Protease-resistant thrombomodulin analogs
AssigneeSchering Corporation
InventorsDavid Richard Light, William H. Andrews, Jeffrey Homer Clarke, Robert Michael Wydro, Patricia Ann Young
Life of this patent
Estimating the term…
Abstract
The present invention relates to the single-chain thrombomodulin ("TM") and analogs thereof that are not susceptible to cleavage by proteases and retain the biological activity of thrombomodulin, as well as methods of use in, for example, antithrombotic therapy. Novel proteins, nucleic acid gene sequences, pharmaceuticals and methods of inhibiting thrombotic activity are disclosed.
Claims16
A method of treating thrombotic disease, comprising administering an effective amount of a thrombomodulin protein analog, wherein the amino acid sequence of a protease cleavage site is modified by substitution or deletion of an amino acid at the protease cleavage site, whereby the analog is resistant to protease cleavage at that site and wherein the analog has at least 50% of the ability to potentiate thrombin-mediated activation of protein C as said uncleaved protein without said modification at the protease cleavage site.
A method of treating thrombotic disease, comprising administering an effective amount of a thrombomodulin protein analog, wherein the amino acid sequence of the N-terminus is modified by substitution or deletion of one or more amino acids at the N-terminus to prevent signal sequence cleavage heterogeneity, whereby the analog has a single N-terminus, and wherein the analog has at least 50% of the ability to potentiate thrombin-mediated activation of protein C as said protein having a native thrombomodulin N-terminus wherein said analog comprises a polypeptide having an amino acid sequence corresponding to the lectin binding, EGF and O-linked glycosylation domains of native thrombomodulin.
A method of treating thrombotic disease, comprising administering an effective amount of a thrombomodulin protein analog, wherein the amino acid sequence of the C-terminus is modified by substitution or deletion of one or more amino acids to provide a C-terminus resistant to exoproteolytic cleavage, whereby the analog has a single C-terminus, and wherein the analog has at least 50% of the ability to potentiate thrombin-mediated activation of protein C as said protein having a native thrombomodulin C-terminus.
Dependencies are inferred from the claim text.