WO2008074032A1 - Factor viia- (poly) sialic acid conjugate having prolonged in vivo half-life - Google Patents

Factor viia- (poly) sialic acid conjugate having prolonged in vivo half-life Download PDF

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Publication number
WO2008074032A1
WO2008074032A1 PCT/US2007/087553 US2007087553W WO2008074032A1 WO 2008074032 A1 WO2008074032 A1 WO 2008074032A1 US 2007087553 W US2007087553 W US 2007087553W WO 2008074032 A1 WO2008074032 A1 WO 2008074032A1
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WIPO (PCT)
Prior art keywords
fviia
life
construct
vivo half
rfviia
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Ceased
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PCT/US2007/087553
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English (en)
French (fr)
Inventor
Peter Turecek
Juergen Siekmann
Friedrich Scheiflinger
Michel Canavaggio
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Baxter Healthcare SA
Baxter International Inc
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Baxter Healthcare SA
Baxter International Inc
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Application filed by Baxter Healthcare SA, Baxter International Inc filed Critical Baxter Healthcare SA
Priority to ES07865679.0T priority Critical patent/ES2521490T3/es
Priority to CA2670618A priority patent/CA2670618C/en
Priority to BRPI0720282A priority patent/BRPI0720282B8/pt
Priority to PL07865679T priority patent/PL2101821T3/pl
Priority to CN200780046301.6A priority patent/CN101557830B/zh
Priority to EP07865679.0A priority patent/EP2101821B1/en
Priority to AU2007333049A priority patent/AU2007333049B2/en
Priority to JP2009541613A priority patent/JP5876208B2/ja
Priority to DK07865679.0T priority patent/DK2101821T3/da
Publication of WO2008074032A1 publication Critical patent/WO2008074032A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/96—Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
    • 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
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
    • 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
    • A61K47/54—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 compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424—Serine endopeptidases (3.4.21)
    • C12N9/6437—Coagulation factor VIIa (3.4.21.21)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21021—Coagulation factor VIIa (3.4.21.21)
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the blood coagulation cascade is divided into three distinct segments: the intrinsic, extrinsic, and common pathways (Schenone et al., Curr Opin Hematol. 2004; 11 :272-7).
  • the cascade involves a series of serine protease enzymes (zymogens) and protein cofactors. When required, an inactive zymogen precursor is converted into the active form, which consequently converts the next enzyme in the cascade,
  • the intrinsic pathway requires the clotting factors VIO, IX, X, XI, and XII. Initiation of the intrinsic pathway occurs when prekallikrein, high-molecular-weight kininogen, factor XI (FXI) and factor XlI (FXII) are exposed to a negatively charged surface. Also required are calcium ions and phospholipids secreted from platelets,
  • FVlI is synthesized in the liver and secreted as a single-chain glycoprotein of 48 kD.
  • FVlIa shares with all vitamin K-dependent serine protease glycoproteins a similar protein domain structure consisting of an amino-terminal gamma-carboxyglutamic acid (GIa) domain with 9-12 residues responsible for the interaction of the protein with lipid membranes, a carboxy-terminal serine protease domain (catalytic domain), and two epidermal growth factor-like domains containing a calcium ion binding site that mediates interaction with tissue factor.
  • GIa amino-terminal gamma-carboxyglutamic acid
  • Hereditary FVII deficiency is a rare autosomal recessive bleeding disorder with a prevalence estimated to be 1 case per 500,000 persons in the general population (Acharya et al., J Thromb Haernost 2004;2248-56). Acquired FVII deficiency from inhibitors is also very rare. Cases have also been reported with the deficiency occurring in association with drugs such as cephalosporins, penicillins, and oral anticoagulants. Furthermore, acquired FVIl deficiency has been reported to occur spontaneously or with other conditions, such as myeloma, sepsis, aplastic anemia, with interleukin-2 and antithymocyte globulin therapy.
  • polysialic acid is biodegradable. Covalent coupling of colominic acid to catalase and asparaginase led to an increase of enzyme stability in the presence of proteolytic enzymes or blood plasma. Comparative studies in vivo with polysialylated and unmodified asparaginase revealed that polysialylation increased the half-life of the enzyme (Fernandas and Gregoriadis, ⁇ nt J Pharm. 2001 ;217:215-24)
  • WO 98/32466A1 suggests that FVII, among many other proteins, may be PEGylated but does not contain any working examples supporting the disclosure.
  • compositions and methods that provide clotting protein preparations comprising improved plasma derived or rFVII, modified FVII, or FVlI-related polypeptide.
  • the aforementioned proteinaceous construct wherein the physiologically acceptable carbohydrate moiety is non- covalently linked to at least one amino acid residue of said FVIIa molecule.
