ES2548214T3 - Variantes del factor de crecimiento de fibroblastos 21 - Google Patents
Variantes del factor de crecimiento de fibroblastos 21 Download PDFInfo
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- ES2548214T3 ES2548214T3 ES12766847.3T ES12766847T ES2548214T3 ES 2548214 T3 ES2548214 T3 ES 2548214T3 ES 12766847 T ES12766847 T ES 12766847T ES 2548214 T3 ES2548214 T3 ES 2548214T3
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- seq
- growth factor
- fibroblast growth
- fgf21
- pma
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- 102000018233 Fibroblast Growth Factor Human genes 0.000 title 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 title 1
- 229940126864 fibroblast growth factor Drugs 0.000 title 1
- 102000003973 Fibroblast growth factor 21 Human genes 0.000 abstract description 15
- 108090000376 Fibroblast growth factor 21 Proteins 0.000 abstract description 15
- 101000846529 Homo sapiens Fibroblast growth factor 21 Proteins 0.000 abstract 1
- 125000003275 alpha amino acid group Chemical group 0.000 abstract 1
- 102000056713 human FGF21 Human genes 0.000 abstract 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 21
- 235000019445 benzyl alcohol Nutrition 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- 102220475127 Ectodysplasin-A_L98D_mutation Human genes 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 150000001413 amino acids Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000013628 high molecular weight specie Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 241001515942 marmosets Species 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07K14/475—Growth factors; Growth regulators
- C07K14/50—Fibroblast growth factor [FGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
- A61K38/18—Growth factors; Growth regulators
- A61K38/1825—Fibroblast growth factor [FGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Obesity (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Toxicology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Una variante del factor de crecimiento de fibroblastos 21 (FGF21) humano, en la que la secuencia de aminoácidos es**Fórmula**
Description
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E12766847
23-09-2015
en presencia o ausencia de Tween 80 al 0,02 %. Se prepararon las muestras a 30 mg/ml y se incubaron a 4 ºC, 25 ºC y 40 ºC durante 4 semanas. Las variantes de FGF21 formuladas recientemente (es decir, a tiempo cero) y aquellas incubadas durante 4 semanas se analizaron para el % de PMA mediante el procedimiento CEM. La tabla 6 resume los resultados del análisis, comparando las muestras de tiempo cero ("Iniciales") y aquellas incubadas 4 semanas a 40 ºC.
Tabla 6: Propensión a la agregación y compatibilidad con conservantes a una concentración de laFormulación de 30 mg/ml
- variante de FGF21 de SEC ID Nº: 9 (L98L)
- variante de FGF21 de SEC ID Nº: 1 (L98D)
- Composición de Tampón
- (% de PMA) 4 semanas a 40 ºC (% de PMA A) Inicial (% de PMA) 4 semanas a 40 ºC (% de PMA A)
- Histidina 10 mM pH 7,0, pH 7,0, NaCl 150 mM
- 0,97 18,3 6,0 5,6
- Histidina 10 mM pH 7,0, NaCl 150 mM, alcohol bencílico al 0,9 %
- 11,0 33,9 4,2 6,0
- Histidina 10 mM pH 7,0, NaCl 150 mM, alcohol bencílico al 0,9 % Tween-80 al 0,02 %
- 11,0 32,1 4,3 5,3
La variante de FGF21 de SEC ID Nº: 1 contenía la sustitución de aminoácidos L98D. La variante de FGF21 de SEC ID Nº: 9 no contenía la sustitución de aminoácidos L98D y en cambio contenía el aminoácido leucina de tipo silvestre en la posición 98. El beneficio de la sustitución de aminoácidos L98D se observó cuando se formuló cada proteína a 30 mg/ml en las condiciones de formulación (Tabla 6). En todas las condiciones ensayadas, el estrés de las variantes FGF21 durante 4 semanas a 40 ºC dio como resultado un % de PMA sustancialmente más alto para la variante de FGF21 de SEC ID Nº: 9 en comparación con la variante de FGF21 de SEC ID Nº: 1. Además, la adición de alcohol bencílico al 0,9 %, un conservante común usado en una preparación farmacéutica multiusos, exacerbó el aumento del % de PMA para la variante de FGF21 de SEC ID Nº: 9 pero no para la variante de FGF21 de SEC ID Nº: 1. Esta incompatibilidad con alcohol bencílico también se observó en el análisis de la preparación de la muestra inicial, en el que el % de PMA en presencia de alcohol bencílico al 0,9 % es del 11 %, en comparación con únicamente el 0,97 % en ausencia de alcohol bencílico. Ni la variante de FGF21 de SEC ID Nº: 9 ni la variante de FGF21 de SEC ID Nº: 1 contienen el resto P115W, por lo tanto, la poca estabilidad física en estas condiciones no puede atribuirse al resto P114W. Después de que se hiciera la sustitución L98D, se observó una estabilidad física aumentada en presencia de alcohol bencílico al 0,9 %.
