Urokinase Patents (Class 435/215)
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Publication number: 20040002137Abstract: This invention features a nucleic acid expression vector that includes a bicistronic coding unit that comprises a first segment that encodes a human tissue urokinase plasminogen activator protein and a second segment that encodes an amplifiable dominant selectable marker (e.g., dihydrofolate reductase); and a promoter (e.g., a cytomegalovirus promoter) operably linked to the bicistronic coding unit.Type: ApplicationFiled: March 27, 2003Publication date: January 1, 2004Applicant: Global Biotech, Inc. a Taiwan corporationInventors: Paul Porwen Hung, Bryan T. H. Wu
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Publication number: 20030211094Abstract: Modifications of vitamin K-dependent polypeptides that lead to enhanced protein function on a weight or molar basis and/or increase of protein lifetime in the circulation are described. Both objectives are important for using vitamin K-dependent polypeptides for pro- and anti-coagulation therapies, as well as for other uses in the circulation.Type: ApplicationFiled: December 30, 2002Publication date: November 13, 2003Inventor: Gary L. Nelsestuen
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Patent number: 6585972Abstract: A process for inhibiting vascular proliferation introduces a composition into the eye inducing posterior vitreous detachment. The composition includes a combination of plasminogen, a collagen crosslinking agent and at least one plasminogen activator selected from the group consisting of urokinase, streptokinase, tissue plasminogen activator, chondroitinase, pro-urokinase, retavase, metaloproteinase, and thermolysin. The composition is introduced into the vitreous in an amount effective to induce crosslinking of the vitreous and to induce substantially complete or partial posterior vitreous detachment from the retina without causing inflammation of the retina. In one embodiment, a gaseous material is introduced into the vitreous before or simultaneously with the composition to compress the vitreous against the retina while the composition induces the posterior vitreous detachment.Type: GrantFiled: October 18, 2001Date of Patent: July 1, 2003Inventor: Gholam A. Peyman
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Publication number: 20030109017Abstract: The present invention provides compositions effective in decontaminating either biological pathogens or both chemical and biological pathogens. These compositions are particularly suitable for the decontamination of biological warfare agents or both chemical and biological warfare agents The compositions comprise generally a blend of biocides, and may additionally comprise a protein and an enzyme. Further, the composition is contained in a buffered foam forming material for ease in distribution The compositions are nontoxic, noncorrosive and nonflammable.Type: ApplicationFiled: July 31, 2002Publication date: June 12, 2003Inventors: Lisa L. Conerly, Daniel J. Ehntholt, Alan S. Louie, Richard H. Whelan
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Patent number: 6569636Abstract: An assay is disclosed for determining whether a test compound modulates the activity of an enzyme having a metallated active site. The assay method employs a comparison of the binding ability of the metallated and unmetallated forms of the enzyme to the test compound.Type: GrantFiled: May 27, 1999Date of Patent: May 27, 2003Assignee: Hawaii Biotechnology Group, Inc.Inventors: Paul G. Grothaus, Dana E. Davis, Sean O'Malley
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Patent number: 6548276Abstract: Compositions and methods are provided for the enhanced in vitro synthesis of polypeptides containing disulfide bonds. In order to improve the performance of in vitro protein synthesis reactions, pre-treatment and redox buffering of the reaction mix is performed in order to optimize the redox potential. Exogenous enzymes that enhance protein folding and disulfide bond formation may also be added to the reaction.Type: GrantFiled: September 5, 2001Date of Patent: April 15, 2003Assignee: The Board of Trustees of the Leland Stanford Junior UniversityInventors: James Robert Swartz, Dong-Myung Kim
