US4698387A
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Allosteric conjugates of hemoglobin and use as blood substitutes
Assignee: Intermedicat GmbH
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Filing: 1984-10-26
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Granted: 1987-10-06
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Expires: 2004-10-26
Abstract
Abstract The invention relates to an allosterically active conjugate composition comprising one or more hemoglobin tetramers and one or more adducts of a physiologically safe macromolecular agent covalently linked to one or more ligands, such that the adduct is bound to the allosteric binding site of the hemoglobin in a reversible, non-covalent manner; the invention also relates to methods for producing such conjugate compositions; and to blood substitutes or plasma extenders containing such conjugates.
Inventors
- 👤 Karl-Heinz Schmidt
- 👤 Wolfgang Feller
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 14:55
CPC Classifications
C; C07; C07K; C07K17/00; C07K17/02; A; A61; A61K; A61K47/00; A61K47/50; A61K47/51; A61K47/56; A61K47/59; A61K47/60; A61K47/61; A61P; A61P7/00; A61P7/08; C07K14/00; C07K14/795; C07K14/805; A61K38/00; Y; Y10; Y10S; Y10S530/00; Y10S530/81; Y10S530/812; Y10S530/813; Y10S530/815; Y10S530/816
Claims Analysis
Total Claims: 28
Claim 1
Independent Claim
76 words
An allosterically active conjugate composition of hemoglobin which comprises at least one tetramer of hemoglobin and at least one adduct of a physiologically acceptable polymeric agent non-toxic to biological systems covalently linked to at least one ligand such that the adduct is bound to the allosteric binding site of the hemoglobin in a reversible, non-covalent manner and the ligand does not contain any reactive functional group that would be capable of reacting covalently with the hemoglobin.
Claim 2
Dependent Claim
76 words
An allosterically active conjugate composition of hemoglobin which comprises at least one tetramer of hemoglobin and at least one adduct of a physiologically acceptable polymeric agent non-toxic to biological systems covalently linked to at least one ligand such that the adduct is bound to the allosteric binding site of the hemoglobin in a reversible, non-covalent manner and the ligand does not contain any reactive functional group that would be capable of reacting covalently with the hemoglobin.
Claim 3
Dependent Claim
29 words
The composition according to claim 1, wherein the polymeric agent is a water-soluble polymer, the hemoglobin is hemoglobin A substantially free of endogenous ligands, and the ligand is anionic.
Claim 4
Dependent Claim
23 words
The composition according to claim 1, wherein the molecular weight of the polymeric agent is from about 400 D to about 500,000 D.
Claim 5
Dependent Claim
27 words
The composition according to claim 1, wherein the polymeric agent is a water soluble polymer with a molecular weight from about 400 D to about 50,000 D.
Claim 6
Dependent Claim
60 words
The composition according to claim 1, wherein the physiologically acceptable polymeric agent is selected from the group consisting of polyvinylpyrolidone, dextran, a polyvinyl alcohol, a soluble starch, a hydroxyalkyl starch, a polypropylene glycol, a mucopolysaccharide, polyethylene glycol or a copolymer thereof, a liposome, a protein , surfactant, a polymethylacrylate, an emulsion of oil in water, and derivatives of said compounds.
Claim 7
Dependent Claim
52 words
The composition according to claim 1, wherein the ligand is selected from the group consisting of an inositol phosphate, an inositol sulfate, a nucleotide phosphate, a pyridoxal phosphate, a pyridoxal sulfate, a sulfated mucopolysaccharide, a beta-naphthol phosphate, salicylic acid, p-hydroxybenzoic acid, an aromatic aldehyde, a benzenesulfonic acid, and derivatives of said compounds.
Claim 8
Dependent Claim
31 words
The composition according to claim 1, wherein the polymeric agent is selected from the group consisting of 3-bromo-2-hydroxypropyl dextran, alpha, omega-disubstituted derivatives of polyethlene glycol, and diglycidyl ether of polyethylene glycol.
Claim 9
Dependent Claim
26 words
The composition according to claim 1, wherein the ligand is selected from the group consisting of sodium inositol hexaphosphate, adenosin triphosphate, fructose-1, 6-diphosphate, and 4-isothio-cyanate-benzenesulfonic acid.
Claim 10
Dependent Claim
25 words
The composition according to claim 1, wherein the ligand and polymeric agent molecule are separated by a spacer molecule to which both are covalently bonded.
