Urokinase Patents (Class 435/215)
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Patent number: 5472851Abstract: The present invention relates to the use of a substance which inhibits the plasma proteins .alpha..sub.2 -AP and/or .alpha..sub.2 -M in the field of the determination and assay of plasminogen activators and inhibitors of said plasminogen activators. It relates in particular to a method of determining (i) a plasminogen activator selected from the group consisting of tissue plasminogen activators (tPAs) and urokinase plasminogen activators (uPAs), and (ii) an inhibitor (PAI) of said plasminogen activator, said method, which involves converting plasminogen to plasmin and then assaying the plasmin resulting from said conversion, comprising inhibition of the plasma proteins .alpha..sub.2 -antiplasmin and/or .alpha..sub.2 -macroglobulin by means of a substance selected from the group consisting of metalloproteinase materials.Type: GrantFiled: May 10, 1991Date of Patent: December 5, 1995Assignee: SerbioInventors: Genevieve Pussard nee Contant, Jean-Luc Martinolli, Gerad Quentin
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Patent number: 5426044Abstract: A novel human protein, minactivin, can be produced by recombinant DNA technology, Biologically active native minactivin, peptides derived from minactivin, and their amino acid sequences can also be purified.Type: GrantFiled: April 30, 1991Date of Patent: June 20, 1995Assignees: Biotechnology Australia, Pty., Ltd., Australian National UniversityInventors: Toni M. Antalis, Thomas M. Barnes, Michelle A. Clark, Peter L. Devine, Neil H. Goss, Philip R. Lehrbach
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Patent number: 5416006Abstract: Phosphorylated plasminogen activator, such as phosphorylated pro-urokinase (pro-u-PA), which is substantially free from unphosphorylated plasminogen activator, may be obtained by phosphorylating unphosphorylated plasminogen activator with a phosphorylating enzyme or by separating phosphorylated plasminogen activator from a mixture of phosphorylated plasminogen activator and unphosphorylated plasminogen activator. Phosphorylated pro-u-PA, which is substantially free from unphosphorylated pro-u-PA, is converted by plasmin into phosphorylated u-PA. The phosphorylated plasminogen activators such as phosphorylated pro-u-PA, u-PA and t-PA are useful as thrombolytic agents.Type: GrantFiled: December 18, 1991Date of Patent: May 16, 1995Inventors: Francesco Blasi, Maria P. Stoppelli, Maria R. Mastronicola, Karen G. Welinder, Isabel Correas
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Patent number: 5409700Abstract: The present invention relates to pharmaceutical compositions comprising a combination of two different plasminogen activators which are used for the prophylaxis and therapie of thrombosis.Type: GrantFiled: April 7, 1993Date of Patent: April 25, 1995Assignee: Ciba-Geigy CorporationInventors: Jutta Heim, Fredericus A. M. Asselbergs, Rolf Burgi
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Patent number: 5389538Abstract: A mutant human prourokinase wherein a neutral amino acid in the epidermal growth factor (EGF) region of human prourokinase (human PUK) has been replaced with a basic amino acid, or an acidic amino acid has been replaced with a non-acidic amino acid, and a method for producing a mutant human PUK which comprises expression of mutant human PUK by cultivating a host transformed by a plasmid inserted with a DNA sequence coding for said mutant human PUK. By replacing a neutral amino acid in the EGF region of human PUK which is a fibrinolysin with a basic amino acid, or an acidic amino acid with a non-acidic amino acid, half-life in blood can be prolonged, and affinity for fibrin can be improved.Type: GrantFiled: October 6, 1992Date of Patent: February 14, 1995Assignee: The Green Cross CorporationInventors: Toshizumi Tanabe, Masanori Morita, Masaaki Hirose, Yasuo Amatsuji
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Patent number: 5376547Abstract: Des-epidermal growth factor homologous--plasminogen activators with greatly diminished affinity for liver membranes.Type: GrantFiled: January 29, 1988Date of Patent: December 27, 1994Assignee: American Home Products CorporationInventors: Narender K. Kalyan, Shawguang L. Lee, Paul P. Hung
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Patent number: 5366886Abstract: Disclosed are novel variants of tissue plasminogen activator (t-PA) that have surprising biological/pharmacokinetic properties compared with native t-PA. For example, certain of the variants hereof demonstrate increased half-life profiles, and show good fibrin binding activity even though fibrin binding regions of the molecule are deleted. All associated means and methods for preparing such variants recombinantly and for using such variants are also disclosed.Type: GrantFiled: February 11, 1993Date of Patent: November 22, 1994Assignee: Genentech, Inc.Inventors: Stephen P. Anderson, Deborah L. Higgins, Adair J. Hotchkiss, Cara B. Marks
