EP1480682A1 - Kopplung von proteinen an ein modifiziertes polysaccharid - Google Patents
Kopplung von proteinen an ein modifiziertes polysaccharidInfo
- Publication number
- EP1480682A1 EP1480682A1 EP03743359A EP03743359A EP1480682A1 EP 1480682 A1 EP1480682 A1 EP 1480682A1 EP 03743359 A EP03743359 A EP 03743359A EP 03743359 A EP03743359 A EP 03743359A EP 1480682 A1 EP1480682 A1 EP 1480682A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- protein
- hydroxyalkyl starch
- group
- reaction
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B31/00—Preparation of derivatives of starch
- C08B31/18—Oxidised starch
- C08B31/185—Derivatives of oxidised starch, e.g. crosslinked oxidised starch
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2/00—Peptides of undefined number of amino acids; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B31/00—Preparation of derivatives of starch
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B31/00—Preparation of derivatives of starch
- C08B31/18—Oxidised starch
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08H—DERIVATIVES OF NATURAL MACROMOLECULAR COMPOUNDS
- C08H1/00—Macromolecular products derived from proteins
Definitions
- Solubility problems also occur very frequently in the expression of glycoproteins in prokaryotic systems such as E. coli, since these are then expressed without natural glycosylation, which in some cases results in a considerably reduced solubility. This may require the use of much more expensive eukaryotic expression systems.
- proteins When used therapeutically in the body, many proteins are quickly removed from the bloodstream or broken down.
- Systemically applied proteins with a molecular weight of more than about 70 kD can be withdrawn from the circulation by the reticuloendothelial system or specific interactions with cellular receptors.
- Smaller proteins with a molecular weight of less than about 70 kD can also be removed to a large extent by glomerular filtration in the kidney (cut-off limit about 70 kD).
- a recent approach to remedying the problems described has been to couple such problematic proteins with readily water-soluble biocompatible polymers, such as, for example, polyethylene glycol and dextran.
- the coupling allows the molecular weight to be increased beyond the threshold of 70 kD, so that the plasma residence time of smaller proteins is drastic can be increased, on the other hand, the solubility in the aqueous environment can be improved by the hydrophilic polymer content.
- Dextran couplings have only been described for a few proteins, e.g. Streptokinase, plasmin, hemoglobin or aprotinin.
- dextran conjugates often show high allergenicity, presumably caused by degradation products of dextran, low metabolic stability and in many cases low yields in the coupling reactions. As a result, none of these dextran coupling products has been approved for therapeutic use in humans or animals.
- Phase III contains PEG hemoglobin and a PEG adduct of superoxide dismutase (SOD), which is the best-studied protein in terms of polymer coupling.
- SOD superoxide dismutase
- WO 99/49897 describes conjugates of hemoglobin which are formed by reacting the aldehyde groups of oxidatively ring-opened polysaccharides such as hydroxyethyl starch or dextran with primary amine groups of the protein.
- the polysaccharides used act as polyfunctional reagents, which result in a very heterogeneous product mixture with properties that are difficult to adjust.
- the object of the invention is therefore to provide such alternatives and to develop simple and efficient methods for producing such alternative protein derivatives.
- hydroxyalkyl starch-protein conjugates which are characterized in that the binding interaction between the hydroxyalkyl starch molecule and the protein is based on a covalent bond, which is the result of a coupling reaction between the terminal aldehyde group or a functional group of the hydroxyalkyl starch molecule resulting from this aldehyde group by chemical reaction and a functional group of the hydroxyalkyl starch molecule reactive with this aldehyde group or resulting therefrom Is protein, and the bond resulting directly from the coupling reaction can optionally be modified by a further reaction to form the above-mentioned covalent bond.
- the invention further encompasses pharmaceutical compositions containing these conjugates, the use of these conjugates and compositions for the prophylactic or therapeutic treatment of the human or animal body, and methods for producing these conjugates and compositions.
- the aqueous reaction medium for the coupling reaction is preferably water or a mixture of water and an organic solvent, the water content in the mixture being at least about 70% by weight, preferably at least about 80% by weight, more preferably at least about 90% by weight. -%.
- the molar ratio of hydroxyalkyl starch (HAS) to protein in the coupling reaction is usually about 20: 1 to 1: 1, preferably about 5: 1 to 1: 1.
- the residual biological activity of the hydroxyalkyl starch-protein conjugates according to the invention is generally at least 40%, preferably at least 50%, more preferably at least 70%, more preferably at least 90%, most preferably at least 95%.
- the hydroxyalkyl starch (HAS) used according to the invention can be prepared using a known method, for example hydroxyalkylation of starch at the C 2 - and / or C 6 ⁇ position of the anhydroglucose units with alkylene oxide or 2-chloroalkanol, for example 2-chloroethanol (see, for example, US 5,218,108 for Hydroxyethylation of starch), with various desired molecular weight ranges and degrees of substitution.
- alkyl grouping in "hydroxyalkyl starch” as used here includes methyl, ethyl, isopropyl and n-propyl, with ethyl being particularly preferred.
- HES major advantage of the HES is that it is already officially approved as a biocompatible plasma expander and in clinically.
- the average molecular weight of the hydroxyalkyl starch can range from about 3 kD to several million Daltons, preferably from about 4 kD to about 1000 kD, more preferably from about 4 kD to about 50 kD, or from about 70 kD to about 1000 kD preferably about 130 kD.
- the average molecular weight of the hydroxyalkyl starch is preferably chosen so that the above-mentioned threshold of 70 kD for the conjugates is exceeded, while for the coupling to large proteins the molecular weight of the hydroxyalkyl starch will preferably be in the lower range of the spectrum mentioned , Since coupling at several sites of a protein is possible, it may also be advantageous to couple several small polymer chains instead of one high molecular one.
- the degree of substitution (ratio of the number of modified anhydroglucose units to the number of total anhydroglucose units) can also vary and will often range from about 0.2 to 0.8, preferably about 0.3 to 0.7, more preferably about 0.5 , (Note: The numbers refer to the "Degree of Substitution", which is between 0 and 1).
- the ratio of C 2 to C 6 substitution is usually in the range from 4 to 16, preferably in the range from 8 to 12.
- HES hydroxyethyl starch
- Hydroxyethyl starch preparations with an average molecular weight of 130 kD and a degree of substitution of 0.5 or with an average molecular weight of 200 kD and a degree of substitution of 0.25 have already been used clinically as blood substitutes and are also suitable for use in the present invention .
- any protein which has the required functional group e.g. has a free amino group, thiol group or carboxyl group for reaction with the functional group of the HAS molecule.
- the protein can also be reacted with a suitable, physiologically compatible, bifunctional linker molecule.
- the remaining reactive functional group of the coupled linker molecule is then also regarded as “reactive functional group of the protein” for the purposes of the present invention.
- Suitable linker molecules contain at one end a group which can form a covalent bond with a reactive functional group of the protein, for example an amino, thiol or carboxyl group, and at the other end a group which is through with the terminal aldehyde group or one of them chemical reaction resulting functional group, for example a carboxyl group, activated carboxyl group, amino or thiol group, can enter into a covalent bond.
- a reactive functional group of the protein for example an amino, thiol or carboxyl group
- a group which is through with the terminal aldehyde group or one of them chemical reaction resulting functional group for example a carboxyl group, activated carboxyl group, amino or thiol group
- a suitable biologically compatible bridge molecule Length for example a group derived from an alkane, an (oligo) alkylene glycol group or another suitable oligomer group.
- Preferred groups which can react with amino groups are, for example, N-hydroxysuccinimide esters, sulfo-N-hydroxysuccinimide esters, imido esters and other activated carboxyl groups; preferred groups that can react with thiol groups are, for example, maleimide and carboxyl groups; preferred groups which can react with aldehyde or carboxyl groups are, for example, amino or thiol groups.
- linker molecules for linking SH and NH functions are:
- AMAS N- ⁇ (maleimidoacetoxy) succinimide ester
- BMPS N-ß (Maleimidopropyloxy) succinimide ester
- linker molecules for linking SH and SH functions are:
- BM (PEO) 4 (1.11-bis-maleimidotetraethylene glycol).
- linker molecules for linking NH and NH functions are: BSOCOES (bis (2- (succinimidyloxycarbonyloxy) ethyl) sulfone BS 3 (bis (sulfosuccinimidyl) suberate)
- EGS ethylene glycol bis (succinimidyl succinate)
- linker molecules for linking SH and CHO functions are:
- BMPH N- (ß-maleimidopropionic acid) hydrazide TFA
- PDPH (3- (2-pyridyldithio) propionylhydrazide).
- An exemplary linker molecule for linking SH and OH functions is PMPI (N- (p-maleimidophenyl) isocyanate).
- BMPA N-ß-maleimidopropionic acid
- linker molecules for converting an NH function into a COOH function are MSA (methyl-N-succinimidyl adipate) or longer-chain homologs thereof or corresponding derivatives of ethylene glycol.
- linker molecules for converting a COOH function into an NH function are DAB (1,4-diaminobutane) or longer-chain homologs thereof or corresponding derivatives of ethylene glycol.
- TFCS N- ⁇ (trifluoroacetylcaproyloxy) succinimide ester
- linker molecules are known to those skilled in the art and are commercially available or can be designed as required and depending on the available and desired functional groups of the HAS and the protein to be coupled and can be prepared by known processes.
- protein for the purposes of the present invention is intended to include any amino acid sequence which comprises at least 9-12 amino acids, preferably at least 15 amino acids, more preferably at least 25 amino acids, particularly preferably at least 50 amino acids, and also natural derivatives, for example pre- or pro Forms, glycoproteins, phosphoproteins, or synthetic modified derivatives, eg fusion proteins, neoglycoproteins, or proteins modified by genetic engineering processes, eg fusion proteins, proteins with amino acid exchanges for introducing preferred coupling sites.
