ES2617283T3 - Inmunoconjugados contra el receptor 1 de folato y usos de los mismos - Google Patents

Inmunoconjugados contra el receptor 1 de folato y usos de los mismos Download PDF

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Publication number
ES2617283T3
ES2617283T3 ES11748067.3T ES11748067T ES2617283T3 ES 2617283 T3 ES2617283 T3 ES 2617283T3 ES 11748067 T ES11748067 T ES 11748067T ES 2617283 T3 ES2617283 T3 ES 2617283T3
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seq
light chain
heavy chain
antibody
polypeptide
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ES11748067.3T
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Olga Ab
Daniel Tavares
Lingyun Rui
Gillian Payne
Viktor S. Goldmakher
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Immunogen Inc
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Immunogen Inc
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Abstract

Un inmunoconjugado que tiene la fórmula (A) - (L) - (C), en donde: (A) es un anticuerpo o fragmento de unión al antígeno; (L) es un conector; y (C) es un maitansinoide o un análogo de maitansinoide, en donde dicho conector (L) liga (A) a (C), en donde (A) se selecciona del grupo que consiste en: i) un anticuerpo humanizado o un fragmento de unión al antígeno del mismo que se une específicamente a un receptor 1 de folato humano, en donde el anticuerpo o fragmento de unión al antígeno del mismo comprende: (a) una CDR1 de cadena pesada que comprende GYFMN (SEQ ID NO: 1); una CDR2 de cadena pesada que comprende RIHPYDGDTFYNQKFQG (SEQ ID NO: 2); y una CDR3 de cadena pesada que comprende YDGSRAMDY (SEQ ID NO: 3); y (b) una CDR1 de cadena ligera que comprende KASQSVSF AGTSLMH (SEQ ID NO: 7); una CDR2 de cadena ligera que comprende RASNLEA (SEQ ID NO: 8); y una CDR3 de cadena ligera que comprende QQSREYPYT (SEQ ID NO: 9), ii) un anticuerpo humanizado o un fragmento de unión al antígeno del mismo que se une específicamente al receptor 1 de folato humano que comprende el dominio variable de la cadena pesada de SEQ ID NO: 4 y el dominio variable de la cadena ligera de SEQ ID NO: o SEQ ID NO: 11, iii) un anticuerpo humanizado o un fragmento de unión al antígeno del mismo que se une específicamente al receptor 1 de folato humano que comprende la cadena pesada de SEQ ID NO: 6 y la cadena ligera de SEQ ID NO: 12 o 13, o iv) un anticuerpo humanizado o un fragmento de unión al antígeno del mismo que comprende una cadena pesada codificada por el ADN plasmídico depositado en la ATCC el 7 de abril de 2010 y que tiene el depósito en ATCC n.º PTA-10772 y una cadena ligera codificada por el ADN plasmídico depositado en la ATCC el 7 de abril de 2010 y que tiene el depósito en ATCC n.º PTA-10773 o 10774.

