TW202229359A - Her2標靶藥物 - Google Patents
Her2標靶藥物 Download PDFInfo
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- TW202229359A TW202229359A TW110144472A TW110144472A TW202229359A TW 202229359 A TW202229359 A TW 202229359A TW 110144472 A TW110144472 A TW 110144472A TW 110144472 A TW110144472 A TW 110144472A TW 202229359 A TW202229359 A TW 202229359A
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- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
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Abstract
本發明提供一種結合於在癌細胞中表現之HER2或其片段之抗體或其抗原結合性片段、包含該等之任一者之HER2標靶藥物、包含該HER2標靶藥物之醫藥組合物。
Description
本發明係關於一種HER2標靶藥物。
HER2係受體型酪胺酸激酶,具有與上皮生長因子受體(EGFR)類似之結構,亦稱為EGFR2、ERBB2、CD340、或NEU。已知HER2蛋白於正常細胞中亦表現,參與細胞之增殖及分化之調節,但HER2基因之擴增及/或變異導致無法控制細胞之增殖,從而使得細胞惡性化,於唾液腺癌、胃癌、乳癌、卵巢癌等較多癌症中有HER2表現。曲妥珠單抗係特異性結合於在癌細胞之表面表現之HER2之抗體醫藥。曲妥珠單抗可藉由結合於癌細胞上之HER2而抑制刺激癌細胞增殖之信號,或者誘導免疫之作用來破壞癌細胞。
為了對癌細胞特異性地產生此種細胞增殖抑制作用或細胞毒殺作用,需要僅特異性結合於癌細胞之抗體。作為製作對癌細胞具有特異性之抗體之技術,開發出CasMab法(非專利文獻1~3)。於CasMab法中,以於具有特異性之糖鏈圖譜之神經膠母細胞瘤細胞株之LN229細胞中表現之抗原蛋白質作為免疫原而製作抗體。
先前技術文獻
非專利文獻
非專利文獻1:Kato and Kaneko, 2014, Sci. Rep., 4: 5924
非專利文獻2:Yamada et al., 2017, Monoclon. Antib. Immunodiagn. Immunother., 36(2): 72
非專利文獻3:Kaneko et al., 2020, Biochem. Biophys. Rep., 24: 100826
本發明提供一種結合於HER2之抗體或其抗原結合性片段。本發明較佳為提供一種特異性結合於HER2之抗體或其抗原結合性片段。本發明提供一種對在癌細胞上表現之HER2具有結合親和性之抗體或其抗原結合性片段。本發明更佳為提供一種相較於對於在非癌細胞上表現之HER2而對於在癌細胞上表現之HER2可具有更強結合親和性之抗體或其抗原結合性片段。本發明進而較佳為提供一種不會與在非癌細胞上表現之HER2顯著地反應而可與癌細胞上表現之HER2特異性地反應的抗體或其抗原結合性片段。又,本發明提供一種使用上述結合於HER2之抗體或其抗原結合性片段來於患者中處置癌之方法。進而,本發明提供一種檢測HER2陽性之癌細胞之方法,其包括使上述結合於HER2之抗體或其抗原結合性片段與自該患者獲得之癌樣本接觸。又,本發明提供一種確定患者對於使用上述結合於HER2之抗體或其抗原結合性片段之HER2標靶療法是否為應答性之方法。
本發明者等人製作出特異性地識別於癌細胞上表現之HER2之抗體。又,本發明者等人發現,藉由抗體可區別在正常細胞上表現之HER2與在癌細胞上表現之HER2,並製作出可區別該等之抗體。本發明係基於此種見解之發明。
根據本發明,提供以下形態。
[0]一種經單離之抗體或其抗原結合性片段,其對在癌細胞上表現之HER2具有結合反應性。
[1]一種經單離之抗體或其抗原結合性片段,其相較於對於在非癌細胞上表現之HER2,對於在癌細胞上表現之HER2具有更強之結合反應性。
[2]如上述[0]或[1]所記載之抗體或其抗原結合性片段,其(i)結合於包含選自由序列編號:31~37之胺基酸序列(例如序列編號:31~36之胺基酸序列)所組成之群中之任一胺基酸序列之肽。
[3]如上述[0]、[1]或[2]所記載之抗體或其抗原結合性片段{下述中HER2之胞外域之一部分可為序列編號:2所記載之胺基酸序列之胺基酸編號613~622之區域},其(ii)相較於對於在包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有選自由W614A、K615A、及F616A所組成之群中之1種以上胺基酸突變之HER2之胞外域之突變體,對於包含序列編號:3所記載之HER2之胞外域之肽具有更強之結合親和性(或反應性),例如相較於對於在包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有包含W614A之點突變之肽、或者具有包含K615A或F616A之點突變之肽,對於包含序列編號:3所記載之HER2之胞外域之肽具有更強之反應性。
[4]如上述[0]、及[1]至[3]中任一項所記載之抗體或其抗原結合性片段,其(iii)包含重鏈可變區及輕鏈可變區,上述重鏈可變區包含
具有序列編號:18之胺基酸序列之重鏈CDR1、
具有序列編號:19之胺基酸序列之重鏈CDR2、及
具有序列編號:20之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含
具有序列編號:21之胺基酸序列之輕鏈CDR1、
具有序列編號:22之胺基酸序列之輕鏈CDR2、及
具有序列編號:23之胺基酸序列之輕鏈CDR3;
(iv)包含重鏈可變區及輕鏈可變區,上述重鏈可變區包含
具有序列編號:24之胺基酸序列之重鏈CDR1、
具有序列編號:25之胺基酸序列之重鏈CDR2、及
具有序列編號:26之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含
具有序列編號:27之胺基酸序列之輕鏈CDR1、
具有序列編號:28之胺基酸序列之輕鏈CDR2、及
具有序列編號:29之胺基酸序列之輕鏈CDR3;或
於上述(iii)或(iv)之一者以上之CDR中具有至少1個置換、附加或缺失。
[5]如上述[0]、及[1]至[4]中任一項所記載之抗體或其抗原結合性片段,其(vii)包含具有序列編號:14之胺基酸序列之重鏈可變區、及
具有序列編號:15之胺基酸序列之輕鏈可變區;
(viii)包含具有序列編號:16之胺基酸序列之重鏈可變區、及
具有序列編號:17之胺基酸序列之輕鏈可變區;或
於上述(vii)或(viii)之各可變區中具有至少1個置換、附加或缺失。
[6]如上述[0]、及[1]至[5]中任一項所記載之抗體或其抗原結合性片段,其與由神經膠母細胞瘤細胞株之LN229細胞所產生且包含序列編號:3所記載之HER2之胞外域之肽結合。
[7]如上述[0]、及[1]至[6]中任一項所記載之抗體或其抗原結合性片段,其中癌細胞為乳癌細胞株之SK-BR-3細胞,非癌細胞為正常人類表皮角化細胞株之HaCaT細胞。
[8]一種醫藥組合物,其包含含有如上述[0]、及[1]至[7]中任一項所記載之抗體或其抗原結合性片段之HER2標靶藥物作為有效成分。
[9]如上述[0]、及[1]至[7]中任一項所記載之抗體或其抗原結合性片段,其複合有細胞毒殺劑。
[10]一種醫藥組合物,其包含如上述[9]所記載之抗體或其抗原結合性片段作為有效成分。
[11]如上述[8]或[10]所記載之醫藥組合物,其係用於處置癌。
[12]一種癌之處置劑,其包含如上述[0]、及[1]至[7]中任一項所記載之抗體或其抗原結合性片段作為有效成分。
[13]一種核酸分子,其編碼如上述[2]至[6]中任一項所記載之抗體或其抗原結合性片段。
[14]一種抗體或其抗原結合性片段,其特異性結合於HER2之胞外域之表位,且(iii)包含重鏈可變區及輕鏈可變區,上述重鏈可變區包含具有序列編號:18之胺基酸序列之重鏈CDR1、
具有序列編號:19之胺基酸序列之重鏈CDR2、及
具有序列編號:20之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:21之胺基酸序列之輕鏈CDR1、
具有序列編號:22之胺基酸序列之輕鏈CDR2、及
具有序列編號:23之胺基酸序列之輕鏈CDR3;
(iv)包含重鏈可變區及輕鏈可變區,上述重鏈可變區包含具有序列編號:24之胺基酸序列之重鏈CDR1、
具有序列編號:25之胺基酸序列之重鏈CDR2、及
具有序列編號:26之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:27之胺基酸序列之輕鏈CDR1、
具有序列編號:28之胺基酸序列之輕鏈CDR2、及
具有序列編號:29之胺基酸序列之輕鏈CDR3;或
於上述(iii)或(iv)之一者以上之CDR中具有至少1個置換、附加或缺失。
[15]一種抗體或其抗原結合性片段,其不會與在非癌細胞上表現之HER2顯著地反應而可與在癌細胞上表現之HER2特異性地反應。
[16]一種製造、選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括如下步驟:
自結合於HER2或其片段之抗體群或抗體之抗原結合性片段群中製造、選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而可與在癌細胞上表現之HER2特異性地反應的抗體或抗體之抗原結合性片段。
[17]一種製造、選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括如下步驟:
自結合於HER2或其片段之抗體群或抗體之抗原結合性片段群製造、選擇或鑑定滿足選自由下述(i)~(iii)所組成之群中之至少一者之抗體或抗體之抗原結合性片段。
(i)結合於包含選自由序列編號:31~37之胺基酸序列(例如序列編號:31~36之胺基酸序列)所組成之群中之任一胺基酸序列之肽;及
(ii)相較於對於包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有選自由W614A、K615A、及F616A所組成之群中之1種以上胺基酸突變之HER2之胞外域之突變體,對於包含序列編號:3所記載之HER2之胞外域之肽具有更強之結合親和性(或反應性),例如相較於對於包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有包含W614A之點突變之肽、或者具有包含K615A或F616A之點突變之肽,對於包含序列編號:3所記載之HER2之胞外域之肽具有更強之反應性;以及
(iii)相較於對於在非癌細胞上表現之HER2,對於在癌細胞上表現之HER2具有更強之結合反應性。
[18]一種製造、選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括如下步驟:
自滿足選自由下述(i)~(ii)所組成之群中之至少一者之抗體群或抗體之抗原結合性片段群中製造、選擇或鑑定結合於HER2或其片段之抗體或其抗原結合性片段。
(i)結合於包含選自由序列編號:31~37之胺基酸序列(例如序列編號:31~36之胺基酸序列)所組成之群中之任一胺基酸序列之肽;及
(ii)相較於對於包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有選自由W614A、K615A、及F616A所組成之群中之1種以上胺基酸突變之肽,對於包含序列編號:3所記載之HER2之胞外域之肽具有更強之反應性。
[19]如上述[17]或[18]所記載之方法,其進而包括如下步驟:自所獲得之抗體或抗體之抗原結合性片段群中製造、選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而可與在癌細胞上表現之HER2特異性地反應的抗體或抗體之抗原結合性片段。
[20]一種製造、選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括如下步驟:
自於(iii)、(iv)、及(xii)之任意且至少一個CDR中具有選自由置換、附加、插入、及缺失所組成之群中之至少1個以上胺基酸之變異(例如1個~10個,例如1個、2個、3個、4個、5個、6個等)之抗體群或抗體之抗原結合性片段群中製造、選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而可與在癌細胞上表現之HER2特異性地反應的抗體或抗體之抗原結合性片段。
[20]如上述[16]至[19]中任一項所記載之方法,其包括使所選擇或鑑定之抗體或抗體之抗原結合性片段產生抗體產生細胞(例如CHO細胞)。
[21]一種抗體,其係藉由如上述[20]之方法獲得。
[22]如上述[16]至[20]中任一項所記載之方法,其中抗體為單株抗體(例如經單離之單株抗體)。
[23]一種醫藥組合物,其包含具有如上述[1]至[7]中任一項所記載之抗體或其抗原結合性片段之HER2標靶藥物。
[24]一種醫藥組合物,其包含如上述[9]所記載之抗體或其抗原結合性片段。
[25]如上述[23]或[24]所記載之醫藥組合物,其係用於處置癌。
[101]如上述[0]或[1]所記載之抗體或其抗原結合性片段,其(xi)結合於包含選自由序列編號:37之胺基酸序列所組成之群中之任一胺基酸序列之肽。
[102](xii)如上述[0]、[1]至[3]、及[101]中任一項所記載之抗體或其抗原結合性片段,其包含如下重鏈可變區及輕鏈可變區:
上述重鏈可變區包含具有序列編號:81所記載之胺基酸序列之重鏈CDR1、
具有序列編號:82所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:83所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:84所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:85所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:86所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:87所記載之胺基酸序列之重鏈CDR1、
具有序列編號:88所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:89所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:90所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:91所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:92所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:93所記載之胺基酸序列之重鏈CDR1、
具有序列編號:94所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:95所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:96所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:97所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:98所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:99所記載之胺基酸序列之重鏈CDR1、
具有序列編號:100所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:101所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:102所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:103所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:104所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:105所記載之胺基酸序列之重鏈CDR1、
具有序列編號:106所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:107所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:108所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:109所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:110所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:111所記載之胺基酸序列之重鏈CDR1、
具有序列編號:112所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:113所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:114所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:115所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:116所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:117所記載之胺基酸序列之重鏈CDR1、
具有序列編號:118所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:119所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:120所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:121所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:122所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:123所記載之胺基酸序列之重鏈CDR1、