- the protein in question will perform a certain desired function in the body.
- the protein therefore preferably has e.g. a regulatory or catalytic function, a signaling or transport function or a function in the immune response or triggering an immune response.
- the protein can, for example, be selected from the group consisting of enzymes, antibodies, antigens, transport proteins, bioadhesion proteins, hormones, growth factors, cytokines, receptors, suppressors, activators, inhibitors or a functional derivative or fragment thereof.
- “Functional derivative or fragment” in this context means a derivative or fragment that wholly or partly, for example, at least 10-30%, more preferably more than 50%, even more preferably more than 70%, of a desired biological property or activity of the parent molecule. , most preferably more than 90% ",
- PCT / EP03 / 02083 10 has.
- Antibody fragments are particularly preferred examples of such a fragment.
- ⁇ -, ⁇ - or ⁇ -interferon interleukins, e.g. IL-1 to IL-18, growth factors, e.g. epidermal growth factor (EGF), platelet growth factor (PDGF), fibroblast growth factor (FGF), brain-derived growth factor (BDGF), nerve growth factor (NGF), B-cell growth factor (BCGF), brain-derived neurotrophic growth factor (BDNF), ciliary neurotrophic factor (CNTF), transforming growth factors, e.g. B.
- EGF epidermal growth factor
- PDGF platelet growth factor
- FGF fibroblast growth factor
- BDGF brain-derived growth factor
- NGF nerve growth factor
- B-cell growth factor BCGF
- BDNF brain-derived neurotrophic growth factor
- CNTF ciliary neurotrophic factor
- transforming growth factors e.g. B.
- TGF- ⁇ or TGF-ß colony-stimulating factors (CSF), for example GM-CSF, G-CSF, BMP ("bone morphogenic proteins"), growth hormones, for example human growth hormone, tumor necrosis factors, for example TNF- ⁇ or TNF-ß, somatostatin, somatotropin, somatomedine, serum proteins, e.g. the coagulation factors II-XIII, albumin, erythropoietin, myoglobin, hemoglobin, plasminogen activators, e.g. tissue plasminogen activator, hormones or prohormones, e.g.
- hypothalamic hormones e.g. antidiuretic hormones (ADH) and oxytocin, as well as liberins and statins, parathyroid hormone, thyroid hormones, e.g.
- GLP-1 GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1, GLP-1
- exendin-4 leptin, vasopressin, gastrin, secretin, integrins, glycoprotein hormones (e.g. LH, FSH etc.), pigment hormones, lipoproteins and apo-lipoproteins, e.g.
- apo-B, apo-E, apo-L a Immunoglobulins, eg IgG, IgE, IgM, IgA, IgD or he a fragment thereof, hirudin, "tissue pathway" inhibitor, plant proteins, for example lectin or ricin, bee venom, snake venom, immunotoxins, antigen E, butroxobina, alpha-proteinase inhibitor, ragweed allergen, melanin, oligolysin proteins, RGD Proteins or, if appropriate, corresponding receptors for one of these proteins; or a functional derivative or fragment of one of these proteins or receptors.
- tissue pathway plant proteins, for example lectin or ricin, bee venom, snake venom, immunotoxins, antigen E, butroxobina, alpha-proteinase inhibitor, ragweed allergen, melanin, oligolysin proteins, RGD Proteins or, if appropriate, corresponding receptors for one of these proteins; or
- Suitable enzymes can be selected, for example, from the groups of carbohydrate-specific enzymes, proteolytic enzymes, oxidases, oxidoreductases, transferases, hydrolases, lyases, isomerases, kinases and ligases.
- non-limiting examples are asparaginase, arginase, arginine deaminase, Adenosine deaminase, glutaminase, glutaminase-asparaginase, phenylalanine ammonium lyase, tryptophanase, tyrosinase, superoxide dismutase, an endotoxinase, a catalase, peroxidase, kallikrein, trypsin, chymotrypsin, elastase, thermolysin, a lipase, phosphinase, a uriclase, a uriclase Bilirubin oxidase, a glucose oxidase, glucodase, gluconate oxidase, galactosidase, glucocerebrosidase, glucuronidase, hyaluronidase
- the functional group of the HAS molecule involved in the coupling reaction is the terminal aldehyde group or a group resulting therefrom by chemical reaction.
- Such a chemical reaction is the selective oxidation of this aldehyde group with a gentle oxidizing agent, e.g. iodine, bromine or some metal ions, or also by means of electrochemical oxidation to a carboxyl group or activated carboxyl group, e.g. an ester, lactone, amide, the carboxyl group optionally being converted into the activated derivative in a second reaction.
- a gentle oxidizing agent e.g. iodine, bromine or some metal ions
- electrochemical oxidation to a carboxyl group or activated carboxyl group, e.g. an ester, lactone, amide, the carboxyl group optionally being converted into the activated derivative in a second reaction.
- This carboxyl group or activated carboxyl group can then be coupled to a primary amino or thiol group of the protein to form an amide bond or thioester bond.
- this aldehyde group is selectively oxidized with a molar excess of iodine, preferably in a molar ratio of iodine to HAS of 2: 1 to 20: 1, particularly preferably about 5: 1 to 6: 1, in aqueous basic solution.
- a molar excess of iodine preferably in a molar ratio of iodine to HAS of 2: 1 to 20: 1, particularly preferably about 5: 1 to 6: 1, in aqueous basic solution.
- an aqueous NaOH solution in a molar concentration that is about 5-15 times, preferably about 10 times, the iodine solution is slowly added dropwise at intervals of several minutes to the reaction solution until the solution starts after the addition PT / EP03 / 02083
- the selective oxidation with alkaline stabilized solutions of metal ions for example Cu ** or Ag + , likewise takes place in approximately quantitative yield (example 2).
- An approximately 3-1 times molar excess of the oxidizing agent is preferably used.
- ox-HAS selectively oxidized hydroxyalkyl starch
- activation reagents are, for example, N-hydroxysuccinimide, N-hydroxyphthalimide, thiophenol, p-nitrophenol, o, p-dinitrophenol, trichlorophenol, trifluorophenol, pentachlorophenol, pentafluorophenol, 1-hydroxy-1 H-benzotriazole (HOBtNSA, HOOBt Hydroxypyridine, 3-hydroxypyridine, 3,4-dihydro-4-oxobenzotriazin-3-ol, 4-hydroxy-2,5-diphenyl-3 (2H) -thiophenone-1,1-dioxide, 3-phenyl-1- ( p-nitrophenyl) -2-pyrazoiin-5-one), [1-benzotriazolyl-N-oxy-
- EDC 3-Dimethyaminopropyl
- DCC dicyclohexylcarbodiimide
- DIPC diisopropylcarbodiimide
- cysteines are usually involved in S-S bridges and are therefore not available for a coupling reaction.
- free cysteines are present, they often play an important role in catalysis or are involved in the contact point of subunits. Modification of these cysteines will then result in partial or complete loss of biological activity.
- free cysteines could be removed using common genetic engineering methods such as directed mutagenesis or chemical peptide synthesis are introduced at those sites in the protein that are known to play no role in activity. In this way, optimal control of the coupling location is possible. In the same way, other reactive amino acids, e.g. Lys, His, Arg, Asp, Glu, are specifically introduced into the protein.
- the reactive group of the hydroxyalkyl starch molecule can also be an amino or thiol group formed by chemical reaction of the terminal aldehyde group.
- reductive amination of the aldehyde group can be carried out by reaction with ammonia in the presence of hydrogen and a catalyst or in the presence of sodium cyanoborohydride.
- the resulting amino or thiol group can then react with a free carboxyl group of the protein (for example an optionally activated glutamic or aspartic acid) to form an amide or thioester bond.
- the terminal aldehyde group of the hydroxyalkyl starch molecule or a functional group resulting therefrom by chemical reaction can also be reacted with a suitable physiologically compatible, bifunctional linker molecule.
- the “functional group resulting from the terminal aldehyde group of the hydroxyalkyl starch molecule by chemical reaction” is the remaining reactive functional group of the bifunctional linker molecule with which the terminal aldehyde group or the functional group resulting therefrom has been reacted. In this way, the terminal aldehyde group can also be converted into a desired functional group.
- Suitable linker molecules contain at one end a group which is linked to the terminal aldehyde group or a functional group resulting therefrom by chemical reaction, e.g. a carboxyl group, activated carboxyl group, amino or thiol group, can form a covalent bond, and at the other end a group which can be linked to a reactive functional group of the protein, e.g. an amino, thiol or carboxyl group, can form a covalent bond.
- a biologically compatible bridge molecule of suitable length e.g. a group derived from an alkane, an (oligo) alkylene glycol group or another suitable oligomer group.
- Preferred groups that can react with amino groups are e.g. N-hydroxy succinimide esters, sulfo-N-hydroxysuccinimide esters, imido esters or other activated carboxyl groups; preferred groups that can react with thiol groups are e.g. Maleimide and carboxyl groups; preferred groups that can react with aldehyde or carboxyl groups are e.g. Amino or thiol groups.
- the terminal aldehyde group is reacted directly with a primary amino group (eg, a lysine or arginine residue or the N-terminus) of the protein to form a Schiff base.
- a primary amino group eg, a lysine or arginine residue or the N-terminus
- the Schiff base formed is reduced by reaction with a suitable reducing agent, as a result of which a stable bond between protein and HAS is formed in the aqueous environment.
