ES2632078T3 - Variantes del factor de crecimiento de fibroblastos 21 - Google Patents
Variantes del factor de crecimiento de fibroblastos 21 Download PDFInfo
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- ES2632078T3 ES2632078T3 ES13729210.8T ES13729210T ES2632078T3 ES 2632078 T3 ES2632078 T3 ES 2632078T3 ES 13729210 T ES13729210 T ES 13729210T ES 2632078 T3 ES2632078 T3 ES 2632078T3
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- growth factor
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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 17
- 108090000376 Fibroblast growth factor 21 Proteins 0.000 abstract description 17
- 125000003275 alpha amino acid group Chemical group 0.000 abstract 1
- 210000004369 blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- 239000008103 glucose Substances 0.000 description 8
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 108010076504 Protein Sorting Signals Proteins 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000003971 Fibroblast Growth Factor 1 Human genes 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 101000766306 Homo sapiens Serotransferrin Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000004335 litholrubine BK Substances 0.000 description 1
- 150000002680 magnesium Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 239000003643 water by type Substances 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
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/81—Carrier - bound or immobilized peptides or proteins and the preparation thereof, e.g. biological cell or cell fragment as carrier
- Y10S530/812—Peptides or proteins is immobilized on, or in, an organic carrier
- Y10S530/813—Carrier is a saccharide
- Y10S530/814—Cellulose or derivatives thereof
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Toxicology (AREA)
- Biophysics (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- General Chemical & Material Sciences (AREA)
- Obesity (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Child & Adolescent Psychology (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), en donde la secuencia de aminoácidos es**Fórmula**
Description
Tabla 1: Estabilidad física
- Variante del FGF21 de SEC. ID. N.º 7
- Inicial
- % de APM a 30 mg/ml(t=0) % de APM a 30 mg/ml (t=4semanas)
- 10 mM de histidina, pH7, 150 mM deNaCI
- 0,15 % 0,9 %
- 4 ºC
- 1,1 %
- 25 ºC
- 1,5 %
- 40 ºC
- 2,3 %
- 10 mM de histidina, pH7,
- 0,2 % 3,2 %
- 4 ºC
- 2,5 %
- 25 ºC
- 2,9 %
- 40 ºC
- 6,6 %
- Variante del FGF21 de SEC. ID. N.º 1
- Inicial
- % de APM a 30 mg/ml(t=0) % de APM a 30 mg/ml (t=4semanas)
- 10 mM de histidina, pH7, 150 mM deNaCI
- 0,15 % 0,7 %
- 4 ºC
- 0,8 %
- 25 ºC
- 0,8 %
- 40 ºC
- 1,7 %
- 10 mM de histidina, pH7,
- 0,13 % 1,0 %
- 4 ºC
- 0,6 %
- 25 ºC
- 1,1 %
- 40 ºC
- 5,3 %
Ejemplo 4
Heterogeneidad de la expresión de R175 y E180
5 La producción de un producto de una variante homogénea es deseable puesto que asegura mejor un producto consistente y bien caracterizado. Para evaluar la heterogeneidad del producto, una alícuota de 10 µl de la muestra se mezcla con 90 µl de SSTFD. La muestra se analiza mediante cromatografía líquida-espectrometría de masas (CL-EM), utilizando las siguientes condiciones: la fase móvil A es ATF al 0,05 %, la fase móvil B es ATF al 0,04 % en acetonitrilo, la columna es una columna PLRPS de 2,1 X 50 mm, el volumen de inyección es de 15 μl.
10 Tabla 2: Condiciones del gradiente para la separación por cromatografía líquida
- Tiempo (min)
- 0 1 15 16 20 20,1 30
- % B
- 5 35 40 90 90 5 5
- Flujo (µl/min)
- 200 200 200 200 200 200 200
Un espectrómetro de masas Waters Micromass LCT Premier™ se calibró hasta un intervalo de masas comprendido entre 400 a 1990 amu, polaridad ES+, capilar 3000, cono de muestra de 40 V, la abertura 1 es de 25 V, la temperatura de la fuente es de 105 ºC, el cono del flujo de gas se encuentra a 50 l/hora, la temperatura de
15 evaporación del solvente es de 150 ºC, y el flujo de gas de evaporación del solvente es de 600 l/hora.
