ES2620255T3 - Anticuerpos para el receptor del factor de crecimiento epidérmico 3 (HER3) - Google Patents

Anticuerpos para el receptor del factor de crecimiento epidérmico 3 (HER3) Download PDF

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ES2620255T3
ES2620255T3 ES11746252.3T ES11746252T ES2620255T3 ES 2620255 T3 ES2620255 T3 ES 2620255T3 ES 11746252 T ES11746252 T ES 11746252T ES 2620255 T3 ES2620255 T3 ES 2620255T3
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kabat
chothia
her3
mor10703
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Winfried Elis
Seth Ettenberg
Andrew Paul Garner
Nicole Haubst
Christian Carsten Silvester Kunz
Elizabeth Anne Reisinger Sprague
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Novartis AG
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Abstract

Un anticuerpo aislado o un fragmento del mismo que reconoce un epítopo conformacional de un receptor HER3, en donde el epítopo conformacional comprende residuos de aminoácidos 265-377, 315 dentro del dominio 2 y residuos de aminoácidos 571, 582-584, 596-597, 600-602, 609-615 dentro del dominio 4 del receptor HER3 de SEQ ID NO:1, y en donde el anticuerpo o el fragmento del mismo bloquea la transducción de señales tanto dependiente del ligando como independiente del ligando de HER3.

Description

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anticuerpos un dominio VL que tiene una secuencia de aminoácidos de las SEQ ID NOs: 14, 32, 50, 68, 86, 104, 122, 140, 158, 176, 194, 212, 230, 248, 266, 284, 302, 320, 338, 356, y 374. La presente divulgación también proporciona anticuerpos que se enlazan específicamente con la proteína de HER3 (por ejemplo, HER3 humano y/o de cinomolgo), comprendiendo estos anticuerpos una VH CDR que tiene una secuencia de
5 aminoácidos de cualquiera de las VH CDRs enlistadas en la Tabla 1 más adelante. En particular, la divulgación proporciona anticuerpos que se enlazan específicamente a la proteína de HER3 (por ejemplo, HER3 humano y/o de cinomolgo), comprendiendo estos anticuerpos (o de una manera alternativa, consistiendo en) una, dos, tres, cuatro, cinco o más VH CDRs que tienen una secuencia de aminoácidos de cualquiera de las VH CDRs enlistadas en la Tabla 1 más adelante.
10 Otros anticuerpos de la divulgación incluyen aminoácidos que se han mutado, y no obstante tienen cuando menos el 60, 70, 80, 90, 95, o 98 % de identidad en las regiones CDR con las regiones CDR ilustradas en las secuencias descritas en la Tabla 1. En algunas realizaciones, incluye secuencias de aminoácidos mutantes en donde no más de 1, 2, 3, 4 o 5 aminoácidos han sido mutados en las regiones CDR, cuando se comparan con las regiones CDR ilustradas en la secuencia descrita en la Tabla 1, mientras que todavía mantienen su
15 especificidad por el epítopo del anticuerpo original.
Otros anticuerpos de la divulgación incluyen aminoácidos que se han mutado, y no obstante tienen cuando menos el 60, 70, 80, 90, 95, o 98 % de identidad en las regiones de estructura con las regiones de estructura ilustradas en las secuencias descritas en la Tabla 1. En algunas realizaciones, incluye secuencias de aminoácidos mutantes en donde no más de 1, 2, 3, 4, 5, 6, o 7 aminoácidos se han mutado en las regiones de
20 estructura, cuando se comparan con las regiones de estructura ilustradas en la secuencia descrita en la Tabla 1, mientras que todavía mantienen su especificidad por el epítopo del anticuerpo original. La presente divulgación también proporciona secuencias de ácidos nucleicos que codifican VH, VL, la cadena pesada de longitud completa, y la cadena ligera de longitud completa de los anticuerpos que se enlazan específicamente a la proteína de HER3 (por ejemplo, HER3 humano y/o de cinomolgo).
25 Los anticuerpos de HER3 de la divulgación se enlazan al epítopo conformacional de HER3, el cual comprende los residuos de aminoácidos a partir del dominio 2 y del dominio 4 de HER3.
Tabla 1
Ejemplos de anticuerpos HER3 de la presente divulgación
SEQ ID NO:
Región Ab
MOR09823
SEQ ID NO: 2 (Kabat)
HCDR1 SYAMS
SEQ ID NO: 3 (Kabat)
HCDR2 VTGAVGRTYYPDSVKG
SEQ ID NO: 4 (Kabat)
HCDR3 WGDEGFDI
SEQ ID NO: 5 (Kabat)
LCDR1 RASQGISNWLA
SEQ ID NO: 6 (Kabat)
LCDR2 GASSLQS
SEQ ID NO: 7 (Kabat)
LCDR3 QQYSSFPTT
SEQ ID NO: 8 (Chothia)
HCDR1 GFTFSSY
SEQ ID NO: 9 (Chothia)
HCDR2 GAVGR
SEQIDNO: 10 (Chothia)
HCDR3 WGDEGFDI
SEQ ID NO:
Región Ab
SEQIDNO: 11 (Chothia)
LCDR1 SQGISNW
SEQIDNO: 12 (Chothia)
LCDR2 GAS
SEQ ID NO: (Chothia) 13
