ES2667420T3 - Anticuerpos biespecíficos contra cd3epsilon y bcma - Google Patents
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- ES2667420T3 ES2667420T3 ES14705304.5T ES14705304T ES2667420T3 ES 2667420 T3 ES2667420 T3 ES 2667420T3 ES 14705304 T ES14705304 T ES 14705304T ES 2667420 T3 ES2667420 T3 ES 2667420T3
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Abstract
Un anticuerpo biespecífico que se une específicamente a los dos objetivos: CD3ε humano y antígeno de maduración de la célula B humana (BCMA), el anticuerpo biespecífico comprende: (a) un primer fragmento Fab de un anticuerpo que se une específicamente a BCMA (primer fragmento Fab del anticuerpo anti-BCMA); (b) un segundo fragmento Fab del anticuerpo que se une específicamente a BCMA (segundo fragmento Fab del anticuerpo anti-BCMA); (c) una parte Fc; y (d) un fragmento Fab de un anticuerpo que se une específicamente a CD3ε (fragmento Fab del anticuerpo anti- CD3ε), en el que los dominios variables VL y VH o los dominios constantes CL y CH1 del fragmento Fab del anticuerpo anti-CD3ε son reemplazados el uno por otro, en el que el primer fragmento Fab del anticuerpo anti-BCMA se une a través de su extremo C al extremo N de la región bisagra de la parte Fc, el fragmento Fab del anticuerpo anti CD3ε se une mediante su extremo C al extremo N de la región bisagra de la parte Fc, y el segundo fragmento Fab del anticuerpo anti-BCMA se une químicamente a través de su extremo C al extremo N del fragmento Fab del anticuerpo anti-CD3ε.
Description
Anticuerpos biespecíficos contra CD3ε y bcma
5 [0001] La presente invención se refiere a nuevos anticuerpos biespecíficos contra CD3ε y BCMA, su fabricación y uso.
10 [0002] Blanco de maduración de células B humanas, también conocido como BCMA; TR17_HUMAN, TNFRSF17 (UniProt Q02223), es un miembro de la superfamilia de receptores de necrosis tumoral que se expresa preferentemente en células plasmáticas diferenciadas [Laabi et al. 1992; Madry et al. 1998]. BCMA es una proteína transmembrana tipo III no glicosilada, que participa en la maduración, el crecimiento y la supervivencia de las células
B. BCMA es un receptor para dos ligandos de la superfamilia TNF: APRIL (un ligando inductor de proliferación), el
15 ligando de alta afinidad para BCMA y el factor de activación de células B BAFF, el ligando de baja afinidad para BCMA (THANK, BlyS, estimulador de linfocitos B, TALL-1 y zTNF4). ABRIL y BAFF muestran similitud estructural y especificidad de unión al receptor al que se unen, pero distintas. El regulador negativo TACI también se une a BAFF y APRIL. La unión coordinada de APRIL y BAFF a BCMA y/o TACI activa el factor de transcripción NF-κB y aumenta la expresión de los miembros de la familia pro-supervivencia Bcl-2 (por ejemplo, Bcl-2, Bcl-xL, Bcl-w, Mcl-1, Al) y la
20 regulación a la baja de los factores pro-apoptóticos (por ejemplo, Bid, Bad, Bik, Bim, etc.), lo que inhibe la apoptosis y promueve la supervivencia. Esta acción combinada promueve la diferenciación, proliferación, supervivencia y producción de anticuerpos de las células B (como se revisó en Rickert RC y col., Immunol Rev (2011) 244 (1): 115133). Los anticuerpos contra BCMA se describen, p. ej. en Gras M-P. et al. Int Immunol. 7 (1995) 1093-1106, WO200124811 y WO200124812. El uso de anticuerpos anti-BCMA para el tratamiento de linfomas y mieloma
25 múltiple se menciona, p. ej. en los documentos WO2002066516 y WO2010104949.
