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ES2694857T3 - Smoothened mutante y métodos de uso de la misma - Google Patents

Smoothened mutante y métodos de uso de la misma Download PDF

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ES2694857T3
ES2694857T3 ES15705757.1T ES15705757T ES2694857T3 ES 2694857 T3 ES2694857 T3 ES 2694857T3 ES 15705757 T ES15705757 T ES 15705757T ES 2694857 T3 ES2694857 T3 ES 2694857T3
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smo
vismodegib
residues
kabat
cells
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Frederic J. De Sauvage
Robert L. Yauch
Gerrit J.P. DIJKRAAF
Hayley SHARPE
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Genentech Inc
Curis Inc
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Curis Inc
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Abstract

Una molécula de ácido nucleico aislada que codifica una proteína SMO mutante que comprende una secuencia de aminoácidos que es idéntica en al menos el 95 % a la SEQ ID NO: 1 en donde la secuencia de aminoácidos comprende un aminoácido distinto del triptófano en la posición de aminoácido que corresponde a la posición 281 de la SEQ ID NO: 1.

Description

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sus siglas en inglés). La Figura 11D es un gráfico que muestra los resultados de la incorporación de metil-[3H]timidina de células precursoras de neuronas de gránulos cerebelares de pacientes infectados con virus Cre (tRFP-IRES-eGFPcre), virus Control (solo tRFP) o sin transducir (sin virus), cultivadas con o sin SHH. La incorporación de metil-[3H]-timidina se expresa en recuentos por minuto (RPM) y los datos representados son la media +/- DT
5 de los triplicados. La Figura 11E es un gráfico de barras que muestra el porcentaje de células precursoras de neuronas de gránulos cerebelares (PNGC) Ptch1loxp/loxp Tp53loxp/loxp Rosa26LSL-tdTomato (PPT) positivas para la expresión de TdTomato después de la infección con las construcciones víricas indicadas, según se determinó por FACS para 10.000 acontecimientos celulares y activación en células no transducidas. La Figura 11F es un gráfico de barras que muestra la cuantificación de niveles de ARNm de SMO humano en las PNGC de PPT del panel E mediante RT-PCR (reacción en cadena de la polimerasa-transcriptasa inversa, por sus siglas en inglés) cuantitativa. Los datos son valores de 2-ΔCt con respecto al gen constitutivo murino Rpl19 y se representan como la media +/- DT de los triplicados. La Figura 12A es un gráfico que muestra la actividad indicadora de Gli-luciferasa normalizada en células C3H10T½ transfectadas con construcciones de SMO indicadas, después de una respuesta a la dosis con vismodegib. Los
15 valores se normalizaron para la actividad sin tratar y los datos representados son la media +/- desviación típica (DT) de los triplicados. Los valores de CI50 se calcularon después del ajuste de regresión no lineal. La Figura 12B es un gráfico de barras que muestra la unión de [3H]-vismodegib a células HEK-293 transfectadas con construcciones de SMO indicadas. VV significa vector vacío y la unión del fármaco se midió en recuentos por minuto (rpm). La unión específica se calculó después de la competencia con un exceso de vismodegib sin marcar restando la unión no específica de la unión total. Los datos mostrados son la media +/-DT. La Figura 12C es un diagrama del esquema de transducción vírica de las PNGC primarias. Solo las PNGC transducidas proliferan en ausencia de SHH, lo que permite a los inventores someter a ensayo específicamente la capacidad de las variantes de SMO para promover la proliferación en presencia de vismodegib. La Figura 12D es una serie de gráficos que muestran la incorporación de metil-[3H]-timidina normalizada de PNGC de PPT transducidas con virus indicados,
25 después de una respuesta a la dosis con vismodegib después de la eliminación del ligando SHH. Cada gráfico muestra los mismos datos de control. Los datos representados son la media +/- DT de los triplicados. La Figura 13A es un modelo que muestra que se predice que un total de 21 restos (bolas de color gris oscuro) tendrán átomos dentro de 4,5 Å de vismodegib (bolas de color gris claro) unidos a la estructura TM de SMO (hélices de color gris). La Figura 13B es un modelo que muestra que N219, D384 y S387 forman una red de enlaces de hidrógeno (líneas discontinuas). Es probable que la mutación de cualquiera de estos restos cambie la forma del bolsillo de unión de vismodegib. La Figura 13C muestra una actividad indicadora de Gli-luciferasa en células C3H10T½ transfectadas con construcciones de SMO indicadas y tratadas con vismodegib 1 μM. Los valores se normalizaron a niveles de actividad sin tratar para cada construcción y los datos representados son la media +/-DT de los triplicados.