- Preferred reducing agents are sodium borohydride, sodium cyanoborohydride, organic boron complexes, for example a 4- (dimethylamino) pyridine boron complex, N-ethyldiisopropylamine boron complex, N-ethylmorpholine boron complex, N-methylmorpholine boron complex, N-phenylmorpholine boron complex, lut -Bor complex, triethylamine-boron complex, trimethylamine-boron complex;
- Suitable stereoselective reducing agents are, for example, sodium triacetate borohydride, sodium triethyl borohydride, sodium trimethoxy borohydride, potassium tri-sec-butyl borohydride (K-Selectride), sodium tri-sec-butyl borohydride (N-Selectride), lithium tri-sec-butyl borohydride (L-Selectride) , Potassium triamyl
- the yields can be improved by suitable variation of the reaction conditions.
- the parameters for such optimization attempts are the pH of the reaction mixture (possible protein degradation by alkaline borohydride), the temperature and duration of the incubation, and the type of reducing agent for the one-pot reaction.
- Another alternative is the possibility of carrying out the reaction in two steps, wherein an immobilized reducing agent can be used for the reduction step.
- the reaction products of the coupling can be examined using known methods and the coupling efficiency can be determined.
- the free primary amino groups in the protein can be determined before and after coupling with trinitrobenzenesulfonic acid (Habeeb, ASAF, Anal. Biochem. 14, 328-336 (1966)).
- the coupling yield of reactions involving primary amino acids could also be determined by derivatizing the unreacted amines with fluorescamine and determining the fluorescence.
- the molecular weight distribution can be determined by SDS-PAGE and gel permeation.
- Conjugate can be detected by SDS-PAGE and subsequent silver staining, while the saccharide content can be determined by glycan-specific staining of the bands separated by SDS-PAGE after blotting on a membrane.
- a quantitative glycan determination is also possible.
- a precise identification of the coupling site on the protein is possible by peptide mapping and / or MALDI-TOF mass spectroscopy or electrospray ionization mass spectroscopy. In this way, the coupling can be optimized and the molecular weight distribution and possibly (e.g. if the reactive groups on the protein react differently) even the coupling point of the products can be predetermined.
- the conjugates of the present invention can optionally be used as such or in the form of a pharmaceutical composition for the prophylactic or therapeutic treatment of the human or animal body.
- compositions comprise a pharmaceutically effective amount of a conjugate according to the invention as an active ingredient as well as a pharmaceutically suitable carrier and optionally other therapeutic or galenic ingredients or auxiliaries.
- auxiliaries can e.g. Include diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants) and substances which serve to make the formulation isotonic with the blood of the intended recipient.
- a pharmaceutically effective amount is that amount which is sufficient to have a desired positive effect when administered once or several times as part of a treatment for the relief, healing or prevention of a disease state.
- a pharmaceutically acceptable carrier is a carrier that is compatible with both the drug ingredient and the patient's body.
- compositions will vary depending on the desired or appropriate route of administration.
- a preferred route is parenteral administration, for example subcutaneous, intramuscular, intravenous, intraarterial, intra-articular, intra- 83
- compositions may conveniently be presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical arts.
- the conjugates of the present invention can also be used in all other fields in which other protein-polymer conjugates, e.g. B. PEG-protein conjugates were used.
- Some specific, non-limiting examples are the use of a HAS-protein conjugate as an immobilized catalyst or reaction partner for a reaction in a heterogeneous phase or as a column material for (immune) affinity chromatography.
- Other possible uses will be readily apparent to those skilled in the art, knowing the properties of the HAS-protein conjugates according to the invention disclosed here.
- the following examples are intended to explain the invention in more detail, but without restricting it thereto.
- analogous reactions can also be carried out with hydroxymethyl starch and hydroxypropyl starch and similar results can be achieved.
- the partially desalted solution was subjected to chromatography on a cation exchange column (Amberiite IR-120, H + form) in order to convert the aldonate groups into aldonic acid groups.
- the water was then removed by lyophilization and the lactone form thus obtained.
- 1 ml of alkaline copper reagent (3.5 g of Na 2 P0 4 , 4.0 g of K-Na tatrat in 50 ml of H 2 O, plus 10 ml of 1 N NaOH, 8.0 ml of 10% strength (wt ./Vol.) CuS0 4 solution and 0.089 g K-iodate in 10 ml H 2 O, after adding 18 g Na sulfate make up to 100 ml). It is heated at 100 ° C for 45 minutes. After cooling, 0.2 ml of 2.5% Kl solution and 0.15 ml of 1 MH 2 SO 4 are added.
- Hydroxyethyl starches with a higher molar mass e.g. 130 kD, 250 kD, 400 kD
- hydroxyethyl starches with a lower molar mass e.g. 10 kD, 25 kD, 40 kD
- a solution of 0.24 mmol of HES-130 kD in 10 ml of deionized water was prepared with heating. This solution was heated in a 100 ml round-bottom flask to a temperature of 70-80 ° C., and 1.17 mmol of stabilized Cu 2+ (eg Rochelle salt as stabilizer or other stabilizers) and aqueous dilute NaOH solution were added (final concentration 0.1 N NaOH). The temperature was then raised to 100 ° C. and the reaction was allowed to continue until a reddish color had developed. The reaction was stopped and the reaction mixture was cooled to 4 ° C. The reddish precipitate was removed by filtration. The filtrate was against T EP03 / 02083
- HES e.g. HES-10 kD, HES-25 kD, HES-40 kD
- HES higher molecular HES species
- HES selectively oxidized high molecular weight HES
- HSA human serum albumin
- ox-HES-130 kD and 200 mg of HSA were completely dissolved in water in a round-bottomed flask with a magnetic stirrer while heating gently.
- EDC ethyldimethylaminopropylcarbodiimide
- HES selectively oxidized low molecular weight HES
- HSA human serum albumin
- a volume of an aqueous solution of ox-HES-10 kD (1.05 g / ml) was incubated with a volume of a 7 mg / ml SOD solution (Sigma, Taufkirchen) in 50 mM phosphate buffer, pH 7.6, at room temperature.
- the coupling reaction was initiated by adding 280 mg EDC in 5 portions over a period of 24 h.
- the course of the reaction was followed by GPC analysis in phosphate buffer and detection at 280 nm.
- 81% of the protein was found in the high molecular weight region of the separation column and the reaction was stopped after this time.
- the reaction mixture was subjected to diafiltration with a 30 kD membrane and then lyophilized. Mass spectrometric analysis of the product showed on average a molar ratio of HES to protein of approx. 3: 1.
- hTNF ⁇ (Sigma, Taufkirchen) was added to 86 mg of ox-HES-25 kD in approx. 0.4 ml of 0.1 M phosphate buffer (pH 7.0). The cloudy solution was stirred for about 2 h before 1 mg EDC and 0.5 mg HOBt were added. The stirring was continued for about 6 h, during which the solution became clear in the course of the reaction time.
- the coupling product was isolated by ultrafiltration and freeze drying and analyzed by GPC and detection at 280 nm. A coupling yield of approximately 74% was found.
- HES-130 kD high molecular weight HES
- HSA human serum albumin
- HES-130 kD 9.75 g of HES-130 kD were completely dissolved in water (6-7 ml) and then 50 mg of HSA, dissolved in 1 ml of 0.1 M phosphate buffer (pH 7.4), were added. The reaction mixture was stirred with a magnetic stirrer. The solution was then mixed with NaBH 3 CN (50-70 mg) and stirred gently for a few minutes. The solution was further stirred every two hours for 15 minutes. Another aliquot of NaBH 3 CN (approximately 50 mg) was then added. At the end (after a reaction time of almost 36 h), a total of 285 mg NaBH 3 CN had been used. The solution was then dialyzed and lyophilized. The analysis was carried out as described in Example 4. The coupling efficiency was about 65%.
- HES-10 kD low molecular weight HES
- HSA human serum albumin
- HES-130 kD were completely dissolved in water (approx. 6 ml).
- the reducing agent NaBH 3 CN 60 mg in 30 ml was slowly added dropwise over a period of 8 h. The mixture was then stirred for a further 24 h and the reaction mixture by ultrafiltration (30th kD) freed from salts and unreacted reagents.
- a stable coupling product was obtained by lyophilization. Approximately 55% of the insulin used was recovered as an HES conjugate.
- Glucagon (66 x 10 "9 mol, 0.23 mg), oxHES 70 kD (6.6 x 10 " 6 mol, 123 mg) were dissolved in phosphate buffer (1 ml, pH 5) in a round bottom flask. 26 mg EDC were added in 10 portions at intervals of 1 h. After a reaction time of 24 h, the reaction was stopped by adding 10 ml of water. The coupling product was purified by after dialysis against water by GPC and ion exchange chromatography. After freeze-drying, 88 mg of white coupling product (73%) were obtained.
