Hemoglobins Or Globins Patents (Class 530/385)
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Patent number: 5917020Abstract: Crosslinking reagents for protein modification are provided, which comprise four functional, leaving groups capable of reacting with amino acid residues on the protein chains, one pair at each end of a relatively rigid chemical spacer group comprising aromatic residues joined by amide linkages. Such crosslinking reagents react with hemoglobin to effect intramolecular crosslinking of two dimeric hemoglobin units to stabilize the tetramers, by use of the respective pairs of functional groups, and to produce dimers of such tetrameric units, i.e. bis-tetrameric, intramolecularly crosslinked and stabilized hemoglobin, to the exclusion of higher molecular weight hemoglobin species.Type: GrantFiled: January 15, 1997Date of Patent: June 29, 1999Inventors: Ronald H. Kluger, Jodi J.L. Lock-O'Brien
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Patent number: 5914391Abstract: The present invention relates to hemoglobin compositions stabilized against the formation of aggregates. Such compositions contain at least a surfactant, said surfactant not being an adduct of a polymer and an anionic ligand. The present invention further relates to methods of making such hemoglobin compositions.Type: GrantFiled: November 17, 1997Date of Patent: June 22, 1999Assignee: Baxter Biotech Technology SarlInventors: Michael J. Gerber, Douglas L. Looker, Bruce A. Kerwin
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Patent number: 5906974Abstract: Low doses of stroma-free diaspirin cross-linked hemoglobin are administered to patients undergoing hemodialysis, to achieve hemostabilization and avoid hypotensive episodes in susceptible patients. Hemoglobin therapy when implemented prophylactically in hemodialysis also partially obviates the need for further interventions to control circulatory system instability.Type: GrantFiled: August 21, 1996Date of Patent: May 25, 1999Assignee: Baxter International, Inc.Inventors: John Blue, Jan W. Garber, Janet C. Gonder, Gary R. Marchand, Robert J. Przybelski, Kathleen N. Stern
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Patent number: 5907035Abstract: The present invention relates to methods of purifying proteins having surface active, electron-rich amino acids using an aqueous two phase system. The methods include the use of salts and inert hydrophobic molecules, such as polymers, to produce the aqueous two phase system and the use a polymer-chelator-metal complex to purify the target proteins.Type: GrantFiled: May 22, 1997Date of Patent: May 25, 1999Assignee: Baxter Biotech Technology SarlInventor: Martin R. Guinn
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Patent number: 5905141Abstract: A blood substitute and plasma expander comprising a cross-linked, substantially endotoxin-free hemoglobin solution and process for preparing same. The process comprises fractionating whole blood, separating out a stromal-free, sterile hemoglobin solution, chromatographically separating endotoxins from said hemoglobin solution and crosslinking the resulting endotoxin-free hemoglobin solution.Type: GrantFiled: April 8, 1997Date of Patent: May 18, 1999Assignee: Biopure CorporationInventors: Carl W. Rausch, Mario Feola
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Patent number: 5900477Abstract: A method of treating a mammal suffering from hemorrhagic shock or reducing hypotension secondary to hemorrhagic shock in a mammal suffering from hemorrhagic shock by administering intermolecularly- or intramolecularly-crosslinked stroma-free hemoglobin to the mammal.Type: GrantFiled: February 27, 1998Date of Patent: May 4, 1999Assignee: Baxter International, Inc.Inventor: Robert J. Przybelski
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Patent number: 5900402Abstract: A method of reducing side-effects associated with administering oxygen-carrying proteins to mammals is disclosed. The method includes:a) reacting an oxygen-carrying protein with a substantially non-antigenic polymer to form a oxygen-carrying protein-substantially non-antigenic polymer conjugate; andb) administering the oxygen-carrying protein-substantially non-antigenic polymer conjugate to a mammal in need of the oxygen-carrying protein. Preferred oxygen-carrying proteins include recombinantly prepared hemoglobins and preferred non-antigenic polymers include polyethylene glycol.Type: GrantFiled: May 29, 1997Date of Patent: May 4, 1999Assignee: Enzon, Inc.Inventor: Robert G. L. Shorr
