WO2009000522A1 - Hydrolysable polymeric fmoc-linker - Google Patents
Hydrolysable polymeric fmoc-linker Download PDFInfo
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- WO2009000522A1 WO2009000522A1 PCT/EP2008/005155 EP2008005155W WO2009000522A1 WO 2009000522 A1 WO2009000522 A1 WO 2009000522A1 EP 2008005155 W EP2008005155 W EP 2008005155W WO 2009000522 A1 WO2009000522 A1 WO 2009000522A1
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- Prior art keywords
- alkyl
- psa
- protein
- compound
- polymer
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- 0 **1C=C(C(COC(ON(C(CC2)=O)C2=O)=O)C2=C3C=C*(C(*)(*)*N(C(C=C4)=O)C4=O)C=C2)C3=CC=C1 Chemical compound **1C=C(C(COC(ON(C(CC2)=O)C2=O)=O)C2=C3C=C*(C(*)(*)*N(C(C=C4)=O)C4=O)C=C2)C3=CC=C1 0.000 description 3
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
- C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- 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
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
- C07C43/14—Unsaturated ethers
- C07C43/164—Unsaturated ethers containing six-membered aromatic rings
- C07C43/168—Unsaturated ethers containing six-membered aromatic rings containing six-membered aromatic rings and other rings
Definitions
- the present invention relates to the preparation of a hydrolysable linker, which is bound to at least one semi-synthetic polymer. These hydrolysable linker are useful for extending the in-vivo circulation of protein and peptide drugs.
- An attractive strategy for improving clinical properties of protein or peptide drugs is a modification of the drugs with polymers e.g. polyalkylene-oxides (Roberts et al., Advan Drug Rev. 54, 459-476 (2002)) or polysaccharides like polysialic acid (Femandes et al., Biochim Biophys Acta 1341 , 26-34 (1997)), dextranes or hydroxyl alkyl starch. (All documents cited in the specification are incorporated by reference.)
- the modification with poly(ethylene glycol) (PEG) has been known for a while. However, modification of proteins with PEG often leads to reduction of the activity of the protein.
- Polysialic acid also known as colominic acid (CA) is a natural occurring polysaccharide. It is a homopolymer of N-acetylneuraminic acid with ⁇ (2 ⁇ 8) ketosidic linkage and contains vicinal diol groups at its non-reducing end. PSA is negatively charged and is a natural constituent of the human body. It can easily be produced from bacteria in large quantities with pre-determined physical characteristics (US 5,846,951). Being chemically and immunologically identical to polysialic acid in the human body, bacterial polysialic acid is non-immunogenic even when coupled to proteins. Unlike other polymers (e.g.; PEG), polysialic acid is biodegradable.
- Short PSA polymeric chains with only 1-4 sialic acid units have also been synthesized (Kang et al., Chem Commun., 227-228 (2000); Ress et a!., Current Organic Synthesis 1 , 31-46 (2004)).
- the protein-polymer conjugate can be regarded as a prodrug and the activity of the protein can be released from the conjugate via a controlled release mechanism.
- im- proved pharmacokinetic properties of the drug can be obtained (Zhao et al., Bio- conjugate Chem. 17, 341-351 (2006)).
- the present invention provides a hydrolysable linker, which is bound to at least one semi-synthetic biopolymer, wherein the hydrolysable linker is conjugated to a protein or peptide drug in order to improve its in-vivo properties such as the in- vivo circulation.
- the present invention provides a compound of the general formula 1 :
- Z a leaving group and at least one of position 1 , 2, 3, 4, 5, 6, 7 or 8 is bound to radical Y.
- Y is a radical containing a semi-synthetic biopolymer, which is bound to a N- succinimidyl moiety.
- radical Y the compound of formula 1 may optionally be bound to radical X in at least one of the available position 1 , 2, 3, 4, 5, 6, 7 or 8.
- X is -SO 3 -R 3 .