LCDR3 YSSFPT
SEQ ID NO: 14
VL imagen26
MOR09823
SEQ ID NO: 15
VH imagen27
imagen28
SEQ ID NO: 16
ADN VL imagen29
SEQ ID NO: 17
ADN VH imagen30
SEQ ID NO: 18
Ligera Kappa imagen31
SEQ ID NO: 19
Pesada IgG1 imagen32
MOR09824
SEQIDNO: 20 (Kabat)
HCDR1 SYAMS
SEQIDNO: 21 (Kabat)
HCDR2 VISAWGHVKYYADSVKG
SEQIDNO: 22 (Kabat)
HCDR3 WGDEGFDI
SEQIDNO: 23 (Kabat)
LCDR1 RASQGISNWLA
SEQIDNO: 24 (Kabat)
LCDR2 GASSLQS
SEQ ID NO:
Región Ab
SEQIDNO: 25 (Kabat)
LCDR3 QQYSSFPTT
SEQIDNO: 26 (Chothia)
HCDR1 GFTFSSY
SEQIDNO: 27 (Chothia)
HCDR2 SAWGHV
SEQIDNO: 28 (Chothia)
HCDR3 WGDEGFDI
MOR09824
SEQIDNO: 29 (Chothia)
LCDR1 SQGISNW
SEQIDNO: 30 (Chothia)
LCDR2 GAS
SEQIDNO: 31 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 32
VL imagen33
SEQ ID NO: 33
VH imagen34
SEQ ID NO: 34
ADN VL imagen35
SEQ ID NO: 35
ADN VH imagen36
SEQ ID NO: 36
Ligera Kappa imagen37
SEQ ID NO: 37
Pesada IgG1 imagen38
imagen39
MOR09825
SEQIDNO: 38 (Kabat)
HCDR1 SYAMS
SEQ ID NO:
Región Ab
SEQIDNO: 39 (Kabat)
HCDR2 AINSQGKSTYYADSVKG
SEQIDNO: 40 (Kabat)
HCDR3 WGDEGFDI
SEQIDNO: 41 (Kabat)
LCDR1 RASQGISNWLA
SEQIDNO: 42 (Kabat)
LCDR2 GASSLQS
MOR09825
SEQIDNO: 43 (Kabat)
LCDR3 QQYSSFPTT
SEQIDNO: 44 (Chothia)
HCDR1 GFTFSSY
SEQIDNO: 45 (Chothia)
HCDR2 NSQGKS
SEQIDNO: 46 (Chothia)
HCDR3 WGDEGFDI
SEQIDNO: 47 (Chothia)
LCDR1 SQGISNW
SEQIDNO: 48 (Chothia)
LCDR2 GAS
SEQIDNO: 49 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 50
VL imagen40
SEQ ID NO: 51
VH imagen41
SEQ ID NO: 52
ADN VL imagen42
SEQ ID NO: 53
ADN VH imagen43
SEQ ID NO: 54
Ligera Kappa imagen44
SEQ ID NO:
Región Ab
SEQ ID NO: 55
Pesada IgG1 imagen45
MOR09974
SEQIDNO: 56 (Kabat)
HCDR1 SYAMS
MOR09974
SEQIDNO: 57 (Kabat)
HCDR2 VINPSGNFTNYADSVKG
SEQIDNO: 58 (Kabat)
HCDR3 WGDEGFDI
SEQIDNO: 59 (Kabat)
LCDR1 RASQGISNWLA
SEQIDNO: 60 (Kabat)
LCDR2 GASSLQS
SEQIDNO: 61 (Kabat)
LCDR3 QQYSSFPTT
SEQIDNO: 62 (Chothia)
HCDR1 GFTFSSY
SEQIDNO: 63 (Chothia)
HCDR2 NPSGNF
SEQIDNO: 64 (Chothia)
HCDR3 WGDEGFDI
SEQIDNO: 65 (Chothia)
LCDR1 SQGISNW
SEQIDNO: 66 (Chothia)
LCDR2 GAS
SEQID NO: 67 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 68
VL imagen46
SEQ ID NO: 69
VH imagen47
SEQ ID NO: 70
ADN VL imagen48
SEQ ID NO:
Región Ab
SEQ ID NO: 71
ADN VH imagen49
SEQ ID NO: 72
Ligera Kappa imagen50
MOR09974
SEQ ID NO: 73
Pesada IgG1 imagen51
MOR10452
SEQIDNO: 74 (Kabat)
HCDR1 SYAMS
SEQIDNO: 75 (Kabat)
HCDR2 NTSPIGYTYYAGSVKG
SEQIDNO: 76 (Kabat)
HCDR3 WGDEGFDI
SEQIDNO: 77 (Kabat)
LCDR1 RASQGISNWLA
SEQIDNO: 78 (Kabat)
LCDR2 GASSLQS
SEQIDNO: 79 (Kabat)
LCDR3 QQYSSFPTT
SEQIDNO: 80 (Chothia)
HCDR1 GFTFSSY
SEQIDNO: 81 (Chothia)
HCDR2 SPIGY
SEQIDNO: 82 (Chothia)
HCDR3 WGDEGFDI
SEQIDNO: 83 (Chothia)
LCDR1 SQGISNW
SEQIDNO: 84 (Chothia)
LCDR2 GAS
SEQIDNO: 85 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 86
VL imagen52
SEQ ID NO:
Región Ab
SEQ ID NO: 87
VH imagen53
SEQ ID NO: 88
ADN VL imagen54
MOR10452
SEQ ID NO: 89
ADN VH imagen55
SEQ ID NO: 90
Ligera Kappa imagen56
imagen57
SEQ ID NO: 91
Pesada Chain (only VH and CH1 domains) imagen58
MOR10701
SEQIDNO: 92 (Kabat)
HCDR1 SYAMS
SEQIDNO: 93 (Kabat)
HCDR2 VTGAVGRSTYYPDSVKG
SEQIDNO: 94 (Kabat)
HCDR3 WGDEGFDI
SEQIDNO: 95 (Kabat)
LCDR1 RASQGISNWLA
SEQIDNO: 96 (Kabat)
LCDR2 GASSLQS
SEQIDNO: 97 (Kabat)
LCDR3 QQYSSFPTT
SEQIDNO: 98 (Chothia)
HCDR1 GFTFSSY
SEQIDNO: 99 (Chothia)
HCDR2 GAVGRS
SEQ ID NO: 100 (Chothia)
HCDR3 WGDEGFDI
SEQ ID NO: 101 (Chothia)
LCDR1 SQGISNW
SEQ ID NO: 102 (Chothia)
LCDR2 GAS
SEQ ID NO:
Región Ab
SEQ ID NO: 103 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 104
VL imagen59
SEQ ID NO: 105
VH imagen60
MOR10701
SEQ ID NO: 106
ADN VL imagen61
SEQ ID NO: 107
ADN VH imagen62
SEQ ID NO: 108
Ligera Kappa imagen63
SEQ ID NO: 109
Pesada IgG1 imagen64
MOR10702
SEQ ID NO: 110 (Kabat)
HCDR1 SYAMS
SEQ ID NO: 111 (Kabat)
HCDR2 VISAWGHVKYYADSVKG
SEQ ID NO: 112 (Kabat)
HCDR3 WGDEGFDI
SEQ ID NO: 113 (Kabat)
LCDR1 RASQGISNWLA
SEQ ID NO: 114 (Kabat)
LCDR2 GASSLQS
SEQ ID NO: 115 (Kabat)
LCDR3 QQYSSFPTT
SEQ ID NO: 116 (Chothia)
HCDR1 GFTFSSY
SEQ ID NO: 117 (Chothia)
HCDR2 SAWGHV
SEQ ID NO:
Región Ab
SEQ ID NO: 118 (Chothia)
HCDR3 WGDEGFDI
SEQ ID NO: 119 (Chothia)
LCDR1 SQGISNW
SEQ ID NO: 120 (Chothia)
LCDR2 GAS
SEQ ID NO: 121 (Chothia)
LCDR3 YSSFPT
MOR10702
SEQ ID NO: 122
VL imagen65
SEQ ID NO: 123
VH imagen66
SEQ ID NO: 124
ADN VL imagen67
SEQ ID NO: 125
ADN VH imagen68
SEQ ID NO: 126
Ligera Kappa imagen69
SEQ ID NO: 127
Pesada IgG1 imagen70
MOR10703
SEQ ID NO: 128 (Kabat)
HCDR1 SYAMS
SEQ ID NO: 129 (Kabat)
HCDR2 AINSQGKSTYYADSVKG
SEQ ID NO: 130 (Kabat)
HCDR3 WGDEGFDI
