ES2659829T3 - Prevención de la reducción de enlaces disulfuro durante la producción recombinante de polipéptidos - Google Patents
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Abstract
Un metodo para la prevencion de la reduccion de un enlace disulfuro en un polipeptido expresado en una celula hospedadora recombinante durante el procesamiento posterior a la fermentacion, que comprende, despues de la fermentacion: disminuir el pH del liquido de cultivo celular recogido de dicha celula hospedadora recombinante, en donde dicha celula hospedadora recombinante es una celula de ovario de hamster chino (CHO).
Description
limitantes.
Un "fragmento biológicamente funcional" de un anticuerpo comprende solo una parte de un anticuerpo intacto, en donde la parte conserva al menos una, y tantas como la mayoría o todas, de las funciones normalmente asociadas a
5 esa parte cuando están presentes en un anticuerpo intacto. En una realización, un fragmento biológicamente funcional de un anticuerpo comprende un sitio de unión a antígeno del anticuerpo intacto y, por lo tanto, conserva la capacidad de unirse al antígeno. En otra realización, un fragmento biológicamente funcional de un anticuerpo, por ejemplo uno que comprende la región Fc, conserva al menos una de las funciones biológicas normalmente asociadas a la región Fc cuando está presente en un anticuerpo intacto, tal como la unión a FcRn, la modulación de la semivida del anticuerpo, la función CCDA y unión al complemento. En una realización, un fragmento biológicamente funcional de un anticuerpo es un anticuerpo monovalente que tiene una semivida in vivo sustancialmente similar a la de un anticuerpo intacto. Por ejemplo, dicho fragmento biológicamente funcional de un anticuerpo puede comprender un brazo de unión a antígeno unido a una secuencia de Fc capaz de conferir estabilidad in vivo al fragmento.
15 Las expresiones "inhibidor de tiorredoxina" e "inhibidor de Trx" se utilizan indistintamente, e incluyen todos los agentes y medidas efectivos para inhibir la actividad de la tiorredoxina. Por lo tanto, los inhibidores de tiorredoxina (Trx) incluyen todos los agentes y medidas que bloquean cualquier componente de los sistemas de enzimas Trx, G6PD y / o hexocinasa. En este contexto, la "inhibición" incluye la eliminación completa (bloqueo) y la reducción de la actividad de la tiorredoxina y, en consecuencia, la eliminación completa o parcial de la reducción del enlace disulfuro en una proteína, tal como un anticuerpo.
Un anticuerpo "aislado" es uno que se ha identificado y separado y / o recuperado de un componente de su entorno natural. Los componentes contaminantes de su entorno natural son materiales que interferirían con la investigación, 25 el diagnóstico o los usos terapéuticos del anticuerpo, y pueden incluir enzimas, hormonas y otros solutos proteicos o no proteicos. En algunas realizaciones, un anticuerpo se purifica (1) a más de 95 % en peso de anticuerpo como se determina mediante, por ejemplo, el método Lowry, y en algunas realizaciones, hasta más de 99 % en peso; (2) a un grado suficiente para obtener al menos 15 restos de la secuencia de aminoácidos N-terminal o interna utilizando, por ejemplo, un secuenciador de copa giratoria, o (3) a homogeneidad mediante SDS-PAGE en condiciones reductoras
o no reductoras utilizando, por ejemplo, tinción con azul de Coomassie o plata. El anticuerpo aislado incluye el anticuerpo in situ dentro de células recombinantes ya que al menos un componente del entorno natural del anticuerpo no estará presente. Sin embargo, habitualmente, el anticuerpo aislado se preparará mediante al menos una etapa de purificación.