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Publication number: 20030040095Abstract: The present invention discloses a method for the production of a mature recombinant protein into the culture medium of an eukaryotic cell line genetically transfected with a cloned precursor cDNA sequence, which comprises an incubation of said cell line in the cell culture medium wherein alkanoic acids, their derivatives or salts thereof have been added for a period of time of at least 24 hours. The process allows the secretion of recombinant proteins into the culture medium in their physiologically active (mature) form.Type: ApplicationFiled: March 16, 2001Publication date: February 27, 2003Inventors: Achille Arini, Raffaella Coppolecchia, Francesca Paola Pagani, Detlev Herbst, Antonio Tognini
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Patent number: 6488927Abstract: Compositions and methods for prevention and treatment of uncontrolled formation of intravascular fibrin clots are provided wherein fibrinolytic or anticoagulant drugs are biocompatibly coupled to red blood cell carriers.Type: GrantFiled: December 3, 1999Date of Patent: December 3, 2002Assignee: Trustees of the University of PennsylvaniaInventors: Vladimir R. Muzykantov, Abd Al-Roof Higazi, Juan Carlos Murciano, Douglas Cines
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Publication number: 20020106775Abstract: The present disclosure describes a biologically active modified urokinase and high resolution crystalline forms of modified urokinase. Polynucleotides which encode modified urokinase and methods for making modified urokinase are also disclosed.Type: ApplicationFiled: March 5, 1999Publication date: August 8, 2002Inventors: JIEYI WANG, VICKI L. NIENABER, JACK HENKIN, RICHARD A. SMITH, KARL A. WALTER, JEAN M. SEVERIN, ROHINTON EDALJI, ROBERT W. JOHNSON, THOMAS F. HOLZMAN
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Patent number: 6423685Abstract: A method is provided for preparing a biologically active molecule having an increased serum half-life. The method involves conjugating a polymer such as polyethylene glycol to the biologically active molecule. Also provided are polypeptide drugs having an increased serum half-life, e.g., human urokinase plasminogen activator (human “uPA” or “hUPA”) or a fragment or derivative thereof. Pharmaceutical compositions containing such molecules and methods of using them to treat uPA-mediated and uPA receptor-mediated disorders are also provided.Type: GrantFiled: March 5, 1999Date of Patent: July 23, 2002Assignee: Chiron CorporationInventors: Robert J. Drummond, Steve Rosenberg
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Publication number: 20020086819Abstract: A method is provided for preparing a biologically active molecule having an increased serum half-life. The method involves conjugating a polymer such as polyethylene glycol to the biologically active molecule. Also provided are polypeptide drugs having an increased serum half-life, e.g., human urokinase plasminogen activator (human “uPA” or “hUPA”) or a fragment or derivative thereof. Pharmaceutical compositions containing such molecules and methods of using them to treat uPA-mediated and uPA receptor-mediated disorders are also provided.Type: ApplicationFiled: March 5, 1999Publication date: July 4, 2002Inventors: ROBERT DRUMMOND, STEVE ROSENBERG
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Patent number: 6403556Abstract: A pharmaceutical preparation contains protein C and a thrombolytically active substance that does not activate protein C. This preparation prevents reocclusion usually occurring in the course of thrombolysis therapy.Type: GrantFiled: June 17, 1992Date of Patent: June 11, 2002Assignee: Baxter AktiengesellschaftInventors: Johann Eibl, Anton Philapitsch, Hans Peter Schwarz
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Patent number: 6355243Abstract: The invention provides an improved method of thrombolytic therapy by the direct admiistration of active plasmin to a clot site via catheter. An active, stable preparation of plasmin is provided, as is a process for activation and isolation of active plasmin.Type: GrantFiled: November 13, 1999Date of Patent: March 12, 2002Assignee: Bayer CorporationInventors: Valery V. Novokhatny, Gary J. Jesmok, Kyle A. Landskroner, Kathryn K. Taylor, Thomas P. Zimmerman
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Publication number: 20010046495Abstract: The present invention relates to the cross-linked scuPA/suPAR complex and/or tcuPA/suPAR cross-linked complex, the process of preparation of the covalently bound single compound having fibrinolytic activity and use of the cross-linked scuPA/suPAR or tcuPA/suPAR complex in the prevention and/or treatment of thrombolytic disorders. The invention further relates to combination compositions and/or therapy regimens, comprising the cross-linked scuPA/suPAR complex or tcuPA/suPAR and one or more currently used plasminogen activators to achieve improved therapeutic efficacy and/or reduce side effects.Type: ApplicationFiled: July 10, 2001Publication date: November 29, 2001Inventor: Abd. Al-Roof Higazi
