ES2649990T3 - Conjugados de anticuerpos anti-CD22-pirrolobenzodiazepinas - Google Patents

Conjugados de anticuerpos anti-CD22-pirrolobenzodiazepinas Download PDF

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ES2649990T3
ES2649990T3 ES13786186.0T ES13786186T ES2649990T3 ES 2649990 T3 ES2649990 T3 ES 2649990T3 ES 13786186 T ES13786186 T ES 13786186T ES 2649990 T3 ES2649990 T3 ES 2649990T3
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antibody
adc
cell
compound
conjugate
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Patricius Hendrikus Cornelis VAN BERKEL
Philip Wilson Howard
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ADC Therapeutics SA
MedImmune Ltd
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MedImmune Ltd
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    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • A61K47/68035—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a pyrrolobenzodiazepine
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    • C07K16/112—Retroviridae (F), e.g. leukemia viruses
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Abstract

Un conjugado de fórmula ConjA:**Fórmula** ConjB:**Fórmula** ConjC:**Fórmula** ConjD:**Fórmula** o ConjE:**Fórmula** en el que Ab es un anticuerpo que se une a CD22, comprendiendo el anticuerpo un dominio VH emparejado con un dominio VL, teniendo los dominios VH y VL secuencias de SEQ ID NO. 1 emparejada con la SEQ ID NO. 2; y en el que la carga de fármaco (p) de fármacos (D) al anticuerpo (Ab) es un número entero de 1 a aproximadamente 8.

Description

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Optimización de contenidos de la cadena humana
Este procedimiento compara la secuencia no humana (por ejemplo, de ratón) con el repertorio de genes de la línea germinal humana y las diferencias se puntúan como contenido de la cadena humana (HSC) que cuantifica una
5 secuencia al nivel de posibles epítopes de MHC/linfocitos T. A continuación, la secuencia diana se humaniza maximizando su HSC en vez de usando una medida de identidad global para generar múltiples variantes humanizadas diversas (descritas en Molecular Immunology, 44, (2007) 1986-1998).
Barajado de regiones estructurales
Las CDR del anticuerpo no humano están fusionadas en marco con conjuntos de ADNc que engloban todas las regiones estructurales de genes de la línea germinal humana de cadenas pesadas y ligeras conocidas. A continuación, los anticuerpos humanizados se seleccionan, por ejemplo, por inmunopurificación de la biblioteca de anticuerpos expresados en fago. Esto se describe en Methods 36, 43-60 (2005).
15
Conjugados
La presente invención proporciona un conjugado que comprende un compuesto de PBD conectado al anticuerpo a través de una unidad conectora.
La presente invención es adecuada para su uso en la provisión de un compuesto PBD a un sitio preferido en un sujeto. En las realizaciones preferidas, el conjugado permite la liberación de un compuesto de PBD activo que no retiene ninguna parte del conector. No hay ningún cabo presente que pueda afectar la reactividad del compuesto de PBD.
25 Los enlazadores del ADC previenen preferentemente la agregación de moléculas de ADC y mantienen el ADC libremente soluble en medios acuosos y en un estado monomérico.
Los enlazadores del ADC son preferentemente estables extracelularmente. Antes del transporte o de la administración en una célula, el conjugado anticuerpo-fármaco (ADC) es preferentemente estable y permanece intacto, es decir, el anticuerpo permanece unido al resto del fármaco. Los enlazadores son estables fuera de la célula diana y pueden escindirse a alguna velocidad eficaz dentro de la célula. Un enlazador eficaz: (i) mantendrá las propiedades de unión específicas del anticuerpo; (ii) permitirá la administración intracelular del conjugado o resto de fármaco; (iii) permanecerá estable e intacto, es decir no escindido, hasta que el conjugado se haya sido
35 administrado o transportado a su sitio diana; y (iv) mantendrá un efecto citotóxico, de muerte celular o un efecto citostático del resto de fármaco PBD. La estabilidad del ADC se puede medir mediante técnicas analíticas estándar tales como espectroscopía de masas, HPLC, y la técnica de separación/análisis CL/EM .