35 La Figura 14A muestra un modelo computacional de vismodegib (bolas de color gris claro) acoplado a la estructura cristalina de la región TM de SMO (hélices de color gris; Wang et al., 2013). Los restos mutantes distales al bolsillo de unión al fármaco se resaltan en color gris oscuro. La Figura 14B es un gráfico de barras que muestra los resultados de una actividad indicadora de Gli-luciferasa en células C3H10T½ transfectadas con construcciones de SMO indicadas. Los valores se normalizaron a niveles de actividad de SMO-WT y los datos representados son la media +/- DT de los triplicados. La Figura 15A es un gráfico que muestra la actividad indicadora de Gli-luciferasa normalizada en células C3H10T½ transfectadas con construcciones de SMO indicadas, después de una respuesta a la dosis con vismodegib. Los datos representados son la media +/-DT de los triplicados. La Figura 15B es un gráfico de barras que ilustra la unión de [3H]-vismodegib a células HEK-293 transfectadas con la construcción de SMO indicada. Las células sin
45 transfectar (Sin) y las células transfectadas con un vector vacío (VV) se incluyeron como controles. La unión del fármaco se midió en recuentos por minuto (rpm) y la unión específica se calculó después de la competición con un exceso de vismodegib sin marcar restando la unión no específica de la unión total. La Figura 15C es una tabla que muestra la expresión en la superficie celular de mutantes de SMO activadores en células HEK-293. Los valores mostrados son el porcentaje de células viables con expresión en la superficie celular de SMO, según se determina por FACS para 10.000 acontecimientos celulares y activación en células transfectadas con vector vacío y PI. La Figura 15D es un gráfico que muestra la incorporación de metil-[3H]-timidina normalizada de PNGC de PPT transducidas con virus indicados, después de una respuesta a la dosis con vismodegib después de la eliminación del ligando SHH. Los datos representados son la media +/- DT de los triplicados. Se muestran dos experimentos independientes.
55 La Figura 16A muestra la incorporación de metil-[3H]-timidina normalizada de PNGC de PPT transducidas con diversas variantes de SMO y tratadas con 500 nM de compuestos indicados. Para cada conjunto de datos para el tipo silvestre (WT, por sus siglas en inglés) o mutante de SMO evaluado, los datos para cada una de las siguientes condiciones de tratamiento se presentan como barras en el siguiente orden de izquierda a derecha: vismodegib, LY2940680, LDE225 y compuesto 5. Los valores se normalizaron a niveles de proliferación sin fármaco y los datos representados son la media +/- DT de los triplicados. Téngase en cuenta que la proliferación residual de SMO-WT en presencia de fármaco se debe a la contaminación de estos cultivos de PNGC primarias por fibroblastos y células gliales. La Figura 16B muestra los mismos datos que en 16A, pero las PNGC transducidas se trataron con 1 μM de vismodegib o JQ1. Téngase en cuenta que hay menos proliferación residual en SMO-WT con JQ1, lo que sugiere que este compuesto también inhibe la proliferación celular independiente de Hh.
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Descripción detallada
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Se usan varias delineaciones de HVR y se incluyen en el presente documento. Las regiones determinantes de complementariedad de Kabat (CDR, del inglés Kabat Complementarity Determining Regions) se basan en la variabilidad de secuencia y son las utilizadas más habitualmente (Kabat et al., Sequences of Proteins of Immunological 5 Interest, 5ª Ed., Servicio de Salud Pública, Institutos Nacionales de Salud de los EE.UU., Bethesda, MD. (1991)). Chothia se refiere en cambio a la localización de los bucles estructurales (Chothia y Lesk, J. Mol Biol 196: 901-917 (1987)). Las HVR del AbM representan un término medio entre las HVR de Kabat y los bucles estructurales de Chothia y son utilizadas por el software de modelado de anticuerpos AbM de Oxford Molecular. Las HVR de "contacto" se basan en un análisis de las estructuras cristalinas complejas disponibles. Los restos de cada una de estas HVR se
10 señalan a continuación.
