ES2588306T3 - Proteínas de unión similares a anticuerpos con regiones variables duales con una orientación de entrecruzamiento de la región de unión - Google Patents

Proteínas de unión similares a anticuerpos con regiones variables duales con una orientación de entrecruzamiento de la región de unión Download PDF

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ES2588306T3
ES2588306T3 ES12716818.5T ES12716818T ES2588306T3 ES 2588306 T3 ES2588306 T3 ES 2588306T3 ES 12716818 T ES12716818 T ES 12716818T ES 2588306 T3 ES2588306 T3 ES 2588306T3
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codv
tnfα
heavy chain
immunoglobulin
amino acid
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Nicolas Baurin
Christian Beil
Carsten Corvey
Christian Lange
Danxi Li
Vincent Mikol
Anke Steinmetz
Ercole Rao
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Sanofi SA
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Abstract

Una proteína de unión similar a anticuerpo que comprende cuatro cadenas polipeptídicas que forman cuatro sitios de unión a antígeno, en donde dos cadenas polipeptídicas tienen una estructura representada por la fórmula: VL1-L1-VL2-L2-CL [I] y dos cadenas polipéptídicas tienen una estructura representada por la fórmula: VH2-L3-VH1-L4-CH1-Fc [II] en donde: VL1 es un primer dominio variable de cadena ligera de inmunoglobulina; VL2 es un segundo dominio variable de cadena ligera de inmunoglobulina; 10 VH1 es un primer dominio variable de cadena pesada de inmunoglobulina; VH2 es un segundo dominio variable de cadena pesada de inmunoglobulina; CL es un dominio constante de la cadena ligera de inmunoglobulina; CH1 es el dominio constante de la cadena pesada CH1 de inmunoglobulina; Fc es la región de bisagra de inmunoglobulina y CH2, CH3 son los dominios constantes de la cadena pesada de inmunoglobulina; L1, L2, L3 y L4 son enlazadores de aminoácidos; en donde: L1 es 3 a 12 residuos aminoácidos de longitud; L2 es 3 a 14 residuos aminoácidos de longitud; L3 es 1 a 8 residuos aminoácidos de longitud; L4 es 1 a 3 residuos aminoácidos de longitud; y en donde los polipéptidos de fórmula I y los polipéptidos de fórmula II forman un par de cadena ligera-cadena pesada de entrecruzamiento.

Description

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entrecruzamiento para adaptarse a la cadena ligera del molde (véase la Figura 5, Panel A). Seguidamente se evaluó si los enlazadores cortos colocados específicamente en la cadena pesada para mantener una disposición de revestimiento en la cadena pesada hicieron que la cadena pesada fuese la cadena "molde", y si el patrón se repetiría y serían necesarios enlazadores más grandes para permitir que la cadena no molde se plegara correctamente y
5 alojara ahora la cadena pesada del molde (véase la Figura 5, Panel B).
La Figura 6 ilustra estos principios de diseño CODV-Ig sobre la base de tener a la cadena ligera o a la cadena pesada como "molde". Para evaluar el carácter genérico de este concepto, se generaron construcciones CODV-Ig con enlazadores de cadena pesada L3 y L4 que varía entre 1 y 8 residuos para L3 y 0 ó 1 residuos para L4. La cadena pesada contenía anti-IL4 como el dominio de unión N-terminal y anti-IL13 como el dominio de unión C
10 terminal seguido de CH1-Fc. Los enlazadores de la cadena ligera L1 y L2 se variaron de 3 a 12 residuos para L1 y de 3 a 14 residuos para L2. La cadena ligera contenía anti-IL13 como el dominio de unión N-terminal y anti-IL4 como el dominio de unión C-terminal seguido de CL1.
