WO2005035565A1 - Il-21 derivatives - Google Patents

Il-21 derivatives Download PDF

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Publication number
WO2005035565A1
WO2005035565A1 PCT/DK2004/000686 DK2004000686W WO2005035565A1 WO 2005035565 A1 WO2005035565 A1 WO 2005035565A1 DK 2004000686 W DK2004000686 W DK 2004000686W WO 2005035565 A1 WO2005035565 A1 WO 2005035565A1
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WO
WIPO (PCT)
Prior art keywords
derivatives
peg
acid
group
variants
Prior art date
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Ceased
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PCT/DK2004/000686
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English (en)
French (fr)
Inventor
Bernd Peschke
Christine Bruun SCHIØDT
Helle WÖLDIKE
Florencio Zaragoza DÖRWALD
Anne Worsaae
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Novo Nordisk AS
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Novo Nordisk AS
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Filing date
Publication date
Priority to AT04762905T priority Critical patent/ATE481420T1/de
Priority to JP2006529654A priority patent/JP2007533298A/ja
Priority to EP04762905A priority patent/EP1673387B1/en
Priority to CN2004800296630A priority patent/CN1867581B/zh
Priority to DE602004029173T priority patent/DE602004029173D1/de
Priority to EP10163849A priority patent/EP2263684A1/en
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Priority to CA002542179A priority patent/CA2542179A1/en
Publication of WO2005035565A1 publication Critical patent/WO2005035565A1/en
Priority to US11/401,005 priority patent/US20060228331A1/en
Anticipated expiration legal-status Critical
Priority to US12/189,849 priority patent/US8450459B2/en
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • 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
    • A61K47/59—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 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/61—Growth hormone [GH], i.e. somatotropin