Bucle C Contacto
L1 LLL L30-L36
L2 LLL L46-L55
L3 LLL L89-L96
H1 H31-H35B H26-H35B H H30 (Numeración de Kabat)
H1 HHH H30 (Numeración de Chothia)
H2 HHH H47-H58
H3 H95-H102 H95-H102 H9 H93-H101
Las HVR puede comprender "HVR extendidas" como se indica a continuación: 24-36 o 24-34 (L1), 46-56 o 50-56 (L2) y 89-97 o 89-96 (L3) en el VL y 26-35 (H1), 50-65 o 49-65 (H2) y 93-102, 94-102 o 95-102 (H3) en el VH. Los restos
15 del dominio variable se numeran de acuerdo con Kabat et al., citado anteriormente, para cada una de estas definiciones.
Los restos de la "región marco conservada" o "FR" son aquellos restos del dominio variable diferentes de los restos de la HVR como se define en el presente documento.
20 La expresión "numeración de restos del dominio variable como en Kabat" o "numeración de la posición de aminoácidos como en Kabat" y variaciones de las mismas, se refieren al sistema de numeración utilizado para los dominios variables de cadena pesada o dominios variables de cadena ligera de la compilación de anticuerpos en Kabat et al., citado anteriormente. Usando este sistema de numeración, la secuencia de aminoácidos lineal real puede contener menos o
25 más aminoácidos correspondientes a un acortamiento o una inserción en una FR o HVR del dominio variable. Por ejemplo, un dominio variable de cadena pesada puede incluir un inserto de un solo aminoácido (resto 52a de acuerdo con Kabat) después del resto 52 de H2 y restos insertados (por ejemplo, restos 82a, 82b y 82c, etc. de acuerdo con Kabat) después del resto FR de cadena pesada 82. La numeración de Kabat de restos puede determinarse para un anticuerpo dado mediante la alineación en regiones de homología de la secuencia del anticuerpo con una secuencia
30 numerada "patrón" de Kabat.
El sistema de numeración de Kabat se usa generalmente cuando se refiere a un resto en el dominio variable (aproximadamente los restos 1-107 de la cadena ligera y los restos 1-113 de la cadena pesada) (por ejemplo, Kabat et al., Sequences of Proteins of Immunological Interest, 5ª Ed., Servicio de Salud Pública, Institutos Nacionales de 35 Salud de los EE.UU., Bethesda, Md. (1991)). El "sistema de numeración EU" o "índice EU " se utiliza generalmente cuando se refiere a un resto en una región constante de la cadena pesada de la inmunoglobulina (por ejemplo, el índice EU publicado en Kabat et al., citado anteriormente). El "índice EU como en Kabat" se refiere a la numeración de los restos del anticuerpo humano IgG1 EU. A menos que se indique lo contrario en el presente documento, las referencias a los números de restos en el dominio variable de los anticuerpos significan la numeración de los restos
40 por el sistema de numeración de Kabat. A menos que se indique lo contrario en el presente documento, las referencias a los números de restos en el dominio constante de los anticuerpos significan la numeración de los restos por el sistema de numeración EU (por ejemplo, véase la Solicitud Provisional de Los EE.UU. N.º 60/640.323, Figures for EU numbering).
45 Un anticuerpo de "afinidad madurada" es uno con una o más alteraciones en una o más HVR del mismo que dan como resultado una mejora en la afinidad del anticuerpo por el antígeno, en comparación con un anticuerpo precursor que no posee esa o esas alteraciones. En una realización, los anticuerpos de afinidad madurada tendrán afinidades nanomolares o incluso picomolares por el antígeno diana. Los anticuerpos de afinidad madurada se producen mediante procedimientos conocidos en la técnica. Marks et al. Bio/Technology 10: 779-783 (1992) describe la
50 maduración de la afinidad por redistribución del dominio VH y VL. La mutagénesis aleatoria de los restos HVR y/o FR se describe, por ejemplo, por Barbas et al. Proc Nat. Acad. Sci USA 91: 3809-3813 (1994); Schier et al. Gene 169: 147-155 (1995); Yelton et al. J. Immunol. 155: 1994-2004 (1995); Jackson et al., J. Immunol. 154(7): 3310-9 (1995) y Hawkins et al, J. Mol. Biol. 226: 889-896 (1992).
