ES2655474T3 - Prevención de la reducción de enlaces disulfuro durante la producción recombinante de polipéptidos - Google Patents
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Abstract
Un método para la prevención de la reducción de un enlace disulfuro en un polipéptido expresado en una célula hospedadora recombinante durante el procesamiento después de la fermentación, que comprende, después de la fermentación, complementar el líquido de cultivo celular (LCC) prerecogido o el líquido de cultivo celular recogido (LCCR) de dicha célula hospedadora recombinante con un inhibidor de tiorredoxina, en donde dicho inhibidor de tiorredoxina es: (i) un inhibidor directo de tiorredoxina; (ii) un inhibidor específico de tiorredoxina reductasa; (iii) sulfato cúprico; (a) añadido en una concentración entre aproximadamente 5 μM y aproximadamente 100 μM; (b) añadido en una concentración entre aproximadamente 10 μM a aproximadamente 80 μM; (c) añadido en una concentración entre aproximadamente 15 μM y aproximadamente 50 μM; o (d) añadido a una concentración de al menos aproximadamente dos veces la concentración de tiorredoxina en dicho líquido de cultivo prerecogido o recogido. (iv) un inhibidor de G6PD, seleccionado del grupo que consiste en piridoxal 5'-fosfato, 1 fluor-2,4 dinitrobenceno, deshidroepiandrosterona (DHEA) y epiandrosterona (EA); (v) un inhibidor de la actividad de hexocinasa, inhibidor que es (a) un quelante de iones metálicos; o (b) se selecciona del grupo constituido por sorbosa-1-fosfato, polifosfatos, 6-desoxi-6-fluoroglucosa, 2-C-hidroximetilglucosa, xilosa y lixosa; (vi) un anticuerpo que se une específicamente a una tiorredoxina reductasa; o (vii) una medida que indirectamente da como resultado la inhibición de la actividad de la tiorredoxina, cuya medida es la inyección de aire en el líquido de cultivo recogido de dicha célula hospedadora recombinante.
Description
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mamífero es un ser humano.
Un "ARN interferente" o "ARN interferente pequeño (ARNip)" es una molécula de ARN bicatenaria con una longitud menor de aproximadamente 30 nucleótidos, que reduce la expresión de un gen diana. Los ARN interferentes se pueden identificar y sintetizar utilizando métodos conocidos (Shi Y., Trends in Genetics 19 (1): 9-12 (2003), WO/2003056012 y WO2003064621), y en el comercio se dispone de bibliotecas de ARNip, por ejemplo, de Dharmacon, Lafayette, Colorado. Con frecuencia, los ARNip pueden diseñarse satisfactoriamente para dirigirse al extremo 5 'de un gen.
II. Composiciones y métodos de la invención
La práctica de la presente invención empleará, a menos que se indique lo contrario, técnicas convencionales de biología molecular y similares, que están dentro de los conocimientos de la técnica. Dichas técnicas se explican con detalle en la bibliografía. Véase, por ejemplo, Molecular Cloning: A Laboratory Manual, (J. Sambrook et al., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., 1989); Current Protocols in Molecular Biology (F. Ausubel et al., eds., 1987 updated); Essential Molecular Biology (T. Brown ed., IRL Press 1991); Gene Expression Technology (Goeddel ed., Academic Press 1991); Methods for Cloning and Analysis of Eukaryotic Genes (A. Bothwell et al., eds., Bartlett Publ. 1990); Gene Transfer and Expression (M. Kriegler, Stockton Press 1990); Recombinant DNA Methodology II (R. Wu et al., eds., Academic Press 1995); PCR: A Practical Approach (M. McPherson et al., IRL Press at Oxford University Press 1991); Oligonucleotide Synthesis (M. Gait ed., 1984); Cell Culture for Biochemists
- (R.
- Adams ed., Elsevier Science Publishers 1990); Gene Transfer Vectors for Mammalian Cells (J. Miller & M. Calos eds., 1987); Mammalian Cell Biotechnology (M. Butler ed., 1991); Animal Cell Culture (J. Pollard et al., eds., Humana Press 1990); Culture of Animal Cells, 2ªd Ed. (R. Freshney et al., eds., Alan R. Liss 1987); Flow Cytometry and Sorting (M. Melamed et al., eds., Wiley-Liss 1990); the series Methods in Enzymology (Academic Press, Inc.);Wirth
- M.
- and Hauser H. (1993); Immunochemistry in Practice, 3ª edición, A. Johnstone & R. Thorpe, Blackwell Science, Cambridge, MA, 1996; Techniques in Immunocytochemistry, (G. Bullock & P. Petrusz eds., Academic Press 1982, 1983, 1985, 1989); Handbook of Experimental Immunology, (D. Weir & C. Blackwell, eds.); Current Protocols in Immunology (J. Coligan et al., eds. 1991); Immunoassay (E. P. Diamandis & T.K. Christopoulos, eds., Academic Press, Inc., 1996); Goding (1986) Monoclonal Antibodies: Principles and Practice (2d ed) Academic Press, New York; Ed Harlow and David Lane, Antibodies A laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1988; Antibody Engineering, 2ª editción (C. Borrebaeck, ed., Oxford University Press, 1995); y la serie Annual Review of Immunology ; la serie Advances in Immunology.