Tabla 3: Caracterización por CL/EM de las variantes del FGF21
- Variante del FGF21
- 1-181 1-180 1-179
- Variante del FGF21 de SEC. ID. N.º 7
- 33,7 % 63 % 3,3 %
- Variante del FGF21 de SEC. ID. N.º 1
- 100 %
7 5
10
15
20
25
30
35
40
La Tabla 3 notifica la heterogeneidad resultante en cada variante del FGF21 que se determina por el método CL/EM. El producto 1-181 representa la variante del FGF21 de longitud completa de SEC. ID. N.º 7. La variante del FGF21 de SEC. ID. N.º 7 es susceptible a truncamientos en el extremo C-terminal, especialmente la eliminación del residuo de aminoácidos glicina en la posición 181. Como se muestra en la Tabla 3, el 33,7 % del producto purificado para la variante del FGF21 de SEC. ID. N.º 7 es el fragmento 1-181 de longitud completa previsto; el fragmento 1-180 constituye la porción más grande del producto purificado. Además, también se detectaron pequeñas cantidades de producto 1-179.
La variante del FGF21 de SEC. ID. N.º 1 tiene el residuo de aminoácidos en 181 delecionado en la construcción genética y el residuo de aminoácidos 180 se ha sustituido con ácido glutámico (E). Estos cambios protegen el extremo C-terminal de la degradación durante la expresión de CHO, dando como resultado un producto 1-180 purificado homogéneo al 100 %.
Ejemplo 5
Disminución de glucosa en un modelo de ratón Ob/ob
Los ratones macho ob/ob y los controles (delgados) con la misma edad ob/m tienen 7 semanas de edad a su llegada y 8-9 semanas de edad al inicio del tratamiento. A su llegada, todos los ratones se alojaron solos y se les permitió aclimatarse durante 1-2 semanas antes del comienzo del tratamiento. Los ratones se alimentaron con Purina Rodent Chow 5015 y se les dio agua potable ad libitum de un dispensador. Los ratones se alojan en un ciclo de 12 horas de luz/oscuridad con una temperatura ambiente establecida a 23,8 ºC (75 º F). Uno a dos días antes del inicio del tratamiento, se recogen muestras de sangre por medio de la extracción de sangre de la cola. Se miden los niveles de glucosa en sangre utilizando un glucómetro en sangre AccuCheck Avivia (Roche) y se recogen las muestras de suero para el ensayo de insulina utilizando el kit de ensayo de insulina ratón/rata Meso Scale. En el día del inicio del tratamiento (día 0), se clasifican los ratones en grupos basándose en el pre-tratamiento del peso corporal, la glucosa en sangre y la insulina en suero (software de clasificación BRAT). En el día 0 y en el día 3, los ratones se dosifican por vía SC con 0,1 a 30 nmol/kg de la variante del FGF21 de SEC. ID. N.º 5, en un volumen de 10 ml/kg. El vehículo dosificador es TFS estéril (HyClone SSTFD/magnesio y calcio modificados) que contiene albúmina de suero de ratón al 0,03 % (ASR, Sigma A3139). La glucosa en sangre se mide diariamente durante 7 días y se determina la ABC. Los cálculos de la DE50 para la disminución de glucosa se basan en la ABC. Los homogeneizados de hígado se recogen en el momento del sacrificio y los triglicéridos del hígado se miden en el analizador clínico Hitachi Modular
P.
En el día 14, los ratones tratados con un vehículo fueron hiperglucémicos con unos niveles de glucosa en sangre medios medidos a 348 ± 19,5 mg/dl (media ± EEM), mientras que los ratones de control delgados ob/m tenían niveles de glucosa en sangre de 165 ± 3,2 mg/dl (media ± EEM). La variante del FGF21 de SEC. ID. N.º 1 disminuyó la glucosa en sangre hasta niveles comparables con los controles delgados ob/m. La DE50 de la variante del FGF21 de SEC. ID. N.º 1 fue de 1,296 nmol/kg, (intervalo de confianza del 95 % = -0,07-0,30).