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Patent number: 5350578Abstract: The method of preventing arterial thrombotic occlusion or thromboembolism by administering plasma-derived or recombinant produced protein C alone or in combination with a thrombolytic agent or combinations of thrombolytic agents.Type: GrantFiled: October 25, 1991Date of Patent: September 27, 1994Assignee: Scripps Clinic and Research FoundationInventors: John H. Griffin, Andras Gruber, Stephen R. Hanson, Lawrence A. Harker
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Patent number: 5342775Abstract: A novel plasminogen activator which is identical in peptide sequence to naturally occurring human prourokinase except that the 155th amino acid counting from the N-terminal amino acid (serine)] is other than the 155th amino acid (proline) of naturally occurring human prourokinase, optionally with the addition of methionine at the N terminus.Type: GrantFiled: June 16, 1992Date of Patent: August 30, 1994Assignee: Kyowa Hakko Kogyo Co. Ltd.Inventors: Shigeyoshi Yasumura, Tatsunari Nishi, Seiga Ito
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Patent number: 5336602Abstract: An expression enhancer has a DNA sequence which is capable of forming a t-RNA clover-leaf structure after transcription and hybridizes in that region of the DNA which, after transcription, forms the anticodon loop in the clover-leaf structure with an oligonucleotide with the sequence 5'-GACTTAGAAGGTCGTT-3' or its complementary sequence (5'-AACGACCTTCTAAGTC-3'). It can be used to increase the yield in the expression of a recombinant gene by transformation of suitable host cells with an expression vector containing the recombinant gene, whereby it is likewise introduced into the host cells in a form capable of expression and expressed.Type: GrantFiled: January 22, 1993Date of Patent: August 9, 1994Assignee: Boehringer Mannheim GmbHInventors: Ulrich Brinkmann, Ralf Mattes, Peter Buckel
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Patent number: 5324648Abstract: Substituted isocoumarins, their use in inhibiting serine proteases with trypsin-like, chymotrypsin-like and elastase-like specificity and their roles as anti-inflammatory agents.Type: GrantFiled: June 17, 1992Date of Patent: June 28, 1994Assignee: Georgia Tech Research CorporationInventors: James C. Powers, Chih-Min Kam, Josef Oleksyszyn, J. A. Glinski, M. A. Hernandez
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Patent number: 5316934Abstract: Human prourokinase-like polypeptides of which oligopeptides having a structure to form a covalent bond with blood clot (thrombus) through enzymatic action of human blood coagulation factor XIII are attached to the NH.sub.2 -terminal sides of human prourokinase derivatives.Type: GrantFiled: February 12, 1991Date of Patent: May 31, 1994Assignee: Nippon Soda Co., Ltd.Inventors: Yoh-ichi Kobayashi, Ken Watabe, Yukuo Mukohara, Masayuki Satoh, Hiroaki Nakamura
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Patent number: 5308617Abstract: A pharmaceutical composition is prepared wherein a biologically active conjugated protein is selectively conjugated to at least one heparin fragment having a terminal 2,5-anhydro-D-mannose residue which has an aldehyde not involved in intramolecular hemiacetal formation. The resulting conjugate has a prolonged half-life as compared to native protein and is able to deliver heparin to the site of clots or to prevent reocclusion within the blood stream. Typical proteins include enzymes such as plasminogen activators, and in particular tissue plasminogen activators, and erythropoietin, hormones, antibodies and the like.Type: GrantFiled: June 10, 1991Date of Patent: May 3, 1994Assignee: Halzyme Ltd.Inventor: Albert P. Halluin
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Patent number: 5298401Abstract: In a process for the quantitative determination of the function and antigenic concentration of a substance contained in a biological liquid, the substance is immobilized, the function is determined by the addition of a specific substrate which is then removed by washing, and in a subsequent step the immunological concentration of the bound substance is determined using an appropriate specific detector system with or without the use of an antibody.Type: GrantFiled: January 5, 1989Date of Patent: March 29, 1994Inventor: Bernd Binder