SEQ ID NO: 131 (Kabat)
LCDR1 RASQGISNWLA
SEQ ID NO:
Región Ab
SEQ ID NO: 132 (Kabat)
LCDR2 GASSLQS
SEQ ID NO: 133 (Kabat)
LCDR3 QQYSSFPTT
SEQ ID NO: 134 (Chothia)
HCDR1 GFTFSSY
SEQ ID NO: 135 (Chothia)
HCDR2 NSQGKS
SEQ ID NO: 136 (Chothia)
HCDR3 WGDEGFDI
MOR10703
SEQ ID NO: 137 (Chothia)
LCDR1 SQGISNW
SEQ ID NO: 138 (Chothia)
LCDR2 GAS
SEQ ID NO: 139 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 140
VL imagen65
SEQ ID NO: 141
VH imagen71
SEQ ID NO: 142
ADN VL imagen67
SEQ ID NO: 143
ADN VH imagen72
SEQ ID NO: 144
Ligera Kappa imagen73
imagen74
SEQ ID NO: 145
Pesada IgG1 imagen75
MOR10703 N52S
SEQ ID NO:
Región Ab
SEQ ID NO: 146 (Kabat)
HCDR1 SYAMS
SEQ ID NO: 147 (Kabat)
HCDR2 AISSQGKSTYYADSVKG
SEQ ID NO: 148 (Kabat)
HCDR3 WGDEGFDI
SEQ ID NO: 149 (Kabat)
LCDR1 RASQGISNWLA
SEQ ID NO: 150 (Kabat)
LCDR2 GASSLQS
MOR10703 N52S
SEQ ID NO: 151 (Kabat)
LCDR3 QQYSSFPTT
SEQ ID NO: 152 (Chothia)
HCDR1 GFTFSSY
SEQ ID NO: 153 (Chothia)
HCDR2 SSQGKS
SEQ ID NO: 154 (Chothia)
HCDR3 WGDEGFDI
SEQ ID NO: 155 (Chothia)
LCDR1 SQGISNW
SEQ ID NO: 156 (Chothia)
LCDR2 GAS
SEQ ID NO: 157 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 158
VL imagen76
SEQ ID NO: 159
VH imagen77
SEQ ID NO: 160
DNA VL imagen78
SEQ ID NO: 161
DNA VH imagen79
SEQ ID NO: 162
Light Kappa imagen80
SEQ ID NO:
Región Ab
SEQ ID NO: 163
Heavy IgG1 imagen81
MOR10703 N52G
SEQ ID NO: 164 (Kabat)
HCDR1 SYAMS
SEQ ID NO: 165 (Kabat)
HCDR2 AIGSQGKSTYYADSVKG
MOR10703 N52G
SEQ ID NO: 166 (Kabat)
HCDR3 WGDEGFDI
SEQ ID NO: 167 (Kabat)
LCDR1 RASQGISNWLA
SEQ ID NO: 168 (Kabat)
LCDR2 GASSLQS
SEQ ID NO: 169 (Kabat)
LCDR3 QQYSSFPTT
SEQ ID NO: 170 (Chothia)
HCDR1 GFTFSSY
SEQ ID NO: 171 (Chothia)
HCDR2 GSQGKS
SEQ ID NO: 172 (Chothia)
HCDR3 WGDEGFDI
SEQ ID NO: 173 (Chothia)
LCDR1 SQGISNW
SEQ ID NO: 174 (Chothia)
LCDR2 GAS
SEQ ID NO: 175 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 176
VL imagen76
SEQ ID NO: 177
VH imagen82
SEQ ID NO: 178
DNA VL imagen61
SEQ ID NO:
Región Ab
SEQ ID NO: 179
DNA VH imagen83
SEQ ID NO: 180
Light Kappa imagen84
SEQ ID NO: 181
Heavy IgG1 imagen85
MOR10703 N52S_S52aN
SEQ ID NO: 182 (Kabat)
HCDR1 SYAMS
SEQ ID NO: 183 (Kabat)
HCDR2 AISNQGKSTYYADSVKG
SEQ ID NO: 184 (Kabat)
HCDR3 WGDEGFDI
SEQ ID NO: 185 (Kabat)
LCDR1 RASQGISNWLA
SEQ ID NO: 186 (Kabat)
LCDR2 GASSLQS
SEQ ID NO: 187 (Kabat)
LCDR3 QQYSSFPTT
SEQ ID NO: 188 (Chothia)
HCDR1 GFTFSSY
SEQ ID NO: 189 (Chothia)
HCDR2 SNQGKS
SEQ ID NO: 190 (Chothia)
HCDR3 WGDEGFDI
SEQ ID NO: 191 (Chothia)
LCDR1 SQGISNW
SEQ ID NO: 192 (Chothia)
LCDR2 GAS
SEQ ID NO: 193 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 194
VL imagen86
SEQ ID NO:
Región Ab
SEQ ID NO: 195
VH imagen87
SEQ ID NO: 196
DNA VL imagen88
SEQ ID NO: 197
DNA VH imagen89
SEQ ID NO: 198
Light Kappa imagen90
MOR10703 N52S_S52aN
SEQ ID NO: 199
Heavy IgG1 imagen91
MOR10703 A50V_N52S
SEQ ID NO: 200 (Kabat)
HCDR1 SYAMS
SEQ ID NO: 201 (Kabat)
HCDR2 VISSQGKSTYYADSVKG
SEQ ID NO: 202 (Kabat)
HCDR3 WGDEGFDI
SEQ ID NO: 203 (Kabat)
LCDR1 RASQGISNWLA
SEQ ID NO: 204 (Kabat)
LCDR2 GASSLQS
SEQ ID NO: 205 (Kabat)
LCDR3 QQYSSFPTT
SEQ ID NO: 206 (Chothia)
HCDR1 GFTFSSY
SEQ ID NO: 207 (Chothia)
HCDR2 SSQGKS
SEQ ID NO: 208 (Chothia)
HCDR3 WGDEGFDI
SEQ ID NO:
Región Ab
SEQ ID NO: 209 (Chothia)
LCDR1 SQGISNW
SEQ ID NO: 210 (Chothia)
LCDR2 GAS
SEQ ID NO: 211 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 212
VL imagen28
imagen28
SEQ ID NO: 213
VH imagen92
SEQ ID NO: 214
DNA VL imagen88
MOR10703 A50V_N52S
SEQ ID NO: 215
DNA VH imagen93
SEQ ID NO: 216
Light Kappa imagen94
SEQ ID NO: 217
Heavy IgG1 imagen95
MOR10703 A50V_N52G
SEQ ID NO: 218 (Kabat)
HCDR1 SYAMS
SEQ ID NO: 219 (Kabat)
HCDR2 VIGSQGKSTYYADSVKG
SEQ ID NO: 220 (Kabat)
HCDR3 WGDEGFDI
SEQ ID NO: 221 (Kabat)
LCDR1 RASQGISNWLA
SEQ ID NO: 222 (Kabat)
LCDR2 GASSLQS
SEQ ID NO:
Región Ab
SEQ ID NO: 223 (Kabat)
LCDR3 QQYSSFPTT
SEQ ID NO: 224 (Chothia)
HCDR1 GFTFSSY
SEQ ID NO: 225 (Chothia)
HCDR2 GSQGKS
SEQ ID NO: 226 (Chothia)
HCDR3 WGDEGFDI
SEQ ID NO: 227 (Chothia)
LCDR1 SQGISNW
SEQ ID NO: 228 (Chothia)
LCDR2 GAS
SEQ ID NO: 229 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 230
VL imagen96
MOR10703 A50V_N52G
SEQ ID NO: 231
VH imagen97
SEQ ID NO: 232
DNA VL imagen98
imagen99
SEQ ID NO: 233
DNA VH imagen100
SEQ ID NO: 234
Light Kappa imagen101
SEQ ID NO: 235
Heavy IgG1 imagen102
MOR10703 S52aA
SEQ ID NO: 236 (Kabat)
HCDR1 SYAMS
SEQ ID NO:
Región Ab
SEQ ID NO: 237 (Kabat)
HCDR2 AINAQGKSTYYADSVKG
SEQ ID NO: 238 (Kabat)
HCDR3 WGDEGFDI
SEQ ID NO: 239 (Kabat)
LCDR1 RASQGISNWLA
SEQ ID NO: 240 (Kabat)