1. Prevención de la reducción de enlaces disulfuro
La presente invención se refiere a métodos para la prevención de la reducción de enlaces disulfuro de proteínas durante la producción recombinante. En particular, la invención se refiere a métodos para prevenir la reducción de enlaces disulfuro de proteínas recombinantes durante el procesamiento después de la fermentación. Los métodos de la invención son particularmente valiosos para la producción a gran escala, tal como a escala de fabricación, de proteínas que contienen enlaces disulfuro. En una realización, los métodos de la invención son útiles para la producción de proteínas a gran escala, a una escala mayor de 5.000 l.
Se ha descubierto experimentalmente que la reducción del enlace disulfuro tiene lugar durante el procesamiento del líquido de cultivo celular recogido (LCCR) producido durante la fabricación de proteínas recombinantes que contienen enlaces disulfuro. Generalmente, esta reducción se observa después de la lisis celular, especialmente la lisis celular mecánica durante las operaciones de recogida, cuando alcanza un determinado umbral, tal como, por ejemplo, de aproximadamente 30 % a aproximadamente 70 %, o de aproximadamente 40 % a aproximadamente 60 %, o de aproximadamente 50 % a aproximadamente 60 % de lisis celular total. Este umbral variará, dependiendo de la naturaleza de la proteína (por ejemplo, anticuerpo) producida, del huésped recombinante, del sistema de producción, de los parámetros de producción utilizados, y similares, y puede determinarse fácilmente de manera experimental.
Teóricamente, dicha reducción podría resultar de varios factores y condiciones durante el proceso de fabricación, y podría estar causada por varios agentes reductores. La presente invención se basa, al menos en parte, en el reconocimiento de que la causa fundamental de esta reducción es un sistema activo de tiorredoxina (Trx) o de tipo tiorredoxina en el LCCR.
El sistema enzimático de Trx, constituido por Trx, tiorredoxina reductasa (TrxR) y NADPH (nicotinamida adenina dinucleótido fosfato), es un sistema donador de hidrógeno para la reducción de enlaces disulfuro en proteínas. La Trx es una proteína monomérica pequeña con un motivo de sitio activo CXXC que cataliza muchas reacciones redox a través del intercambio de tiol-disulfuro. La Trx oxidada puede reducirse mediante NADPH a través de TrxR. La Trx reducida es capaz de catalizar la reducción de disulfuros en proteínas. El NADPH requerido para el sistema de tiorredoxina se proporciona mediante reacciones en la ruta de la pentosa fosfato y la glucólisis. Los resultados presentados en este documento demuestran que el NADPH, que se requiere para la actividad del sistema Trx, es proporcionado por la actividad de la glucosa-6-fosfato deshidrogenasa (G6PD), que genera NADPH a partir de glucosa y ATP por hexocinasa (véase la Figura 4). Estas enzimas celulares (sistema Trx, G6PD y hexocinasa) junto
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glucoproteína resultante. En un aspecto preferido, la fase de producción del proceso de cultivo celular está precedida por una fase de transición del cultivo celular en la que se emplean parámetros para la fase de producción del cultivo celular. Detalles adicionales de este proceso se encuentran en la patente de Estados Unidos No. 5.721.121, y en Chaderjian et al., Biotechnol. Prog. 21 (2): 550-3 (2005), cuyas descripciones completas se incorporan expresamente como referencia en la presente memoria.
Después de la fermentación, las proteínas se purifican. Los procedimientos para la purificación de proteínas de restos celulares dependen inicialmente del lugar de expresión de la proteína. Algunas proteínas pueden secretarse directamente desde la célula al interior los medios de crecimiento circundantes; otras se preparan intracelularmente. Para estas últimas proteínas, la primera etapa de un proceso de purificación implica la lisis de la célula, lo que puede realizarse mediante varios de métodos, incluyendo cizalla mecánica, choque osmótico o tratamientos enzimáticos. Dicha alteración libera todo el contenido de la célula en el homogeneizado, y además produce fragmentos subcelulares que son difíciles de eliminar debido a su pequeño tamaño. Estos generalmente se eliminan por centrifugación diferencial o por filtración. El mismo problema surge, aunque a menor escala, con proteínas secretadas directamente debido a la muerte natural de las células y a la liberación de proteínas y componentes de células hospedadoras intracelulares en el transcurso de la producción de proteínas.