Abstract
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DE10209821A DE10209821A1 (de) | 2002-03-06 | 2002-03-06 | Kopplung von Proteinen an ein modifiziertes Polysaccharid |
PCT/EP2003/002083 WO2003074087A1 (de) | 2002-03-06 | 2003-02-28 | Kopplung von proteinen an ein modifiziertes polysaccharid |
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Families Citing this family (68)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10112825A1 (de) * | 2001-03-16 | 2002-10-02 | Fresenius Kabi De Gmbh | HESylierung von Wirkstoffen in wässriger Lösung |
DE10209822A1 (de) | 2002-03-06 | 2003-09-25 | Biotechnologie Ges Mittelhesse | Kopplung niedermolekularer Substanzen an ein modifiziertes Polysaccharid |
DE10209821A1 (de) | 2002-03-06 | 2003-09-25 | Biotechnologie Ges Mittelhesse | Kopplung von Proteinen an ein modifiziertes Polysaccharid |
US9101687B2 (en) | 2002-07-15 | 2015-08-11 | University Of Leeds | Beta sheet tapes ribbons in tissue engineering |
US8586539B2 (en) | 2002-07-15 | 2013-11-19 | University Of Leeds | Beta sheet tapes ribbons in tissue engineering |
BR0314227A (pt) | 2002-09-11 | 2005-10-25 | Fresenius Kabi De Gmbh | Derivados de amido de hidroxialquila |
DE10242076A1 (de) * | 2002-09-11 | 2004-03-25 | Fresenius Kabi Deutschland Gmbh | HAS-Allergen-Konjugate |
DE60323756D1 (de) | 2002-10-08 | 2008-11-06 | Fresenius Kabi De Gmbh | Pharmazeutisch aktive oligosaccharid-conjugate |
JP2007501870A (ja) * | 2003-08-08 | 2007-02-01 | フレゼニウス・カビ・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | ヒドロキシアルキルデンプンとg−csfの複合体 |
SG145746A1 (en) * | 2003-08-08 | 2008-09-29 | Fresenius Kabi De Gmbh | Conjugates of hydroxyalkyl starch and g-csf |
RU2370281C2 (ru) * | 2003-08-08 | 2009-10-20 | Фрезениус Каби Дойчланд Гмбх | Конъюгаты гидроксиалкилкрахмала и g-csf |
WO2005014655A2 (en) * | 2003-08-08 | 2005-02-17 | Fresenius Kabi Deutschland Gmbh | Conjugates of hydroxyalkyl starch and a protein |
EP2368579A1 (de) | 2004-01-21 | 2011-09-28 | Novo Nordisk Health Care AG | Tranglutaminase vermittelte konjugation von peptiden. |
EP1708752B1 (de) * | 2004-01-27 | 2012-02-22 | University Of Southern California | Therapeutisches krebsmittel mit polymergebundenem antikörper |
AU2005210142A1 (en) * | 2004-02-09 | 2005-08-18 | Noxxon Pharma Ag | Method for producing conjugates of polysaccharides and polynucleotides |
WO2005092391A2 (en) * | 2004-03-11 | 2005-10-06 | Fresenius Kabi Deutschland Gmbh | Conjugates of hydroxyalkyl starch and a protein |
TW200603818A (en) * | 2004-03-11 | 2006-02-01 | Fresenius Kabi De Gmbh | Conjugates of hydroxyethyl starch and erythropoietin |
JP5191729B2 (ja) * | 2004-03-11 | 2013-05-08 | フレゼニウス・カビ・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | 還元的アミノ化によって製造される、ヒドロキシアルキルデンプンとタンパク質とのコンジュゲート |
EP1725583B1 (de) * | 2004-03-17 | 2010-12-01 | AntiCancer, Inc. | Methoden zur steigerung der protein polyethylenglykol (peg) konjugation |
AU2005259487A1 (en) * | 2004-06-30 | 2006-01-12 | Novartis Ag | Conjugates of antibody and duoarmycin derivatives as antitumor agents |
TW200643033A (en) * | 2005-03-08 | 2006-12-16 | Chugai Pharmaceutical Co Ltd | Conjugate of water-soluble modified hyaluronic acid and glp-1 analogue |
KR20070110902A (ko) * | 2005-03-11 | 2007-11-20 | 프레제니우스 카비 도이치란트 게엠베하 | 비활성 출발 물질로부터 생물활성 당단백질의 생산 |
WO2006094826A2 (en) * | 2005-03-11 | 2006-09-14 | Fresenius Kabi Deutschland Gmbh | Method for coupling enzymatically activated glycoconjugates to a hydroxyalkyl starch |
EP1762250A1 (de) * | 2005-09-12 | 2007-03-14 | Fresenius Kabi Deutschland GmbH | Konjugate welche durch chemische Ligation zwischen Hydroxyalkylstärken und aktiven Substanzen mit Bildung eines Thiazolidin-Ringes entstehen |
PL2029740T3 (pl) | 2006-05-31 | 2012-11-30 | Genzyme Corp | Zastosowanie polisacharydów do promowania aktywności enzymatycznej |
PT2197919E (pt) | 2007-08-27 | 2014-07-17 | Ratiopharm Gmbh | Formulação líquida de conjugado de g-csf |
EP2070951A1 (de) | 2007-12-14 | 2009-06-17 | Fresenius Kabi Deutschland GmbH | Verfahren zur Herstellung eines Hydroxyalkylstärkederivats mit zwei Linkern |
EP2070950A1 (de) | 2007-12-14 | 2009-06-17 | Fresenius Kabi Deutschland GmbH | Hydroxyalkylstärkederivate und deren Herstellungsverfahren |
US20100317057A1 (en) * | 2007-12-28 | 2010-12-16 | Novo Nordisk A/S | Semi-recombinant preparation of glp-1 analogues |
MX2011000859A (es) | 2008-07-23 | 2011-02-24 | Ambrx Inc | Polipeptidos g-csf bovinos modificados y sus usos. |
IT1392655B1 (it) * | 2008-11-20 | 2012-03-16 | Bio Ker S R L | Site-specific monoconjugated insulinotropic glp-1 peptides. |
CN103816870B (zh) | 2008-12-03 | 2016-11-23 | 株式会社钟化 | 含有甲酰基的多孔性载体、使用该多孔性载体的吸附体以及它们的制造方法 |
CN102238966B (zh) | 2008-12-06 | 2014-08-06 | 贝朗医疗有限公司 | 转运介导的胶体药用化合物 |
CA2750269A1 (en) | 2009-01-28 | 2010-08-05 | Smartcells, Inc. | Crystalline insulin-conjugates |
JP5508438B2 (ja) | 2009-01-28 | 2014-05-28 | スマートセルズ・インコーポレイテツド | 制御された薬物送達のための複合体に基づくシステム |
WO2010088268A1 (en) | 2009-01-28 | 2010-08-05 | Smartcells, Inc. | Exogenously triggered controlled release materials and uses thereof |
EP2391217A4 (de) | 2009-01-28 | 2015-05-20 | Smartcells Inc | Synthetische konjugate und ihre verwendung |
AU2010226243A1 (en) | 2009-03-20 | 2011-09-22 | Smartcells, Inc. | Terminally-functionalized conjugates and uses thereof |
EP2408470A4 (de) | 2009-03-20 | 2012-08-29 | Smartcells Inc | Lösliche nichtdepot-insulinkonjugate und ihre verwendung |
CN102365099A (zh) * | 2009-03-31 | 2012-02-29 | B·布朗·梅尔松根有限公司 | 胺化多糖粘合制品 |
RU2012127383A (ru) * | 2009-12-02 | 2014-01-10 | Акселерон Фарма Инк. | Композиции и способы для увеличения времени полужизни fc-слитых белков в сыворотке |
EA201290541A1 (ru) | 2009-12-21 | 2013-05-30 | Амбркс, Инк. | Модифицированные бычьи соматотропиновые полипептиды и их применение |
PE20121799A1 (es) | 2009-12-21 | 2013-01-02 | Ambrx Inc | Polipeptidos de somatotropina porcina modificados y sus usos |
US8933207B2 (en) | 2010-07-28 | 2015-01-13 | Smartcells, Inc. | Drug-ligand conjugates, synthesis thereof, and intermediates thereto |
US9068013B2 (en) | 2010-07-28 | 2015-06-30 | Smart Cells, Inc. | Recombinant lectins, binding-site modified lectins and uses thereof |
JP2013535467A (ja) | 2010-07-28 | 2013-09-12 | スマートセルズ・インコーポレイテツド | 組換えにより発現されたインスリンポリペプチドおよびその使用 |
TWI480288B (zh) | 2010-09-23 | 2015-04-11 | Lilly Co Eli | 牛顆粒細胞群落刺激因子及其變體之調配物 |
US11407978B2 (en) | 2010-10-25 | 2022-08-09 | Albert-Ludwigs-Universität Freiburg | Extracellular matrices which can be used as scaffold for living cells |
ES2725207T3 (es) * | 2010-11-23 | 2019-09-20 | Allergan Pharmaceuticals Int Ltd | Preparación y/o formulación de proteínas reticuladas con polisacáridos |
EP2718328A4 (de) | 2011-06-08 | 2014-12-24 | Acceleron Pharma Inc | Zusammensetzungen und verfahren zur erhöhung der halbwertszeit von serum |
US20140314722A1 (en) | 2011-08-18 | 2014-10-23 | Albert-Ludwigs Universität Freiburg | Matrices comprising a modified polysaccharide |
WO2013113503A1 (en) | 2012-01-31 | 2013-08-08 | Fresenius Kabi Deutschland Gmbh | Conjugates of hydroxyalkyl starch and an oligonucleotide |
PL221351B1 (pl) | 2012-03-14 | 2016-03-31 | Politechnika Warszawska | Sposób otrzymywania nanocząstek polisacharydowych |
DK2849567T3 (da) * | 2012-05-17 | 2022-06-20 | Extend Biosciences Inc | Bærestoffer til forbedret lægemiddeladministration |
GB201306338D0 (en) * | 2013-04-08 | 2013-05-22 | Univ Leeds | Novel proteoglycans |
EP3052134B1 (de) | 2013-10-04 | 2021-05-05 | Merck Sharp & Dohme Corp. | Auf glucose reagierende insulinkonjugate |
