ES2544608T3 - Conjugados de anticuerpo y de alaninil-maitansinol - Google Patents
Conjugados de anticuerpo y de alaninil-maitansinolInfo
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- ES2544608T3 ES2544608T3 ES11793586.6T ES11793586T ES2544608T3 ES 2544608 T3 ES2544608 T3 ES 2544608T3 ES 11793586 T ES11793586 T ES 11793586T ES 2544608 T3 ES2544608 T3 ES 2544608T3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Un compuesto seleccionado de la Fórmula I:**Fórmula** en la que: L es:**Fórmula** E es**Fórmula** n es 2, 3, 4, 5 o 6; m es 2, 3 o 4; y q es 0 o 1.
Description
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solo determinante en el antígeno. Además de su especificidad, los anticuerpos monoclonales son ventajosos porque se pueden sintetizar sin contaminarse por otros anticuerpos. El adjetivo "monoclonal" indica que el anticuerpo se obtiene de una población básicamente homogénea de anticuerpos, y no se debe interpretar como que se requiere la producción del anticuerpo mediante cualquier método en particular. Por ejemplo, los anticuerpos monoclonales que se van a usar de acuerdo con la presente invención se pueden preparar mediante el método de hibridoma que fue descrito por primera vez por Kohler et al. (1975) Nature 256: 495, o se pueden preparar mediante métodos de ADN recombinante (véanse, por ejemplo, los documentos US 4816567; US 5807715). Los anticuerpos monoclonales también se pueden aislar de bibliotecas de anticuerpos de fagos usando las técnicas que se describen, por ejemplo, en Clackson et al. (1991) Nature, 352: 624-628; Marks et al. (1991) J. Mol. Biol., 222: 581-597.
Los anticuerpos monoclonales del presente documento incluyen específicamente anticuerpos "quiméricos" en los que una parte de la cadena pesada y/o ligera es idéntica u homóloga a las secuencias correspondientes de los anticuerpos derivados de una especie en particular o que pertenecen a una clase o subclase de anticuerpo en particular, mientras que el resto de la cadena o cadenas es idéntico u homólogo a las secuencias correspondientes de los anticuerpos derivados de otra especie, o que pertenecen a otra clase o subclase de anticuerpo, así como fragmentos de dichos anticuerpos, siempre que presenten la actividad biológica deseada (documento US 4816567; y Morrison et al. (1984) Proc. Natl. Acad. Sci. EE.UU., 81:6851-6855). Los anticuerpos quiméricos de interés en el presente documento incluyen anticuerpos "primatizados" que comprenden secuencias de unión al antígeno de dominio variable derivadas de un primate no humano (por ejemplo, Mono del Viejo Mundo o Simio) y secuencias de región constante humanas.
Un "anticuerpo intacto", en el presente documento, es aquel que comprende un dominio de VL y de VH, así como un dominio constante de cadena ligera (CL) y dominios constantes de cadena pesada, CH1, CH2 y CH3. Los dominios constantes pueden ser dominios constantes de secuencias nativas (por ejemplo, dominios constantes de secuencias nativas humanas) o variante de secuencias de aminoácidos de los mismos. El anticuerpo intacto puede tener una o más "funciones efectoras", que se refieren a las actividades biológicas atribuibles a la región constante de Fc (una región de Fc de secuencia nativa o región de Fc de variante de secuencia de aminoácidos) de un anticuerpo. Los ejemplos de funciones efectoras de anticuerpos incluyen unión a C1q; citotoxicidad dependiente del complemento; unión al receptor de Fc; citotoxicidad mediada por células dependiente de anticuerpos (ADCC); fagocitosis; y regulación negativa de receptores de la superficie celular tales como receptor de linfocitos B y BCR.