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Patent number: 5268273Abstract: The present invention discloses the Pichia pastoris acid phospbatase gene, which includes the 5' regulatory region, signal sequence, structural gene, and 3' transcription termination sequence. Also disclosed are methods of using these fragments, which include but are not limited to the secretion of proteins from cells and the regulation of the transcription of DNA. DNA vectors containing the acid phospbatase gene or fragments thereof and hosts transformed with these vectors are also disclosed. Additionally, integrative vectors which direct integration at the Pichia pastoris PHO1 locus and a method of identifying these disruptants is disclosed.Type: GrantFiled: December 14, 1990Date of Patent: December 7, 1993Assignee: Phillips Petroleum CompanyInventor: Richard G. Buckholz
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Patent number: 5256642Abstract: The present invention relates to compositions comprising soluble complement receptor 1 (CR1) and a thrombolytic agent. In a specific embodiment, the thrombolytic agent is anisoylated human plasminogen-streptokinase activator complex (ASPAC). The invention further relates to methods for treating thrombotic conditions in humans and animals by administering a composition comprising soluble CR1 and a thrombolytic agent. In particular, the compositions and methods are useful both for reducing reperfusion injury and ameliorating the other effects of myocardial infarction.Type: GrantFiled: September 24, 1990Date of Patent: October 26, 1993Assignees: The Johns Hopkins University, Brigham and Women's Hospital, T Cell Sciences, Inc.Inventors: Douglas T. Fearon, Lloyd B. Klickstein, Winnie W. Wong, Gerald R. Carson, Michael F. Concino, Stephen H. Ip, Savvas Makrides, Henry C. Marsh, Jr.
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Patent number: 5242819Abstract: Novel single-chain hybrid plasminogen activators having an amino acid sequence composed of at least two subsequences corresponding in amino acid identity and number to subsequences of human t-PA and of human u-PA, and mutants thereof in which at least one of the N-glycosylation sites is modified such that glycosylation cannot take place at these sites exhibit valuable pharmacological properties. The hybrid plasminogen activators are produced by recombinant DNA technology.Type: GrantFiled: December 13, 1991Date of Patent: September 7, 1993Assignee: Ciba-Geigy CorporationInventors: Bhanu Rajput, Bhabatosh Chaudhuri, Fredericus A. M. Asselbergs, Bernd Meyhack, Jutta Heim, Jan van Oostrum, Sefik Alkan
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Patent number: 5227297Abstract: A tripeptide ligand of the formula -X-Y-Argininal is used to purify plasminogen activators.Type: GrantFiled: June 5, 1992Date of Patent: July 13, 1993Assignee: SmithKline Beecham CorporationInventors: Arun Patel, A. Hirotoshi Nishikawa
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Patent number: 5223408Abstract: A screening method for the selection of mutagenized proteins that are normally secreted by cells is described. The method includes the development of a cloning vector for the expression of secretory proteins as fusion proteins on the cell surface of transfected mammalian cells. The secreted protein is displayed on the cell surface by fusion with the glycophospholipid membrane anchor of decay accelerating factor (DAF). Tissue-type plasminogen activator (t-PA), which is normally secreted, is used as a model protein. PCR mutagenesis is used to generate random mutations within the Kringle 1 (K1) domain of t-PA. Fluorescence activated cell sorting (FACS) is employed to screen for t-PA mutants possessing a loss of an epitope to a specific Mab, whose nonlinear binding domains overlap with the t-PA clearance receptor contact regions novel t-PA mutants designated N115S, N1425S, and K159R were discovered by this method.Type: GrantFiled: July 11, 1991Date of Patent: June 29, 1993Assignee: Genentech, Inc.Inventors: David V. Goeddel, Glenn C. Rice, David W. H. Leung
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Patent number: 5219569Abstract: Novel single-chain protease resistant urokinase derivatives are provided. In particular, derivatives are provided wherein the Lys.sub.135 Lys.sub.136 and Arg.sub.156 to Lys.sub.158 sites are rendered less susceptible to proteolytic cleavage are provided by occluding the sites or by covalently modifying them. Preferred covalent modifications are amino acid sequence variants at the sites where proteolysis of urokinase occurs. These are optimally produced by synthesis of single-chain urokinase mutants in recombinant cell culture. The novel urokinase derivatives herein offer the advantage of avoiding the generation of substantial two-chain urokinase, either in vivo or during recombinant cell culture. However, the derivatives continue function to activate plasminogen in initiating blood clot lysis.Type: GrantFiled: August 16, 1985Date of Patent: June 15, 1993Assignee: Genentech, Inc.Inventors: Michael Blaber, Herbert L. Heyneker, Gordon A. Vehar