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Publication number: 20010046663Abstract: A method to determine whether a test compound modulates the activity of an enzyme that has a metallated active site, comprising:Type: ApplicationFiled: May 27, 1999Publication date: November 29, 2001Inventors: PAUL G. GROTHAUS PH.D, DANA E. DAVIS, SEAN O'MALLEY
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Patent number: 6284475Abstract: The present invention provides methods for diagnosing and/or monitoring thrombophilic disease in a patient that can result from the antiphospholipid antibody syndrome (aPL syndrome). The methods of the invention are premised on the inhibition of binding of an anticoagulant protein, annexin, preferably annexin-V, to phospholipids by antiphospholipid (aPL) antibodies in a patient blood sample.Type: GrantFiled: July 10, 1998Date of Patent: September 4, 2001Assignee: Mount Sinai School of Medicine of the City of New YorkInventor: Jacob H. Rand
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Publication number: 20010014356Abstract: The present invention relates to a plasminogen activator inhibitor, an external preparation for skin comprising the same, a method for improving rough skin and in particular, to improvement of an effective inorganic component.Type: ApplicationFiled: December 21, 2000Publication date: August 16, 2001Inventors: Yuzo Yoshida, Eriko Kawai
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Patent number: 6239106Abstract: The invention relates to novel protease-inhibitors which are obtainable from leeches. It also relates to uses thereof, for instance as a medicament, thus pharmaceutical preparations are provided, as are derivatives, mutants, genes encoding, vectors comprising and cells provided with such genes and/or vectors. In particular the invention relates to a family of proteinaceous protease-inhibitors having a molecular weight of about 5.5 kD and the following primary sequences: DDNCGGKVCSKGQLCHDGHCECTPIRCLIFCPNGFAVDENGCELPCSCKHQ, DDDCGGQVCSKGQLCVDGQCKCTPIRCRIYCPKGFEVDENGCELPCTCLQ and DGNCGGQVCSKGQLCVDGQCKCTPIRCRIYCPKGFEVDENGCELPCTCLQ. This invention also relates to HIV-inhibitors and other therapeutically interesting, low molecular weight, and low antigenic substances from leeches.Type: GrantFiled: March 27, 1998Date of Patent: May 29, 2001Assignee: Clodica, S.A.Inventor: Gerard Voerman
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Patent number: 6190659Abstract: The present invention describes a novel polypeptide, and methods of its use in effective thrombolytic therapy in the treatment of coronary and pulmonary thrombosis. Its use is also disclosed in vaccines to abrogate a streptococcal infection. Pharmaceutical compositions containing the novel polypeptide are included. One particular form of the novel polypeptide is streptococcal surface enolase (SEN), a specific binding protein for human plasmin and/or human plasminogen on group A streptococci that displays classical &agr;-enolase activity, i.e., it can catalyze the dehydration of D-glycerate-2-phosphate to phosphoenolpyruvate. In addition, SEN impedes the inhibition of the fibrinolytic activity of plasmin by &agr;2-antiplasmin and can bind plasminogen without preventing streptokinase from cleaving this plasmin precursor.Type: GrantFiled: September 17, 1996Date of Patent: February 20, 2001Assignee: The Rockefeller UniversityInventors: Vijaykumar Pancholi, Vincent A. Fischetti
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Patent number: 6120765Abstract: Purified uPA peptides having, mitogenic activity and containing as few as six amino acids of the EGF-like domain of uPA.Type: GrantFiled: October 25, 1993Date of Patent: September 19, 2000Assignee: Shiseido Co. Ltd.Inventors: Toshihiko Hibino, Tadahito Takahashi, Izumi Horii, Paul F. Goetinck
