ES2560657T3 - Glicosilación con unión en O de péptidos G-CSF - Google Patents

Glicosilación con unión en O de péptidos G-CSF Download PDF

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ES2560657T3
ES2560657T3 ES05711345.8T ES05711345T ES2560657T3 ES 2560657 T3 ES2560657 T3 ES 2560657T3 ES 05711345 T ES05711345 T ES 05711345T ES 2560657 T3 ES2560657 T3 ES 2560657T3
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p61lssc
sequence
group
mutant peptide
galnac
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Shawn Defrees
David A. Zopf
Zhi-Guang Wang
Henrik Clausen
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Ratiopharm GmbH
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Abstract

Un polipéptido G-CSF aislado que comprende una secuencia de péptido mutante, en el que la secuencia de péptido mutante codifica un sitio de glicosilación con unión en O que no existe en un polipéptido de tipo silvestre correspondiente al polipéptido aislado, en donde la secuencia de péptido mutante se selecciona del grupo que consiste en MVTPLGP, MQTPLGP, MIATPLGP, MATPLGP, MPTQGAMPLGP, MVQTPLGP, MQSTPLGP, MGQTPLGP, MAPTSSSPLGP y MAPTPLGPA, o en donde la secuencia de péptido mutante se selecciona del grupo que consiste en MTPTLGP, MTPTQLGP, MTPTSLGP, MTPTQGP, MTPTSSP, M1TPQTP, M1TPTGP, M1TPLTP, M1TPNTGP, MTPLGP, M1TPVTP, M1TPMVTP y MT1P2TQGL3G4P5A6S7, o en donde la secuencia de péptido mutante se selecciona del grupo que consiste en P129ATQPT, P129TLGPT, P129TQGPT, P129TSSPT, P129TQGAPT, P129NTGPT, PALQPTQT, P129ALTPT, P129MVTPT, P129ASSTPT, MAP129ATQPTQGAM y MP129ATTQPTQGAM, o en donde la secuencia de péptido mutante se selecciona del grupo que consiste en LGIPTA P61LSSC, LGIPTQ P61LSSC, LGIPTQG P61LSSC, LGIPQT P61LSSC, LGIPTS P61LSSC, LGIPTS P61LSSC, LGIPTQP61LSSC, LGTPWAP61LSSC, LGTPFA P61LSSC y SLGAP58TAP61LSS, o en donde la secuencia de péptido mutante se selecciona del grupo que consiste en RHLAQTP175, RHLAGQTP175, QP175TQGAMP, RHLAQTP175AM, QP175TSSAP, QP175TSSAP, QP175TQGAMP, QP175TQGAM, QP175TQGA, QP175TVM, QP175NTGP y QP175QTLP, o en donde la secuencia de péptido mutante se selecciona del grupo que consiste en P133TQTAMP139, P133TQGTMP, P133TQGTNP, P133TQGTLP, PALQP133TQTAMPA, P129TTQP, P129NTLP, P129TLQP, P61TSSC, P61TSSAC, P61FTP y LGSTLGI.

Description

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secuencia indicada explícitamente. En concreto, las sustituciones de codones degenerados se pueden realizar generando secuencias en las que la tercera posición de uno o más codones seleccionados (o de todos) está sustituida con restos de base mixta y/o desoxiinosina (Batzer et al., Nucleic Acid Res. 19: 5081 (1991); Ohtsuka et al., J. Biol. Chem. 260: 2605-2608 (1985); y Rossolini et al., Mol. Cell. Probes 8: 91-98 (1994)). La expresión ácido nucleico se usa indistintamente con gen, ADNc y ARNm codificado por un gen.
El término "gen" significa el segmento de ADN implicado en la producción de una cadena polipeptídica. Puede incluir regiones precedentes y siguientes a la región de codificación (líder y remolque), así como secuencias intermedias (intrones) entre segmentos individuales de codificación (exones).
