US2005113565A1PendingUtilityA1

Pegylated factor VII glycoforms

49
Priority: Jun 21, 2002Filed: Jun 30, 2003Published: May 26, 2005
Est. expiryJun 21, 2022(expired)· nominal 20-yr term from priority
Inventors:Niels Kristian KlausenSoren BjornCarsten BehrensPatrick William Garibay
A61P 7/02A61P 7/00A61K 38/4846C07K 14/755A61K 47/60A61P 7/04
49
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Claims

Abstract

The invention concerns a preparation comprising a plurality of Factor VII polypeptides or Factor VII-related polypeptides, wherein the polypeptides comprise asparagine-linked and/or serine-linked oligosaccharide chains, and wherein at least one oligosaccharide group is covalently attached to at least one polymeric group.

Claims

exact text as granted — not AI-modified
1 . A preparation comprising a Factor VII polypeptide or Factor VII-related polypeptide, wherein the polypeptide comprises one or more asparagine-linked and/or serine-linked oligosaccharide chains, and wherein at least one of said oligosaccharide groups is covalently attached to at least one polymeric group.  
     
     
         2 . A preparation according to  claim 1 , wherein the oligosaccharide to which the polymeric group is attached is a sialic acid moiety.  
     
     
         3 . A preparation according to  claim 1 , wherein said preparation comprises a plurality of Factor VII polypeptides or Factor VII-related polypeptides and wherein between about 94-100% of the polypeptide-linked oligosaccharide chains in the preparation comprise at least one sialic acid moiety.  
     
     
         4 . A preparation according to  claim 3 , wherein between about 94-100% of the oligosaccharide chains comprise at least one sialic acid moiety, and wherein less than about 25% of the oligosaccharide chains contain at least one uncapped antenna.  
     
     
         5 . A preparation according to  claim 4 , wherein less than about 10% of the oligosaccharide chains contain at least one uncapped antenna  
     
     
         6 . A preparation according to  claim 5 , wherein less than about 5% of the oligosaccharide chains contain at least one uncapped antenna  
     
     
         7 . A preparation according  claim 4 , wherein between about 96-100% of the oligosaccharide chains comprise at least one sialic acid moiety.  
     
     
         8 . A preparation according to  claim 7 , wherein between about 98-100% of the oligosaccharide chains comprise at least one sialic acid moiety.  
     
     
         9 . A preparation according to  claim 1 , wherein the asparagine-linked oligosaccharide chains are located in positions corresponding to amino acid residues Asn-145 and Asn-322 of wild-type human FVIIa ( FIG. 1 ).  
     
     
         10 . A preparation according to  claim 1 , wherein the serine-linked oligosaccharide chains are located in positions corresponding to amino acid residues Ser-52 and Ser-60 of wild-type human FVIIa ( FIG. 1 ).  
     
     
         11 . A preparation according to  claim 1 , wherein the polymer is selected from the group of polyalkylene oxide (PAO), polyalkylene glycol (PAG), polyethylene glycol (PEG), polypropylene glycol (PPG), branched PEGs, polyvinyl alcohol (PVA), polycarboxylate, poly-vinylpyrolidone, polyethylene-co-maleic acid anhydride, polystyrene-co-maleic acid anhydride, dextran, carboxymethyl-dextran, polyurethane, polyesters and polyamides.  
     
     
         12 . A preparation according to  claim 11 , wherein the polymer is a polyethylene glycol (PEG)  
     
     
         13 . A preparation according to  claim 12 , wherein the polyethylene glycol is PEG with a molecular weight of 300-100,000 Da.  
     
     
         14 . A preparation according to  claim 13 , wherein the PEG has a molecular weight of about 500-20,000 Da.  
     
     
         15 . A preparation according to  claim 14 , wherein the PEG has a molecular weight of about 500-15,000 Da,  
     
     
         16 . A preparation according to  claim 15 , wherein the PEG has a molecular weight of about 10 kDa.  
     
     
         17 . A preparation according to  claim 1 , wherein the polypeptide has the amino acid sequence of wild-type human Factor VII ( FIG. 1 ).  
     