LCDR2 GASSLQS
SEQ ID NO: 241 (Kabat)
LCDR3 QQYSSFPTT
SEQ ID NO: 242 (Chothia)
HCDR1 GFTFSSY
SEQ ID NO: 243 (Chothia)
HCDR2 NAQGKS
SEQ ID NO: 244 (Chothia)
HCDR3 WGDEGFDI
MOR10703 S52aA
SEQ ID NO: 245 (Chothia)
LCDR1 SQGISNW
SEQ ID NO: 246 (Chothia)
LCDR2 GAS
SEQ ID NO: 247 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 248
VL imagen76
SEQ ID NO: 249
VH imagen103
SEQ ID NO: 250
DNA VL imagen67
SEQ ID NO: 251
DNA VH imagen104
SEQ ID NO: 252
Light Kappa imagen105
SEQ ID NO:
Región Ab
SEQ ID NO: 253
Heavy IgG1 imagen106
MOR10703 S52aT
SEQ ID NO: 254 (Kabat)
HCDR1 SYAMS
SEQ ID NO: 255 (Kabat)
HCDR2 AINTQGKSTYYADSVKG
SEQ ID NO: 256 (Kabat)
HCDR3 WGDEGFDI
SEQ ID NO: 257 (Kabat)
LCDR1 RASQGISNWLA
SEQ ID NO: 258 (Kabat)
LCDR2 GASSLQS
SEQ ID NO: 259 (Kabat)
LCDR3 QQYSSFPTT
MOR10703 S52aT
SEQ ID NO: 260 (Chothia)
HCDR1 GFTFSSY
SEQ ID NO: 261 (Chothia)
HCDR2 NTQGKS
SEQ ID NO: 262 (Chothia)
HCDR3 WGDEGFDI
SEQ ID NO: 263 (Chothia)
LCDR1 SQGISNW
SEQ ID NO: 264 (Chothia)
LCDR2 GAS
SEQ ID NO: 265 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 266
VL imagen76
SEQ ID NO: 267
VH imagen107
SEQ ID NO: 268
DNA VL imagen61
SEQ ID NO:
Región Ab
SEQ ID NO: 269
DNA VH imagen108
SEQ ID NO: 270
Light Kappa imagen109
SEQ ID NO: 271
Heavy IgG1 imagen110
imagen111
MOR10701 R55S
SEQID NO: 272 (Kabat)
HCDR1 SYAMS
SEQID NO: 273 (Kabat)
HCDR2 VTGAVGSSTYYPDSVKG
MOR10701 R55S
SEQ ID NO: 274 (Kabat)
HCDR3 WGDEGFDI
SEQ ID NO: 275 (Kabat)
LCDR1 RASQGISNWLA
SEQ ID NO: 276 (Kabat)
LCDR2 GASSLQS
SEQ ID NO: 277 (Kabat)
LCDR3 QQYSSFPTT
SEQ ID NO: 278 (Chothia)
HCDR1 GFTFSSY
SEQ ID NO: 279 (Chothia)
HCDR2 GAVGSS
SEQ ID NO: 280 (Chothia)
HCDR3 WGDEGFDI
SEQ ID NO: 281 (Chothia)
LCDR1 SQGISNW
SEQ ID NO: 282 (Chothia)
LCDR2 GAS
SEQ ID NO: 283 (Chothia)
LCDR3 YSSFPT
SEQ ID NO:
Región Ab
SEQ ID NO: 284
VL imagen112
SEQ ID NO: 285
VH imagen113
SEQ ID NO: 286
DNA VL imagen114
SEQ ID NO: 287
DNA VH imagen115
SEQ ID NO: 288
Light Kappa imagen116
SEQ ID NO: 289
Heavy IgG1 imagen117
MOR10701 R55G
SEQ ID NO: 290 (Kabat)
HCDR1 SYAMS
SEQ ID NO: 291 (Kabat)
HCDR2 VTGAVGGSTYYPDSVKG
SEQ ID NO: 292 (Kabat)
HCDR3 WGDEGFDI
SEQ ID NO: 293 (Kabat)
LCDR1 RASQGISNWLA
SEQ ID NO: 294 (Kabat)
LCDR2 GASSLQS
SEQ ID NO: 295 (Kabat)
LCDR3 QQYSSFPTT
SEQ ID NO: 296 (Chothia)
HCDR1 GFTFSSY
SEQ ID NO: 297 (Chothia)
HCDR2 GAVGGS
SEQ ID NO: 298 (Chothia)
HCDR3 WGDEGFDI
SEQ ID NO:
Región Ab
SEQ ID NO: 299 (Chothia)
LCDR1 SQGISNW
SEQ ID NO: 300 (Chothia)
LCDR2 GAS
SEQ ID NO: 301 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 302
VL imagen76
SEQ ID NO: 303
VH imagen118
SEQ ID NO: 304
DNA VL imagen119
SEQ ID NO: 305
DNA VH imagen120
SEQ ID NO: 306
Light Kappa imagen84
MOR10701 R55G
SEQ ID NO: 307
Heavy IgG1 imagen121
MOR10701 R55K
SEQ ID NO: 308 (Kabat)
HCDR1 SYAMS
SEQ ID NO: 309 (Kabat)
HCDR2 VTGAVGKSTYYPDSVKG
SEQ ID NO: 310 (Kabat)
HCDR3 WGDEGFDI
SEQ ID NO: 311 (Kabat)
LCDR1 RASQGISNWLA
SEQID NO: 312 (Kabat)
LCDR2 GASSLQS
SEQ ID NO:
Región Ab
SEQ ID NO: 313 (Kabat)
LCDR3 QQYSSFPTT
SEQ ID NO: 314 (Chothia)
HCDR1 GFTFSSY
SEQ ID NO: 315 (Chothia)
HCDR2 GAVGKS
SEQ ID NO: 316 (Chothia)
HCDR3 WGDEGFDI
SEQ ID NO: 317 (Chothia)
LCDR1 SQGISNW
SEQ ID NO: 318 (Chothia)
LCDR2 GAS
SEQ ID NO: 319 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 320
VL imagen122
SEQ ID NO: 321
VH imagen123
SEQ ID NO: 322
DNA VL imagen61
MOR10701 R55K
SEQ ID NO: 323
DNA VH imagen124
SEQ ID NO: 324
Light Kappa imagen90
SEQ ID NO: 325
Heavy IgG1 imagen125
MOR10701 deletion S56
SEQID NO: 326 (Kabat)
HCDR1 SYAMS
SEQ ID NO:
Región Ab
SEQ ID NO: 327 (Kabat)
HCDR2 VTGAVGRTYYPDSVKG
SEQ ID NO: 328 (Kabat)
HCDR3 WGDEGFDI
SEQ ID NO: 329 (Kabat)
LCDR1 RASQGISNWLA
SEQ ID NO: 330 (Kabat)
LCDR2 GASSLQS
SEQ ID NO: 331 (Kabat)
LCDR3 QQYSSFPTT
SEQ ID NO: 332 (Chothia)
HCDR1 GFTFSSY
SEQ ID NO: 333 (Chothia)
HCDR2 GAVGRT
SEQ ID NO: 334 (Chothia)
HCDR3 WGDEGFDI
SEQID NO: 335 (Chothia)
LCDR1 SQGISNW
SEQ ID NO: 336 (Chothia)
LCDR2 GAS
SEQ ID NO: 337 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 338
VL imagen86
MOR10701 deletion S56
SEQ ID NO: 339
VH imagen126
SEQ ID NO: 340
DNA VL imagen127
SEQ ID NO: 341
DNA VH imagen128
SEQ ID NO: 342
Light Kappa imagen129
SEQ ID NO:
Región Ab
SEQ ID NO: 343
Heavy IgG1 imagen130
MOR12609
SEQ ID NO: 344 (Kabat)
HCDR1 SYAMS
SEQ ID NO: 345 (Kabat)
HCDR2 VINGLGYTTFYADSVKG
SEQ ID NO: 346 (Kabat)
HCDR3 WGDEGFDI
SEQ ID NO: 347 (Kabat)
LCDR1 RASQGISNWLA
SEQ ID NO: 348 (Kabat)
LCDR2 GASSLQS
SEQ ID NO: 349 (Kabat)
LCDR3 QQYSSFPTT
SEQ ID NO: 350 (Chothia)
HCDR1 GFTFSSY