La Tabla 8 resume los resultados para el rendimiento, la agregación (tal como se mide por cromatografía de exclusión por tamaño) y la afinidad de unión para CODV-Ig que tienen diferentes combinaciones de tamaños de los 15 enlazadores y en donde la cadena pesada se mantiene en una disposición lineal como la cadena de molde y se permite que la cadena ligera se pliegue en una configuración de entrecruzamiento. Los resultados revelaron que no podían producirse las moléculas de CODV-Ig en las que L4 era generalmente cero, o en los casos en los que se produjo la proteína, había un alto nivel de agregación (similar a las moléculas en las que L2 era igual a cero) (véanse los Lotes de Nºs de ID 207-209, 211-212, 219-224, 231-236, 243-252 y 263-266 en la Tabla 8). Una excepción era el
20 Lote de Nº de ID 210, en el que L1 era 7, L2 era 5, L3 era 2 y L4 era cero. Esta disposición produjo una cantidad suficiente de proteína y tenía un nivel aceptable de la agregación y de unión, lo que sugirió que alguna combinación de los tamaños de enlazador se pudo encontrar para compensar un enlazador de longitud cero en L4 en algunas circunstancias.
Tabla 8. Optimización de los Tamaños de Enlazador con Cadena Pesada como Molde
Lote ID
Alineación sobre HC* L1 L2 L3 L4 Rendimiento [mg/L] Agregación [%] KD (Antigeno1) IL4 [pM] KD (Antigeno2) IL13 [pM]
201
IL4 x IL13 5 3 1 2 6,3 12 4 72
202
IL4 x IL13 5 5 1 2 10,5 7,0 9 54
203
IL4 x IL13 7 3 1 2 19,3 9,4 80 46
204
IL4 x IL13 7 5 1 2 15,3 5,2 3 25
205
IL4 x IL13 10 3 1 2 4,7 4,0 8 58
206
IL4 x IL13 10 5 1 2 9,1 3,9 4 58
207
IL4 x IL13 5 3 2 0 6,7 25,3 3 33
208
IL4 x IL13 5 5 2 0 10,2 18,4 10 77
209
IL4 x IL13 7 3 2 0 16,2 22,2 5 47
210
IL4 x IL13 7 5 2 0 14,7 9,7 4 47
211
IL4 x IL13 10 3 2 0 2,1 12,8 7 53
212
IL4 x IL13 10 5 2 0 7,0 36,3 10 29
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Lote ID
Alineación sobre HC* L1 L2 L3 L4 Rendimiento [mg/L] Agregación [%] KD (Antigeno1) IL4 [pM] KD (Antigeno2) IL13 [pM]
257
IL4 x IL13 6 10 6 2 1,9 29,8 7 30
258
IL4 x IL13 6 14 6 2 2,5 24,6 5 70
259
IL4 x IL13 10 6 6 2 1,4 16,4 8 71
260
IL4 x IL13 10 8 6 2 0,8 16,6 10 71
261
IL4 x IL13 12 6 6 2 1,2 12,3 5 265
262
IL4 x IL13 12 8 6 2 1,1 13,2 4 111
263
IL4 x IL13 10 6 8 0 2,4 10,8 2 74
264
IL4 x IL13 10 8 8 0 0,8 8,0 7 22
265
IL4 x IL13 12 6 8 0 1,0 9,5 8 66
266
IL4 x IL13 12 8 8 0 2,0 9,3 3 69
267
IL4 x IL13 10 6 8 2 1,4 15,0 9 170
268
IL4 x IL13 10 8 8 2 1,0 12,9 4 52
269
IL4 x IL13 12 6 8 2 1,2 8,8 5 66
270
IL4 x IL13 12 8 8 2 2,4 11,7 3 72
* La alineación en la cadena ligera debe ser IL13VL-L1-IL4VL-L2-CL1
Los resultados de las Tablas 7 y 8 demuestran claramente que se requieren enlazadores entre los dominios variables y constantes para permitir un plegamiento óptimo. Sólo en raras disposiciones se toleró un enlazador igual a cero (véanse los Lotes de Nºs de ID 103 a 105, en donde L1 (LC) era cero, y el Lote Nº 210, en que L4 era cero).
