WO2006050959A2 - Molecules which promote hematopoiesis - Google Patents
Molecules which promote hematopoiesis Download PDFInfo
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- WO2006050959A2 WO2006050959A2 PCT/EP2005/012075 EP2005012075W WO2006050959A2 WO 2006050959 A2 WO2006050959 A2 WO 2006050959A2 EP 2005012075 W EP2005012075 W EP 2005012075W WO 2006050959 A2 WO2006050959 A2 WO 2006050959A2
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- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
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- YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 description 1
- 230000000913 erythropoietic effect Effects 0.000 description 1
- XSXLCQLOFRENHC-UHFFFAOYSA-N ethyl n-benzylcarbamate Chemical class CCOC(=O)NCC1=CC=CC=C1 XSXLCQLOFRENHC-UHFFFAOYSA-N 0.000 description 1
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- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
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- 125000003651 hexanedioyl group Chemical group C(CCCCC(=O)*)(=O)* 0.000 description 1
- 102000044890 human EPO Human genes 0.000 description 1
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- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- 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
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- X 10 is a non-conservative exchange of proline; or Xg and X 10 are substituted by a single amino acid;
- X 14 Js D, E, I, L or V; Xi 5 is C, A, K, ⁇ -amino- ⁇ -bromobutyric acid or homocysteine (hoc) provided that either X 6 or X 15 is C or hoc.
- X 6 is C
- N terminal and end (C terminal) of the described individual peptide sequences up to five amino acids may be removed and/or added. It is self-evident that size is not of relevance as long as the peptide function is preserved. Furthermore, please note that individual peptide sequences that might be too short to enfold their activity as monomers usually function as agonists upon dimerisation. Such peptides are thus preferably used in their dimeric form.
- peptides selected from the group consisting of SEQ ID NOS 2, 4-9 given below. Especially preferred is a peptide with a K in position 10 and a K in position 17 as is the case in SEQ ID NO 2.
- peptide dimers or multimers are formed on the basis of the monomers according to SEQ ID NO 2 and 4 to 9 as given above or modifications thereof.
- the peptides described herein can e.g. also be modified by a conservative exchange of single amino acids, wherein preferably, not more than 1, 2 or 3 amino acids are exchanged.
- This embodiment of the invention allows the custom-made design of a suitable linker by molecular modeling in order to avoid distortions of the bioactive conformation.
- a linker composed of 3 to 5 amino acids is especially preferred.
- the linker between the functional domains (or monomeric units) of the final bivalent or multivalent peptides can be either a distinct part of the peptide or can be composed - fully or in parts - of amino acids which are part of the monomeric functional domains.
- the glycine residues in amino acid positions 1 and 2 and 19 and 20 can form part of the linker. Examples are given with Seq. 11 to 14.
- linker is thus rather defined functionally than structurally, since an amino acid might form part of the linker unit as well as of the monomeric subunits.
- This sequence presents a continuous bivalent peptide according to the invention harboring two slightly different (heterogeneous) binding domains. Such bivalent peptides would not be accessible economically with a prior art dimerization approach (see above). Also these binding domains can be applied as a monomer as
- a further example is
- the peptide optionally carries an additional amino acid, preferably one with a reactive side chain such as cysteine at the N-terminus such as e.g. in the following sequences C-GGTYSCHFGKLTWVCKKQGG-GGTYSCHFGKLTWVCKKQGG
- the first sequence depicts a serine in position X 7 . It was found that a new hydrogen bridge is created through the introduction of the hydroxyl group when this sequence is incorporated in a dimer. The use of a serine in position X 7 is thus especially favourable for dimers since the bioactive conformation is stabilised.
- This can include:
- the dimeric molecules known in the state of the art provide merely one target respectively receptor binding unit per dimer. Thus only one receptor complex is generated upon binding of the dimeric compound thereby inducing only one signal transduction process.
- two monomeric EPO mimetic peptides are connected via PEG to form a peptide dimer thereby facilitating dimerisation of the receptor monomers necessary for signal transduction (Johnson et. al., 1997).
- the supravalent compounds according to the invention comprise several already di- or multimeric respective receptor binding units.