35 Las expresiones "Proteína A" y "ProA" se utilizan indistintamente en la presente memoria y abarcan Proteína A recuperada de una fuente nativa de la misma, Proteína A producida sintéticamente (p. ej. mediante síntesis peptídica
o mediante técnicas recombinantes) y variantes de la misma que conservan la capacidad de unir proteínas que tienen una región CH2/CH3, tal como una región Fc. La proteína A se puede adquirir en el comercio en Repligen, GE Healthcare y Fermatech. La proteína A generalmente se inmoviliza sobre un material de soporte en fase sólida. El término "ProA" también se refiere a una resina o columna de cromatografía de afinidad que contiene una matriz de soporte sólida cromatográfica a la que está unida de manera covalente la Proteína A.
El término "cromatografía" se refiere al proceso mediante el cual un soluto de interés en una mezcla se separa de otros solutos en una mezcla como resultado de las diferencias en las velocidades a las que los solutos individuales
45 de la mezcla migran a través de un medio estacionario bajo la influencia de una fase de movimiento, o en procesos de unión y elución.
Las expresiones “cromatografía de afinidad" y "cromatografía de afinidad de proteínas" se utilizan indistintamente en la presente memoria y se refieren a una técnica de separación de proteínas en la que una proteína o un anticuerpo de interés se une de forma reversible y específica a un ligando bioespecífico. Preferiblemente, el ligando biespecífico se une de manera covalente a un material cromatográfico en fase sólida y es accesible a la proteína de interés en la solución cuando la solución entra en contacto con el material cromatográfico en fase sólida. La proteína de interés (por ejemplo, anticuerpo, enzima o proteína receptora) conserva su afinidad de unión específica por el ligando bioespecífico (antígeno, sustrato, cofactor u hormona, por ejemplo) durante las etapas cromatográficas, mientras
55 que otros solutos y / o proteínas en la mezcla no se unen apreciable o específicamente al ligando. La unión de la proteína de interés al ligando inmovilizado permite que las proteínas contaminantes o las impurezas de proteínas pasen a través del medio cromatográfico mientras que la proteína de interés permanece específicamente unida al ligando inmovilizado en el material de fase sólida. La proteína de interés específicamente unida se elimina después en forma activa del ligando inmovilizado con ligando competidor de bajo pH, alto pH, alto contenido en sal y similares, y se hace pasar a través de la columna cromatográfica con el tampón de elución, carente de las proteínas contaminantes o impurezas de proteínas que antes se les permitía pasar a través de la columna. Como ligando puede utilizarse cualquier componente para purificar su respectiva proteína de unión específica, por ejemplo, anticuerpo.
65 Las expresiones "cromatografía de no afinidad" y "purificación de no afinidad" se refieren a un proceso de purificación en el que no se utiliza la cromatografía de afinidad. La cromatografía de no afinidad incluye técnicas
11
recogida.
Como alternativa o adicionalmente, también pueden utilizarse otros métodos inespecíficos para impedir la reducción del enlace disulfuro después de la fermentación durante la producción recombinante de proteínas recombinantes, tal como la inyección de aire o el ajuste del pH. En la siguiente Tabla 1, se enumeran determinados métodos de inhibición de la reducción contemplados en este documento.
Tabla 1: Métodos de inhibición de la reducción
- Método1
- Propósito
- Adición de EDTA, EGTA o citrato
- Para inhibir hexocinasa
- Adición de sorbosa-1-fosfato, polifosfatos, 6-desoxi-6fluoroglucosa, 2-C-hidroxi-metilglucosa, xilosa o lixosa
- Para inhibir hexocinasa
- Adición de epiandrosterona o deshidropiandrosterona (DHEA)
- Para inhibir G6PD
- Adición de piridoxal 5'-fosfato o 1-fluor-2,4-dinitrobenceno
- Para inhibir G6PD
- Adición de iones metálicos, tales como, Cu2+, Zn2+ Hg2+ , Co2+ o Mn2+
- Para inhibir el sistema Trx
- Adición de disulfuros de alquil-2-imidazolilo y compuestos relacionados (por ejemplo, disulfuro de 1 metilpropil-2imidazolilo)2 o derivados de naftoquinona espirocetales (p. ej. palmarumicina CP12)
- Para inhibir Trx
- Adición de aurotioglucosa (ATG) o aurotiomalato (ATM)
- Para inhibir TrxR
- Inyección de aire
- Para reducir G6P y NADPH; agente oxidante
- Cistina
- Agente oxidante
- Glutatión oxidada
- Agentes oxidantes
- Ajuste de pH por debajo de 6,0
- Para reducir la tasa de intercambio de tioldisulfuro y la actividad del sistema Trx
- 1 Aplicado al LCC antes de la recogida o en el LCCR inmediatamente después de la recogida.