具有序列編號:124所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:125所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:126所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:127所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:128所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:129所記載之胺基酸序列之重鏈CDR1、
具有序列編號:130所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:131所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:132所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:133所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:134所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:135所記載之胺基酸序列之重鏈CDR1、
具有序列編號:136所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:137所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:138所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:139所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:140所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:141所記載之胺基酸序列之重鏈CDR1、
具有序列編號:142所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:143所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:144所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:145所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:146所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:147所記載之胺基酸序列之重鏈CDR1、
具有序列編號:148所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:149所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:150所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:151所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:152所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:153所記載之胺基酸序列之重鏈CDR1、
具有序列編號:154所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:155所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:156所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:157所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:158所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:159所記載之胺基酸序列之重鏈CDR1、
具有序列編號:160所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:161所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:162所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:163所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:164所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:165所記載之胺基酸序列之重鏈CDR1、
具有序列編號:166所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:167所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:168所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:169所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:170所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:171所記載之胺基酸序列之重鏈CDR1、
具有序列編號:172所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:173所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:174所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:175所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:176所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:177所記載之胺基酸序列之重鏈CDR1、
具有序列編號:178所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:179所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:180所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:181所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:182所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:183所記載之胺基酸序列之重鏈CDR1、
具有序列編號:184所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:185所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:186所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:187所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:188所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:189所記載之胺基酸序列之重鏈CDR1、
具有序列編號:190所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:191所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:192所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:193所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:194所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:195所記載之胺基酸序列之重鏈CDR1、
具有序列編號:196所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:197所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:198所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:199所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:200所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:201所記載之胺基酸序列之重鏈CDR1、
具有序列編號:202所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:203所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:204所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:205所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:206所記載之胺基酸序列之輕鏈CDR3。
[103]如上述[0]、[1]至[3]、[101]及[102]中任一項所記載之抗體或其抗原結合性片段,其係(xiii)
(a)包含具有序列編號:39之胺基酸序列之重鏈可變區、及具有序列編號:40之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(b)包含具有序列編號:41之胺基酸序列之重鏈可變區、及具有序列編號:42之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(c)包含具有序列編號:43之胺基酸序列之重鏈可變區、及具有序列編號:44之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(d)包含具有序列編號:45之胺基酸序列之重鏈可變區、及具有序列編號:46之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(e)包含具有序列編號:47之胺基酸序列之重鏈可變區、及具有序列編號:48之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(f)包含具有序列編號:49之胺基酸序列之重鏈可變區、及具有序列編號:50之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(g)包含具有序列編號:51之胺基酸序列之重鏈可變區、及具有序列編號:52之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(h)包含具有序列編號:53之胺基酸序列之重鏈可變區、及具有序列編號:54之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(i)包含具有序列編號:55之胺基酸序列之重鏈可變區、及具有序列編號:56之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(j)包含具有序列編號:57之胺基酸序列之重鏈可變區、及具有序列編號:58之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(k)包含具有序列編號:59之胺基酸序列之重鏈可變區、及具有序列編號:60之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(l)包含具有序列編號:61之胺基酸序列之重鏈可變區、及具有序列編號:62之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(m)包含具有序列編號:63之胺基酸序列之重鏈可變區、及具有序列編號:64之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(n)包含具有序列編號:65之胺基酸序列之重鏈可變區、及具有序列編號:66之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(o)包含具有序列編號:67之胺基酸序列之重鏈可變區、及具有序列編號:68之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(p)包含具有序列編號:69之胺基酸序列之重鏈可變區、及具有序列編號:70之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(q)包含具有序列編號:71之胺基酸序列之重鏈可變區、及具有序列編號:72之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(r)包含具有序列編號:73之胺基酸序列之重鏈可變區、及具有序列編號:74之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(s)包含具有序列編號:75之胺基酸序列之重鏈可變區、及具有序列編號:76之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(t)包含具有序列編號:77之胺基酸序列之重鏈可變區、及具有序列編號:78之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(u)包含具有序列編號:79之胺基酸序列之重鏈可變區、及具有序列編號:80之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;或
(xiv)於上述(xiii)(a)~(u)之任一項所記載之抗體或其抗原結合性片段之可變區之至少一者以上中分別具有至少1個置換、附加或缺失。
[104]一種製造、選擇或鑑定抗體或其結合性片段之方法,其包括
由結合於HER2或其片段之抗體群或其抗原結合性片段群製造、選擇或鑑定滿足下述(xi)之抗體或其抗原結合性片段。
[105]一種製造、選擇或鑑定抗體或其抗原結合性片段之方法,其包括
由結合於HER2或其片段之抗體群或其抗原結合性片段群製造、選擇或鑑定滿足下述(xii)之抗體或其抗原結合性片段。
[106]一種製造、選擇或鑑定抗體或其抗原結合性片段之方法,其包括
由結合於HER2或其片段之抗體群或其抗原結合性片段群製造、選擇或鑑定滿足下述(xiii)之抗體或其抗原結合性片段。
[107]一種製造、選擇或鑑定抗體或其抗原結合性片段之方法,其包括
由結合於HER2或其片段之抗體群或其抗原結合性片段群製造、選擇或鑑定滿足下述(xiv)之抗體或其抗原結合性片段。
[110]如上述[101]至[103]中任一項所記載之方法,其包括使所選擇或鑑定之抗體或其抗原結合性片段產生抗體產生細胞(例如CHO細胞)。
[111]一種抗體,其係藉由如上述[104]至[107]中任一項之方法所獲得。
[112]如上述[104]至[107]中任一項所記載之方法,其中抗體為單株抗體(例如經單離之單株抗體)。
[113]一種醫藥組合物,其包含含有如上述[101]至[103]中任一項所記載之抗體或其抗原結合性片段之HER2標靶藥物。
[114]一種醫藥組合物,其包含如上述[101]至[103]中任一項所記載之抗體或其抗原結合性片段。
[115]如上述[113]或[114]所記載之醫藥組合物,其係用於處置癌。
[120]如上述[104]至[107]中任一項所記載之方法,其中上述HER2係於LN229細胞上表現之HER2。
[121]如上述[104]至[107]中任一項所記載之方法,其中HER2之片段為包含選自由序列編號:31~37所記載之胺基酸序列(例如序列編號:31~36所記載之胺基酸序列)所組成之群中之任一胺基酸序列之肽。
根據本發明,本發明之抗體或其抗原結合性片段可用作HER2標靶藥物。根據本發明,本發明之抗體或其抗原結合性片段例如可用於癌細胞之檢測及/或癌之處置。
<定義>
於本說明書中,「對象」可為哺乳動物,較佳為以人類為對象之「患者」。更佳為罹患有腫瘤或癌、或者具有罹患風險之「癌症患者」。
於本說明書中,「抗體」意指免疫球蛋白,指採用藉由雙硫鍵穩定化之兩條重鏈(H鏈)與兩條輕鏈(L鏈)締合而成之結構之蛋白質。重鏈包含重鏈可變區VH、重鏈恆定區CH1、CH2、CH3、及位於CH1與CH2之間之鉸鏈域,輕鏈包含輕鏈可變區VL與輕鏈恆定區CL。其中,包含VH與VL之可變區片段(Fv)係直接參與抗原結合而對抗體賦予多樣性之區域。又,將包含VL、CL、VH、CH1之抗原結合區域稱為Fab區域,將包含鉸鏈域、CH2、CH3之區域稱為Fc區域。
可變區中直接與抗原接觸之區域之變化尤其大,被稱為互補決定區(complementarity-determining region:CDR)。將CDR以外之變異相對較少之部分稱為架構區(framework region:FR)。於輕鏈與重鏈之可變區分別存在3個CDR,分別自N末端側起依序稱為重鏈CDR1~3及輕鏈CDR1~3。抗體可為重組蛋白(重組抗體),例如可由中國倉鼠卵巢細胞(CHO細胞)等動物細胞產生。抗體之來源並無特別限定,例如可例舉非人類動物之抗體、非人類哺乳動物之抗體(例如小鼠抗體、大鼠抗體、駱駝抗體)、及人類抗體。又,抗體可為嵌合抗體、人類化抗體、及全人類化抗體。抗體可為多株抗體或單株抗體,較佳為單株抗體。「嵌合抗體」係於重鏈可變區及輕鏈可變區分別連結有不同種類之重鏈恆定區及輕鏈恆定區之抗體。人類化抗體意指以來自非人類之抗體中特徵性之胺基酸序列置換人類抗體之相對應之位置而成之抗體,例如可例舉具有免疫小鼠或大鼠所製作之抗體之重鏈CDR1~3及輕鏈CDR1~3、包含重鏈及輕鏈之各4個架構區(FR)在內之其他全部區域來自人類抗體者。該抗體亦存在稱為CDR移植抗體之情形。「人類化抗體」亦存在包含人類嵌合抗體之情形。「人類嵌合抗體」係於來自非人類之抗體中將來自非人類之抗體之恆定區置換為人類之抗體之恆定區之抗體。於人類嵌合抗體中,就提高ADCC(Antibody-dependent cellular cytotoxicity,抗體依賴性細胞毒殺)活性之觀點而言,例如用於恆定區之人類之抗體之亞型可設為IgG1。「全人類化抗體」意指包含FR及CDR之可變區以及恆定區之兩者均來自人類抗體之抗體。又,就增強抗體之細胞毒殺性之目的而言,亦可將抗體設為抗體-藥物複合體之形態。又,抗體亦可為多特異性抗體,例如可為雙特異性抗體、或三特異性抗體。抗體可為經單離之抗體、或經純化之抗體。