Dependiendo de la secuencia de aminoácidos del dominio constante de sus cadenas pesadas, los anticuerpos intactos se pueden asignar a diferentes "clases". Existen cinco clases principales de anticuerpos de inmunoglobulina intactos: IgA, IgD, IgE, IgG e IgM, y varios de estos se pueden dividir además en "subclases" (isotipos), por ejemplo, IgG1, IgG2, IgG3, IgG4, IgA e IgA2. Los dominios constantes de cadena pesada que corresponden a las diferentes clases de anticuerpos se denominan α, δ, ε, γ y µ, respectivamente. Las estructuras de las subunidades y las configuraciones tridimensionales de las diferentes clases de inmunoglobulinas son bien conocidas. Las formas de Ig incluyen modificaciones bisagra o formas sin bisagra (Roux et al. (1998) J. Immunol. 161:4083-4090; Lund et al. (2000) Eur. J. Biochem. 267:7246-7256; US 2005/0048572; US 2004/0229310).
Un "aminoácido de cisteína libre" se refiere a un resto de aminoácido de cisteína que ha sido modificado genéticamente para formar un anticuerpo parental, tiene un grupo funcional tiol (-SH) y no está enlazado como un puente disulfuro intramolecular o intermolecular.
El término "valor de reactividad del tiol" es una caracterización cuantitativa de la reactividad de los aminoácidos de cisteína libres. El valor de la reactividad del tiol es el porcentaje de un aminoácido de cisteína libre de un anticuerpo modificado genéticamente con cisteína que reacciona con un agente reactivo con tiol, y se convierte en un valor máximo de 1. Por ejemplo, un aminoácido de cisteína libre de un anticuerpo modificado genéticamente con cisteína que reacciona con un rendimiento del 100 % con un agente reactivo con tiol, tal como un reactivo de biotinamaleimida, para formar un anticuerpo marcado con biotina tiene un valor de reactividad del tiol de 1,0. Otro aminoácido de cisteína modificado genéticamente para formar el mismo o diferente anticuerpo parental que reacciona con un rendimiento del 80 % con un agente reactivo con tiol tiene un valor de reactividad del tiol de 0,8. Otro aminoácido de cisteína modificado genéticamente para formar el mismo o diferente anticuerpo parental que no reacciona en absoluto con un agente reactivo con tiol tiene un valor de reactividad del tiol de 0. La determinación del valor de la reactividad del tiol de una determinada cisteína se puede realizar mediante ensayo ELISA, espectroscopia de masas, cromatografía líquida, autorradiografía u otros ensayos analíticos cuantitativos.
Un "anticuerpo parental" es un anticuerpo que comprende una secuencia de aminoácidos en la que uno o más restos de aminoácidos están reemplazados por uno o más restos de cisteína. El anticuerpo parental puede comprender una secuencia de tipo nativo o silvestre. El anticuerpo parental puede tener modificaciones de la secuencia de aminoácidos preexistentes (tales como adiciones, eliminaciones y/o sustituciones) con respecto a otras formas modificadas, de tipo nativo o de tipo silvestre de un anticuerpo. Un anticuerpo parental se puede dirigir contra un antígeno diana de interés, por ejemplo, un polipéptido biológicamente relevante. También se contemplan los anticuerpos dirigidos contra antígenos no polipeptídicos (tales como antígenos glucolípidos asociados a tumores; véase el documento US 5091178).
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Referencias cruzadas: GI:37182378; AAQ88991.1; AY358628_1.