Definitions

  • Inhibition of biologic activity can be measured by, e.g., the Ba F3 assay where Ba F3 cells stably transfected with human IL-21 R (IL- 21 R-Ba F3) undergo proliferation when IL-21 is added to the culture.
  • Addition of IL-21 antagonists to the IL-21 R-Ba F3 cells desirably partially or fully inhibits IL-21 -dependent proliferation of IL-21 R-Ba F3 cells.
  • the term "polymeric molecule”, or “polymeric group” or “polymeric moiety” or “polymer molecule” encompasses molecules formed by covalent linkage of two or more monomers wherein none of the monomers is an amino acid residue.
  • serum half-life examples include plasma half-life, circulating half-life, circulatory half-life, serum clear- ance, plasma clearance, and clearance half-life.
  • the functionality to be retained is normally selected from procoagulant, proteolytic, co-factor binding, receptor binding activity, or other type of biological activity associated with the particular protein.
  • the present invention further provides a variety of other polypeptide fusions [and re- lated multimeric proteins comprising one or more polypeptide fusions].
  • a IL-21 polypeptide can be prepared as a fusion to a dimerizing protein as disclosed in U.S. Patents Nos. 5,155,027 and 5,567,584 and derivatised according to the invention.
  • Preferred dimerizing proteins in this regard include immunoglobulin constant region domains.
  • Immunoglobu- lin-IL-21 polypeptide fusions can be expressed in genetically engineered cells. Auxiliary do- mains can be fused to IL-21 polypeptides to target them to specific cells, tissues, or macro- molecules (e.g., collagen).
  • the petides of the present invention including full-length peptides, peptide fragments (e.g. ligand-binding fragments), and fusion polypeptides can be produced in genetically engineered host cells according to conventional techniques.
  • Suitable host cells are those cell types that can be transformed or transfected with exogenous DNA and grown in culture, and include bacteria, fungal cells, and cultured higher eukaryotic cells. Eukaryotic cells, particularly cultured cells of multicellular organisms, are preferred.
  • DNA sequences encoding human IL-21 related polypeptides or IL-21 variants may be isolated by preparing a genomic or cDNA library and screening for DNA sequences coding for all or part of the protein by hybridization using synthetic oligonucleotide probes in accordance with standard techniques (cf. Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1989).
  • the DNA sequence encoding the protein is preferably of human origin, i.e. derived from a human genomic DNA or cDNA library.
  • the DNA sequences encoding the IL-21 variants may also be prepared synthetically by established standard methods, e.g.
  • oligonucleotides are synthesized, e.g. in an automatic DNA synthesizer, purified, annealed, ligated and cloned in suitable vectors.
  • the invention also comprises chemical modifications of the IL-21 polypeptide, variant thereof or fusion proteins comprising IL-21 or variants thereof.
  • the chemical modification comprises covalent modifications with an organic agent capable of reacting with a selected side chain or a terminal residue.
  • a lipophilic substituent is attached to one or more amino acid residues at a position relative to the amino acid sequence of SEQ ID NO:1 or 2 as described above. It is to be understood that an amino acid residues at the posi- tion relative to the amino acid sequence of SEQ ID NO:2 may be any amino acid residue and not only the amino acid residue naturally present at that position.
  • the lipophilic substituent is attached to a lysine.
  • lysines in IL-21 could be derivatives as described in the application.
  • additional lysines are substituted, inserted into the se- quence or added at the N-terminal or C-terminal, and then optionally derivatised.
  • Other aspects of the invention includes addition of asp, glu, cys, gin, ser, thr, or tyr which carries function groups in the side chain for derivatising.
  • lipophilic substituent is characterised by comprising 4-40 carbon atoms and having a solubility in water at 20°C in the range from about 0.1 mg/100 ml water to about 250 mg/100 ml water, such as in the range from about 0.3 mg/100 ml water to about 75 mg/100 ml water.
  • octanoic acid (C8) has a solubility in water at 20°C of 68 mg/100 ml
  • decanoic acid (C10) has a solubility in water at 20°C of 15 mg/100 ml
  • octadecanoic acid (C18) has a solubility in water at 20°C of 0.3 mg/100 ml.
  • the lipophilic substituent comprises from 8 to 25 carbon atoms. In one embodiment of the invention the lipophilic substituent comprises from 12 to 20 carbon atoms.
  • the spacer is an unbranched alkane ⁇ , ⁇ -dicarboxylic acid group having from 1 to 7 methylene groups, such as two methylene groups which spacer forms a bridge between an amino group of the IL-21 peptide and an amino group of the lipophilic substituent.
  • the spacer is an amino acid residue except a Cys residue, or a dipeptide.
  • suitable spacers includes ⁇ -alanine, gamma-aminobutyric acid (GABA), ⁇ -glutamic acid, succinic acid, Lys, Glu or Asp, or a dipeptide such as Gly-Lys.
  • a reactive aldehyde is polyethylene glycol propionaldehyde, or mono-(C1-C10) alkoxy, or aryloxy derivatives thereof (see, for example, Harris, et al., U.S. Patent No. 5,252,714).
  • the polymer may be branched or un- branched.
  • a mixture of polymers can be used to produce IL-21 conjugates.
  • IL-21 conjugates used for therapy can comprise pharmaceutically acceptable water-soluble polymer moieties.
  • the peptide is derivatised with a N-terminal PEG group by oxidation of a serine with sodium periodate, followed by reaction of PEG-derivative, to which a hydroxylamine was attached, yielding an oxime.