  • the aforementioned proteinaceous construct is provided wherein said physiologically acceptable carbohydrate moiety is a polysialic acid or a derivative thereof.
  • vectors can be used for the preparation of the rFVIIa and can be selected from eukaryotic and prokaryotic expression vectors.
  • vectors for prokaryotic expression include plasmids such as pRSET, pET, pBAD, etc., wherein the promoters used in prokaryotic expression vectors include lac, trc, trp, recA, araBAD, etc.
  • Polysaccharide compounds of particular use for the invention are those produced by bacteria. Some of these naturally occurring polysaccharides are known as glycolipids. It is particularly advantageous if the polysaccharide compounds are substantially free of terminal galactose units, which tend to be recognized by galactose receptors of hepatocytes and Kupffer cells. LiMMGE
  • FVIIa may be covalently linked to the polysaccharide compounds by any of various techniques known to those of skill in the art. Various examples are identified at column 7, line 15, through column 8, line 5 of U.S. Patent No. 5,846,951.
  • Examples include linkage through the peptide bond between a carboxyl group on one of either the FVIIa or polysaccharide and an amine group of the other, or an ester linkage between a carboxyl group of one and a hydroxyl group of the other.
  • Another linkage by which the active ingredient, e.g., FVIIa, could be covalently bonded to the polysaccharide compound is via a Schiff base, between a free amino group on the active ingredient being reacted with an aldehyde group formed at the non-reducing end of the polymer by periodate oxidation (Jennings and Lugowski, J Immunol.
  • proteiiiaceous construct of the present invention may be administered by injection, such as intravenous, intramuscular, or intraperitoneal injection.
  • an effective amount includes a dose suitable for treating a mammal having a bleeding disorder as outlined above.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a proteinaceous construct as defined above.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, diluent, salt, buffer, or excipient.
  • the pharmaceutical composition can be used for treating the above-defined bleeding disorders.
  • the pharmaceutical composition of the invention may be a solution or a lyophilized product.
  • Figure 1 shows a SDS-PAGE of rFVIIa after conjugation with PSA
  • Figure 2 shows the pharmacokinetics of rF VIIa-PS A-conjugate and unmodified rFVIIa in rats
  • Figure 4 shows a SDS-PAGE of rFVIIa after N-terminal conj ugation with PSA
  • Figure 5 shows a capillary electrophoresis of mono-SA rFVIIa and Tri-SA-rFVHa
  • the CA conjugated protein was eluted with elution buffer (2OmM HEPES / IM NaCl, pH 8.0).
  • rFVlIa-PSA The enzymatic activity of rFVlIa-PSA was determined by a clotting assay, where FVIIa was added to a human FVI ⁇ -def ⁇ cient plasma and the clotting was triggered by a truncated tissue factor reacting with FVlIa but not with FVlI (Staclot, Diagnostica Stage, Asnieres, France).
  • the FVIlI-bypassing activity of rFVII- PSA was measured by a thrombin generation assay (TGA), where FVIIa was added to a severe haemophilia A plasma, containing a high titer of anti-FVlII inhibitor in the presence of a thrombin-specific fluorescence peptide-substrate. Coagulation was triggered with a tissue factor-phospho lipid complex and thrombin generation was continuously measured by the cleavage rate of the fluorophore of the substrate. The thrombin generation activity was calculated from the peak thrombin, i.e. the maximum thrombin concentration observed during the assay. In both cases a NovoSeven recombinant FVIIa preparation (Novo Nordisk, Copenhagen, Denmark) was used as reference.
  • TGA thrombin generation assay
  • RFVIIa was conjugated with N-acetytneurarninic acid as described in US 3,487,890.
  • 350 mg synthetic N-acetylneuraminic acid (Sigma- Aldrich) were dissolved in 10 mL 0.1 M HEPES buffer, pH 9.0.
  • 430 mg CNBr (Fluka, Steinhamm, Germany) were added to this solution and the pH was adjusted to 9.5 with 0.5 M NaOH during the activation procedure. After 30 rain the pH value was 9.5. Then the pH value was adjusted to 8.4 by addition of 0.1 M HCl.
  • [0097J RFVIIa was conjugated to a synthetic N-acetylneuraminic acid trimer obtained from TimTec, LLC (Newark, USA) as described in US 3,487,890 for N-acetylneuramim ' c acid.
  • 350 mg of the N-acetylneuraminic acid trimer were dissolved in 10 mL 0.1 M HEPES buffer, pH 9.0.
  • 430 mg CNBr (Fluka) were added to this solution and the pH was adjusted to 9.5 with 0.5 M NaOH during the activation procedure. After 30 min the pH value was at 9.5.
  • the pH value was adjusted to 8.4 by addition of 0.1 M HCl.
  • the temperature was controlled by use of an ice bath and kept at 20 - 25°C. Then the conjugation of the activated trimer with FVIIa was performed as described in Example 5.
  • NaCNBHa was added to give a final concentration of 50 mg/mL and the pH was corrected to pH 7.0 by addition of 0.1 M HCl.
  • the mixture was incubated at 37°C under gentle stirring for 48h.
  • the solution was concentrated by UF/DF using a 10 kD membrane (regenerated cellulose/ Millipore) against 20 mM Hepes buffer, 150 mM NaCl, pH 7.4.