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Patent number: 6113897Abstract: A monoclonal or polyclonal antibody directed against urokinase plasminogen activator receptor (u-PAR), or a subsequence, analogue or glycosylation variant thereof. Antibodies are disclosed which react with free u-PAR or with complexes between u-PA and u-PAR and which are capable of 1) catching u-PAR in ELISA, or 2) detecting u-PAR, e.g. in blotting, or 3) in radioimmunoprecipitation assay precipitate purified u-PAR in intact or fragment form, or 4) is useful for immunohistochemical detection of u-PAR, e.g. in immunostaining of cancer cells, such as in tissue sections at the invasive front, or 5) inhibits the binding of pro-u-PA and active u-PA and thereby inhibits cell surface plasminogen activation. Methods are disclosed 1) for detecting or quantifying u-PAR, 2) for targeting a diagnostic to a cell containing a u-PAR on the surface, 3) for preventing or counteracting proteolytic activity in a mammal.Type: GrantFiled: December 28, 1995Date of Patent: September 5, 2000Assignee: Cancerforskiningsfonden af 1989Inventors: Keld Dan.o slashed., Ebbe R.o slashed.nne, Niels Behrendt, Vincent Ellis, Gunilla H.o slashed.yer-Hansen, Charles Pyke, Nils Bruenner
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Patent number: 6022854Abstract: A therapeutic compound comprises a KGD-containing peptide, tandem repeats thereof, combinations thereof, or combinations thereof with an RGD-containing peptide or tandem repeats thereof, or peptide analogues or non-peptide organic analogues of the RGD and KGD tripeptides, and a pharmaceutical agent. A therapeutic composition comprises the compound of this invention and a pharmaceutically acceptable carrier. A polydeoxyribonucleotide comprises a DNA sequence, and a polyribonucleotide comprises an RNA sequence, encoding the compound of the invention, where the pharmaceutical agent is a peptide. A self-replicating DNA carries the polydeoxyribonucleotide described above and a transformed host cell comprises the self-replicating DNA. Therapeutic platelets are loaded with a therapeutic compound comprising a peptide comprising RGD or KGD, peptide analogues or organic analogues thereof, tandem repeats thereof, or combinations thereof, and a pharmaceutical agent operatively linked to the peptide.Type: GrantFiled: April 17, 1995Date of Patent: February 8, 2000Assignee: The Regents of the University of CaliforniaInventor: Marc A. Shuman
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Patent number: 5976532Abstract: Platelet-specific, chimeric immunoglobulin and immunoglobulin fragments are described. The chimeric molecules are made up of a nonhuman antigen binding region and a human constant region. Preferred immunoglobulins are specific for glycoprotein IIb/IIIa receptor in its complexed form; they block ligand binding to the receptor and prevent platelet aggregation. The immunoglobulins are useful in anti-thrombotic therapy when administered alone or in conjunction with thrombolytic agents, as well as in thrombus imaging.Type: GrantFiled: May 17, 1995Date of Patent: November 2, 1999Assignee: Centocor, Inc.Inventors: Barry S. Coller, David M. Knight
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Patent number: 5935789Abstract: Autonomously replicating sequences(ARS), glyceraldehyde-3-phosphate dehydrogenase(GAPDH) gene and GAPDH promoter derived from Hansenula polymorpha DL-1(ATCC 26012); a vector for H. polymorpha which contains the novel ARS and is capable of inserting tandem repeating multiple copies of a polynucleotide encoding a foreign protein to the chromosome of H. polymorpha; a process for the production of a foreign protein in H. polymorpha by employing said vector; and a method for the selection of transformed H. polymorpha having multiple copies of integrated foreign genes.Type: GrantFiled: July 31, 1997Date of Patent: August 10, 1999Assignee: Korea Institute of Science and TechnologyInventors: Sang-Ki Rhee, Eui-Sung Choi, Chul-Ho Kim, Jung-Hoon Sohn, Hyun-Ah Kang, Hwa-Young Kim
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Patent number: 5880259Abstract: A peptide of formula (I)(H.sub.2 N--X.sub.1 --Thr--X.sub.2 --CO).sub.n --R (I)whereX.sub.1 and X.sub.2, different one another, are an amino acid residue of arginine or tyrosine in configuration L or D, wherein the hydroxy group of threonine and tyrosine and the guanidine moiety of arginine may be protected by a compound conventionally used in peptide chemistry for protecting the hydroxy group and the guanidine moiety, respectively, n is 1, 2, 3 or 4, andR, when n is 2, 3 or 4, is a group suitable for forming a dimer, trimer or tetramer, while, when n is 1, R is OH, a single amino acid residue, or a peptide chain containing up to 7 amino acid residues.Type: GrantFiled: June 20, 1996Date of Patent: March 9, 1999Assignee: Tecnogen S.C.p.A.Inventors: Giorgio Fassina, Antonio Verdoliva, Menotti Ruvo