El término "aislado", cuando se aplica a un ácido nucleico o a una proteína, indica que el ácido nucleico o la proteína está sustancialmente exento de otros componentes celulares con los que se asocia en el estado natural. Está preferentemente en un estado homogéneo, aunque puede estar en una solución bien seca o acuosa. Por lo general, la pureza y la homogeneidad se determinan usando técnicas de química analítica, tales como electroforesis en gel de poliacrilamida o cromatografía de líquidos de alto rendimiento. Una proteína que es la especie predominante presente en una preparación está sustancialmente purificada. En particular, un gen aislado se separa de los marcos de lectura abierta que flanquean el gen y que codifican una proteína que no sea el gen de interés. El término "purificado" indica que un ácido nucleico o una proteína da lugar a sustancialmente una banda en un gel electroforético. En particular, significa que el ácido nucleico o la proteína que tiene una pureza del al menos 85 %, más preferentemente del al menos 95 % y lo más preferentemente del al menos 99 %.
El término "aminoácido" se refiere a aminoácidos de origen natural y sintéticos, así como a análogos de aminoácidos y miméticos de aminoácidos que funcionan de una manera similar a los aminoácidos de origen natural. Los aminoácidos de origen natural son los codificados por el código genético, así como aquellos aminoácidos que se modifican posteriormente, por ejemplo, hidroxiprolina, γ-carboxiglutamato y O-fosfoserina. Análogos de aminoácidos se refiere a compuestos que tienen la misma estructura química básica que un aminoácido de origen natural, es decir, un carbono α que está unido a un hidrógeno, un grupo carboxilo, un grupo amino y un grupo R, por ejemplo, homoserina, norleucina, sulfóxido de metionina, metilsulfonio de metionina. Dichos análogos tienen grupos R modificados (por ejemplo, norleucina) o cadenas principales peptídicas modificadas, pero conservan la misma estructura química básica que un aminoácido de origen natural. "Miméticos de aminoácidos" se refiere a compuestos químicos que tienen una estructura que es diferente de la estructura química general de un aminoácido, pero que funcionan de una manera similar a un aminoácido de origen natural.
En la técnica, existen diversos métodos conocidos que permiten la incorporación de un derivado de aminoácido no natural o análogo en una cadena polipeptídica de una manera específica de sitio, véase, por ejemplo, el documento WO 02/086075.
En el presente documento, los aminoácidos se pueden indicar bien por los símbolos de tres letras comúnmente conocidos o por los símbolos de una letra recomendados por la Comisión de Nomenclatura Bioquímica de la IUPAC-IUB. Del mismo modo, los nucleótidos, se pueden indicar mediante sus códigos de una sola letra comúnmente aceptados.
"Variantes modificadas de manera conservadora" se aplica tanto a secuencias de aminoácidos como de ácido nucleico. Con respecto a las secuencias de ácido nucleico en particular, "variantes modificadas de manera conservadora" se refiere a los ácidos nucleicos que codifican secuencias de aminoácidos idénticas o sustancialmente idénticas, o en las que el ácido nucleico no codifica una secuencia de aminoácidos, a secuencias sustancialmente idénticas. Debido a la degeneración del código genético, hay un gran número de ácidos nucleicos funcionalmente idénticos que codifican cualquier proteína dada. Por ejemplo, todos los codones GCA, GCC, GCG y GCU codifican el aminoácido alanina. Por lo tanto, en cada posición en la que una alanina está especificada por un codón, el codón se puede modificar a cualquiera de los codones correspondientes descritos sin alterar el polipéptido codificado. Dichas variaciones de ácido nucleico son "variaciones silenciosas", que son una especie de variaciones modificadas de manera conservadora. En el presente documento, cada secuencia de ácido nucleico que codifica un polipéptido también describe cada variación silenciosa posible del ácido nucleico. Un experto reconocerá que todos los codones de un ácido nucleico (a excepción de AUG, que es habitualmente el único codón para la metionina y TGG, que es habitualmente el único codón para el triptófano) se pueden modificar para producir una molécula funcionalmente idéntica. Por consiguiente, cada variación silenciosa de un ácido nucleico que codifica un polipéptido está implícita en cada secuencia descrita.