5 Sin embargo, en cada caso, el enlazador de transición correspondiente entre la región variable y la región constante en la otra cadena podría no ser cero.
Los resultados anteriores indicaron que las combinaciones de L1 = 7, L2 = 5, L3 = 1 y L4 = 2 eran un buen punto de partida para la optimización de un nuevo CODV-Ig en el que la cadena pesada es el molde. Los intervalos en la Tabla 9 demostraron ser intervalos razonables para la modificación por ingeniería con éxito un nuevo CODV-Ig a
10 partir de dos anticuerpos parentales.
Tabla 9. Intervalos de Tamaños de Enlazador para cada LC o HC como Molde Ejemplo 8. Aplicabilidad Universal de Formato CODV-Ig
Enlazador
imagen41 LC como Molde HC como Molde
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imagen43 Intervalo Máx. Intervalo Mín. Intervalo Máx. Intervalo Mín.
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Enlazador
LC como Molde HC como Molde
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Intervalo Máx. Intervalo Mín. Intervalo Máx. Intervalo Mín.
L1
1-3 1-2 3-12 5-10
L2
1-4 1-2 3-14 5-8
L3
2-15 4-12 1-8 1-5
L4
2-15 2-12 1-3 1-2
Para evaluar la idoneidad del formato CODV-Ig para la ingeniería de nuevas proteínas de unión similares a anticuerpos de las regiones variables de numerosos anticuerpos humanos y humanizados existentes que tienen
5 especificidad para el receptor del factor de crecimiento similar a la insulina 1 (IGF1R(1)), un segundo receptor del factor de crecimiento similar a la insulina 1 (IGF1R(2)), receptor 2 de factor de crecimiento epidérmico humano (HER2), receptor del factor de crecimiento epidérmico (EGFR), factor de necrosis tumoral - alfa (TNFα), interleuquinas 12 y 23 (IL-12/23) e interleuquina 1beta (IL-1β) se incorporaron en el formato CODV-Ig (véase la Tabla 10).
10 Tabla 10. Códigos Descriptivos para Cadenas Pesadas y Ligeras utilizados en CODV-Ig Biespecífico
Código*
Cadenas Pesadas (extremos N a C) SEQ ID NO:
HC10
IGF1R(1) VH -(Gly)-HER2 VH -(Gly2)-CH1-Fc 32
HC11
HER2 VH -(Glv)- IGF1R(1) VH -(Gly2)-CH1-Fc 33
HC12
IGF1R(2) VH -(Gly)-EGFR VH -(Gly2)-CH1-Fc 34
HC13
EGFR VH -(Gly)- IGF1R(2) VH -(Gly2)- CH1-Fc 35
HC14
TNFα VH -(Gly)-IL12/23 VH -(Gly2)- CH1-Fc 36
HC15
IL12/23 VH -(Gly)-TNFα VH -(Gly2)- CH1-Fc 37
HC16
TNFα VH-(Gly)-IL1β VH-(Gly2)-CH1-Fc 38
HC17
IL1β VH -(Gly)-TNFα VH -(Gly2)- CH1-Fc 39