  • the serine could also have been an internal serine residue or an added serine residue as described above.
  • Other methods for attaching PEG groups are described in G. Pasut, A. Guiotto, F. M. Veronese Expert Opin. Ther. Patents 2004, 14, 859-894.
  • Variants of IL-21 suitable for attachment of polymeric groups may be obtained as described above.
  • IL-21 is attached in the C-terminal of the peptide.
  • the functional groups of X and Y are selected from amongst car- bonyl groups, such as keto and aldehyde groups, and amino derivatives, such as hydrazine derivatives -NH-NH 2 , hydrazine carboxylate derivatives -O-C(O)-NH-NH 2 , semicarbazide derivatives -NH-C(O)-NH-NH 2 , thiosemicarbazide derivatives -NH-C(S)-NH-NH 2 , carbonic acid dihydrazide derivatives -NHC(O)-NH-NH-C(O)-NH-NH 2 , carbazide derivatives -NH-NH-C(O)-NH-NH 2 , thiocarbazide derivatives -NH-NH-C(S)-NH-NH 2 , aryl hydrazine derivatives -NH-C(O)-C 6 H 4 -NH-NH 2 , and hydrazide derivatives -C
  • mPEG has a molecular weight of 10kDa, 20 kDa, 30kDa or 40kDa,
  • n 1 , 2, 3, 4, 5 or 6 and mPEG has a molecular weight of 10kDa, 20 kDa, 30kDa or40kDa,
  • mPEG has a molecular weight of 10kDa, 20 kDa, 30kDa or 40kDa,
  • methoxypolyethylene glycol is of interest since its coupling chemistry is relatively simple (only one reactive group is available for conjugating with attachment groups on the polypeptide). Consequently, the risk of cross-linking is eliminated, the resulting poly- peptide conjugates are more homogeneous and the reaction of the polymer molecules with the polypeptide is easier to control.
  • the hydroxyl end groups of the polymer molecule are provided in activated form, i.e. with reactive functional groups.
  • Suitable activated polymer molecules are commercially available, e.g. from Shearwater Corp., Huntsville, Ala., USA, or from PolyMASC Pharmaceuticals pic, UK.
  • polymer molecules with a lower molecular weight will be used. This is also the case if a high degree of epitope shielding is desired.
  • 2-8 polymers with a molecular weight of e.g. about 5,000 Da, such as 3-6 such polymers may for example be used.
  • aqueous formulation is defined as a formulation comprising at least 50 %w/w water.
  • aqueous solution is defined as a solution comprising at least 50 %w/w water, and the term “aqueous suspension” is defined as a suspension comprising at least 50 %w/w water.
  • the pharmaceutical formulation is a freeze-dried formulation, whereto the physician or the patient adds solvents and/or diluents prior to use.
  • the pharmaceutical formulation is a dried formulation (e.g. freeze-dried or spray-dried) ready for use without any prior dissolution.
  • the pH of the formulation is selected from the list consisting of 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5,
  • the formulation further comprises an isotonic agent.
  • the isotonic agent is selected from the group consisting of a salt (e.g. sodium chloride), a sugar or sugar alcohol, an amino acid (e.g. L- glycine, L-histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine), an alditol (e.g. glycerol (glycerine), 1 ,2-propanediol (propyleneglycol), 1,3-propanediol, 1,3- butanediol) polyethyleneglycol (e.g.
  • the formulation further comprises a surfactant.
  • the surfactant is selected from a detergent, ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, polyoxypropylene-polyoxyethylene block polymers (eg. poloxamers such as Pluronic ® F68, poloxamer 188 and 407, Triton X-100 ), polyoxyethylene sorbitan fatty acid esters, polyoxyethylene and polyethylene derivatives such as alkylated and alkoxylated derivatives (tweens, e.g.
  • N-alkyl-N,N-dimethylammonio-1-propanesulfonates 3-cholamido-1-propyldimethylammonio-1-propanesulfonate
  • cationic surfactants quaternary ammonium bases
  • cetyl-trimethylammonium bromide cetylpyridinium chloride
  • non- ionic surfactants eg. Dodecyl ⁇ -D-glucopyranoside
  • poloxamines eg.
  • dichloromethane at -78°C to a mixture of oxalyl chloride and dimethylsulfoxidein dichloromethane, which has been formed at -78°C, followed by addition of a suitable amino-base such as e.g. triethylamine and subsequent warming to room temperature.
  • a suitable amino-base such as e.g. triethylamine and subsequent warming to room temperature.
  • the formed tert-butyl ⁇ /-(3-formylbenzyl)carbamate may be reacted to yield tert- butyl ⁇ /-(3-((hydroxylimino)methyl)benzyl) by reaction with the free base or a suitable salt of hydroxylamine in a solution of e.g. sodium hydroxide in water.
  • the BOC-protection group may be removed from tert-butyl ⁇ /-(3-((hydroxylimino)methyl)benzyl) by methods described in the literature (e.g. T.W. Green, P. G. M Wuts Protective groups in organic synthesis 2 nd ed. Wiley, New York, 1991) e.g. by treatment with a 50% solution of trifluoroacetic acid in dichloromethane to give 3-(aminomethyl)benzaldehyde oxime.
  • ⁇ /-(2-(mPEG20000yl)ethyl) 11 -azidoundecanoic amide may be performed by reaction of commercially available methyl 11-bromoundecanoic ester with sodium azide in an appropriate solvent such as e.g. ⁇ /, ⁇ /-dimethyIformamide at an appropriate temperature as e.g. 60°C.
  • an appropriate solvent such as e.g. ⁇ /, ⁇ /-dimethyIformamide
  • the formed methyl 11-azidoundecanoic ester may be saponified by a method known to a person skilled in the art and described in the literature (e.g. T.W. Green, P. G. M Wuts Protective groups in organic synthesis 2 nd ed. Wiley, New York, 1991) such as e.g.
  • E.coli with a N-terminal extension (Met-Ser-Glu-Ala-Glu-hlL21).
  • the N-terminal Met residue is removed by the protease systems present in E.coli, leaving Ser-Glu-Ala-Glu-hlL21.
  • Blood samples will be drawn from the orbital venous plexus. Approximately 0.1-0.2 ml blood will be drawn at each sampling time. Three blood samples will be taken from each animal. Blood samples from two mice will be drawn at each time point.