     
         18 . A preparation according to  claim 1 , wherein the polypeptide is plasma-derived human Factor VIIa.  
     
     
         19 . A preparation according to  claim 1 , wherein the Factor VII polypeptide is selected from the group consisting of: S52A-Factor VII, S60A-Factor VII, Factor VII that has been proteolytically cleaved between residues 290 and 291; Factor VII that has been proteolytically cleaved between residues 315 and 316; Factor VII that has been oxidized, L305V-FVII, L305V/M306D/D309S-FVII, L3051-FVII, L305T-FVII, F374P-FVII, V158T/M298Q-FVII, V158D/E296V/M298Q-FVII, K337A-FVII, M298Q-FVII, V158D/M298Q-FVII, L305V/K337A-FVII, V158D/E296V/M298Q/L305V-FVII, V158D/E296V/M298Q/K337A-FVII, V158D/E296V/M298Q/L305V/K337A-FVII, K 157A-FVII, E296V-FVII, E296V/M298Q-FVII, V158D/E296V-FVII, V158D/M298K-FVII, S336G-FVII; Factor VII-sequence variants wherein the amino acid residue in positions 290 and/or 291 have been replaced, Factor VII-sequence variants wherein the amino acid residue in positions 315 and/or 316 have been replaced, and combinations of any of the foregoing.  
     