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imagen48 imagen49
Código*
Cadenas Ligeras (extremos N a C) imagen50
LC10
HER2 VL-(Gly7)-IGF1R(1) VL -(Gly5)-CL1 40
LC11
IGF1R(1) VL -(Gly7)- HER2 VL-(Gly5)- CL1 41
imagen51
=
imagen52
imagen53
imagen54
Tabla 11. Uso Universal de Formato CODV-Ig para Proteínas de Unión similares a Anticuerpos Biespecíficas
Lote ID DC/LC Códigos1
Alineación sobre HC L1 L2 L3 L4 Rendimiento [mg/L] Agregación [%] KD (Antígeno 1) [pM] KD (Antígeno 2) [pM] IC50 [pM] TNFα Ensayo Celular
301 HC10/LC10
IGF1R(1) x HER2 7 5 1 2 70 5,9 n.m. 153 (HER2) -
302 HC11/LC11
HER2 x IGF1R(1) 7 5 1 2 60 1,8 163 (HER2) n.m. -
303 HC12/LC12
IGF1R(2) x EGFR 7 5 1 2 17 2,7 n.m. - -
304 HC13/LC13
EGFR x IGF1R(2) 7 5 1 2 9,5 4,3 - n.m. -
305 HC14/LC14
TNFα x IL12/23 7 5 1 2 7,1 7,5 321 (TNFα) 65 (IL23) 95
306 HC15/LC15
IL12/23 x TNFα 7 5 1 2 11,9 7,1 118 (IL23) 543 (TNFα) 138
307 HC16/LC16
TNFα x IL1β 7 5 1 2 6,6 13,6 340 (TNFα) 155 (IL1β) 136
308 HC17/LC17
IL1β x TNFα 7 5 1 2 2,4 5,7 97,5 (IL1β) 358 (TNFα) 138
*n.m.= no medibles por Biacore 1 – La cadena pesada y las cadenas ligeras correspondientes a los códigos pueden encontrarse en la Tabla 10.
imagen55
imagen56
Tabla 12. Uso del Formato CODV-Ig para Fragmentos similares a Fab
imagen57
Lote ID
Muestra-ID Formato L1 L2 L3 L4 Rendimiento [mg/L] Agregación [%] KD (Antígeno 1) [pM] KD (Antígeno 2) [pM] IC50 [pM] TNFα Ensayo Celular
401
TNFα x IL12/23 CODV-Ig 7 5 1 2 7,1 7,5 321 (TNFα) 90 (IL23) 95
402
IL12/23 x TNFα CODV-Ig 7 5 1 2 11,9 7,1 118 (IL23) 543 (TNFα) 138
403
TNFα x IL12/23 CODV-Fab 7 5 1 2 18,7 1,7 232 (TNFα) 41 (IL23) 785
404
TNFα x IL12/23 TBTI (G4S)2 0 (G4S)2 0 26,0 8,7 219 (TNFα) 399 (IL23) -
405
TNFα x IL12/23 CODV-Ig 0 0 0 0 3,5 71 - - -
406
IL1β x TNFα CODV-Ig 7 5 1 2 2,4 5,7 98 (IL1β) 358 (TNFα) 139
407
TNFα x IL1β CODV-Ig 7 5 1 2 6,6 13,6 340 (TNFα) 155 (IL1β) 122
408
IL1β x TNFα CODV-Fab 7 5 1 2 8,6 0 179 (IL1β) - -
409
IL1β x TNFα TBTI (G4S)2 0 (G4S)2 0 1,3 40,5 133 (IL1β) 456 (TNFα) -
410
TNFα x IL1β CODV-Ig 0 0 0 0 n,p. - - - -
411
EGFR x IGF1R(2) CODV-Ig 7 5 1 2 9,5 4,3 124nM (EGFR) n.m. -
412
IGF1R(2) x EGFR CODV-Ig 7 5 1 2 17 2,7 n.m. - -
413
EGFR x IGF1R(2) CODV-Fab 7 5 1 2 13,3 0 42nM (EGFR) n.m. -
414
EGFR x IGF1R(2) TBTI (G4S)2 0 (G4S)2 0 2,1 2,9 7nM (EGFR) n.m. -
415
EGFR x IGF1R(2) CODV-Ig 0 0 0 0 4,4 100 - - -