Secuencias
SEC. ID. N.º 1 -Variante del FGF21
SEC. ID. N.º 2 -FGF21 de tipo natural (Homo Sapiens)
SEC. ID. N.º 3 -Péptido señal de la transferrina humana (hTrf)
MRLAVGALLVCAVLGLCLA
SEC. ID. N.º 4 -Péptido señal de la proteína de unión al factor de crecimiento de fibroblastos 1 (hFGFP-1)
MKICSLTLLSFLLLAAQVLLVEG
8
Claims (1)
-
imagen1
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261658110P | 2012-06-11 | 2012-06-11 | |
| US201261658110P | 2012-06-11 | ||
| PCT/US2013/044192 WO2013188182A1 (en) | 2012-06-11 | 2013-06-05 | Fibroblast growth factor 21 variants |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2632078T3 true ES2632078T3 (es) | 2017-09-08 |
Family
ID=48626674
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES13729210.8T Active ES2632078T3 (es) | 2012-06-11 | 2013-06-05 | Variantes del factor de crecimiento de fibroblastos 21 |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US9422353B2 (es) |
| EP (1) | EP2859014B1 (es) |
| JP (1) | JP6181752B2 (es) |
| KR (1) | KR20150006059A (es) |
| CN (1) | CN104364261B (es) |
| AU (1) | AU2013274639A1 (es) |
| CA (1) | CA2871656A1 (es) |
| EA (1) | EA201492064A1 (es) |
| ES (1) | ES2632078T3 (es) |
| MX (1) | MX2014015258A (es) |
| WO (1) | WO2013188182A1 (es) |
| ZA (1) | ZA201407938B (es) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105601748B (zh) | 2011-07-01 | 2021-08-27 | 恩格姆生物制药公司 | 用于代谢病症和疾病治疗的组合物、应用和方法 |
| US9290557B2 (en) | 2012-11-28 | 2016-03-22 | Ngm Biopharmaceuticals, Inc. | Compositions comprising variants and fusions of FGF19 polypeptides |
| HK1214832A1 (zh) | 2012-11-28 | 2016-08-05 | 恩格姆生物制药公司 | 用於代謝病症和疾病治療的組合物和方法 |
| ES2915851T3 (es) | 2012-12-27 | 2022-06-27 | Ngm Biopharmaceuticals Inc | Péptidos quiméricos de FGF19 para usar en el tratamiento de trastornos de ácidos biliares |
| 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 |
| CA2927592C (en) | 2013-10-28 | 2020-08-18 | Ngm Biopharmaceuticals, Inc. | Fgf-19 variants for treating a fgf-19 dependent cancer or tumor |
| PE20170256A1 (es) | 2014-01-24 | 2017-04-22 | Ngm Biopharmaceuticals Inc | Proteinas de union y sus metodos de uso |
| 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 |
| RU2729161C2 (ru) | 2014-10-23 | 2020-08-04 | ЭнДжиЭм БАЙОФАРМАСЬЮТИКАЛЗ, ИНК. | Фармацевтические композиции, содержащие варианты пептидов, и способы их применения |
| 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 |
| US10800843B2 (en) | 2015-07-29 | 2020-10-13 | Ngm Biopharmaceuticals, Inc. | Beta klotho-binding proteins |
| JP6728352B2 (ja) | 2015-11-09 | 2020-07-22 | エヌジーエム バイオファーマシューティカルス，インコーポレーテッド | 胆汁酸に関係した障害の治療方法 |
| TW201731867A (zh) | 2015-12-02 | 2017-09-16 | 賽諾菲公司 | Ｆｇｆ２１變異體 |
| US20190201491A1 (en) | 2016-08-22 | 2019-07-04 | Elanco Us Inc. | Bovine fibroblast growth factor 21 and ketosis in dairy cattle |
| CA3034399A1 (en) | 2016-08-26 | 2018-03-01 | Ngm Biopharmaceuticals, Inc. | Methods of treating fibroblast growth factor 19-mediated cancers and tumors |