     
         20 . A preparation according to  claim 1 , wherein the Factor VII polypeptides are selected from the group consisting of: L305V/K337A-FVII, L305V/V158D-FVII, L305V/E296V-FVII, L305V/M298Q-FVII, L305V/V158T-FVII, L305V/K337A/V158T-FVII, L305V/K337A/M298Q-FVII, L305V/K337A/E296V-FVII, L305V/K337A/V158D-FVII, L305V/V158D/M298Q-FVII, L305V/V158D/E296V-FVII, L305V/V158T/M298Q-FVII, L305V/V158T/E296V-FVII, L305V/E296V/M298Q-FVII, L305V/V158D/E296V/M298Q-FVII, L305V/V158T/E296V/M298Q-FVII, L305V/V158T/K337A/M298Q-FVII, L305V/V158T/E296V/K337A-FVII, L305V/V158D/K337A/M298Q-FVII, L305V/V158D/E296V/K337A-FVII, L305V/V158D/E296V/M298Q/K337A-FVII, L305V/V158T/E296V/M298Q/K337A-FVII, S314E/K316H-FVII, S314E/K316Q-FVII, S314E/L305V-FVII, S314E/K337A-FVII, S314E/V158D-FVII, S314E/E296V-FVII, S314E/M298Q-FVII, S314E/V158T-FVII, K316H/L305V-FVII, K316H/K337A-FVII, K316H/V158D-FVII, K316H/E296V-FVII, K316H/M298Q-FVII, K316H/V158T-FVII, K316Q/L305V-FVII, K316Q/K337A-FVII, K316Q/V158D-FVII, K316Q/E296V-FVII, K316Q/M298Q-FVII, K316Q/V158T-FVII, S314E/L305V/K337A-FVII, S314E/L305V/V158D-FVII, S314E/L305V/E296V-FVII, S314E/L305V/M298Q-FVII, S314E/L305V/V158T-FVII, S314E/L305V/K337A/V158T-FVII, S314E/L305V/K337A/M298Q-FVII, S314E/L305V/K337A/E296V-FVII, S314E/L305V/K337A/V158D-FVII, S314E/L305V/V158D/M298Q-FVII, S314E/L305V/V158D/E296V-FVII, S314E/L305V/V158T/M298Q-FVII, S314E/L305V/V158T/E296V-FVII, S314E/L305V/E296V/M298Q-FVII, S314E/L305V/V158D/E296V/M298Q-FVII, S314E/L305V/V158T/E296V/M298Q-FVII, S314E/L305V/V158T/K337A/M298Q-FVII, S314E/L305V/V158T/E296V/K337A-FVII, S314E/L305V/V158D/K337A/M298Q-FVII, S314E/L305V/V158D/E296V/K337A-FVII, S314E/L305V/V158D/E296V/M298Q/K337A-FVII, S314E/L305V/V158T/E296V/M298Q/K337A-FVII, K316H/L305V/K337A-FVII, K316H/L305V/V158D-FVII, K316H/L305V/E296V-FVII, K316H/L305V/M298Q-FVII, K316H/L305V/V158T-FVII, K316H/L305V/K337A/V158T-FVII, K316H/L305V/K337A/M298Q-FVII, K316H/L305V/K337A/E296V-FVII, K316H/L305V/K337A/V158D-FVII, K316H/L305V/V 158D/M298Q-FVII, K316H/L305V/V158D/E296V-FVII, K316H/L305V/V158T/M298Q-FVII, K316H/L305V/V158T/E296V-FVII, K316H/L305V/E296V/M298Q-FVII, K316H/L305V/V158D/E296V/M298Q-FVII, K316H/L305V/V158T/E296V/M298Q-FVII, K316H/L305V/V158T/K337A/M298Q-FVII, K316H/L305V/V158T/E296V/K337A-FVII, K316H/L305V/V158D/K337A/M298Q-FVII, K316H/L305V/V158D/E296V/K337A-FVII, K316H/L305V/V158D/E296V/M298Q/K337A-FVII, K316H/L305V/V158T/E296V/M298Q/K337A-FVII, K316Q/L305V/K337A-FVII, K316Q/L305V/V158D-FVII, K316Q/L305V/E296V-FVII, K316Q/L305V/M298Q-FVII, K316Q/L305V/V158T-FVII, K316Q/L305V/K337A/V158T-FVII, K316Q/L305V/K337A/M298Q-FVII, K316Q/L305V/K337A/E296V-FVII, K316Q/L305V/K337A/V158D-FVII, K316Q/L305V/V158D/M298Q-FVII, K316Q/L305V/V158D/E296V-FVII, K316Q/L305V/V158T/M298Q-FVII, K316Q/L305V/V158T/E296V-FVII, K316Q/L305V/E296V/M298Q-FVII