CN104017069A (zh) * | 2014-06-23 | 2014-09-03 | 山东齐都药业有限公司 | 含醛基羟乙基淀粉衍生物修饰的牛血清白蛋白偶联物及其制备方法 |
CN104072608A (zh) * | 2014-06-23 | 2014-10-01 | 山东齐都药业有限公司 | 含羧基羟乙基淀粉衍生物修饰的牛血清白蛋白偶联物及其制备方法 |
CN104606127B (zh) * | 2015-01-21 | 2017-07-21 | 浙江峰盛生物工程有限公司 | 靶向egfr的载铂类药物白蛋白纳米粒及其制备与应用 |
CN109929020A (zh) * | 2017-12-15 | 2019-06-25 | 浙江京新药业股份有限公司 | 一种眼镜蛇毒的纯化方法及其产品 |
CN108642031B (zh) * | 2018-07-02 | 2022-01-07 | 四川德博尔制药有限公司 | 一种弹性蛋白酶及其提取方法 |
CN108837299B (zh) * | 2018-07-18 | 2020-08-07 | 武汉大学 | 一种智能调节血糖的微针贴片及其制备方法 |
CN109125707B (zh) * | 2018-10-19 | 2022-01-04 | 艾伟伦 | GnRH类似物缓释组合物及其制备方法 |
CN109628436B (zh) * | 2019-01-18 | 2022-03-29 | 重庆派金生物科技有限公司 | 一种固定重组人精氨酸酶的制备方法 |
CN110038132A (zh) * | 2019-01-29 | 2019-07-23 | 苏州杰纳生物科技有限公司 | 天然高分子-蛋白复合物及其制备方法和应用 |
WO2021160234A2 (en) | 2019-08-26 | 2021-08-19 | Bioresources Technology & Engineering Gmbh (Bite) | Antimicrobial peptides from medicinal leeches |
WO2022051889A1 (zh) * | 2020-09-08 | 2022-03-17 | 三诺生物传感股份有限公司 | 提高电化学活性的氧化还原酶及含有该氧化还原酶的生物传感器 |
CN114601970A (zh) * | 2022-03-28 | 2022-06-10 | 东莞市人民医院 | 一种具有修饰蛋白涂层材料、其制备方法及应用 |
Family Cites Families (202)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE279486C (de) | ||||
US3191291A (en) | 1959-01-21 | 1965-06-29 | Continental Can Co | Art of producing very thin steel and like sheets in wide strips |
CH385787A (de) * | 1960-10-04 | 1964-09-15 | Hoechst Ag | Verfahren zur Herstellung von nassechten Färbungen auf Cellulosetextilmaterialien |
DE2233977A1 (de) | 1971-07-14 | 1973-02-01 | Unilever Nv | Verfahren zur herstellung oxydierter kohlenhydrate |
GB1419080A (en) | 1972-12-29 | 1975-12-24 | Cheminova As | Chemical compounds having juvenile hormone activity |
US4179337A (en) | 1973-07-20 | 1979-12-18 | Davis Frank F | Non-immunogenic polypeptides |
US4125492A (en) | 1974-05-31 | 1978-11-14 | Pedro Cuatrecasas | Affinity chromatography of vibrio cholerae enterotoxin-ganglioside polysaccharide and the biological effects of ganglioside-containing soluble polymers |
US4001200A (en) * | 1975-02-27 | 1977-01-04 | Alza Corporation | Novel polymerized, cross-linked, stromal-free hemoglobin |
US4001401A (en) * | 1975-02-02 | 1977-01-04 | Alza Corporation | Blood substitute and blood plasma expander comprising polyhemoglobin |
US4061736A (en) * | 1975-02-02 | 1977-12-06 | Alza Corporation | Pharmaceutically acceptable intramolecularly cross-linked, stromal-free hemoglobin |
US4053590A (en) * | 1975-02-27 | 1977-10-11 | Alza Corporation | Compositions of matter comprising macromolecular hemoglobin |
FR2309082A1 (fr) | 1975-04-24 | 1976-11-19 | Serras Paulet Edouard | Dispositif a bouton poussoir de commande de commutation d'un circuit electronique ou electrique |
CA1055932A (en) | 1975-10-22 | 1979-06-05 | Hematech Inc. | Blood substitute based on hemoglobin |
DE2616086C2 (de) | 1976-04-13 | 1986-04-03 | Dr. Eduard Fresenius, Chemisch-pharmazeutische Industrie KG, 6380 Bad Homburg | Substanz zur Verwendung in einem kolloidalen Blutvolumenersatzmittel aus Hydroxyethylstärke und Hämoglobin |
GB1578348A (en) | 1976-08-17 | 1980-11-05 | Pharmacia Ab | Products and a method for the therapeutic suppression of reaginic antibodies responsible for common allergic |
FR2378094A2 (fr) | 1977-01-24 | 1978-08-18 | Inst Nat Sante Rech Med | Nouveaux reactifs biologiques constitues par des supports solides sur lesquels sont couples des composes organiques comportant un residu glucidique |
EP0019403B1 (de) | 1979-05-10 | 1985-07-31 | American Hospital Supply Corporation | Arzneimittelträger auf der Basis von Hydroxyalkyl-Stärke |
DE3029307A1 (de) | 1980-08-01 | 1982-03-04 | Dr. Eduard Fresenius, Chemisch-pharmazeutische Industrie KG, 6380 Bad Homburg | Haemoglobin enthaltendes blutersatzmittel |
US4454161A (en) * | 1981-02-07 | 1984-06-12 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Process for the production of branching enzyme, and a method for improving the qualities of food products therewith |
JPS57206622A (en) | 1981-06-10 | 1982-12-18 | Ajinomoto Co Inc | Blood substitute |
FI82266C (fi) | 1982-10-19 | 1991-02-11 | Cetus Corp | Foerfarande foer framstaellning av il-2 -mutein. |
IE58011B1 (en) | 1983-05-27 | 1993-06-16 | Texas A & M Univ Sys | Method for producing a recombinant baculovirus expression vector |
IE57931B1 (en) | 1983-10-11 | 1993-05-19 | Fidia Spa | Hyaluronic acid fractions having pharmaceutical activity,methods for preparation thereof,and pharmaceutical compositions containing the same |
US4703008A (en) | 1983-12-13 | 1987-10-27 | Kiren-Amgen, Inc. | DNA sequences encoding erythropoietin |
NZ210501A (en) | 1983-12-13 | 1991-08-27 | Kirin Amgen Inc | Erythropoietin produced by procaryotic or eucaryotic expression of an exogenous dna sequence |
US4496689A (en) * | 1983-12-27 | 1985-01-29 | Miles Laboratories, Inc. | Covalently attached complex of alpha-1-proteinase inhibitor with a water soluble polymer |
US4952496A (en) | 1984-03-30 | 1990-08-28 | Associated Universities, Inc. | Cloning and expression of the gene for bacteriophage T7 RNA polymerase |
IL77081A (en) | 1984-12-04 | 1999-10-28 | Genetics Inst | AND sequence encoding human erythropoietin, a process for its preparation and a pharmacological preparation of human erythropoietin |
DE3501616A1 (de) | 1985-01-17 | 1986-07-17 | Schering AG, 1000 Berlin und 4709 Bergkamen | Verfahren zur herstellung von hydroxylamin-derivaten |
US4667016A (en) | 1985-06-20 | 1987-05-19 | Kirin-Amgen, Inc. | Erythropoietin purification |
US4766106A (en) | 1985-06-26 | 1988-08-23 | Cetus Corporation | Solubilization of proteins for pharmaceutical compositions using polymer conjugation |
US5217998A (en) | 1985-07-02 | 1993-06-08 | Biomedical Frontiers, Inc. | Composition for the stabilization of deferoxamine to chelate free ions in physiological fluid |
US4863964A (en) | 1985-07-02 | 1989-09-05 | Biomedical Frontiers, Inc. | Method for the stabilization of deferoxamine to chelate free ions in physiological fluid |
GB8610551D0 (en) | 1986-04-30 | 1986-06-04 | Hoffmann La Roche | Polypeptide & protein derivatives |
IT1203814B (it) | 1986-06-30 | 1989-02-23 | Fidia Farmaceutici | Esteri dell'acido alginico |
FR2600894B1 (fr) * | 1986-07-02 | 1989-01-13 | Centre Nat Rech Scient | Conjugues macromoleculaires d'hemoglobine, leur procede de preparation et leurs applications |
US5214132A (en) | 1986-12-23 | 1993-05-25 | Kyowa Hakko Kogyo Co., Ltd. | Polypeptide derivatives of human granulocyte colony stimulating factor |
US5362853A (en) | 1986-12-23 | 1994-11-08 | Kyowa Hakko Kogyo Co., Ltd. | Polypeptide derivatives of human granulocyte colony stimulating factor |
JP2594123B2 (ja) * | 1987-09-12 | 1997-03-26 | 株式会社林原生物化学研究所 | 減感作剤 |
EP0307827A3 (de) | 1987-09-15 | 1989-12-27 | Kuraray Co., Ltd. | Makromolekulare Komplexe, ihre Herstellung und Verwendung in der Medizin |
IL84252A (en) | 1987-10-23 | 1994-02-27 | Yissum Res Dev Co | Phospholipase inhibiting compositions |
US4904584A (en) | 1987-12-23 | 1990-02-27 | Genetics Institute, Inc. | Site-specific homogeneous modification of polypeptides |
US4847325A (en) | 1988-01-20 | 1989-07-11 | Cetus Corporation | Conjugation of polymer to colony stimulating factor-1 |
DK110188D0 (da) | 1988-03-02 | 1988-03-02 | Claus Selch Larsen | High molecular weight prodrug derivatives of antiinflammatory drugs |
US4994278A (en) | 1988-03-04 | 1991-02-19 | Noven Pharmaceuticals, Inc. | Breathable backing |
US5541297A (en) | 1988-04-01 | 1996-07-30 | Immunomedics, Inc. | Therapeutic conjugates of toxins and drugs |