55 Un anticuerpo "bloqueante" o un anticuerpo "antagonista" es uno que inhibe o reduce la actividad biológica del antígeno
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permitió la visualización y cuantificación de células infectadas. Este sistema también permitió un mejor modelo de genética del paciente porque la mayoría de las mutaciones de SMO se identificaron en tumores que albergaban mutaciones TP53 y se activaron por la pérdida de PTCH1. Las PNGC de PPT infectadas con SMO-WT y Cre tuvieron una CI50 de ~22 nM y la proliferación se inhibió al máximo a 100 nM de vismodegib. En contraste, todas las mutaciones 5 de BUF tuvieron un efecto drástico en la sensibilidad de vismodegib, con células infectadas que continúan proliferando a niveles altos de vismodegib (>1 μM; Figura 12D). Curiosamente, las células infectadas con SMO-W281C continuaron proliferando a niveles casi sin tratar, incluso en presencia de vismodegib 5 μM, lo que posiblemente refleja el papel directo de estos restos en la unión del fármaco. Se confirmó que las PNGC se infectaron a frecuencias similares mediante el análisis de clasificación de células activadas por fluorescencia (FACS) para la expresión del indicador
10 tdTomato dependiente de Cre y que las variantes de SMO se expresaron a niveles equivalentes mediante PCR cuantitativa de transcripción inversa (qRT).
Ejemplo 6: Predicción de la resistencia a vismodegib a través de la mutación del bolsillo de unión del fármaco de SMO
15 Para investigar si otras mutaciones de BUF podrían promover la resistencia al fármaco, se usó un modelo computacional para identificar los 21 restos de SMO con átomos ubicados dentro de 4,5 Å de vismodegib (Figura 13A). Se usó un algoritmo para identificar 160 variantes diferentes de nucleótidos únicos que dieron como resultado cambios no sinónimos en estos restos de BUF, incluidos SMO-W281C y SMO-I408V a partir de este estudio (Tabla 4).
20
Tabla 4: Identificación de restos de SMO con átomos dentro de 4,5 Angstroms de ambos vismodegib y LY2940680
Posición del AA
AA Codón Cabio de un solo nucleótido no sinónimo Cambios de AA Cambios C/G>T/A Comentarios de la mutación
219
N AAC imagen67 Y, D, H, I, S, T, K, K Ninguno N219D redujo la sensibilidad a vismodegib y LDE-225 (Este estudio y Buonamici et al. 2010)
221
L CTC imagen68 I, F, V, H, R, P F L221R redujo la sensibilidad a LDE-225 (Buonamici et al. 2010)
230
M ATG imagen69 L, V, L, K, R, T, I, I, I I
281
W TGG imagen70 R, G, R, *, L, S, *, C, C * W281C, este estudio y Brinkhuizen et al. 2014
325
L CTG imagen68 M.V.Q, R, P Ninguno
384
D GAC imagen71 N, Y, H, V, G, A, E, E N D384N redujo la sensibilidad a vismodegib y LDE-225 (Este estudio y Buonamici et al. 2010)
389
I ATT imagen72 F, V, L, N, S, T, M Ninguno
391
F TTT imagen73 I, V, L, Y, C, S, L, L Ninguno
394
Y TAC imagen74 N, D, H, F, C, S, *, * Ninguno
400
R CGT imagen68 S, C, G, H, L, P C R400A, parcialmente funcional (Dijkgraaf et al. 2011)
408
I ATC imagen75 F, V, L, N, S, T, M Ninguno 1408V, este estudio
470
H CAC imagen76 N, Y, D, L, R, P, Q, Q Y H470A no expresada (Dijkgraaf et al. 2011)
477
Q CAG imagen77 K, *, E, L, R, P, H, H E
70
Posición del AA
AA Codón Cabio de un solo nucleótido no sinónimo Cambios de AA Cambios C/G>T/A Comentarios de la mutación
480
W TGG imagen78 R, G, R, *, L, S, *, C, C * W480A no expresada, (Dijkgraaf et al. 2011)
481
E GAG imagen79 K, *, Q, V, G, A, D, D K