Estos datos indican que determinadas sustituciones pueden afectar a la estabilidad de la proteína total debido a la agregación en especies de peso molecular alto, particularmente en presencia de determinados conservantes tales como el alcohol bencílico. Se prefiere la minimización de esos agregados de PMA para proteínas terapéuticas. Esto puede llevarse a cabo a través de determinadas sustituciones en las proteínas de las variantes de FGF21, tales como L98D en las variantes mostradas en SEC ID Nº: 1. Otras sustituciones, tales como PI 15W, pueden tener efectos perjudiciales, tales como aumentar el nivel de agregación de las variantes.
Ejemplo 6
Degradación Proteolítica In Vivo
A los monos titís machos, n=2/grupo se les dosificó por vía subcutánea 2 mg/kg de una inyección de la variante FGF21 de SEC ID Nº: 1. Se obtuvo el suero a lo largo del curso de tiempo (extracción después de 0,25 a 12 horas) para una evaluación de 24 horas de la proteólisis in vivo por medio de una espectrometría de masas para cuantificar la cantidad de compuesto activo.
Se realizó un análisis por cromatografía líquida con espectrometría de masas (CL/EM). Se inmunoprecipitó una alícuota de 100 µl de cada muestra con anticuerpos monoclonales anti-FGF21 que se unían covalentemente a esferas magnéticas. Las muestras inmunoprecipitadas se separaron en alícuotas independientes, permitiendo la detección de proteínas intactas y proteínas digeridas con tripsina. Las proteínas intactas se inyectaron en una columna Discovery® Biowide Pore, de 100 x 0,32 mm d.i. que contenía partículas de 3 µm recubiertas con C5. Las muestras digeridas con tripsina se inyectaron en una columna Discovery Biowide Pore, de 100 x 0,32 mm d.i. que contenía partículas de 3 µm recubiertas con C5. La condiciones cromatográficas para todas las inyecciones usaron gradientes binarios que consistían en una fase móvil A (ácido fórmico:agua al 0,1/100) y una fase móvil B (ácido fórmico:acetonitrilo al 0,1/100). El efluente de la CL se conectó directamente con un espectrómetro de masas Micromass Synapt® Q-Tof para la detección del espectro de masas en modo de iones positivos. Los datos del espectrofotómetro de masas Q-Tof se recogieron usando los programas informáticos de deconvolución Masslinx (v 4.1) y MaxEnt1.
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Claims (1)
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imagen1
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161542906P | 2011-10-04 | 2011-10-04 | |
US201161542906P | 2011-10-04 | ||
PCT/US2012/057053 WO2013052311A1 (en) | 2011-10-04 | 2012-09-25 | Fibroblast growth factor 21 variants |
Publications (1)
Publication Number | Publication Date |
---|---|
ES2548214T3 true ES2548214T3 (es) | 2015-10-14 |
Family
ID=46964112
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ES12766847.3T Active ES2548214T3 (es) | 2011-10-04 | 2012-09-25 | Variantes del factor de crecimiento de fibroblastos 21 |
Country Status (27)
Country | Link |
---|---|
US (2) | US8541369B2 (es) |
EP (1) | EP2763689B1 (es) |
JP (1) | JP6060167B2 (es) |
KR (1) | KR20140059271A (es) |
CN (1) | CN103906530B (es) |
AP (1) | AP2014007532A0 (es) |
AR (1) | AR087973A1 (es) |
AU (1) | AU2012318956A1 (es) |
BR (1) | BR112014007532A2 (es) |
CA (1) | CA2843520A1 (es) |
CL (1) | CL2014000801A1 (es) |
CO (1) | CO6910165A2 (es) |
CR (1) | CR20140142A (es) |
DO (1) | DOP2014000050A (es) |
EA (1) | EA201490521A1 (es) |