於本說明書中,「抗原結合性片段」意指與抗原之結合性得以維持之抗體之一部分。抗原結合性片段可包含本發明之抗體之重鏈可變區或輕鏈可變區或其等兩者。抗原結合性片段可經嵌合化或人類化。作為抗原結合性片段,例如可例舉Fab、Fab'、F(ab')
2、Fv。又,抗體結合性片段可包含藉由重組所生產之結合體或功能性等效物(例如具有scFv(單鏈Fv)、雙功能抗體、scDb、串聯scFv、白胺酸拉鏈型、sc(Fv)
2(單鏈(Fv)
2)等形態之其他抗體之一部分)。此種抗體之抗原結合性片段並無特別限定,例如可利用酶處理抗體而獲得。例如若利用木瓜酶消化抗體,則可獲得Fab。或若利用胃蛋白酶消化抗體,則可獲得F(ab')
2,若將其進一步還原,則可獲得Fab'。於本說明書中,可使用此種抗體之抗原結合性片段。於scFv中,VL及VH經人工之多肽連接子所連結,可維持與原來之抗體相同之抗原特異性。VL及VH可自N末端側起以VH及VL或VL及VH之順序連結。連接子具有10~25個胺基酸左右之長度,富含甘胺酸,就提高水溶性之目的而言,可包含絲胺酸或蘇胺酸等胺基酸。
於本說明書中,「結合速度常數」(ka)及「解離速度常數」(kd)係2分子之結合解離反應中之速度常數。ka及kd為業者所周知之常數,可適當使用周知之技術、例如表面電漿子共振法確定。抗體之結合解離常數(K
D)可藉由kd/ka求出。抗體對於靶分子可具有例如10
-7M以下、10
-8M以下、10
-9M以下、10
-10M以下、10
-11M以下、或10
-12M以下之K
D值。
於本說明書中,結合親和性較強(或較高)意指較強地結合於抗原,例如意指K
D值相對較小。結合親和性較弱(或較低)意指較弱地結合於抗原,結合親和性之高低例如於結合對象為細胞之情形時,可為藉由流式細胞分析結合於細胞之標記抗體之標記量之高低。
於本說明書中,結合於HER2(或其片段)之抗體可為特異性結合於HER2(或其片段)之抗體。此處,特異性意指相較於結合於其他分子(其他種類之分子、突變體、受到其他修飾之分子、或未受到修飾之分子)時之結合親和性,結合於所規定之分子(例如HER2)時之結合親和性更強。特異性結合之抗體例如對於HER2可具有10
-7M以下、10
-8M以下、10
-9M以下、10
-10M以下、10
-11M以下、或10
-12M以下之K
D值。就結合親和性之強度之觀點而言,對於HER2之結合親和性於K
D值方面可較對於下述所特定出之突變體之任一者之結合親和性強2倍以上、3倍以上、4倍以上、5倍以上、6倍以上、7倍以上、8倍以上、9倍以上、10倍以上、100倍以上、1,000倍以上、10,000倍以上、或100,000倍以上。結合親和性之強弱可為統計學上顯著之差異(例如p<0.05、p<0.01、p<0.005、或p<0.0001)。
於本說明書中,「抗體-藥物複合體」(ADC)意指抗體與藥物連結(複合)而成之物質。於ADC中,作為抗體,可有利地使用單株抗體或其抗原結合片段。於ADC中,單株抗體與藥物可經由合適之連接子連結。ADC結合於細胞膜上之膜成分(例如受體等跨膜蛋白),藉由內噬作用或內化作用被吸收至細胞內,與抗體分離而釋放至細胞內。藉由在細胞內於抗體與藥物之間預先導入裂解性連接子,能夠於細胞內、例如內體內使連接子裂解而使藥物自抗體背離從而釋放至細胞質內。若使用細胞毒殺劑作為藥物,則可使被傳遞到藥物之細胞死滅。作為細胞毒殺劑,可使用化學治療劑、放射性同位素、及毒素。
於本說明書中,「HER2標靶藥物」意指包含對於HER2或其片段之結合分子(例如結合於HER2或其片段之抗體或其抗原結合性片段或者包含該抗原結合性片段之融合蛋白),且以HER2作為其標靶而產生其藥效之藥劑。作為HER2標靶藥物,例如可例舉結合於HER2或其片段之抗體或其抗原結合性片段或者包含該等之任一者之藥劑。藥劑可為具有ADCC活性之抗體自身。藥劑例如可為細胞毒殺劑。又,藥劑可為具有細胞毒殺活性之細胞(例如免疫細胞(例如T細胞、NK細胞等))。
於本說明書中,「核酸」意指核糖核酸(RNA)及去氧核糖核酸(DNA)等核苷酸相連而成之高分子。蛋白質係由DNA編碼,並自mRNA轉譯。編碼蛋白質之DNA可與控制序列(例如啟動子)以可作動之方式連結。又,與控制序列以可作動之方式連結之編碼蛋白質之DNA亦可組入至基因表現載體中。編碼蛋白質之DNA亦可為藉由反轉錄而由mRNA製作之cDNA。編碼蛋白質之mRNA可於5'末端具有m7G端帽,於3'末端具有多腺核苷酸尾(poly-A tail)。核糖體結合於編碼蛋白質之mRNA,自mRNA轉譯成蛋白質。
於本說明書中,「癌」係以細胞之無法控制之增殖為特徵之疾病。關於癌細胞,存在局部擴散者、及經由血流或淋巴系統擴散至全身者。作為癌之非限定性之例,例如可例舉實體腫瘤。作為癌之非限定性之例,例如可例舉造血器官腫瘤。作為實體腫瘤,例如可例舉:肺癌、胰腺癌、頭頸部癌、攝護腺癌、膀胱癌、乳癌、食道癌、胃癌、大腸癌、子宮癌、卵巢癌、皮膚癌、甲狀腺癌、胸腺癌、腎癌、睾丸癌、陰莖癌、肝癌、膽道癌、腦瘤、骨軟組織腫瘤、腹膜後腫瘤、血管/淋巴管肉瘤、及該等之轉移性癌(例如轉移性實體腫瘤)。又,作為造血器官腫瘤,可例舉:白血病、急性白血病、慢性白血病、真性紅血球增多症、淋巴瘤、霍奇金病、非霍奇金淋巴瘤(無症狀型及高級別型)、多發性骨髓瘤、華氏巨球蛋白血症、重鏈蛋白質病、骨髓化生不良症候群、毛狀細胞白血病及骨髓化生不良。作為急性白血病,例如可例舉:急性淋巴球性白血病、急性骨髓急性白血病、急性骨髓性白血病、骨髓母細胞性白血病、前骨髓細胞性白血病、骨髓單核球性白血病、單核球性白血病及紅血球性白血病。又,作為慢性白血病,可例舉:慢性骨髓細胞性(粒細胞性)白血病、慢性骨髓性白血病及慢性淋巴球性白血病。癌尤其可為HER2陽性之癌。是否為HER2陽性可由業者使用周知之方法來適當確定。亦可使用本發明之抗體或其抗原結合性片段來確定是否為HER2陽性。
於本說明書中,「處置」包括預防性處置及治療性處置,意指對於患有疾病之患者,減輕或去除疾病之原因,延遲或停止其進展,減輕、緩和、改善或去除其症狀,及/或抑制其症狀之惡化,於疾病為「癌」之情形時,亦包括抑制癌之轉移。
於本說明書中,「HER2」例如可為人HER2。人HER2例如可由以Genebank寄存編號:X03363登錄之鹼基序列(序列編號:1)所編碼。又,人HER2可具有以UniprotKB ID:P04626登錄之胺基酸序列(序列編號:2)。人HER2於序列編號:2之胺基酸序列中,胺基酸編號1~22之胺基酸區域為訊息肽,胺基酸編號23~652之胺基酸區域為胞外域(可具有序列編號:3之胺基酸序列),胺基酸編號653~675之胺基酸區域為跨膜區,胺基酸編號676~1255之胺基酸區域為細胞質域。HER2可包含天然發現之HER2之變種。HER2為標靶,因此其功能可降低或喪失,但亦可保持或增強功能。作為可識別為表位之HER2,例如可具有序列編號:2之胺基酸序列之胺基酸編號611~618之胺基酸區域(MPIWKFPD:序列編號:34)。又,作為可識別為表位之HER2,例如可具有序列編號:2之胺基酸序列之胺基酸編號612~618之胺基酸區域(PIWKFPD:序列編號:35)。於本說明書中,將包含序列編號:2之胺基酸序列之胺基酸編號23~652之胺基酸區域(序列編號:3)之肽稱為「HER2ec」。
HER2可藉由免疫組織化學(IHC)法或螢光原位雜交(FISH)法來檢查其表現或基因擴增。
於IHC法中,可基於2018 ASCO/CAP準則將表現量進行分數化(參照Wolff AC, et al: J Clin Oncol 36 (20), 2018: 2105-2122)。於2018 ASCO/CAP準則中,可以如下4個評分來將HER2之表現量進行分數化:
3+:超過10%之腫瘤細胞可見較強之完全之全周性之膜染色;
2+:超過10%之腫瘤細胞可見弱~中等度之全周性之膜染色;
1+:超過10%之腫瘤細胞可見微弱/勉強可識別之不完全之膜染色;
0:未見染色圖像、或10%以下之腫瘤細胞可見不完全之微弱/勉強可識別之膜染色。
又,於FISH中,可基於2007 ASCO/CAP準則評價基因擴增之程度。HER2基因存在於17號染色體上,因此可藉由測定17號染色體之HER2基因相對於中節數之比而評價基因擴增之程度。HER2之檢查可使用市售之套組實施。
於本說明書中,「與~相對應之胺基酸序列」意指為對準時所對應之胺基酸序列。
2個胺基酸序列之對準例如可使用CLUSTAL W演算法,按照內定參數進行2個或複數個胺基酸序列之對準。對準演算法可使用快速(fast)及慢速(slow)、較佳為慢速(slow)。內定參數例如可設為滿足選自由GAP OPEN:10、GAP EXTENSION:0.1、KTUP:1、WINDOW LENGTH:5、TOPDIAG:5、及PAIRGAP:3所組成之群中之1個以上或全部參數者。藉此,可特定出所對應之胺基酸序列。又,藉此,可確定胺基酸序列之同一性。
於本說明書中,「抗體競爭性地向HER2結合」意指抗體因HER2上之結合部位(表位)重疊、互相爭奪HER2之結合部位等原因,導致兩抗體無法同時結合於HER2。可藉由抗體之競爭試驗確定抗體是否競爭性地向HER2結合。
於本說明書中,「表位」意指抗體所結合之靶分子表面上之部位。
<本發明之抗體或其抗原結合性片段>
本發明之抗體或其抗原結合性片段係結合於HER2或其片段之抗體或其抗原結合性片段。本發明之抗體或其抗原結合性片段可包含具有選自由1~數個胺基酸之插入、缺失、附加及置換所組成之群中之變異之抗體或其抗原結合性片段。於某一實施方式中,提供一種包含與本發明之抗體或其抗原結合性片段中之至少一個CDR、至少兩個、至少三個、或其以上之CDR實質上相同之至少一個CDR、至少兩個、至少三個、或其以上之CDR的抗體或其抗原結合性片段。於其他實施方式中,包含具有與本發明之抗體或其抗原結合性片段中、或者來自本發明之抗體或其抗原結合性片段之至少兩個、三個、四個、五個、或六個CDR實質上相同之至少兩個、三個、四個、五個、或六個CDR的抗體。於某一實施方式中,包含與本發明之抗體或其抗原結合性片段中之至少一個、兩個、或三個CDR至少約85%、86%、87%、88%、89%、90%、95%、96%、97%、98%、或99%相同之至少一個、兩個、三個、四個、五個、或六個CDR。於某一實施方式中,至少一個、兩個、三個、四個、五個、或六個CDR於本發明之抗體或其抗原結合性片段中、或者來自本發明之抗體或其抗原結合性片段之至少一個、兩個、三個、四個、五個、或六個CDR中包含至少一個插入、缺失、附加或置換。本發明之抗體或其抗原結合性片段可包含具有80%以上、85%以上、90%以上、或95%以上之胺基酸序列之同一性、具有抗體之抗原特異性之抗體或其抗原結合性片段。本發明之抗體或其抗原結合性片段可包含於重鏈可變區或輕鏈可變區之架構(FR)區中具有選自由1~數個胺基酸之插入、缺失、附加及置換所組成之群中之變異的抗體或其抗原結合性片段。
本發明之抗體或其抗原結合性片段較佳可為特異性結合於HER2之抗體。本發明之抗體或其抗原結合性片段對在癌細胞上表現之HER2具有結合親和性(或反應性)。因此,可用於對於癌細胞之標靶化。本發明之抗體或其抗原結合性片段更佳為相較於對於在非癌細胞上表現之HER2,而可對於在癌細胞上表現之HER2具有更強之結合親和性(或反應性)。因此,可用於對於癌細胞之特異性之標靶化。本發明之抗體或其抗原結合性片段進而較佳可為與在非癌細胞上表現之HER2不會顯著地反應(例如完全不反應、或無實質性之反應),而與在癌細胞上表現之HER2特異性地反應。因此,可用於對於癌細胞之標靶化(尤其是特異性之標靶化)。
本發明之抗體或其抗原結合性片段就用作醫藥成分之觀點而言,較佳可為單株抗體。本發明之抗體或其抗原結合性片段就用作醫藥成分之觀點而言,較佳為經單離之單株抗體或經單離之單株抗體之抗原結合性片段。根據本發明,可提供一種包含經單離之單株抗體或經單離之單株抗體之抗原結合性片段及醫藥上可容許之添加劑之醫藥組合物。
即,本發明之抗體或其抗原結合性片段係
(i)結合於包含選自由序列編號:31~37之胺基酸序列(例如序列編號:31~36之胺基酸序列)所組成之群中之任一胺基酸序列之肽、抗體或其抗原結合性片段;或
(ii)相較於對於包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有選自由W614A、K615A、及F616A所組成之群中之1種以上胺基酸突變之HER2之胞外域之突變體,對於包含序列編號:3所記載之HER2之胞外域之肽具有更強之結合親和性(或反應性),例如相對於對於包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有包含W614A之點突變之HER2之胞外域之突變體、具有包含F616A之點突變之HER2之胞外域之突變體、具有包含W614A與F616A之2種點突變之變異的HER2之胞外域之突變體、或具有包含K615A與F616A之2種點突變之變異的HER2之胞外域之突變體,對於包含序列編號:3所記載之HER2之胞外域之肽具有更強之結合親和性(或反應性)之抗體或其抗原結合性片段{上述中,HER2之胞外域之一部分可為序列編號:2所記載之胺基酸序列之胺基酸編號613~622之區域}。此處,W614A意指序列編號2所記載之HER2之胺基酸序列中與胺基酸編號614之色胺酸(W)相對應之胺基酸殘基被置換為丙胺酸(A),K615A意指序列編號2所記載之HER2之胺基酸序列中與胺基酸編號615之離胺酸(K)相對應之胺基酸殘基被置換為丙胺酸(A),F616A意指序列編號2所記載之HER2之胺基酸序列中與胺基酸編號616之苯丙胺酸(F)相對應之胺基酸殘基被置換為丙胺酸(A)。上述肽可為合成多肽。上述肽於某一較佳之形態中未受到糖鏈修飾。
對於HER2之結合反應性亦可藉由酵素結合免疫吸附分析(ELISA)進行評價。於ELISA中,例如對於連結於抗體之酵素之存在或量,可藉由相對於該酵素之基質之反應物之量進行評價。例如,若使用辣根過氧化酶(HRP)作為酵素,使用3,3',5,5'-四甲基聯苯胺(TMB)作為基質,則將TMB氧化,顯色為於370 nm與652 nm具有最大吸收之藍色。若使其進而接觸含有硫酸之反應停止液,則顯色為於450 nm具有最大吸收之黃色。例如,藉由測定652 nm之吸光,可推定所反應之抗體量,基於所反應之抗體之量可對抗體對於抗原之反應性進行評價。並且,所反應之抗體之量越多,可評價為抗體對於抗原之反應性越高。並且,於結合反應性(反應之抗體量)方面可較對於上述突變體之結合反應性強1.5倍以上、2倍以上、3倍以上、4倍以上、5倍以上、6倍以上、7倍以上、8倍以上、9倍以上、10倍以上、100倍以上、1,000倍以上、10,000倍以上、或100,000倍以上。結合反應性之強弱可為統計學上顯著之差異(例如p<0.05、p<0.01、p<0.005、或p<0.0001)。
以下,對本發明之抗體或其抗原結合性片段進行詳細說明。
本發明之抗體或其抗原結合性片段均結合於在癌細胞(例如LN229細胞)上表現之HER2。本發明之抗體或其抗原結合性片段較佳為相較於對於在非癌細胞上表現之HER2,對於在癌細胞上表現之HER2具有更強之結合反應性。本發明之抗體或其抗原結合性片段於某一形態中,更佳為結合於在癌細胞(例如LN229細胞)上表現之HER2,對於在非癌細胞(例如正常細胞)上表現之HER2未表現出顯著之結合。
本發明之抗體或其抗原結合性片段
(i)可為結合於包含選自由序列編號:31~37之胺基酸序列(例如序列編號:31~36之胺基酸序列)所組成之群中之任一胺基酸序列之肽的抗體或其抗原結合性片段。包含選自由序列編號:31~37之胺基酸序列(例如序列編號:31~36之胺基酸序列)所組成之群中之任一胺基酸序列之肽可為序列編號:2之胺基酸序列之部分肽。包含選自由序列編號:31~37之胺基酸序列(例如序列編號:31~36之胺基酸序列)所組成之群中之任一胺基酸序列之肽可為序列編號:2之胺基酸序列之部分肽,且為10~20個胺基酸長度、11~19個胺基酸長度、12~18個胺基酸長度、13~17個胺基酸長度、14~16個胺基酸長度、或約15個胺基酸長度。包含選自由序列編號:31~37之胺基酸序列(例如序列編號:31~36之胺基酸序列)所組成之群中之任一胺基酸序列之肽可為包含選自由序列編號:31~37之胺基酸序列(例如序列編號:31~36之胺基酸序列)所組成之群中之任一胺基酸序列之肽。認為該區域於在癌細胞膜上表現之HER2中具有抗體可進出之立體組態,因此,以該區域為標靶之抗體可以強於對於非癌細胞之結合親和性(或反應性)結合於癌細胞。於某一較佳之形態中,以該區域為標靶之抗體不會與在非癌細胞上表現之HER2顯著地反應,而可與在癌細胞上表現之HER2特異性地反應。肽自身無需具有糖鏈修飾,肽可不具有糖鏈修飾。
此處,上述肽並無特別限定,較佳可為合成肽。
本發明之抗體或其抗原結合性片段
(ii)可為相較於對於包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有選自由W614A、K615A、及F616A所組成之群中之1種以上胺基酸突變之HER2之胞外域之突變體,對於包含序列編號:3所記載之HER2之胞外域之肽具有更強之結合親和性(或反應性)的抗體或其抗原結合性片段,或
可為相較於對於包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有包含W614A之點突變之HER2之胞外域之突變體或具有包含K615A與F616A之2種點突變之變異的HER2之胞外域之突變體,對於包含序列編號3所記載之HER2之胞外域之肽具有更強之結合親和性(或反應性)的抗體或其抗原結合性片段,或
可為相較於對於包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有包含K615A之點突變之HER2之胞外域之突變體肽、或具有包含F616A之點突變之HER2之胞外域之突變體肽、或具有包含W614A與F616A之2種點突變之變異的HER2之胞外域之突變體肽,對於包含序列編號3所記載之HER2之胞外域之肽具有更強之結合親和性(或反應性)的抗體或其抗原結合性片段。結合於該區域或其周邊之抗體可以強於對於非癌細胞之結合親和性(或反應性)結合於癌細胞。上述中,HER2之胞外域之一部分可為序列編號:2所記載之胺基酸序列之胺基酸編號613~622之區域。
此處,上述胞外域可為於非癌細胞或癌細胞表現之肽或合成肽。上述胞外域較佳可為合成肽。又,該等抗體可互相競爭性地向包含HER2之胞外域之一部分(胺基酸編號603~622之區域)之肽結合。又,該等抗體可互相競爭地向在癌細胞(例如LN229細胞)上表現之HER2結合。
本發明之抗體或其抗原結合性片段可為
(iii)包含重鏈可變區及輕鏈可變區之抗體或其抗原結合性片段,上述重鏈可變區包含具有序列編號:18之胺基酸序列之重鏈CDR1、
具有序列編號:19之胺基酸序列之重鏈CDR2、及
具有序列編號:20之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:21之胺基酸序列之輕鏈CDR1、