- an appropriate carrier unit is a homobifunctional polymer, of for example polyethylene glycol (bis-maleimide, bis-carboxy, bis-amino etc.).
- the attachment can occur e.g. via a reactive amino acid of the peptide units e.g. lysine, cysteine, histidine, arginine, aspartic acid, glutamic acid, serine, threonine, tyrosine or the N- terminal amino group and the C-terminal carboxylic acid.
- a reactive amino acid of the peptide units e.g. lysine, cysteine, histidine, arginine, aspartic acid, glutamic acid, serine, threonine, tyrosine or the N- terminal amino group and the C-terminal carboxylic acid.
- Acylating groups which react with the amino groups of the protein, for example acid anhydride groups, N-acylimidazoIe groups, azide groups, N-carboxy anhydride groups, diketene groups, dialkyl pyrocarbonate groups, imidoester groups, and carbodiimide-activated carboxyl-groups. All of the above groups are known to react with amino groups on proteins/peptides to form covalent bonds, involving acyl or similar linkages;
- ester and amide forming groups which react with a carboxyl group of the protein, such as diazocarboxylate groups, and carbodiimide and amine groups together;
- the compound according to the invention may be made by - optionally - first modifying the polymer chemically to produce a polymer having at least one chemical group thereon which is capable of reacting with an available or introduced chemical group on the peptide unit, and then reacting together the - optionally - modified polymer and the peptide unit to form a covalently bonded complex thereof utilising the chemical group of the - if necessary - modified polymer.
- the coupling of the peptide units to the polymeric carrier unit is performed using reactions principally known to the person skilled in the art. E.g. there are number of PEG and HES attachment methods available to those skilled in the art (see for example WO 2004/100997 giving further references, Roberts et al., 2002; US 4,064,118; EP 1 398 322; EP 1 398 327; EP 1 398 328; WO 2004/024761 ; all herein incorporated by reference).
- one embodiment of the present invention teaches the use of a polymeric carrier unit that is composed of at least two subunits.
- the polymeric subunits are connected via biodegradable covalent linker structures.
- the molecular weight of the large carrier molecule for example 40 kD
- several small or intermediate sized subunits for example each subunit having a molecular weight of 5 to 1OkD
- the molecular weights of the modular subunits add up thereby generating the desired molecular weight of the carrier molecule.
- the biodegradable linker structures can be broken up in the body thereby releasing the smaller carrier subunits (e.g. 5 to 1OkD).
- the small carrier subunits show a better renal clearance than a polymer molecule having the overall molecular weight (e.g. 4OkD).
- An example is given in Fig. 16.
- the linker structures are selected according to known degradation properties and time scales of degradation in body fluids.
- the breakable structures can, for instance, contain cleavable groups like carboxylic acid derivatives as amide/peptide bonds or esters which can be cleaved by hydrolysis (see e.g. Roberts, 2002 herein incorporated by reference).
- PEG succinimidyl esters can also be synthesized with various ester linkages in the PEG backbone to control the degradation rate at physiological pH (Zhao, 1997, herein incorporated by reference).
- Other breakable structures like disulfides of benzyl urethanes can be cleaved under mild reducing environments, such as in endosomal compartments of a cell (Zalipsky, 1999) and are thus also suitable.
- This embodiment has the advantage that a supravalent composition is created due to the first carrier which is however, very durable due to the presence of the second carrier, which is constituted preferably by PEG units of 3 to 5 or 1OkD.
- the whole entity is very well degradable, since the first carrier (e.g. HES) and the peptide units are biodegradable and the second carrier, e.g. PEG is small enough to be easily cleared from the body.
- cleavage solution 50 ⁇ l of the cleavage solution was added to each well and the cleavage was performed for 10 min, this procedure was repeated three times.
- the cleaved peptide was eluted with 200 ⁇ l cleavage solution by gravity flow into the deep well plate.
- the deprotection of the side chain function was performed for another 2.5 h within the deep well plate.
- the peptide was precipitated with ice cold ether/hexane and centrifuged.
- the peptides were solved in neutral aqueous solution and the cyclization was incubated over night at 4° C.
