ES2600491T3 - Una variante estabilizada de receptor IIB de activina - Google Patents

Una variante estabilizada de receptor IIB de activina Download PDF

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Publication number
ES2600491T3
ES2600491T3 ES09761055.4T ES09761055T ES2600491T3 ES 2600491 T3 ES2600491 T3 ES 2600491T3 ES 09761055 T ES09761055 T ES 09761055T ES 2600491 T3 ES2600491 T3 ES 2600491T3
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polypeptide
sequence
svactriib
seq
signal sequence
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Jeonghoon Sun
Lei-Ting Tony Tam
Mark Leo Michaels
Thomas C. Boone
Rohini Deshpande
Yue-Sheng Li
Hq Han
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Amgen Inc
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Amgen Inc
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    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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Abstract

Una proteína aislada que comprende un polipéptido receptor IIB de activina estabilizado, en la que dicho polipéptido se selecciona del grupo consistente en: (a) un polipéptido consistente en la secuencia expuesta en el grupo consistente en las SEQ ID NO: 4, 6, 12 y 14; (b) un polipéptido que tiene al menos un 90 % de identidad de secuencia con (a), en la que el polipéptido tiene W o Y en la posición correspondiente a la posición 28 de la SEQ ID NO:2 y T en la posición correspondiente a la posición 44 de la SEQ ID NO:2, en la que el polipéptido es capaz de unirse a miostatina, activina A o GDF-11, y (c) polipéptidos que tienen al menos un 95 % de identidad de secuencia con (a), en la que el polipéptido tiene W o Y en la posición correspondiente a la posición 28 de la SEQ ID NO:2 y T en la posición correspondiente a la posición 44 de la SEQ ID NO:2, en la que el polipéptido es capaz de unirse a miostatina, activina A o GDF-11.