Description

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inmunoglobulina humana. Ejemplos de procedimientos usados para generar anticuerpos humanizados se describen en las patentes de EE.UU. 5.225.539 o 5.639.641.
Una "región variable" de un anticuerpo se refiere a la región variable de la cadena ligera del anticuerpo o a la región variable de la cadena pesada del anticuerpo, solo o en combinación. Las regiones variables de las cadenas pesada y ligera constan cada una de cuatro regiones marco (FR) conectadas por tres regiones determinantes de complementariedad (CDR) también conocidas como regiones hipervariables. Las CDR de cada cadena se mantienen unidas en estrecha proximidad por las FR y, con las CDR de la otra cadena, contribuyen a la formación del sitio de los anticuerpos de unión al antígeno. Existen al menos dos técnicas para determinar las CDR: (1) un enfoque basado en la variabilidad de la secuencia de especies cruzadas (es decir, Kabat et al., Sequences of Proteins of Immunological Interest, (5ª ed., 1991, National Institutes of Health, Bethesda Md.)); y (2) un enfoque basado en estudios cristalográficos de complejos antígeno-anticuerpo (Al-lazikani et al. (1997) J. Molec. Biol. 273: 927-948)). Además, a veces se utilizan en la técnica combinaciones de estos dos enfoques para determinar las CDR.
El sistema de numeración Kabat se utiliza generalmente cuando se hace referencia a un resto en el dominio variable (aproximadamente restos 1-107 de la cadena ligera y restos 1-113 de la cadena pesada) (p. ej., Kabat et al., Sequences of Immunological Interest, 5º Ed., Public Health Service, National Institutes of Health, Bethesda, Md. (1991).
La numeración de la posición de los aminoácidos como en Kabat, se refiere al sistema de numeración utilizado para dominios variables de cadena pesada o dominios variables de cadena ligera de la compilación de anticuerpos en Kabat et al., Sequences of Proteins of Immunological Interest, 5ª Ed., Public Health Service, National Institutes of Health, Bethesda, Md. (1991). Utilizando este sistema de numeración, la secuencia de aminoácidos lineal real puede contener menos o adicionales aminoácidos que corresponden a un acortamiento de, o inserción en, una FR o CDR del dominio variable. Por ejemplo, un dominio variable de la cadena pesada puede incluir un único inserto de aminoácido (resto 52a según Kabat) después del resto 52 de H2 y restos insertados (p. ej., restos 82a, 82b y 82c, etc., según Kabat) después de resto 82 de la FR de cadena pesada. La numeración de Kabat de restos puede determinarse para un anticuerpo dado por alineamiento en regiones de homología de la secuencia del anticuerpo con una secuencia numerada Kabat “estándar”. Chothia se refiere en cambio a la localización de los bucles estructurales (Chothia y Lesk J. Mol. Biol. 196: 901-917 (1987)). El final del bucle CDR-H1 de Chothia cuando se numeran usando la convención de numeración de Kabat varía entre H32 y H34 dependiendo de la longitud del bucle (esto se debe a que el esquema de numeración de Kabat coloca las inserciones en H35A y H35B, si ni 35A ni 35B están presentes, el bucle termina en 32, si sólo está presente 35A, el bucle termina en 33, si están presentes tanto 35A como 35B, el bucle termina en 34). Las regiones hipervariables de los AbM representan un compromiso entre las CDR de Kabat y los bucles estructurales de Chothia, y se utilizan por el software de modelado de anticuerpos AbM de Oxford Molecular.
Bucle Kabat AbM Chothia
L1
L24-L34 L24-L34 L24-L34
L2
L50-L56 L50-L56 L50-L56
L3
L89-L97 L89-L97 L89-L97
H1
H31-H35B H26-H35B H26-H32..34
(Numeración de Kabat)
H1 H31-H35 H26-H35 H26-H32 (Numeración de Chothia)
H2 H50-H65 H50-H58 H52-H56 H3 H95-H102 H95-H102 H95-H102
La expresión “anticuerpo humano” significa un anticuerpo producido por un humano o un anticuerpo que tiene una secuencia de aminoácidos correspondiente a un anticuerpo producido por un humano fabricado usando cualquier técnica conocida en la tecnología. Esta definición de anticuerpo humano incluye anticuerpos intactos o de longitud completa, fragmentos de los mismos, y/o anticuerpos que comprenden al menos un polipéptido humano de cadena pesada y/o ligera tal como, por ejemplo, un anticuerpo que comprende polipéptidos de cadena ligera de murino y
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anticuerpos humanizados o fragmentos de unión al antígenos que se unen específicamente a un receptor 1 de folato humano, en donde el anticuerpo comprende: (a) una CDR1 de cadena pesada que comprende TSYTMH o una variante de la misma que comprende 1, 2, 3 o 4 sustituciones conservadas de aminoácidos; y/o una CDR2 de cadena pesada que comprende YINPISGYTN (SEQ ID NO: 79) o una variante de la misma que comprende 1, 2, 3 o 4 sustituciones conservadas de aminoácidos; y/o una CDR3 de cadena pesada que comprende GGAYGRKPMDY (SEQ ID NO: 80) o una variante de la misma que comprende 1, 2, 3 o 4 sustituciones conservadas de aminoácidos; y/o (b) una CDR1 de cadena ligera que comprende KASQNVGPNVA (SEQ ID NO: 75) o una variante de la misma que comprende 1, 2, 3 o 4 sustituciones conservadas de aminoácidos; y/o una CDR2 de cadena ligera que comprende SASYRYS (SEQ ID NO: 76) o una variante de la misma que comprende 1, 2, 3 o 4 sustituciones conservadas de aminoácidos; y/o una CDR3 de cadena ligera que comprende QQYNSYPYT (SEQ ID NO: 77) o una variante de la misma que comprende 1, 2, 3 o 4 sustituciones conservadas de aminoácidos.