- R 3 is selected from the group consisting of hydrogen, (Ci-Cs)-alkyl and (C 1 -
- R 4 is a polymer
- Fig. 1 shows the in-vitro hydrolysis of a FVIIa-PSA conjugate at pH 8.3.
- the release of the FVIIa activity was measured with the Staclot - assay (Diagnostica Stago, Asnieres, France).
- Fig. 2 shows the shows the in-vitro hydrolysis of a FVIIa-trimer PSA conjugate at pH 8.3.
- the release of the FVIIa activity was measured with the Staclot - assay (Diagnostica Stago, Asnieres, France).
- Fig. 3 shows FVIIa activity in plasma measured with a clotting assay (Staclot, Diagnostica Stago, Asnieres, France). For FVIIa clotting activity the dose adjusted - A -
- AUC area under curve
- Fig. 4 shows the determination of the FVIIa antigen by ELISA with a polyclonal anti-human FVII antibody.
- the dose adjusted AUC (0 - infinity) increased from 0.010 (unmodified rFVila) to 0.014 (rFVila - conjugate), the terminal half life increased from 1.4 to 2.3 hours and the MRT from 1.5 to 2.2 hours.
- Fig. 5 shows FVIIa activity in plasma, measured with a clotting assay (Staclot, Di- agnostica Stago, Asnieres, France).
- the pharmacokinetic of rFVIIa-trimer-PSA conjugates is improved (-O-) compared to native rFVila (- ⁇ — ).
- the present invention provides a hydrolysable linker, which is bound to at least one semi-synthetic biopolymer, wherein the hydrolysable linker can be further conjugated to a protein or peptide drug in order to improve their in-vivo properties such as in-vivo circulation.
- the activity of the protein or peptide drug can be released from the conjugate via a controlled release mechanism.
- C 1 -C 8 -alkyl refers to monovalent alkyl groups having 1 to 8 carbon atoms. This term is exemplified by groups such as methyl, ethyl, propyl, butyl, hexyl and the like. Linear and branched alkyls are included.
- Leaving groups refers to groups, which are capable of reacting with a nu- cleophile present on the protein or peptide drug that forms the conjugate. This term is exemplified by groups such as N-hydroxysuccimimidyl, N- hydroxybenzotriazolyl, halogen, N-hydroxyphthalimidyl, p-nitrophenoxy, imidazolyl, thiazolidinyl thione, O-acyl ureas or other suitable leaving groups will be apparent to those of ordinary skill.
- the protein or peptide drug thus contains one or more groups for displacement, such as an amine.
- Protein or peptide drug are plasma proteins or blood coagulation factors such as FVIII, VWF, FVIIa and FIX.
- a “semi-synthetic biopolymer” refers to a manufactured organic polymer, which is based on a naturally occurring polymer.
- a semi-synthetic biopolymer may also be functionalized by reactive groups in order to conjugate these functionalized semi-synthetic biopolymers to other compounds.
- This term "semi-synthetic biopolymer” is exemplified by linear or branched polymers such as carbohydrates, specifically such as polysaccharides. Examples of polysaccharides are PSA (poly- sialic acid) and HAS (hydroxyalkylstarch).
- “Hydrolysable” linker refers to a linker system, in which the protein is released in native form. The protein is released and the linker is split off completely. Synonyms for hydrolysable are “degradable” or “releasable” linkers.
- the present invention provides a compound of the general formula 1 :
- Z a leaving group and at least one of position 1 , 2, 3, 4, 5, 6, 7 or 8 is bound to radical Y.
- Y is a radical containing a semi-synthetic biopolymer, which is bound to a N- succinimidyl moiety.
- the compound of formula 1 may optionally be bound to radical X in at least one of the available position 1 , 2, 3, 4, 5, 6, 7 or 8.
- X is -SO 3 -R 3 .
- R 3 is selected from the group consisting of hydrogen, (Ci-Cs)-alkyl and (C 1 - C 8 )-alkyl-R 4 .
- R 4 is a polymer.
- examples are hydrophilic polymers such as poly(ethylene glycol) (PEG).