K316Q/L305V/V158D/E296V/M298Q-FVII, K316Q/L305V/V158T/E296V/M298Q-FVII, K316Q/L305V/V158T/K337A/M298Q-FVII, K316Q/L305V/V158T/E296V/K337A-FVII, K316Q/L305V/V158D/K337A/M298Q-FVII, K316Q/L305V/V158D/E296V/K337A-FVII, K316Q/L305V/V158D/E296V/M298Q/K337A-FVII, K316Q/L305V/V158T/E296V/M298Q/K337A-FVII, F374Y/K337A-FVII, F374Y/V158D-FVII, F374Y/E296V-FVII, F374Y/M298Q-FVII, F374Y/V158T-FVII, F374Y/S314E-FVII, F374Y/L305V-FVII, F374Y/L305V/K337A-FVII, F374Y/L305V/V158D-FVII, F374Y/L305V/E296V-FVII, F374Y/L305V/M298Q-FVII, F374Y/L305V/V158T-FVII, F374Y/L305V/S314E-FVII, F374Y/K337A/S314E-FVII, F374Y/K337A/V158T-FVII, F374Y/K337A/M298Q-FVII, F374Y/K337A/E296V-FVII, F374Y/K337A/V158D-FVII, F374Y/V158D/S314E-FVII, F374Y/V158D/M298Q-FVII, F374Y/V158D/E296V-FVII, F374Y/V158T/S314E-FVII, F374Y/V158T/M298Q-FVII, F374Y/V158T/E296V-FVII, F374Y/E296V/S314E-FVII, F374Y/S314E/M298Q-FVII, F374Y/E296V/M298Q-FVII, F374Y/L305V/K337A/V158D-FVII, F374Y/L305V/K337A/E296V-FVII, F374Y/L305V/K337A/M298Q-FVII, F374Y/L305V/K337A/V158T-FVII, F374Y/L305V/K337A/S314E-FVII, F374Y/L305V/V158D/E296V-FVII, F374Y/L305V/V158D/M298Q-FVII, F374Y/L305V/V158D/S314E-FVII, F374Y/L305V/E296V/M298Q-FVII, F374Y/L305V/E296V/V158T-FVII, F374Y/L305V/E296V/S314E-FVII, F374Y/L305V/M298Q/V158T-FVII, F374Y/L305V/M298Q/S314E-FVII, F374Y/L305V/V158T/S314E-FVII, F374Y/K337A/S314E/V158T-FVII, F374Y/K337A/S314E/M298Q-FVII, F374Y/K337A/S314E/E296V-FVII, F374Y/K337A/S314E/V158D-FVII, F374Y/K337A/V158T/M298Q-FVII, F374Y/K337A/V158T/E296V-FVII, F374Y/K337A/M298Q/E296V-FVII, F374Y/K337A/M298Q/V158D-FVII, F374Y/K337A/E296V/V158D-FVII, F374Y/V158D/S314E/M298Q-FVII, F374Y/V158D/S314E/E296V-FVII, F374Y/V158D/M298Q/E296V-FVII, F374Y/V158T/S314E/E296V-FVII, F374Y/V158T/S314E/M298Q-FVII, F374Y/V158T/M298Q/E296V-FVII, F374Y/E296V/S314E/M298Q-FVII, F374Y/L305V/M298Q/K337A/S314E-FVII, F374Y/L305V/E296V/K337A/S314E-FVII, F374Y/E296V/M298Q/K337A/S314E-FVII, F374Y/L305V/E296V/M298Q/K337A-FVII, F374Y/L305V/E296V/M298Q/S314E-FVII, F374Y/V158D/E296V/M298Q/K337A-FVII, F374Y/V158D/E296V/M298Q/S314E-FVII, F374Y/L305V/V158D/K337A/S314E-FVII, F374Y/V158D/M298Q/K337A/S314E-FVII, F374Y/V158D/E296V/K337A/S314E-FVII, F374Y/L305V/V158D/E296V/M298Q-FVII, F374Y/L305V/V158D/M298Q/K337A-FVII, F374Y/L305V/V158D/E296V/K337A-FVII, F374Y/L305V/V158D/M298Q/S314E-FVII, F374Y/L305V/V158D/E296V/S314E-FVII, F374Y/V158T/E296V/M298Q/K337A-FVII, F374Y/V158T/E296V/M298Q/S314E-FVII, F374Y/L305V/V158T/K337A/S314E-FVII, F374Y/V158T/M298Q/K337A/S314E-FVII, F374Y/V158T/E296V/K337A/S314E-FVII, F374Y/L305V/V158T/E296V/M298Q-FVII, F374Y/L305V/V158T/M298Q/K337A-FVII, F374Y/L305V/V 158T/E296V/K337A-FVII, F374Y/L305V/V158T/M298Q/S314E-FVII, F374Y/L305V/V158T/E296V/S314E-FVII, F374Y/E296V/M298Q/K337A/V158T/S314E-FVII, F374Y/V158D/E296V/M298Q/K337A/S314E-FVII, F374Y/L305V/V158D/E296V/M298Q/S314E-FVII, F374Y/L305V/E296V/M298Q/V158T/S314E-FVII, F374Y/L305V/E296V/M298Q/K337A/V158T-FVII, F374Y/L305V/E296V/K337A/V158T/S314E-FVII, F374Y/L305V/M298Q/K337A/V158T/S314E-FVII, F374Y/L305V/V158D/E296V/M298Q/K337A-FVII, F374Y/L305V/V158D/E296V/K337A/S314E-FVII, F374Y/L305V/V158D/M298Q/K337A/S314E-FVII, F374Y/L305V/E296V/M298Q/K337A/V158T/S314E-FVII, F374Y/L305V/V158D/E296V/M298Q/K337A/S314E-FVII, S52A-Factor VII, S60A-Factor VII; and P11Q/K33E-FVII, T106N-FVII, K143N/N145T-FVII, V253N-FVII, R290N/A292T-FVII, G291N-FVII, R315N/V317T-FVII, K143N/N145T/R315N/V317T-FVII; FVII having substitutions, additions or deletions in the amino acid sequence from 233Thr to 240Asn, FVII having substitutions, additions or deletions in the amino acid sequence from 304Arg to 329Cys, FVII having substitutions, deletions, additions in the amino acid sequence Ile153-Arg223, and combinations of any of the foregoing.  
     
