In vivo temporal control of activatable matrix-degrading enzymes
First Claim
1. A method for treating a disease or condition of the extracellular matrix (ECM), comprising sub-epidermally administering to the ECM an activatable matrix-degrading enzyme (AMDE) and an activator, wherein:
- the AMDE is inactive in the ECM in the absence of the activator;
the activator, when administered to the ECM, provides an activating condition for the enzyme such that the AMDE is active; and
the activating condition is not present in the ECM prior to administration of the activator.
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Accused Products
Abstract
Methods and combinations are provided for controlling the duration of action, in vivo, of matrix-degrading enzymes. The methods and combinations permit temporary in-vivo activation of matrix-degrading enzymes upon administration to the extra cellular matrix (or “ECM”). Matrix-degrading enzymes having a controlled duration of action can be used to treat ECM-mediated diseases or disorders characterized by increased deposition or accumulation of one or more ECM components.
77 Citations
95 Claims
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1. A method for treating a disease or condition of the extracellular matrix (ECM), comprising sub-epidermally administering to the ECM an activatable matrix-degrading enzyme (AMDE) and an activator, wherein:
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the AMDE is inactive in the ECM in the absence of the activator; the activator, when administered to the ECM, provides an activating condition for the enzyme such that the AMDE is active; and the activating condition is not present in the ECM prior to administration of the activator. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58)
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22. A method for treating a disease or condition of the extracellular matrix (ECM), comprising administering an activatable matrix-degrading enzyme (AMDE) and an activator, wherein:
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the AMDE is inactive at neutral pH; the activator provides an acidic pH activating condition for the enzyme such that the AMDE is active upon or after administration; the activating condition is not present at the site of administration prior to administration of the activator; and the AMDE is substantially active at pH 5.5. - View Dependent Claims (23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40)
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41. A method for treating a disease or condition of the extracellular matrix (ECM), comprising administering to the ECM an activatable matrix-degrading enzyme (AMDE) and an activator, wherein:
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the AMDE is inactive in the ECM in the absence of the activator; the activator, when administered to the ECM, provides an activating condition for the enzyme such that the AMDE is active; the activating condition is not present in the ECM prior to administration of the activator; and the activator is selected from among metal ions, temperature and ionic strength. - View Dependent Claims (42)
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59. A method of treating a disease or condition of the extracellular matrix (ECM), comprising sub-epidermally administering an activatable matrix-degrading enzyme (AMDE), an activator, a hyaluronidase, lidocaine and epinephrine wherein:
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the AMDE is inactive in the ECM in the absence of the activator; the activator, when administered to the ECM, provides an activating condition for the enzyme such that the AMDE is active; and the activating condition is not present in the ECM prior to administration of the activator. - View Dependent Claims (60, 61)
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62. A method of treating a disease or condition of the extracellular matrix (ECM), comprising administering an activatable matrix-degrading enzyme (AMDE) and an activator wherein:
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the AMDE is inactive in the ECM in the absence of the activator; the activator, when administered, provides an activating condition for the enzyme such that the AMDE is active; the activating condition is not present in the ECM prior to administration of the activator; and the activator is selected from among a metal ion, temperature or ionic strength; and administration is selected from among subcutaneous, intramuscular, intralesional, intradermal, topical, transdermal, intravenous, oral and rectal.
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63. A method of treating a collagen-mediated disease or condition, comprising sub-epidermally administering to the ECM a therapeutically effective amount of an activatable cathepsin L and an activator, wherein:
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the activatable cathepsin L is inactive in the ECM in the absence of the activator; the activator, when administered to the ECM, provides an activating condition for the activatable cathepsin L such that the activatable cathepsin L is active; the activating condition is not present in the ECM prior to administration of the activator; and the activating condition is acidic pH. - View Dependent Claims (64, 65)
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66. A container, comprising two compartments, wherein:
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a first compartment contains a therapeutically effective amount of an activatable matrix-degrading enzyme (AMDE), wherein the amount is for single dosage or a plurality of dosages and a single dosage is effective for treatment of a disease or condition of the ECM; and a second compartment contains an activator, wherein the activator is one that activates the AMDE. - View Dependent Claims (67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 86)
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77. A container, comprising two compartments, wherein:
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a first compartment contains a therapeutically effective amount of an activatable cathepsin L, wherein the amount is effective for treatment of a disease or condition of the extracellular matrix (ECM); and a second compartment contains an acidic buffer that is one that activates the cathepsin L. - View Dependent Claims (82, 83, 84, 85, 87)
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- 88. A combination, comprising an activatable cathepsin L and a hyaluronidase, wherein the cathepsin L and hyaluronidase are provided separately and/or are in lyophilized form.
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90. A pharmaceutical composition, comprising an amount of cathepsin L for treatment of an ECM-mediated disease or condition upon administration simultaneously or sequentially with an acidic buffer, wherein:
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the composition is formulated for single dosage administration; and the buffer has a pH that activates cathepsin L. - View Dependent Claims (91)
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92. A method of treating a disease or condition of the extracellular matrix (ECM), comprising sub-epidermally administering an activatable matrix-degrading enzyme (AMDE), an activator, a hyaluronan degrading enzyme, lidocaine and epinephrine wherein:
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the AMDE is inactive in the ECM in the absence of the activator; the activator, when administered to the ECM, provides an activating condition for the enzyme such that the AMDE is active; and the activating condition is not present in the ECM prior to administration of the activator. - View Dependent Claims (93, 94, 95)
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Specification