SEQ ID NO: 351 (Chothia)
HCDR2 NGLGYT
SEQ ID NO: 352 (Chothia)
HCDR3 WGDEGFDI
SEQ ID NO: 353 (Chothia)
LCDR1 SQGISNW
MOR12609
SEQ ID NO: 354 (Chothia)
LCDR2 GAS
SEQ ID NO: 355 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 356
VL imagen28
imagen28
SEQ ID NO: 357
VH imagen131
SEQ ID NO: 358
DNA VL imagen132
SEQ ID NO:
Región Ab
SEQ ID NO: 359
DNA VH imagen133
SEQ ID NO: 360
Light Kappa imagen134
SEQ ID NO: 361
Heavy IgG1 imagen135
MOR12610
SEQ ID NO: 362 (Kabat)
HCDR1 SYAMS
SEQ ID NO: 363 (Kabat)
HCDR2 GTGPYGGTYYPDSVKG
SEQ ID NO: 364 (Kabat)
HCDR3 WGDEGFDI
SEQ ID NO: 365 (Kabat)
LCDR1 RASQGISNWLA
SEQ ID NO: 366 (Kabat)
LCDR2 GASSLQS
SEQ ID NO: 367 (Kabat)
LCDR3 QQYSSFPTT
SEQ ID NO: 368 (Chothia)
HCDR1 GFTFSSY
MOR12610
SEQ ID NO: 369 (Chothia)
HCDR2 GPYGG
SEQ ID NO: 370 (Chothia)
HCDR3 WGDEGFDI
SEQ ID NO: 371 (Chothia)
LCDR1 SQGISNW
SEQ ID NO: 372 (Chothia)
LCDR2 GAS
SEQ ID NO: 373 (Chothia)
LCDR3 YSSFPT
SEQ ID NO: 374
VL imagen136
SEQ ID NO:
Región Ab
SEQ ID NO: 375
VH imagen137
SEQ ID NO: 376
DNA VL imagen138
imagen139
SEQ ID NO: 377
DNA VH imagen140
SEQ ID NO: 378
Light Kappa imagen141
SEQ ID NO: 379
Heavy IgG1 imagen142
Otros anticuerpos de la divulgación incluyen aquéllos en donde los aminoácidos o ácidos nucleicos que codifican los aminoácidos se han mutado, tienen cuando menos el 60, 70, 80, 90, 95, 96, 97, 98, y 99 % de identidad con las secuencias descritas en la Tabla 1. En algunas realizaciones, incluyen secuencias de
5 aminoácidos mutantes, en donde se han mutado no más de 1, 2, 3, 4 o 5 aminoácidos en las regiones variables cuando se comparan con las regiones variables ilustradas en la secuencia descrita en la Tabla 1, mientras que conservan sustancialmente la misma actividad terapéutica.
Debido a que cada uno de estos anticuerpos o fragmentos de los mismos puede enlazarse a HER3, las secuencias VH, VL, de cadena ligera de longitud completa, y de cadena pesada de longitud completa (las 10 secuencias de aminoácidos y las secuencias de nucleótidos que codifican las secuencias de aminoácidos) se pueden "mezclar y emparejar" para crear otros anticuerpos de enlace con HER3 de la divulgación. Estos anticuerpos de enlace con HER3 "mezclados y emparejados" se pueden probar utilizando los ensayos de enlace conocidos en la materia (por ejemplo, ELISAs, y otros ensayos descritos en la sección de Ejemplos). Cuando estas cadenas se mezclan y se emparejan, una secuencia VH a partir de un emparejamiento de VH/VL particular 15 debe ser reemplazada con una secuencia VH estructuralmente similar. De la misma manera, una secuencia de cadena pesada de longitud completa a partir de un emparejamiento particular de cadena pesada de longitud completa / cadena ligera de longitud completa, debe ser reemplazada con una secuencia de cadena pesada de longitud completa estructuralmente similar. De la misma manera, una secuencia VL a partir de un emparejamiento de VH/VL particular debe ser reemplazada con una secuencia VL estructuralmente similar. De 20 la misma manera, una secuencia de cadena ligera de longitud completa a partir de un emparejamiento particular de cadena pesada de longitud completa / cadena ligera de longitud completa debe ser reemplazada con una secuencia de cadena ligera de longitud completa estructuralmente similar. De conformidad con lo anterior, en un aspecto, la divulgación proporciona un anticuerpo monoclonal aislado o un fragmento del mismo, que tiene: una región variable de cadena pesada que comprende una secuencia de aminoácidos seleccionada a partir del 25 grupo que consiste en las SEQ ID NO: 15, 33, 51, 69, 87, 105, 123, 141, 159, 177, 195, 213, 231, 249, 267, 285, 303, 321, 339, 357, y 375; y una región variable de cadena ligera, la cual comprende una secuencia de aminoácidos seleccionada a partir del grupo que consiste en las SEQ ID NOs: 14, 32, 50, 68, 86, 104, 122, 140, 158, 176, 194, 212, 230, 248, 266, 284, 302, 320, 338, 356, y 374; en donde el anticuerpo se enlaza
imagen143
imagen144
imagen145
utilizando la numeración de Kabat. Las posiciones de CDR se resaltan en negrillas. La anotación utilizada en las Tablas con las secuencias de la línea germinal es como sigue: MOR10701-VH_3-07 significa ciclos de MOR10701 CDR en las regiones de estructura de la secuencia de la línea germinal VH 3-07 (la nomenclatura es de acuerdo con Vbase), MOR10703-VK_L1 significa CDR a partir de MOR10703 en las regiones de la línea germinal de estructura a partir de VK_L1, en donde VK es la cadena ligera kappa.