[0003] El complejo TCR/CD3 de linfocitos T consiste en un heterodímero TCR alfa (α)/beta (β) o TCR gamma (γ)/delta (δ) coexpresado en la superficie celular con las subunidades invariables de CD3 marcadas gamma (γ), delta (δ), épsilon (ε), zeta (ζ) y eta (η). El CD3ε humano se describe en UniProt P07766 (CD3E_HUMAN). Un anticuerpo 30 anti CD3ε descrito en la técnica más reciente es SP34 (Yang SJ, The Journal of Immunology (1986) 137; 10971100). SP34 reacciona con CD3 de primate y humano. SP34 está disponible en Pharmingen. Otro anticuerpo anti CD3 descrito en la técnica más reciente es UCHT-1 (véase el documento WO2000041474). Otro anticuerpo anti CD3 descrito en la técnica más reciente es BC-3 (Fred Hutchinson Cancer Research Institute, usado en los ensayos de Fase I/II de GvHD, Anasetti y col., Transplantation 54: 844 (1992)). SP34 difiere de UCHT-1 y BC-3 en que SP-34 35 reconoce un epítopo presente únicamente en la cadena ε de CD3 (véase Salmeron y col., (1991) J. Immunol. 147: 3047) mientras que UCHT-1 y BC-3 reconocen un epítopo aportado por las cadenas ε y γ. La secuencia de un anticuerpo con la misma secuencia que el anticuerpo SP34 se menciona en WO2008119565, WO2008119566, WO2008119567, WO2010037836, WO2010037837 y WO2010037838. En el documento US 8236308 (WO2007042261) se menciona una secuencia que es idéntica en un 96 % a VH del anticuerpo SP34. Las
40 secuencias VH y VL de un anticuerpo adicional con las mismas secuencias que SP34 se muestran en SEQ ID NO:7 y 8.
[0004] Se ha desarrollado una amplia variedad de formatos de anticuerpos biespecíficos recombinantes en el pasado reciente, p. ej. por fusión de, p. ej. un formato de anticuerpo IgG y dominios monocatenarios (véase
45 Kontermann RE, mAbs 4: 2, (2012) 1-16). Los anticuerpos biespecíficos en los que los dominios variables VL y VH o los dominios constantes CL y CH1 se reemplazan entre sí se describen en los documentos WO2009080251 y WO2009080252.
[0005] Un procedimiento para eludir el problema de subproductos erróneos, que se conoce como "knobs-into
50 holes", tiene como objetivo forzar el emparejamiento de dos cadenas pesadas de anticuerpos diferentes mediante la introducción de mutaciones en los dominios CH3 para modificar la interfaz de contacto. En una cadena, los aminoácidos voluminosos fueron reemplazados por aminoácidos con cadenas laterales cortas para crear un "agujero". Por el contrario, los aminoácidos con cadenas laterales grandes se introdujeron en el otro dominio CH3, para crear un "botón". Al coexpresar estas dos cadenas pesadas (y dos cadenas ligeras idénticas, que deben ser
55 apropiadas para ambas cadenas pesadas), altos rendimientos de formación de heterodímeros ("agujero-botón") frente a la formación de homodímeros ("agujero-agujero" o "botón-botón") se observaron (Ridgway JB, Presta LG, Carter P y WO1996027011). El porcentaje de heterodímero podría aumentarse adicionalmente mediante la remodelación de las superficies de interacción de los dos dominios CH3 usando un procedimiento de presentación en fagos y la introducción de un puente disulfuro para estabilizar los heterodímeros (Merchant AM, et al, Nature
2
generan por PCR y/o síntesis génica y se ensamblan con métodos y técnicas recombinantes conocidos por conexión de los segmentos de ácido nucleico correspondientes, p. ej. usando sitios de restricción únicos en los respectivos vectores. Las secuencias de ácido nucleico subclonado se verifican por secuenciación de ADN. Para las transfecciones transitorias, se preparan cantidades mayores de los plásmidos mediante preparación de plásmido a
5 partir de cultivos de E. coli transformados (Nucleobond AX, Macherey-Nagel).
b) Generación de vectores de expresión de anticuerpos y antígenos La región variable de las secuencias de ADN de la cadena pesada y ligera se subclonó en el marco con la cadena pesada constante IgGI humana o la cadena ligera constante IgGI hum previamente insertada en el vector de
10 expresión de mamífero receptor respectivo. La expresión del anticuerpo fue impulsada por un promotor de MPSV quimérico que comprende un potenciador de CMV y un promotor de MPSV seguido por un 5' UTR, un intrón y un elemento kappa MAR. La transcripción se termina mediante una secuencia de señal poliA sintética en el extremo 3' del CDS. Todos los vectores llevan una secuencia de ADN del extremo 5' que codifica un péptido líder que se dirige a proteínas para la secreción en células eucarióticas. Además, cada vector contiene una secuencia de EBV OriP
15 para la replicación del plásmido episomal en células que expresan EBV EBNA.