具有序列編號:22之胺基酸序列之輕鏈CDR2、及
具有序列編號:23之胺基酸序列之輕鏈CDR3;
(iv)包含重鏈可變區及輕鏈可變區之抗體或其抗原結合性片段,上述重鏈可變區包含具有序列編號:24之胺基酸序列之重鏈CDR1、
具有序列編號:25之胺基酸序列之重鏈CDR2、及
具有序列編號:26之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:27之胺基酸序列之輕鏈CDR1、
具有序列編號:28之胺基酸序列之輕鏈CDR2、及
具有序列編號:29之胺基酸序列之輕鏈CDR3;
(v)與上述(iii)之抗體競爭性地與HER2結合之抗體或其抗原結合性片段;或
(vi)與上述(iv)之抗體競爭性地與HER2結合之抗體或其抗原結合性片段。又,本發明之抗體或其抗原結合性片段可為於上述(iii)或(iv)之至少一個CDR中具有選自由置換、附加、插入、及缺失所組成之群中之至少1個以上(例如數個,例如2個、3個、4個、或5個)胺基酸之變異的本發明之抗體或其抗原結合性片段。該等抗體或其抗原結合性片段可以強於對於非癌細胞之結合親和性結合於癌細胞。該等抗體或其抗原結合性片段較佳為不會與在非癌細胞上表現之HER2顯著地反應,而可與在癌細胞上表現之HER2特異性地反應。本發明之抗體或其抗原結合性片段可為非人類動物抗體或其抗原結合性片段。非人類動物例如可為嚙齒類,例如可為小鼠。又,本發明之抗體或其抗原結合性片段較佳可為嵌合抗體或人類嵌合抗體。本發明之抗體或其抗原結合性片段更佳可為人類化抗體或人類化抗體之抗原結合性片段。
本發明之抗體或其抗原結合性片段可為
(vii)包含具有序列編號:14之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:15之輕鏈可變區之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(viii)包含具有序列編號:16之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:17之輕鏈可變區之胺基酸序列之輕鏈可變區之抗體或其抗原結合性片段;
(ix)與上述(vii)之抗體競爭性地與HER2{例如包含HER2之胞外域之一部分(胺基酸編號603~622之區域)之肽、或於LN229細胞表現之HER2}結合的抗體或其抗原結合性片段;或
(x)與上述(viii)之抗體競爭性地與HER2{例如包含HER2之胞外域之一部分(胺基酸編號603~622之區域)之肽、或於LN229細胞表現之HER2}結合的抗體或其抗原結合性片段。
又,本發明之抗體或其抗原結合性片段可為於上述(vii)或(viii)之各可變區中具有選自由至少1個置換、附加、插入、及缺失所組成之群中之至少1個以上(例如數個)胺基酸之變異的本發明之抗體或其抗原結合性片段。於某一形態中,各可變區中之選自由置換、附加、插入、及缺失所組成之群中之至少1個以上(例如數個)胺基酸之變異可為CDR以外之變異。
本發明之抗體或其抗原結合性片段可為
(xi)結合於包含序列編號:37之胺基酸序列之肽的抗體或其抗原結合性片段。
本發明之抗體或其抗原結合性片段可為
(xii)包含重鏈可變區及輕鏈可變區之抗體或其抗原結合性片段,上述重鏈可變區包含具有序列編號:81所記載之胺基酸序列之重鏈CDR1、
具有序列編號:82所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:83所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:84所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:85所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:86所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:87所記載之胺基酸序列之重鏈CDR1、
具有序列編號:88所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:89所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:90所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:91所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:92所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:93所記載之胺基酸序列之重鏈CDR1、
具有序列編號:94所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:95所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:96所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:97所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:98所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:99所記載之胺基酸序列之重鏈CDR1、
具有序列編號:100所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:101所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:102所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:103所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:104所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:105所記載之胺基酸序列之重鏈CDR1、
具有序列編號:106所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:107所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:108所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:109所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:110所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:111所記載之胺基酸序列之重鏈CDR1、
具有序列編號:112所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:113所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:114所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:115所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:116所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:117所記載之胺基酸序列之重鏈CDR1、
具有序列編號:118所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:119所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:120所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:121所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:122所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:123所記載之胺基酸序列之重鏈CDR1、
具有序列編號:124所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:125所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:126所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:127所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:128所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:129所記載之胺基酸序列之重鏈CDR1、
具有序列編號:130所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:131所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:132所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:133所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:134所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:135所記載之胺基酸序列之重鏈CDR1、
具有序列編號:136所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:137所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:138所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:139所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:140所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:141所記載之胺基酸序列之重鏈CDR1、
具有序列編號:142所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:143所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:144所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:145所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:146所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:147所記載之胺基酸序列之重鏈CDR1、
具有序列編號:148所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:149所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:150所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:151所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:152所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:153所記載之胺基酸序列之重鏈CDR1、
具有序列編號:154所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:155所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:156所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:157所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:158所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:159所記載之胺基酸序列之重鏈CDR1、
具有序列編號:160所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:161所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:162所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:163所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:164所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:165所記載之胺基酸序列之重鏈CDR1、
具有序列編號:166所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:167所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:168所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:169所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:170所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:171所記載之胺基酸序列之重鏈CDR1、
具有序列編號:172所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:173所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:174所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:175所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:176所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:177所記載之胺基酸序列之重鏈CDR1、
具有序列編號:178所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:179所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:180所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:181所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:182所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:183所記載之胺基酸序列之重鏈CDR1、
具有序列編號:184所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:185所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:186所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:187所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:188所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:189所記載之胺基酸序列之重鏈CDR1、
具有序列編號:190所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:191所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:192所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:193所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:194所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:195所記載之胺基酸序列之重鏈CDR1、
具有序列編號:196所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:197所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:198所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:199所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:200所記載之胺基酸序列之輕鏈CDR3;
上述重鏈可變區包含具有序列編號:201所記載之胺基酸序列之重鏈CDR1、
具有序列編號:202所記載之胺基酸序列之重鏈CDR2、及
具有序列編號:203所記載之胺基酸序列之重鏈CDR3,
上述輕鏈可變區包含具有序列編號:204所記載之胺基酸序列之輕鏈CDR1、
具有序列編號:205所記載之胺基酸序列之輕鏈CDR2、及
具有序列編號:206所記載之胺基酸序列之輕鏈CDR3。
本發明之抗體或其抗原結合性片段可為