- the invention relates to a compound of formula 1 , wherein Z is an N-succinimidyl ester and at least one of position 1 , 2, 3, 4, 5, 6, 7 or 8 is bound to radical Y, wherein Y is:
- POLYMER is a semi-synthetic biopolymer, preferably with a molecular weight of 1 ,000 Da to 300,000 Da. In one embodiment the molecular weight is 5,000-25,000, preferably 5,000-
- said semi-synthetic biopolymer is a carbohydrate, preferably a polysaccharide, preferably comprising at least 3 units of a monosaccharide.
- said polysaccharide comprises between 2-200 units, preferably between 10-100 units of a monosaccharide.
- the semi-synthetic biopolymer is a PSA derivative.
- the semi-synthetic biopolymer is bound to the suc- cinimidyl moiety via a thioether linkage.
- R 1 is at each occurrence independently a (Ci-C ⁇ )-alkyl.
- R 1 is at each occurrence independently selected from the group consisting of methyl, ethyl, propyl, butyl, and hexyl.
- R 2 is independently selected from the group consisting of -C(O)NR-, - C(O)NR-(C r C 8 )-alkyl-NR-, -NRC(O)- and -NRC(O)-(d-C 8 )-alkyl-NR, wherein R is independently either hydrogen or (Ci-C ⁇ )-alkyl.
- R 2 is -C(O)NH-.
- R 2 is -NHC(O)-.
- the compound of formula 1 is bound to radical Y in at least one of position 1 , 2, 3 or 4.
- the compound of formula 1 is bound to radical Y in at least one of position 1 , 2, 3, or 4 and is further bound to radical X in at least one of position 5, 6, 7, or 8.
- the compound of formula 1 is bound to at least one radical Y in at least one of position 2 or 3 is further bound to radical X in at least one of position 7 or 8.
- the compound of formula 1 is bound to radical Y in positions 2 and 7.
- the compound of formula 1 is bound to radical Y and radical X in positions 2 and 7, respectively.
- the invention relates to the preparation of a compound of formula 1.
- POLYMER is a semi-synthetic biopolymer; R 1 is at each occurrence independently a (Ci-C 8 )-alkyl; R 2 is independently selected from the group consisting Of -C(O)NR-, - C(O)NR-(C 1 -C 8 ) ⁇ IKyI-NR-, -NRC(O)- and -NRC(O)-(C r C 8 )-alkyl-NR, wherein R is independently either hydrogen or Ci-C 8 -alkyl.
- R is independently either hydrogen or (CrC 8 )-alkyl;
- X is -SO 3 -R 3 ;
- R 3 is independently selected from the group consisting of hydrogen, (C 1 -C 8 )- alkyl and (C r C 8 )-alkyl-R 4 ;
- R 4 is a polymer;
- n is an integer selected from 0, 1 , 2, 3, or 4; and
- m is an integer selected from 1 , 2, 3, or 4.
- HS-POLYMER is a thiol-derivatized semi-synthetic biopolymer, such as
- a compound of formula 2 can be easily reacted with a protein or peptide drug containing one or more groups for displacement, such as amines.
- Preferred protein or peptide drug are blood coagulation factors such as FVIII, VWF, FVIIa, FIX.
- Protein and peptide drugs modified according to the above protocol have a significantly increased in-vivo circulation.
- the hydrolability of the linker allows that the activity can be regained after hydrolysis, by release of the protein in its native form.
- An example is shown in Figs. 1 and 2.
- the restoration of the biological activity of a protein conjugate is shown in Figs. 3 and 4.
- PSA containing terminal SH groups Polysialic acid (Sigma) was oxidized with NaIO 4 (Fernandes et al., Biochim Bio- phys Acta 1341 , 26-34 (1997)), and a terminal aldehyde group was formed. Then a reductive amination step with NH 4 CI was carried out as described in WO 05/016973 and the Schiff Base was reduced with NaCNBH 3 to form PSA-NH 2 containing a terminal amino group. Subsequently a reaction with 2-iminothiolane (Pierce 26101) was performed according to the instruction leaflet of the manufacturer to prepare a modified PSA containing a terminal SH group.