Los polipéptidos que comprenden una de las cadenas ligeras o cadenas pesadas individuales descritas en el presente documento, así como los polipéptidos (p. ej., anticuerpos) que comprenden tanto una cadena ligera como una cadena pesada, también se proporcionan en forma de inmunoconjugados. Los polipéptidos de SEQ ID NO: 4 y 6 comprenden el dominio variable de la cadena pesada de huMov19, y la cadena pesada de huMov19, respectivamente. Los polipéptidos de SEQ ID NO: 10-13 comprenden la versión 1.00 de cadena ligera de dominio variable, la versión 1.60 de cadena ligera de dominio variable, la versión 1.00 de cadena ligera y la versión 1.60 de cadena ligera de huMov19, respectivamente. Los polipéptidos de las SEQ ID NO: 42 y 46 comprenden el dominio variable de la cadena pesada de huFR1-21 y la cadena pesada de huFR1-21, respectivamente. Los polipéptidos de las SEQ ID NO: 41 y 45 comprenden la cadena ligera del dominio variable y la cadena ligera de huFR1-21, respectivamente. Los polipéptidos de SEQ ID NO: 97 y 113 comprenden el dominio variable de la cadena pesada de huFR1-48 y la cadena pesada de huFR1-48, respectivamente. Los polipéptidos de SEQ ID NO: 96 y 112 comprenden la cadena ligera de dominio variable y la cadena ligera de huFR1-48, respectivamente. Los polipéptidos de las SEQ ID NO: 99 y 115 comprenden el dominio variable de la cadena pesada de huFR1-49 y la cadena pesada de huFR1-49, respectivamente. Los polipéptidos de SEQ ID NO: 98 y 114 comprenden la cadena ligera de dominio variable y la cadena ligera de huFR1-49, respectivamente. Los polipéptidos de las SEQ ID NO: 101 y 117 comprenden el dominio variable de la cadena pesada de huFR1-57 y la cadena pesada de huFR1-57, respectivamente. Los polipéptidos de las SEQ ID NO: 100 y 116 comprenden la cadena ligera de dominio variable y la cadena ligera de huFR1-57, respectivamente. Los polipéptidos de SEQ ID NO: 103 y 119 comprenden el dominio variable de la cadena pesada de huFR1-65 y la cadena pesada de huFR1-65, respectivamente. Los polipéptidos de SEQ ID NO: 102 y 118 comprenden la cadena ligera de dominio variable y la cadena ligera de huFR1-65, respectivamente.
También se describen polipéptidos que comprenden: (a) un polipéptido que tiene al menos aproximadamente 90% de identidad de secuencia con SEQ ID NO: 4 o 6; y/o (b) un polipéptido que tiene al menos aproximadamente un 90% de identidad de secuencia con las SEQ ID NO: 10-13. También se describen polipéptidos que comprenden: (a) un polipéptido que tiene aproximadamente un 90% de identidad de secuencia con SEQ ID NO: 42 o 46; y/o (b) un polipéptido que tiene al menos aproximadamente 90% de identidad de secuencia con SEQ ID NO: 41 y 45. También se describen polipéptidos que comprenden: (a) un polipéptido que tiene al menos aproximadamente 90% de identidad de secuencia con SEQ ID NO: 97 o 113; y/o (b) un polipéptido que tiene al menos aproximadamente 90% de identidad de secuencia con SEQ ID NO: 96 o 112. También se describen polipéptidos que comprenden: (a) un polipéptido que tiene al menos aproximadamente un 90% de identidad de secuencia con SEQ ID NO: 99 o 115; y/o
(b)
un polipéptido que tiene al menos aproximadamente 90% de identidad de secuencia con SEQ ID NO: 98 o 114. También se describen polipéptidos que comprenden: (a) un polipéptido que tiene al menos aproximadamente un 90% de identidad de secuencia con SEQ ID NO: 101 o 117; y/o (b) un polipéptido que tiene al menos aproximadamente un 90% de identidad de secuencia con SEQ ID NO: 100 o 116. También se describen polipéptidos que comprenden: (a) un polipéptido que tiene al menos aproximadamente un 90% de identidad de secuencia con SEQ ID NO: 103 o 119; y/o (b) un polipéptido que tiene al menos aproximadamente 90% de identidad de secuencia con SEQ ID NO: 102 o 118. El polipéptido puede comprender un apolipéptido que tiene al menos aproximadamente un 95%, al menos aproximadamente un 96%, al menos aproximadamente un 97%, al menos aproximadamente un 98% o al menos aproximadamente un 99% de identidad de secuencia con las SEQ ID NO: 4, 6, 10-13, 41, 42, 45 o 46. Así, el polipéptido puede comprender (a) un polipéptido que tiene al menos aproximadamente 95% De identidad de secuencia con SEQ ID NO: 4 o 6, y/o (b) un polipéptido que tiene al menos aproximadamente 95% de identidad de secuencia con SEQ ID NO: 10-13. El polipéptido puede comprender (a) un polipéptido que tiene al menos aproximadamente 95% de identidad de secuencia con SEQ ID NO: 42 o 46, y/o (b) un polipéptido que tiene al menos aproximadamente 95% de identidad de secuencia con SEQ ID NO: 41 o 45 También se describen polipéptidos que comprenden: (a) un polipéptido que tiene al menos aproximadamente 95% de identidad de secuencia con SEQ ID NO: 97 o 113; y/o (b) un polipéptido que tiene al menos aproximadamente 95% de identidad de secuencia con SEQ ID NO: 96 o 112. También se describen polipéptidos que comprenden: (a) un polipéptido que tiene al menos aproximadamente 95% de identidad de secuencia con SEQ ID NO: 99 o 115; y/o
(b)
un polipéptido que tiene al menos aproximadamente 95% de identidad de secuencia con SEQ ID NO: 98 o 114. También se describen polipéptidos que comprenden: (a) un polipéptido que tiene al menos aproximadamente un 95% de identidad de secuencia con SEQ ID NO: 101 o 117; y/o (b) un polipéptido que tiene al menos aproximadamente 95% de identidad de secuencia con SEQ ID NO: 100 o 116. También se describen polipéptidos que comprenden: (a) un polipéptido que tiene al menos aproximadamente un 95% de identidad de secuencia con
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