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Patent number: 5900403Abstract: The invention is directed to a method for the prophylaxis or treatment of an animal for deleterious physiological effects such as systemic hypotension caused by nitric oxide production induced by a biological response modifier. Examples of such biological response modifiers include but are not limited to a cytokine and an endotoxin. The invention is also direction to a method for the treatment of septic shock.Type: GrantFiled: October 2, 1997Date of Patent: May 4, 1999Assignees: Board of Regents, The University of Texas System, Duke University, Apex Bioscience, Inc.Inventors: Robert G. Kilbourn, Joseph De Angelo, Joseph Bonaventura
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Patent number: 5895810Abstract: The present invention relates to a composition of matter comprising a stable polymerized hemoglobin solution, useful for forming blood-substitutes, and to a method for forming said stable polymerized hemoglobin solution. The stable polymerized hemoglobin solution, and derived blood-substitutes, of this invention comprise polymerized hemoglobin and a sulfhydryl compound, both in solution, wherein the sulfhydryl compound stabilizes the polymerized hemoglobin.The method of this invention comprises deoxygenating hemoglobin in a hemoglobin solution and then mixing the deoxygenated hemoglobin with a sulfhydryl compound to form an oxidation-stabilized, deoxygenated hemoglobin solution. Subsequently, the oxidation-stabilized deoxygenated hemoglobin solution is mixed with a cross-linking agent to form a polymerization reaction mixture, which is then polymerized to form a stable polymerized hemoglobin solution.Type: GrantFiled: June 7, 1995Date of Patent: April 20, 1999Assignee: Biopure CorporationInventors: William R. Light, Maria S. Gawryl, Anthony J. Laccetti
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Patent number: 5888766Abstract: The present invention relates to a method for producing human myoglobin by inserting a DNA sequence comprising a human myoglobin gene into a tryptophan promoter-containing vector, followed by making E. coli with the thus-obtained expression vector express a holo-type human myoglobin. Using this method, it is possible to directly and efficiently produce a heme-structured, holo-type human myoglobin by gene recombination technology.Type: GrantFiled: September 29, 1995Date of Patent: March 30, 1999Assignee: Oriental Yeast Co., Ltd.Inventors: Toshihiro Ishizuka, Yasunori Kihira, Toshio Tanaka, Yushi Matuo
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Patent number: 5880266Abstract: The invention relates to new protein derivatives of blood, blood-protein containing raw materials and hemoglobin, and more particularly to processed globin products, and to processes for producing these products. The processed globin products have an isoelectric point at a pH value below 5.5, an iron content of less than 1000 ppm, a ratio of His : Lys between 0.6 and 1.5, a Tyrosine content of at least 0.5% by weight, a Methionine content of at least 0.5% by weight, and a Lysine content of at least 5% by weight. The method for the production of the processed globin products according to the invention comprises treating the starting material at a pH above 12 and an the oxidizing treatment step the pH is kept below 12 while maintaining the temperature below 50.degree. C.Type: GrantFiled: March 21, 1997Date of Patent: March 9, 1999Assignee: Veos N.V.Inventor: Dirk R. De Buyser
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Patent number: 5877288Abstract: Disclosed are anti-sickling human hemoglobins for use as sickle cell anemia therapeutics.Type: GrantFiled: June 17, 1994Date of Patent: March 2, 1999Assignee: The UAB Research FoundationInventors: Tim M. Townes, Steven L. McCune
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Patent number: 5872227Abstract: Disclosed is a process which achieves effective separation of components from red blood cells by aggregating cell membranes with an addition of a pH lowering agent, whereupon the solution is made subject to a separation step where a water soluble fraction is separated from cell membranes, and whereupon the cell membranes are extracted, and where lipids may be selectively separated and recovered by lowering the temperature of the extract.Type: GrantFiled: October 6, 1995Date of Patent: February 16, 1999Assignee: Gramineer ABInventors: Karin Erlansson, Hans Jungvid, Bo Mattiasson, Goran Nilsson, Thomas Olin, Torbjorn Sund
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Patent number: 5864029Abstract: Disclosed are anti-sickling human hemoglobins for use as sickle cell anemia therapeutics.Type: GrantFiled: June 5, 1995Date of Patent: January 26, 1999Assignee: The UAB Research FoundationInventors: Tim M. Townes, Steven L. McCune