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PCT/US2007/087553 2006-12-15 2007-12-14 Factor viia- (poly) sialic acid conjugate having prolonged in vivo half-life Ceased WO2008074032A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
ES07865679.0T ES2521490T3 (es) 2006-12-15 2007-12-14 Conjugado de factor VIIa - ácido (poli)siálico con una vida media in vivo prolongada.
CA2670618A CA2670618C (en) 2006-12-15 2007-12-14 Factor viia- (poly) sialic acid conjugate having prolonged in vivo half-life
BRPI0720282A BRPI0720282B8 (pt) 2006-12-15 2007-12-14 construção proteica, composição farmacêutica, e, kit
PL07865679T PL2101821T3 (pl) 2006-12-15 2007-12-14 Koniugat czynnik viia-(poli)kwas sjalowy o przedłużonym okresie półtrwania in vivo
CN200780046301.6A CN101557830B (zh) 2006-12-15 2007-12-14 具有延长的体内半衰期的因子VIIa-聚唾液酸结合物
EP07865679.0A EP2101821B1 (en) 2006-12-15 2007-12-14 Factor viia- (poly) sialic acid conjugate having prolonged in vivo half-life
AU2007333049A AU2007333049B2 (en) 2006-12-15 2007-12-14 Factor VIIa-(poly)sialic acid conjugate having prolonged in vivo half-life
JP2009541613A JP5876208B2 (ja) 2006-12-15 2007-12-14 延長されたｉｎｖｉｖｏ半減期を有する第ＶＩＩａ因子−（ポリ）シアル酸結合体
DK07865679.0T DK2101821T3 (da) 2006-12-15 2007-12-14 Faktor VIIA-(poly)sialinsyre-konjugat med forlænget halveringstid in vivo

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US87521706P 2006-12-15 2006-12-15
US60/875,217 2006-12-15

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WO2008074032A1 true WO2008074032A1 (en) 2008-06-19

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US (4) US8637007B2 (https=)
EP (3) EP2532369B1 (https=)
JP (4) JP5876208B2 (https=)
CN (3) CN105838699A (https=)
AU (1) AU2007333049B2 (https=)
BR (1) BRPI0720282B8 (https=)
CA (1) CA2670618C (https=)
DK (1) DK2101821T3 (https=)
ES (2) ES2655639T3 (https=)
HK (1) HK1198172A1 (https=)
PL (1) PL2101821T3 (https=)
PT (1) PT2101821E (https=)
WO (1) WO2008074032A1 (https=)

Cited By (25)