EC (1) | ECSP14013285A (es) |
ES (1) | ES2548214T3 (es) |
IL (1) | IL230754A0 (es) |
IN (1) | IN2014CN00782A (es) |
MA (1) | MA35458B1 (es) |
MX (1) | MX2014004159A (es) |
PE (1) | PE20142044A1 (es) |
SG (1) | SG11201401792UA (es) |
TN (1) | TN2014000096A1 (es) |
TW (1) | TWI461435B (es) |
WO (1) | WO2013052311A1 (es) |
ZA (1) | ZA201400882B (es) |
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SG10201806648TA (en) | 2011-07-01 | 2018-09-27 | Ngm Biopharmaceuticals Inc | Compositions, uses and methods for treatment of metabolic disorders and diseases |
WO2013173158A1 (en) * | 2012-05-15 | 2013-11-21 | Eli Lilly And Company | Therapeutic uses of fibroblast growth factor 21 proteins |
EP2859014B1 (en) | 2012-06-11 | 2017-04-26 | Eli Lilly and Company | Fibroblast growth factor 21 variants |
TWI513705B (zh) | 2012-06-11 | 2015-12-21 | Lilly Co Eli | 纖維母細胞生長因子21蛋白質 |
US9963494B2 (en) | 2012-11-28 | 2018-05-08 | Ngm Biopharmaceuticals, Inc. | Methods of using compositions comprising variants and fusions of FGF19 polypeptides for reducing glucose levels in a subject |
US9290557B2 (en) | 2012-11-28 | 2016-03-22 | Ngm Biopharmaceuticals, Inc. | Compositions comprising variants and fusions of FGF19 polypeptides |
US9273107B2 (en) | 2012-12-27 | 2016-03-01 | Ngm Biopharmaceuticals, Inc. | Uses and methods for modulating bile acid homeostasis and treatment of bile acid disorders and diseases |
CN108888757A (zh) | 2012-12-27 | 2018-11-27 | 恩格姆生物制药公司 | 用于调节胆汁酸体内稳态及治疗胆汁酸紊乱和疾病的方法 |
MX2016004822A (es) | 2013-10-28 | 2016-08-17 | Ngm Biopharmaceuticals Inc | Modelos de cancer y metodos asociados. |
MX2016009555A (es) | 2014-01-24 | 2016-12-08 | Ngm Biopharmaceuticals Inc | Proteinas de union y metodos para utilizarlas. |
WO2015138278A1 (en) * | 2014-03-11 | 2015-09-17 | Novartis Ag | Methods of treating metabolic disorders associated with lipodystrophies and defects in insulin production or signaling |
WO2015183890A2 (en) | 2014-05-28 | 2015-12-03 | Ngm Biopharmaceuticals, Inc. | Methods and compositions for the treatment of metabolic disorders and diseases |
AU2015277438B2 (en) | 2014-06-16 | 2020-02-27 | Ngm Biopharmaceuticals, Inc. | Methods and uses for modulating bile acid homeostasis and treatment of bile acid disorders and diseases |
UA123763C2 (uk) | 2014-10-23 | 2021-06-02 | Енджіем Байофармасьютикалз, Інк. | Фармацевтична композиція для контролю або лікування захворювання або порушення, пов’язаного з fgf19 |
CA2965502A1 (en) | 2014-10-24 | 2016-04-28 | Bristol-Myers Squibb Company | Modified fgf-21 polypeptides and uses thereof |
US10434144B2 (en) | 2014-11-07 | 2019-10-08 | Ngm Biopharmaceuticals, Inc. | Methods for treatment of bile acid-related disorders and prediction of clinical sensitivity to treatment of bile acid-related disorders |
WO2017019957A2 (en) | 2015-07-29 | 2017-02-02 | Ngm Biopharmaceuticals, Inc. | Binding proteins and methods of use thereof |
AU2016353988B2 (en) | 2015-11-09 | 2019-09-26 | Ngm Biopharmaceuticals, Inc. | Methods for treatment of bile acid-related disorders |
TW201731867A (zh) * | 2015-12-02 | 2017-09-16 | 賽諾菲公司 | Fgf21變異體 |
WO2017220706A1 (en) * | 2016-06-22 | 2017-12-28 | Novo Nordisk A/S | Pharmaceutical compositions of fgf21 derivatives and uses thereof |
US11370841B2 (en) | 2016-08-26 | 2022-06-28 | Ngm Biopharmaceuticals, Inc. | Methods of treating fibroblast growth factor 19-mediated cancers and tumors |