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Patent number: 5861483Abstract: The present invention provides polypeptides and compositions containing same which include a hemoglobin alpha chain wherein the C-terminal hydrophobic domain has been modified.Type: GrantFiled: April 3, 1996Date of Patent: January 19, 1999Assignee: Pro-Neuron, Inc.Inventor: Stephen D. Wolpe
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Patent number: 5861488Abstract: Gene therapy methods and compositions for high level expression of anti-sickling globin proteins in erythroid cells for treating Sickle Cell disease are described.Type: GrantFiled: September 23, 1997Date of Patent: January 19, 1999Assignee: Massachusetts Institute of TechnologyInventors: Philippe LeBoulch, Irving M. London
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Patent number: 5854041Abstract: Myoglobin is shown to have Manganese (Mn.sup.2') binding and peroxidase capacity. Mn binding and peroxidase activity is enhanced by modification of the amino acid sequence of myoglobin to provide a Mn binding site on the surface of the protein near the heme group. Peroxidase activity of myoglobin not specific to Mn is enhanced by substituting amino acids at residues 39, 45, 46, 97 and 107 of myolglobin.Type: GrantFiled: September 16, 1996Date of Patent: December 29, 1998Assignee: The University of British ColumbiaInventors: Gary D. Brayer, Hung Lee, A. Grant Mauk, Michael Smith, Harry Tong, Lianglu Wan
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Patent number: 5854209Abstract: The present invention relates to a method of therapeutically, or prophylactically, treating a vertebrate to increase tissue oxygenation, or maintain issue oxygenation, in tissue of a vertebrate wherein the tissue has a reduced red blood cell flow, and wherein the vertebrate has a normovolemic blood volume and at least a normal systemic vascular resistance. The method comprises introducing into the circulatory system of the vertebrate at least one dose of hemoglobin.Type: GrantFiled: March 23, 1995Date of Patent: December 29, 1998Assignee: Biopure CorporationInventors: Edward E. Jacobs, Jr., Carl W. Rausch
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Patent number: 5849510Abstract: The invention provides compounds which specifically inhibit factor Xa activity. The compounds consist of the structure X.sub.1 -YIR-X.sub.2, wherein X.sub.1 is H, acyl, alkyl, acylalkyl, arylalkyl or one or more amino acids, and X.sub.2 is a modified C-terminal group, one or more carboxy-protecting groups or one or more amino acids or other substituent, and Y, I and R are tyrosine, isoleucine and arginine, respectively, or peptidomimetic or organic structures that possess the same functional activity as Y, I and R, respectively. In addition, the present invention provides a compound having the structure A1-A2-(A3).sub.m --B, where m is 0 or 1. A compound of the invention can be linear or cyclic and can be about 2 and 43 residues in length. A compound of the invention is characterized, in part, in that it exhibits a specific inhibition of factor Xa activity with a K.sub.i of .ltoreq.100 .mu.M, preferably .ltoreq.Type: GrantFiled: October 8, 1997Date of Patent: December 15, 1998Assignee: Selectide CorporationInventors: Fahad Al-Obeidi, Michal Lebl, James A. Ostrem, Pavel Safar, Alena Stierandova, Peter Strop, Armin Walser
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Patent number: 5849688Abstract: Transgenic, recombinantly cross-linked polymeric human hemoglobins suitable as cell-free blood substitutes have been produced. A plurality of DNA constructs have been designed for efficient expression of modified human hemoglobins in the erythrocytes of the non-human transgenic animals. Substantially pure, non-immunogenic, artificial human hemoglobins are then easily obtained from the erythroid cells of the transgenic animals.Type: GrantFiled: March 11, 1997Date of Patent: December 15, 1998Assignee: The UAB Research FoundationInventors: Tim M. Townes, Steven L. McCune
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Patent number: 5844088Abstract: The alpha subunits of hemoglobin, which in nature are formed as separate polypeptide chains which bind noncovalently to the beta subunits, are here provided in the form of the novel molecule di-alpha globin, a single polypeptide chain defined by connecting the two alpha subunits either directly via peptide bond or indirectly by a flexible amino acid or peptide linker. Di-alpha globin may be combined in vivo or in vitro with beta globin and heme to form hemoglobin. Di-alpha globin is expressed by recombinant DNA techniques. Di-beta globin may be similarly obtained.We further describe the production of tetrameric human hemoglobin and di-alpha/beta.sub.2 hemoglobin in the yeast Saccharomyces cerevisiae. The synthesis of the protein is directed by a synthetic promotor consisting of two functional parts, an upstream activator sequence (UAS) that confers inducible transcription by galactose from a consensus yeast transcriptional initiation site.Type: GrantFiled: May 19, 1995Date of Patent: December 1, 1998Assignee: Somatogen, Inc.Inventors: Stephen J. Hoffman, Douglas L. Looker, Mary S. Rosendahl, Gary L. Stetler, Michael Wagenbach, David C. Anderson, Antony James Mathews, Kiyoshi Nagai