(xiii)(a)包含具有序列編號:39之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:40之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(b)包含具有序列編號:41之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:42之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(c)包含具有序列編號:43之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:44之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(d)包含具有序列編號:45之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:46之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(e)包含具有序列編號:47之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:48之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(f)包含具有序列編號:49之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:50之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(g)包含具有序列編號:51之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:52之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(h)包含具有序列編號:53之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:54之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(i)包含具有序列編號:55之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:56之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(j)包含具有序列編號:57之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:58之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(k)包含具有序列編號:59之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:60之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(l)包含具有序列編號:61之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:62之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(m)包含具有序列編號:63之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:64之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(n)包含具有序列編號:65之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:66之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(o)包含具有序列編號:67之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:68之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(p)包含具有序列編號:69之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:70之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(q)包含具有序列編號:71之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:72之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(r)包含具有序列編號:73之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:74之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(s)包含具有序列編號:75之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:76之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(t)包含具有序列編號:77之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:78之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;
(u)包含具有序列編號:79之重鏈可變區之胺基酸序列之重鏈可變區、及具有序列編號:80之輕鏈可變區之胺基酸序列之輕鏈可變區的抗體或其抗原結合性片段;或
(xiv)與上述(xii)(a)~(u)之各抗體競爭性地與HER2{例如包含HER2之胞外域之一部分(胺基酸編號603~622之區域)之肽、或於LN229細胞表現之HER2}結合的抗體或其抗原結合性片段。
如業者所明瞭,上述(xi)~(xiv)之抗體或其抗原結合性片段可應用下文記載之本發明之抗體或其抗原結合性片段之說明等。
本發明之抗體或其抗原結合性片段可為相較於對於在非癌細胞上表現之HER2而對於在癌細胞上表現之HER2具有更強之結合親和性(或反應性)的經單離之單株抗體或抗體之抗原結合性片段,更佳為不會與在非癌細胞上表現之HER2顯著地反應而可與在癌細胞上表現之HER2特異性地反應的經單離之單株抗體或抗體之抗原結合性片段,且
滿足上述(i)~(xiv)之任一者以上。
於該形態中,本發明之抗體或其抗原結合性片段可具有上述(i)或(ii)之任一者以上之輪廓。進而,具體而言,亦可僅具有上述(i)之輪廓、僅具有上述(ii)之輪廓、或具有上述(i)及(ii)之輪廓。
於該形態中,本發明之抗體或其抗原結合性片段可滿足選自由上述(v)、(vi)、(ix)、(x)、(xi)、(xii)、(xiii)、及(xiv)所組成之群中之一者以上與上述(i)。於該形態中,本發明之抗體或其抗原結合性片段可滿足選自由上述(v)、(vi)、(ix)、(x)、(xi)、(xii)、(xiii)、及(xiv)所組成之群中之一者以上與上述(ii)。於該形態中,本發明之抗體或其抗原結合性片段可滿足選自由上述(v)、(vi)、(ix)、(x)、(xi)、(xii)、(xiii)、及(xiv)所組成之群中之一者以上與上述(i)及(ii)。該等抗體或其抗原結合性片段可以強於對於非癌細胞之結合親和性(或反應性)結合於癌細胞。該等抗體或其抗原結合性片段較佳為不會與在非癌細胞上表現之HER2顯著地反應,而可與在癌細胞上表現之HER2特異性地反應。
本發明之抗體或其抗原結合性片段可為滿足上述(i)~(xiv)之任一者以上之抗體或其抗原結合性片段。
於該形態中,本發明之抗體或其抗原結合性片段可具有上述(i)及(ii)之任一者以上之輪廓。進而,具體而言,可僅具有上述(i)之輪廓、僅具有上述(ii)之輪廓、或具有上述(i)及(ii)之輪廓。該等抗體或其抗原結合性片段可以強於對於非癌細胞之結合親和性(或反應性)結合於癌細胞。該等抗體或其抗原結合性片段較佳為不會與在非癌細胞上表現之HER2顯著地反應,而可與在癌細胞上表現之HER2特異性地反應。
於該形態中,本發明之抗體或其抗原結合性片段可滿足選自由上述(v)、(vi)、(ix)、(x)、(xi)、(xii)、(xiii)、及(xiv)所組成之群中之一者以上與上述(i)。於該形態中,本發明之抗體或其抗原結合性片段可滿足選自由上述(v)、(vi)、(ix)、(x)、(xi)、(xii)、(xiii)、及(xiv)所組成之群中之一者以上與上述(ii)。於該形態中,本發明之抗體或其抗原結合性片段可滿足選自由上述(v)、(vi)、(ix)、(x)、(xi)、(xii)、(xiii)、及(xiv)所組成之群中之一者以上與上述(i)及(ii)。
本發明之抗體可具有抗體依賴性細胞毒殺(ADCC)活性及/或補體依賴性細胞毒殺(CDC)活性。ADCC活性意指於本發明之抗體結合於靶細胞之細胞表面抗原時,Fcγ受體保有細胞(效應細胞)經由Fcγ受體結合於其Fc部分,而對靶細胞造成傷害之活性。
ADCC活性可藉由將表現HER2之靶細胞(癌細胞、例如LN229細胞或SK-BR-3細胞)、效應細胞及本發明之抗體混合並測定ADCC之程度而進行評價。作為效應細胞,例如可利用小鼠脾細胞、自人周邊血液或骨髓分離之單核細胞。作為靶細胞,例如可使用HER2陽性乳癌細胞。預先以
51Cr等標記靶細胞,於其中加入本發明之抗體加以培養,其後添加相對於靶細胞之比合適之效應細胞(效應細胞可經活化)進行培養。培養後,採集上清液,對上清液中之上述標記進行計數,藉此可測定ADCC活性。CDC活性意指利用補體系統之細胞毒殺活性。CDC活性可藉由在ADCC活性之試驗中使用補體代替效應細胞而測定。
本發明之抗體可為於Fc區域結合1條以上N-結合型糖鏈且於該N-結合型糖鏈之還原末端之N-乙醯葡糖胺未結合岩藻糖之抗體。例如於IgG抗體之Fc區域存在兩處N-結合型糖鏈之結合部位,於該部位結合有複合型糖鏈。N-結合型糖鏈係指結合於Asn-X-Ser/Thr序列之Asn之糖鏈,具有共通之結構Man3GlcNAc2-Asn。根據結合於非還原末端之2個甘露糖(Man)之糖鏈之種類,而分類為高甘露糖型、混成型、及複合型等。已知可於N-結合型糖鏈之還原末端之N-乙醯葡糖胺(GlcNAc)結合岩藻糖,但於未結合該岩藻糖之情形時,與結合之情形相比,ADCC活性顯著上升。該內容例如記載於國際公開第2002/031140號說明書中,其揭示整體藉由參照併入本說明書中。藉由ADCC活性顯著提高,於將抗體用作醫藥之情形時可減少投予量,因此可減輕副作用,並且亦可降低治療費。為了提高ADCC活性,可將用於抗體之恆定區的人類之抗體之亞型設為IgG1。
<抗體-藥物複合體>
根據本發明,提供一種本發明之抗體或其抗原結合片段與藥物之複合體(抗體-藥物複合體;ADC)。於本發明之ADC中,抗體或其抗原結合片段與藥物(例如為具有毒殺細胞之特性之成分,例如為細胞毒殺劑)可經由連接子連結。於本發明之ADC中,作為細胞毒殺劑,可例舉:化學治療劑(例如市售之抗癌劑等抗癌劑,例如奧瑞他汀(奧瑞他汀E、奧瑞他汀F苯二胺(AFP)、單甲基奧瑞他汀E、單甲基奧瑞他汀F及該等之衍生物)、美登木素生物鹼DM1及DM4及該等之衍生物)、喜樹鹼(SN-38、托泊替康及依喜替康及該等之衍生物)、DNA小溝結合劑(烯二炔、Lexitropsin、多卡米星及該等之衍生物)、紫杉烷(紫杉醇及歐洲紫杉醇及該等之衍生物)、聚酮化合物(圓皮海綿內酯及其衍生物)、蒽醌系(米托蒽醌及其衍生物)、苯二氮呯(吡咯并苯二氮呯、吲哚啉苯二氮呯、及㗁唑啶酮苯二氮呯及該等之衍生物)、長春花屬生物鹼(長春新鹼、長春花鹼、長春地辛、及長春瑞賓及該等之衍生物)、多柔比星類(多柔比星、嗎啉-多柔比星、及氰基嗎啉-多柔比星及該等之衍生物)、強心苷(洋地黃毒苷或其衍生物)、卡奇黴素、埃博黴素、念珠藻素、西馬多丁、西馬多丁、根瘤菌素、紡錘黴素、考布他汀、軟珊瑚醇、依託泊苷、T67(Tularik)、及諾考達唑)、放射性同位素(例如
32P、
60C、
90Y、
111In、
131I、
125I、
153Sm、
186Re、
188Re、及
212Bi)、及毒素(例如白喉毒素A、假單胞菌內毒素、蓖麻毒蛋白、皂草素等),可用作本發明之ADC中之細胞毒殺劑。細胞毒殺劑均可使用癌之處置所使用者。
抗體較理想為內化於癌細胞內之抗體,但亦可使用不內化之抗體。其原因在於:只要將抗癌劑傳遞至癌周邊組織,則可藉由旁觀者效應毒殺癌。
於本發明之某一形態中,連接子可為非裂解性連接子或裂解性連接子。抗體與連接子之結合例如可經由馬來醯亞胺基連結於抗體之硫氫基。連接子可視需要包含聚乙二醇嵌段。
例如,作為裂解性連接子,可例舉纈胺酸-瓜胺酸(Val-Cit)及苯丙胺酸-離胺酸(Phe-lys)連接子等肽連接子、或pH值依賴性地裂解之腙連接子。又,作為裂解性連接子,可例舉包含胺基甲酸酯鍵或酯鍵之連接子,該等可於細胞內酶性分解。該等連接子亦可組合使用。
於本發明之某一形態中,可藉由馬來醯亞胺基-PEG(Polyethylene Glycol,聚乙二醇)-Val-Cit將抗體與細胞毒殺劑連結。於本發明之某一形態中,可使用本案實施例所使用之連接子(例如馬來醯亞胺基-PEG-Val-Cit-PABA-細胞毒殺劑)。
又,亦可於連接子與細胞毒殺劑之間介存間隔子。
<本發明之抗體之製造方法>
本發明之抗體可藉由以(i)包含選自由序列編號:31~37之胺基酸序列(例如序列編號:31~36之胺基酸序列)所組成之群中之任一者以上之胺基酸序列之肽作為免疫原投予至動物而獲得。於某一形態中,本發明之抗體可藉由以包含序列編號:31之胺基酸序列之肽作為免疫原投予至動物而獲得。於某一形態中,本發明之抗體可藉由以包含序列編號:32之胺基酸序列之肽作為免疫原投予至動物而獲得。於某一形態中,本發明之抗體可藉由以包含序列編號:33之胺基酸序列之肽作為免疫原投予至動物而獲得。於某一形態中,本發明之抗體可藉由以包含序列編號:34之胺基酸序列之肽作為免疫原投予至動物而獲得。於某一形態中,本發明之抗體可藉由以包含序列編號:35之胺基酸序列之肽作為免疫原投予至動物而獲得。於某一形態中,本發明之抗體可藉由以包含序列編號:36之胺基酸序列之肽作為免疫原投予至動物而獲得。又進而,本發明之抗體可藉由以包含序列編號:37之胺基酸序列之肽作為免疫原投予至動物而獲得。肽可為合成肽。
又,本發明之抗體可藉由以HER2ec等HER2之胞外域部分作為免疫原投予至動物而獲得。又,本發明之抗體亦可藉由噬菌體呈現等業者所周知之方法而獲得。HER2之胞外域部分可為合成肽。HER2之胞外域部分可表現於細胞、例如非癌細胞或癌細胞、例如癌細胞株(例如LN229細胞)。
免疫原對動物之免疫可藉由業者周知之方法進行。例如可使用自經免疫之動物獲得之體液(例如血液、血漿、或血清)或免疫細胞(例如脾臟細胞)確認是否已產生對於HER2或其部分肽之抗體。單株抗體可由業者藉由融合瘤法等周知之方法製作。融合瘤可藉由業者所周知之方法製作。製作後,藉由極限稀釋法將融合瘤製成單純系。單株抗體可分泌至融合瘤上清液中。業者可藉由結合分析(結合試驗)確認單株抗體是否具有所需之結合特性。
例如,抗體是否以強於對於非癌細胞之結合親和性結合於癌細胞、即是否不會與在非癌細胞上表現之HER2顯著地反應而可與在癌細胞上表現之HER2特異性地反應可由業者容易地試驗。試驗較佳可為試管內之試驗。試驗例如可使用癌細胞株、尤其是HER2陽性之癌細胞株(例如SK-BR-3細胞)作為癌細胞。又,試驗例如可使用非癌細胞株或正常細胞株、尤其是HER2陽性之非癌細胞株或正常細胞株(例如HaCaT細胞)作為非癌細胞。例如將細胞進行單細胞化,藉由流式細胞分析對與標記抗體之相互作用進行分析,藉此可確定是否以強於對於非癌細胞之結合親和性結合於癌細胞。標記可使用螢光標記等業者所周知之標記。又,對於表現HER2之癌細胞之結合反應性(反應之抗體量)可較對於表現HER2之正常細胞之結合反應性強1.5倍以上、2倍以上、3倍以上、4倍以上、5倍以上、6倍以上、7倍以上、8倍以上、9倍以上、10倍以上、100倍以上、1,000倍以上、10,000倍以上、或100,000倍以上。結合反應性之強弱可為統計學上顯著之差異(例如p<0.05、p<0.01、p<0.005、或p<0.0001)。對於癌細胞之結合反應性例如可使用流式細胞分析進行評價。於藉由流式細胞分析確定結合親和性或反應性之情形時,例如可將峰值加以比較。抗體對於非癌細胞(例如正常細胞)未表現出顯著之結合可藉由試驗抗體對於非癌細胞株(例如正常細胞株、尤其是HER2陽性之非癌細胞株或正常細胞株(例如HaCaT細胞))是否表現出顯著之結合而確定。
例如,本發明之抗體或其抗原結合性片段是否滿足上述(i)可藉由分析而試驗融合瘤上清液與包含選自由序列編號:31~37之胺基酸序列(例如序列編號:31~36之胺基酸序列)所組成之群中之任一胺基酸序列之肽各者是否結合。例如,可藉由常規方法將肽固相化,分析融合瘤上清液中之抗體是否與其結合,並使用與融合瘤所產生之抗體特異性地反應之標記二次抗體進行檢測。亦可使用表面電漿子共振(SPR)進行檢測。同樣地,本發明之抗體或其抗原結合性片段是否滿足上述(ii)可藉由如下方法確定:藉由分析試驗融合瘤上清液中之抗體與包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有選自由W614A、K615A、及F616A所組成之群中之1種以上胺基酸突變之肽(例如具有包含W614A之點突變之HER2之胞外域之突變體;或具有包含K615A與F616A之2種點突變之變異的HER2之胞外域之突變體;或具有包含K615A之點突變之HER2之胞外域之突變體、或具有包含F616A之點突變之HER2之胞外域之突變體、或具有包含W614A與F616A之2種點突變之變異的HER2之胞外域之突變體)是否結合;及藉由分析試驗融合瘤上清液中之抗體與包含序列編號3所記載之HER2之胞外域之肽是否結合。例如,若使用表面電漿子共振(SPR),則可求出結合解離常數(K
D),以K
D之大小作為指標,可簡單地確定是否滿足上述(ii)。因此,根據本發明,可提供一種選擇或鑑定抗體或其抗原結合性片段之方法,其包括自抗體或其抗原結合性片段群、例如結合於HER2或其片段之抗體或其抗原結合性片段群中選擇或鑑定滿足上述(i)之抗體或其抗原結合性片段。又,根據本發明,可提供一種選擇或鑑定抗體或其抗原結合性片段之方法,其包括自抗體或其抗原結合性片段群、例如結合於HER2或其片段之抗體或其抗原結合性片段群中選擇或鑑定滿足上述(ii)之抗體或其抗原結合性片段。該等方法可包括自藉由該等方法所選擇或鑑定之抗體或其抗原結合性片段群中進一步選擇或鑑定相較於對於在非癌細胞上表現之HER2而對於在癌細胞上表現之HER2具有更強之結合反應性的抗體或其抗原結合性片段、即不會與在非癌細胞上表現之HER2顯著地反應而可與在癌細胞上表現之HER2特異性地反應之抗體或其抗原結合性片段。再者,上述中,於HER2之胞外域之一部分為序列編號:2所記載之胺基酸序列之胺基酸編號603~622之區域之情形時,可使用該肽中具有上述點突變之突變體,藉由同樣之分析試驗抗體或其抗原結合性片段。
抗體競爭性地向HER2結合、及抗體具有互相類似之結合特性之情況可藉由競爭分析來進行驗證。與某一抗體競爭性地與抗原(例如HER2或其片段)結合之抗體可藉由業者所周知之競爭分析等來獲得。只要藉由競爭分析可阻斷例如至少20%、較佳為至少20~50%、進而較佳為至少50%、更佳為60%、更佳為70%、更佳為80%、尤佳為90%以上之所需之抗體之結合,則可製成於對於相同之抗原之結合中競爭之抗體。競爭之抗體可藉由交叉阻斷分析、流式細胞分析、螢光能量轉移測定法(FRET)或螢光微量測定(FMAT(註冊商標))、較佳為競爭ELISA分析進行確認。於交叉阻斷分析中,將抗原塗佈於例如微量滴定盤上,於其中添加成為候補之競爭抗體存在進行培養,而形成抗原與候補抗體之結合。其後,於標記所需之抗體後,進而添加至孔中進行培養並洗淨,對所需之抗體之結合量進行定量,藉此可判斷抗體是否競爭。於競爭之情形時,殘存於孔中之標記量應當會減少。