     
         21 . A preparation according to  claim 1 , wherein the Factor VII-related polypeptides are selected from the group consisting of: R1 52E-Factor VII, S344A-Factor VII, FFR-Factor VII, and Factor VIIa lacking the Gla domain.  
     
     
         22 . A preparation according to  claim 1 , wherein the Factor VII-related polypeptide exhibits at least about 25% of the specific activity of wild-type Factor VIIa that has been produced in the same cell type, when tested in one or more of a clotting assay, proteolysis assay, or TF binding assay.  
     
     
         23 . A preparation according to  claim 1 , wherein the Factor VII-related polypeptide exhibits less than about 25% of the specific activity of wild-type Factor VIIa that has been produced in the same cell type when tested in one or more of a clotting assay, proteolysis assay, or TF binding assay.  
     
     
         24 . A preparation according to  claim 1 , wherein the preparation exhibits a bioavailability that is at least about 110% of the bioavailability of a reference preparation.  
     
     
         25 . A preparation according to  claim 1 , wherein the preparation exhibits a serum half-life that is at least about 125% of the half-life of a reference preparation.  
     
     
         26 . A method for producing a preparation according to  claim 1 , said method comprising contacting Factor VII or Factor VII-related polypeptides with a polymer molecule under conditions in which the at least one polymer molecule is covalently attached to at least one of the oligosaccharide chains of the polypeptides.  
     
     
         27 . A pharmaceutical formulation comprising (i) a preparation as defined in  claim 1  and (ii) a pharmaceutically acceptable carrier or adjuvant.  
     
     
         28 . A method for treating a Factor VII-responsive syndrome, the method comprising administering a pharmaceutical formulation as defined in  claim 27  to a patient in need of such treatment, under conditions that result in a decrease in bleeding and/or an increase in blood clotting, wherein the formulation comprises Factor VII polypeptides.  
     
     
         29 . The method according to  claim 28 , wherein the syndrome is selected from the group consisting of haemophilia A, haemophilia B, Factor XI deficiency, Factor VII deficiency, thrombocytopenia, von Willebrand's disease, presence of a clotting factor inhibitor, surgery, trauma, and anticoagulant therapy, including dilutional coagulopathy, intercranial haemorrhage, stem cell transplantation, upper gastrointestinal bleedings, and liver disease.  
     
     
         30 . A method for preventing unwanted bleeding, the method comprising administering a pharmaceutical formulation as defined in  claim 27  to a patient in need of such treatment, under conditions that result in a decrease in bleeding and/or an increase in blood clotting, wherein the formulation comprises Factor VII polypeptides.  
     
     
         31 . A method for preventing unwanted blood clotting, the method comprising administering a pharmaceutical formulation as defined in  claim 27  to a patient in need of such treatment, under conditions effective for inhibiting coagulation, wherein the formulation comprises Factor VII-related polypeptides.  
     
     
         32 . A method for preventing tissue factor mediated reactions, the method comprising administering a pharmaceutical formulation as defined in  claim 27  to a patient in need of such treatment, under conditions effective for inhibiting coagulation, wherein the formulation comprises Factor VII-related polypeptides.  
     
     
         33 . A method as defined in  claim 31 , wherein the unwanted blood clotting is associated with a condition selected from the group consisting of: angioplasty, deep vein thrombosis, pulmonary embolism, stroke, disseminated intravascular coagulation (DIC), fibrin deposition in lungs and kidneys associated with gram-negative endotoxemia, and myocardial infarction.  
     
     
         34 . A method as defined in  claim 32 , wherein the tissue factor mediated reactions are associated with a condition selected from the group consisting of inflammation, cancer, tumour growth, metastasis, angiogenesis, Systemic Inflammatory Response Syndrome (SIRS), Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS), Multiple Organ Failure (MOF), Hemolytic Uremic Syndrome (HUS), and thrombotic thrombocytopenic purpura (TTP).

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