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Patent number: 5866358Abstract: A method is provided for producing non-glycosylated single chain prourokinase (proUK). The method comprises cultivating bacterial strains of E. coli which have been transformed with plasmids carrying the cDNA sequence coding for proUK.Type: GrantFiled: July 11, 1990Date of Patent: February 2, 1999Assignee: Vascular Laboratory Inc.Inventors: Anna Brandazza, Paolo Sarmientos, Gaetano Orsini
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Patent number: 5830467Abstract: A pharmaceutical preparation contains protein C and a thrombolytically active substance that does not activate protein C. This preparation prevents reocclusion usually occurring in the course of thrombolysis therapy.Type: GrantFiled: June 1, 1995Date of Patent: November 3, 1998Assignee: Immuno AktiengesellschaftInventors: Johann Eibl, Anton Philapitsch, Hans Peter Schwarz
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Patent number: 5811252Abstract: Detection or determination of a protease in a sample by incubating the sample with a substrate of the protease and observing proteolytic cleavage of said substrate. The substrate is a modified proenzyme containing a recognition site, e.g., an activation site, cleavable by said protease. Proteolytic cleavage of the modified proenzyme is detected by observing the resulting activity using a suitable substrate of the activated proenzyme. The protease may be e.g. an aspartic protease or a metalloprotease, and the modified proenzyme e.g. pro-urokinase having a mutant activation site which is cleavable by the protease to be determined.Type: GrantFiled: July 6, 1995Date of Patent: September 22, 1998Assignee: Nederlandse Organisatie voor toegepast-natuurwetenschappelijk Onderzoek TNOInventor: Johan Hendrikus Verheijen
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Patent number: 5770425Abstract: 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: July 18, 1994Date of Patent: June 23, 1998Assignee: Genentech, Inc.Inventors: Stephen P. Anderson, Deborah L. Higgins, Adair J. Hotchkiss, Cara B. Marks
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Patent number: 5759542Abstract: A fusion drug including an isolated portion of the A-chain of a urokinase-type plasminogen activator linked to a drug, wherein the A-chain portion binds stably to an outer membrane of a platelet. The T.sub.1/2 of the fusion drug in plasma is thereby increased to about 4 to 5 days, and the fusion drug is automatically targeted to forming thrombi and sites of vascular injury. The fusion drug can thus be used to treat cardiovascular diseases, e.g., as adjunctive therapy to inhibit reocclusions in a patient after thrombolytic therapy or angioplasty.Type: GrantFiled: August 5, 1994Date of Patent: June 2, 1998Assignee: New England Deaconess Hospital CorporationInventor: Victor Gurewich
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Patent number: 5750172Abstract: This invention relates to the production of recombinant proteins, such as coagulation factors VIII and IX, tissue plasminogen activator (TPA), urokinase, growth hormone, insulin, interferons, interleukins, peptide hormones and immunoglobulins, in mammals' milk. Particularly, this invention relates to an expression system which when transgenically incorporated into a mammal permits the female species of that mammal to produce the desired recombinant protein in or along with its milk. This invention also relates to the transgenic mammal that produces the desired recombinant product in its milk.Type: GrantFiled: June 5, 1995Date of Patent: May 12, 1998Assignee: Pharming B.V.Inventors: Harry Meade, Nils Lonberg
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Patent number: 5736512Abstract: The invention relates to serine protease variants derived from precursor serine proteases via recombinant and/or chemical methods to form protease variants having improved peptide ligase activity. The invention also includes novel ligation substrates which in combination with the serine protease variants and a second ligation substrate are capable of forming a ligation product. The invention also relates to methods for forming such ligation products and the products formed thereby.Type: GrantFiled: June 7, 1995Date of Patent: April 7, 1998Assignee: Genentech, Inc.Inventors: Lars Abrahmsen, John Burnier, James A. Wells, David T. Jackson