- the peptides were lyophilized.
- the working-up was performed via ultra filtration and freeze-drying
- TNBS 2,4,6-trinitrobenzole sulphonic acid
- a cysteine containing peptide was used which had either a free (Pep-IA) or a biotinytated (Pep-IB) N-term.
- a 4:1 mixture of Pep-IA/B was converted over night in excess (approx. 6 equivalents with MaIPA-HES in phosphate-buffer, 50 mM, pH 6.5/DMF 80:20; working up occurred with ultra filtration and freeze-drying.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Biophysics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Priority Applications (18)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2005303887A AU2005303887A1 (en) | 2004-11-10 | 2005-11-10 | Molecules which promote hematopoiesis |
| MX2007005640A MX2007005640A (es) | 2004-11-10 | 2005-11-10 | Moleculas que promueven la hematopoyesis. |
| CA002586915A CA2586915A1 (en) | 2004-11-10 | 2005-11-10 | Molecules which promote hematopoiesis |
| EP05819212A EP1812461A2 (en) | 2004-11-10 | 2005-11-10 | Molecules which promote hematopoiesis |
| JP2007540582A JP2008519589A (ja) | 2004-11-10 | 2005-11-10 | 造血を促進する分子 |
| US11/667,290 US20090118195A1 (en) | 2004-11-10 | 2005-11-10 | Molecules Which Promote Hematopoiesis |
| EA200701031A EA200701031A1 (ru) | 2004-11-10 | 2005-11-10 | Молекулы, способствующие гематопоэзу |
| BRPI0518025-2A BRPI0518025A (pt) | 2004-11-10 | 2005-11-10 | moléculas que promovem hematopoiese |
| JP2008517435A JP2008546732A (ja) | 2005-06-23 | 2006-06-23 | 多価化合物 |
| CA002648732A CA2648732A1 (en) | 2005-06-23 | 2006-06-23 | Supravalent compounds |
| US11/917,991 US20100145006A1 (en) | 2005-06-23 | 2006-06-23 | Supravalent compounds |
| BRPI0611745-7A BRPI0611745A2 (pt) | 2005-06-23 | 2006-06-23 | compostos supravalentes |
| PCT/EP2006/006097 WO2006136450A2 (en) | 2005-06-23 | 2006-06-23 | Supravalent compounds |
| EP06754540A EP1907417A2 (en) | 2005-06-23 | 2006-06-23 | Supravalent compounds |
| EA200800109A EA200800109A1 (ru) | 2005-06-23 | 2006-06-23 | Суправалентные соединения |
| IL182843A IL182843A0 (en) | 2004-11-10 | 2007-04-29 | Peptides that bind to the erythropoietin receptor, compounds incorporating the same, methods for the preparation thereof and pharmaceutical compositions containing the same |
| NO20072856A NO20072856L (no) | 2004-11-10 | 2007-06-05 | Molekyler som fremmer hematopoiese |
| IL188153A IL188153A0 (en) | 2005-06-23 | 2007-12-16 | Supravalent peptide compounds and processor for the preparation thereof |
Applications Claiming Priority (14)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102004054422.0 | 2004-11-10 | ||
| DE102004054422 | 2004-11-10 | ||
| EP04029536 | 2004-12-14 | ||
| EP04029536.2 | 2004-12-14 | ||
| US11/041,207 | 2005-01-25 | ||
| US11/041,207 US7589063B2 (en) | 2004-12-14 | 2005-01-25 | Molecules which promote hematopoiesis |
| EP05002113.8 | 2005-02-02 | ||
| EP05002113 | 2005-02-02 | ||
| EP05012637 | 2005-06-13 | ||
| EP05012637.4 | 2005-06-13 | ||
| EP05013594.6 | 2005-06-23 | ||
| EP05013594 | 2005-06-23 | ||
| EP05020035 | 2005-09-14 | ||
| EP05020035.1 | 2005-09-14 |
Publications (2)
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| WO2006050959A2 true WO2006050959A2 (en) | 2006-05-18 |
| WO2006050959A3 WO2006050959A3 (en) | 2006-12-21 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2005/012075 WO2006050959A2 (en) | 2004-11-10 | 2005-11-10 | Molecules which promote hematopoiesis |
Country Status (7)