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- ETBR (receptor de endotelina de tipo B, Nº de acceso en Genbank AY275463); Nakamuta M., et al., Biochem. Biophys. Res. Commun. 177, 34-39, 1991; Ogawa Y., et al., Biochem. Biophys. Res. Commun. 178, 248-255, 1991; Arai H., et al. Jpn. Circ. J. 56, 1303-1307, 1992; Arai H., et al. J. Biol. Chem. 268, 3463-3470, 1993; Sakamoto A., Yanagisawa M., et al. Biochem. Biophys. Res. Commun. 178, 656-663, 1991; Elshourbagy N. A., et al. J. Biol. Chem. 268, 3873-3879, 1993; Haendler B., et al. J. Cardiovasc. Pharmacol. 20, s1-S4, 1992; Tsutsumi M., et al. Gene 228, 43-49, 1999; Strausberg R. L., et al. Proc. Natl. Acad. Sci. EE.UU. 99, 16899-16903, 2002; Bourgeois C., et al. J. Clin. Endocrinol. Metab. 82, 3116-3123, 1997; Okamoto Y., et al. Biol. Chem. 272, 21589-21596, 1997; Verheij J. B., et al. Am. J. Med. Genet. 108, 223-225, 2002; Hofstra R. M. W., et al., Eur. J. Hum. Genet. 5, 180-185, 1997; Puffenberger E.G., et al. Cell 79, 12571266, 1994; Attie T., et al., Hum. Mol. Genet. 4, 2407-2409, 1995; Auricchio A., et al., Hum. Mol. Genet. 5:351354, 1996; Amiel J., et al. Hum. Mol. Genet. 5, 355-357, 1996; Hofstra R. M. W., et al., Nat. Genet. 12, 445-447, 1996; Svensson P. J., et al. Hum. Genet. 103, 145-148, 1998; Fuchs S., et al. Mol. Med. 7, 115-124, 2001; Pingault V., et al. (2002) Hum. Genet. 111, 198-206; documento WO2004045516 (Reivindicación 1); documento WO2004048938 (Ejemplo 2); documento WO2004040000 (Reivindicación 151); documento WO2003087768 (Reivindicación 1); documento WO2003016475 (Reivindicación 1); documento WO2003016475 (Reivindicación 1); documento WO200261087 (Fig. 1); documento WO2003016494 (Fig. 6); documento WO2003025138 (Reivindicación 12; pág. 144); documento WO200198351 (Reivindicación 1; pág. 124-125); documento EP522868 (Reivindicación 8; Fig. 2); documento WO200177172 (Reivindicación 1; pág. 297-299); documento US2003109676; documento US6518404 (Fig. 3); documento US5773223 (Reivindicación 1a; Col 31-34); documento WO2004001004.
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- MSG783 (RNF124, proteína hipotética FLJ20315, Nº de acceso en Genbank NM_017763); documento WO2003104275 (Reivindicación 1); documento WO2004046342 (Ejemplo 2); documento WO2003042661 (Reivindicación 12); documento WO2003083074 (Reivindicación 14; pág. 61); documento WO2003018621 (Reivindicación 1); documento WO2003024392 (Reivindicación 2; Fig. 93); documento WO200166689 (Ejemplo 6); Referencias cruzadas: LocusID:54894; NP_060233.2; NMR_017763_1.
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- STEAP2 (HGNC_8639, IPCA-1, PCANAP1, STAMP1, STEAP2, STMP, gen 1 asociado al cáncer de próstata, proteína 1 asociada al cáncer de próstata, seis antígenos epiteliales transmembrana de próstata 2, seis proteínas de próstata transmembrana, Nº de acceso en Genbank AF455138) Lab. Invest. 82 (11):1573-1582 (2002)); documento WO2003087306; documento US2003064397 (Reivindicación 1; Fig. 1); documento WO200272596 (Reivindicación 13; pág. 54-55); documento WO200172962 (Reivindicación 1; Fig. 4B); documento WO2003104270 (Reivindicación 11); documento WO2003104270 (Reivindicación 16); documento US2004005598 (Reivindicación 22); documento WO2003042661 (Reivindicación 12); documento US2003060612 (Reivindicación 12; Fig. 10); documento WO200226822 (Reivindicación 23; Fig. 2); documento WO200216429 (Reivindicación 12; Fig. 10); Referencias cruzadas: GI:22655488; AAN04080.1; AF455138_1.