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Patent number: 5731186Abstract: rDSPA .alpha.1 is produced in commercial quantities and a purity adequate for clinical standards. The production methods utilize a series of chromatographic steps: cation exchange chromatography, followed by hydrophobic interaction chromatography, and ending with affinity chromatography.Type: GrantFiled: February 5, 1996Date of Patent: March 24, 1998Assignee: Schering AktiengesellschaftInventors: Michael McCaman, Erno Pungor, Carol Souders, Mei P. Tan
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Patent number: 5728564Abstract: The present invention relates to serine protease mutants of the chymotrypsin superfamily that are resistant to inhibition by their cognate inhibitors, and genes that encode the same. The present invention also relates to serine protease inhibitor mutants that inhibit the serine protease mutants of the present invention, and genes that encode the same. The serine protease, mutants and serine protease inhibitor mutants are useful as, e.g., pharmacological agents.Type: GrantFiled: May 21, 1996Date of Patent: March 17, 1998Assignee: The Board of Regents of the University of Texas SystemInventors: Joseph F. Sambrook, Edwin L. Madison, Elizabeth J. Goldsmith, Maryjane H. Gething, Robert D. Gerard
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Patent number: 5688503Abstract: 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: May 15, 1995Date of Patent: November 18, 1997Inventors: Francesco Blasi, Maria Patrizia Stoppelli, Maria Rosaria Mastronicola, Karen Gjersing Welinder, Isabel Correas
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Patent number: 5653979Abstract: A multimolecular complex made up of a plasminogen activator conjugated to anti-ACE Mab 9B9 capable of delivering the plasminogen activator to the pulmonary endothelium is provided. Methods of using this complex to selectively deliver the plasminogen activator to the pulmonary endothelium to enhance fibrinolysis in the lungs of an animal are also provided. In addition, a method of prolonging the time a plasminogen activator is present in the circulation of an animal by conjugating the plasminogen activator to anti-ACE Mab 9B9 is also provided.Type: GrantFiled: March 30, 1995Date of Patent: August 5, 1997Assignee: Trustees of the University of PennsylvaniaInventors: Vladimir R. Muzykantov, Elliot S. Barnathan
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Patent number: 5648253Abstract: Mutants of human urokinase are produced which have an altered amino acid sequence in the domain responsible for binding of plasminogen activator inhibitor(s). One example of an inhibitor resistant mutant is described in detail. Six amino acids (179-184), R H R G G S, have been deleted from the mature urokinase. The gene encoding inhibitor resistant preprourokinase is chemically synthesized according to computer-designed nucleotide sequences containing convenient restriction endonuclease cleavage sites, a signal for the initiation of translation, a sequence encoding the signal peptide of mouse whey acid protein and a complete coding sequence for mature inhibitor-resistant urokinase. The gene was used to transform cultured mouse cells to produce clones that stably incorporate the gene in the genome. Clones with high levels of expression were used as the hosts for production of this protein.Type: GrantFiled: September 8, 1992Date of Patent: July 15, 1997Assignee: TSI CorporationInventor: Cha-Mer Wei
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Patent number: 5637299Abstract: This invention provides an improved method for enhancing the activity of thrombolytic agents, including t-PA, scu-PA, tcu-PA, streptokinase, acylated plasminogen-streptokinase activator complex (APSAC), mixtures of these, and other activators of plasminogen. The enhancement method comprises supplementation of plasma plasminogen levels with deglycosylated forms of glu- and lys-plasminogen. Deglycosylated plasminogen refers herein to glu- or lys-plasminogen 2 having a single oligosaccharide chain at Thr.sub.345, plasminogens having a single oligosaccharide chain at Asn.sub.288, and unglycosylated forms of plasminogen. The work described herein shows that a less glycosylated form of plasminogen (glu-plasminogen 2) has a higher affinity for fibrin clots than a more glycosylated plasminogen (glu-plasminogen 1).Type: GrantFiled: June 5, 1995Date of Patent: June 10, 1997Assignee: Beth Israel HospitalInventors: Jan McDonagh, Myoung H. Lee