通常於競爭分析中,不可僅因為抗體A使抗體B與抗原之結合解離,便認為抗體B使抗體A與抗原之結合解離。關於該情況,考慮抗體A相較於抗體B而對抗原表現出極強之結合之情形便可容易地理解。為了獲得結合特性相近之抗體,確認抗體A使抗體B與抗原之結合解離,且抗體B使抗體A與抗原之結合解離即可,於本說明書中,將此種競爭狀態稱為「抗體A與抗體B於與抗原之結合中互相競爭」。
因此,本發明之抗體或其抗原結合性片段是否滿足上述(v)、(vi)、(ix)、及(x)之任一者可分別藉由確認是否與上述(iii)、(iv)、(vii)、(viii)及(xiii)之任一抗體競爭性地與HER2或其片段(包含表位之肽等)結合而確定。因此,根據本發明,提供一種選擇或鑑定抗體或其抗原結合性片段之方法,其包括自結合於HER2或其片段之抗體或其抗原結合性片段群中選擇或鑑定與上述(iii)、(iv)、(vii)、(viii)及(xiii)之任一抗體競爭性地與HER2或其片段(包含表位之肽等)結合的抗體或其抗原結合性片段。該方法可包括自藉由該等方法所選擇或鑑定之抗體或其抗原結合性片段群中進一步選擇或鑑定相較於對於在非癌細胞上表現之HER2而對於在癌細胞上表現之HER2具有更強之結合反應性的抗體或其抗原結合性片段。作為HER2之片段,可使用包含選自由序列編號:31~37之胺基酸序列(例如序列編號:31~36之胺基酸序列)所組成之群中之任一胺基酸序列之肽。作為HER2之片段,可使用HER2ec。作為HER2,可使用於LN229細胞膜上表現之HER2。根據本發明,可以上述方式獲得本發明之抗體或其抗原結合性片段。
可以上述方式選擇具有本發明之抗體之結合特性的單株抗體而獲得。所獲得之單株抗體之胺基酸序列可於獲得抗體後確定。例如,自產生單株抗體之融合瘤提取RNA,合成cDNA,並確定編碼免疫球蛋白之cDNA之序列,藉此可確定編碼所獲得之單株抗體之基因之鹼基序列。可根據鹼基序列確定單株抗體之胺基酸序列。可自單株抗體之胺基酸序列推定重鏈CDR1~3之胺基酸序列及輕鏈CDR1~3之胺基酸序列。CDR之推定例如可藉由Kabat之編號系統(Kabat E. A. et al., (1991) Sequences of proteins of immunological interest. NIH Publication 91-3242))、Chothia(Al-lazikani et al., (1997) J. Mol. Biol. 273: 927-948)、Aho、IMGT、CCG等或該等各方法之組合而進行。又,根據編號系統所推定之CDR區域可變化亦為周知之事實。以上述方式,可設計、或製作具有重鏈CDR1~3之胺基酸序列及輕鏈CDR1~3之胺基酸序列之抗體。
抗體之抗原結合性片段可藉由業者所周知之方法製作。例如,Fab片段可藉由利用木瓜酶消化抗體而製作。例如,F(ab')
2可藉由利用胃蛋白酶消化抗體而製作。例如,Fab'可藉由利用還原劑處理F(ab')
2而製作。例如,scFv可藉由各種方法構建。例如,可將重鏈可變區之C末端連結於輕鏈可變區之N末端。通常將連接子(例如(GGGGS)
4,序列編號:38)於重鏈可變區與輕鏈可變區之間配置。但,可連結鏈之順序可設為相反,可將輕鏈可變區之C末端連結於重鏈可變區之N末端。可包含使scFv之檢測或純化變得容易之標籤(例如Myc標籤、His標籤或FLAG標籤)。
根據本發明,提供一種抗體或其抗原結合性片段之製造方法。本發明之製造方法可包括以HER2之肽(例如包含序列編號:31~37之胺基酸序列之任一者之肽、例如包含序列編號:31~36之胺基酸序列之肽、例如包含序列編號:31所記載之胺基酸序列之肽、例如包含序列編號:32所記載之胺基酸序列之肽、例如包含序列編號:33所記載之胺基酸序列之肽、例如包含序列編號:34所記載之胺基酸序列之肽、例如包含序列編號:35所記載之胺基酸序列之肽、例如包含序列編號:36所記載之胺基酸序列之肽、例如包含序列編號37所記載之胺基酸序列之肽)或於癌細胞中表現之HER2(例如HER2之胞外域)作為免疫原投予至動物。又,本發明之製造方法可包括試驗(或確認)所獲得之抗體對於在癌細胞中表現之HER2表現出較於非癌細胞中表現之HER2更強之反應性。又,本發明之製造方法可包括試驗(或確認)不會與在非癌細胞上表現之HER2顯著地反應而可與在癌細胞上表現之HER2特異性地反應。又,本發明之製造方法可包括試驗(或確認)所獲得之抗體為本發明之抗體(具有本發明之抗體之結合特性)。若確認所獲得之抗體對於在癌細胞中表現之HER2表現出較於非癌細胞中表現之HER2更強之反應性、不會與在非癌細胞上表現之HER2顯著地反應而可與在癌細胞上表現之HER2特異性地反應及/或為本發明之抗體(具有本發明之抗體之結合特性),則可選擇該抗體。抗體可使用包含編碼抗體之核酸之重組抗體產生細胞(例如CHO細胞等)而產生。於本發明之製造方法中,於必要之情形時,可將所產生之抗體純化。
根據本發明,提供一種選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括自結合於HER2(例如於LN229細胞表現之HER2、包含序列編號:31~37之胺基酸序列之任一者之肽、例如包含序列編號:31~36之胺基酸序列之肽)之抗體群或其抗原結合性片段群中選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而對於在癌細胞上表現之HER2具有特異性之反應性的抗體或其抗原結合性片段。於某一形態中,結合於HER2或其片段之抗體或其抗原結合性片段群可結合於由LN229細胞產生之HER2ec蛋白質。於某一形態中,結合於HER2或其片段之抗體或其抗原結合性片段群可結合於包含序列編號:31~37之胺基酸序列(例如序列編號:31~36之胺基酸序列)之任一者之肽。
根據本發明,提供一種選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括自上述任一抗體或抗體之抗原結合性片段中選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而對於在癌細胞株(例如LN229細胞)上表現之HER2具有特異性之反應性之抗體或抗體之抗原結合性片段。
例如,根據本發明,提供一種選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括自可結合於由LN229細胞產生之HER2ec蛋白質之抗體群或其抗原結合性片段群中選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而對於在癌細胞上表現之HER2具有特異性之反應性的抗體或其抗原結合性片段。
又,根據本發明,提供一種選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括自可結合於包含選自由序列編號:31~37之胺基酸序列(例如序列編號:31~36之胺基酸序列)之任一者所組成之群中之任一胺基酸序列的肽之抗體群或其抗原結合性片段群中選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而對於在癌細胞上表現之HER2具有特異性之反應性的抗體或其抗原結合性片段。
進而,根據本發明,提供一種選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括自相較於對於包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有選自由W614A、K615A、及F616A所組成之群中之1種以上胺基酸突變之HER2之胞外域之突變體而對包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽具有更強之結合親和性(或反應性)之抗體群或其抗原結合性片段群中選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而對於在癌細胞上表現之HER2具有特異性之反應性的抗體或其抗原結合性片段。
進而又,根據本發明,提供一種選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括自相較於對於包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有包含W614A之點突變之肽、或者具有包含K615A或F616A之點突變之肽而對包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽具有更強之反應性之抗體群或其抗原結合性片段群中選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而對於在癌細胞上表現之HER2具有特異性之反應性的抗體或其抗原結合性片段。
進而又,根據本發明,提供一種選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括自相較於對於包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有包含F616A之點突變之HER2之胞外域之突變體、具有包含W614A與F616A之2種點突變之變異的肽而對包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽具有更強之反應性之抗體群或其抗原結合性片段群中選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而對於在癌細胞上表現之HER2具有特異性之反應性的抗體或其抗原結合性片段。
又,本發明之抗體或其抗原結合性片段可藉由自上述(iii)、(iv)、及(xii)之任意且至少一個CDR中具有選自由置換、附加、插入、及缺失所組成之群中之至少1個以上(例如數個)胺基酸之變異的抗體或其抗原結合性片段群中選擇不會與在非癌細胞上表現之HER2顯著地反應而對於在癌細胞上表現之HER2具有特異性之反應性的抗體或其抗原結合性片段而獲得。因此,根據本發明,提供一種選擇或鑑定抗體或其抗原結合性片段之方法,其包括自上述(iii)、(iv)、及(xii)之任意且至少一個CDR中具有選自由置換、附加、插入、及缺失所組成之群中之至少1個以上(例如數個)胺基酸之變異的抗體或其抗原結合性片段群中選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而對於在癌細胞上表現之HER2具有特異性之反應性的抗體或其抗原結合性片段。
又,本發明之抗體或其抗原結合性片段可藉由自如下抗體或其抗原結合性片段群中選擇不會與在非癌細胞上表現之HER2顯著地反應而對在癌細胞上表現之HER2具有特異性之反應性的抗體或其抗原結合性片段而獲得,上述抗體或其抗原結合性片段群在上述(vii)、(viii)、及(xiii)之任意且至少一個可變區中具有選自由置換、附加、插入、及缺失所組成之群中之至少1個以上(例如數個)之胺基酸變異。因此,根據本發明,提供一種選擇或鑑定抗體或其抗原結合性片段之方法,其包括自如下抗體或其抗原結合性片段群中選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而對在癌細胞上表現之HER2具有特異性之反應性的抗體或其抗原結合性片段,上述抗體或其抗原結合性片段群在上述(vii)、(viii)、及(xiii)之任意且至少一個可變區中具有選自由置換、附加、插入、及缺失所組成之群中之至少1個以上(例如數個)之胺基酸變異。
如上所述,可選擇或鑑定本發明之抗體或抗體之抗原結合性片段。於選擇或鑑定本發明之抗體或抗體之抗原結合性片段後,可將編碼該等之基因導入抗體產生細胞(例如CHO細胞等),而自抗體產生細胞回收該等抗體或抗體之抗原結合性片段。本發明之抗體或抗體之抗原結合性片段可視需要進行人類化。本發明之抗體或抗體之抗原結合性片段可經單離,例如可使用蛋白A或G柱進行單離。進而,經單離之本發明之抗體或抗體之抗原結合性片段可與藥學上可容許之賦形劑混合。或者,經單離之本發明之抗體或抗體之抗原結合性片段可與藥物(例如細胞毒殺劑)複合。藉此,本發明之抗體或抗體之抗原結合性片段可將藥物靶向表現HER2之癌細胞。
根據本發明,可提供一種選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括
自可結合於HER2(例如於LN229細胞表現之HER2)或其片段之抗體群或抗體之抗原結合性片段群中選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而對在癌細胞上表現之HER2具有特異性之反應性的抗體或抗體之抗原結合性片段。
又,根據本發明,提供一種選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括
自結合於HER2或其片段之抗體群或抗體之抗原結合性片段群中選擇或鑑定滿足選自上述(i)或(ii)中之至少一者之抗體或抗體之抗原結合性片段:
(i)結合於包含選自由序列編號:31~37之胺基酸序列(例如序列編號:31~36之胺基酸序列)所組成之群中之任一胺基酸序列之肽;或
(ii)相較於對於在包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有選自由W614A、K615A、及F616A所組成之群中之1種以上之胺基酸突變的HER2之胞外域之突變體,對於包含序列編號:3所記載之HER2之胞外域之肽具有更強結合親和性(或反應性),或者
相較於對於在包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有包含W614A之點突變之肽、或者具有包含K615A或F616A之點突變之肽,對於包含序列編號:3所記載之HER2之胞外域之肽具有更強之反應性。
進而,根據本發明,提供一種選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括
自滿足選自上述(i)或(ii)中之至少一者之抗體群或抗體之抗原結合性片段群中選擇或鑑定結合於HER2或其片段之抗體或其抗原結合性片段:
(i)結合於包含選自由序列編號:31~37之胺基酸序列(例如序列編號:31~36之胺基酸序列)所組成之群中之任一胺基酸序列之肽;或
(ii)相較於對於在包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有選自由W614A、K615A、及F616A所組成之群中之1種以上之胺基酸突變的HER2之胞外域之突變體,對於包含序列編號:3所記載之HER2之胞外域之肽具有更強之結合親和性(或反應性),或者
相較於對於在包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有包含W614A之點突變之肽、或者具有包含K615A或F616A之點突變之肽,對於包含序列編號:3所記載之HER2之胞外域之肽具有更強之反應性。
於該等形態中,本發明可進而包括自所獲得之抗體或抗體之抗原結合性片段群中選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而對在癌細胞上表現之HER2具有特異性之反應性的抗體或抗體之抗原結合性片段。
又,根據本發明,提供一種選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括
自上述(iii)或(iv)之任意且至少一個CDR中具有選自由置換、附加、插入、及缺失所組成之群中之至少1個以上胺基酸之變異的抗體群或抗體之抗原結合性片段群中選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而對於在癌細胞上表現之HER2具有特異性之反應性之抗體或抗體之抗原結合性片段。
又,根據本發明,提供一種選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括
自上述(vii)或(viii)之任意且至少一個可變區中具有選自由置換、附加、插入、及缺失所組成之群中之至少1個以上胺基酸之變異的抗體群或抗體之抗原結合性片段群中選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而對於在癌細胞上表現之HER2具有特異性之反應性之抗體或抗體之抗原結合性片段。
又,根據本發明,提供一種選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括
自上述(xii)或(xiii)之任意且至少一個CDR或可變區中具有選自由置換、附加、插入、及缺失所組成之群中之至少1個以上胺基酸之變異的抗體群或抗體之抗原結合性片段群中選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而對於在癌細胞上表現之HER2具有特異性之反應性之抗體或抗體之抗原結合性片段。
本發明之選擇或鑑定抗體或抗體之抗原結合性片段之方法可為選擇或鑑定經人類化之抗體或抗體之抗原結合性片段、或者人類抗體或人類抗體之抗體結合性片段之方法。本發明之選擇或鑑定抗體或抗體之抗原結合性片段之方法亦可為選擇或鑑定經單離及/或純化之抗體或抗體之抗原結合性片段之方法。
根據本發明,提供一種包括選擇或鑑定上述本發明之抗體或抗體之抗原結合性片段之抗體或抗體之抗原結合性片段之製造方法。於該製造方法中,抗體或抗體之抗原結合性片段可將編碼其之基因導入抗體產生細胞而自抗體產生細胞產生。抗體或抗體之抗原結合性片段亦可進行人類化而製成人類化抗體或人類化抗體之抗原結合性片段。抗體或抗體之抗原結合性可進行單離及/或純化而加以應用。例如,抗體或抗體之抗原結合性片段可與藥學上可容許之賦形劑混合並製劑化而製成醫藥組合物。
<本發明之醫藥組合物>
根據本發明,提供一種包含本發明之抗體或其抗原結合性片段之醫藥組合物。本發明之醫藥組合物可包含本發明之抗體或其抗原結合性片段與藥學上可容許之載體或添加物。作為載體及添加物之例,可例舉:水、食鹽水、磷酸緩衝液、右旋糖、丙三醇、乙醇等藥學上所容許之有機溶劑、膠原蛋白、聚乙烯醇、聚乙烯吡咯啶酮、羧基乙烯基聚合物、羧甲基纖維素鈉、聚丙烯酸鈉、海藻酸鈉、水溶性聚葡萄糖、羧甲基澱粉鈉、果膠、甲基纖維素、乙基纖維素、三仙膠、阿拉伯膠、酪蛋白、瓊脂、聚乙二醇、雙甘油、甘油、丙二醇、凡士林、石蠟、硬脂醇、硬脂酸、人血清白蛋白、甘露醇、山梨醇、乳糖、界面活性劑等,但不限定於該等。
根據本發明,可提供一種含有包含本發明之抗體或其抗原結合性片段之HER2標靶藥物(亦稱為HER2靶向療法藥)之醫藥組合物。本發明之醫藥組合物可用於處置癌。
根據本發明,提供一種包含本發明之抗體或其抗原結合性片段之標靶藥物、及包含該標靶藥物之醫藥組合物。例如,根據本發明,提供一種包含本發明之抗體或其抗原結合性片段與藥物(例如細胞毒殺劑)之抗體藥物複合體(ADC)之醫藥組合物。本發明之醫藥組合物可用於處置癌。