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- TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, canal catiónico potencial receptor transitorio, subfamilia M, miembro 4, Nº de acceso en Genbank NM_017636) Xu, X. Z., et al. Proc. Natl. Acad. Sci. EE.UU. 98 (19):10692-10697 (2001), Cell 109 (3):397-407 (2002), J. Biol. Chem. 278 (33):30813-30820 (2003)); documento US2003143557 (Reivindicación 4); documento WO200040614 (Reivindicación 14; pág. 100-103); documento WO200210382 (Reivindicación 1; Fig. 9A); documento WO2003042661 (Reivindicación 12); documento WO200230268 (Reivindicación 27; pág. 391); documento US2003219806 (Reivindicación 4); documento WO200162794 (Reivindicación 14; Fig. 1A-D); Referencias cruzadas: MIM:606936; NP_060106.2; NM_017636_1.
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- CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, factor de crecimiento derivado de teratocarcinoma, Nº de acceso en Genbank 10 NP_003203 o NM_003212). Ciccodicola, A., et al. EMBO J. 8 (7):1987-1991 (1989), Am. J. Hum. Genet. 49 (3):555-565 (1991)); documento US2003224411 (Reivindicación 1); documento WO2003083041 (Ejemplo 1); documento WO2003034984 (Reivindicación 12); documento WO200288170 (Reivindicación 2; pág. 52-53); documento WO2003024392 (Reivindicación 2; Fig. 58); documento WO200216413 (Reivindicación 1; pág. 94-95, 105); documento WO200222808 (Reivindicación 2; Fig. 1); documento US5854399 (Ejemplo 2; Col 17-18); documento US5792616 (Fig. 2); Referencias cruzadas: MIM:187395; NP_003203.1; NMR_003212_1.
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- CD21 (CR2 (Receptor del complemento 2) o C3DR (C3d/receptor del virus de Epstein Barr) o Hs.73792 Nº de acceso en Genbank M26004). Fujisaku et al. (1989) J. Biol. Chem. 264 (4):2118-2125); Weis J. J., et al. J. Exp. Med. 167, 1047-1066, 1988; Moore M., et al., Proc. Natl. Acad. Sci. EE.UU. 84, 9194-9198, 1987; Barel M., et al., Mol. Immunol. 35, 10251031, 1998; Weis J. J., et al. Proc. Natl. Acad. Sci. EE.UU. 83, 5639-5643, 1986; Sinha S. K., et al. (1993) J. Immunol. 150, 5311-5320; documento WO2004045520 (Ejemplo 4); documento US2004005538 (Ejemplo 1); documento WO2003062401 (Reivindicación 9); documento WO2004045520 (Ejemplo 4); documento
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El anticuerpo parental también puede ser una proteína de fusión que comprende una secuencia de péptido de unión a la albúmina (ABP) (Dennis et al. (2002) "Albumin Binding As A General Strategy For Improving The Pharmacokinetics Of Proteins" J Biol Chem. 277:35035-35043; documento WO 01/45746). Los anticuerpos de la invención incluyen proteínas de fusión con secuencias de ABP enseñadas por: (i) Dennis et al. (2002) J Biol Chem. 277:35035-35043 en las Tablas III y IV, pág. 35038; (ii) documento US 20040001827 en el párrafo [0076]; y (iii) documento WO 01/45746 en las pág. 12-13.
Para preparar un anticuerpo modificado genéticamente con cisteína por mutagénesis, se prepara el ADN que codifica una variante de la secuencia de aminoácidos del polipéptido de partida mediante varios métodos conocidos en la técnica. Estos métodos incluyen, pero sin limitación, la preparación por mutagénesis dirigida (o mediada por oligonucleótidos), la mutagénesis por PCR y la mutagénesis de casete de un DNA preparado anteriormente que codifique el polipéptido. También se pueden construir variantes de anticuerpos recombinantes mediante la manipulación de fragmentos de restricción o por PCR de extensión de solapamiento con oligonucleótidos sintéticos. Los cebadores mutagénicos codifican una o varias sustituciones de codones de cisteína. Se pueden emplear técnicas de mutagénesis convencionales para generar ADN que codifique dichos anticuerpos mutantes modificados genéticamente con cisteína. En Sambrook et al. “Molecular Cloning, A Laboratory Manual”, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y., 1989; y Ausubel et al. “Current Protocols in Molecular Biology”, Greene Publishing and Wiley-Interscience, Nueva York, N. Y., 1993, se pueden encontrar las directrices generales.