Realizaciones
Las realizaciones de la presente invención incluyen ConjA, en el que el anticuerpo es como se ha definido anteriormente.
Las realizaciones de la presente invención incluyen ConjB, en el que el anticuerpo es como se ha definido 45 anteriormente.
Las realizaciones de la presente invención incluyen ConjC, en el que el anticuerpo es como se ha definido anteriormente.
Las realizaciones de la presente invención incluyen ConjD, en el que el anticuerpo es como se ha definido anteriormente.
Las realizaciones de la presente invención incluyen ConjE, en el que el anticuerpo es como se ha definido anteriormente.
55 Carga de fármaco
La carga de fármaco es el número promedio de fármacos de PBD por anticuerpo. Si los compuestos de la invención están unidos a cisteínas, la carga de fármaco puede oscilar de 1 a 8 fármacos (D) por anticuerpo, es decir, en los que 1, 2, 3, 4, 5, 6, 7 y 8 restos de fármaco están covalentemente unidos al anticuerpo. Las composiciones de conjugados incluyen colecciones de anticuerpos, conjugados con un intervalo de fármacos, de 1 a 8.
El número promedio de fármacos por anticuerpo en preparaciones de ADC de reacciones de conjugación puede caracterizarse mediante medios convencionales tales como UV, HPLC de fase inversa, HIC, espectroscopía de 65 masas, ensayo de ELISA y electroforesis. También puede determinarse la distribución cuantitativa de ADC en términos de p. Por ELISA, puede determinarse el valor promediado de p en una preparación particular de ADC
13
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AntiCancer Drugs 6:398-404). El procedimiento de ensayo homogéneo implica añadir el único reactivo (reactivo CellTiter-Glo®) directamente a las células cultivadas en medio complementado con suero. No se requieren el lavado de células, eliminación de medio y múltiples etapas de pipeteado. El sistema detecta tan solo 15 células/pocillo en un formato de 384 pocillos en 10 minutos después de añadir reactivo y mezclar. Las células pueden tratarse
5 continuamente con ADC, o pueden tratarse y separarse de ADC. Generalmente, las células tratadas brevemente, es decir, 3 horas, mostraron los mismos efectos de potencia que las células continuamente tratadas.
El formato “añadir-mezclar-medir” homogéneo produce la lisis celular y generación de una señal luminiscente proporcional a la cantidad de ATP presente. La cantidad de ATP es directamente proporcional al número de células presentes en el cultivo. El ensayo CellTiter-Glo® genera una señal luminiscente “de tipo brillo”, producida por la reacción de la luciferasa, que tiene una semivida generalmente superior a cinco horas, dependiendo del tipo de célula y del medio usado. Las células viables se reflejan en unidades relativas de luminiscencia (URL). El sustrato, luciferina de escarabajo, se descarboxila oxidativamente por luciferasa de luciérnaga recombinante, con la conversión concomitante de ATP en AMP y generación de fotones.
15 La potencia in vitro de conjugados de anticuerpo-fármaco también puede medirse por un ensayo de citotoxicidad. Se lavan células adherentes cultivadas con PBS, se desprenden con tripsina, se diluyen en medio completo, que contiene 10 % de SBF, se centrifugan, se resuspenden en medio fresco y se cuentan con un hemocitómetro. Los cultivos en suspensión se cuentan directamente. Suspensiones monodispersas de células adecuadas para el recuento pueden requerir la agitación de la suspensión por aspiración repetida para romper los grupos de células.
La suspensión de células se diluye a la densidad de siembra deseada y se dispensa (100 µl por pocillo) en placas de 96 pocillos negras. Se incuban placas de líneas de células adherentes durante la noche para permitir la adherencia. Pueden usarse cultivos celulares en suspensión el día de la siembra.