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Patent number: 5844089Abstract: The alpha subunits of hemoglobin, which in nature are formed as separate polypeptide chains which bind noncovalently to the beta subunits, are here provided in the form of the novel molecule di-alpha globin, a single polypeptide chain defined by connecting the two alpha subunits either directly via peptide bond or indirectly by a flexible amino acid or peptide linker. Di-alpha globin may be combined in vivo or in vitro with beta globin and heme to form hemoglobin. Di-alpha globin is expressed by recombinant DNA techniques. Di-beta globin may be similarly obtained.Type: GrantFiled: May 25, 1995Date of Patent: December 1, 1998Assignee: Somatogen, Inc.Inventors: Stephen J. Hoffman, Douglas L. Looker, Mary S. Rosendahl, Gary L. Stetler, Michael Wagenbach, David C. Anderson, Antony James Mathews, Kiyoshi Nagai
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Patent number: 5844090Abstract: The present invention relates to modified hemoglobin-like compounds. The novel compounds include a globin-like polypeptide containing at least two di-alpha domains and multimeric hemoglobin-like proteins having a core hemoglobin-like moiety directly attached to at least two other hemoglobin-like moieties. The invention also relates to nucleic acid molecules encoding the novel polypeptides. Methods of making the multimeric hemoglobin-like proteins are also provided, as well as compositions containing the proteins.Type: GrantFiled: June 7, 1995Date of Patent: December 1, 1998Assignee: Somatogen, Inc.Inventors: David C. Anderson, Antony J. Mathews, Stephen P. Trimble, Spencer Anthony-Cahill
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Patent number: 5843888Abstract: A non-naturally occurring mutant hemoglobin (.alpha.96Val.fwdarw.Trp) is provided that has a lower oxygen affinity than that of native hemoglobin, but high cooperativity in oxygen binding. The mutant hemoglobin is preferably obtained by recombinant DNA techniques. Such a mutant hemoglobin may be used as a component of a blood substitute.Type: GrantFiled: May 1, 1995Date of Patent: December 1, 1998Assignee: Carnegie Mellon UniversityInventors: Chien Ho, Hyun-Won Kim, Tong-Jian Shen
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Patent number: 5840852Abstract: The present invention relates to a method of therapeutically, or prophylactically, treating a vertebrate to increase tissue oxygenation, or maintain issue oxygenation, in tissue of a vertebrate wherein the tissue has a reduced red blood cell flow, and wherein the vertebrate has a normovolemic blood volume and at least a normal systemic vascular resistance. The method comprises introducing into the circulatory system of the vertebrate at least one dose of hemoglobin.Type: GrantFiled: June 2, 1995Date of Patent: November 24, 1998Assignee: Biopure CorporationInventors: Carl W. Rausch, Maria S. Gawryl, Robert A. Houtchens, Anthony J. Laccetti, William R. Light
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Patent number: 5840851Abstract: The present invention generally relates to methods for purifying hemoglobin solutions and to hemoglobin solutions obtained by the methods. In one aspect, such methods include removing contaminants in crude hemoglobin-containing lysates with heat treatment. In a further aspect, the present invention provides methods for producing substantially purified hemoglobin solutions using immobilized metal affinity chromatography, optionally following by anion exchange chromatography.Type: GrantFiled: May 10, 1995Date of Patent: November 24, 1998Inventors: J. Jeffrey Plomer, James R. Ryland, Maura-Ann H. Matthews, David W. Traylor, Erin E. Milne, Steven L. Durfee, Antony J. Mathews, Justinian O. Neway