[0110] Los antígenos que se han usado para las campañas de selección de presentación en fagos y para caracterizar las propiedades de unión de los anticuerpos seleccionados se expresaron a partir de vectores de expresión de antígenos de mamífero con secuencias de ADN pre-insertadas que codifican marcadores C-terminales. 20 Se ha usado un marcador Avi para la biotinilación in vivo o in vitro del antígeno respectivo. Para la purificación y homodimerización o heterodimerización del antígeno, se fusionó un hum IgGI Fc wt o un Fc knob para el término C del casete de expresión de antígeno. La expresión del antígeno fue dirigida por un promotor de MPSV quimérico que comprende un potenciador de CMV y un promotor de MPSV seguido por un 5' UTR, un intrón y un elemento kappa MAR. La transcripción se terminó mediante una secuencia de señal poliA sintética en el extremo 3' del CDS. Todos
25 los vectores llevan una secuencia de ADN del extremo 5' que codifica un péptido líder que se dirige a proteínas para la secreción en células eucarióticas. Además, cada vector contiene una secuencia de EBV OriP para la replicación del plásmido episomal en células que expresan EBV EBNA.
30 [0111] Las técnicas de cultivo celular habituales se usan como se describe en Current Protocols in Cell Biology (2000), Bonifacino, J.S., Dasso, M., Harford, J.B., Lippincott-Schwartz, J. y Yamada, K.M. (eds.), John Wiley & Sons, Inc.
[0112] Los anticuerpos biespecíficos se expresan por cotransfección transitoria de los respectivos plásmidos de expresión en HEK293-EBNA que crece adherentemente o en células HEK293-F que crecen en suspensión como se describe a continuación.
40
[0113] Los anticuerpos biespecíficos se expresan mediante cotransfección transitoria de los plásmidos de expresión respectivos (por ejemplo, que codifican la cadena pesada y la pesada modificada, así como la luz 45 correspondiente y la cadena ligera modificada) en células HEK293-EBNA de crecimiento adherente (células de riñón embrionario humano línea celular 293 que expresa el objetivo nuclear del virus de Epstein-Barr; número de depósito de la colección de cultivo estadounidense ATCC # CRL-10852, lote 959 218) cultivadas en DMEM (medio de Eagle modificado de Dulbecco, Gibco) suplementado con 10 % de FCS con IgG ultra bajo (suero de ternera fetal, Gibco), L-glutamina 2 mM (Gibco), y Geneticina 250 µg/ml (Gibco). Para la transfección, el reactivo de transfección 50 FuGENE™ 6 (Roche Molecular Biochemicals) se utiliza en una relación de reactivo FuGENE ™ (µl) a ADN (µg) de
4:1 (que varía de 3:1 a 6:1).
[0114] Las proteínas se expresan a partir de los plásmidos respectivos usando una relación molar de plásmidos que codifican cadena ligera y cadena pesada (modificada y de tipo salvaje) de 1:1 (equimolar) que varían
55 de 1:2 a 2 1, respectivamente. Las células se alimentan el día 3 con L Glutamina ad 4 mM, Glucosa [Sigma] y NAA [Gibco]. Los sobrenadantes de cultivo celular que contienen anticuerpo biespecífico se recogen del día 5 al 11 después de la transfección por centrifugación y se almacenan a -200 ºC. Información general con respecto a la expresión recombinante de inmunoglobulinas humanas en, p. ej., las células HEK293, se da en: Meissner, P. y col., Biotechnol. Bioeng. 75 (2001) 197-203.
