ES2550027T3 - Anticuerpos monoclonales contra la claudina-18 para el tratamiento del cáncer - Google Patents

Anticuerpos monoclonales contra la claudina-18 para el tratamiento del cáncer Download PDF

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Publication number
ES2550027T3
ES2550027T3 ES10011773.8T ES10011773T ES2550027T3 ES 2550027 T3 ES2550027 T3 ES 2550027T3 ES 10011773 T ES10011773 T ES 10011773T ES 2550027 T3 ES2550027 T3 ES 2550027T3
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seq
amino acid
acid sequence
fragment
sequence represented
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Inventor
Ugur Sahin
Özlem TÜRECI
Dirk Usener
Stefan Fritz
Christoph Uherek
Gunda Brandenburg
Harald-Gerhard Geppert
Anja Kristina SCHRÖDER
Philippe Thiel
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Johannes Gutenberg Universitaet Mainz
Ganymed Pharmaceuticals GmbH
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Johannes Gutenberg Universitaet Mainz
Ganymed Pharmaceuticals GmbH
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    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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Abstract

Anticuerpo monoclonal que presenta la capacidad de unirse a la CLD18A2 y mediar la destrucción de las células que expresan CLD18A2, en el que el anticuerpo se une a un epítopo localizado sobre la CLD18A2-bucle1 o la CLD18A2-bucleD3 y en el que la destrucción es inducida uniendo el anticuerpo a la CLD18A2 expresada por dichas células, en el que el anticuerpo media la destrucción de las células induciendo la lisis mediada por citotoxicidad dependiente de complemento (CDC) y/o la lisis mediada por citotoxicidad celular dependiente de anticuerpo (ADCC).