Tabla 2
Versiones de la línea germinal diferentes de un número seleccionado de anticuerpos representativos
SEQ ID NO:
Nombre de secuencia Secuencia de Aminoácidos
Dominio MOR10701 VH
SEQ ID NO: 380
MOR10701-VH_3-07 imagen146
SEQ ID NO: 381
MOR10701-VH_3-09 imagen147
SEQ ID NO: 382
MOR10701-VH_3-11 imagen148
SEQ ID NO: 383
MOR10701-VH_3-13 imagen149
SEQ ID NO: 384
MOR10701-VH_3-15 imagen150
SEQ ID NO: 385
MOR10701-VH_3-20 imagen151
SEQ ID NO: 386
MOR10701-VH_3-21 imagen152
SEQ ID NO: 387
MOR10701-VH_3-23 imagen153
SEQ ID NO: 388
MOR10701-VH_3-30 imagen154
SEQ ID NO: 389
MOR10701-VH_3-30.3 imagen155
SEQ ID NO: 390
MOR10701-VH_3-30.5 imagen154
Dominio MOR10701 VH
SEQ ID NO: 391
MOR10701-VH_3-33 imagen156
SEQ ID NO: 392
MOR10701-VH_3-43 imagen157
SEQ ID NO: 393
MOR10701-VH_3-48 imagen158
SEQ ID NO: 394
MOR10701-VH_3-49 imagen159
SEQ ID NO: 395
MOR10701-VH_3-53 imagen160
SEQ ID NO: 396
MOR10701-VH_3-64 imagen161
SEQ ID NO:
Nombre de secuencia Secuencia de Aminoácidos
SEQ ID NO: 397
MOR10701-VH_3-66 imagen162
SEQ ID NO: 398
MOR10701-VH_3-72 imagen163
SEQ ID NO: 399
MOR10701-VH_3-73 imagen164
SEQ ID NO: 400
MOR10701-VH_3-74 imagen165
SEQ ID NO: 401
MOR10701-VH_3-d imagen166
Dominio MOR10703 VH
SEQ ID NO: 402
MOR10703-VH_3-07 imagen167
SEQ ID NO: 403
MOR10703-VH_3-09 imagen168
SEQID NO: 404
MOR10703-VH_3-11 imagen169
SEQ ID NO: 405
MOR10703-VH_3-13 imagen170
SEQ ID NO: 406
MOR10703-VH_3-15 imagen171
SEQ ID NO: 407
MOR10703-VH_3-20 imagen172
SEQ ID NO: 408
MOR10703-VH_3-21 imagen173
SEQ ID NO: 409
MOR10703-VH_3-23 imagen174
SEQ ID NO: 410
MOR10703-VH_3-30 imagen175
Dominio MOR10703 VH
SEQ ID NO: 411
MOR10703-VH_3-30.3 imagen176
SEQ ID NO: 412
MOR10703-VH_3-30.5 imagen177
SEQ ID NO: 413
MOR10703-VH_3-33 imagen176
SEQ ID NO: 414
MOR10703-VH_3-43 imagen178
SEQ ID NO: 415
MOR10703-VH_3-48 imagen179
SEQ ID NO: 416
MOR10703-VH_3-49 imagen180
SEQ ID NO: 417
MOR10703-VH_3-53 imagen181
SEQ ID NO:
Nombre de secuencia Secuencia de Aminoácidos
SEQ ID NO: 418
MOR10703-VH_3-64 imagen182
SEQ ID NO: 419
MOR10703-VH_3-66 imagen183
SEQ ID NO: 420
MOR10703-VH_3-72 imagen184
SEQID NO: 421
MOR10703-VH_3-73 imagen185
SEQ ID NO: 422
MOR10703-VH_3-74 imagen186
SEQ ID NO: 423
MOR10703-VH_3-d imagen187
Dominio MOR10701 VK
SEQ ID NO: 424
MOR10701-VKI_012 (same as MOR10701 wt) imagen188
SEQ ID NO: 425
MOR10701-VKI_O2 imagen189
SEQ ID NO: 426
MOR10701-VKI_O18 imagen190
SEQ ID NO: 427
MOR10701-VKI_O8 imagen191
SEQ ID NO: 428
MOR10701-VKI_A20 imagen192
SEQ ID NO: 429
MOR10701-VKI_A30 imagen193
SEQ ID NO: 430
MOR10701-VKI_L14 imagen194
SEQ ID NO: 431
MOR10701-VKI_L1 imagen195
Dominio MOR10703 VH
SEQ ID NO: 432
MOR10701-VKI_L15 imagen196
SEQ ID NO: 433
MOR10701-VKI_L4 imagen197
SEQ ID NO: 434
MOR10701-VKI_L18 imagen198
SEQ ID NO: 435
MOR10701-VKI_L5 imagen199
SEQ ID NO: 436
MOR10701-VKI_L19 imagen199
SEQ ID NO: 437
MOR10701-VKI_L8 imagen200
SEQ ID NO: 438
MOR10701-VKI_L23 imagen201
SEQ ID NO:
Nombre de secuencia Secuencia de Aminoácidos
SEQ ID NO: 439
MOR10701-VKI_L9 imagen202
SEQ ID NO: 440
MOR10701-VKI_L24 imagen203
SEQ ID NO: 441
MOR10701-VKI_L11 imagen204
SEQ ID NO: 442
MOR10701-VKI_L12 imagen205
Dominio MOR10701 VK
SEQ ID NO: 443
MOR10703-VKI_O12 (same as MOR10703 wt) imagen206
SEQ ID NO: 444
MOR10703-VKI_O2 imagen189
SEQ ID NO: 445
MOR10703-VKI_O18 imagen190
SEQ ID NO: 446
MOR10703-VKI_O8 imagen191
SEQ ID NO: 447
MOR10703-VKI_A20 imagen207
SEQ ID NO: 448
MOR10703-VKI_A30 imagen208
SEQ ID NO: 449
MOR10703-VKI_L14 imagen209
SEQ ID NO: 450
MOR10703-VKI_L1 imagen195
SEQ ID NO: 451
MOR10703-VKI_L15 imagen210
SEQ ID NO: 452
MOR10703-VKI_L4 imagen197
Dominio MOR10701 VK
SEQ ID NO: 453
MOR10703-VKI_L18 imagen198
SEQ ID NO: 454
MOR10703-VKI_L5 imagen211
SEQ ID NO: 455
MOR10703-VKI_L19 imagen212
SEQ ID NO: 456
MOR10703-VKI_L8 imagen213
SEQ ID NO: 457
MOR10703-VKI_L23 imagen201
SEQ ID NO: 458
MOR10703-VKI_L9 imagen214
SEQ ID NO: 459
MOR10703-VKI_L24 imagen215
imagen216
SEQ 477
ID NO: MOR10701-VKI_02_JK1 imagen28
SEQ 478
ID NO: MOR10701-VKI_02_JK4 imagen28
SEQ 479
ID NO: MOR10703-VKI_A20_JK4 imagen28
SEQ 480
ID NO: MOR10703-VKI_A20_JK1 imagen28
Una vez que la VH se ha combinado con JH y la VK con JK, entonces se puede utilizar cualquier combinación de VH o JH con VK o JK. En una realización, cualquiera de las regiones de la línea germinal VH se puede combinar con cualquiera de las regiones de la línea germinal VK (VL) para cada anticuerpo. Un número representativo de los ejemplos de combinaciones se muestra en la Tabla 7.