484
F TTC imagen80 I, V, L, Y, C, S, L, L Ninguno
515
L CTT imagen68 I, F, V, H, R, P F L515A expresada, activadora, sensible a la inhibición 1 mM por vismodegib (Dijkgraaf et al. 2011)
518
E GAG imagen81 K, *, Q, V, G, A, D, D K E518K y E518A redujeron la sensibilidad a vismodegib (Dijkgraaf et al. 2011)
521
N AAC imagen82 Y, D, H, I, S, T, K, K Ninguno N521A no expresada (Dijkgraaf et al.2011)
522
L CTG imagen68 M, V, Q, R, P Ninguno
525
M ATG imagen83 L, V, L, K, R, T, I, I, I I
321
V GTG imagen68 M, L, L, E, G, A M V321 M, este estudio y Brinkhuizen et al. 2014
387
S AGT imagen84 C, G, R, N, I, T, R, R N S387N redujo la sensibilidad a vismodegib y LDE-225 (Este estudio y Buonamici et al. 2010)
459
A GCC imagen68 T, S, P, D, V, G V A459V, este estudio
473
D GAC imagen85 N, Y, H, V, G, A, E, E N D473H (Yauch et al. 2009). Todos los aa excepto P reducen la sensibilidad a vismodegib (Dijkgraaf et al. 2011)
Los aminoácidos correspondientes a las posiciones 219, 221, 281, 384, 408 y 518 de la SEQ ID NO: 1 están en el bolsillo de unión de vismodegib. Los aminoácidos correspondientes a las posiciones 321, 387, 459 y 473 de la SEQ ID NO: 1 se asocian a mutaciones clínicas, pero no se encuentran dentro de los 4,5 Angstroms de vismodegib cuando 5 se unen a SMO. SMO-D473 no se identificó con este método, pero la estructura cristalina de SMO reveló que D473 forma una red de enlace de hidrógeno con varios restos que hacen contacto directo con vismodegib, incluyendo R400, H470, E518 y N521 (Wang et al., 2013; Yauch et al., 2009). SMOE518 se identificó anteriormente por mutagénesis de rastreo con alanina como un resto que afecta la sensibilidad al vismodegib cuando se muta (Dijkgraaf et al., 2011). Este enfoque también identificó restos que se habían implicado anteriormente en modelos preclínicos de resistencia 10 al inhibidor de SMO sonidegib (LDE225), incluyendo N219 y D384 (Tabla 4; Buonamici et al., 2010), que se predice que estabilizan la conformación de SMO a través de una red de enlace de hidrógeno (Figura 13B). Sorprendentemente, SMO-N219D, SMO-D384N y SMO-S387N mostraron una sensibilidad reducida a vismodegib en comparación con SMO-WT en el ensayo de indicador de Hh basado en Gli luciferasa (Figura 13C). Además, se descubrió que el inhibidor de SMO LY2940680 y vismodegib comparten 14 restos de contacto (Tabla 4). Sin desear quedar ligados a la teoría,
15 esto sugiere que los inhibidores químicamente distintos interactúan con restos de SMO superpuestos y que la resistencia cruzada entre los inhibidores podría producirse en la clínica.
Ejemplo 7: Mutaciones de SMO más allá del bolsillo de unión al fármaco confieren resistencia a vismodegib
20 Las mutaciones de SMO localizadas distalmente con respecto al bolsillo de unión de vismodegib también se asociaron a la resistencia a vismodegib (Figura 14A). Curiosamente, SMO-A459V mostró una mayor actividad basal sobre SMO-WT, aunque en menor medida que las mutaciones oncogénicas establecidas (Figura 14B). Esta actividad elevada se correlacionó con una sensibilidad reducida a la inhibición tanto por vismodegib (Figuras 15A) como por sobreexpresión de PTCH1, con SMO-A459V cambiando la CI50 de vismodegib aproximadamente 9 veces, respectivamente.
25 Adicionalmente, todos los mutantes de activación sometidos a ensayo mostraron una unión alterada de vismodegib a
71
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