| BR112019012693A2 (pt) | 2016-12-22 | 2019-11-19 | Sanofi | combinações de composto de fgf21/agonista do glp-1r com razão de atividade otimizada |
| WO2018166461A1 (en) | 2017-03-14 | 2018-09-20 | Sunshine Lake Pharma Co., Ltd. | Dual-target fusion proteins comprising the fc portion of an immunoglobulin |
| CN107056925B (zh) * | 2017-04-28 | 2022-01-14 | 中国科学院合肥物质科学研究院 | 人fgf21突变体、其制备方法及用途 |
| AU2019218147B2 (en) | 2018-02-08 | 2023-06-08 | Sunshine Lake Pharma Co., Ltd. | FGF21 variant, fusion protein and application thereof |
| KR102094184B1 (ko) | 2018-05-18 | 2020-03-27 | 고려대학교 산학협력단 | Crtc 2의 간 특이적 조절에 의한 지방간 및 비만 제어용 조성물 |
| EP3935075A4 (en) | 2019-03-05 | 2023-01-18 | Sunshine Lake Pharma Co., Ltd. | POLYPEPTIDE MOLECULE AND APPLICATION THEREOF |
| 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 |
| US20240165202A1 (en) * | 2021-03-19 | 2024-05-23 | Sunshine Lake Pharma Co., Ltd. | Uses of fgf21 polypeptides and fusion polypeptides thereof |
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| GB8601597D0 (en) | 1986-01-23 | 1986-02-26 | Wilson R H | Nucleotide sequences |
| US7459540B1 (en) | 1999-09-07 | 2008-12-02 | Amgen Inc. | Fibroblast growth factor-like polypeptides |
| US20040259780A1 (en) | 2001-07-30 | 2004-12-23 | Glasebrook Andrew Lawrence | Method for treating diabetes and obesity |
| EP2270163A1 (en) | 2003-12-10 | 2011-01-05 | Eli Lilly and Company | Muteins of fibroblast growth factor 21 |
| EP2194064A1 (en) | 2004-05-13 | 2010-06-09 | Eli Lilly & Company | FGF-21 fusion proteins |
| KR100854198B1 (ko) | 2004-09-02 | 2008-08-26 | 일라이 릴리 앤드 캄파니 | 섬유아세포 성장 인자 21의 뮤테인 |
| CN107501407B (zh) | 2007-03-30 | 2022-03-18 | Ambrx公司 | 经修饰fgf-21多肽和其用途 |
| US8034770B2 (en) | 2008-06-04 | 2011-10-11 | Amgen Inc. | FGF21 polypeptides comprising two or more mutations |
| CA2739615C (en) | 2008-10-10 | 2017-12-05 | Amgen Inc. | Fgf21 mutants comprising polyethylene glycol and uses thereof |
| WO2010065439A1 (en) * | 2008-12-05 | 2010-06-10 | Eli Lilly And Company | Variants of fibroblast growth factor 21 |
| CN102361647B (zh) | 2009-01-23 | 2018-02-16 | 诺沃-诺迪斯克有限公司 | 具有白蛋白结合剂a‑b‑c‑d‑e‑的fgf21衍生物及其应用 |
| CN101520547B (zh) * | 2009-04-17 | 2011-05-18 | 东南大学 | 挠曲柱面反射式聚光镜制造方法 |
| WO2010129600A2 (en) | 2009-05-05 | 2010-11-11 | Amgen Inc. | Fgf21 mutants and uses thereof |
| WO2010129503A1 (en) | 2009-05-05 | 2010-11-11 | Amgen Inc. | Fgf21 mutants and uses thereof |
| WO2011154349A2 (en) * | 2010-06-08 | 2011-12-15 | Novo Nordisk A/S | Fgf21 analogues and derivatives |
| EP2461808A2 (en) | 2009-08-07 | 2012-06-13 | UCB Pharma S.A. | Methods for enhancing the cognitive function |
| AR087973A1 (es) * | 2011-10-04 | 2014-04-30 | Lilly Co Eli | Variantes del factor 21 del crecimiento de fibroblastos |
| TWI513705B (zh) * | 2012-06-11 | 2015-12-21 | Lilly Co Eli | 纖維母細胞生長因子２１蛋白質 |
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| WO2013188182A1 (en) | 2013-12-19 |
| EA201492064A1 (ru) | 2015-02-27 |
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