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| EP2018835A2 (de) | 2007-07-09 | 2009-01-28 | Augustinus Bader | Wirkstoff abgebendes Pflaster |
| WO2009094551A1 (en) | 2008-01-25 | 2009-07-30 | Amgen Inc. | Ferroportin antibodies and methods of use |
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| US7589063B2 (en) | 2004-12-14 | 2009-09-15 | Aplagen Gmbh | Molecules which promote hematopoiesis |
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| WO2011012306A2 (en) | 2009-07-30 | 2011-02-03 | Aplagen Gmbh | Use of emps for antagonising epo-stimulatory effects on epo-responsive tumors while maintaining erythropoiesis |
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| WO2017192287A1 (en) | 2016-05-02 | 2017-11-09 | Amgen Inc. | Syringe adapter and guide for filling an on-body injector |
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| WO2018004842A1 (en) | 2016-07-01 | 2018-01-04 | Amgen Inc. | Drug delivery device having minimized risk of component fracture upon impact events |
| WO2018034784A1 (en) | 2016-08-17 | 2018-02-22 | Amgen Inc. | Drug delivery device with placement detection |
| WO2018081234A1 (en) | 2016-10-25 | 2018-05-03 | Amgen Inc. | On-body injector |
| WO2018136398A1 (en) | 2017-01-17 | 2018-07-26 | Amgen Inc. | Injection devices and related methods of use and assembly |
| WO2018152073A1 (en) | 2017-02-17 | 2018-08-23 | Amgen Inc. | Insertion mechanism for drug delivery device |
| WO2018151890A1 (en) | 2017-02-17 | 2018-08-23 | Amgen Inc. | Drug delivery device with sterile fluid flowpath and related method of assembly |
| WO2018165499A1 (en) | 2017-03-09 | 2018-09-13 | Amgen Inc. | Insertion mechanism for drug delivery device |
| WO2018165143A1 (en) | 2017-03-06 | 2018-09-13 | Amgen Inc. | Drug delivery device with activation prevention feature |
| WO2018164829A1 (en) | 2017-03-07 | 2018-09-13 | Amgen Inc. | Needle insertion by overpressure |
| WO2018172219A1 (en) | 2017-03-20 | 2018-09-27 | F. Hoffmann-La Roche Ag | Method for in vitro glycoengineering of an erythropoiesis stimulating protein |
| EP3381445A2 (en) | 2007-11-15 | 2018-10-03 | Amgen Inc. | Aqueous formulation of antibody stablised by antioxidants for parenteral administration |
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| WO2018226515A1 (en) | 2017-06-08 | 2018-12-13 | Amgen Inc. | Syringe assembly for a drug delivery device and method of assembly |
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| WO2019090079A1 (en) | 2017-11-03 | 2019-05-09 | Amgen Inc. | System and approaches for sterilizing a drug delivery device |
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| WO2019231582A1 (en) | 2018-05-30 | 2019-12-05 | Amgen Inc. | Thermal spring release mechanism for a drug delivery device |
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| EP3593839A1 (en) | 2013-03-15 | 2020-01-15 | Amgen Inc. | Drug cassette |
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Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006136450A2 (en) * | 2005-06-23 | 2006-12-28 | Aplagen Gmbh | Supravalent compounds |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3924746A1 (de) * | 1989-07-26 | 1991-01-31 | Behringwerke Ag | Erythropoietin (epo)-peptide und dagegen gerichtete antikoerper |
| CA2223833C (en) * | 1995-06-07 | 2010-12-21 | Nicholas C. Wrighton | Compounds and peptides that bind to the erythropoietin receptor |
| WO2004002424A2 (en) * | 2002-06-28 | 2004-01-08 | Centocor, Inc. | Mammalian epo mimetic ch1 deleted mimetibodies, compositions, methods and uses |