Description

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(i) la VH comprende una secuencia de aminoácidos representada por SEC ID nº 132 o un fragmento de la misma y la VL comprende una secuencia de aminoácidos representada por SEC ID nº 139 o un fragmento de la misma,
5 (ii) la VH comprende una secuencia de aminoácidos representada por SEC ID nº 133 o un fragmento de la misma y la VL comprende una secuencia de aminoácidos representada por SEC ID nº 138 o un fragmento de la misma,
(iii) la VH comprende una secuencia de aminoácidos representada por SEC ID nº 134 o un fragmento de la misma y la VL comprende una secuencia de aminoácidos representada por SEC ID nº 140 o un fragmento de la misma,
(iv) la VH comprende una secuencia de aminoácidos representada por SEC ID nº 136 o un fragmento de la
misma y la VL comprende una secuencia de aminoácidos representada por SEC ID nº 143 o un fragmento de 15 la misma,
(v)
la VH comprende una secuencia de aminoácidos representada por SEC ID nº 135 o un fragmento de la misma y la VL comprende una secuencia de aminoácidos representada por SEC ID nº 142 o un fragmento de la misma,
(vi)
la VH comprende una secuencia de aminoácidos representada por SEC ID nº 137 o un fragmento de la misma y la VL comprende una secuencia de aminoácidos representada por SEC ID nº 141 o un fragmento de la misma,
25 (vii) la VH comprende una secuencia de aminoácidos representada por SEC ID nº 137 o un fragmento de la misma y la VL comprende una secuencia de aminoácidos representada por SEC ID nº 144 o un fragmento de la misma,
(viii) la VH comprende una secuencia de aminoácidos representada por SEC ID nº 137 o un fragmento de la misma y la VL comprende una secuencia de aminoácidos representada por SEC ID nº 145 o un fragmento de la misma,
(ix) la VH comprende una secuencia de aminoácidos representada por SEC ID nº 137 o un fragmento de la
misma y la VL comprende una secuencia de aminoácidos representada por SEC ID nº 146 o un fragmento 35 de la misma.
En otro aspecto, el anticuerpo de la invención comprende
(i)
una cadena pesada que comprende una secuencia de aminoácidos seleccionada de entre el grupo que consiste en SEC ID nº: 115, 116, 117, 118, 119, 120, y un fragmento de la misma y/o
(ii)
una cadena ligera que comprende una secuencia de aminoácidos seleccionada de entre el grupo que consiste en SEC ID nº 121, 122, 123, 124, 125, 126, 127, 128, 129, y un fragmento de la misma.
45 En otro aspecto, el anticuerpo de la invención comprende una combinación de cadenas pesadas y cadenas ligeras seleccionada de entre las posibilidades (i) a (ix) siguientes:
(i)
la cadena pesada comprende una secuencia de aminoácidos representada por SEC ID nº 115 o un fragmento de la misma y la cadena ligera comprende una secuencia de aminoácidos representada por SEC ID nº 122 o un fragmento de la misma,
(ii)
la cadena pesada comprende una secuencia de aminoácidos representada por SEC ID nº 116 o un fragmento de la misma y la cadena ligera comprende una secuencia de aminoácidos representada por SEC ID nº 121 o un fragmento de la misma,
55
(iii) la cadena pesada comprende una secuencia de aminoácidos representada por SEC ID nº 117 o un fragmento de la misma y la cadena ligera comprende una secuencia de aminoácidos representada por SEC ID nº 123 o un fragmento de la misma,
(iv)
la cadena pesada comprende una secuencia de aminoácidos representada por SEC ID nº 119 o un fragmento de la misma y la cadena ligera comprende una secuencia de aminoácidos representada por SEC ID nº 126 o un fragmento de la misma,
(v)
la cadena pesada comprende una secuencia de aminoácidos representada por SEC ID nº 118 o un
65 fragmento de la misma y la cadena ligera comprende una secuencia de aminoácidos representada por SEC ID nº 125 o un fragmento de la misma,
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Además, puede desearse según la presente invención modificar las secuencias de aminoácidos indicadas en la presente memoria, en particular las de regiones constantes de cadena pesada humana para adaptar la secuencia a un alotipo deseado, por ejemplo un alotipo observado en la población caucásica. Dichas modificaciones se seleccionan preferentemente de entre el grupo que consiste de las sustituciones de aminoácidos siguientes en SEC ID nº 46 o en posiciones correspondientes dentro de otras regiones constantes de cadena pesada humana: K93R, D235E y L237M. Preferentemente, la totalidad de dichas modificaciones se encuentra incluida en las secuencias de aminoácidos de las regiones constantes de cadena pesada humana.
Según la invención, la expresión "posiciones correspondientes" se refiere a nucleótidos o residuos aminoácidos que, en una alineación de secuencias de dos ácidos nucleicos o secuencias de proteína, se alinean uno con otro.