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Patent number: 5637503Abstract: Plasmids containing synthetic DNA sequences are described which are suitable for the expression of the intermediate protein of the recombinant scu-PA (i.e., the unglycosylated protein moiety of the single chain prourokinase) in Enterobacteriaceae, especially in E. coli, with expression rates far higher than those obtainable according to prior methods. The plasmids comprise operons that include a regulatable, optionally synthetic, promotor, a Shine-Dalgarno sequence, a start codon, a synthetic structural gene with selected codon usage, and downstream of the structural gene, 1 to 2 transcription terminators. The preparation of the plasmids and of synthetic DNA-sequences starting from commercially available plasmids and intermediates is described. The intermediate protein, expressed in high yields by using the plasmids for transforming suitable hosts, may be refolded to produce the therapeutically useful plasminogen activator recombinant scu-PA.Type: GrantFiled: July 12, 1990Date of Patent: June 10, 1997Assignee: Gruenenthal GmbHInventors: Regina E. Brigelius-Flohe', Leopold Flohe', Wolfgang Hillen, Gerd J. Steffens, Wolfgang Strassburger, Martin R. F. Wilhelm
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Patent number: 5632986Abstract: Conjugates with an affinity for phospholipids are disclosed. The conjugates comprise a first compound having affinity for phospholipids, with a binding constant that is not greater than about 10.sup.-7 M and a second compound that lyses thrombi or is a precursor of a compound that lyses thrombi.Type: GrantFiled: May 15, 1995Date of Patent: May 27, 1997Assignee: The University of WashingtonInventors: Jonathan F. Tait, Kazuo Fujikawa
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Patent number: 5626841Abstract: A method of adjunctive therapy to inhibit reocclusions in a patient, e.g., after thrombolytic therapy or angioplasty, by administering to the patient a bolus of an amount of purified pro-urokinase ("pro-UK") that inhibits the formation of occlusive thrombi without inducing a systemic effect in the patient, the pro-UK is administered after the completion of the thrombolytic treatment and periodically thereafter for the duration of therapy, and becomes incorporated into the outer membrane of the platelets of the patient, thereby increasing the T.sub. 1/2 of the pro-UK in plasma, which is about 7 to 8 minutes, to about 4 to 5 days, and inhibiting reocclusion without inducing a systemic effect.Type: GrantFiled: June 7, 1994Date of Patent: May 6, 1997Inventor: Victor Gurewich
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Patent number: 5593876Abstract: Nitrosylation of proteins and amino acid groups enables selective regulation of protein function, and also endows the proteins and amino acids with additional smooth muscle relaxant and platelet inhibitory capabilities. Thus, the invention relates to novel compounds achieved by nitrosylation of protein thiols. Such compounds include: S-nitroso-t-PA, S-nitroso-cathepsin; S-nitroso-lipoprotein; and S-nitroso-immunoglobulin. The invention also relates to therapeutic use of S-nitroso-protein compounds for regulating protein function, cellular metabolism and effecting vasodilation, platelet inhibition, relaxation of non-vascular smooth muscle, and increasing blood oxygen transport by hemoglobin and myoglobin. The compounds are also used to deliver nitric oxide in its most bioactive form in order to achieve the effects described above, or for in vitro nitrosylation of molecules present in the body.Type: GrantFiled: August 9, 1994Date of Patent: January 14, 1997Assignee: Brigham and Women's HospitalInventors: Jonathan Stamler, Joseph Loscalzo, Daniel Simon, David Singel
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Patent number: 5589169Abstract: A method and pharmaceutical composition for the prevention of fibrin deposition or adhesion formation by topical application of a composition to a site of potential fibrin deposition or adhesion formation comprising a sparingly soluble enzyme that is continuously released at that site for a period of time of from about three days to two weeks which may include an inert adherence enhancing vehicle.Type: GrantFiled: April 13, 1990Date of Patent: December 31, 1996Assignee: Genentech, Inc.Inventors: Marjorie A. Mohler, Tue H. Nguyen
