【手続補正書】
【提出日】平成17年5月13日(2005.5.13)
【手続補正１】
【補正対象書類名】明細書
【補正対象項目名】０１２３
【補正方法】変更
【補正の内容】
【０１２３】HER-2のイントロン8のこれら多型は、新奇なDNA配列およびタンパク質配列と、HER-2を過剰に発現する固形ガンを治療するための新奇な薬理学的組成物と、配列ID番号1、配列ID番号2、配列ID番号12、または配列ID番号13に対応するECD IIIa変異体と結合するモノクローナル抗体とを提供する。HER-2のイントロン8のこれら多型は、ガンの治療および予防のための予後予測方法ならびに診断方法も提供する。
【配列表】
SEQUENCE LISTING
<110>  Oregon Health and Science University
Clinton, Gail M.
Henner, William D
Evans, Adam
<120>  HER-2 BINDING ANTAGONISTS
<130>  49321-50
<140>  PCT/US01/05327
<141>  2001-02-16
<150>  US 09/506,079
<151>  2000-02-16
<160>  13    
<170>  PatentIn version 3.2
<210>  1
<211>  79
<212>  PRT
<213>  Homo sapiens
<220>
<221>  MISC_FEATURE
<222>  (2)..(2)
<223>  Applicants herein disclose Thr and Ser sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (5)..(5)
<223>  Applicants herein disclose Leu and Pro sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (6)..(6)
<223>  Applicants herein disclose Pro and Leu sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (16)..(16)
<223>  Applicants herein disclose Leu and Gln sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (18)..(18)
<223>  Applicants herein disclose Met and Leu sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (21)..(21)
<223>  Applicants herein disclose Gly, Asp, Ala and Val sequence 
variants at this position
<220>
<221>  MISC_FEATURE
<222>  (36)..(36)
<223>  Applicants herein disclose Leu and Ile sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (54)..(54)
<223>  Applicants herein disclose Pro and Arg sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (64)..(64)
<223>  Applicants herein disclose Pro and Leu sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (73)..(73)
<223>  Applicants herein disclose Asp and Asn sequence variants at this 
position
<400>  1
Gly Xaa His Ser Xaa Xaa Pro Arg Pro Ala Ala Val Pro Val Pro Xaa 
1               5                   10                  15      
Arg Xaa Gln Pro Xaa Pro Ala His Pro Val Leu Ser Phe Leu Arg Pro 
20                  25                  30          
Ser Trp Asp Xaa Val Ser Ala Phe Tyr Ser Leu Pro Leu Ala Pro Leu 
35                  40                  45              
Ser Pro Thr Ser Val Xaa Ile Ser Pro Val Ser Val Gly Arg Gly Xaa 
50                  55                  60                  
Asp Pro Asp Ala His Val Ala Val Xaa Leu Ser Arg Tyr Glu Gly 
65                  70                  75                  
<210>  2
<211>  419
<212>  PRT
<213>  Homo sapiens
<220>
<221>  MISC_FEATURE
<222>  (342)..(342)
<223>  Applicants herein disclose Thr and Ser sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (345)..(345)
<223>  Applicants herein disclose Leu and Pro sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (346)..(346)
<223>  Applicants herein disclose Pro and Leu sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (356)..(356)
<223>  Applicants herein disclose Leu and Gln sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (358)..(358)
<223>  Applicants herein disclose Met and Leu sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (361)..(361)
<223>  Applicants herein disclose Gly, Asp, Ala and Val sequence 
variants at this position
<220>
<221>  MISC_FEATURE
<222>  (376)..(376)
<223>  Applicants herein disclose Leu and Ile sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (394)..(394)
<223>  Applicants herein disclose Pro and Arg sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (404)..(404)
<223>  Applicants herein disclose Pro and Leu sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (413)..(413)
<223>  Applicants herein disclose Asp and Asn sequence variants at this 
position
<400>  2
Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu 
1               5                   10                  15      
Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys 
20                  25                  30          
Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His 
35                  40                  45              
Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr 
50                  55                  60                  
Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val 
65                  70                  75                  80  
Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu 
85                  90                  95      
Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr 