Una vez que se ha obtenido una solución clarificada que contiene la proteína de interés, habitualmente se intenta su separación de las otras proteínas producidas por la célula utilizando una combinación de diferentes técnicas de cromatografía. Estas técnicas separan las mezclas de proteínas en función de su carga, grado de hidrofobicidad o tamaño. Varias resinas de cromatografía diferentes están disponibles para cada una de estas técnicas, lo que permite una adaptación exacta del esquema de purificación para la proteína particular implicada. La esencia de cada uno de estos métodos de separación es que las proteínas pueden moverse a diferentes velocidades a lo largo de una columna, logrando una separación física que aumenta a medida que pasan más abajo en la columna, o se adhieren selectivamente al medio de separación, siendo entonces eluídas diferencialmente por diferentes disolventes. En algunos casos, la proteína deseada se separa de las impurezas cuando estas últimas se adhieren específicamente a la columna, y la proteína de interés no lo hace, es decir, la proteína de interés está presente en el "flujo continuo". De este modo, la purificación de proteínas recombinantes del cultivo celular de células hospedadoras de mamífero, puede incluir una o más etapas cromatográficas de afinidad (por ejemplo, proteína A) y/o de intercambio iónico.
La cromatografía de intercambio iónico es una técnica cromatográfica que se utiliza habitualmente para la purificación de proteínas. En la cromatografía de intercambio iónico, los parches cargados en la superficie del soluto son atraídos por cargas opuestas unidas a una matriz de cromatografía, siempre que la fuerza iónica del tampón circundante sea baja. La elución generalmente se logra aumentando la fuerza iónica (es decir, la conductividad) del tampón para competir con el soluto por los sitios cargados de la matriz de intercambio iónico. Cambiar el pH y por lo tanto alterar la carga del soluto es otra forma de lograr la elución del soluto. El cambio en la conductividad o pH puede ser gradual (elución en gradiente) o escalonado (elución en etapas). En el pasado, estos cambios han sido progresivos; es decir, el pH o la conductividad aumentan o disminuyen en una sola dirección.
Para más detalles sobre la purificación industrial de anticuerpos terapéuticos, véase, por ejemplo, Fahrner et al., Biotechnol. Genet. Eng. Rev. 18: 301 -27 (2001), cuya descripción completa se incorpora expresamente como referencia en la presente memoria.
Además de células hospedadoras de mamífero, como células huésped para la expresión de la proteína recombinante, pueden utilizarse otros organismos eucariotas. Para la expresión en células hospedadoras de levadura, tales como la levadura de panadería común o Saccharomyces cerevisiae, como vectores adecuados se incluyen vectores de replicación episómica basados en el plásmido de 2 micras, vectores de integración y vectores cromosómicos artificiales de levadura (YAC, yeast artificial chromosome). Otras levaduras adecuadas para la producción recombinante de proteínas heterólogas incluyen Schizosaccharomyces pombe (Beach y Nurse, Nature,
290: 140 (1981), documento EP 139 383 publicado el 2 de mayo de 1985); hospedadores de Kluyveromyces (Patente de los Estados Unidos N.º 4.943.529, Fleer et al., Bio/Technology, 2: 968.975 (1991)) tales como, por ejemplo, K. lactis (MW98-8C, CBS683, CBS4574; Louvencourt et al., J. Bacteriol., 737 (1983)), K. fragilis (ATCC 12.424), K. bulgaricus (ATCC 16.045), K. wickeramii (ATCC 24.178), K Waltii (ATCC 56.500), K. drosophilarum (ATCC 36.906; Van den Berg et al., Bio/Technology, 8: 135 (1990)), K. thermotolerans y K. marxianus; Yarrowia (documento EP 402.226); Pichia pastoris (documento EP 183.070; Sreekrishna et al., J. Basic Microbiol., 28: 265 278 (1988)); Candida; Trichoderma reesia (documento EP 244.234); Neurospora crassa (Case et al., Proc. Natl. Acad. Sci. USA, 76: 5259 5263 (1979)); Schwanniomyces tal como Schwanniomyces occidentalis (documento EP 394.538 publicado el 31 de octubre de 1990); y hongos filamentosos tales como, por ejemplo, Neurospora, Penicillium, Tolypocladium (documento WO 91/00357 publicado el 10 de enero de 1991), y hospedadores de Aspergillus tales como A. nidulans (Ballance et al., Biochem. Biophys. Res. Commun., 112: 284 289 (1983); Tilburn et al., Gene, 26: 205 221 (1983); Yelton et al., Proc. Natl. Acad. Sci. USA, 81: 1470 1474 (1984)) y A. niger (Kelly and Hynes, EMBO J., 4: 475 479 (1985)). Las levaduras metilotróficas son adecuadas en este documento e incluyen, pero sin limitación, una levadura capaz de crecer en metanol seleccionada de los géneros que consisten en Hansenula, Candida, Kloeckera, Pichia, Saccharomyces, Torulopsis y Rhodotorula. Una lista de especies específicas que son a modo de ejemplo de esta clase de levaduras se puede encontrar en C. Anthony, The
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