FR2630329B1 (fr) | 1988-04-20 | 1991-07-05 | Merieux Inst | Conjugues macromoleculaires d'hemoglobine, leur procede de preparation et leurs applications |
IT1219942B (it) | 1988-05-13 | 1990-05-24 | Fidia Farmaceutici | Esteri polisaccaridici |
US4900780A (en) * | 1988-05-25 | 1990-02-13 | Masonic Medical Research Laboratory | Acellular resuscitative fluid |
US4925677A (en) * | 1988-08-31 | 1990-05-15 | Theratech, Inc. | Biodegradable hydrogel matrices for the controlled release of pharmacologically active agents |
US5420105A (en) | 1988-09-23 | 1995-05-30 | Gustavson; Linda M. | Polymeric carriers for non-covalent drug conjugation |
US5218092A (en) | 1988-09-29 | 1993-06-08 | Kyowa Hakko Kogyo Co., Ltd. | Modified granulocyte-colony stimulating factor polypeptide with added carbohydrate chains |
DE3836600A1 (de) | 1988-10-27 | 1990-05-03 | Wolff Walsrode Ag | Kohlensaeureester von polysacchariden und verfahren zu ihrer herstellung |
JP2989002B2 (ja) | 1988-12-22 | 1999-12-13 | キリン―アムジエン・インコーポレーテツド | 化学修飾顆粒球コロニー刺激因子 |
US5166322A (en) | 1989-04-21 | 1992-11-24 | Genetics Institute | Cysteine added variants of interleukin-3 and chemical modifications thereof |
US6261800B1 (en) | 1989-05-05 | 2001-07-17 | Genentech, Inc. | Luteinizing hormone/choriogonadotropin (LH/CG) receptor |
WO1990015628A1 (en) | 1989-06-14 | 1990-12-27 | Cetus Corporation | Polymer/antibiotic conjugate |
DE19975071I2 (de) | 1989-06-16 | 2000-02-03 | Fresenius Ag | Hydroxyethylstaerke als Plasmaexpander Verfahren zu ihrer Herstellung und Verwendung als kolloidales Plasmaersatzmittel |
JP2896580B2 (ja) * | 1989-08-25 | 1999-05-31 | チッソ株式会社 | アミロース―リゾチームハイブリッドと活性化糖およびその製造法 |
JP2838800B2 (ja) * | 1989-09-02 | 1998-12-16 | 株式会社林原生物化学研究所 | 減感作剤 |
KR100263845B1 (ko) | 1989-10-13 | 2000-08-16 | 스튜어트 엘.왓트 | 에리트로포이에틴 동형체와 그의 제조방법 및 그를 포함하는제약학적 조성물 |
JP2975632B2 (ja) | 1990-03-30 | 1999-11-10 | 生化学工業株式会社 | グリコサミノグリカン修飾プロテイン |
US5169784A (en) | 1990-09-17 | 1992-12-08 | The Texas A & M University System | Baculovirus dual promoter expression vector |
ES2059299T3 (es) | 1990-12-19 | 1997-10-01 | Advanced Magnetics Inc | Direccionado de agentes terapeuticos utilizando polisacaridos. |
DK130991D0 (da) | 1991-07-04 | 1991-07-04 | Immunodex K S | Polymere konjugater |
US5281698A (en) | 1991-07-23 | 1994-01-25 | Cetus Oncology Corporation | Preparation of an activated polymer ester for protein conjugation |
DE4130807A1 (de) | 1991-09-17 | 1993-03-18 | Wolff Walsrode Ag | Verfahren zur herstellung von polysaccharidcarbonaten |
WO1993024476A1 (en) | 1992-06-04 | 1993-12-09 | Clover Consolidated, Limited | Water-soluble polymeric carriers for drug delivery |
AU677789B2 (en) | 1992-07-02 | 1997-05-08 | Collagen Corporation | Biocompatible polymer conjugates |
US6172208B1 (en) | 1992-07-06 | 2001-01-09 | Genzyme Corporation | Oligonucleotides modified with conjugate groups |
WO1994005332A2 (en) | 1992-09-01 | 1994-03-17 | Berlex Laboratories, Inc. | Glycolation of glycosylated macromolecules |
GB2270920B (en) | 1992-09-25 | 1997-04-02 | Univ Keele | Alginate-bioactive agent conjugates |
WO1994013697A1 (en) | 1992-12-07 | 1994-06-23 | Magainin Pharmaceuticals, Inc. | Treatment of septic shock with conjugated biologically active peptides |
NO934477L (no) | 1992-12-09 | 1994-06-10 | Ortho Pharma Corp | PEG hydrazon- og PEG oksim-bindingdannende reagenser og proteinderivater derav |
NZ250375A (en) | 1992-12-09 | 1995-07-26 | Ortho Pharma Corp | Peg hydrazone and peg oxime linkage forming reagents and protein derivatives |
CA2110543A1 (en) | 1992-12-09 | 1994-06-10 | David E. Wright | Peg hydrazone and peg oxime linkage forming reagents and protein derivatives thereof |
EP0601417A3 (de) | 1992-12-11 | 1998-07-01 | Hoechst Aktiengesellschaft | Physiologisch verträglicher und physiologisch abbaubarer, Kohlenhydratrezeptorblocker auf Polymerbasis, ein Verfahren zu seiner Herstellung und seine Verwendung |
US5581476A (en) | 1993-01-28 | 1996-12-03 | Amgen Inc. | Computer-based methods and articles of manufacture for preparing G-CSF analogs |
CN1046292C (zh) | 1993-03-16 | 1999-11-10 | 赫姆索尔公司 | 化学修饰用作血液替代物中氧转运者的血红蛋白的方法 |
AU7097094A (en) | 1993-06-01 | 1994-12-20 | Enzon, Inc. | Carbohydrate-modified polymer conjugates with erythropoietic activity |
US5621039A (en) | 1993-06-08 | 1997-04-15 | Hallahan; Terrence W. | Factor IX- polymeric conjugates |
IL192290A0 (en) | 1993-08-17 | 2008-12-29 | Kirin Amgen Inc | Erythropoietin analogs |
GB9317618D0 (en) | 1993-08-24 | 1993-10-06 | Royal Free Hosp School Med | Polymer modifications |
US5840900A (en) | 1993-10-20 | 1998-11-24 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
ATE214940T1 (de) | 1993-11-10 | 2002-04-15 | Enzon Inc | Verbesserte interferon-polymerkonjugate |
JPH07188291A (ja) | 1993-12-27 | 1995-07-25 | Hayashibara Biochem Lab Inc | 蛋白質とその製造方法並びに用途 |
US5824784A (en) | 1994-10-12 | 1998-10-20 | Amgen Inc. | N-terminally chemically modified protein compositions and methods |
WO1996041813A2 (en) | 1994-11-09 | 1996-12-27 | Offord Robin E | Functionalized polymers for site-specific attachment |
AU709008B2 (en) | 1994-12-22 | 1999-08-19 | Access Pharmaceuticals, Inc. | Complexes of dermatan sulfate and drugs, giving improved pharmacokinetics |
US5876980A (en) | 1995-04-11 | 1999-03-02 | Cytel Corporation | Enzymatic synthesis of oligosaccharides |
US6214331B1 (en) | 1995-06-06 | 2001-04-10 | C. R. Bard, Inc. | Process for the preparation of aqueous dispersions of particles of water-soluble polymers and the particles obtained |
US5736533A (en) | 1995-06-07 | 1998-04-07 | Neose Technologies, Inc. | Bacterial inhibition with an oligosaccharide compound |
WO1996040662A2 (en) | 1995-06-07 | 1996-12-19 | Cellpro, Incorporated | Aminooxy-containing linker compounds and their application in conjugates |
US5981507A (en) | 1995-12-14 | 1999-11-09 | Advanced Magnetics, Inc. | Polymeric carriers linked to nucleotide analogues via a phosphoramide bond |
US5723589A (en) | 1995-12-21 | 1998-03-03 | Icn Pharmaceuticals | Carbohydrate conjugated bio-active compounds |
CA2242488A1 (en) | 1996-02-15 | 1997-08-21 | Novo Nordisk A/S | Conjugation of polypeptides |
CN1304058C (zh) | 1996-03-12 | 2007-03-14 | Pg-Txl有限公司 | 水溶性紫杉醇产品 |
DE69734709D1 (de) | 1996-04-15 | 2005-12-29 | Asahi Chemical Ind | Arzneimittelkomplexe enthaltend taxan-verbindungen oder steroiden |
US5795397A (en) | 1996-05-06 | 1998-08-18 | National Starch And Chemical Investment Holding Corporation | Chemically derivatized maltodextrins |
US5696152A (en) | 1996-05-07 | 1997-12-09 | Wisconsin Alumni Research Foundation | Taxol composition for use as organ preservation and cardioplegic agents |
TW517067B (en) | 1996-05-31 | 2003-01-11 | Hoffmann La Roche | Interferon conjugates |
DE19628705A1 (de) * | 1996-07-08 | 1998-01-15 | Fresenius Ag | Neue Sauerstoff-Transport-Mittel, diese enthaltende Hämoglobin-Hydroxyethylstärke-Konjugate, Verfahren zu deren Herstellung, sowie deren Verwendung als Blutersatzstoffe |
US5770645A (en) | 1996-08-02 | 1998-06-23 | Duke University Medical Center | Polymers for delivering nitric oxide in vivo |
US5851984A (en) * | 1996-08-16 | 1998-12-22 | Genentech, Inc. | Method of enhancing proliferation or differentiation of hematopoietic stem cells using Wnt polypeptides |
EP0934331B1 (de) | 1996-08-30 | 2002-11-27 | Jens Peter Fürste | Spiegelselektion und spiegelevolution von nucleinsäuren |
AU715555B2 (en) | 1996-09-30 | 2000-02-03 | University Of Arkansas, The | Method of producing active immunity with vaccine conjugate |
DE19640791A1 (de) | 1996-10-02 | 1998-04-16 | Syntesome Ges Fuer Medizinisch | Glycokonjugate als Inhibitoren der viralen Zelladhäsion |