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Patent number: 5827693Abstract: The invention is directed to a substantially pure mammalian globin chain or heme-binding fragment thereof. The invention is further directed to recombinant DNA vectors capable of expressing at least one globin chain or substantially homologous variant thereof in yeast. The invention also relates to methods for expressing at least one globin chain or substantially homologous variant thereof in yeast. Expressed alpha-like globin and beta-like globin chains or variants thereof may be combined with a source of heme to produce hemoglobin or a substantially homologous variant thereof. Additionally, expressed gamma-globin chains may be combined with a source of heme to produce hemoglobin or a substantially homologous variant thereof. The invention also relates to methods for expressing hemoglobin or variants thereof in yeast where the heme is produced by the yeast and ligated to globins to form hemoglobin in vivo.Type: GrantFiled: June 7, 1995Date of Patent: October 27, 1998Assignee: Apex Bioscience, Inc.Inventors: Joseph De Angelo, Nalini M. Motwani, Wajeeh Bajwa, Joseph Bonaventura
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Patent number: 5824781Abstract: Compositions and processes to alleviate free radical toxicity are disclosed based on the use of nitroxides in association with physiologically compatible macromolecules. In particular, hemoglobin-based red cell substitutes are described featuring stable nitroxide free radicals for use in cell-free hemoglobin solutions, encapsulated hemoglobin solutions, stabilized hemoglobin solutions, polymerized hemoglobin solutions, conjugated hemoglobin solutions, nitroxide-labelled albumin, and nitroxide-labelled immunoglobulin. Formulations are described herein that interact with free radicals, acting as antioxidant enzyme-mimics, which preserve nitroxides in their active form in vivo. Applications are described including blood substitutes, radioprotective agents, imaging agents, agents to protect against ischemia and reperfusion injury, and in vivo enzyme mimics among others.Type: GrantFiled: June 7, 1995Date of Patent: October 20, 1998Inventor: Jen-Chang Hsia
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Patent number: 5814601Abstract: Compositions, and methods of use thereof, for use as blood substitute products comprise aqueous mixtures of oxygen-carrying and non-oxygen carrying plasma expanders and methods for the use thereof. The oxygen-carrying component may consist of any hemoglobin-based oxygen carrier, while the non-oxygen carrying plasma expander my consist of an oncotic colloid-like starch.Type: GrantFiled: February 28, 1997Date of Patent: September 29, 1998Assignee: The Regents of the University of CaliforniaInventors: Robert M. Winslow, Marcos Intaglietta
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Patent number: 5811521Abstract: Multifunctional chemical reagents useful in cross-linking hemoglobin and having the capability of leaving two or more reaction sites available for further chemical reactions, after completion of the cross-linking process. These reagents are broadly defied as aromatic compounds comprising an aromatic nucleus including but not limited phenyl, biphenyl, naphthyl and binaphthyl, with at least four independently selected electronegative substituent groups bonded directly or indirectly to the aromatic nucleus.Type: GrantFiled: April 11, 1997Date of Patent: September 22, 1998Inventors: Ronald H. Kluger, Krisztina Paal
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Patent number: 5811264Abstract: Mutated protein having a sequence with a non-proline amino acid replacement for a proline at amino acid position 4. The mutated protein is not methylated on its N-terminus when expressed in bacteria. The mutated protein is a mutation of a methylated protein that is at least partially methylated on its N-terminus when expressed in bacteria.Type: GrantFiled: February 29, 1996Date of Patent: September 22, 1998Assignee: Somatogen, Inc.Inventors: Jacqueline F. Aitken, Izydor Z. Apostol, Julie A. Lippincott, Joseph D. Levine
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Patent number: 5808011Abstract: A method for removing a prion from a solution comprising the prion and at least one additional biomolecule, comprising directing the solution through an anion-exchange chromatography column under conditions that cause a gradient elution, whereby the prion is separated from at least one of the biomolecules, thereby causing said biomolecule to be collected in an eluate fraction that is distinct from an eluate fraction that includes the prion. In one embodiment, the gradient is a pH gradient, for example, a step gradient. The prion can be a causal agent for a spongiform encephalopathy, such as Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinken syndrome, scrapie, or bovine spongiform encephalopathy.Type: GrantFiled: July 1, 1996Date of Patent: September 15, 1998Assignee: Biopure CorporationInventors: Maria S. Gawryl, Robert A. Houtchens, William R. Light