100                 105                 110         
Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro 
115                 120                 125             
Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser 
130                 135                 140                 
Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln 
145                 150                 155                 160 
Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn 
165                 170                 175     
Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys 
180                 185                 190         
His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser 
195                 200                 205             
Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys 
210                 215                 220                 
Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys 
225                 230                 235                 240 
Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu 
245                 250                 255     
His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val 
260                 265                 270         
Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg 
275                 280                 285             
Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu 
290                 295                 300                 
Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln 
305                 310                 315                 320 
Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys 
325                 330                 335     
Pro Cys Ala Arg Gly Xaa His Ser Xaa Xaa Pro Arg Pro Ala Ala Val 
340                 345                 350         
Pro Val Pro Xaa Arg Xaa Gln Pro Xaa Pro Ala His Pro Val Leu Ser 
355                 360                 365             
Phe Leu Arg Pro Ser Trp Asp Xaa Val Ser Ala Phe Tyr Ser Leu Pro 
370                 375                 380                 
Leu Ala Pro Leu Asp Pro Thr Ser Val Xaa Ile Ser Pro Val Ser Val 
385                 390                 395                 400 
Gly Arg Gly Xaa Asp Pro Asp Ala His Val Ala Val Xaa Leu Ser Arg 
405                 410                 415     
Tyr Glu Gly 
<210>  3
<211>  19
<212>  DNA
<213>  Artificial Sequence
<220>
<223>  HER-2-specific oligonucleotide primer
<400>  3
tgagcaccat ggagctggc                                                  19
<210>  4
<211>  22
<212>  DNA
<213>  Artificial Sequence
<220>
<223>  HER-2-specific oligonucleotide primer
<400>  4
tccggcagaa atgccaggct cc                                              22
<210>  5
<211>  22
<212>  DNA
<213>  Artificial Sequence
<220>
<223>  HER-2 cDNA-specific oligonucleotide primer
<400>  5
aacacagcgg tgtgagaagt gc                                              22
<210>  6
<211>  21
<212>  DNA
<213>  Artificial Sequence
<220>
<223>  HER-2 ECDIIIa-region-specific oligonucleotide primer
<400>  6
ataccgggac aggtcaacag c                                               21
<210>  7
<211>  20
<212>  DNA
<213>  Artificial Sequence
<220>
<223>  HER-2 ECDIIIa-region-specific oligonucleotide primer
<400>  7
tctgggtacc cactcactgc                                                 20
<210>  8
<211>  22
<212>  DNA
<213>  Artificial Sequence
<220>
<223>  HER-2 exon-specific oligonucleotide primer
<400>  8
ttcacactgg cacgtccaga cc                                              22
<210>  9
<211>  27
<212>  DNA
<213>  Artificial Sequence
<220>
<223>  HER-2 cDNA-specific oligonucleotide primer
<400>  9
gcacggatcc atagcagact gaggagg                                         27
<210>  10
<211>  240
<212>  DNA
<213>  Homo sapiens
<220>
<221>  exon
<222>  (1)..(240)
<223>  ECDIIIa reqion coding sequence
<220>
<221>  misc_feature
<222>  (62)..(62)
<223>  Applicants disclose C, T, A and G variants at this position
<400>  10
ggt wcc cac tca cyg cyc ccg agg cca gct gca gtt cct gtc cct cwg       48
Gly Xaa His Ser Xaa Xaa Pro Arg Pro Ala Ala Val Pro Val Pro Xaa         
1               5                   10                  15              
cgc atr cag cct gnc cca gcc cac cct gtc cta tcc ttc ctc aga ccc       96
Arg Xaa Gln Pro Xaa Pro Ala His Pro Val Leu Ser Phe Leu Arg Pro         
20                  25                  30                  