CN106397607A (zh) * | 2016-09-13 | 2017-02-15 | 河南师范大学 | 重组人成纤维细胞生长因子21融合蛋白及其在制备治疗代谢疾病药物中的应用 |
CN106220724B (zh) * | 2016-09-13 | 2019-10-11 | 河南师范大学 | 人成纤维细胞生长因子21重组蛋白及其制备方法和应用 |
CN106432509B (zh) * | 2016-09-13 | 2019-05-21 | 河南师范大学 | 一种治疗代谢疾病的重组人成纤维细胞生长因子21融合蛋白及其制备方法和应用 |
WO2018166461A1 (en) | 2017-03-14 | 2018-09-20 | Sunshine Lake Pharma Co., Ltd. | Dual-target fusion proteins comprising the fc portion of an immunoglobulin |
MX2020002206A (es) | 2017-09-08 | 2020-07-20 | Bristol Myers Squibb Co | Factor de crecimiento de fibroblastos 21 (fgf-21) modificado para usarse en metodos para tratar la esteatohepatitis no alcoholica (nash). |
US11679143B2 (en) | 2018-02-08 | 2023-06-20 | Sunshine Lake Pharma Co., Ltd. | FGF21 variant, fusion protein and application thereof |
WO2020010117A2 (en) | 2018-07-03 | 2020-01-09 | Bristol-Myers Squibb Company | Fgf21 formulations |
CN109836486B (zh) * | 2019-01-30 | 2020-09-08 | 北京双因生物科技有限公司 | 成纤维生长因子21变体、其融合蛋白及其用途 |
CN111944055B (zh) | 2019-05-16 | 2022-08-02 | 浙江道尔生物科技有限公司 | 一种治疗代谢疾病的融合蛋白 |
IL294534A (en) | 2020-01-08 | 2022-09-01 | Bristol Myers Squibb Co | Formulations of fgf-21 conjugates |
CN115322794A (zh) | 2020-01-11 | 2022-11-11 | 北京质肽生物医药科技有限公司 | Glp-1和fgf21的融合蛋白的缀合物 |
EP4192495A1 (en) | 2020-08-07 | 2023-06-14 | Bristol-Myers Squibb Company | Fgf21 combined with ccr2/5 antagonists for the treatment of fibrosis |
KR102495299B1 (ko) * | 2020-11-03 | 2023-02-06 | 토드제약 주식회사 | Fgf21의 열탄력성을 이용한 fgf21 생산 방법 |
US20240123031A1 (en) | 2020-11-25 | 2024-04-18 | Bristol-Myers Squibb Company | Methods of treating liver diseases |
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US7459540B1 (en) | 1999-09-07 | 2008-12-02 | Amgen Inc. | Fibroblast growth factor-like polypeptides |
WO2003011213A2 (en) | 2001-07-30 | 2003-02-13 | Eli Lilly And Company | Method for treating diabetes and obesity |
EA200601121A1 (ru) * | 2003-12-10 | 2006-10-27 | Эли Лилли Энд Компани | Мутеины фактора роста фибробластов 21 |
BRPI0514790A (pt) | 2004-09-02 | 2008-06-24 | Lilly Co Eli | muteìna de fgf-21 de humano, ou um seu peptìdeo biologicamente ativo, método para produzir a muteìna, composição farmacêutica, e, uso da muteìna de fgf-21 de humano |
EP1789443A1 (en) | 2004-09-02 | 2007-05-30 | Eli Lilly And Company | Muteins of fibroblast growth factor 21 |
KR20140012199A (ko) | 2007-03-30 | 2014-01-29 | 암브룩스, 인코포레이티드 | 변형된 fgf-21 폴리펩티드 및 그 용도 |
JOP20190083A1 (ar) * | 2008-06-04 | 2017-06-16 | Amgen Inc | بولي ببتيدات اندماجية طافرة لـfgf21 واستخداماتها |
WO2010065439A1 (en) * | 2008-12-05 | 2010-06-10 | Eli Lilly And Company | Variants of fibroblast growth factor 21 |
WO2010129600A2 (en) | 2009-05-05 | 2010-11-11 | Amgen Inc. | Fgf21 mutants and uses thereof |
TWI560197B (en) | 2009-05-05 | 2016-12-01 | Amgen Inc | Fgf21 mutants and uses thereof |
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2012
- 2012-09-20 AR ARP120103466A patent/AR087973A1/es unknown
- 2012-09-21 TW TW101134800A patent/TWI461435B/zh not_active IP Right Cessation
- 2012-09-25 PE PE2014000472A patent/PE20142044A1/es not_active Application Discontinuation
- 2012-09-25 CA CA2843520A patent/CA2843520A1/en not_active Abandoned
- 2012-09-25 MX MX2014004159A patent/MX2014004159A/es unknown
- 2012-09-25 KR KR1020147008644A patent/KR20140059271A/ko not_active Application Discontinuation
- 2012-09-25 WO PCT/US2012/057053 patent/WO2013052311A1/en active Application Filing
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