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PCT/DK2004/000686 2003-10-10 2004-10-08 Il-21 derivatives Ceased WO2005035565A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
JP2006529654A JP2007533298A (ja) 2003-10-10 2004-10-08 Ｉｌ−２１の誘導体
EP04762905A EP1673387B1 (en) 2003-10-10 2004-10-08 Il-21 derivatives
CN2004800296630A CN1867581B (zh) 2003-10-10 2004-10-08 Il-21衍生物
DE602004029173T DE602004029173D1 (de) 2003-10-10 2004-10-08 Il-21-derivate
EP10163849A EP2263684A1 (en) 2003-10-10 2004-10-08 IL-21 derivatives
AT04762905T ATE481420T1 (de) 2003-10-10 2004-10-08 Il-21-derivate
CA002542179A CA2542179A1 (en) 2003-10-10 2004-10-08 Il-21 derivatives
US11/401,005 US20060228331A1 (en) 2003-10-10 2006-04-10 IL-21 Derivatives and variants
US12/189,849 US8450459B2 (en) 2003-10-10 2008-08-12 IL-21 derivatives and variants

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
DKPA200301496 2003-10-10
DKPA200301496 2003-10-10
US51089203P 2003-10-14 2003-10-14
US60/510,892 2003-10-14
DKPA200301529 2003-10-17
DKPA200301529 2003-10-17
US51342203P 2003-10-22 2003-10-22
US60/513,422 2003-10-22
DKPA200400707 2004-05-04
DKPA200400707 2004-05-04
US56956604P 2004-05-10 2004-05-10
US60/569,566 2004-05-10

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US11/401,005 Continuation US20060228331A1 (en) 2003-10-10 2006-04-10 IL-21 Derivatives and variants

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WO2005035565A1 true WO2005035565A1 (en) 2005-04-21

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PCT/DK2004/000686 Ceased WO2005035565A1 (en) 2003-10-10 2004-10-08 Il-21 derivatives

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EP (2) EP2263684A1 (https=)
JP (1) JP2007533298A (https=)
CN (2) CN1867581B (https=)
AT (1) ATE481420T1 (https=)
CA (1) CA2542179A1 (https=)
DE (1) DE602004029173D1 (https=)
WO (1) WO2005035565A1 (https=)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005070468A3 (en) * 2004-01-21 2006-03-16 Novo Nordisk As Transglutaminase mediated conjugation of peptides
WO2006131515A3 (en) * 2005-06-06 2007-04-12 Novo Nordisk As Stabilised il-21 compositions
US8034326B2 (en) 2005-04-18 2011-10-11 Novo Nordisk A/S IL-21 variants
US8211420B2 (en) 2006-12-21 2012-07-03 Novo Nordisk A/S Interleukin-21 variants with altered binding to the IL-21 receptor
US8293708B2 (en) 2005-08-30 2012-10-23 Novo Nordisk Health Care A/G Liquid formulations N-terminal serine of pegylated growth hormone
US8475784B2 (en) 2006-10-26 2013-07-02 Novo Nordisk A/S IL-21 variants
US8921518B2 (en) 2005-12-23 2014-12-30 Novo Nordisk A/S Purification of proteins using preparative reverse phase chromatography (RPC)
WO2015000585A1 (en) * 2013-07-02 2015-01-08 Walter Sebald Muteins of cytokines of the gamma-chain receptor family conjugated to a non-protein group
US9175061B2 (en) 2006-07-07 2015-11-03 Novo Nordisk Health Care Ag Protein conjugates and methods for their preparation
CN113557060A (zh) * 2019-01-21 2021-10-26 赛诺菲 用于晚期实体瘤癌症的治疗性rna
WO2025242835A1 (en) 2024-05-22 2025-11-27 Ose Immunotherapeutics Molecules comprising masking linkers and uses thereof for the treatment of cancer

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Publication number Priority date Publication date Assignee Title
CN105198999A (zh) * 2014-05-27 2015-12-30 上海生物制品研究所有限责任公司 一种融合蛋白、其制备方法及其应用
CA3249997A1 (en) * 2022-06-29 2024-01-04 Beijing Neox Biotech Limited IL-21 POLYPEPTIDES AND METHODS OF USE
CN117645661A (zh) * 2022-09-02 2024-03-05 北京志道生物科技有限公司 一种聚乙二醇修饰的il-21衍生物及其应用

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US4902502A (en) * 1989-01-23 1990-02-20 Cetus Corporation Preparation of a polymer/interleukin-2 conjugate
WO2000053761A2 (en) * 1999-03-09 2000-09-14 Zymogenetics, Inc. Human cytokine as ligand of the zalpha receptor and uses thereof
US20030186387A1 (en) * 1998-05-29 2003-10-02 Human Genome Sciences, Inc. Interleukins-21 and 22

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CN1867581A (zh) 2006-11-22
DE602004029173D1 (de) 2010-10-28
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CN102516386A (zh) 2012-06-27
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