25 Se prepara una solución madre (1 ml) de ADC (20 µg/ml) en el medio de cultivo celular apropiado. Se preparan diluciones de 10 veces en serie de ADC de solución madre en tubos de centrífuga de 15 ml transfiriendo en serie 100 µl a 900 µl de medio de cultivo celular.
Se dispensan cuatro pocillos por duplicado de cada dilución de ADC (100 µl) en placas de 96 pocillos negras, previamente sembradas con suspensión de células (100 µl), produciendo un volumen final de 200 µl. Los pocillos de control reciben medio de cultivo celular (100 µl).
Si el tiempo de duplicación de la línea celular es superior a 30 horas, la incubación de ADC es durante 5 días, si no 35 se hace una incubación de cuatro días.
Al final del periodo de incubación, se evalúa la viabilidad celular con el ensayo de azul Alamar. Se dispensa azul Alamar (Invitrogen) sobre la placa completa (20 µl por pocillo) y se incuba durante 4 horas. Se mide la fluorescencia de azul Alamar a la excitación de 570 nm, emisión de 585 nm sobre el lector de placas Varioskan Flash. El porcentaje de supervivencia celular se calcula a partir de la fluorescencia media en los pocillos tratados con ADC en comparación con la fluorescencia media en los pocillos de control.
Uso
45 Los conjugados de la invención pueden usarse para proporcionar un compuesto de PBD en una localización diana.
La localización diana es preferentemente una población de células proliferativas. El anticuerpo es un anticuerpo para un antígeno presente sobre una población de células proliferativas.
En una realización, el antígeno está ausente o presente a un nivel reducido en una población de células no proliferativas en comparación con la cantidad de antígeno presente en la población de células proliferativas, por ejemplo, una población de células tumorales.
En la localización diana, el conector puede escindirse de manera que libere un compuesto RelA, RelB, RelC, RelD o 55 ReIBRelE. Así, el conjugado puede usarse para proporcionar selectivamente un compuesto RelA, RelB, Rel C, RelD
o ReIBRelE a la localización diana.
El conector puede escindirse por una enzima presente en la localización diana.
La localización diana puede ser in vitro, in vivo o ex vivo.
Los compuestos de conjugado de anticuerpo-fármaco (ADC) de la invención incluyen aquellos con utilidad para actividad contra el cáncer. En particular, los compuestos incluyen un anticuerpo conjugado, es decir, covalentemente unido por un conector, a un resto de fármaco de PBD, es decir, toxina. Si el fármaco no está conjugado a un
65 anticuerpo, el fármaco de PBD tiene un efecto citotóxico. La actividad biológica del resto de fármaco de PBD se modula así por conjugación con un anticuerpo. Los conjugados de anticuerpo-fármaco (ADC) de la invención
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espesantes y solutos que convierten la formulación en isotónica con la sangre (u otro fluido corporal relevante) del receptor previsto. Ejemplos de excipientes incluyen, por ejemplo, agua, alcoholes, polioles, glicerol, aceites vegetales y similares. Ejemplos de vehículos isotónicos adecuados para su uso en tales formulaciones incluyen inyección de cloruro sódico, solución de Ringer o inyección de Ringer con lactato. Normalmente, la concentración del
5 principio activo en el líquido es de aproximadamente 1 ng/ml a aproximadamente 10 µg/ml, por ejemplo, de aproximadamente 10 ng/ml a aproximadamente 1 µg/ml. Las formulaciones pueden presentarse en recipientes cerrados de dosis unitaria o multi-dosis, por ejemplo, ampollas y viales, y puede almacenarse en una condición secada por congelación (liofilizada) que requiere solo la adición del vehículo líquido estéril, por ejemplo, agua para inyecciones, inmediatamente antes de uso. Pueden prepararse soluciones y suspensiones para inyección extemporánea a partir de polvos estériles, gránulos y comprimidos.