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Patent number: 5218137Abstract: Light activated acyl-enzymes of the formula: ##STR1## are disclosed. In the compounds of Formula (III), ENZ is an enzyme, X is O or S, Y is --NR.sub.3 R.sub.4, --OR.sub.5, or --SR.sub.5, and Z is a nucleophile. m is 0 to 3 and n is 1 or 2. Y is substituted on the ring at either or both of the 4 and 6 position.R.sub.1 and R.sub.2 are each independently H, C1 to C4 alkyl, C3 to C4 unconjugated alkenyl, or C3 to C4 unconjugated alkynyl.R.sub.3 and R.sub.4 are each independently H, C1 to C4 alkyl, C3 to C4 unconjugated alkenyl, or C3 to C4 unconjugated alkynyl, except that R.sub.3 and R.sub.4 are not simultaneously both H. R.sub.5 is C1 to C4 alkyl, C3 to C4 unconjugated alkenyl, or C3 to C4 unconjugated alkynyl.Methods of using the acyl-enzymes and intermediates for making the acyl-enzymes are disclosed.Type: GrantFiled: March 25, 1992Date of Patent: June 8, 1993Assignee: Duke UniversityInventors: Ned A. Porter, John D. Bruhnke
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Patent number: 5204255Abstract: A hybrid plasminogen activator-like polypeptide comprising a polypeptide region responsible for an affinity to fibrin derived from a tissue plasminogen activator polypeptide and a polypeptide region responsible for an enzyme activity derived from a prourokinase polypeptide; a DNA segment coding for the hybrid polypeptide; plasmid containing the DNA segment; a microorganism transformed with the DNA; and a process for production of the hybrid polypeptide comprising culturing the microorganism and recovering the hybrid polypeptide from the cultured cells.Type: GrantFiled: July 3, 1991Date of Patent: April 20, 1993Assignees: Sagami Chemical Research Center, Central Glass Company, Limited, Hodogaya Chemical Co., Ltd., Nippon Soda Company, Limited, Nissan Chemical Industries, Limited, Toyo Soda Manufacturing Co., Ltd.Inventors: Michito Tagawa, Masakatsu Wada, Masayuki Yamada, Midori Yokoyama, Naganori Numao
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Patent number: 5188829Abstract: A human prourokinase-like polypeptide having the following amino acid sequence:(Met).Ser.sup.1 -X.sup.156.Y.sup.157.Z.sup.158 --wherein Met is an occasionally present methionine, Ser is the first N-terminal serine, X is the 156th arginine or other amino acid, Y is the 157th proline, glycine, alanine or valine, Z is the 158th lysine or arginine, and the solid lines represent the same amino acid sequences as corresponding parts of an amino acid sequence of a natural type human prourokinase or a human prourokinase-like polypeptide wherein the 135th lysine is changed to an amino acid other than a basic amino acid, or substantially the same amino acid sequence as the above-mentioned amino acid sequence, is provided.Moreover, a DNA segment coding for the above-mentioned polypeptide; a plasmid containing the DNA segment; E. coli transformed with the plasmid; a process for production of the polypeptide characterized by culturing the E.Type: GrantFiled: April 10, 1989Date of Patent: February 23, 1993Assignees: Sagami Chemical Research Center, Central Glass Company, Limited, Hodogaya Chemical Co., Ltd., Nippon Soda Company, Limited, Nissan Chemical Industries, Limited, Tosoh CorporationInventors: Yo-ichi Kobayashi, Muneki Omori, Chikako Yamada
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Patent number: 5175105Abstract: Novel human plasminogen activators of the urokinase type are produced by yeast cells transformed with a hybrid vector comprising a DNA sequence coding for said human plasminogen activator. Novel hybrid vectors, yeast hosts transformed with such hybrid vectors and processes for the production thereof are also provided.Type: GrantFiled: April 8, 1988Date of Patent: December 29, 1992Assignee: Ciba-Geigy CorporationInventors: Bernd Meyhack, Jutta Heim, Rolf Burgi