<其他>
根據本發明,提供一種於自對象獲得之癌樣本中檢測HER2陽性之癌細胞之方法,其包括使上述癌樣本與本發明之抗體或抗體或其抗原結合性片段接觸。於該方法中,於生物樣本中之HER2與抗HER2抗體或其抗原結合性片段形成複合體時,可確定檢測到HER2陽性之癌細胞。又,根據本發明,可提供一種對利用包含本發明之抗體或抗體或其抗原結合性片段之HER2標靶藥物進行之HER2靶向療法之有效性進行確定的方法,其包括:使自對象獲得之生物樣本與抗HER2抗體或其抗原結合性片段(較佳為本發明之抗體或其抗原結合性片段)接觸;及於生物樣本中之HER2與抗HER2抗體或其抗原結合性片段形成複合體時,確定HER2靶向療法對於該對象有效。又,根據本發明,提供一種對利用包含本發明之抗體或抗體或其抗原結合性片段之HER2標靶藥物進行之HER2靶向療法之有效性進行確定的方法,其包括:使自對象獲得之生物樣本與抗HER2抗體或其抗原結合性片段(較佳為本發明之抗體或其抗原結合性片段)接觸,形成生物樣本中之HER2與抗HER2抗體或其抗原結合性片段之複合體;及對該複合體進行檢測,若檢測出該複合體,則表明HER2靶向療法對於該對象有效。此處,於生物樣本為活組織檢查之情形時,複合體形成可基於生物樣本結合於活組織檢查樣本之情況來進行檢測,於生物樣本為液體樣本之情形時,複合體形成可藉由ELISA等業者所周知之方法來確定。於該形態中,方法可為試管內之方法。又,於該形態中,方法為產業上可利用之方法。於該形態中,方法可不包括診斷之步驟。根據本發明,可提供一種用於該方法之包含本發明之HER2抗體或其抗原結合性片段之診斷試劑、或診斷套組。本發明之HER2抗體或其抗原結合性片段經標記,藉此亦可檢測本發明之HER2抗體或其抗原結合性片段,或者,亦可藉由會識別本發明之HER2抗體或其抗原結合性片段之標記二次抗體來檢測本發明之HER2抗體或其抗原結合性片段。因此,診斷套組可進而包含會識別本發明之HER2抗體或其抗原結合性片段之標記二次抗體。標記可為鹼性磷酸酶或辣根過氧化酶等酶標記法中所使用之標記,可使用對於該等之顯色受質來檢測標記之存在。因此,診斷套組可進而包含顯色受質。
根據本發明,可提供一種用於在藉由上述方法確定HER2靶向療法有效之對象中處置癌之含有包含本發明之抗體或其抗原結合性片段之HER2標靶藥物的醫藥組合物。又,根據本發明,可提供一種用於在患有與本發明之抗體或抗體或其抗原結合性片段具有反應性之HER2陽性腫瘤之對象中處置癌之含有包含本發明之抗體或其抗原結合性片段之HER2標靶藥物的醫藥組合物。本發明之HER2標靶藥物可與其他抗癌劑等併用。
根據本發明,提供一種於對象中處置癌之方法,其包括向該對象投予治療上有效量之包含本發明之抗體或其抗原結合性片段之HER2標靶藥物。又,根據本發明,提供一種在對象中處置癌之方法所使用之對於該對象之包含本發明之抗體或其抗原結合性片段之HER2標靶藥物。進而,根據本發明,提供一種用於製造在對象中處置癌之方法所使用之醫藥之對於該對象之包含本發明之抗體或其抗原結合性片段之HER2標靶藥物的用途。於該等形態中,對象可為藉由上述方法確定HER2靶向療法有效之對象。又,對象可為患有與本發明之抗體或抗體或其抗原結合性片段具有反應性之HER2陽性腫瘤之對象。治療上有效量係產生醫學上顯著利益之醫藥成分之量。
根據本發明,提供一種於患有HER2陽性之癌之對象中使抗體或其抗原結合性片段結合於該癌細胞之方法,其包括對該對象投予有效量之本發明之抗體或其抗原結合性片段。又,根據本發明,提供一種於患有HER2陽性之癌之對象中使包含抗體或其抗原結合性片段之HER2標靶藥物結合於該癌細胞之方法,其包括對該對象投予有效量之包含本發明之抗體或其抗原結合性片段之HER2標靶藥物。
實施例
以下記載實施例。具體而言,以下實施例所使用之試劑類使用實施例中所記載之製品,但亦可用其他製造商(Sigma-Aldrich、FUJIFILM Wako Pure Chemical股份有限公司、Nacalai Tesque股份有限公司、R&D Systems、USCN Life Science INC等)之同等品來代替。
實 施 例 1 : CasMab 抗 HER2 抗體之 產 生(1)細胞
人神經膠母細胞瘤細胞株LN229、人乳癌細胞株SK-BR-3、中國倉鼠卵巢(CHO)-K1、及小鼠骨髓瘤細胞株P3U1係自American type culture collection(美國菌種中心,ATCC)購入。正常人類表皮角化細胞株HaCaT係自Cosmo Bio購入。作為HER2,使用具有序列編號:2之胺基酸序列之人HER2。作為HER2ec,使用具有序列編號:3之胺基酸序列之人HER2之胞外域(分泌型HER2)。使用脂染胺(Lipofectamine)LTX(Thermo Fisher Scientific, Inc.),將N末端附加有PA標籤(Protein Expr Purif., 95, 240-247, 2014)且C末端附加有RAP標籤(Fujii et al., Monoclon. Antib. Immunodiagn. Immunother. Apr; 36(2): 68-71, 2017)、及MAP標籤(Fujii et al., Monoclon. Antib. Immunodiagn. Immunother., 35(6), 293-299. 2016)之HER2蛋白之表現質體(pCAG/PA-HER2-RAP-MAP;上述Fujii et al., 2016;參照圖1A)轉染至CHO-K1,利用抗PA標籤抗體(Protein Expr Purif., 95, 240-247, 2014)分選HER2表現細胞後,於藥劑選擇下建立穩定表現細胞株CHO/HER2。又,使用Neon轉染系統(Thermo Fisher Scientific, Inc.),將N末端附加有PA標籤且C末端附加有RAP標籤、及MAP標籤之HER2蛋白(PA-HER2-RAP-MAP)或者N末端附加有PA標籤且C末端附加有RAP標籤、及MAP標籤之HER2ec(PA-HER2ec-RAP-MAP;上述Fujii et al., 2016;參照圖1B)之表現質體(pCAG/PA-HER2-RAP-MAP或pCAG/PA-HER2ec-RAP-MAP)分別導入至LN229。利用抗PA標籤抗體分選PA-HER2-RAP-MAP表現細胞後,於藥劑選擇下製作穩定表現細胞株LN229/HER2。又,對於HER2ec之高表現細胞株,藉由對於RAP標籤之抗體(PMab-2)與對於PA標籤之抗體(NZ-1)之三明治ELISA,進行培養上清液之篩選,而製作LN229/HER2ec(分泌型)。CHO-K1、CHO/HER2及P3U1係使用RPMI(Roswell Park Memorial Institute,羅斯韋爾帕克紀念研究所)1640培養基(Nacalai Tesque股份有限公司)作為基礎培養基。LN229、LN229/HER2ec、LN229/HER2、SK-BR-3及HaCaT係使用杜爾貝科改良伊格爾培養基(Nacalai Tesque股份有限公司)作為基礎培養基。於培養基中添加10%胎牛血清(Thermo Fisher Scientific, Inc.)、青黴素(100 units/mL)、鏈黴素(100 units/mL)及雙性黴素B(0.25 mg/mL),於37℃、5%CO
2下進行培養。
(2)單株抗體之製作
用作免疫動物之BALB/c小鼠(4週齡,雌性)係自CLEA Japan購入。抗體係使用CasMab法(Kato and Kaneko, Sci. Rep., 4: 5924, 2014)製作。利用抗MAP標籤抗體(上述Fujii et al., 2016)將由LN229細胞產生之HER2ec蛋白質進行親和純化。其後,將100 μg之HER2ec蛋白質與Imject
TMAlum(Thermo Fisher Scientific, Inc.)混合,對BALB/c小鼠進行初次免疫。作為追加免疫(合計3次),每週腹腔內投予自LN229/HER2ec純化而得之100 μg之HER2ec蛋白質。其後,於脾臟摘除之2天前,作為最終免疫而投予100 μg之HER2ec。使用PEG1500(Roche Diagnostics)使由所摘除之脾臟所製備之脾細胞與P3U1進行細胞融合。於細胞融合後,利用添加有次黃嘌呤、胺基喋呤、胸苷(Thermo Fisher Scientific, Inc.)之RPMI 1640進行培養,使用HER2ec,利用下文記載之ELISA法進行培養上清液之1次篩選。藉由極限稀釋法對1次篩選中成為陽性之融合瘤實施選殖。單株抗體之製備使用利用無血清培養基(融合瘤-SFM,Thermo Fisher Scientific, Inc.)所培養之融合瘤上清液,使用蛋白G瓊脂糖凝膠4快流(Protein G Sepharose 4 Fast Flow)(GE Healthcare UK Ltd)進行純化。又,繼而如下文所記載般,實施流式細胞分析、西方墨點、及免疫組織化學染色。結果,經由利用流式細胞分析、西方墨點、及免疫組織化學染色縮小範圍,而由包含對照抗體之H
2Mab-119抗體之約250個純系獲得複數個被認為識別癌特異性之HER2之癌特異性抗體之純系。以下,將2個純系分別命名為H
2Mab-214、及H
2Mab-250(以下有時合併而簡記為本發明之抗體)。將自該純系獲得之抗體分別稱為H
2Mab-214抗體及H
2Mab-250抗體。
(3)ELISA
將HER2ec(經磷酸緩衝食鹽水(PBS)稀釋)以1 μg/ml之濃度於37℃於96孔板固相化30分鐘。於37℃與1%牛血清白蛋白(BSA)/0.05% Tween20 in PBS(PBST)反應30分鐘,進行阻斷。其後,使培養上清液於37℃反應30分鐘後,使用0.05% PBST進行3次洗淨。進而,使二次抗體(1/2000稀釋,Agilent Technologies, Inc.)於37℃反應30分鐘,使用0.05%PBST進行3次洗淨。最後利用一步法超TMB-ELISA(1-Step Ultra TMB-ELISA)(Thermo Fisher Scientific, Inc.)使其顯色,於微盤讀取器之OD655 nm下進行吸光度之測定。
(4)流式細胞分析
使用0.25%胰蛋白酶/1 mM EDTA(ethylenediamine tetraacetic acid,四乙酸乙二胺)(Nacalai Tesque股份有限公司)回收各種接著細胞,利用0.1%BSA/PBS洗淨後,於4℃下使其與上述(2)中所製作之抗體(1 μg/mL)進行反應。利用0.1% BSA/PBS洗淨細胞後,使其與俄勒岡綠(Oregon Green)標記抗小鼠IgG抗體(1000倍稀釋,Thermo Fisher Scientific, Inc.)反應30分鐘。螢光強度係利用EC800細胞分析器(cell Analyzer)(Sony Corp.)進行測定。
(5)西方墨點
將經含有2-巰基乙醇之SDS(Sodium Dodecyl Sulfate,十二烷基硫酸鈉)樣品緩衝液(Nacalai Tesque股份有限公司)調整之細胞助溶液於5~20%聚丙烯醯胺凝膠(FUJIFILM Wako Pure Chemical股份有限公司)中進行電泳,並轉錄於聚偏二氟乙烯(PVDF)膜(Merck KGaA)上。利用添加有4%脫脂乳之PBST將聚偏二氟乙烯PDVF膜阻斷後,使其與上述(2)中所製作之抗體(5 μg/mL)或抗b-肌動蛋白抗體(純系AC-15,Sigma-Aldrich Corp.)進行反應。其後,使其與過氧化酶標記抗小鼠IgG抗體(1000稀釋,Agilent Technologies, Inc.)進行反應。檢測使用化學發光試劑(ImmunoStar LD,FUJIFILM Wako Pure Chemical股份有限公司),利用Sayaca-Imager(DRC股份有限公司)檢測訊號。
(6)免疫組織化學染色
使用自BioChain公司購入之乳癌組織(目錄編號:B904111)與自BioChain Institute, Inc.購入之正常乳腺組織(目錄編號:B803077)。利用二甲苯將組織切片進行脫石蠟、脫水,並浸漬於檸檬酸緩衝液(pH值6.0,Agilent Technologies, Inc.)中,進行20分鐘高壓釜處理。繼而,利用上述(2)中所製作之抗體(1 μg/mL)於室溫下反應1小時,其後利用Envision+套組、小鼠(Agilent Technologies, Inc.)處理30分鐘。利用3,3'-二胺基聯苯胺四鹽酸鹽處理2分鐘使其顯色,並利用蘇木精進行對比染色。染色強度係基於上述2018 ASCO/CAP準則按照0、1+、2+、及3+進行評價。
實 施 例 2 : CasMab 抗 HER2 抗體之定序(1)H
2Mab-214抗體、及H
2Mab-250抗體之胺基酸序列及鹼基序列之確定
使用RNeasy加迷你套組(Plus mini kit)(QIAGEN)自H
2Mab-214融合瘤細胞及H
2Mab-250融合瘤細胞1×10
6提取總RNA。使用SuperScript IV cDNA合成系統(Thermo Fisher Scientific, Inc.)由總RNA 5 μg合成cDNA。於以下實驗中使用cDNA作為模板。
重鏈(H鏈)之擴增使用以下引子。
InF.HindIII-H2-214H(序列編號4)
InF.HindIII-H2-250H(序列編號5)
InFr.IgG1terNotI(序列編號6)
PCR(polymerase chain reaction,聚合酶鏈反應)反應使用HotStar HiFidelity DNA聚合酶(QIAGEN)。溫度條件最初設為95℃5分鐘,繼而設為35個循環之94℃15秒、50℃1分鐘、72℃1分鐘,最後設為72℃10分鐘。所擴增之PCR產物藉由FastGene凝膠/PCR提取(NIPPON Genetics股份有限公司)進行純化。
H
2Mab-214抗體H鏈之PCR產物利用限制酶HindIII及NotI於37℃處理1小時,使用InFusion-HD選殖套組(Takara Bio股份有限公司)次選殖於經FastGene凝膠/PCR提取套組(NIPPON Genetics股份有限公司)純化之pCAG載體,根據載體引子進行鹼基序列之確認。
H
2Mab-250抗體H鏈之PCR產物利用限制酶HindIII及NotI於37℃處理1小時,使用InFusion-HD選殖套組(Takara Bio股份有限公司)次選殖於經FastGene凝膠/PCR提取套組(NIPPON Genetics股份有限公司)純化之pCAG載體,根據載體引子進行鹼基序列之確認。
輕鏈(L鏈)之擴增使用以下引子。
InF.HindIII-H2-214L(序列編號7)
InF.HindIII-H2-250L(序列編號8)
InF.mIgCKterNotI(序列編號9)
PCR反應使用HotStar HiFidelity DNA聚合酶(QIAGEN)。溫度條件最初設為95℃5分鐘,繼而設為35個循環之94℃15秒、50℃1分鐘、72℃1分鐘,最後設為72℃10分鐘。所擴增之PCR產物藉由FastGene凝膠/PCR提取(NIPPON Genetics股份有限公司)進行純化。
H
2Mab-214抗體L鏈之PCR產物利用限制酶HindIII及NotI於37℃處理1小時,使用InFusion-HD選殖套組(Takara Bio股份有限公司)次選殖於經FastGene凝膠/PCR提取套組(NIPPON Genetics股份有限公司)純化之pCAG載體,根據載體引子進行鹼基序列之確認。
H
2Mab-250抗體L鏈之PCR產物利用限制酶HindIII及NotI於37℃處理1小時,使用InFusion-HD選殖套組(Takara Bio股份有限公司)次選殖於經FastGene凝膠/PCR提取套組(NIPPON Genetics股份有限公司)純化之pCAG載體,根據載體引子進行鹼基序列之確認。
其結果為,編碼H
2Mab-214抗體之H鏈之DNA之鹼基序列如序列編號:10所示,編碼H
2Mab-214抗體之L鏈之DNA之鹼基序列如序列編號:11所示。同樣地,編碼H
2Mab-250抗體之H鏈之DNA之鹼基序列如序列編號:12所示,編碼H
2Mab-250抗體之L鏈之DNA之鹼基序列如序列編號:13所示。
根據H
2Mab-214抗體之各鹼基序列預測胺基酸序列。H
2Mab-214抗體之H鏈胺基酸序列如序列編號:14所示,H
2Mab-214抗體之L鏈胺基酸序列如序列編號:15所示。同樣地,根據H
2Mab-250抗體之各鹼基序列預測胺基酸序列。H
2Mab-250抗體之H鏈胺基酸序列如序列編號:16所示,H
2Mab-250抗體之L鏈胺基酸序列如序列編號:17所示。
(2)H
2Mab-214抗體、H
2Mab-250抗體之CDR(互補決定區)之確定
利用以下URL之主頁(abYsis,http://www.abysis.org/abysis/index.html)所提供之免疫球蛋白之序列預測軟體(Kabat編號)自上述(1)中所確定之鹼基序列特定出CDR之部位。
其結果為,H
2Mab-214抗體之重鏈CDR1~3及輕鏈CDR1~3之胺基酸序列分別特定為如序列編號:18~20及序列編號:21~23所示。同樣地,H
2Mab-250抗體之重鏈CDR1~3及輕鏈CDR1~3之胺基酸序列分別特定為如序列編號:24~26及序列編號:27~29所示。
實 施 例 3 : CasMab 抗 HER2 抗體之 評 價(1)流式細胞分析
藉由以下方法對正常人類表皮角化細胞株HaCaT(Cosmo Bio)、及乳癌細胞株SK-BR-3(ATCC)進行流式細胞分析解析。
使用0.25%胰蛋白酶/1 mM EDTA(Nacalai Tesque股份有限公司)回收各種接著細胞,利用0.1%BSA/PBS洗淨後,於4℃下使其與各種抗HER2單株抗體(對照抗體(H
2Mab-119抗體,參照Monoclon. Antib. Immunodiagn. Immunother., vol.36(6), 287-290, 2017)、H
2Mab-214抗體、及H
2Mab-250抗體、各培養上清液)進行反應。利用0.1%BSA/PBS洗淨細胞後,使其與俄勒岡綠標記抗小鼠IgG抗體(1000倍稀釋,Thermo Fisher Scientific, Inc.)反應30分鐘。螢光強度係利用EC800細胞分析器(Sony Corp.)進行測定。
其結果為,如圖2所示,對照抗體(H
2Mab-119抗體)不僅與作為癌細胞株之SK-BR-3進行反應,而且對作為正常細胞株之HaCaT表現出中程度之反應性。另一方面,本發明之抗體對於作為癌細胞株之SK-BR-3表現出中程度之反應性,但完全不與作為正常細胞株之HaCaT反應。由此表明,本發明之抗體具有癌特異性。
(2)免疫組織化學染色
藉由以下方法對自BioChain公司獲得之HER2陰性乳癌之組織微陣列(目錄編號:B904111)進行免疫組織化學染色。