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- 2005-11-10 WO PCT/EP2005/012075 patent/WO2006050959A2/en active Application Filing
- 2005-11-10 JP JP2007540582A patent/JP2008519589A/ja active Pending
- 2005-11-10 EP EP05819212A patent/EP1812461A2/en not_active Withdrawn
- 2005-11-10 AU AU2005303887A patent/AU2005303887A1/en not_active Abandoned
- 2005-11-10 KR KR1020077012937A patent/KR20070092706A/ko not_active Ceased
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Cited By (161)
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|---|---|---|---|---|
| US7589063B2 (en) | 2004-12-14 | 2009-09-15 | Aplagen Gmbh | Molecules which promote hematopoiesis |
| US20130079283A1 (en) * | 2005-06-03 | 2013-03-28 | Affymax, Inc. | Erythropoitein Receptor Peptide Formulations and Uses |
| US8324159B2 (en) * | 2005-06-03 | 2012-12-04 | Affymax, Inc. | Erythropoietin receptor peptide formulations and uses |
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| WO2007101698A3 (en) * | 2006-03-09 | 2008-08-21 | Aplagen Gmbh | Modified molecules which promote hematopoiesis |
| EP2018835A2 (de) | 2007-07-09 | 2009-01-28 | Augustinus Bader | Wirkstoff abgebendes Pflaster |
| US8178745B2 (en) | 2007-07-09 | 2012-05-15 | Augustinus Bader | Plaster which releases active compound |
| US10653781B2 (en) | 2007-09-27 | 2020-05-19 | Amgen Inc. | Pharmaceutical formulations |
| US9320797B2 (en) | 2007-09-27 | 2016-04-26 | Amgen Inc. | Pharmaceutical formulations |
| US9173947B2 (en) | 2007-10-23 | 2015-11-03 | Nektar Therapeutics | Hydroxyapatite-targeting multiarm polymers and conjugates made therefrom |
| US8440787B2 (en) | 2007-10-23 | 2013-05-14 | Nektar Therapeutics | Hydroxyapatite-targeting multiarm polymers and conjugates made therefrom |
| US8815227B2 (en) | 2007-10-23 | 2014-08-26 | Nektar Therapeutics | Hydroxyapatite-targeting multiarm polymers and conjugates made therefrom |
| EP3381445A2 (en) | 2007-11-15 | 2018-10-03 | Amgen Inc. | Aqueous formulation of antibody stablised by antioxidants for parenteral administration |
| US9688759B2 (en) | 2008-01-25 | 2017-06-27 | Amgen, Inc. | Ferroportin antibodies and methods of use |
| WO2009094551A1 (en) | 2008-01-25 | 2009-07-30 | Amgen Inc. | Ferroportin antibodies and methods of use |
| EP2574628A1 (en) | 2008-01-25 | 2013-04-03 | Amgen Inc. | Ferroportin antibodies and methods of use |
| US9175078B2 (en) | 2008-01-25 | 2015-11-03 | Amgen Inc. | Ferroportin antibodies and methods of use |
| EP2803675A2 (en) | 2008-01-25 | 2014-11-19 | Amgen, Inc | Ferroportin antibodies and methods of use |
| US20090209457A1 (en) * | 2008-02-15 | 2009-08-20 | Affymax, Inc. | Treatment of anti-erythropoietin antibody-mediated disorders with synthetic peptide-based epo receptor agonists |
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| JP2015063532A (ja) * | 2008-04-09 | 2015-04-09 | コーネル ユニバーシティー | コフェロンならびにその作製および使用方法 |
| EP2620448A1 (en) | 2008-05-01 | 2013-07-31 | Amgen Inc. | Anti-hepcidin antibodies and methods of use |
| EP2816059A1 (en) | 2008-05-01 | 2014-12-24 | Amgen, Inc | Anti-hepcidin antibodies and methods of use |
| EP3693014A1 (en) | 2008-11-13 | 2020-08-12 | The General Hospital Corporation | Methods and compositions for regulating iron homeostasis by modulation bmp-6 |
| WO2010056981A2 (en) | 2008-11-13 | 2010-05-20 | Massachusetts General Hospital | Methods and compositions for regulating iron homeostasis by modulation bmp-6 |