En cuanto a las secuencias de aminoácidos, un experto reconocerá que sustituciones, eliminaciones o adiciones individuales de un ácido nucleico, péptido, polipéptido o secuencia de proteínas que altera, añade o elimina un solo aminoácido o un pequeño porcentaje de aminoácidos en la secuencia codificada es una "variante modificada de forma conservadora", en la que la modificación genera la sustitución de un aminoácido con un aminoácido químicamente similar. Las tablas de sustituciones conservadoras que proporcionan aminoácidos funcionalmente similares son bien conocidas en la técnica. Dichas variantes modificadas de manera conservadora se suman a y no excluyen variantes polimórficas, homólogos entre especies y alelos de la invención.
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un proceso altamente regulado que muestra un alto grado de conservación entre los organismos multicelulares.
La primera etapa de la glicosilación con unión en O de tipo mucina está catalizada por uno o más miembros de una gran familia de UDP-GalNAc: las N-acetilgalactosaminiltransferasas polipeptídicas (GalNAc-transferasas) (EC 2.4.1.41), que transfieren GalNAc a sitios aceptores de serina y de treonina (Hassan et al., J. Biol. Chem. 275: 38197-38205 (2000)). Hasta la fecha, se han identificado y caracterizado doce miembros de la familia de GalNActransferasa de mamíferos (Schwientek et al., J. Biol. Chem. 277: 22623-22638 (2002)) y se han predicho varios supuestos miembros adicionales de esta familia genética a partir del análisis de bases de datos del genoma. Las isoformas de la GalNAc-transferasa tienen diferentes propiedades cinéticas y muestran patrones de expresión diferenciales temporal y espacialmente, lo que sugiere que tienen funciones biológicas distintas (Hassan et al., J. Biol. Chem. 275: 38197-38205 (2000)). El análisis de secuencias de GalNAc-transferasas ha conducido a la hipótesis de que estas enzimas contienen dos subunidades distintas: una unidad catalítica central y una unidad Cterminal con similitud en la secuencia con la de la lectina ricina vegetal, denominada "dominio de lectina" (Hagen et al., J. Biol. Chem. 274: 6797-6803 (1999); Hazes, Protein Eng. 10: 1353-1356 (1997); Breton et al., Curr. Opin. Struct. Biol. 9: 563-571 (1999)). Experimentos previos que implican mutagénesis específica del sitio de restos conservados seleccionados confirmaron que mutaciones en el dominio catalítico eliminaban la actividad catalítica. Por el contrario, las mutaciones en el "dominio de lectina" no tenían efectos significativos en la actividad catalítica de la isoforma de GalNAc-transferasa, GalNAc-T1 (Tenno et al., J. Biol. Chem. 277(49): 47088-96 (2002)). Por lo tanto, se creía que el "dominio de lectina" C-terminal no era funcional y no desempeñaba papeles para las funciones enzimáticas de las GalNAc-transferasas (Hagen et al., J. Biol. Chem. 274: 6797-6803 (1999)).
No obstante, pruebas recientes demuestran que algunas GalNAc-transferasas presentan actividades únicas con glicopéptidos parcialmente GalNAc-glicosilados. Las acciones catalítica de al menos tres isoformas de GalNActransferasa, GalNAc-T4, -T7 y -T10, actúan selectivamente en los glicopéptidos que corresponden a dominios de repetición en tándem de mucina en los que solamente algunas de las secuencias de glicosilación potencial agrupadas han sido glicosiladas con GalNAc por otras GalNAc-transferasas (Bennett et al., FEBS Letters 460: 226230 (1999); Ten Hagen et al., J. Biol. Chem. 276: 17395-17404 (2001); Bennett et al., J. Biol. Chem. 273: 3047230481 (1998); Ten Hagen et al., J. Biol. Chem. 274: 27867-27874 (1999)). GalNAc-T4 y -T7 reconocen diferentes polipéptidos glicosilados con GalNAc y catalizan la transferencia de GalNAc a sitios de sustrato aceptor además de los que se han utilizado anteriormente. Se predice que una de las funciones de dichas actividades de GalNActransferasa representa una etapa de control de la densidad de ocupación de O-glicano en mucinas y en glicoproteínas de tipo mucina con alta densidad de glicosilación con unión en O.
