Modified protein C

Details Modified protein C Modified protein C

1996-11-08

1998-11-17

Prouty, Rebecca E.

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

536 231, 530381, 530384, 435 911, C07H 2104

Patent

active

058378430

ABSTRACT:
Modified Protein C molecules have been made which substitute the gamma carboxylglutamic acid (Gla) region of another Vitamin K dependent protein, most preferably prothrombin, for the native region of the Protein C. The modified or chimeric protein C has advantages over the wild-type protein C since it is less sensitive to inhibition by natural inhibitors of protein C (which would otherwise decrease the ability of the protein C to act as an anticoagulant) and which does not need the same cofactors or same amounts of cofactors, and can therefore be effective in patients with lowered levels of the cofactors such as protein S or the lipids present in activated platelets such as phosphatidyl ethanolamine (PE).

REFERENCES:
patent: 4968626 (1990-11-01), Foster et al.
patent: 5009889 (1991-04-01), Taylor, Jr. et al.
patent: 5225537 (1993-07-01), Foster
Gene et al. (1995) Biochemistry, vol. 34, pp. 8449-8457, 1995.
Yu et al. (1994) Biochemistry, vol. 33, pp. 823-831, 1994.
Zhong et al. (1993) Biotechniques, vol. 15, No. 5, pp. 874-878, 1993.
Friezner et al. (1987) Biochemistry, vol. 26, pp. 6165-6177, 1987.
Geng et al. (Aug. 26, 1996) Thrombosis and Haemostasis, vol. 76, No. 2, pp. 205-207, 1996.
Armstrong, et al., "The Active Site of Membrane-bound Meizothrombin," J. Biol. Chem. 265(11):6210-6218 (1990).
Bertina, et al., "Mutation in blood coagulation factor V associated with resistance to activated protein C" Nature 369(6475):64-67 (1994).
Bevers, et al., "Changes in Membrane Phospholipid Distribution During Platelet Activation," Biochem. Biophys. Acta 736:57-66 (1993).
Billy, et al., "Prothrombin Contributes to the Assembly of the Factor Va-Factor Xa Complex at Phosphatidylserine-containing Phospholipid Membranes," J. Biol. Chem. 270(45):26883-26889 (1995).
Bock*, "Active Site Selective Labeling of Serine Proteases with Spectroscopic Probes Using Thioester Peptide Cholromethyl Ketones Demonstration of Thrombin Labeling Using N.sup..alpha. 27:6633-6639 (1988).
Castellino F.J., "Human Protein C and Activated Protein C. Components of the Human Anticoagulation System," Trends Cardiovasc. Med., 5(2):55-62 (1995).
Conway, et al., "Tumor Necrosis Factor Suppresses Transcription of the Thrombomodulin Gene in Endothelial Cells," Mol. Cell. Biol. 8(12):5588-5592 (1988).
D'angelo, et al., "Acquired Deficiencies of Protein S. Protein S Activity During Oral Anticoagulation, in Liver Disease, and in Disseminated Intravascular Coagulation," J. Clin. Invest. 81:1445-1454 (1988).
Dahlback, "Protein S and C4b-Binding Protein: Components Involved in the Regulation of the Protein C Anticoagulant System," Thromb. Haemostas. 66(1):49-61 (1991).
Dahback, "Inhibition of Protein C.sub.a Cofactor Function of Human and Bovine Protein S by C4b-binding Protein," J. Biol. Chem. 261(26):12022-12027 (1986).
Dahlback, "Inherited thrombophilia: resistance to activated protein C as a pathogenic factor of venous thromboembolism" Blood 85(3):607-614 (1995).
Devaux, "Static and Dynamic Lipid Asymmetry in Cell Membranes," Biochemistry 30(5): 1163-1173 (1991).
Dittman, "Thrombomodulin, Biology and Protein Cardiovascular Applications," Trends Cardiovasc. Med. 1(8):331-336 (1991).
Dittman, et al., "Review Article--Structure and Function of Thrombomodulin: A Natural Anticoagulant," Blood 75(2):329-336 (1990).
Dreyfus, et al., "Treatment of Homozygous Protein C Deficiency and Neonatal Purpura Fulminans with a Purified Protein C Concentrate," N. Engl. J. Med. 325(22):1565-1568 (1991).
Esmon, "The Function of Factor V In P rothrombin Activation," (Ph.D. Dissertation), Washington University, St. Louis (Dec., 1973).
Esmon, "The Roles of Protein C and Thrombomodulin in the Regulation of Blood Coagulation," J. Biol. Chem. 264(9):4743-4746 (1989).
Esmon, et al., "Protein C Activation," Methods. Enzymology 222:359-385 (Academic Press, Inc. 1993).
Esmon, "Protein S and Protein C--Biochemistry, Physiology, and Clinical Manifestation of Deficiencies," Trends Cardiovasc. Med. 2(6):214-220 (1992).