| WO2011012306A2 (en) | 2009-07-30 | 2011-02-03 | Aplagen Gmbh | Use of emps for antagonising epo-stimulatory effects on epo-responsive tumors while maintaining erythropoiesis |
| US9771345B2 (en) | 2009-10-07 | 2017-09-26 | Cornell University | Coferons and methods of making and using them |
| WO2011050333A1 (en) | 2009-10-23 | 2011-04-28 | Amgen Inc. | Vial adapter and system |
| WO2011098095A1 (en) | 2010-02-09 | 2011-08-18 | Aplagen Gmbh | Peptides binding the tpo receptor |
| WO2011156373A1 (en) | 2010-06-07 | 2011-12-15 | Amgen Inc. | Drug delivery device |
| WO2012003960A1 (en) | 2010-07-06 | 2012-01-12 | Augustinus Bader | Topical application of erythropoietin for the treatment of eye disorders and injuries |
| WO2012135315A1 (en) | 2011-03-31 | 2012-10-04 | Amgen Inc. | Vial adapter and system |
| EP4074355A1 (en) | 2011-04-20 | 2022-10-19 | Amgen Inc. | Autoinjector apparatus |
| EP3498323A2 (en) | 2011-04-20 | 2019-06-19 | Amgen Inc. | Autoinjector apparatus |
| WO2013055873A1 (en) | 2011-10-14 | 2013-04-18 | Amgen Inc. | Injector and method of assembly |
| EP3045187A1 (en) | 2011-10-14 | 2016-07-20 | Amgen, Inc | Injector and method of assembly |
| EP3744371A1 (en) | 2011-10-14 | 2020-12-02 | Amgen, Inc | Injector and method of assembly |
| EP3269413A1 (en) | 2011-10-14 | 2018-01-17 | Amgen, Inc | Injector and method of assembly |
| EP3335747A1 (en) | 2011-10-14 | 2018-06-20 | Amgen Inc. | Injector and method of assembly |
| EP3045189A1 (en) | 2011-10-14 | 2016-07-20 | Amgen, Inc | Injector and method of assembly |
| EP3045190A1 (en) | 2011-10-14 | 2016-07-20 | Amgen, Inc | Injector and method of assembly |
| EP3045188A1 (en) | 2011-10-14 | 2016-07-20 | Amgen, Inc | Injector and method of assembly |
| EP3081249A1 (en) | 2012-11-21 | 2016-10-19 | Amgen, Inc | Drug delivery device |
| EP4234694A2 (en) | 2012-11-21 | 2023-08-30 | Amgen Inc. | Drug delivery device |
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| US11439745B2 (en) | 2012-11-21 | 2022-09-13 | Amgen Inc. | Drug delivery device |
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| US10682474B2 (en) | 2012-11-21 | 2020-06-16 | Amgen Inc. | Drug delivery device |
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| WO2014081780A1 (en) | 2012-11-21 | 2014-05-30 | Amgen Inc. | Drug delivery device |
| US10239941B2 (en) | 2013-03-15 | 2019-03-26 | Intrinsic Lifesciences Llc | Anti-hepcidin antibodies and uses thereof |
| WO2014143770A1 (en) | 2013-03-15 | 2014-09-18 | Amgen Inc. | Body contour adaptable autoinjector device |
| US9803011B2 (en) | 2013-03-15 | 2017-10-31 | Intrinsic Lifesciences Llc | Anti-hepcidin antibodies and uses thereof |
| EP3593839A1 (en) | 2013-03-15 | 2020-01-15 | Amgen Inc. | Drug cassette |
| WO2014144096A1 (en) | 2013-03-15 | 2014-09-18 | Amgen Inc. | Drug cassette, autoinjector, and autoinjector system |
| US9657098B2 (en) | 2013-03-15 | 2017-05-23 | Intrinsic Lifesciences, Llc | Anti-hepcidin antibodies and uses thereof |
| EP3831427A1 (en) | 2013-03-22 | 2021-06-09 | Amgen Inc. | Injector and method of assembly |
| WO2014149357A1 (en) | 2013-03-22 | 2014-09-25 | Amgen Inc. | Injector and method of assembly |
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| EP3421066A1 (en) | 2013-10-24 | 2019-01-02 | Amgen, Inc | Injector and method of assembly |
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| WO2015061389A1 (en) | 2013-10-24 | 2015-04-30 | Amgen Inc. | Drug delivery system with temperature-sensitive control |
| WO2015061386A1 (en) | 2013-10-24 | 2015-04-30 | Amgen Inc. | Injector and method of assembly |