Un ejemplo de ello es la glicosilación de la mucina asociada con el cáncer MUC1. La MUC1 contiene una región glicosilada con unión en O de repetición en tándem de 20 restos (HGVTSAPDTRPAPGSTAPPA) con cinco posibles sitios de glicosilación con unión en O. GalNAc-T1, -T2 y -T3 pueden iniciar la glicosilación de la repetición en tándem de MUC1 y se pueden incorporar solamente en tres sitios (HGVTSAPDTRPAPGSTAPPA, se subrayan los sitios de unión a GalNAc). La GalNAc-T4 es única en que es la única isoforma de GalNAc-transferasa identificada hasta el momento que puede completar la unión del glicano con unión en O a los cinco sitios aceptores en la secuencia de repetición en tándem de 20 aminoácidos de la mucina asociada con el cáncer de mama. MUC1. GalNAc-T4 transfiere GalNAc a al menos dos sitios no usados por otras isoformas de GalNAc-transferasa en el glipopéptido GalNAc4TAP24 (TAPPAHGVTSAPDTRPAPGSTAPP, los sitios de unión a GalNAc-T4 únicos están en negrita) (Bennett et al., J. Biol. Chem. 273: 30472-30481 (1998). Parece que una actividad tal como la que presenta GalNAc-T4 es necesaria para la producción de la glicoforma de MUC1 expresada por células cancerosas cuando todos los sitios potenciales están glicosilados (Muller et al., J. Biol. Chem. 274: 18165-18172 (1999)). La MUC1 normal de las glándulas mamarias lactantes tiene aproximadamente 2,6 glicanos con unión en O por repetición (Muller et al., J. Biol. Chem. 272: 24780-24793 (1997) y la MUC1 derivada de la línea celular de cáncer T47D tiene 4,8 glicanos con unión en O por repetición (Muller et al., J. Biol. Chem. 274: 18165-18172 (1999)). La forma de MUC1 asociada al cáncer está asociada, por tanto, con una mayor densidad de ocupación de glicano con unión en O y esto se consigue mediante una actividad de GalNAc-transferasa idéntica o similar a la de GalNAc-T4.
Las GalNAc-transferasas polipeptídicas, que no han presentado especificidades aparentes hacia GalNAcglicopéptido, también parecen estar moduladas por sus supuestos dominios de lectina (documento PCT WO 01/85215 A2). Recientemente, se encontró que las mutaciones en el supuesto dominio de lectina de GalNAc-T1, al igual que las que se han analizado anteriormente en GalNAc-T4 (Hassan et al., J. Biol. Chem. 275:38197-38205 (2000)), modificaban la actividad de la enzima de una forma similar a GalNAc-T4. Por lo tanto, aunque la GalNAc-T1 de tipo silvestre añadía múltiples restos de GalNAc consecutivos a un sustrato peptídico con múltiples sitios aceptores, la GalNAc-T1 mutada no añadía más de un resto de GalNAc al mismo sustrato (Tenno et al., J. Biol. Chem. 277(49): 47088-96 (2002)).
Dado que se ha demostrado que las mutaciones de las GalNAc transferasas se pueden utilizar para producir patrones de glicosilación que sean distintos de los producidos por las enzimas de tipo silvestre, la utilización de una
o más GalNAc-transferasas mutantes en la preparación de los péptidos glicosilados con unión en O de la invención pertenece al alcance de la presente invención.
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