Dosificación
Se apreciará por un experto en la materia que las dosificaciones apropiadas del compuesto de conjugado, y
15 composiciones que comprenden el compuesto de conjugado, pueden variar de paciente a paciente. Determinar la dosificación óptima implicará generalmente equilibrar el nivel de beneficio terapéutico contra cualquier riesgo o efectos secundarios perjudiciales. El nivel de dosificación seleccionado dependerá de varios factores que incluyen, pero sin limitaciones, la actividad del compuesto particular, la vía de administración, el momento de administración, la tasa de eliminación del compuesto, la duración del tratamiento, otros fármacos, compuestos y/o materiales usados en combinación, la gravedad de la afección, y la especie, sexo, edad, peso, afección, salud general e historia médica previa del paciente. La cantidad de compuesto y la vía de administración serán por último lugar a criterio del médico, veterinario o profesional clínico, aunque generalmente la dosificación se seleccionará para lograr concentraciones locales en el sitio de acción que consiguen el efecto deseado sin causar efectos secundarios nocivos o perjudiciales sustanciales.
25 La administración puede efectuarse en una dosis, continuamente o intermitentemente (por ejemplo, en dosis divididas a intervalos apropiados) durante el transcurso del tratamiento. Procedimientos de determinación de los medios más eficaces y de dosificación de la administración son muy conocidos para aquellos expertos en la materia y variarán con la formulación usada para la terapia, el fin de la terapia, la(s) célula(s) diana(s) que está(n) tratándose y el sujeto que está tratándose. Pueden llevarse a cabo administraciones individuales o múltiples con el nivel de dosis y patrón que se selecciona por el médico práctico, veterinario o profesional clínico.
En general, una dosis adecuada del compuesto activo está en el intervalo de aproximadamente 100 ng a aproximadamente 25 mg (más normalmente aproximadamente 1 µg a aproximadamente 10 mg) por kilogramo de
35 peso corporal del sujeto por día. Si el compuesto activo es una sal, un éster, una amida, un profármaco o similar, la cantidad administrada se calcula basándose en el compuesto parental y así el peso real que va a usarse se aumenta proporcionalmente.
En una realización, el compuesto activo se administra a un paciente humano conforme al siguiente régimen de dosificación: aproximadamente 100 mg, 3 veces al día.
En una realización, el compuesto activo se administra a un paciente humano según la siguiente pauta de dosificación: aproximadamente 150 mg, 2 veces al día.
45 En una realización, el compuesto activo se administra a un paciente humano según la siguiente pauta de dosificación: aproximadamente 200 mg, 2 veces al día.
Sin embargo en una realización, el compuesto de conjugado se administra a un paciente humano según la siguiente pauta de dosificación: aproximadamente 50 o aproximadamente 75 mg, 3 o 4 veces al día.
En una realización, el compuesto de conjugado se administra a un paciente humano según la siguiente pauta de dosificación: aproximadamente 100 o aproximadamente 125 mg, 2 veces al día.
Las cantidades de dosificación descritas anteriormente pueden aplicarse al conjugado (incluyendo el resto de PBD y
55 el conector al anticuerpo) o a la cantidad eficaz de compuesto de PBD proporcionada, por ejemplo, la cantidad de compuesto que es liberable después de la escisión del conector.