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Patent number: 5804551Abstract: A method for improving recovery after surgery or an invasive procedure is provided, including administering a hemoglobin preparation to a patient before surgery or an invasive procedure.Type: GrantFiled: November 12, 1996Date of Patent: September 8, 1998Assignee: Baxter International Inc.Inventor: Kenneth E. Burhop
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Patent number: 5801019Abstract: The alpha subunits of hemoglobin, which in nature are formed as separate polypeptide chains which bind noncovalently to the beta subunits, are here provided in the form of the novel molecule di-alpha globin, a single polypeptide chain defined by connecting the two alpha subunits either directly via peptide bond or indirectly by a flexible amino acid or peptide linker. Di-alpha globin may be combined in vivo or in vitro with beta globin and heme to form hemoglobin. Di-alpha globin is expressed by recombinant DNA techniques. Di-beta globin may be similarly obtained.Type: GrantFiled: May 19, 1995Date of Patent: September 1, 1998Assignee: Somatogen, Inc.Inventors: David C. Anderson, Antony James Mathews
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Patent number: 5798227Abstract: The alpha subunits of hemoglobin, which in nature are formed as separate polypeptide chains which bind noncovalently to the beta subunits, are here provided in the form of the novel molecule di-alpha globin, a single polypeptide chain defined by connecting the two alpha subunits either directly via peptide bond or indirectly by a flexible amino acid or peptide linker. Di-alpha globin may be combined in vivo or in vitro with beta globin and heme to form hemoglobin. Di-alpha globin is expressed by recombinant DNA techniques. Di-beta globin may be similarly obtained.We further describe the production of tetrameric human hemoglobin and di-alpha/beta.sub.2 hemoglobin in the yeast Saccharomyces cerevisiae. The synthesis of the protein is directed by a synthetic promotor consisting of two functional parts, an upstream activator sequence (UAS) that confers inducible transcription by galactose from a consensus yeast transcriptional initiation site.Type: GrantFiled: May 19, 1995Date of Patent: August 25, 1998Assignee: Somatogen, Inc.Inventors: Stephen J. Hoffman, Douglas L. Looker, Gary L. Stetler, Michael Wagenbach
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Patent number: 5789376Abstract: Compositions and processes to alleviate oxygen toxicity are disclosed based on the addition of nitroxides to physiologically compatible macromolecules. In particular, hemoglobin-based red cell substitutes are described featuring stable nitroxide free radicals for use in cell-free hemoglobin solutions, encapsulated hemoglobin solutions, stabilized hemoglobin solutions, polymerized hemoglobin solutions, conjugated hemoglobin solutions, nitroxide-labelled albumin, and nitroxide-labelled immunoglobulin. The formulations described herein interact with free radicals, act as antioxidant enzyme-mimics, and alleviate oxidative stress and oxygen-related toxicity.Type: GrantFiled: January 6, 1997Date of Patent: August 4, 1998Inventor: Jen-Chang Hsia
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Patent number: 5780593Abstract: A method of isolating a biomolecule from a medium containing biomolecules by ion exchange wherein the ion exchange material consists of a material having ion exchanging groups which can be transformed from a charged form to an uncharged form; the eluant comprises a charge neutralizing acid or base transforming the ion exchanging groups from the charged form to the uncharged form; and the charge neutralizing acid or base has a concentration in the eluant which is twice, preferably equal to or less than the concentration of the ion exchanging groups of the ion exchange material; the ion exchange material being in a packed, hydrated state. Preferably the method is for the isolation of phosphopeptides from a medium containing casein hydrolysates and the use of such isolated biomolecules is for the production of a food, a feed, a health care product, a cosmetic, or a pharmaceutical.Type: GrantFiled: July 12, 1995Date of Patent: July 14, 1998Assignees: Kem-En-Tec A/S, Md Foods AMBAInventors: Allan Otto Fog Lihme, Margit Irene Aagesen, Claus Gammelg.ang.rd-Larsen, Katrine Hvid Elleg.ang.rd