Esmon, "The Subunit Structure of Thrombin-activated Factor V," J. Biol. chem. 254(3): 964-973 (1979).
Florell, et al., "Inherited thrombotic disorders: An Update" Am. J. Hematol. 54(1):53-60 (1997).
Friezner, et al., "Nucleotide Sequence of the Gene for Human Prothrombin," Biochemistry, 26(18):6165-6177 (1987).
Furie, et al., "Molecular Basis of Blood Coagulation," Cell 53:505-518 (1988).
Geng, et al., "The Propeptides of Human Protein C, Factor VII, and Factor IX Are Exchangeable with Regard to Directing Gamma-Carboxylation of these Proteins," Thrombosis and Haemostasis, 76(2):205-207 (1996).
Geng, et al., "Transfer of Specific Endothelial Cell-Binding Properties from the Procoagulant Protein Human Factor IX into the Anticoagulant Protein Human Protein C," Biochemistry, 34:8449-8457 (1995).
Gerson, et al., "Severe Acquired Protein C Deficiency in Purpura Fulminans Associated with Disseminated Intravascular Coagluation Treatment with Protein C Concentrate," Pediatrics 91(2)L418-422 (1993).
Gilbert, et al., "Phosphatidylethanolamine Induces High Affinity Binding Sites for Factor VIII on Membranes Containing Phosphatidyl-L-serine," J. Biol. Chem. 270(31):18500-18505 (1995).
Ginsberg, et al., "Increased Thrombin Generation and Activity in Patients with Systemic Lupus Erythematosus and Anticardiolipin Antibodies: Evidence for a Prothrombotic State," Blood 81(11):2958-2963 (1993).
Heeb, et al., "Binding of Protein S to Factor Va Associated with Inhibition of Prothrombinase That is Independent of Activated Protein," J. Biol. Chem. 268(4):2872-2877 (1993).
Kalafatis, et al., "Characterization of the molecular defect in factor V.sup.R506Q," J. Biol. Chem. 270(8):4053-4057 (1995).
Kalafatis, et al., "The mechanism of inactivation of human factor V and human factor Va by activated protein C" J. Biol. Chem.269(50):31869-31880 (1994).
Le Bonniec, et al., "The Role of Calcium Ions in Factor X Activation by Thrombin E192Q", J. Biol. Chem. 267(10):6970-6976 (1992).
Lentz, et al., "Regulation of Thrombomodulin by Tumor Necrosis-.alpha.: Comparison of Transcriptional and Posttranscriptional Mechanism," Blood 77(3):543-550 (1991).
Mann, et al., "Cofactor Proteins in the Assembly and Expression of Blood Clotting Enzyme Complexes," Ann. Rev. Biochem. 57:915-956 (1988).
Mann, et al., "Surface Dependent Hemostasis," Sem. Hematol. 29(3):213-226 (1992).
Moore, et.al., "Tumor Necrosis Factor Leads to the Internalization and Degradation of Thrombomodulin From the Surface of Bovine Aortic Endothelial Cells in Culture," blood 73(1)159-165 (1989).
Nelsestuen, "Interaction of Vitamin K Dependent Proteins with Membranes," Biochemistry 17(11):2134-2138 (1978).
Neuenschwander, et al., "Phosphatidylethanolamine Augments Factor VIIa-Tissue Factor Activity: Enhancement of Sensitivity to Phosphatidylserine," Biochemistry 34(43): 13988-13993 (1995).
Owen, et al., "The Conversion of Prothrombin to Thrombin," J. Biol. Chem. 249(2):594-605 (1974).
Pei, et al., "Specific Contribution of Different Phospholipid Surfaces to the Activation of Prothrombin by the Fully Assembled Protrombinase," J. Biol. Chem. 268(5):3226-3233 (1992).
Pierangeli, et al., "Effect of Human IgG Antiphospholipid Antibodies on an In Vivo Thrombosis Model in Mice," Thromb. H.ae butted.mostas. 71(5):670-674 (1994).
Rauch, et al., "Human Hybridoma Lupus Anticoagulants Distinguish Between Lamellar and Hexagonal Phase Lipid Systems," J. Biol. Chem. 261(21):9672-9677 (1986).
Rezaie, et al., "The Function of Calcium in Protein C Activation by Thrombin and the Thrombin-Thrombomodulim Complex Can Be Distinguished by Mutational Analysis of Protein C Derivatives," J. Biol. Chem. 267(36):26104-26109 (1992).
Rezaie, et al., "Conversion of Glutamic Acid 192 to Glutamine in Activated Protein C Changes to Subtrate Specificity and Increases Reactivity Toward Macromolecular Inhibitors," J. Biol. Chem. 268(27). 19943-19948 (1993).
Seligsohn, et al., "Homozygous Protein C Deficiency Manifested by Massive Venous Thrombosis in the Newborn," N. Eng. J. Med. 310(9):559-562 (1984).
Smeets, et al., "Contribution of Different Phospholipid C

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