Para la prevención o tratamiento de enfermedad, la dosificación apropiada de un ADC de la invención dependerá del tipo de enfermedad que va a tratarse, como se ha definido anteriormente, la gravedad y transcurso de la enfermedad, si la molécula se administra para fines preventivos o terapéuticos, terapia previa, la historia clínica del paciente y respuesta al anticuerpo, y el criterio del médico adjunto. La molécula se administra adecuadamente al paciente de una vez o durante una serie de tratamientos. Dependiendo del tipo y gravedad de la enfermedad, aproximadamente 1 µg/kg a 15 mg/kg (por ejemplo, 0,1-20 mg/kg) de molécula es una dosificación candidata inicial para administración al paciente, tanto, por ejemplo, por una como más administraciones separadas, o por infusión 65 continua. Una dosificación diaria típica podría oscilar de aproximadamente 1 µg/kg a 100 mg/kg o más, dependiendo de los factores mencionados anteriormente. Una dosificación a modo de ejemplo de ADC que va a administrarse a
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se lavó con H2O, éter dietílico y se secó en el desecador al vacío para proporcionar 8 (30,1 g, 99 %). [α]23 D = +234° (c = 0,41, CHCl3); RMN 1H (400 MHz, CDCl3) δ 8,65 (s, 2H, NH), 7,44 (s, 2H), 6,54 (s, 2H), 4,50 (p, 2H, J = 5,38 Hz), 4,21-4,10 (m, 6H), 3,87 (s, 6H), 3,73-3,63 (m, 4H), 2,85-2,79 (m, 2H), 2,36-2,29 (m, 2H), 2,07-1,99 (m, 2H), 0,86 (s, 18H), 0,08 (s, 12H); RMN 13C (100 MHz, CDCl3) δ 170,4, 165,7, 151,4, 146,6, 129,7, 118,9, 112,8, 105,3, 69,2, 65,4,
5 56,3, 55,7, 54,2, 35,2, 28,7, 25,7, 18,0, -4,82 and -4,86; IR (ATR, CHCl3) 3235, 2955, 2926, 2855, 1698, 1695, 1603, 1518, 1491, 1446, 1380, 1356, 1251, 1220, 1120, 1099, 1033 cm-1; MS (ES+) m/z (intensidad relativa) 825 ([M + H]+·, 62), 721 (14), 440 (38); HRMS [M + H]+, teórico C41H60N4O10Si2 m/z 825,3921, hallado (ES+) m/z 825,3948.
(g) 1,1’-[[(Propan-1,3-diil)dioxi]bis(11aS,2R)-2-(terc-butildimetilsililoxi)-7-metoxi-10-((2-(trimetilsi-lil)etoxi)meti)1,2,3,10,11,11a-hexahidro-5H-pirrolo[2,1-c][1,4]-benzodiazepin-5,11-diona] (9)
Se añadió gota a gota una solución de n-BuLi (68,3 ml de una solución 1,6 M en hexano, 109 mmoles) a una suspensión agitada de la tetralactama 8 (30,08 g, 36,4 mmol) en THF anhidro (600 ml) a -30 ºC (hielo seco/etilenglicol) bajo una atmósfera de nitrógeno. La mezcla de reacción se dejó agitar a esta temperatura durante 15 1 hora (ahora un color naranja rojizo), punto en el que se añadió gota a gota una solución de SEMCl (19,3 ml, 18,2 g, 109 mmol) en THF anhidro (120 ml). La mezcla de reacción se dejó calentar lentamente hasta la temperatura ambiente y se agitó durante 16 horas bajo una atmósfera de nitrógeno. La reacción se consideró completa, según se juzgó mediante TLC (EtOAc) (4,77 min (ES +) m/z (intensidad relativa) 1085 ([M + H]+, 100). El THF se eliminó por evaporación al vacío y el residuo resultante se disolvió en EtOAc (750 ml), se lavó con H2O (250 ml), salmuera (250 ml), se secó (MgSO4), se filtró y se evaporó a vacío para proporcionar la tetralactama cruda protegida con N10-SEM 9 como un aceite (maxm 39,5 g, 100 %). El producto se llevó a la siguiente etapa sin purificación. [α]23 D = +163° (c = 0,41, CHCl3); RMN 1H (400 MHz, CDCl3) δ 7,33 (s, 2H), 7,22 (s, 2H), 5,47 (d, 2H, J = 9,98 Hz), 4,68 (d, 2H, J = 9,99 Hz), 4,57 (p, 2H, J = 5,77 Hz), 4,29-4,19 (m, 6H), 3,89 (s, 6H), 3,79-3,51 (m, 8H), 2,87-2,81 (m, 2H), 2,41 (p, 2H, J = 5,81 Hz), 2,03-1,90 (m, 2H), 1,02-0,81 (m, 22H), 0,09 (s, 12H), 0,01 (s, 18H); RMN RMN 13C (100 MHz, CDCl3) δ
25 170,0, 165,7, 151,2, 147,5, 133,8, 121,8, 111,6, 106,9, 78,1, 69,6, 67,1, 65,5, 56,6, 56,3, 53,7, 35,6, 30,0, 25,8, 18,4, 18,1, -1,24, -4,73; IR (ATR, CHCl3) 2951, 1685, 1640, 1606, 1517, 1462, 1433, 1360, 1247, 1127, 1065 cm-1; MS (ES+) m/z (intensidad relativa) 1113 ([M + Na]+, 48), 1085 ([M + H]+, 100), 1009 (5), 813 (6); HRMS [M + H]+' teórico C53H88N4O12Si4 m/z 1085,5548, hallado (ES+) m/z 1085,5542.