- the molarity of the generated SH - groups was determined using Ellmans reagent. In addition the same procedure was used to introduce a SH-group in a N-Acetylneuramic acid trimer, which was obtained from TimTec, LLC, Newark, USA.
- the PSA-rFVIIa containing solution was applied to the column, which was subsequently washed with 10 CV equilibration buffer (20 mM sodium citrate, 20 mM NaCI, pH 6.5). Then the polysialylated rFVIIa was eluted with elu- tion buffer (20 mM sodium citrate, 500 mM NaCI, pH 6.1). The eluate contained 0.06 mg/ml protein, the evidence of bound PSA in the conjugate was proven by the resorcinol assay (Svennerholm et al., Biochim Biophys Acta 24, 604-11 (1957)).
- EXAMPLE 4 Conjugation of Human Serum Albumin with PSA using the MAL-FMS-OSU linker Human Serum Albumin (HSA) is incubated with the bifunctional linker MaI-FMS- OSU linker (prepared as outlined by Tsubery et al., J Biol Chem. 279, 38118- 38124 (2004)) in 25 mM sodium acetate buffer, pH 6.2 for 1 hour. Then the excess linker is separated by gelfiltration using Sephadex G-25 (GE-Healthcare) using the same buffer system The protein containing fractions are collected and PSA-SH (prepared according to Example 1) is added. The mixture is incubated for 2 hours at RT.
- HSA Human Serum Albumin
- the conjugate is purified by anion-exchange chromatography using DEAE-Sepharose FF (GE Healthcare).
- the Protein-PSA conjugate is eluted with 25 mM sodium acetate buffer pH 4.5.
- the conjugate containing fractions are pooled and concentrated by ultrafiltration using a 10K membrane. Then the solution is diafiltrated against 25 mM sodium acetate buffer, pH 6.2.
- a rFVI Ia-PSA conjugate was prepared according to Example 2 using a concentration of MAL-FMS-OSU of 0.05 mg/mg protein.
- 8 normal rats (4 male, 4 female) were anaesthetized and the rFVI la-PSA-conjugate in buffer (1.3 g/L glycylglycine, 3 g/L sodium chloride, 30 g/L mannitol, 1.5 g/L CaCI 2 X 2H 2 O, 0.1 g/L Tween 80, pH 5.5) was applied by intravenous injection into the tail vein in a volume dose of 10 ml per kg (1200 ⁇ g protein/kg).
- Unmodified rFVIIa in a dose of 1200 ⁇ g protein/kg was used as control in 8 normal rats (4 male, 4 female). Blood samples were taken from the tail artery 5 minutes, 1 hour, 2, 4, 7, 10 and 24 hours after substance application and citrated plasma was prepared and frozen for further analysis.
- FVIIa activity in plasma was measured with a clotting assay (Staclot, Diagnostica Stago, Asnieres, France), FVII antigen was determined with an ELISA (polyclonal anti-human FVII antibody). The results were evaluated statistically.
- a clotting assay Staclot, Diagnostica Stago, Asnieres, France
- FVII antigen was determined with an ELISA (polyclonal anti-human FVII antibody). The results were evaluated statistically.
- AUC dose adjusted area under curve
- the terminal half-life increased from 2.3 to 4.4 hours and the mean residence time (MRT) from 1.4 to 2.4 hours.
- the PSA derivative was added to the mixture (concentration: 32 mg PSA-SH / mg protein - 100 fold molar excess) and incubated for additional 2 hours at RT. The reaction was stopped by adding an aqueous solution of 0.1 M glycine (final concentration 10 mM) and 5 mM cysteine (end concentration 0.5 mM). The free reagents were separated from the rFIX-PSA conjugate by Hydrophobic Interaction Chromatography using a pre- packed Butyl Sepharose column (HiTrap Butyl FF 5 ml, GE Healthcare).