WO1998020905A2 (en) | 1996-11-08 | 1998-05-22 | Biomedical Frontiers, Inc. | Treatment of iron overload disorders |
US6011008A (en) | 1997-01-08 | 2000-01-04 | Yissum Research Developement Company Of The Hebrew University Of Jerusalem | Conjugates of biologically active substances |
EP0921817B1 (de) | 1997-01-29 | 2001-03-28 | PolyMASC Pharmaceuticals plc | Pegylationsverfahren |
US5952347A (en) | 1997-03-13 | 1999-09-14 | Merck & Co., Inc. | Quinoline leukotriene antagonists |
US6299881B1 (en) | 1997-03-24 | 2001-10-09 | Henry M. Jackson Foundation For The Advancement Of Military Medicine | Uronium salts for activating hydroxyls, carboxyls, and polysaccharides, and conjugate vaccines, immunogens, and other useful immunological reagents produced using uronium salts |
JPH10287554A (ja) | 1997-04-16 | 1998-10-27 | Sankyo Co Ltd | 機能性リポソーム |
US5990237A (en) | 1997-05-21 | 1999-11-23 | Shearwater Polymers, Inc. | Poly(ethylene glycol) aldehyde hydrates and related polymers and applications in modifying amines |
US6338843B1 (en) | 1997-06-12 | 2002-01-15 | Ml Laboratories | Biologically active materials |
EP1003760B1 (de) | 1997-08-07 | 2004-07-28 | The University Of Utah | Prodrugs und konjugate von selenolenthaltenden verbindungen und ihre verwendung |
US5847110A (en) * | 1997-08-15 | 1998-12-08 | Biomedical Frontiers, Inc. | Method of reducing a schiff base |
BR9815388A (pt) | 1997-10-03 | 2001-08-21 | Galenica Pharmaceuticals Inc | Polissacarìdeos formadores de iminas, sua preparação e seu uso como adjuvantes e imunoestimulantes |
US6875594B2 (en) | 1997-11-13 | 2005-04-05 | The Rockefeller University | Methods of ligating expressed proteins |
US6624142B2 (en) | 1997-12-30 | 2003-09-23 | Enzon, Inc. | Trimethyl lock based tetrapartate prodrugs |
DE19808079A1 (de) | 1998-02-20 | 1999-08-26 | Schering Ag | Hydroxyethylstärke-Konjugate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Mittel |
DE69909987T2 (de) | 1998-03-05 | 2004-05-27 | Asahi Glass Co., Ltd. | Sputtertarget, transparenter leitender film und verfahren zu dessen herstellung |
CA2233725A1 (en) * | 1998-03-31 | 1999-09-30 | Hemosol Inc. | Hemoglobin-hydroxyethyl starch complexes |
US6153655A (en) | 1998-04-17 | 2000-11-28 | Enzon, Inc. | Terminally-branched polymeric linkers and polymeric conjugates containing the same |
FR2781767B1 (fr) | 1998-07-31 | 2000-10-13 | Valois Sa | Dispositif de distribution de produit fluide |
FR2783838B1 (fr) | 1998-09-25 | 2000-12-01 | Roquette Freres | Procede de preparation d'un melange d'enzymes de branchement de l'amidon extraites d'algues |
US6660843B1 (en) | 1998-10-23 | 2003-12-09 | Amgen Inc. | Modified peptides as therapeutic agents |
US6261594B1 (en) | 1998-11-25 | 2001-07-17 | The University Of Akron | Chitosan-based nitric oxide donor compositions |
EP1035137A1 (de) | 1999-03-12 | 2000-09-13 | Pasteur Merieux Serums Et Vaccins | Verfahren zur reduktiven aminierung von polysacchariden |
FR2792941B1 (fr) | 1999-04-30 | 2001-07-27 | Roquette Freres | Polymeres solubles de glucose branches et leur procede d'obtention |
JP2003504312A (ja) | 1999-06-18 | 2003-02-04 | エムエル ラボラトリーズ ピーエルシー | 生物学的に活性な材料 |
CZ299516B6 (cs) | 1999-07-02 | 2008-08-20 | F. Hoffmann-La Roche Ag | Konjugát erythropoetinového glykoproteinu, zpusobjeho výroby a použití a farmaceutická kompozice sjeho obsahem |
US7279176B1 (en) | 1999-09-02 | 2007-10-09 | Rice University | Nitric oxide-producing hydrogel materials |
US20020065410A1 (en) | 1999-12-02 | 2002-05-30 | Antrim Richard L. | Branched starches and branched starch hydrolyzates |
US6555660B2 (en) | 2000-01-10 | 2003-04-29 | Maxygen Holdings Ltd. | G-CSF conjugates |
US6749865B2 (en) | 2000-02-15 | 2004-06-15 | Genzyme Corporation | Modification of biopolymers for improved drug delivery |
MXPA02008247A (es) | 2000-03-21 | 2004-04-05 | Igeneon Krebs Immuntherapie | Conjugado de polisacarido-polipeptido. |
US6586398B1 (en) | 2000-04-07 | 2003-07-01 | Amgen, Inc. | Chemically modified novel erythropoietin stimulating protein compositions and methods |
JP2001294601A (ja) | 2000-04-11 | 2001-10-23 | Akita Prefecture | 高度分岐澱粉と該高度分岐澱粉の製造方法 |
JP2002003398A (ja) | 2000-04-17 | 2002-01-09 | Ltt Institute Co Ltd | 徐放製剤、その製造法及びワクチン |
MXPA02010758A (es) | 2000-05-01 | 2005-05-31 | Eth Zuerich | Matrices de proteina modificada con factor de crecimiento para tejido producido por ingenieria. |
DE10023051B4 (de) | 2000-05-11 | 2004-02-19 | Roche Diagnostics Gmbh | Verfahren zur Herstellung von Fluoresceinisothiocyanat-Sinistrin, dessen Verwendung und Fluoresceinisothiocyanat-Sinistrin enthaltende diagnostische Zubereitung |
US6242482B1 (en) | 2000-06-05 | 2001-06-05 | United Therapeutics Corporation | Prostaglandin compounds and derivatives thereof, compositions containing the same and method of using the same for the treatment of congestive heart failure |
KR100396983B1 (ko) | 2000-07-29 | 2003-09-02 | 이강춘 | 고반응성의 가지 달린 고분자 유도체 및 고분자와 단백질또는 펩타이드의 접합체 |
DE10041541A1 (de) | 2000-08-24 | 2002-03-14 | Michael Duchene | Rekombinante Allergene aus der Motte Plodia interpunctella |
US6417347B1 (en) | 2000-08-24 | 2002-07-09 | Scimed Life Systems, Inc. | High yield S-nitrosylation process |
CN1458846A (zh) | 2000-09-08 | 2003-11-26 | 格莱风治疗公司 | 促红细胞生成性合成蛋白 |
US6967251B2 (en) | 2000-10-02 | 2005-11-22 | Molecular Probes, Inc. | Reagents for labeling biomolecules having aldehyde or ketone moieties |
IT1319666B1 (it) | 2000-11-17 | 2003-10-23 | Pharma Biotech Ltd | Addotti di antibiotici con polimeri polisaccaridici naturali in formadi soluzioni acquose. |
DE10105921A1 (de) | 2001-02-09 | 2002-08-14 | Braun Melsungen Ag | An Kolloide gebundene Arzneiwirkstoffe |
DE10112825A1 (de) | 2001-03-16 | 2002-10-02 | Fresenius Kabi De Gmbh | HESylierung von Wirkstoffen in wässriger Lösung |
DE10126158A1 (de) | 2001-05-30 | 2002-12-12 | Novira Chem Gmbh | Eine Methode zur Synthese von Gemischen einfach aktivierter und nicht aktivierter Polyoxyalkylene zur Modifizierung von Proteinen |
DE10129369C1 (de) | 2001-06-21 | 2003-03-06 | Fresenius Kabi De Gmbh | Wasserlösliches, einen Aminozucker aufweisendes Antibiotikum in Form eines Pol ysaccharid-Konjugats |
DE10135694A1 (de) | 2001-07-21 | 2003-02-06 | Supramol Parenteral Colloids | Amphiphile Stärke-und Hydroxyethylstärke-Konjugate |
US6908963B2 (en) | 2001-10-09 | 2005-06-21 | Nektar Therapeutics Al, Corporation | Thioester polymer derivatives and method of modifying the N-terminus of a polypeptide therewith |
US7179617B2 (en) | 2001-10-10 | 2007-02-20 | Neose Technologies, Inc. | Factor IX: remolding and glycoconjugation of Factor IX |
US7214660B2 (en) | 2001-10-10 | 2007-05-08 | Neose Technologies, Inc. | Erythropoietin: remodeling and glycoconjugation of erythropoietin |
EP2042196B1 (de) | 2001-10-10 | 2016-07-13 | ratiopharm GmbH | Neumodellierung und Glykokonjugation von Granulozyten-Kolonie stimulierender Faktor (G-CSF) |
US7125843B2 (en) | 2001-10-19 | 2006-10-24 | Neose Technologies, Inc. | Glycoconjugates including more than one peptide |
DK2431377T3 (en) * | 2001-10-26 | 2017-08-14 | Noxxon Pharma Ag | Modified L-nucleic acids |
US6375846B1 (en) | 2001-11-01 | 2002-04-23 | Harry Wellington Jarrett | Cyanogen bromide-activation of hydroxyls on silica for high pressure affinity chromatography |
DE10155098A1 (de) | 2001-11-09 | 2003-05-22 | Supramol Parenteral Colloids | Mittel zur Prävention von mykotischen Kontaminationen bei der Zell- und Gewebekultur bakteriellen, pflanzlichen, animalischen und humanen Ursprungs, bestehend aus Polyen-Makrolid-Konjugaten mit Polysacchariden |