| WO2015119906A1 (en) | 2014-02-05 | 2015-08-13 | Amgen Inc. | Drug delivery system with electromagnetic field generator |
| EP3785749A1 (en) | 2014-05-07 | 2021-03-03 | Amgen Inc. | Autoinjector with shock reducing elements |
| WO2015171777A1 (en) | 2014-05-07 | 2015-11-12 | Amgen Inc. | Autoinjector with shock reducing elements |
| US11213624B2 (en) | 2014-06-03 | 2022-01-04 | Amgen Inc. | Controllable drug delivery system and method of use |
| WO2015187797A1 (en) | 2014-06-03 | 2015-12-10 | Amgen Inc. | Controllable drug delivery system and method of use |
| WO2015187793A1 (en) | 2014-06-03 | 2015-12-10 | Amgen Inc. | Drug delivery system and method of use |
| WO2015187799A1 (en) | 2014-06-03 | 2015-12-10 | Amgen Inc. | Systems and methods for remotely processing data collected by a drug delivery device |
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| US11992659B2 (en) | 2014-06-03 | 2024-05-28 | Amgen Inc. | Controllable drug delivery system and method of use |
| EP4362039A2 (en) | 2014-06-03 | 2024-05-01 | Amgen Inc. | Controllable drug delivery system and method of use |
| US11738146B2 (en) | 2014-06-03 | 2023-08-29 | Amgen Inc. | Drug delivery system and method of use |
| WO2016049036A1 (en) | 2014-09-22 | 2016-03-31 | Intrinsic Lifesciences Llc | Humanized anti-hepcidin antibodies and uses thereof |
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| WO2016061220A2 (en) | 2014-10-14 | 2016-04-21 | Amgen Inc. | Drug injection device with visual and audio indicators |
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| US10799630B2 (en) | 2014-12-19 | 2020-10-13 | Amgen Inc. | Drug delivery device with proximity sensor |
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| WO2017120178A1 (en) | 2016-01-06 | 2017-07-13 | Amgen Inc. | Auto-injector with signaling electronics |
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| WO2017197222A1 (en) | 2016-05-13 | 2017-11-16 | Amgen Inc. | Vial sleeve assembly |
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| WO2017209899A1 (en) | 2016-06-03 | 2017-12-07 | Amgen Inc. | Impact testing apparatuses and methods for drug delivery devices |
| WO2018004842A1 (en) | 2016-07-01 | 2018-01-04 | Amgen Inc. | Drug delivery device having minimized risk of component fracture upon impact events |
| WO2018034784A1 (en) | 2016-08-17 | 2018-02-22 | Amgen Inc. | Drug delivery device with placement detection |
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| WO2018183039A1 (en) | 2017-03-28 | 2018-10-04 | Amgen Inc. | Plunger rod and syringe assembly system and method |
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| EP4241807A2 (en) | 2017-03-28 | 2023-09-13 | Amgen Inc. | Plunger rod and syringe assembly system and method |
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| WO2018226515A1 (en) | 2017-06-08 | 2018-12-13 | Amgen Inc. | Syringe assembly for a drug delivery device and method of assembly |
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| US12415039B2 (en) | 2024-01-11 | 2025-09-16 | Amgen Inc. | Drug delivery device with proximity sensor |
Also Published As
| Publication number | Publication date |
|---|---|
| NO20072856L (no) | 2007-08-08 |
| WO2006050959A3 (en) | 2006-12-21 |
| JP2008519589A (ja) | 2008-06-12 |
| EP1812461A2 (en) | 2007-08-01 |
| KR20070092706A (ko) | 2007-09-13 |
| CA2586915A1 (en) | 2006-05-18 |
| AU2005303887A1 (en) | 2006-05-18 |
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