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WO2009000522A1 (en) * 2007-06-26 2008-12-31 Baxter International Inc. Hydrolysable polymeric fmoc-linker
WO2010045568A1 (en) * 2008-10-17 2010-04-22 Baxter International Inc. Modified blood factors comprising a low degree of water soluble polymer
WO2010014708A3 (en) * 2008-08-01 2010-04-22 Baxter International Inc. Factor viii polymer conjugates
WO2010102886A1 (en) 2009-02-19 2010-09-16 Novo Nordisk A/S Modification of factor viii
WO2011017055A3 (en) * 2009-07-27 2011-04-07 Baxter International Inc. Blood coagulation protein conjugates
US7982010B2 (en) 2006-03-31 2011-07-19 Baxter International Inc. Factor VIII polymer conjugates
US7985839B2 (en) 2006-03-31 2011-07-26 Baxter International Inc. Factor VIII polymer conjugates
WO2011101267A1 (en) 2010-02-16 2011-08-25 Novo Nordisk A/S Conjugated fviii variants
US8053561B2 (en) 2006-03-31 2011-11-08 Baxter International Inc. Pegylated factor VIII
EP2517714A1 (en) * 2007-04-26 2012-10-31 Inspiration Biopharmaceuticals, Inc. Recombinant vitamin K dependent proteins with high sialic acid content and methods of preparing same
US8637007B2 (en) 2006-12-15 2014-01-28 Baxter International Inc. Factor VIIa-polysialic acid conjugate having prolonged in vivo half-life
US8642737B2 (en) 2010-07-26 2014-02-04 Baxter International Inc. Nucleophilic catalysts for oxime linkage
WO2014060397A1 (en) * 2012-10-15 2014-04-24 Novo Nordisk Health Care Ag Factor vii conjugates
US8809501B2 (en) 2009-07-27 2014-08-19 Baxter International Inc. Nucleophilic catalysts for oxime linkage
US8945897B2 (en) 2010-07-26 2015-02-03 Baxter International Inc. Materials and methods for conjugating a water soluble fatty acid derivative to a protein
JP2015155469A (ja) * 2015-06-01 2015-08-27 バクスター・インターナショナル・インコーポレイテッドＢａｘｔｅｒ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｉｎｃｏｒｐ０Ｒａｔｅｄ 第ｆｖｉｉｉ因子ポリマー結合体
WO2015154139A1 (en) * 2014-04-11 2015-10-15 Csl Limited Half-life extended factor fviia protein for prevention and treatment of bleeding and dosing regimens therefor
JP2015227385A (ja) * 2009-07-27 2015-12-17 バクスター・インターナショナル・インコーポレイテッドＢａｘｔｅｒ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｉｎｃｏｒｐ０Ｒａｔｅｄ 血液凝固タンパク質複合体
US9371370B2 (en) 2013-10-15 2016-06-21 Novo Nordisk Healthcare Ag Coagulation factor VII polypeptides
US9474790B2 (en) 2013-04-18 2016-10-25 Novo Nordisk A/S Stable, protracted GLP-1/glucagon receptor co-agonists for medical use
US9486506B2 (en) 2011-09-23 2016-11-08 Novo Nordisk A/S Glucagon analogues
US9795683B2 (en) 2009-07-27 2017-10-24 Lipoxen Technologies Limited Glycopolysialylation of non-blood coagulation proteins
JP2018115170A (ja) * 2018-03-02 2018-07-26 バクスアルタ ゲーエムベーハー 第ｆｖｉｉｉ因子ポリマー結合体
US10570184B2 (en) 2014-06-04 2020-02-25 Novo Nordisk A/S GLP-1/glucagon receptor co-agonists for medical use
US12029780B2 (en) 2013-10-21 2024-07-09 Opko Biologics Ltd. Long-acting polypeptides and methods of producing and administering same

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US12203113B2 (en) 2009-07-09 2025-01-21 Opko Biologics Ltd. Long-acting coagulation factors and methods of producing same
KR101808751B1 (ko) 2009-11-13 2017-12-13 그리폴스 테라퓨틱스 인코포레이티드 폰 빌레브란트 인자(ｖＷＦ)-함유 제제, 및 그와 관련된 방법, 키트 및 용도
GB201007356D0 (en) 2010-04-30 2010-06-16 Leverton Licence Holdings Ltd Conjugated factor VIIa
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