(h) 1,1,1’-[[(Propan-1,3-diil)dioxi]bis(11aS,2R)-2-hidroxi-7-metoxi-10-((2-(trimetilsilil)etoxi)meti)-1,2,3,10,11,11ahexahidro-5H-pirrolo[2,1-c][1,4]-benzodiazepin-5,11-diona] (10)
Se añadió una solución de TBAF (150 ml de una solución 1,0 M en THF, 150 mmol) a una solución agitada del éter bis-silílico crudo 9 [84,0 g (maxm 56,8 g), 52,4 mmol] en THF (800 ml) a temperatura ambiente. Después de agitar 35 durante 1 hora, el análisis de la mezcla de reacción por TLC (95:5 v/v CHCl3/MeOH) reveló la finalización de la reacción. El THF se eliminó por evaporación a presión reducida a temperatura ambiente y el residuo resultante se disolvió en EtOAc (500 ml) y se lavó con NH4Cl (300 ml). Las capas orgánicas combinadas se lavaron con salmuera (60 ml), se secaron (MgSO4), se filtraron y se evaporaron a presión reducida para proporcionar el producto bruto. La purificación por cromatografía ultrarrápida (gradiente de elución: 100 % CHCl3 a 96:4 v/v CHCl3/MeOH) dio la tetralactama pura 10 como una espuma blanca (36,0 g, 79 %). LC/MS 3,33 min (ES+) m/z (intensidad relativa) 879 ([M + Na]+, 100), 857 ([M + H]+, 40); [α]23 D = +202°(c = 0,34, CHCl3); RMN 1H (400 MHz, CDCl3) δ 7,28 (s, 2H), 7,20 (s, 2H), 5,44 (d, 2H, J = 10,0 Hz), 4,72 (d, 2H, J = 10,0 Hz), 4,61-4,58 (m, 2H), 4,25 (t, 4H, J = 5,83 Hz), 4,20-4,16 (m, 2H), 3,91-3,85 (m, 8H), 3,77-3,54 (m, 6H), 3,01 (br s, 2H, OH), 2,96-2,90 (m, 2H), 2,38 (p, 2H, J = 5,77 Hz), 2,112,05 (m, 2H), 1,00-0,91 (m, 4H), 0,00 (s, 18H); RMN 13C (100 MHz, CDCl3) δ 169,5, 165,9, 151,3, 147,4, 133,7,
45 121,5, 111,6, 106,9, 79,4, 69,3, 67,2, 65,2, 56,5, 56,2, 54,1,35,2, 29,1, 18,4, -1,23; IR (ATR, CHCl3) 2956, 1684, 1625, 1604, 1518, 1464, 1434, 1361, 1238, 1058, 1021 cm-1; MS (ES+) m/z (intensidad relativa) 885 ([M+29]+, 70), 857 ([M + H]+, 100), 711 (8), 448 (17); HRMS [M + H]+, teórico C41H60N4O12Si2 m/z 857,3819, hallado (ES+) m/z 857,3826.