- a buffer containing 5 M NaCI (50 mM Hepes-buffer, 5M NaCI, 0.01% Tween 80, 6.7 mM CaCI 2 , pH 6.9) was added to the PSA-rFIX containing solution to give a final concentration of 3M NaCI.
- This mixture was applied to the column, which was subse- quently washed with 10 CV equilibration buffer (50 mM Hepes-buffer, 3M NaCI 1 0.01% Tween 80, 6.7 mM CaCI 2 , pH 6.9) and the elution of the rFIX-PSA conjugate was carried out with 50 mM Hepes-buffer, pH 7.4, containing 6.7 mM CaCI 2 .
- the pH was adjusted to pH 6.9.
- the eluate contained 0.24 mg/ml protein as measured by the BCA-assay, the evidence of bound PSA in the conjugate was proven by the resorcinol assay (Svennerholm, Biochim Biophys Acta 24, 604-611 (1957)).
- the eluate was concentrated 10 fold by ultrafiltration/diafiltration (UF/DF) using a 30 kD membrane (regenerated cellulose/ Millipore) against 20 mM Hepes, 50 mM NaCI, 1mM CaCI 2 , pH 7.4.
- the free reagents were separated from the rFVIII-PSA conjugate by Hydrophobic Interaction Chromatography using a prepacked Butyl Sepharose column (HiTrap Butyl FF 5 ml, GE Healthcare).
- a buffer containing 5 M NaCI 50 mM Hepes-buffer, 5M NaCI, 0.01 % Tween 80, 6.7 mM CaCI 2 , pH 6.9 was added to the PSA-rFVIII containing solution to give a final concentration of 3M NaCI.
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Abstract
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Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2690554A CA2690554C (en) | 2007-06-26 | 2008-06-25 | Hydrolysable polymeric fmoc - linker |
AU2008267360A AU2008267360B2 (en) | 2007-06-26 | 2008-06-25 | Hydrolysable polymeric Fmoc-linker |
NZ582669A NZ582669A (en) | 2007-06-26 | 2008-06-25 | Hydrolysable polymeric FMOC-linker |
CN2008800218771A CN101687048B (en) | 2007-06-26 | 2008-06-25 | Hydrolysable polymeric FMOC- linker |
DK08759334.9T DK2173383T3 (en) | 2007-06-26 | 2008-06-25 | HYDROLYSIBLE POLYMERIC FMOC LINKER |
JP2010513749A JP5622569B2 (en) | 2007-06-26 | 2008-06-25 | Hydrolyzable polymer FMOC-linker |
MX2009013682A MX2009013682A (en) | 2007-06-26 | 2008-06-25 | Hydrolysable polymeric fmoc-linker. |
EP08759334.9A EP2173383B1 (en) | 2007-06-26 | 2008-06-25 | Hydrolysable polymeric fmoc-linker |
BRPI0813772-2A2A BRPI0813772A2 (en) | 2007-06-26 | 2008-06-25 | COMPOUND, PROCESS FOR PREPARING A COMPOUND, AND, CONJUGATED |
ES08759334.9T ES2644453T3 (en) | 2007-06-26 | 2008-06-25 | Fmoc polymeric hydrolysable connector |
HK10109423.6A HK1142828A1 (en) | 2007-06-26 | 2010-09-30 | Hydrolysable polymeric fmoc-linker |
Applications Claiming Priority (4)
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US93716907P | 2007-06-26 | 2007-06-26 | |
US60/937,169 | 2007-06-26 | ||
US12326308P | 2008-04-07 | 2008-04-07 | |
US61/123,263 | 2008-04-07 |
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WO2009000522A1 true WO2009000522A1 (en) | 2008-12-31 |
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PCT/EP2008/005155 WO2009000522A1 (en) | 2007-06-26 | 2008-06-25 | Hydrolysable polymeric fmoc-linker |
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US (3) | US7700551B2 (en) |
EP (1) | EP2173383B1 (en) |
JP (1) | JP5622569B2 (en) |
KR (1) | KR101654375B1 (en) |
CN (1) | CN101687048B (en) |
