Superior thrombomodulin analogs for pharmaceutical use
AssigneeSchering Corporation
InventorsCharles B. Glaser, Michael J. Morser, David R. Light
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Abstract
The present invention relates to the use of analogs of thrombomodulin ("TM") that have the ability to enhance the thrombin-mediated activation of protein C but which have a significantly reduced ability to inhibit the direct procoagulant activities of thrombin, such as, for example, thrombin-mediated conversion of fibrinogen to fibrin. These analogs are useful in, for example, antithrombotic therapy. Novel proteins, nucleic acid gene sequences, pharmaceuticals and methods of inhibiting thrombotic activity are disclosed. Included are methods for increasing the circulating half life of the proteins.
Claims26
A method of treating a thrombotic disease or condition by administering a therapeutically effective dose of a purified thrombomodulin analog, wherein said analog comprises a polypeptide having an amino acid sequence corresponding to the six epidermal growth factor and the O-linked glycosylation domains of native thrombomodulin, and wherein the O-lined glycosylation domain is modified by:
- a. modification of the amino acid sequence of the O-linked glycosylation domain or deletion of an amino acid residue forming a glycosylation site,
- b. removal of sulfate substituents on sugars in the O-linked glycosylation domain, or
- c. deletion of the O-linked glycosylation domain, whereby addition of glycosaminoglycan to serine or threonine residues in the 0linked glycosylation domain is attenuated, said analog having approximately native ability to potentiate thrombin-mediated activation of protein C and having a reduced ability to inactivate thrombin-mediated conversion of fibrinogen to fibrin, each ability as compared with native thrombomodulin.
A sterile composition useful for treating a thrombotic disease or condition in mammals, comprising a therapeutically effective dose of a purified thrombomodulin analog, wherein said analog comprises a polypeptide having an amino acid sequence corresponding to the six epidermal growth factor and the O-linked glycosylation domains of native thrombomodulin, and wherein the O-lined glycosylation domain is modified by:
- a. modification of the amino acid sequence of the O-linked glycosylation domain or deletion of an amino acid residue forming a glycosylation site,
- b. removal of sulfate substituents on sugars in the O-linked glycosylation domain, or
- c. deletion of the O-linked glycosylation domain, whereby addition of glycosaminoglycan to serine or threonine residues in the O-link glycosylation domain is attenuated, said analog having approximately native ability to potentiate thrombin-mediated activation of protein C and having a reduced ability to inactivate thrombin-mediated conversion of fibrinogen to fibrin, each ability as compared with native thrombomodulin.
Dependencies are inferred from the claim text.