Description

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ActRIIB-Fc
Secuencia de ActRIIB Ligador de bisagra Fc de IgG2
svActRIIB-IgG2Fc (E28W, S44T)
imagen19 imagen20 imagen21
(SEQ ID NO: 10)
imagen20 imagen22
ActRIIB-IgG2Fc (E28W) (SEQ ID NO: 21)
imagen23 imagen20 imagen24
Ejemplo 2
Caracterización de polipéptidos
5 Se diluyeron muestras de polipéptidos svActRIIB-Fc (E28W, S44T) (SEQ ID NO: 10) purificado mediante la etapa de MabSelect™ y ActRIIB-Fc (E28W) (SEQ ID NO: 21) purificado mediante la etapa de columna SP-HP, como se describe anteriormente, con PBS, pH 7,4 a 0,2 mg/ml. Se determinó entonces el perfil de glicosilación de los polipéptidos usando SEC como se describe a continuación.
Cromatografía de exclusión por tamaño (SEC). Se efectuaron los experimentos en un sistema de HPLC Agilent 1100
10 con dos columnas (TOSOHAAS G3000swxl, 7,8 x 300 mm) en serie. Se usó 2x PBS como fase móvil a 0,5 ml/minuto.
La Figura 1 muestra una comparación entre ActRIIB-Fc (E28W) y svActRIIB-Fc (E28W, S44T) en una columna de SEC usando los protocolos descritos anteriormente. svActRIIB-Fc (E28W, S44T) muestra un solo pico en comparación con ActRIIB-Fc (E28W), que muestra tres picos. Estos corresponden al grado de glicosilación N-ligada 15 en la posición N42 de los dímeros de Fc de ambas proteínas. El pico único del polipéptido svActRIIB-Fc (E28W, S44T) corresponde a asparaginas N-ligadas totalmente glicosiladas en la posición N42 del dímero. Los tres picos de ActRIIB-Fc (E28W) corresponden a (de izquierda a derecha) asparaginas totalmente glicosiladas en N42, asparaginas parcialmente glicosiladas en N42 y asparaginas no glicosiladas en N42. Por lo tanto, esto demuestra que la molécula de svActRIIB-Fc (E28W, S44T) está totalmente glicosilada en comparación con ActRIIB-Fc (E28W),
20 que es heterogénea con respecto a este sitio de glicosilación, y por tanto más difícil de purificar. Además, estudios preliminares indican que la molécula de svActRIIB-Fc (E28W, S44T) tiene además propiedades de fabricabilidad mejoradas como se expone a continuación. Estudios adicionales demostraron también que el pico menos glicosilado de ActRIIB-Fc (E28W) tiene menor estabilidad física y térmica que las moléculas parcial y totalmente glicosiladas.
La determinación de los valores de KD y CI50 de los polipéptidos receptores para activina A, miostatina y GDF-11 se 25 obtuvo como se describe a continuación.
Ensayos de equilibrio KINEX A™
Se usaron ensayos de unión en equilibrio basados en disolución usando la tecnología KinExA™ (Sapidyne Instruments, Inc.) para determinar el equilibrio de disociación (KD) de la unión de ligando a polipéptidos ActRIIB-Fc. Se prerrecubrieron perlas UltraLink Biosupport (Pierce) con aproximadamente 100 µg/ml de cada uno de miostatina, 30 GDF-11 y activina A durante una noche y se bloquearon entonces con BSA. Se incubaron muestras de ActRIIB-Fc (E28W) (SEQ ID NO: 21) y svActRIIB-Fc (E28W, S44T) (SEQ ID NO: 10) 1 pM y 3 pM con diversas concentraciones
20
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SEQ ID NO:
DESCRIPCIÓN
4
polipéptido de svActRIIB (E28W, S44T) con secuencia señal
polinucleótido de svActRIIB (E28W, S44T) sin secuencia señal
6
polipéptido de svActRIIB (E28W, S44T) sin secuencia señal
7
polinucleótido de svActRIIB-Fc (E28W, S44T) con secuencia señal
8
polipéptido de svActRIIB-Fc (E28W, S44T) con secuencia señal
9
polinucleótido de svActRIIB-Fc (E28W, S44T) sin secuencia señal
polipéptido de svActRIIB-Fc (E28W, S44T) sin secuencia señal
11
polinucleótido de svActRIIB (E28Y, S44T) con secuencia señal
12
polipéptido de svActRIIB (E28Y, S44T) con secuencia señal
13
polinucleótido de svActRIIB (E28Y, S44T) sin secuencia señal
14
polipéptido de svActRIIB (E28Y, S44T) sin secuencia señal
polinucleótido de svActRIIB-Fc (E28Y, S44T) con secuencia señal
16
polipéptido de svActRIIB-Fc (E28Y, S44T) con secuencia señal
17
polinucleótido de svActRIIB-Fc (E28Y, S44T) sin secuencia señal
18
polipéptido de svActRIIB-Fc (E28Y, S44T) sin secuencia señal
19
polipéptido de ActRIIB (E28W) sin secuencia señal
polinucleótido de ActRIIB-Fc (E28W) sin secuencia señal
21
polipéptido de ActRIIBFc (E28W) sin secuencia señal
22
secuencia polipeptídica de IgG2Fc
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secuencia polipeptídica de IgG1Fc
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secuencia polipeptídica de IgG4Fc
secuencia aminoacídica de ligador
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secuencia polinucleotídica de ligador de bisagra nº 1
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secuencia peptídica de ligador de bisagra nº 1
28
región de bisagra de IgG2
29
región de bisagra de IgG1
región de bisagra de IgG4
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SEQ ID NO:
DESCRIPCIÓN
31
secuencia señal alternativa, polipéptido
32
secuencia señal, polipéptido
33
ActRIIB de tipo silvestre de acceso NP 001097
34
secuencia polipeptídica de activina
35
secuencia polipeptídica de miostatina
36
secuencia polipeptídica de GDF-11
37
secuencia de ligador de bisagra nº 2, polinucleótido
38
secuencia de ligador de bisagra nº 2, péptido
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secuencia de ligador de bisagra nº 3, polinucleótido
40
secuencia de ligador de bisagra nº 3, péptido
41
secuencia de ligador de bisagra nº 4, polinucleótido
42
secuencia de ligador de bisagra nº 4, péptido
43
secuencia de ligador de bisagra nº 5, polinucleótido
44
secuencia de ligador de bisagra nº 5, péptido
45
secuencia de ligador de bisagra nº 6, péptido
46
secuencia de ligador de bisagra nº 7, péptido
47
secuencia polipeptídica de Fc de IgG1 modificada
48
secuencia de ligador de bisagra nº 8, péptido
49
secuencia de ligador de bisagra nº 9, péptido
50
secuencia de ligador de bisagra nº 10, péptido
La presente invención no está limitada en el alcance por las realizaciones específicas descritas en la presente memoria, que se pretenden como simples ilustraciones de aspectos individuales de la invención, y métodos y componentes funcionalmente equivalentes están dentro del alcance de la invención. Es más, resultarán evidentes para el especialista en la materia diversas modificaciones de la invención, además de las mostradas y descritas en la presente memoria, a partir de la descripción anterior y los dibujos acompañantes. Dichas modificaciones pretenden entrar dentro del alcance de las reivindicaciones adjuntas.
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Claims (1)

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    imagen2
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ES09761055.4T 2008-11-26 2009-11-24 Una variante estabilizada de receptor IIB de activina Active ES2600491T3 (es)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US20025008P 2008-11-26 2008-11-26
US200250P 2008-11-26
US25906009P 2009-11-06 2009-11-06
US259060P 2009-11-06
PCT/US2009/006252 WO2010062383A2 (en) 2008-11-26 2009-11-24 Stabilized receptor polypeptides and uses thereof

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ES2600491T3 true ES2600491T3 (es) 2017-02-09

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