TNF-alpha converting enzyme
AssigneeImmunex Corporation
InventorsRoy A. Black, Charles Rauch, Carl J. March, Douglas P. Cerretti
Life of this patent
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Abstract
A metalloprotease that converts TNF-α from the 26 kD cell form to the 17 kD form has been isolated and purified and the cDNA sequence known. In particular, the protease has a molecular weight of approximately 80 kD. The isolated and purified protease is useful for designing an inhibitor thereof, and may find use as a therapeutic agent. Assays for detecting the protease-inhibiting activity of a molecule are also an aspect of the invention.
Claims19
An isolated and purified TACE polypeptide.
A method for detecting the TNF-cleaving ability of a molecule, comprising incubating said molecule with a substrate that comprises the amino acid sequence Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser, and determining the extent of substrate cleavage.
An isolated nucleic acid selected from the group consisting of:
- (a) the coding region of a native mammalian TACE gene;
- (b) cDNA comprising nucleotides 52-2472 of SEQ ID NO:
- 1;
- (c) nucleic acid that is at least 80% identical to the nucleic acid of (a) or (b) and that encodes a polypeptide that converts TNF-A from the 26 kD form to the 17 kD form;
- and
- (d) nucleic acid which is degenerate as a result of the genetic code to a nucleic acid defmed in (a), (b) or (c) and which encodes biologically active TACE.
A method of inhibiting the cleavage of TNF-A from cell membranes in a mammal comprising administering to such manmmal an effective amount of a compound that inhibits the TNF-α proteolytic activity of an enzyme comprising the sequence of amino acids 18-671 of SEQ ID NO:2.
A method of inhibiting TNF-α cleavage from cell membranes comprising blocking the binding of TNF-α with an enzyme having the sequence of amino acids 18-671 of SEQ ID NO:2.
A method for treating a mammal having a disease characterized by an overproduction or an upregulated production of TNF-α, comprising administering to the mammal a composition comprising an amount of a compound that effectively inhibits the TNF-α proteolytic activity of an enzyme comprising the sequence of amino acids 18-671 of SEQ ID NO:2.
Dependencies are inferred from the claim text.