tct tgg gac mta gtc tct gcc ttc tac tct cta ccc ctg gcc ccc ctc      144
Ser Trp Asp Xaa Val Ser Ala Phe Tyr Ser Leu Pro Leu Ala Pro Leu         
35                  40                  45                      
agc cct aca agt gtc cst ata tcc cct gtc agt gtg ggg agg ggc cyg      192
Ser Pro Thr Ser Val Xaa Ile Ser Pro Val Ser Val Gly Arg Gly Xaa         
50                  55                  60                          
gac cct gat gct cat gtg gct gtt sac ctg tcc cgg tat gaa ggc tga      240
Asp Pro Asp Ala His Val Ala Val Xaa Leu Ser Arg Tyr Glu Gly             
65                  70                  75                              
<210>  11
<211>  274
<212>  DNA
<213>  Homo sapiens
<220>
<221>  exon
<222>  (1)..(240)
<223>  ECDIIIa reqion coding sequence
<220>
<221>  misc_feature
<222>  (62)..(62)
<223>  Applicants disclose C, T, A and G variants at this position
<400>  11
ggt wcc cac tca cyg cyc ccg agg cca gct gca gtt cct gtc cct cwg       48
Gly Xaa His Ser Xaa Xaa Pro Arg Pro Ala Ala Val Pro Val Pro Xaa         
1               5                   10                  15              
ygc atr cag cct gnc cca gcc cac cct gtc cta tcc ttc ctc aka ccc       96
Xaa Xaa Gln Pro Xaa Pro Ala His Pro Val Leu Ser Phe Leu Xaa Pro         
20                  25                  30                  
tct tgg gac mta gtc tct gcc ttc tac tct cta ccc ctg gcc ccc ctc      144
Ser Trp Asp Xaa Val Ser Ala Phe Tyr Ser Leu Pro Leu Ala Pro Leu         
35                  40                  45                      
agc cct aca agt gtc cst ata tcc cct gtc agt gtg ggg agg ggc cyg      192
Ser Pro Thr Ser Val Xaa Ile Ser Pro Val Ser Val Gly Arg Gly Xaa         
50                  55                  60                          
gac cct gat gct cat gtg gct gtt vac ctg tcc cgg tat gaa ggc tga      240
Asp Pro Asp Ala His Val Ala Val Xaa Leu Ser Arg Tyr Glu Gly             
65                  70                  75                              
gacggcccct tcccccacyc acccccacct cctc                                274
<210>  12
<211>  79
<212>  PRT
<213>  Homo sapiens
<220>
<221>  misc_feature
<222>  (2)..(2)
<223>  Applicants herein disclose Thr and Ser sequence variants at this 
position
<220>
<221>  misc_feature
<222>  (5)..(5)
<223>  Applicants herein disclose Leu and Pro sequence variants at this 
position
<220>
<221>  misc_feature
<222>  (6)..(6)
<223>  Applicants herein disclose Pro and Leu sequence variants at this 
position
<220>
<221>  misc_feature
<222>  (16)..(16)
<223>  Applicants herein disclose Leu and Gln sequence variants at this 
position
<220>
<221>  misc_feature
<222>  (17)..(17)
<223>  Applicants herein disclose Arg and Cys sequence variants at this 
position
<220>
<221>  misc_feature
<222>  (18)..(18)
<223>  Applicants herein disclose Met and Leu sequence variants at this 
position
<220>
<221>  misc_feature
<222>  (21)..(21)
<223>  Applicants herein disclose Gly, Asp, Ala and Val sequence 
variants at this position
<220>
<221>  misc_feature
<222>  (31)..(31)
<223>  Applicants herein disclose Arg and Ile sequence variants at this 
position
<220>
<221>  misc_feature
<222>  (36)..(36)
<223>  Applicants herein disclose Leu and Ile sequence variants at this 
position
<220>
<221>  misc_feature
<222>  (54)..(54)
<223>  Applicants herein disclose Pro and Arg sequence variants at this 
position
<220>
<221>  misc_feature
<222>  (64)..(64)
<223>  Applicants herein disclose Pro and Leu sequence variants at this 
position
<220>
<221>  misc_feature
<222>  (73)..(73)
<223>  Applicants herein disclose Asp and Asn sequence variants at this 
position
<400>  12
Gly Xaa His Ser Xaa Xaa Pro Arg Pro Ala Ala Val Pro Val Pro Xaa 
1               5                   10                  15      
Xaa Xaa Gln Pro Xaa Pro Ala His Pro Val Leu Ser Phe Leu Xaa Pro 
20                  25                  30          
Ser Trp Asp Xaa Val Ser Ala Phe Tyr Ser Leu Pro Leu Ala Pro Leu 
35                  40                  45              
Ser Pro Thr Ser Val Xaa Ile Ser Pro Val Ser Val Gly Arg Gly Xaa 
50                  55                  60                  
Asp Pro Asp Ala His Val Ala Val Xaa Leu Ser Arg Tyr Glu Gly 
65                  70                  75                  
<210>  13
<211>  419
<212>  PRT
<213>  Homo sapiens
<220>
<221>  MISC_FEATURE
<222>  (342)..(342)