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Patent number: 5776890Abstract: Cysteine substitution mutants of alpha and/or beta globin mutants are produced by recombinant DNA techniques and used in the construction, intracellularly or otherwise, of mutant hemoglobins in which alpha- and beta-globin like subunits are crosslinked by disulfide bonds. Solutions of these mutant hemoglobins are used as blood substitutes. Preferably, these mutant hemoglobins contain further mutations which reduce their affinity for oxygen. Hemoglobins are preferably obtained by recombinant DNA techniques. Both alpha and beta globin chains can now be readily expressed, making possible the commercial production of wholly artificial hemoglobin, whether conventional or mutant in form. Solutions of wholly artificial hemoglobins are also used as blood substitutes. Expression of the alpha globin gene was substantially improved by means of a beta globin gene "header".Type: GrantFiled: May 30, 1995Date of Patent: July 7, 1998Assignee: Somatogen, Inc.Inventors: Stephen J. Hoffman, Kiyoshi Nagai
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Patent number: 5776898Abstract: A method is disclosed treating a tumor in a host by administering a nonemulsified ultrapurified polymerized hemoglobin solution to the host and also administering a chemotherapeutic agent to the host. In a particularly preferred embodiment, the hemoglobin is bovine hemoglobin.Type: GrantFiled: June 7, 1995Date of Patent: July 7, 1998Assignees: Dana-Farber Cancer Institute, Biopure CorporationInventors: Beverly A. Teicher, Carl W. Rausch, Robert E. Hopkins, II
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Human serum albumin-porphyrin complexes with the ability to bind oxygen and therapeutic uses thereof
Patent number: 5773417Abstract: The invention is directed to human serum albumin-porphyrin (HSA-P) complexes which are capable of reversible oxygen binding and their uses. These complexes may be used in applications requiring physiological oxygen carriers such as in blood substitute solutions, or in applications requiring plasma expanders. Methods for the production of these complexes are provided. In a specific example, HSA-P complexes are shown to exhibit reversible oxygen binding. In another example, the HSA-P complex does not exhibit appreciable vasoactivity.Type: GrantFiled: August 6, 1997Date of Patent: June 30, 1998Assignee: Duke UniversityInventor: Joseph Bonaventura -
Patent number: 5770404Abstract: Hemin-like porphyrins can be prepared from chlorophylls which may be used as intermediates to form functionally active hemoproteins. The porphyrins can be reacted with apoproteins in vitro or added to a cell culture and combined intracellularly with apoproteins to form functionally active hemoproteins.Type: GrantFiled: June 6, 1996Date of Patent: June 23, 1998Inventor: Gerald W. Camiener
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Patent number: 5770560Abstract: The invention relates to the use of fish hemoglobins that exhibit a Root effect to increase tissue oxygenation in patients suffering from disease states associated with compromised oxygen delivery to tissues.Type: GrantFiled: June 2, 1995Date of Patent: June 23, 1998Assignee: James J. FischerInventors: James J. Fischer, Susan J. Baserga
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Patent number: 5770727Abstract: A chemically modified, crosslinked hemoglobin product suitable for use as a hemoglobin based oxygen carrier comprises a mixture of hemoglobin species and consists essentially of about 40% tetrameric hemoglobin units of molecular weight about 64,000 daltons, up to 5% dimeric hemoglobin units of molecular weight about 32,000 daltons, and the balance oligomeric hemoglobin units of molecular weight up to about 60,000 daltons, the mixed product containing no polymeric hemoglobin species of molecular weight greater than 600,000 daltons. The product can be made directly by a crosslinking reaction under controlled conditions, without the need for separating therefrom high molecular weight species.Type: GrantFiled: June 28, 1996Date of Patent: June 23, 1998Assignee: Hemosol Inc.Inventors: Diana Pliura, Lawrence T. Wong, Song Swee Er
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Patent number: 5759517Abstract: A tracer, such as a radioisotope, is conjugated to a hemoglobin-like protein, such as normal hemoglobin, for use as an in vitro diagnostic imaging agent.Type: GrantFiled: June 1, 1995Date of Patent: June 2, 1998Assignee: Somatogen, Inc.Inventors: David C. Anderson, Antony James Mathews
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Patent number: 5753465Abstract: Methods for obtaining unmodified recombinant human normal adult hemoglobin involve a novel expression plasmid that coexpresses human .alpha.- and .beta.-globin genes and E. coli methionine aminopeptidase genes under the control of separate tac promoters. Methods are also provided for correcting an abnormal conformation of some of the heme groups incorporated in the proteins expressed by the expression plasmid.Type: GrantFiled: August 30, 1994Date of Patent: May 19, 1998Assignee: Carnegie Mellon UniversityInventors: Chien Ho, Tong-Jian Shen