(i) 1,1,1’-[[(Propan-1,3-diil)dioxi]bis(11aS)-7-metoxi-2-oxo-10-((2-(trimetilsilil)etoxi)metil)-1,2,3,10,11,11a-hexahidro5H-pirrolo[2,1-c][1,4]-benzodiazepin-5,11-diona] (11)
Se disolvieron diol 10 (25,6 g, 30 mmol, 1 eq.), NaOAc (6,9 g, 84 mmol, 2,8 eq.) y TEMPO (188 mg, 1,2 mmol, 0,04 eq.) en DCM (326 ml) en Ar. Esto se enfrió a -8 ºC (temperatura interna) y se añadió TCCA (9,7 g, 42 mmol, 1,4 eq.) 55 en porciones durante 15 minutos. TLC (EtOAc) y LC/MS [3.60 min. (ES+) m/z (intensidad relativa) 854.21 ([M + H]+., 40), (ES-) m/z (intensidad relativa) 887,07 ([M -H + Cl] -, 10)] tras 30 minutos indicó que la reacción se había completado. Se añadió DCM frío (200 ml) y la mezcla se filtró a través de una almohadilla de Celite antes de lavar con una solución de bicarbonato sódico saturado/tiosulfato sódico (1: 1 v/v, 200 ml x 2). La capa orgánica se secó con MgSO4, se filtró y el disolvente se eliminó a vacío para producir una esponja amarilla/naranja. LC/MS [3.60 min. (ES+) m/z (intensidad relativa) 854,21 ([M + H]+, 40); [α]20 D = +291° (c = 0,26, CHCl3); RMN 1H (400 MHz, CDCl3) δ 7,32 (s, 2H), 7,25 (s, 2H), 5,50 (d, 2H, J = 10,1 Hz), 4,75 (d, 2H, J= 10,1 Hz), 4,60 (dd, 2H, J = 9,85, 3,07 Hz), 4,314,18 (m, 6H), 3,89-3,84 (m, 8H), 3,78-3,62 (m, 4H), 3,55 (dd, 2H, J = 19,2, 2,85 Hz), 2,76 (dd, 2H, J = 19,2, 9,90 Hz), 2,42 (p, 2H, J = 5,77 Hz), 0,98-0,91 (m, 4H), 0,00 (s, 18H); RMN 13C (100 MHz, CDCl3) δ 206,8, 168,8, 165,9, 151,8, 148,0, 133,9, 120,9, 111,6, 107,2, 78,2, 67,3, 65,6, 56,3, 54,9, 52,4, 37,4, 29,0, 18,4, -1,24; IR (ATR, CHCl3) 2957, 65 1763, 1685, 1644, 1606, 1516, 1457, 1434, 1360, 1247, 1209, 1098, 1066, 1023 cm-1; MS (ES+) m/z (intensidad relativa) 881 ([M + 29]+·, 38), 853 ([M + H]+·, 100), 707 (8), 542 (12); HRMS [M + H]+· teórica l C41H56N4O12Si2 m/z
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KR101645905B1 (ko) 2012-10-12 2016-08-04 스피로즌 살 피롤로벤조디아제핀 및 그의 컨주게이트
JP6445519B2 (ja) 2013-03-13 2018-12-26 メドイミューン・リミテッドＭｅｄＩｍｍｕｎｅ Ｌｉｍｉｔｅｄ ピロロベンゾジアゼピン及びそのコンジュゲート
WO2018075807A1 (en) * 2016-10-19 2018-04-26 California Institute For Biomedical Research Chimeric antigen receptor effector cell switches with humanized targeting moieties and/or optimized chimeric antigen receptor interacting domains and uses thereof

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