COMPOSITIONS FOR DETECTING CELL DEATH AND METHODS OF USE THEREOF
First Claim
1. An isolated conjugate of a dehydrogenase linked to a detectable label, wherein the detectable label is not an immunoglobulin or dehydrogenase-binding fragment thereof.
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Accused Products
Abstract
The invention provides compounds and methods of their use in the detection of apoptosis and necrosis both in vitro and in vivo. Also provided are compounds and methods of their use in selective delivery of agents to cells undergoing apoptosis or necrosis. The compounds and methods are based on conjugates formed with a dehydrogenase such as lactate dehydrogenase, alcohol dehydrogenase, aldehyde dehydrogenase, and malate dehydrogenase. The compounds and methods are useful in the diagnosis and treatment of conditions characterized by apoptosis, including cancer, cardiac disease, neurologic disease including stroke, and autoimmunity. The compounds and methods offer distinct advantages over corresponding compounds and methods based on Annexin V. Also provided are methods for screening for compounds that modulate, i.e., inhibit or promote, apoptosis.
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Citations
58 Claims
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1. An isolated conjugate of a dehydrogenase linked to a detectable label, wherein the detectable label is not an immunoglobulin or dehydrogenase-binding fragment thereof.
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2-10. -10. (canceled)
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11. An isolated conjugate of a dehydrogenase linked to at least one therapeutic agent.
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12-17. -17. (canceled)
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18. A polynucleotide encoding a dehydrogenase operably linked to a polynucleotide encoding a detectable label.
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19-26. -26. (canceled)
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27. A method for detecting cells undergoing cell death, the method comprising:
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contacting a test population of cells with a conjugate of a dehydrogenase linked to a detectable label, under conditions suitable for uptake of the conjugate by the test population of cells; and detecting the label in the test population of cells, wherein presence of the label in the test population of cells indicates cells undergoing cell death. - View Dependent Claims (28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40)
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41-42. -42. (canceled)
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43. A method for treating a condition associated with apoptosis, the method comprising:
administering to a subject having or suspected to have a condition associated with apoptosis a pharmaceutical composition comprising a conjugate of a dehydrogenase linked to at least one therapeutic agent in an amount effective to treat the condition.
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44-49. -49. (canceled)
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50. A method for selectively delivering an agent to an apoptotic cell, the method comprising:
contacting an apoptotic cell with a conjugate of a dehydrogenase linked to at least one agent.
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51-56. -56. (canceled)
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57. A method for identifying an anti-apoptotic agent, comprising:
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contacting a test cell with a test agent and a conjugate of a dehydrogenase linked to a detectable label, under conditions that otherwise induce apoptosis in the test cell; measuring a test amount of label in the test cell; comparing the test amount of label to a reference amount of label in a reference cell contacted with the conjugate under the conditions that otherwise induce apoptosis in the test cell; and identifying the test agent as an anti-apoptotic agent when the test amount of label is less than the reference amount of label.
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58-65. -65. (canceled)
Specification