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Patent number: 5580559Abstract: 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: September 23, 1994Date of Patent: December 3, 1996Assignee: 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: 5571708Abstract: A new chimeric plasminogen activator with high fibrin affinity was designed to bind to a fibrin clot and initiate clot destruction in the presence of thrombin, but not plasmin. The chimeric molecule has an antibody variable region having a fibrin-specific antigen binding site and a single chain urokinase region having a thrombin activation site but not a plasmin activation site. The preferred embodiment, 59D8-ScuPA-T, has an N-terminal fragment of an anti-fibrin antibody (59DB) and a C-terminal thrombin-activatable low molecular weight single-chain urokinase plasminogen activator (scuPA-T). The scuPA-T portion was obtained by deletion of two amino acids (Phe157 and Lys 158) that make up the plasmin activation site from low molecular weight single chain urokinase-type plasminogen activator (scuPA).Type: GrantFiled: April 19, 1993Date of Patent: November 5, 1996Assignee: Bristol-Myers Squibb CompanyInventors: Wen-Pin Yang, Gary R. Matsueda, Shyh-Yu Shaw
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Patent number: 5514572Abstract: A method for preparing protease-polyethylene glycol adducts is presented wherein the immobilized reversible inhibitor, benzamidine, prevents reaction of activated polyethylene glycol with the active site of the protease. Improved activity against macromolecular substrates is obtained compared to when the benzamidine is in solution during the conjugation reaction.Type: GrantFiled: September 19, 1994Date of Patent: May 7, 1996Assignee: Consiglio Nazionale delle RicercheInventors: Francesco Veronese, Paolo Caliceti, Oddone Schiavon, Sartore Luciana
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Patent number: 5510330Abstract: The invention involves thromboembolically effective compositions and therapeutic methods. Thrombolytically active proteins are combined with anticoagulants, as long as the anticoagulant is not heparin. The anticoagulant is administered in an intravenous bolus form, while the thrombolytically active protein may be administered via intravenous bolus, or intravenous infusion.Type: GrantFiled: March 25, 1994Date of Patent: April 23, 1996Assignee: Boehringer Mannheim GmbHInventors: Ulrich Martin, Stephan Fischer
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Patent number: 5500411Abstract: Discussed are therapeutic approaches to the treatment of thrombolic conditions. The therapies use thrombolytically active proteins which inhibit reocclusion in the subject. The proteins are administered in two or more boli.Type: GrantFiled: June 30, 1994Date of Patent: March 19, 1996Assignee: Boehringer Mannheim GmbHInventors: Ulrich Martin, Reinhard Koenig
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Patent number: 5491082Abstract: A plasminogen activator such as urokinase or tissue plasminogen activator is covalently bonded to a porous body composed of calcium phosphate to form a plasminogen activator-porous body complex. The tricalcium phosphate can be .alpha.-tricalcium phosphate, .beta.-tricalcium phosphate, hydroxyapatite, tetracalcium phosphate, octacalcium phosphate and mixtures thereof. In a preferred embodiment, .beta.-tricalcium phosphate which has excellent biocompatibility with the body or a mixture of .beta.-tricalcium phosphate and hydroxyapatite is used. Preferably, synthetic calcium phosphate is used is to avoid impurities contained by natural calcium phosphate. Covalent bonding is by crosslinking with glutaraldehyde, bismaleimides, dihalogenic aryls or diisocyanates, or by using cyanogen bromide, diazotization or periodic acid. The complex can be filled into a column to form a bioreactor.Type: GrantFiled: May 20, 1994Date of Patent: February 13, 1996Assignees: Director-General of Agency of Industrial Science and Technology, Olympus Optical Co., Ltd.Inventors: Takahiro Suzuki, Sukezo Kawamura, Motohiro Toriyama, Yoshiyuki Yokokawa, Yukari Kawamoto, Yasuharu Hakamatsuka, Hiroyuki Irie
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Patent number: 5472692Abstract: The invention relates to thrombolytically active pro-urokinase (pro-UK) mutants comprising the amino acid sequence of native pro-UK, but including a mutation which causes the pro-UK mutants to induce less fibrinogenolysis and non-specific plasminogen activation than native pro-UK, to have at least a 10-fold lower intrinsic activity than native pro-UK, and to have substantially the same fibrin promotion and thrombolytic activity after plasmin activation compared to native pro-UK when administered to a patient.Type: GrantFiled: July 2, 1993Date of Patent: December 5, 1995Assignee: New England Deaconess Hospital CorporationInventors: Jian-Ning Liu, Victor Gurewich