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Patent number: 5753616Abstract: A method for producing a stable polymerized hemoglobin blood-substitute from blood. The method of this invention includes mixing blood with an anticoagulant to form a blood solution, washing the red blood cells in the blood solution and then separating the washed red blood cells from the white blood cells. This method also includes disrupting the red blood cells to release hemoglobin and form a hemoglobin solution, which is then treated by high performance liquid chromatography to form a hemoglobin eluate. The hemoglobin eluate is then deoxygenated, contacted with a first sulfhydryl compound to form an oxidation-stabilized deoxygenated hemoglobin solution, and mixed with a cross-linking agent to form a polymerization reaction mixture, which is then polymerized.Type: GrantFiled: June 7, 1995Date of Patent: May 19, 1998Assignee: Biopure CorporationInventors: Carl W. Rausch, Maria S. Gawryl, Robert A. Houtchens, Anthony J. Laccetti, William R. Light
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Patent number: 5747649Abstract: An acellular red blood cell substitute which comprises an essentially tetramer-free, substantially stroma-free, cross-linked, polymerized, pyridoxylated hemoglobin and a nontoxic, pharmaceutically acceptable carrier, its use and a process for preparing said acellular red blood cell substitute.Type: GrantFiled: June 7, 1995Date of Patent: May 5, 1998Assignee: Norhtfield Laboratories, Inc.Inventors: Lakshman R. Sehgal, Richard E. De Woskin, Gerald S. Moss, Steven A. Gould, Arthur L. Rosen, Hansa Sehgal
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Patent number: 5744329Abstract: The alpha subunits of hemoglobin, which in nature are formed as separate polypeptide chains which bind noncovalently to the beta subunits, are here provided in the form of the novel molecule di-alpha globin, a single polypeptide chain defined by connecting the two alpha subunits either directly via peptide bond or indirectly by a flexible amino acid or peptide linker. Di-alpha globin may be combined in vivo or in vitro with beta globin and heme to form hemoglobin. Di-alpha globin is expressed by recombinant DNA techniques. Di-beta globin may be similarly obtained.Type: GrantFiled: May 19, 1995Date of Patent: April 28, 1998Assignee: Somatogen, Inc.Inventors: Stephen J. Hoffman, Douglas L. Looker, Mary S. Rosendahl, Gary L. Stetler, Michael Wagenbach, David C. Anderson, Antony James Mathews, Kiyoshi Nagai
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Patent number: 5741893Abstract: Compositions and processes to alleviate free radical toxicity are disclosed based on the use of nitroxides in association with physiologically compatible macromolecules. In particular, hemoglobin-based red cell substitutes are described featuring stable nitroxide free radicals for use in cell-free hemoglobin solutions, encapsulated hemoglobin solutions, stabilized hemoglobin solutions, polymerized hemoglobin solutions, conjugated hemoglobin solutions, nitroxide-labelled albumin, and nitroxide-labelled immunoglobulin. Formulations are described herein that interact with free radicals, acting as antioxidant enzymemimics, which preserve nitroxides in their active form in vivo. Applications are described including blood substitutes, radioprotective agents, imaging agents, agents to protect against ischemia and reperfusion injury, and in vivo enzyme mimics among others.Type: GrantFiled: June 7, 1995Date of Patent: April 21, 1998Inventor: Jen-Chang Hsia
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Patent number: 5741894Abstract: During the purification of pharmaceutical grade crosslinked hemoglobin mixtures of crosslinked and uncrosslinked hemoglobin are heated in the presence of nonstoichiometric amounts of oxygen, resulting in the selective precipitation of the uncrosslinked hemoglobin. After separation of the precipitated uncrosslinked tetramers, the crosslinked hemoglobin remaining in the supernatant is so purified that a further chromatography purification step is unnecessary. This hemoglobin is highly crosslinked absolutely free of chromatography fines, and has a low methemoglobin content.Type: GrantFiled: September 22, 1995Date of Patent: April 21, 1998Assignee: Baxter International, Inc.Inventors: Mahmood Rezazadeh Azari, August A. Ebeling, John E. Picken, Timothy N. Estep