<223>  Applicants herein disclose Thr and Ser sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (345)..(345)
<223>  Applicants herein disclose Leu and Pro sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (346)..(346)
<223>  Applicants herein disclose Pro and Leu sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (356)..(356)
<223>  Applicants herein disclose Leu and Gln sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (357)..(357)
<223>  Applicants herein disclose Arg and Cys sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (358)..(358)
<223>  Applicants herein disclose Met and Leu sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (361)..(361)
<223>  Applicants herein disclose Gly, Asp, Ala and Val sequence 
variants at this position
<220>
<221>  MISC_FEATURE
<222>  (371)..(371)
<223>  Applicants herein disclose Arg and Ile sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (376)..(376)
<223>  Applicants herein disclose Leu and Ile sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (394)..(394)
<223>  Applicants herein disclose Pro and Arg sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (404)..(404)
<223>  Applicants herein disclose Pro and Leu sequence variants at this 
position
<220>
<221>  MISC_FEATURE
<222>  (413)..(413)
<223>  Applicants herein disclose Asp and Asn sequence variants at this 
position
<400>  13
Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu 
1               5                   10                  15      
Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys 
20                  25                  30          
Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His 
35                  40                  45              
Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr 
50                  55                  60                  
Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val 
65                  70                  75                  80  
Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu 
85                  90                  95      
Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr 
100                 105                 110         
Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro 
115                 120                 125             
Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser 
130                 135                 140                 
Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln 
145                 150                 155                 160 
Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn 
165                 170                 175     
Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys 
180                 185                 190         
His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser 
195                 200                 205             
Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys 
210                 215                 220                 
Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys 
225                 230                 235                 240 
Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu 
245                 250                 255     
His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val 
260                 265                 270         
Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg 
275                 280                 285             
Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu 
290                 295                 300                 
Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln 
305                 310                 315                 320 
Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys 
325                 330                 335     
Pro Cys Ala Arg Gly Xaa His Ser Xaa Xaa Pro Arg Pro Ala Ala Val 
340                 345                 350         
Pro Val Pro Xaa Xaa Xaa Gln Pro Xaa Pro Ala His Pro Val Leu Ser 
355                 360                 365             
Phe Leu Xaa Pro Ser Trp Asp Xaa Val Ser Ala Phe Tyr Ser Leu Pro 
370                 375                 380                 
Leu Ala Pro Leu Asp Pro Thr Ser Val Xaa Ile Ser Pro Val Ser Val 
385                 390                 395                 400 
Gly Arg Gly Xaa Asp Pro Asp Ala His Val Ala Val Xaa Leu Ser Arg 
405                 410                 415     
Tyr Glu Gly