AR (1) | AR067627A1 (en) |
AU (1) | AU2008267360B2 (en) |
BR (1) | BRPI0813772A2 (en) |
CA (1) | CA2690554C (en) |
DK (1) | DK2173383T3 (en) |
ES (1) | ES2644453T3 (en) |
HK (1) | HK1142828A1 (en) |
MX (1) | MX2009013682A (en) |
NZ (1) | NZ582669A (en) |
TW (1) | TWI569810B (en) |
WO (1) | WO2009000522A1 (en) |
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WO2011017055A3 (en) * | 2009-07-27 | 2011-04-07 | Baxter International Inc. | Blood coagulation protein conjugates |
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 |
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 |
KR20150110657A (en) * | 2013-01-23 | 2015-10-02 | 뉴바이오 테라퓨틱스, 아이엔씨. | Tridentate connexon and use thereof |
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US9795683B2 (en) | 2009-07-27 | 2017-10-24 | Lipoxen Technologies Limited | Glycopolysialylation of non-blood coagulation proteins |
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BRPI0813772A2 (en) * | 2007-06-26 | 2014-12-30 | Baxter Int | COMPOUND, PROCESS FOR PREPARING A COMPOUND, AND, CONJUGATED |
AU2012286048A1 (en) | 2011-07-18 | 2014-02-20 | Arts Biologics A/S | Long acting luteinizing hormone (LH) compound |
US20150133383A1 (en) | 2012-05-11 | 2015-05-14 | Prorec Bio Ab | Method for diagnosis and treatment of prolactin associated disorders |
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WO2008074032A1 (en) * | 2006-12-15 | 2008-06-19 | Baxter International Inc. | Factor viia- (poly) sialic acid conjugate having prolonged in vivo half-life |
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US6680295B1 (en) * | 1994-09-22 | 2004-01-20 | The Administrators Of The Tulane Educational Fund | Method and pharmaceutical composition for prevention and treatment of brain damage |
US6368814B1 (en) * | 2000-12-22 | 2002-04-09 | Roche Diagnostics Corporation | Tricyclic antidepressant derivatives and immunoassay |
KR101270692B1 (en) * | 2003-08-12 | 2013-06-03 | 리폭센 테크놀로지즈 리미티드 | Polysialic acid derivatives |
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US10350301B2 (en) | 2009-07-27 | 2019-07-16 | Baxalta Incorporated | Blood coagulation protein conjugates |
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Also Published As
Publication number | Publication date |
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US8445544B2 (en) | 2013-05-21 |
MX2009013682A (en) | 2010-08-31 |
NZ582669A (en) | 2011-07-29 |
AU2008267360A1 (en) | 2008-12-31 |
US20090005542A1 (en) | 2009-01-01 |
TWI569810B (en) | 2017-02-11 |
CN101687048B (en) | 2013-02-27 |
AU2008267360B2 (en) | 2013-09-12 |
ES2644453T3 (en) | 2017-11-29 |
CN101687048A (en) | 2010-03-31 |
JP5622569B2 (en) | 2014-11-12 |
TW200908996A (en) | 2009-03-01 |
US7700551B2 (en) | 2010-04-20 |
DK2173383T3 (en) | 2017-09-25 |
US20100121028A1 (en) | 2010-05-13 |
CA2690554C (en) | 2016-08-16 |
AR067627A1 (en) | 2009-10-21 |
EP2173383A1 (en) | 2010-04-14 |
KR20100039854A (en) | 2010-04-16 |
HK1142828A1 (en) | 2010-12-17 |
JP2010531371A (en) | 2010-09-24 |
KR101654375B1 (en) | 2016-09-05 |
US20100121034A1 (en) | 2010-05-13 |
EP2173383B1 (en) | 2017-08-09 |
CA2690554A1 (en) | 2008-12-31 |
BRPI0813772A2 (en) | 2014-12-30 |
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