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Patent number: 5173415Abstract: A membrane filter of 0.025 to 0.05 .mu. in pore size is treated by passing the solution of a water-soluble high molecular substance such as albumin, dextran, polyvinylpyrrolidone, polysorbate 80, gelatin or the like through the membrane filter. Employing the filter thus treated, the solution of a physiologically active substance of human origin such as human growth hormone, kallikrein, trypsin inhibitor, epidermal growth factor, leucocyte interferon etc. is filtered at high recovery rate of the active substance avoiding the adsorption of the active substance onto the filter. By the filtration, harmful viruses such as Creutzfeldt-Jacob disease pathogen which may exist in the physiologically active substance can be removed.Type: GrantFiled: January 14, 1991Date of Patent: December 22, 1992Assignee: Japan Chemical Research Co., Ltd.Inventors: Hajime Hiratani, Jun Tateishi, Tetsuyuki Kitamoto
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Patent number: 5160735Abstract: A novel plasminogen activator which is identical in peptide sequence to naturally occurring human prourokinase except that the 155th amino acid counting from the N-terminal amino acid (serine) is other than the 155th amino acid (proline) of naturally occurring human prourokinase, optionally with the addition of methionine at the N terminus.Type: GrantFiled: June 14, 1990Date of Patent: November 3, 1992Assignee: Kyowa Hakko Kogyo Co. Ltd.Inventors: Shigeyoshi Yasumura, Tatsunari Nishi, Seiga Ito
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Patent number: 5156967Abstract: A process for the purification and pasteurization of urokinase using an ion exchanger is described, the product obtained having a favorable ratio of high molecular weight to low molecular weight urokinase. The product can be used for therapeutic purposes.Type: GrantFiled: September 28, 1990Date of Patent: October 20, 1992Assignee: Hoechst AktiengesellschaftInventor: Eric Paques
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Patent number: 5151359Abstract: A method for the production of human tissue type plasminogen activator (tPa) using cells is disclosed. The method includes a supplementation of a p-aminomethyl benzoic acid derivative to a cell culture medium or a tPA producing medium and further an increase of osmotic pressure in the medium to 350 milliosmoles or more/liter. The invention provides a method for producing single-chain tPA in a high concentration and with a relatively small amount of double-chain tPA in the medium.Type: GrantFiled: May 5, 1989Date of Patent: September 29, 1992Assignee: Mitsui Toatsu Chemicals IncorporatedInventors: Shyoichiro Miyahara, Maki Suzuki, Atsunori Shindo, Nobumi Kusuhara, Nobuyoshi Makiguchi
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Patent number: 5141862Abstract: A method for purifying tPA or a plasminogen activator having an active site resembling that of tPA from an impure solution thereof which comprises contacting the impure solution with a solid support having bound thereto a tripeptide of the formula: -X-Y-argininal, wherein X and Y are amino acids selected from the group consisting of pro, phe, trp and tyr. The method is also used with a tripeptide of the formula: -phe-Y-argininal, wherein Y is selected from the group consisting of phe, pro, trp, tyr, val, ile and glu(PEA).Type: GrantFiled: April 17, 1990Date of Patent: August 25, 1992Assignee: SmithKline Beecham CorporationInventors: Arun Patel, A. Hirotoshi Nishikawa
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Patent number: 5134065Abstract: A novel and unique plasminogen activator inhibitor fragment is obtained from human umbilical vein endothelial cells which has the following characteristics:A. it is derived from a native t-PA inhibitor that binds to and inhibits the activity of t-PA,B. it is dissociated from a complex formed between said native t-PA inhibitor and t-PA, said complex existing in two distinct interconvertible conformations with molecular weight of about 88 KDa and 105 KDa, respectively, and being partially reversible in the presence of fibrin,C. it has a molecular weight of about 40 KDa when dissociated from the complex, andD. it has a novel partial N-terminal amino acid sequence when dissociated from the complex.Type: GrantFiled: May 16, 1986Date of Patent: July 28, 1992Assignee: Monsanto CompanyInventors: Michael A. Sanzo, Arthur J. Wittwer, Jayne C. Marasa, Joseph Feder
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Patent number: 5116613Abstract: A thrombolytic product comprising a fibrin-specific antibody substantially devoid of fibrinogen cross-reactivity coupled to a thrombolytic agent.Type: GrantFiled: January 8, 1985Date of Patent: May 26, 1992Assignee: The General Hospital CorporationInventors: Edgar Haber, Gary R. Matsueda