Preferentemente, el grado de identidad entre una secuencia específica de ácidos nucleicos indicada en la presente memoria y una secuencia de ácidos nucleicos modificada con respecto a dicha secuencia específica de ácidos nucleicos es de por lo menos 70%, preferentemente de por lo menos 75%, más preferentemente de por lo menos 80%, todavía más preferentemente de por lo menos 90% o todavía más preferentemente de por lo menos 95%, 96%, 97%, 98% ó 99%. Preferentemente, las dos secuencias son capaces de hibridarse y formar un dúplex estable una con la otra, llevando a cabo la hibridación preferentemente bajo condiciones que permiten la hibridación específica entre polinucleótidos (condiciones restrictivas). Las condiciones restrictivas se describen en, por ejemplo, Molecular Cloning: A Laboratory Manual, J. Sambrook et al., editores, 2a edición, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989, o en Current Protocols in Molecular Biology, F.M. Ausubel et al., editores, John Wiley & Sons, Inc., New York, y se refieren, por ejemplo, a la hibridación a 65ºC en tampón de hibridación (3,5xSSC, Ficoll al 0,02%, polivinilpirrolidona al 0,02%, albúmina de suero bovino al 0,02%, NaH2PO4 2,5 mM (pH 7), SDS al 0,5%, EDTA 2 mM). SSC es cloruro sódico 0,15 M/citrato sódico 0,15 M, pH 7. Tras la hibridación, la membrana a la que se ha transferido el ADN se lava en, por ejemplo, 2xSSC a temperatura ambiente y después en 0,1-0,5xSSC/0,1xSDS a temperaturas de hasta 68ºC.
Preferentemente, el grado de similitud, preferentemente de identidad entre una secuencia específica de aminoácidos indicada en la presente memoria y una secuencia de aminoácidos modificada con respecto a dicha secuencia específica de aminoácidos, tal como entre secuencias de aminoácidos que muestran homología sustancial, es de por lo menos 70%, preferentemente de por lo menos 80%, más preferentemente de por lo menos 90% o todavía más preferentemente de por lo menos 95%, 96%, 97%, 98% ó 99%.
La totalidad de las secuencias modificadas anteriormente indicadas se encuentran comprendidas dentro del alcance de la presente invención.
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Tab. 1b: protocolos de inmunización detallados
Protocolo de inmunización
Inmunización (sensibilización y refuerzos con ADN) Suero seguimiento Refuerzos con células transfectadas
Con vectores de ADN codificantes de fragmentos de CLD18
Con adyuvante El día El día Células transfectadas con CLD18A2 (SEC ID nº 1) solas Células cotransfectadas con CLD18A2 (SEC ID nº 1) y con ARN murino codificante de CD40L soluble Días antes de la esplenectomía
6
SEC ID nº 15: 50 µg 50 µg de CpG 1 y 10 18 5x107 células MC3T3 transfectadas Ninguna 3
40
SEC ID nº 17: 50 µg 50 µg de CpG 1 y 10 18 5x10 7 células HEK293; 100 µg de CPG a modo de adyuvante 3
45
SEC ID nº 15: 50 µg 50 µg de CpG 1 y 9 16 1x108 células HEK293 3
51
SEC ID nº 15: 25 µg 2,5 µl de PEI-Man* (150 mM) en H2O con glucosa al 5% 1, 16 y 36 22, 30 y 43 5x107 células HEK293 transfectadas Ninguna 3 y 2
53
Sensibilización: SEC ID nº 15: 25 µg, y SEC ID nº 17: 25 µg; Refuerzo: SEC ID nº 17: 50 µg 50 µg de CpG en H2O con glucosa al 5% 1 y 11 20 5x107 células HEK293 transfectadas Ninguna 4, 3 y 2
*jetPEITM-Man in vivo de PolyPlus Transfection
b. Generación de hibridomas productores de anticuerpos monoclonales humanos de CLD18:
5 se aislaron esplenocitos de ratón y se fusionaron con PEG a una línea celular de mieloma de ratón utilizando protocolos estándares. A continuación, los hibridomas resultantes se cribaron para la producción de inmunoglobulinas con especificidad para CLD18 utilizando células HEK293 transfectadas con un ácido nucleico codificante de CLD18 humano mediante análisis FACS.
10 Se fusionaron suspensiones de células individuales de linfocitos esplénicas procedentes de ratones inmunizados con células de mieloma de ratón no secretoras P3X63Ag8U.1 (ATCC nº CRL 1597) en una proporción 2:1 utilizando PEG al 50% (Roche Diagnostics, nº CRL 738641). Se sembraron las células en placas a razón de aproximadamente 3x104/pocillo en placas de microtitulación de fondo plano, seguido de la incubación durante aproximadamente dos
15 semanas en medio selectivo que contenía suero de feto bovino al 10%, fusión de hibridoma al 2% y suplemento de clonación (HFCS, Roche Diagnostics, nº CRL 1 363 735) más HEPES 10 mM, 2-mercaptoetanol 0,055 mM, 50 µg/ml de gentamicina y 1xHAT (Sigma, nº CRL H0262). Tras 10 a 14 días, los pocillos individuales se cribaron mediante citometría de flujo para anticuerpos monoclonales anti-CLD18. Los hibridomas secretores de anticuerpos se sembraron en placa nuevamente, se cribaron nuevamente y, en el caso de que todavía fuesen positivos para
20 anticuerpos monoclonales anti-CLD18, se subclonaron mediante dilución limitante. A continuación, los subclones se
cultivaron in vitro para generar cantidades reducidas de anticuerpo en medio de cultivo de tejidos para la caracterización. Se seleccionó por lo menos un clon de cada hibridoma, que conservó la reactividad de las células parentales (según FACS). Se generaron 9 bancos de células viables para cada clon y se almacenaron en nitrógeno líquido.
25
c. Selección de anticuerpos monoclonales de unión a CLD18:
para determinar el isotipo de los anticuerpos, se llevó a cabo un ELISA de los isotipos. Se utilizó el kit monoAB ID de ratón (Zymed, nº CRL 90-6550) o alternativamente el kit de isotipado de anticuerpos monoclonales de ratón
30 IsoStrip (Roche, nº de cat. 1493027) para determinar las subclases de Ig de los anticuerpos monoclonales identificados como reactivos con CLD18. Definido como Juego1, se generaron diecinueve líneas celulares de
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