Claim 11
Dependent Claim
38 words
The composition according to claim 9, wherein the spacer molecule is selected from the group consisting of dialdehydes and dicarboxylic acids and their derivatives, whose functional groups are connected with one to four carbon atoms by alkylene bridges.
Claim 12
Dependent Claim
22 words
The composition according to claim 1, wherein the hemoglobin is cross-linked intramolecularly or intermolecularly by means of at least one cross-linking agents.
Claim 13
Dependent Claim
19 words
The composition according to claim 1, further comprising a physiologically acceptable carrier in combination with the hemoglobin and adduct.
Claim 14
Independent Claim
91 words
A method for the production of conjugate compositions of hemoglobin and adduct which comprises the steps of: (a) covalently linking by known methods a ligand to a polymeric agent non-toxic to biological systems thereby forming an adduct such that the ligand does not contain any reactive functional group reactive with hemoglobin; (b) purifying the adduct; and (c) mixing the adduct with purified human hemoglobin A isolated and separated from endogenous ligands in aqueous solution at room temperature and permitting the adduct and hemoglobin A to form a non-covalent bond between them.
Claim 15
Independent Claim
91 words
A method for the production of conjugate compositions of hemoglobin and adduct which comprises the steps of: (a) covalently linking by known methods a ligand to a polymeric agent non-toxic to biological systems thereby forming an adduct such that the ligand does not contain any reactive functional group reactive with hemoglobin; (b) purifying the adduct; and (c) mixing the adduct with purified human hemoglobin A isolated and separated from endogenous ligands in aqueous solution at room temperature and permitting the adduct and hemoglobin A to form a non-covalent bond between them.
Claim 16
Dependent Claim
51 words
The method according to claim 13, wherein the polymeric agent is selected from the group consisting of polyvinyl pyrrolidone, dextran, polyvinyl alcohol, soluble starch, hydroxyalkyl starch, mucopolysaccharide, polyethylene glycol or a copolymer thereof, protein, surfactant, polymethacrylate, polymethyl acrylate, a liposome, an emulsion of oil in water and derivatives of said compounds.
Claim 17
Dependent Claim
42 words
The method according to claim 13, wherein the ligand is selected from the group consisting of sugar phophate, inositol phosphate, inositol sulfate, nucleotide phosphate, pyridoxal phosphate, pyridoxal sulfate, a salicylicacid, a phydroxybenzoic acid, aromatic aldehyde, benzenesulfonic acid, and derivatives of said compounds.
Claim 18
Dependent Claim
11 words
The method according to claim 13, wherein the hemoglobin is deoxygenated.
Claim 19
Dependent Claim
21 words
The method according to claim 13, wherein the step of purifying the adduct is achieved by means of diafiltering the adduct.
Claim 20
Dependent Claim
12 words
The method according to claim 13, wherein the aqueous solutions are buffered.
Claim 21
Dependent Claim
17 words
The method according to claim 13, wherein the pH value ranges from about 5.0 to about 8.0.
Claim 22
Dependent Claim
12 words
The method according to claim 13, wherein the pH value is acidic.
Claim 23
Dependent Claim
22 words
The method according to claim 13, wherein the hemoglobin is cross-linked intramolecularly or intermolecularly by means of at least one cross-linking agents.
Claim 24
Dependent Claim
21 words
The method according to claim 13, wherein the macromolecular agent has a molecular weight from about 400 D to 500,000 D.
Claim 25
Dependent Claim
23 words
The method according to claim 13, wherein a spacer molecule is additionally used in the reaction of covalently linking macromolecular agent and ligand.
Claim 26
Dependent Claim
56 words
The method according to claim 13, wherein the hemoglobin is hemoglobin A, the polymeric agent is selected from the group consisting of 3-bromo-2-hydroxypropyl dextran, alpha, omega-disubstituted derivatives of polyethylene glycol and diglycidyl ether of polyethylene glycol and the ligand is selected from the group consisting of sodium inositol hexaphosphate, adenosin triphospshate, fructose-1, 6-diphosphate and 4-isothio-cyanatebenzenesulfonic acid.
Claim 27
Dependent Claim
22 words
The composition according to claim 1, wherein the polymeric agent is selected from the group consisting of a polysaccharide and a polyol.
Claim 28
Dependent Claim
22 words
The composition according to claim 13, wherein the polymeric agent is selected from the group consisting of a polysaccharide and a polyol.
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