20
[0115] Los anticuerpos biespecíficos se generan por transfección transitoria de los plásmidos respectivos (por
5 ejemplo, codificando la cadena pesada y pesada modificada, así como la correspondiente cadena ligera y ligera modificada) usando el sistema HEK293-F (Invitrogen) de acuerdo con las instrucciones del fabricante. Brevemente, células HEK293-F (Invitrogen) que crecen en suspensión en un matraz de agitación o en un fermentador agitado en medio de expresión FreeStyle 293 exento de suero (Invitrogen) se transfectan con una mezcla de los cuatro plásmidos de expresión y 293fectina o fectina (Invitrogen). Para un matraz de agitación de 2 L (Corning), las células
10 HEK293-F se siembran a una densidad de 1,0 x 106 células/ml en 600 ml y se incuban a 120 rpm, 8 % de CO2. El día después de transfectar las células a una densidad celular de aproximadamente 1,5 x 106 células/ml con aproximadamente 42 ml de mezcla de A) 20 ml de Opti-MEM (Invitrogen) con 600 µg de ADN plasmídico total (1 µg/ml) que codifica la cadena pesada o cadena pesada modificada, respectivamente, y la correspondiente cadena ligera en una proporción equimolar y B) 20 ml de Opti -MEM + 1,2 mL de 293 fectina o fectina (2 µl/mL). De acuerdo
15 con el consumo de glucosa, la solución de glucosa se agrega durante el curso de la fermentación. El sobrenadante que contiene el anticuerpo secretado se cosecha después de 5-10 días y los anticuerpos se purifican directamente del sobrenadante o el sobrenadante se congela y se almacena.
20 [0116] La concentración de proteína de anticuerpos y derivados purificados se determina determinando la densidad óptica (OD) a 280 nm, usando el coeficiente de extinción molar calculado sobre la base de la secuencia de aminoácidos según Pace y col., Protein Science, 1995, 4, 2411-1423.
[0117] La concentración de anticuerpos y derivados en sobrenadantes de cultivo celular se estima por inmunoprecipitación con perlas de agarosa de proteína A (Roche). 60 µL de perlas de Agarosa de Proteína A se lavan tres veces en TBS-NP40 (Tris 50 mM, pH 7,5, NaCl 150 mM, Nonidet-P40 al 1 %). Posteriormente, se aplica 1 30 -15 ml de sobrenadante de cultivo celular a las perlas de Agarosa de Proteína A preequilibradas en TBS-NP40. Después de incubar durante 1 h a temperatura ambiente, las perlas se lavan en una columna de filtro Ultrafree-MC (Amicon) una vez con 0,5 ml de TBS-NP40, dos veces con 0,5 ml de solución salina tamponada con fosfato 2x (2xPBS, Roche) y brevemente cuatro veces con 0,5 mL de Na-citrato 100 mM pH 5,0. El anticuerpo unido se eluye mediante la adición de 35 µl de tampón de muestra NuPAGE® LDS (Invitrogen). La mitad de la muestra se combina
35 con NuPAGE® Sample Reducing Agent o se deja sin reducir, respectivamente, y se calienta durante 10 min a 70 °C. En consecuencia, se aplican 5-30 µl a un 4-12 % NuPAGE® Bis-Tris SDS-PAGE (Invitrogen) (con tampón MOPS para SDS-PAGE no reducido y tampón MES con aditivo de tampón de funcionamiento antioxidante NuPAGE® (Invitrogen) para SDS-PAGE reducido) y teñido con azul de Coomassie.
40 [0118] La concentración de anticuerpos y derivados en sobrenadantes de cultivos celulares se mide cuantitativamente mediante cromatografía de HPLC por afinidad. Brevemente, los sobrenadantes del cultivo celular que contienen anticuerpos y derivados que se unen a Proteína A se aplican a una columna Applied Biosystems Poros A/20 en KH2PO4 200 mM, citrato sódico 100 mM, pH 7,4 y se eluyen de la matriz con NaCl 200 mM, ácido cítrico 100 mM, pH 2,5 en un sistema Agilent HPLC 1100. La proteína eluida se cuantifica por absorbancia UV e
45 integración de las áreas de los picos. Un anticuerpo IgGI estándar purificado sirvió como estándar.
[0119] Alternativamente, la concentración de anticuerpos y derivados en sobrenadantes de cultivos celulares se mide mediante Sandwich-IgG-ELISA. Brevemente, las placas de microtitulación de Strepatavidin A-96 StreptaWell High Bind Strepatavidin (Roche) están recubiertas con 100 µL/pocillo de molécula de captura de IgG anti-humana 50 biotinilada F(ab')2<h-Fcγ> BI (Dianova) a 0,1 mg/mL para 1 hora a temperatura ambiente o alternativamente durante la noche a 4 °C y posteriormente se lava tres veces con 200 µl/pocillo de PBS, 0,05 % de Tween® (PBST, Sigma). Se añaden a los pocillos 100 µl/pocillo de una serie de diluciones en PBS (Sigma) del respectivo anticuerpo que contiene sobrenadantes de cultivo celular y se incuban durante 1 -2 h en un agitador de microtitulación a temperatura ambiente. Los pocillos se lavan tres veces con 200 µL/pocillo de PBST y el anticuerpo unido se detecta
55 con 100 µl de F(ab')2<hFcγ> POD (Dianova) a 0,1 µg/mL como anticuerpo de detección durante 1-2 h en un agitador de microtitulación a temperatura ambiente. El anticuerpo de detección no unido se lava tres veces con 200 µL/pocillo de PBST y el anticuerpo de detección unido se detecta mediante la adición de 100 µL de ABTS/pocillo. La determinación de la absorbancia se realiza en un espectrómetro Tecan Fluor a una longitud de onda de medición de 405 nm (longitud de onda de referencia 492 nm).