La mutagénesis dirigida es un método de preparación de variantes de sustitución, es decir, de proteínas mutantes (Carter (1985) et al. Nucleic Acids Res. 13:4431-4443; Ho et al. (1989) Gene (Amst.) 77:51-59; y Kunkel et al. (1987) Proc. Natl. Acad. Sci. EE.UU. 82:488). El ADN de partida se altera primero mediante la hibridación de un oligonucleótido que codifique la mutación deseada con una sola hebra de dicho ADN de partida. Después de la hibridación, se usa una ADN polimerasa para sintetizar una segunda hebra, usando el oligonucleótido hibridado como cebador, y usando la cadena sencilla del ADN de partida como molde. Así pues, el oligonucleótido que codifica la mutación deseada se incorpora al ADN de doble cadena resultante. La mutagénesis dirigida se puede llevar a cabo dentro del gen que exprese la proteína que se vaya a someter a mutagénesis en un plásmido de expresión, y se puede secuenciar el plásmido resultante para confirmar la introducción de las mutaciones de sustitución de cisteínas deseadas (Liu et al. (1998) J. Biol. Chem. 273: 20252-20260). Los protocolos y los formatos de mutagénesis dirigida se pueden obtener fácilmente, por ejemplo, el kit de mutagénesis multidirigida QuikChange® (Stratagene, La Jolla, CA).
La mutagénesis por PCR también es adecuada para preparar variantes de la secuencia de aminoácidos del polipéptido de partida. Véase Higuchi, (1990) en “PCR Protocols”, pág.177-183, Academic Press; Ito et al. (1991) Gene 102:67-70; Bernhard et al. (1994) Bioconjugate Chem., 5:126-132; y Vallette et al. (1989) Nuc. Acids Res., 17:723-733. En resumen, cuando se usan pequeñas cantidades de ADN de molde como material de partida en una PCR, se pueden usar cebadores que difieran ligeramente en la secuencia de la región correspondiente de un ADN de molde para generar cantidades relativamente altas de un fragmento de ADN específico que difiera de la secuencia molde solo en las posiciones donde los cebadores difieren del molde.
Otro método de preparación de variantes, la mutagénesis de casete, se basa en la técnica descrita por Wells et al. (1985) Gene, 34: 315-323. El material de partida es el plásmido (u otro vector) que comprende el ADN del polipéptido de partida que se desea mutar. Se identifican el/los codón/es del ADN de partida que se va a mutar. Debe haber un único sitio de endonucleasa de restricción a cada lado del/de los sitio/s de mutación identificado/s. Si no existen dichos sitios de restricción, se pueden generar usando el método de mutagénesis mediada por oligonucleótidos descrito anteriormente para introducirlos en ubicaciones adecuadas del ADN del polipéptido de partida. El ADN del plásmido se corta en estos sitios para linealizarlo. Se sintetiza un oligonucleótido de doble cadena que codifique la secuencia de ADN entre los sitios de restricción, pero que contenga la/s mutación/es deseada/s, usando procedimientos convencionales, en los que las dos hebras del oligonucleótido se sintetizan por separado y luego se hibridan entre sí usando técnicas convencionales. Este oligonucleótido de doble cadena se conoce como casete. Este casete se diseña para que tenga extremos 5' y 3' que sean compatibles con los extremos del plásmido linealizado, de modo que pueda ligarse directamente al plásmido. Este plásmido contiene ahora la secuencia de ADN mutada. El ADN mutante que contiene las sustituciones de cisteína codificadas se puede confirmar por secuenciación del ADN.