Tabla 7: Ejemplos representativos de las combinaciones de las secuencias de la línea germinal
Combination 1
SEQ 481
ID NO: MOR10701-VH 3-15_JH3 imagen217
SEQ 482
ID NO: MOR10701-VKI_A30_JK4 imagen218
Combination 2
SEQ 483
ID NO: MOR10701-VH_3-30_JH1 imagen219
SEQ 484
ID NO: MOR10701-VKI_L1_JK2 imagen220
Combination 3
SEQ 485
ID NO: MOR10701-VH_3-30_JH2 imagen221
SEQ 486
ID NO: MOR10701-VKI_L1_JK2 imagen222
Combination 4
SEQ 487
ID NO: MOR10703-VH_3-20_JH5 imagen223
SEQ 488
ID NO: MOR10703-VKI_L15_JK3 imagen224
Combination 5
SEQ 489
ID NO: MOR10703-VH_3-33_JH2 imagen225
SEQ 490
ID NO: MOR10703-VKI_A20_JK1 imagen226
Combination 6
SEQ 491
ID NO: MOR10703-VH_3-33_JH3 imagen227
SEQ 492
ID NO: MOR10703-VKI_A20_JK2 imagen228
En una realización, la divulgación pertenece a una región variable de cadena pesada, la cual comprende una
61
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imagen230
imagen231
imagen232
imagen233
imagen234
imagen235
imagen236
imagen237
imagen238
imagen239
imagen240
imagen241
imagen242
imagen243
imagen244
imagen245
imagen246
imagen247
imagen248
imagen249
imagen250
imagen251
imagen252
imagen253
imagen254
imagen255
imagen256
imagen257
imagen258
imagen259
imagen260
Tabla 8
Generación de vectores de expresión de HER3. La numeración de aminoácidos de HER3 se basa en NP_001973 (humana), NP_034283 (ratón), y NP_058914 (rata).
Nombre
Descripción
Hu HER3
CD33-[HER3 humano, residuos 20-640]-TAG
Mu HER3
CD33-[HER3 de murino, residuos 20-643]-TAG
Rata HER3
CD33-[HER3 de rata, residuos 20-643]-TAG
Cino HER3
CD33-[HER3 de cinomolgo, residuos 20-643]-TAG
HER3 D1-2
CD33-[HER3 humano, residuos 20-329]-TAG
HER3 D2
CD33-[HER3 humano, residuos 185-329]-TAG
HER3 D3-4
CD33-[HER3 humano, residuos 330-643]-TAG
HER3 D4
CD33-[HER3 humano, residuos 496-643]-TAG
Hu HER3-Fc
[HER3 humano, residuos 1-643]-Fc
Mu HER3-Fc
[HER3 de murino, residuos 1-643]-Fc
Cino HER3 Fc
[HER3 de cinomolgo, residuos 1-643]-Fc
Rata HER3-Fc
[HER3 de rata, residuos 1-643]-Fc
HER3 D2-Fc
[HER3 humano, residuos 207-329]-Fc
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imagen262
imagen263
imagen264
imagen265
imagen266
imagen267
imagen268
imagen269
imagen270
imagen271
TABLA 9
Valores de KD de IgGs anti-HER3 según se determina mediante titulación en equilibrio en solución (SET). Hu ( humano), Cy ( Cinomolgo), Mu ( múrido) y ra (rata)
MOR#
SET KD (pM)
hu HER3-Marca
cy HER3-Marca mu HER3-Marca ra HER3-Marca
09823
9 4 2 11
09824
3 3 2 7
09825
25 56 24 96
09974
350 200 120 n.d.
10701
4 4 6 10
10702
3 3 5 6
10703
26 23 20 40
12609
10 n.d n.d n.d
12610
37 n.d n.d n.d
10703 N52S
57 n.d n.d n.d
10703 N52G
60 n.d n.d n.d
10703_A50V_N52S
16 n.d n.d n.d
10703_A50V_N52G
22 n.d n.d n.d
10701 R55G
18 n.d n.d n.d
10701 R55K
11 n.d n.d n.d
5 (ii) Determinación de CE50 en célula SK-Br-3
La capacidad de los anticuerpos identificados para unirse a células que expresan HER3 se determina calculando los valores de CE50 para su unión a la línea de célula amplificada con HER2, SK-Br-3 (véase Figura 2 y Tabla 10).
TABLA 10
10 Valores de CE50 de FACS de IgG anti-HER3 en células SK-Br-3. n.d. (no determinado)
MOR#
SK-Br-3 FACS CE50 (pM)
09823
630
09824
324
09825
839
09974
n.d.
10701
n.d.
imagen272
imagen273
Pro
276 2
Tyr
32 VH Pro 276 2
His
277 2
Ala
33 VH Asn 266 2
Leu
268 2
Ser
35 VH Leu 268 2
Val
50 VH Leu 268 2
Thr
269 2
Gly
52 VH Glu 273 2
Thr
269 2
Ala
53 VH Glu 273 2
Pro
274 2
Val
54 VH Glu 273 2
Tyr
58 VH Pro 583 4
Asp
571 4
His
584 4
Thr
269 2
Gln
271 2
Asn
73 VH Asn 315 2
Ser
74 VH Asn 315 2
Trp
98 VH Leu 268 2
Lys
267 2
Asn
266 2
Asp
100 VH Ala 596 4
Lys
597 4
Pro
276 2
His
277 2
Glu
101 VH Lys 267 2
Lys
597 4
Phe
103 VH Leu 268 2

TABLA 12: Interacciones entre la cadena ligera de Fab de MOR09823 y HER3 de humano. Los residuos de VL de Fab se numeran tomando como base su secuencia de aminoácido lineal (SEQ ID NO: 14). Los residuos de HER3 se numeran tomando como base NP_001973. Los residuos de HER3 mostrados tienen por lo menos un átomo dentro de 5Å de un átomo en el Fab de MOR09823.
