B cell proliferation decreasing synthesis of an immunosuppressive cytokine, or decreasing apoptosis of T cells, decreasing tumor-induced apoptosis of hematopoetic cells, the method comprising,
a. providing a cell or organism that can express IL-2, TNF, IFN-γ
, or an immunosuppressive cytokine, or providing a T cell that can proliferate, a B cell that can proliferate, or a tumor cell; and
b. contacting the cell or organism with a compound that inhibits HPK1 expression or activity in an amount and for a time sufficient to inhibit HPK1 expression or activity compared to a reference thereby altering at least one HPK1-mediated effect, the effect comprising increasing IL-2 production, increasing TNF secretion, increasing IFN-γ
production increasing T cell proliferation, increasing B cell proliferation, decreasing synthesis of an immunosuppressive cytokine, or inducing apoptosis of a tumor cell. - View Dependent Claims (63)
- production increasing T cell proliferation, increasing B cell proliferation decreasing synthesis of an immunosuppressive cytokine, or decreasing apoptosis of T cells, decreasing tumor-induced apoptosis of hematopoetic cells, the method comprising,
- 64. A method of specifically altering PGE2 modulation of the immune system, the method comprising contacting an immune cell with a modulator of HPK1, resulting in a change in a PGE2-modulated effect on the immune system.
- 72. A method of promoting anti-tumor immunity, the method comprising administering to a subject a compound that inhibits HPK1 expression or activity, thereby increasing anti-tumor immunity of the subject.
Specification