También se generan mutaciones individuales por mutagénesis dirigida a oligonucleótidos usando ADN de plásmido de doble cadena como molde mediante mutagénesis basada en PCR (Sambrook y Russel, (2001) “Molecular Cloning: A Laboratory Manual”, III Edición; Zoller et al. (1983) Methods Enzymol. 100:468-500; Zoller, M. J. y Smith,
M. (1982) Nucl. Acids Res. 10:6487-6500).
MODIFICACIÓN GENÉTICA Y REACTIVIDAD DEL TIOL DE LOS THIOFAB ANTI-HER2 4D5
Se introdujo cisteína en cada posición de la cadena pesada y la cadena ligera del anticuerpo de fragmento Fab hu4D5Fabv8 anti-HER2 (documento US 5821337; Carter et al. (1992) Proc. Natl. Acad. Sci., 89:4285-4289). Los 440 mutantes de cadena pesada y mutantes de cadena ligera se prepararon de acuerdo con los métodos descritos en el presente documento. Se midió la reactividad del tiol según el ensayo PHESELECTOR. Las secuencias de cadena
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US41453510P | 2010-11-17 | 2010-11-17 | |
US414535P | 2010-11-17 | ||
PCT/US2011/061031 WO2012074757A1 (en) | 2010-11-17 | 2011-11-16 | Alaninyl maytansinol antibody conjugates |
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US (1) | US20120121615A1 (es) |
EP (1) | EP2640727B1 (es) |
JP (1) | JP5889912B2 (es) |
CN (1) | CN103313990B (es) |
CA (1) | CA2816426A1 (es) |
ES (1) | ES2544608T3 (es) |
WO (1) | WO2012074757A1 (es) |
Families Citing this family (76)
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SG183335A1 (en) | 2010-02-23 | 2012-09-27 | Genentech Inc | Compositions and methods for the diagnosis and treatment of tumor |
US9000130B2 (en) | 2010-06-08 | 2015-04-07 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
WO2012087962A2 (en) | 2010-12-20 | 2012-06-28 | Genentech, Inc. | Anti-mesothelin antibodies and immunoconjugates |
DK2675479T3 (en) | 2011-02-15 | 2016-04-11 | Immunogen Inc | cytotoxic benzodiazepine |
AR090549A1 (es) | 2012-03-30 | 2014-11-19 | Genentech Inc | Anticuerpos anti-lgr5 e inmunoconjugados |
BR112014027166A2 (pt) | 2012-05-01 | 2017-06-27 | Genentech Inc | anticorpo, ácido nucleico, célula hospedeira, método para produzir um anticorpo, imunoconjugado, formulação farmacêutica, método de tratamento, método de inibir proliferação e métodos de detecção. |
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-
2011
- 2011-11-16 ES ES11793586.6T patent/ES2544608T3/es active Active
- 2011-11-16 US US13/297,408 patent/US20120121615A1/en not_active Abandoned
- 2011-11-16 CN CN201180064798.0A patent/CN103313990B/zh active Active
- 2011-11-16 CA CA2816426A patent/CA2816426A1/en not_active Abandoned
- 2011-11-16 EP EP20110793586 patent/EP2640727B1/en active Active
- 2011-11-16 JP JP2013539981A patent/JP5889912B2/ja active Active
- 2011-11-16 WO PCT/US2011/061031 patent/WO2012074757A1/en active Application Filing
Also Published As
Publication number | Publication date |
---|---|
JP5889912B2 (ja) | 2016-03-22 |
US20120121615A1 (en) | 2012-05-17 |
CA2816426A1 (en) | 2012-06-07 |
CN103313990A (zh) | 2013-09-18 |
EP2640727A1 (en) | 2013-09-25 |
WO2012074757A1 (en) | 2012-06-07 |
JP2013544253A (ja) | 2013-12-12 |
EP2640727B1 (en) | 2015-05-13 |
CN103313990B (zh) | 2016-07-20 |
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