US6916962B2 (en) | 2001-12-11 | 2005-07-12 | Sun Bio, Inc. | Monofunctional polyethylene glycol aldehydes |
WO2003049699A2 (en) | 2001-12-11 | 2003-06-19 | Sun Bio, Inc. | Novel monofunctional polyethylene glycol aldehydes |
US20050085432A1 (en) | 2001-12-26 | 2005-04-21 | Aviva Lapidot | Methods of using conjugates of saccharides and acetamidino or guanidino compounds for treating bacterial infections |
DE10207072A1 (de) | 2002-02-20 | 2003-08-28 | Supramol Parenteral Colloids | Stärkederivate, ihre Konjugate und Verfahren zur Herstellung derselben |
DE10209822A1 (de) | 2002-03-06 | 2003-09-25 | Biotechnologie Ges Mittelhesse | Kopplung niedermolekularer Substanzen an ein modifiziertes Polysaccharid |
DE10209821A1 (de) | 2002-03-06 | 2003-09-25 | Biotechnologie Ges Mittelhesse | Kopplung von Proteinen an ein modifiziertes Polysaccharid |
DE60315145T2 (de) | 2002-03-13 | 2008-04-30 | Beijing Jiankai Technology Co., Ltd. | Hydrophiles polymerderivat mit y-verzweigung und herstellungsverfahren dafür; obige verbindung enthaltender medizinischer verbundwerkstoff |
DE10217994A1 (de) | 2002-04-23 | 2003-11-06 | Supramol Parenteral Colloids | Konjugate von hyperverzweigten Polysacchariden |
CA2487314A1 (en) * | 2002-06-03 | 2003-12-11 | The Institute For Systems Biology | Methods for quantitative proteome analysis of glycoproteins |
US20040101546A1 (en) | 2002-11-26 | 2004-05-27 | Gorman Anne Jessica | Hemostatic wound dressing containing aldehyde-modified polysaccharide and hemostatic agents |
AU2003254023A1 (en) | 2002-07-19 | 2004-02-09 | The General Hospital Corporation | Oxime conjugates and methods for their formation and use |
EP1591467A1 (de) | 2002-09-09 | 2005-11-02 | Nektar Therapeutics Al, Corporation | Konjugat aus einem Polyethylene Glykol mit einer Alkanal Endgruppe und einem menschlichen Wachstumshormon |
RS20050202A (en) | 2002-09-09 | 2007-08-03 | Nektar Therapeuticals Al.Corporation, | Water-soluble polymer alkanals |
DE10242076A1 (de) * | 2002-09-11 | 2004-03-25 | Fresenius Kabi Deutschland Gmbh | HAS-Allergen-Konjugate |
EP1400533A1 (de) | 2002-09-11 | 2004-03-24 | Fresenius Kabi Deutschland GmbH | Hasylierte Polypeptide, besonders hasyliertes Erythropoietin |
BR0314227A (pt) * | 2002-09-11 | 2005-10-25 | Fresenius Kabi De Gmbh | Derivados de amido de hidroxialquila |
DE60323756D1 (de) | 2002-10-08 | 2008-11-06 | Fresenius Kabi De Gmbh | Pharmazeutisch aktive oligosaccharid-conjugate |
DE10254745A1 (de) | 2002-11-23 | 2004-06-03 | Supramol Parenteral Colloids Gmbh | Imidazolide von Polysaccharid Aldonsäuren, Verfahren zu ihrer Herstellung und Verwendung zur Kopplung an pharmazeutische Wirkstoffe |
DE10256558A1 (de) | 2002-12-04 | 2004-09-16 | Supramol Parenteral Colloids Gmbh | Ester von Polysaccharid Aldonsäuren, Verfahren zu ihrer Herstellung und Verwendung zur Kopplung an pharmazeutische Wirkstoffe |
DE10302520A1 (de) | 2003-01-23 | 2004-08-05 | Supramol Parenteral Colloids Gmbh | Kohlensäurediester von Stärkefraktionen und deren Derivate, Verfahren zu ihrer Herstellung und Verwendung zur Kopplung an pharmazeutische Wirkstoffe |
JP2007501811A (ja) | 2003-08-08 | 2007-02-01 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | 治療的な関心対象のタンパク質に対する遅延分子の選択的な化学物質接合のためのガラクトースオキシダーゼの使用。 |
SG145746A1 (en) * | 2003-08-08 | 2008-09-29 | Fresenius Kabi De Gmbh | Conjugates of hydroxyalkyl starch and g-csf |
WO2005014655A2 (en) | 2003-08-08 | 2005-02-17 | Fresenius Kabi Deutschland Gmbh | Conjugates of hydroxyalkyl starch and a protein |
BRPI0412671A (pt) * | 2003-08-08 | 2006-10-03 | Fresenius Kabi De Gmbh | conjugados de um polìmero e uma proteìna ligados por um grupo de ligação de oxima |
RU2370281C2 (ru) | 2003-08-08 | 2009-10-20 | Фрезениус Каби Дойчланд Гмбх | Конъюгаты гидроксиалкилкрахмала и g-csf |
US20050169941A1 (en) | 2004-01-29 | 2005-08-04 | Andrew Lees | Use of amino-oxy functional groups in the preparation of protein-polysaccharide conjugate vaccines |
AU2005210142A1 (en) | 2004-02-09 | 2005-08-18 | Noxxon Pharma Ag | Method for producing conjugates of polysaccharides and polynucleotides |
DE102004009783A1 (de) | 2004-02-28 | 2005-09-15 | Supramol Parenteral Colloids Gmbh | Hyperverzweigte Stärkefraktion, Verfahren zu ihrer Herstellung und ihre Konjugate mit pharmazeutischen Wirkstoffen |
WO2005092391A2 (en) * | 2004-03-11 | 2005-10-06 | Fresenius Kabi Deutschland Gmbh | Conjugates of hydroxyalkyl starch and a protein |
JP5191729B2 (ja) | 2004-03-11 | 2013-05-08 | フレゼニウス・カビ・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | 還元的アミノ化によって製造される、ヒドロキシアルキルデンプンとタンパク質とのコンジュゲート |
TW200603818A (en) * | 2004-03-11 | 2006-02-01 | Fresenius Kabi De Gmbh | Conjugates of hydroxyethyl starch and erythropoietin |
US20050265958A1 (en) | 2004-05-14 | 2005-12-01 | West Jennifer L | Nitric oxide releasing compositions and associated methods |
KR20070110902A (ko) * | 2005-03-11 | 2007-11-20 | 프레제니우스 카비 도이치란트 게엠베하 | 비활성 출발 물질로부터 생물활성 당단백질의 생산 |
JP5137814B2 (ja) | 2005-04-06 | 2013-02-06 | ジェンザイム・コーポレーション | 治療ターゲティングのための酸不安定リンカーを介するpegおよびポリシアルリソソーム酵素のコンジュゲート |
EP1762250A1 (de) * | 2005-09-12 | 2007-03-14 | Fresenius Kabi Deutschland GmbH | Konjugate welche durch chemische Ligation zwischen Hydroxyalkylstärken und aktiven Substanzen mit Bildung eines Thiazolidin-Ringes entstehen |
WO2007053292A2 (en) | 2005-10-31 | 2007-05-10 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Polysaccharide-derived nitric oxide-releasing carbon-bound diazeniumdiolates |
JP2009093397A (ja) | 2007-10-09 | 2009-04-30 | Panasonic Corp | タッチパネル及びこれを用いた入力装置 |
EP2070950A1 (de) * | 2007-12-14 | 2009-06-17 | Fresenius Kabi Deutschland GmbH | Hydroxyalkylstärkederivate und deren Herstellungsverfahren |
EP2070951A1 (de) * | 2007-12-14 | 2009-06-17 | Fresenius Kabi Deutschland GmbH | Verfahren zur Herstellung eines Hydroxyalkylstärkederivats mit zwei Linkern |
US9434610B2 (en) | 2008-10-07 | 2016-09-06 | Rexahn Pharmaceuticals, Inc. | HPMA—docetaxel conjugates and uses therefore |
-
2002
- 2002-03-06 DE DE10209821A patent/DE10209821A1/de not_active Ceased
-
2003
- 2003-02-28 KR KR10-2004-7013162A patent/KR20040098001A/ko not_active Application Discontinuation
- 2003-02-28 US US10/506,367 patent/US7541328B2/en not_active Expired - Fee Related
- 2003-02-28 PL PL03372481A patent/PL372481A1/xx unknown
- 2003-02-28 CA CA2478478A patent/CA2478478C/en not_active Expired - Fee Related
- 2003-02-28 AU AU2003215617A patent/AU2003215617A1/en not_active Abandoned
- 2003-02-28 WO PCT/EP2003/002083 patent/WO2003074087A1/de active Application Filing
- 2003-02-28 JP JP2003572602A patent/JP2005528349A/ja active Pending
- 2003-02-28 EP EP03743359A patent/EP1480682A1/de not_active Withdrawn
- 2003-02-28 CN CNA038051834A patent/CN1638808A/zh active Pending
- 2003-02-28 IL IL16370203A patent/IL163702A0/xx unknown
-
2009
- 2009-05-28 US US12/473,462 patent/US8916518B2/en not_active Expired - Fee Related
Non-Patent Citations (1)
Title |
---|
See references of WO03074087A1 * |
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US8916518B2 (en) | 2014-12-23 |
US7541328B2 (en) | 2009-06-02 |
DE10209821A1 (de) | 2003-09-25 |
US20090233847A1 (en) | 2009-09-17 |
PL372481A1 (en) | 2005-07-25 |
CN1638808A (zh) | 2005-07-13 |
IL163702A0 (en) | 2005-12-18 |
US20050181985A1 (en) | 2005-08-18 |
KR20040098001A (ko) | 2004-11-18 |
CA2478478A1 (en) | 2003-09-12 |
JP2005528349A (ja) | 2005-09-22 |
CA2478478C (en) | 2012-07-17 |
AU2003215617A1 (en) | 2003-09-16 |
WO2003074087A1 (de) | 2003-09-12 |
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