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Patent number: 5114851Abstract: Light activated acyl-enzymes of the formula: ##STR1## are disclosed. In the compounds of Formula (III), ENZ is an enzyme, X is O or S, Y is --NR.sub.3 R.sub.4, --OR.sub.5, or --SR.sub.5, and Z is a nucleophile. m is 0 to 3 and n is 1 or 2. Y is substituted on the ring at either or both of the 4 and 6 position.R.sub.1 and R.sub.2 are each independently H, C1 to C4 alkyl, C3 to C4 unconjugated alkenyl, or C3 to C4 unconjugated alkynyl.R.sub.3 and R.sub.4 are each independently H, C1 to C4 alkyl, C3 to C4 unconjugated alkenyl, or C3 to C4 unconjugated alkynyl, except that R.sub.3 and R.sub.4 are not simultaneously both H. R.sub.5 is C1 to C4 alkyl, C3 to C4 unconjugated alkenyl, or C3 to C4 unconjugated alkynyl.Methods of using the acyl-enzymes and intermediates for making the acyl-enzymes are disclosed.Type: GrantFiled: August 29, 1989Date of Patent: May 19, 1992Assignee: Duke UniversityInventors: Ned A. Porter, John D. Bruhnke
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Patent number: 5112755Abstract: Human urokinase is produced using recombinant DNA techniques. The invention disclosed thus enables the production of urokinase free of contaminants with which it is ordinarily associated in its native cellular environment. Methods, expression vehicles and various host cells useful in its production are also disclosed.Type: GrantFiled: July 19, 1988Date of Patent: May 12, 1992Assignee: Genentech, Inc.Inventors: Herbert L. Heyneker, William E. Holmes, Gordon A. Vehar
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Patent number: 5098840Abstract: A human prourokinase mutant in which the entire or a partial epidermal growth factor domain of human prourokinase is deleted or a partial epidermal growth factor domain of human prourokinase is replaced by one or more different amino acid residues, said mutant having a longer blood half-life than naturally occurring human prourokinase while retaining prourokinase enzymatic activity. In this human prourokinase mutant the region selected from the group consisting of: (a) from asparagine (10) to cysteine (42); (b) from asparagine (10) to aspartic acid (45); and (c) from asparagine (10) to threonine (49) is missing.Type: GrantFiled: May 18, 1990Date of Patent: March 24, 1992Assignee: The Green Cross CorporationInventors: Shunji Kasai, Ryuji Hiramatsu, Shusei Uno, Masanori Nagai, Hirofumi Arimura, Toshizumi Tanabe, Yasuo Amatsuji, Masaaki Hirose, Masanori Morita, Haruhide Kawabe
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Patent number: 5084274Abstract: The method of preventing arterial thrombotic occulsion or thromboembolism by administering plasma-derived or recombinate produced protein C alone or in combination with a thrombolytic agent or combinations of thrombolytic agents.Type: GrantFiled: November 17, 1987Date of Patent: January 28, 1992Assignee: Scripps Clinic and Research FoundationInventors: John H. Griffin, Andras Gruber, Stephen R. Hanson, Lawrence A. Harker
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Patent number: 5075230Abstract: A plasminogen activator precursor obtainable from a serum-free culture fluid of human kidney cells is stabilized by adding to its solution poly-C1-C5-alkylene glycols, polyethylene-polyoxypropylene copolymers, mandelic acid salts, triethanolamine, acid addition salts of acetylglycillysine methyl ester, guanidine salts, thiocyanic acid salts, alkali metal iodides or serine.Type: GrantFiled: April 20, 1990Date of Patent: December 24, 1991Assignee: The Green Cross CorporationInventors: Kazuo Morimoto, Motoshi Sagane, Kazuhiro Ohara, Shusaku Narita
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Patent number: 5073626Abstract: A method of purifying PAI-1 from a biological fluid source, e.g. conditioned media of Hep G2 or HT 1080 cells, containing PAI-1 is disclosed, which comprises subjecting the biological fluid to a modified urokinase affinity absorbent, e.g. anhydrourokinase ligand bound to a CNBr-activated agarose gel or urokinase mutated at amino acid position 356 from Ser to Gly and bound to the gel, and then eluting PAI-1 from said affinity absorbent. A method of stabilizing and/or activating PAI-1 is also disclosed, which comprises complexing PAI-1 with vitronectin.Type: GrantFiled: June 4, 1990Date of Patent: December 17, 1991Assignee: Monsanto CompanyInventor: Tze-Chein Wun
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Patent number: 5068106Abstract: In the preparation of parenteral solutions for the therapy and prophylaxis of thromboses and embolisms, because of the poor solubility of t-PA hitherto either the infusion of very large volumes has been necessary, or else a solution with a low volume and a high t-PA concentration has been prepared at the expense of setting up a non-physiologically low pH of 2 to 5.Hence, the present invention relates to a process for the preparation of a solution of high concentration of a protein having plasminogen activator activity, where an increase in stability and solubility is achieved by adding at least two substances from the group of D- and/or L-amino acids, their salts, derivatives or homologs. This invention also relates to a process for the pasteurization of a protein solution having t-PA activity, and to a t-PA-containing solution prepared by the claimed process, and to the use of this solution as a fibrinolytic in human and veterinary medicine.Type: GrantFiled: June 3, 1988Date of Patent: November 26, 1991Assignee: Behringwerke AktiengesellschaftInventors: Eric P. Paques, Hans-Arnold Stohr