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2014
- 2014-02-05 JP JP2015555752A patent/JP2016507523A/ja not_active Withdrawn
- 2014-02-05 CN CN201480007526.0A patent/CN104968683B/zh active Active
- 2014-02-05 WO PCT/EP2014/052190 patent/WO2014122144A1/en active Application Filing
- 2014-02-05 ES ES14705304.5T patent/ES2667420T3/es active Active
- 2014-02-05 US US14/764,967 patent/US9963513B2/en active Active
- 2014-02-05 ES ES14702616T patent/ES2829499T3/es active Active
- 2014-02-05 WO PCT/EP2014/052189 patent/WO2014122143A1/en active Application Filing
- 2014-02-05 CN CN201480007525.6A patent/CN104968682A/zh active Pending
- 2014-02-05 CN CN202010603485.9A patent/CN111848796A/zh active Pending
- 2014-02-05 EP EP19189675.2A patent/EP3620468A1/en active Pending
- 2014-02-05 EP EP14702616.5A patent/EP2953972B1/en active Active
- 2014-02-05 EP EP14705304.5A patent/EP2953974B1/en active Active
- 2014-02-05 PL PL14702616T patent/PL2953972T3/pl unknown
- 2014-02-05 JP JP2015555751A patent/JP6636803B2/ja active Active
- 2014-02-05 US US14/764,968 patent/US10077315B2/en active Active
- 2014-02-05 DK DK14702616.5T patent/DK2953972T3/da active
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2016
- 2016-01-20 HK HK16100577.3A patent/HK1212710A1/zh unknown
- 2016-01-20 HK HK16100575.5A patent/HK1212709A1/zh unknown
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2018
- 2018-04-04 US US15/945,554 patent/US10851171B2/en active Active
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2019
- 2019-10-03 JP JP2019183002A patent/JP6918065B2/ja active Active
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2020
- 2020-07-27 JP JP2020126460A patent/JP6944573B2/ja active Active
- 2020-11-04 US US17/089,433 patent/US20210070873A1/en not_active Abandoned
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EP2953972B1 (en) | 2020-07-08 |
JP6636803B2 (ja) | 2020-01-29 |
US20180222991A1 (en) | 2018-08-09 |
CN111848796A (zh) | 2020-10-30 |
US10077315B2 (en) | 2018-09-18 |
WO2014122143A1 (en) | 2014-08-14 |
JP6944573B2 (ja) | 2021-10-06 |
EP3620468A1 (en) | 2020-03-11 |
JP2020023523A (ja) | 2020-02-13 |
PL2953972T3 (pl) | 2021-03-08 |
CN104968683A (zh) | 2015-10-07 |
US10851171B2 (en) | 2020-12-01 |
US20210070873A1 (en) | 2021-03-11 |
ES2829499T3 (es) | 2021-06-01 |
EP2953972A1 (en) | 2015-12-16 |
US20150368351A1 (en) | 2015-12-24 |
US9963513B2 (en) | 2018-05-08 |
JP2020180158A (ja) | 2020-11-05 |
EP2953974A1 (en) | 2015-12-16 |
JP2016507523A (ja) | 2016-03-10 |
HK1212710A1 (zh) | 2016-06-17 |
JP2016508496A (ja) | 2016-03-22 |
EP2953974B1 (en) | 2017-12-20 |
CN104968682A (zh) | 2015-10-07 |
CN104968683B (zh) | 2020-07-17 |
DK2953972T3 (da) | 2020-10-12 |
WO2014122144A1 (en) | 2014-08-14 |
US20150376287A1 (en) | 2015-12-31 |
JP6918065B2 (ja) | 2021-08-11 |
HK1212709A1 (zh) | 2016-06-17 |
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