Methods and compositions for treating secondary tissue damage and other inflammatory conditions and disorders
First Claim
1. A method for inhibiting proliferation or migration of activated immune effector cells, comprising administering a conjugate to an animal, whereby proliferation or migration of the immune effector cells is inhibited, wherein:
- the conjugate comprises a targeted agent or a portion thereof and a chemokine receptor targeting agent or a portion thereof sufficient to bind to a chemokine receptor on immune effector cells and facilitate internalization of the conjugate;
the chemokine receptor targeting agent is a chemokine, an antibody that specifically binds to a chemokine receptor or a fragment of the chemokine or antibody, wherein the chemokine, antibody or fragment thereof binds to the receptor and internalizes the targeted agent in a cell;
the targeted agent or portion thereof, when internalized in a cell, alters metabolism or gene expression in the cell, regulates or alters protein synthesis in the cell, inhibits proliferation of the cell or kills the cell; and
the conjugate binds to a chemokine receptor resulting in internalization of the targeted agent in cells bearing the receptor.
6 Assignments
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Accused Products
Abstract
Conjugates containing as a ligand a chemokine receptor targeting agents, such as chemokines, and a targeted agent, such as a toxin are provided. These conjugates are used to treat inflammatory responses associated with activation, proliferation and migration of immune effector cells, including leukocyte cell types, neutrophiles, macrophages, and eosinophils. The conjugates provided herein are used to lessen or inhibit these processes to prevent or at least lessen the resulting secondary effects. In particular, the conjugates are used to target toxins to receptors on secondary tissue damage-promoting cells. The ligand moiety can be selected to deliver the cell toxin to such secondary tissue damage-promoting cells as mononuclear phagocytes, leukocytes, natural killer cells, dendritic cells, and T and B lymphocytes, thereby suppressing the proliferation, migration, or physiological activity of such cells. Among preferred conjugates are fusion proteins having a chemokine, or a biologically active fragment thereof, as the ligand moiety linked to a cell toxin via a peptide linker of from 2 to about 60 amino acid residues.
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Citations
56 Claims
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1. A method for inhibiting proliferation or migration of activated immune effector cells, comprising administering a conjugate to an animal, whereby proliferation or migration of the immune effector cells is inhibited, wherein:
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the conjugate comprises a targeted agent or a portion thereof and a chemokine receptor targeting agent or a portion thereof sufficient to bind to a chemokine receptor on immune effector cells and facilitate internalization of the conjugate; the chemokine receptor targeting agent is a chemokine, an antibody that specifically binds to a chemokine receptor or a fragment of the chemokine or antibody, wherein the chemokine, antibody or fragment thereof binds to the receptor and internalizes the targeted agent in a cell; the targeted agent or portion thereof, when internalized in a cell, alters metabolism or gene expression in the cell, regulates or alters protein synthesis in the cell, inhibits proliferation of the cell or kills the cell; and the conjugate binds to a chemokine receptor resulting in internalization of the targeted agent in cells bearing the receptor. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 42, 44, 47, 48, 51, 52)
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- 9. A method for inhibiting the proliferation, migration or activity of secondary tissue damage-promoting inflammatory cells, comprising administering to a subject in need thereof an effective amount of a therapeutic agent that inhibits the proliferation, migration or physiological activity of secondary tissue damage-promoting inflammatory cells, wherein the therapeutic agent is a conjugate that comprises a chemokine receptor targeting agent and a targeted agent or portion thereof selected so that conjugate binds to a chemokine receptor and internalizes the targeted agent, which inhibits the proliferation, migration or physiological activity of the secondary tissue damage-promoting cells.
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29. A method of targeted delivery of an agent into cells that express chemokine receptors, comprising associating the agent with a chemokine receptor targeting agent, whereby:
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the chemokine receptor targeting agent binds to a chemokine receptor expressed on the cells; and the agent is internalized by the cells, wherein the cells are immune effector cells. - View Dependent Claims (30, 40, 53, 54, 55, 56)
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31. A method for inhibiting proliferation or migration of activated immune effector cells, comprising contacting immune effector cells with a conjugate that comprises a targeted agent or a portion thereof and a chemokine receptor targeting agent, whereby activation or proliferation of the immune effector cells is inhibited, wherein:
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the targeted agent or portion thereof is a toxin; the chemokine receptor targeting agent is a chemokine or a fragment of thereof that binds to a chemokine receptor and internalizes the targeted agent; and the conjugate binds to a chemokine receptor resulting in internalization of the targeted agent in cells bearing the receptor. - View Dependent Claims (32, 33, 34, 35, 36, 37, 38, 39, 43)
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45. A method of preparing a candidate compound for treating a disease or disorder involving activated immune cells an inflammatory response, comprising:
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identifying immune cells that are activated in the disease or disorder; identifying chemokine receptors expressed on the cells; preparing a conjugate or plurality thereof containing toxin linked to a chemokine or a plurality of chemokines that specifically bind to the identified chemokine receptors and effect or facilitate internalization of the toxin into the cells. - View Dependent Claims (46, 50)
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Specification