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Patent number: 5068179Abstract: The present invention provides a method for the determination of a component of an immune reaction in a plasma sample using an immunoassay at a temperature of from 15.degree. to 40.degree. C., where one of the reactive components is in solid phase. The invention involves adding an amount of plasminogen activator sufficient to eliminate interference by fibrinogen with the component to be determined.Type: GrantFiled: October 18, 1988Date of Patent: November 26, 1991Assignee: Boehringer Mannheim GmbHInventors: Rolf Deeg, Rainer Wehner, Johann Mattersberger, Udo Becker
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Patent number: 5055295Abstract: The thrombolytic effect of the plasminogen activator pro-urokinase is improved synergistically by the co-administration of urokinase. The two components may be administered sequentially or simultaneously, and if simultaneously, either separately or as a mixture. Preferably an initial bolus injection of urokinase is followed by an infusion of pro-urokinase.Type: GrantFiled: May 2, 1989Date of Patent: October 8, 1991Assignee: Vascular Laboratory, Inc.Inventors: Dieter Welzel, Helmut Wolf
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Potentiation of the thrombolytic effect of prourokinase type plasminogen activators by streptokinase
Patent number: 5051264Abstract: The thrombolytic effect of known plasminogen activators such as tissue plasminogen activator (t-PA), prourokinase and modifications of t-PA and prourokinase is enhanced dramatically and unexpectedly when combined with streptokinase. The body is treated with a combination streptokinase and one or more plasminogen activators of the t-PA or prourokinase type to achieve an enhanced effect which has advantage in thrombolytic therapy including the treatment of myocardial infarction.Type: GrantFiled: November 2, 1988Date of Patent: September 24, 1991Assignee: Collaborative Research, Inc.Inventor: Clara M. Ambrus -
Patent number: 5047503Abstract: Thrombin-binding substances are obtained by fractionating human urine by ion-exchange chromatography, affinity chromatography using a thrombin-bound carrier, immune adsorption column chromatography, gel filtration, and/or molecular-weight fractionation. One of the substances has a molecular weight of 46,500.+-.6,000 in reduced condition and 39,000.+-.10,000 in unreduced condition by SDS PAGE and an isoelectric point at pH 5.0-5.3, while the other has a molecular weight of 40,000.+-.8,000 in reduced condition and 31,000.+-.10,000 in unreduced condition by SDS PAGE and an isoelectric point at pH 4.9-5.7. They have strong affinity to thrombin. They are capable of promoting the thrombin catalyzed activation of protein C and prolong clotting time. They are stable to denaturing agents (urea and sodium dodecylsulfate).Type: GrantFiled: July 10, 1987Date of Patent: September 10, 1991Assignee: Kowa Company, Ltd.Inventors: Nobuo Aoki, Shigeru Kimura, Masami Shiratsuchi
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Patent number: 5045315Abstract: Hybrid, third generation, plasminogen activators containing plural, heterologous polypeptide kringles prepared by recombinant DNA techniques as well as the genes coding for the activators, Vectors containing those genes and a method for using the plasminogen activators as thrombolytic agents, are disclosed.Type: GrantFiled: October 23, 1990Date of Patent: September 3, 1991Assignee: American Home Products CorporationInventors: Paul P. Hung, Narender K. Kalyan, Shaw-guang L. Lee
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Patent number: 5037646Abstract: Disclosed herein are improved processes for preparing variant human t-PA proteins exhibiting improved pharmacokinetic properties relative to natural t-PA. One such illustrated variant, devoid of amino acids corresponding to amino acids 1 through 44 of natural t-PA, is shown to exhibit a plasma half-life of greater than about 15 times the plasma half-life to natural t-PA, as well as a clearance rate of less than about 1/10 the clearance rate of natural t-PA. Also disclosed are improved processes for treating vascular disease employing pharmaceutical compositions which incorporate therapeutically effective amounts of such t-PA variants with pharmaceutically acceptable diluents or excipients.Type: GrantFiled: June 18, 1990Date of Patent: August 6, 1991Assignee: Genentech, Inc.Inventors: Deborah L. Higgins, William E. Holmes, Adair J. Hotchkiss