- 2 Actualmente no disponible en el comercio.
10 Como "inhibidores de Trx" para uso en los métodos de la presente divulgación, se incluyen, sin limitación, (1) inhibidores directos de Trx, tales como disulfuros de alquil-2-imidazolilo y compuestos relacionados (por ejemplo, disulfuro de 1 metilpropil-2-imidazolilo) (Kirkpatrick et al., 1998 y 1999, citados anteriormente) y derivados de naftoquinona espirocetales (por ejemplo, palmarumicina CP1 ) (Wipf et al., 2001, citados anteriormente); (2) inhibidores específicos de TrxR, que incluyen complejos de oro, tales como aurotioglucosa (ATG) y aurotiomalato
15 (ATM) (véase, por ejemplo, la revisión de Gromer et al., 2004), que son ejemplos de inhibidores irreversibles de TrxR; (3) iones metálicos, tales como Hg2+, Cu2+, Zn2+, Co2+ y Mn2+, que pueden formar fácilmente complejos con tioles y selenoles, y de este modo se puede utilizar en realizaciones de la presente invención como inhibidores de TrxR o Trx; (4) inhibidores de G6PD, tales como, por ejemplo, piridoxal 5'-fosfato y 1 fluor-2,4-dinitrobenceno (Milhausen y Levy 1975, citados anteriormente), ciertos esteroides, tales como deshidroepiandrosterona (DHEA) y
20 epiandrosterona (EA) (Gordon et al., 1995, citados anteriormente); y (4) inhibidores de la actividad de hexocinasa (y por lo tanto de la producción de G6P para la G6PD), incluidos los quelantes de iones metálicos, por ejemplo, Mg2+ , tales como EDTA, y compuestos que reaccionan con grupos SH, sorbosa-1-fosfato, polifosfatos, 6-desoxi-6fluoroglucosa, 2-C-hidroxi-metilglucosa, xilosa y lixosa (Sols et al., 1958, citados anteriormente; McDonald, 1955, citado anteriormente); en la patente de estados unidos Nº 5.854.067 titulada "Inhibidores de hexocinasa", se
25 desvelan otros inhibidores de hexocinasa. Se entenderá que estos inhibidores se enumeran solo con fines ilustrativos. Existen otros inhibidores de Trx y pueden utilizarse, solos o en diversas combinaciones.
Los "inhibidores de Trx" para utilizar en los métodos de la presente divulgación también incluyen reactivos por los cuales la reducción de anticuerpos o proteínas producidos por medios recombinantes, puede disminuirse o 30 impedirse disminuyendo los niveles de enzimas del sistema Trx, la ruta de la pentosa fosfato o hexocinasa, en varios puntos durante la campaña de producción. En algunas realizaciones, esta reducción de los niveles de enzima se puede lograr utilizando ARNip, nucleótidos antisentido o anticuerpos. Para diseñar RNAip o nucleótidos antisentido dirigidos a los genes que se encuentran en células CHO, estas secuencias génicas están disponibles en bases de datos públicas para seleccionar secuencias para dirigir enzimas en diferentes organismos. Para ejemplos de genes
35 del sistema Trx de E. coli y de ratón véase más adelante el Ejemplo 9.