MOR09823 Fab
HER3 de humano
Residuo
Número Cadena Residuo Número Dominio
Gln
27 VL Arg 611 4
Glu
609 4
Gly
28 VL Arg 611 4
Pro
612 4
Ile
29 VL Pro 612 4
Ser
30 VL Pro 612 4
Cys
613 4
His
614 4
Glu
615 4
Asn
31 VL Glu 615 4
Cys
613 4
Trp
32 VL Lys 267 2
Tyr
265 2
Pro
612 4
Cys
613 4
Ile
600 4
Lys
602 4
Tyr
49 VL Lys 597 4
Gly
66 VL Glu 615 4
Ser
67 VL His 614 4
Glu
615 4
Gln
89 VL Leu 268 2
Tyr
91 VL Lys 267 2
Leu
268 2
Phe
270 2
Ser
92 VL Phe 270 2
Lys
602 4
Pro
612 4
Ser
93 VL Phe 270 2
Glu
609 4
Phe
94 VL Phe 270 2
Leu
268 2
Gly
582 4
Pro
583 4
Thr
96 VL Leu 268 2

TABLA 13: Interacciones entre la cadena pesada de Fab de MOR09825 y HER3 de humano. Los residuos de VH de Fab se numeran tomando como base su secuencia de aminoácido lineal (SEQ ID NO: 51). Los residuos de HER3 se numeran tomando como base NP_001973. Los residuos de HER3 mostrados tienen por lo menos un átomo dentro de 5Å de un átomo en el Fab de MOR09825.
MOR09825 Fab
HER3 de humano
Residuo
Número Cadena Residuo Número Dominio
Ser
30 VH Asn 315 2
Ser
31 VH Pro 274 2
Pro
276 2
Tyr
32 VH Pro 276 2
His
277 2
Ala
33 VH Asn 266 2
Thr
269 2
Ser
35 VH Leu 268 2
Trp
47 VH Leu 268 2
Ala
50 VH Leu 268 2
Asn
52 VH Glu 273 2
Gln
271 2
Thr
269 2
Ser
53 VH Glu 273 2
Pro
274 2
Gln
54 VH Glu 273 2
Pro
274 2
Ser
57 VH Gln 271 2
Tyr
59 VH Pro 583 4
Asp
571 4
His
584 4
Thr
269 2
Gln
271 2
Asn
74 VH Asn 315 2
Trp
99 VH Leu 268 2
Lys
267 2
Asn
266 2
Asp
101 VH Ala 596 4
Lys
597 4
Pro
276 2
His
277 2
Glu
102 VH Lys 267 2
Lys
597 4
Phe
104 VH Leu 268 2
TABLA 14: Interacciones entre la cadena ligera de Fab de MOR09825 y HER3 de humano. Los residuos de VL de Fab se numeran tomando como base su secuencia de aminoácido lineal (SEQ ID NO: 50). Los residuos de HER3 se numeran tomando como base NP_001973. Los residuos de HER3 mostrados tienen por lo menos un átomo dentro de 5Å de un átomo en el Fab de MOR09825.
MOR09825 Fab
HER3 de humano
Residuo
Número Cadena Residuo Número Dominio
Gln
27 VL Arg 611 4
Gly
28 VL Arg 611 4
Pro
612 4
Ile
29 VL Pro 612 4
Ser
30 VL Pro 612 4
Cys
613 4
His
614 4
Glu
615 4
Asn
31 VL Glu 615 4
His
614 4
Cys
613 4
Trp
32 VL Lys 267 2
Tyr
265 2
Pro
612 4
Cys
613 4
Ile
600 4
Lys
602 4
Tyr
49 VL Lys 597 4
Gly
66 VL Glu 615 4
Ser
67 VL His 614 4
Glu
615 4
Gln
89 VL Leu 268 2
Tyr
91 VL Lys 267 2
Leu
268 2
Phe
270 2
Ser
92 VL Phe 270 2
Lys
602 4
Pro
612 4
Arg
611 4
Ser
93 VL Phe 270 2
Glu
609 4
Phe
94 VL Phe 270 2
Gly
582 4
Pro
583 4
Thr
96 VL Leu 268 2
La inspección visual de las estructuras de cristal de MOR09823/MOR09825 resalta que los residuos Lys267 y Leu268 de HER3 forman interacciones múltiples con varias CDRs del anticuerpo lo que sugiere que éstos pueden ser importantes para la unión del anticuerpo. Por consiguiente, Lys267 y/o Leu268 se mutan a alanina,
5 expresan y las proteínas recombinantes resultantes se purifican con el fin de evaluar su impacto sobre la unión del anticuerpo. Las pruebas de unión ELISA indican que la mutación de cualquiera de Lys267 o Leu268 elimina la unión de MOR10703 a HER3 (Figura 5F) lo que sugiere que ambos residuos son una parte integral del epítopo de HER3 y por lo tanto apoyan las interacciones propuestas entre MOR09823/MOR09825 y HER3.
(viii) Inhibición de la señalización celular
10 Para determinar el efecto de los anticuerpos anti-HER3 sobre la actividad de HER3 dependiente del ligando se incuban células MCF7 con IgG antes de la estimulación con neuregulina. Las curvas de inhibición de ejemplo se ilustran en la Figura 6A y se presentan en forma resumida en la Tabla 15. También se estudia el efecto de los anticuerpos anti-HER3 sobre la activación de HER3 mediada por HER2 utilizando la línea celular SK-Br-3 amplificada con HER2 (Figura 6B y Tabla 15).
TABLA 15
CI50 de pHER3 y valores del grado de inhibición de IgG anti-HER3 en células MCF7, y SK-Br-3
MOR#
MCF7 pHER3 SK-Br-3 pHER3
CI50 (pM)
% de inhibición CI50 (pM) % de inhibición
09823
181 89 56 59
09824
103 91 110 64
09825
399 80 169 66
09974
3066 69 1928 67
10701
n.d. n.d. 370 74
10702
n.d. n.d. n.d. n.d.
10703
333 80 167 69
12609
5 86 241 71
12610
126 84 192 75
Para determinar si la inhibición de la actividad de HER3 impacta Akt de señalización celular corriente abajo, también se mide la fosforilación en células amplificadas con HER2 después del tratamiento con anticuerpos 10 anti-HER3 (véase Figura 7 y Tabla 16).
TABLA 16
CI50 de pAkt (S473) y valores del grado de inhibición de IgG anti-HER3 en células SK-Br-3 BT-474 y MCF7
MOR#
SK-Br-3 pAkt BT-474 pAkt MCF7 pAkt
CI50 (pM)
% de inhibición % de inhibición CI50 (pM) % de inhibición
09823
55 92 57 n.d. n.d.
09824
62 93 46 n.d. n.d.
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