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Patent number: 5015583Abstract: A process is described for the purification of plasminogen activator (PA), wherein a solution containing such as plasminogen activator is brought into contact with a carrier-bound polysulfate of a saccharide or sulfated sugar, the liquid is removed, and the PA bound by this material is eluted.Type: GrantFiled: December 12, 1988Date of Patent: May 14, 1991Assignee: Behringwerke AktiengesellschaftInventor: Eric P. Paques
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Patent number: 5011686Abstract: Disclosed is a method of targeting reagents to the locus of a clot, and a family of substances that have affinity for fibrin. The method and substances exploit the discovery that the binding sites on protein A from Staphylococcus aureus have a significant affinity for fibrin. These fragments, analogs thereof, and oligomers of the fragments or analogs, may be attached to fibrinolytic enzymes, remotely detectable radiation emitting moieties, or healing agents to produce reagents which have affinity for the site of a wound or intravascular clot where fibrin has been deposited. Constructs comprising repeats of truncated analogs of the binding domain have low affinity for circulating immunoglobulin and high affinity for fibrin.Type: GrantFiled: November 15, 1989Date of Patent: April 30, 1991Assignee: Creative Biomolecules, Inc.Inventor: Roy H. L. Pang
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Patent number: 5004609Abstract: This invention discloses a fibrinophilic urokinase complex which is a complex of urokinase with a urokinase inhibitor or tissue activator inhibitor and has a molecular weight of 97,500.+-.3,000 and a method for the production of this fibrinophilic urokinase complex from urine. The urokinase complex can be used, as a thombolytic agent exhibiting an outstanding ability to dissolve thrombus.Type: GrantFiled: September 5, 1989Date of Patent: April 2, 1991Assignee: Shiseido Company Ltd.Inventors: Shigeru Hayashi, Kaneo Yamada
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Patent number: 5004802Abstract: A protein called PA binding protein has been isolated which binds specifically and reversibly to tissue plasminogen activator. The protein is characterized by a molecular mass of about 100,000 daltons, and electrophoretic mobility in agarose at pH 8.6 equal to that of plasma .beta.-globulins and an isoelectric point of 6.5 to 7.0. The protein is thermostable up to at least 56.degree. C. and is cleared from the circulation with a half life on the order of days.Type: GrantFiled: July 11, 1986Date of Patent: April 2, 1991Assignee: Nederlandse Centrale Organisatie voor Teegepast-Natturwentenschappelijk OrderzoelInventor: Cornelis Kluft
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Patent number: 5002887Abstract: Thrombolytic proteins are disclosed which have tissue plasminogen-type activity. The proteins are characterized by the presence of 0, 1, 2 or 3 N-linked polysaccharide substituents covalently bonded thereto and by a polypeptide sequence of the formula(a)A-R.sup.1 -B-R.sup.2 -C-R.sup.3 Dwherein A, B, C, and D are the following polypeptide sequences substantially as shown in FIG. 1:A is Gly-.sub.3 or Ser.sub.1 through Trp.sub.116, encompassing domain a;B is Ala.sub.120 through Gly.sub.183 ;C is Ala.sub.187 through Leu.sub.447 ;D is Val.sub.451 through Pro.sub.527 ; anda is a peptide domain comprising a sequence of 0-93 amino acids selected from the sequence Gly.sub.-3 or Ser.sub.1 through Thr.sub.91 ; R.sup.1, R.sup.2 and R.sup.3 are each a tripeptide sequence linking said A, B, C and D by peptide bonds, up to three of R.sup.1, R.sup.2 and R.sup.3 being a tripeptide sequence other than Asn-X-Thr or Asn-X-Ser, wherein X is any amino acid.Type: GrantFiled: July 3, 1986Date of Patent: March 26, 1991Assignee: Genetics Institute, Inc.Inventor: Glenn R. Larsen
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Patent number: 4999194Abstract: A fibrin specific two-chain plasminogen activator in a therapeutic dosage form. A method is also provided for dissolving clots in vivo by application to the body of a fibrin specific two-chain plasminogen activator in therapeutic dosage form.Type: GrantFiled: January 14, 1988Date of Patent: March 12, 1991Assignee: Collaborative Research, Inc.Inventors: Robert J. Broeze, Gerald F. Vovis