Además de utilizar los inhibidores comentados anteriormente, en determinadas realizaciones de la presente
16
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US94867707P | 2007-07-09 | 2007-07-09 | |
US948677P | 2007-07-09 |
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ES12178200.7T Active ES2659829T3 (es) | 2007-07-09 | 2008-07-08 | Prevención de la reducción de enlaces disulfuro durante la producción recombinante de polipéptidos |
ES17196350T Active ES2751022T3 (es) | 2007-07-09 | 2008-07-08 | Prevención de la reducción de enlaces disulfuro durante la producción recombinante de polipéptidos |
ES08781481.0T Active ES2655474T3 (es) | 2007-07-09 | 2008-07-08 | Prevención de la reducción de enlaces disulfuro durante la producción recombinante de polipéptidos |
ES19181777T Active ES2941738T3 (es) | 2007-07-09 | 2008-07-08 | Prevención de la reducción de enlaces disulfuro durante la producción recombinante de polipéptidos |
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ES17196350T Active ES2751022T3 (es) | 2007-07-09 | 2008-07-08 | Prevención de la reducción de enlaces disulfuro durante la producción recombinante de polipéptidos |
ES08781481.0T Active ES2655474T3 (es) | 2007-07-09 | 2008-07-08 | Prevención de la reducción de enlaces disulfuro durante la producción recombinante de polipéptidos |
ES19181777T Active ES2941738T3 (es) | 2007-07-09 | 2008-07-08 | Prevención de la reducción de enlaces disulfuro durante la producción recombinante de polipéptidos |
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US (14) | US20090053786A1 (es) |
EP (8) | EP4245766A3 (es) |
JP (5) | JP5687057B2 (es) |
KR (6) | KR101643514B1 (es) |
CN (3) | CN101932591B (es) |
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DE (1) | DE17196350T1 (es) |
DK (2) | DK3597659T3 (es) |
ES (4) | ES2659829T3 (es) |
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HR (3) | HRP20230461T3 (es) |
HU (4) | HUE061746T2 (es) |
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PT (2) | PT3327026T (es) |
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SG10201504094SA (en) | 2003-11-05 | 2015-06-29 | Roche Glycart Ag | Cd20 antibodies with increased fc receptor binding affinity and effector function |
EP2064314A4 (en) | 2006-09-13 | 2009-12-30 | Abbott Lab | IMPROVEMENTS TO CELL CULTURE |
US8911964B2 (en) | 2006-09-13 | 2014-12-16 | Abbvie Inc. | Fed-batch method of making human anti-TNF-alpha antibody |
CN101932591B (zh) | 2007-07-09 | 2018-02-16 | 健泰科生物技术公司 | 在多肽的重组生产期间防止二硫键还原 |
TWI472339B (zh) | 2008-01-30 | 2015-02-11 | Genentech Inc | 包含結合至her2結構域ii之抗體及其酸性變異體的組合物 |
AR073295A1 (es) | 2008-09-16 | 2010-10-28 | Genentech Inc | Metodos para tratar la esclerosis multiple progresiva. articulo de fabricacion. |
TW201028433A (en) | 2008-10-20 | 2010-08-01 | Abbott Lab | Viral inactivation during purification of antibodies |
JP5808249B2 (ja) | 2008-10-20 | 2015-11-10 | アッヴィ・インコーポレイテッド | プロテインaアフィニティークロマトグラフィーを用いる抗体の単離および精製 |
CA2759370C (en) * | 2009-04-30 | 2020-02-11 | Peter Schotte | Method for the production of domain antibodies |
US9079953B2 (en) * | 2009-06-17 | 2015-07-14 | Abbvie Biotherapeutics Inc. | Anti-VEGF antibodies and their uses |
SG10201901417UA (en) | 2009-08-11 | 2019-03-28 | Genentech Inc | Production of proteins in glutamine-free cell culture media |
AR078161A1 (es) | 2009-09-11 | 2011-10-19 | Hoffmann La Roche | Formulaciones farmaceuticas muy concentradas de un anticuerpo anti cd20. uso de la formulacion. metodo de tratamiento. |
WO2011084496A1 (en) * | 2009-12-16 | 2011-07-14 | Abbott Biotherapeutics Corp. | Anti-her2 antibodies and their uses |
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