416
HER2 x IGF1R(1) CODV-Ig 7 5 1 2 60,0 1,8 163 (HER2) n.m. -
417
IGF1R(1) x HER2 CODV-Ig 7 5 1 2 70 5,9 n.m. 41 (HER2) -
418
HER2 x CODV-Fab 7 5 1 2 34,4 0 190 (HER2) n.m. -
imagen58
imagen59
Tabla 13. Efecto de la Composición del Enlazador sobre CODV-Ig
imagen60
Lote ID
Alineación sobre HC L1 L2 L3 L4 Rendimiento [mg/L] Agregación [%] KD (IL4) [pM] KD (IL13) [pM] IC50 Ensayo Celular IL4 [nM] IC50 Ensayo Celular IL13 [nM]
501
IL4 x IL13 ASTKGPS (SEQ ID NO: 48) TKGPS (SEQ ID NO: 52) S RT 10,8 1,2 1 55 0,034 4,5
502
IL4 x IL13 ASTKGPS (SEQ ID NO: 48) TVAAP (SEQ ID NO: 53) S QP 15,8 2,9 3 61 0,049 2,4
503
IL4 x IL13 ASTKGPS (SEQ ID NO: 48) TVAAP (SEQ ID NO: 53) S SS 11,6 3,5 3 52 0,047 2,1
504
IL4 x IL13 RTVAAPS (SEQ ID NO: 49) QPKAA (SEQ ID NO: 54) S TK 15 1,9 8 71 0,042 1,4
505
IL4 x IL13 GQPKAAP (SEQ ID NO: 50) TKGPS (SEQ ID NO: 52) S RT 71,7 1,9 6 68 0,033 0,9
506
IL4 x IL13 GQPKAAP (SEQ ID NO: 50) TVAAP (SEQ ID NO: 53) S TK 49,3 1,7 7 55 0,045 1,8
507
IL4 x IL13 GQPKAAP (SEQ ID NO: 50) QPKAA (SEQ ID NO: 54) S RT 62,4 2 1 69 0,040 2,0
508
IL4 x IL13 HIDSPNK (SEQ ID NO: 51) QRIEG (SEQ ID NO: 55) V SL 37,7 2,1 1 44 0,054 1.3
imagen61
imagen62
Tabla 14. Efecto de la Estabilización del Puente Disulfuro sobre CODV-Ig
Lote ID
Alineación sobre HC Mutaciones Introducidas IGHG1 L1 L2 L3 L4 Rendimiento [mg/L] Agregación [%] KD (IL4) [pM] KD (IL13) [pM] IC50 Ensayo Celular IL4 [nM] IC50 Ensayo Celular IL13 [nM] Tm [°C]
601
IL4 x IL13 P344C & A432C 7 5 1 2 21,6 0,9 n.d. n.d. 0,032 1,7 64
602
IL4 x IL13 S376C & P397C 7 5 1 2 13,9 0,8 10 100 0,034 1.5 64
603
IL4 x IL13 P446G447 to G446E447C448 7 5 1 2 15,7 1,3 4 64 0,036 1.4 64
Tabla 15. Efecto de la Estabilización del Puente Disulfuro sobre CODV-Ig
imagen63
Lote ID
Alineación sobre HC Formato Mutaciones Introducidas LC Mutaciones Introducidas HC L1 L2 L3 L4 Rendimiento [mg/L] Agregación [%] KD (Antígeno 1) [pM] KD (Antígeno 2) [pM] Tm [°C]
704
IL13 x IL4 CODV - - 7 5 1 2 15,3 5,2 3 25 64
706
IL4 x IL13 CODV G100C & G100C G44C & G44C 7 5 1 2 3,2 17,7 8 61 68
713
IGF1R(1) x HER2 CODV-Ig - - 7 5 1 2 60 1,8 163 (HER2) - 64
714
IGF1R(1) x HER2 CODV-Ig G100C & Q100C G44C & G44C 7 5 1 2 3,4 7,9 362 (HER2) - 68
Tabla 16A. Efecto de la Estabilización del Puente Disulfuro sobre CODV-Ig
imagen64
-
-
-
-
imagen65
-

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