利用二甲苯將組織切片進行脫石蠟、脫水,浸漬於檸檬酸緩衝液(pH值6.0,Agilent Technologies, Inc.)中,進行20分鐘高壓釜處理。繼而,利用本發明之抗體(1 μg/mL)於室溫下反應1小時,其後利用Envision+套組(Agilent Technologies, Inc.)處理30分鐘。利用3,3'-二胺基聯苯胺四鹽酸鹽處理2分鐘使其顯色,並利用蘇木精進行對比染色。染色強度如上所述按照0、1+、2+、3+進行評價。
其結果為,如下述圖3所示,對照抗體(H
2Mab-119抗體)對藉由使用免疫組織化學染色法(IHC)調查癌細胞之HER2表現狀況之診斷試劑判定為HER2陰性之乳癌(HER2陰性乳癌)組織表現出陰性,另一方面,本發明之抗體存在對HER2陰性乳癌組織表現出1+~3+之陽性圖像之核心(core)。由此可知,本發明之抗體於免疫組織染色中表現出較高之感度。
實 施 例 4 : CasMab 抗 HER2 抗體之表位解析 (1)由於本發明之抗體與藉由常規方法所製作之全部缺失突變體(WT-dN23(使人HER2(序列編號:2)之N末至胺基酸編號22至之區域缺失之突變體)、dN200(使人HER2(序列編號:2)之N末至胺基酸編號199至之區域缺失之突變體)、dN300(使人HER2(序列編號:2)之N末至胺基酸編號299至之區域缺失之突變體)、dN400(使人HER2(序列編號:2)之N末至胺基酸編號399至之區域缺失之突變體)、dN500(使人HER2(序列編號:2)之N末至胺基酸編號499至之區域缺失之突變體)及dN600(使人HER2(序列編號:2)之N末至胺基酸編號599至之區域缺失之突變體))反應,故而預想其識別人HER2(序列編號:2)之胺基酸編號600-652之胺基酸序列(序列編號:30)。另一方面,對照抗體(H
2Mab-119抗體)與WT-dN23反應,但不與dN200、dN300、dN400、dN500及dN600反應,因此預想其識別人HER2之胺基酸編號23-199之前之胺基酸區域。再者,本實施例及下文之實施例中之胺基酸編號表示序列編號2之胺基酸序列中之胺基酸之位置。
繼而,藉由ELISA法確認本發明之抗體對HER2ec(23-652)及HER2ec之分別包含23-42、33-52、43-62、53-72、63-82、73-92、83-102、93-112、103-122、113-132、123-142、133-152、143-162、153-172、163-182、173-192、183-202、193-212、203-222、213-232、223-242、233-252、243-262、253-272、263-282、273-292、283-302、293-312、303-322、313-332、323-342、333-352、343-362、353-372、363-382、373-392、383-402、393-412、403-422、413-432、423-442、433-452、443-462、453-472、463-482、473-492、483-502、493-512、503-522、513-532、523-542、533-552、543-562、553-572、563-582、573-592、583-602、593-612、603-622、613-632、623-642、633-652之胺基酸區域之合成肽之反應性(此處,上述胺基酸編號表示序列編號2之胺基酸序列中之胺基酸編號)。即,將各肽以10 μg/ml之濃度於37℃於96孔板固相化30分鐘。於37℃與1% BSA/0.05% PBST反應30分鐘,進行阻斷。其後,於37℃與10 μg/ml之本發明之抗體反應30分鐘後,使用0.05%PBST進行3次洗淨。進而,於37℃與二次抗體(1/2000稀釋,Agilent Technologies, Inc.)反應30分鐘,使用0.05%PBST進行3次洗淨。最後藉由一步法超TMB-ELISA(Thermo Fisher Scientific, Inc.)顯色15分鐘,於微盤讀取器(Bio-Rad)之OD655 nm下進行吸光度之測定。
其結果為,H
2Mab-214抗體及H
2Mab-250抗體與603~622肽及613~632肽強烈反應,因此認為本發明之抗體之表位為人HER2之603-622之胺基酸區域(序列編號:31)、人HER2之613~632之胺基酸區域(序列編號:32)、尤其是613~622之胺基酸區域(序列編號:33)。
因此,以HER2ec作為陽性對照,藉由ELISA法確認本發明之抗體對將人HER2之603~622肽之20個胺基酸分別各置換為1個丙胺酸而成之20種變異型肽之反應性。
其結果為,關於H
2Mab-214抗體,對於於人HER2之603~622之胺基酸中將K615與F616分別置換為丙胺酸而成之K615A肽與F616A肽之反應性較對於野生型HER2肽(人HER2之603~622之胺基酸)之反應性弱,因此可知K615與F616之2個胺基酸及其周邊為H
2Mab-214抗體之表位。
又,關於H
2Mab-250抗體,對於將人HER2之W614置換為丙胺酸而成之W614A肽之反應性較對於野生型HER2肽之反應性弱,因此可知W614之胺基酸及其周邊為H
2Mab-250抗體之表位。
對H
2Mab-214抗體及H
2Mab-250抗體之表位進一步詳細調查。藉由ELISA法確認本發明之抗體對包含614-619、614-620、614-621、614-622、613-618、613-619、613-620、613-621、613-622、612-618、612-619、612-620、612-621、612-622、611-618、611-619、611-620、611-621、611-622、610-618、610-619、610-620、610-621、610-622、609-618、609-619、609-620、609-621、及609-622之人HER2之胺基酸區域的合成肽(各種缺失突變體(deletion mutant))之反應性(此處,上述胺基酸編號表示序列編號2之胺基酸序列中之胺基酸編號)。ELISA係與上述同樣地進行。作為一次抗體,分別以50 μL/孔使用本發明之抗體,作為二次抗體,使用兔抗小鼠IgG/HRP(Agilent Technologies, Inc.,1%BSA/PBS-T,1/2,000稀釋,50 μL/孔)。檢測係使用ELISA POD基質TMB套組(Nacalai Tesque股份有限公司)。使用iMark微盤讀取器測定OD655 nm之吸光度。結果如圖4所示。於圖4中,於胺基酸編號之前標註有「p」。圖4中P.C.表示陽性對照,N.C.表示陰性對照。
如圖4所示,H
2Mab-214抗體對包含612~618之胺基酸區域(序列編號:35)之肽表現出較強之反應性,表現出與包含612~618之胺基酸區域之更長之肽同等之反應性。又,如圖4所示,H
2Mab-250抗體對包含611~618之胺基酸區域(序列編號:34)之肽表現出較強之反應性,表現出與包含611~618之胺基酸區域之更長之肽同等之反應性。
進而,如圖4所示,關於OD值超過0.1者,若評價為具有反應性,則H
2Mab-214抗體及H
2Mab-250抗體均對包含613~619之胺基酸區域(序列編號:36)之肽表現出反應性。然而,該反應性弱於對於包含612~618之胺基酸區域(序列編號:35)之肽、或包含611~618之胺基酸區域(序列編號:34)之肽之反應性,因此可知,第612號胺基酸(及/或第611號胺基酸)對本發明之抗體對HER2之部分肽之反應性的影響較強。
實 施 例 5 : CasMab 抗 HER2 抗體之表位解析 (2)(1)流式細胞分析
藉由使用丙胺酸置換突變體之流式細胞分析(FACS)解析進行H
2Mab-214抗體或H
2Mab-250抗體之表位解析。將目標位置之胺基酸置換為丙胺酸而成之HER2(具有序列編號:2之胺基酸序列之人HER2)基因係使用QuikChange Lightning定點突變套組(Site-Directed Mutagenesis Kit)(Agilent Technologies, Inc.)所製作,藉由鹼基序列之確定進行變異導入之確認。形成有目標之丙胺酸置換變異之HER2基因與野生型HER2基因同樣,於N末附加PA標籤,於C末附加RAP標籤及MAP標籤,並組入表現載體中(參照實施例1)。使用Neon轉染系統(Thermo Fisher Scientific, Inc.)將該質體基因轉殖於CHO-K1細胞,藉由利用抗PA抗體之細胞分選(細胞分選儀SA3800,Sony Corp.)與其後之利用吉歐黴素(0.5 mg/mL,InVivogen公司)之藥劑選擇建立穩定表現細胞株。
使用0.25%胰蛋白酶/1 mM EDTA溶液(Nacalai Tesque股份有限公司)自培養皿回收使將目標位置之胺基酸置換為丙胺酸而成之HER2基因強制穩定表現之CHO-K1細胞,利用0.1%BSA(Nacalai Tesque股份有限公司)/PBS洗淨。利用0.1%BSA/PBS將一次抗體(H
2Mab-214抗體或H
2Mab-250抗體)調整為10 μg/mL,添加至所回收之細胞中加以混合,於冰上反應30分鐘。其後,利用0.1% BSA/PBS洗淨。繼而,利用0.1% BSA/PBS調整螢光標記二次抗體(1/1000稀釋,抗小鼠IgG Alexa Fluor 488,Thermo Fisher Scientific, Inc.),於冰上反應30分鐘。再次利用0.1%BSA/PBS洗淨。利用細胞分析器EC800(Sony Corp.)檢測抗體之反應性。
圖5表示對於PA標籤之抗體(NZ-1)、H
2Mab-214抗體、H
2Mab-250抗體、陽性對照抗體(曲妥珠單抗)之流式細胞分析(FACS解析)之結果。
其結果為,如圖5所示,H
2Mab-214對HER2-K615A及HER2-F616A未表現出顯著之結合,H
2Mab-250對HER2-W614A未表現出顯著之結合。與此相對,於NZ-1抗體中檢測到全部HER2之點突變體,因此可知各點突變體之表現量充分。由此暗示,識別該表位(W614、K615、F616)之本發明之抗體與在非癌細胞上表現之HER2完全不反應,而可與在癌細胞上表現之HER2特異性地反應。又,如圖5所示,曲妥珠單抗對任一點突變體均表現出顯著之結合。由此暗示,曲妥珠單抗雖然與本發明之抗體同樣為識別HER2之區域IV之抗體,但不識別該區域IV中本發明之抗體所識別之表位(W614、K615、F616)。因此可知,不同於曲妥珠單抗,識別該表位(W614、K615、F616)之特性參與癌細胞上之HER2之特異性之識別。
(2)Biacore測定
使用Biacore X100(Cytiva)對H
2Mab-214抗體或H
2Mab-250抗體與各種肽之相互作用進行解析。肽使用人HER2之第603~622號胺基酸序列(p603-622)、將p603-622之1個胺基酸置換為丙胺酸而成者(G603A、V604A、K605A、P606A、D607A、L608A、S609A、Y610A、M611A、P612A、I613A、W614A、K615A、F616A、P617A、D618A、E619A、E620A、G621A)、將p603-622之1個胺基酸置換為甘胺酸而成者(A622G)、使p603-622之胺基酸之一部分缺損而成之HER2之部分肽(p614-619、p614-620、p614-621、p614-622、p613-618、p613-619、p613-620、p613-621、p613-622、p612-618、p612-619、p612-620、p612-621、p612-622、p611-618、p611-619、p611-620、p611-621、p611-622、p610-618、p610-619、p610-620、p610-621、p610-622、p609-618、p609-619、p609-620、p609-621、p609-622)。對於上述各肽,利用乙酸緩衝液(pH值4.0)稀釋H
2Mab-214抗體或H
2Mab-250抗體,藉由胺偶合法固定於CM5晶片。藉由乙醇胺將未反應之NHS(N-hydroxysuccinimidyl,N-羥基丁二醯亞胺)酯阻斷。對固定有H
2Mab-214抗體或H
2Mab-250抗體之CM5晶片添加各種肽,藉此測定相互作用。電泳緩衝液使用包含0.005% (v/v) Tween 20之PBS、或包含0.005% (v/v) Tween 20及1.19% DMSO(dimethyl sulfoxide,二甲基亞碸)之PBS,再生緩衝液使用甘胺酸-HCl(pH值1.5)。全部測定於25℃進行。測定資料係使用BIAevaluation軟體(Cytiva)之1:1結合模型進行解析,求出結合速度常數(ka)、解離速度常數(kd)及解離常數(K
D)。關於無法確定ka或kd者,使用BIAevaluation軟體(Cytiva)之平衡值解析法求出KD。
關於結果,表1及表2表示H
2Mab-214抗體之藉由Biocore測定所得之結合親和性,表3及表4表示H
2Mab-250抗體之藉由Biocore測定所得之結合親和性。再者,表2及4中之胺基酸編號表示所使用之胺基酸區域。
根據實施例4及實施例5之結果可知,各種丙胺酸置換突變體與各種缺失突變體中之本發明之抗體之結合親和性相關,K615與F616之2個胺基酸及其周邊(I613、W614)為H
2Mab-214抗體之表位。
又,可知W614之胺基酸及其周邊(I613、K615、F616、P617)為H
2Mab-250抗體之表位。
實 施 例 6 : 進 一步 之 抗體群於本實施例中,嘗試獲得進一步之抗HER2抗體。
小鼠自CLEA Japan購入6週齡之BALB/c小鼠。
免疫原作為免疫原,合成於HER2之604-622胺基酸(19個胺基酸)之C末附加Cys而成之20個胺基酸(HER2_604-622C,
NH2-VKPDLSYMPIWKFPDEEGAC-
COOH,序列編號37)(Eurofins),藉由常規方法附加KLH(keyhole limpet hemocyanin,匙孔螺血氰蛋白)。肽之純化純度設為90%以上。
免疫法將HER2_604-622C以100 μg/隻小鼠(100 μl)與ImjectAlum(Thermo Fisher Scientific, Inc.)100 μl混合,進行第1次免疫。其後,作為第2次、第3次、第4次、第5次免疫,每週以100 μg/小鼠(100 μl)實施(無ImjectAlum)。於第5次免疫之2天後,藉由常規方法從自小鼠摘除之脾臟分離脾細胞,以脾細胞:小鼠骨髓瘤細胞(P3U1)=10:1之比率進行細胞融合。關於細胞融合,藉由常規方法使用PEG1500(Roche Diagnostics)進行。
融合瘤之培養使用添加有HAT(Hypoxanthine-Aminopterin-Thymidine,次黃嘌呤-胺基喋呤-胸苷)(Thermo Fisher Scientific, Inc.)之10% FBS(Thermo Fisher Scientific, Inc.) in RPMI(Nacalai Tesque股份有限公司),將融合瘤接種於96孔板。
篩選6天後,藉由ELISA進行篩選。ELISA係以如下方式實施。利用DMSO將HER2p604-622C溶解為10 mg/mL後,利用PBS進行稀釋(1 μg/ml)。肽之固相化係將HER2p604-622C以50 ng/孔(50 μL/孔)添加至孔板,於37℃培養30分鐘。阻斷係將1% BSA/PBS-Tween(0.05%)以100 μL/孔添加,於37℃培養30分鐘。各添加50 μl之融合瘤之培養上清液,於37℃培養30分鐘。二次抗體係各添加50 μl之抗小鼠免疫球蛋白/HRP(Agilent,以1% BSA/PBS-0.05% Tween稀釋為1/2000),於37℃培養30分鐘。顯色係各添加50 μl之ELISA POD基質TMB套組(Nacalai Tesque股份有限公司),於室溫下培養10分鐘。測定係利用iMark微盤讀取器(OD 655 nm)進行15分鐘。
單細 胞 選 殖對陽性孔進行單細胞選殖。藉由目視確認純系,藉由ELISA建立陽性純系。將純系名命名為H
2Mab-279~299。
亞 型 之確定藉由常規方法確定亞型(與H
2Mab-214、250相同)。
[表5]
表 5 : 進一步之 抗體 純 系之 亞 型與 輕鏈
純系名 | 亞型 | 輕鏈 |
H 2Mab-279 | IgG 3 | κ |
H 2Mab-280 | IgG 1 | κ |
H 2Mab-281 | IgG 1 | κ |
H 2Mab-282 | IgG 2a | κ |
H 2Mab-283 | IgG 1 | κ |
H 2Mab-284 | IgG 1 | κ |
H 2Mab-285 | IgG 3 | κ |
H 2Mab-286 | IgG 1 | κ |
H 2Mab-287 | IgG 1 | κ |
H 2Mab-288 | IgG 1 | κ |
H 2Mab-289 | IgG 1 | κ |
H 2Mab-290 | IgG 1 | κ |
H 2Mab-291 | IgG 3 | κ |
H 2Mab-292 | IgG 3 | κ |
H 2Mab-293 | IgG 3 | κ |
H 2Mab-294 | IgG 1 | κ |
H 2Mab-295 | IgG 1 | κ |
H 2Mab-296 | IgG 1 | κ |
H 2Mab-297 | IgG 2a | κ |
H 2Mab-298 | IgG 1 | κ |
H 2Mab-299 | IgG 1 | κ |
如實施例1(1)般進行各抗體之純化。純化管柱使用Ab-Capcher
TM(ProteNova)。將經純化之抗體供於表位解析、FACS、及免疫組織化學染色。FACS係如實施例1(4)所記載般進行,免疫組織化學染色係如實施例1(6)所記載般進行。表位解析係如實施例4所記載般,藉由ELISA法進行。
於表位解析中,於對藉由丙胺酸掃描變化為丙胺酸之肽進行試驗之抗體使結合親和性降低或消失之情形時,確定該變化為丙胺酸之胺基酸為抗體之推定表位。表位解析之結果如圖6A~6E所示。再者,於圖6A~6E中,以下底線表示推定表位。如圖6A~6E所示,上述抗體純系之推定表位均可見於W614、K615、及F616之區域。
於FACS解析中,對圖中所示之活細胞與各抗體純系之結合性進行試驗。使用Met5A細胞作為間皮瘤細胞株,使用HaCaT細胞作為人類表皮角化細胞株,使用MCF10A-III作為非腫瘤上皮細胞株,使用A431作為人類表皮癌細胞株,使用SK-BR-3作為乳癌細胞株。結果如圖7A~7G所示。如圖7A~7G所示,於以序列編號:37之胺基酸作為免疫原之大部分細胞純系中,未與正常細胞結合,而對陽性之癌細胞表現出結合性。
免疫組織化學染色之結果如圖8A~8F所示。如圖8A~8F所示,以序列編號:37之胺基酸作為免疫原之任一抗體純系均與癌組織強烈反應,但對於正常組織幾乎未見反應。
抗體基因 選 殖如實施例2所記載般,實施抗體基因選殖、重鏈可變區及輕鏈可變區之推定、及CDR推定。重組抗體之活性可藉由FACS進行確認。
序列編號:14~17及39~80之胺基酸序列中之重鏈可變區及輕鏈可變區之胺基酸編號分別如以下表所示。所推定之CDR之序列分別示於序列編號:81~206。
[表6]
表 6 :各重 鏈 之胺基酸序列中之重 鏈 可 變 區及各 輕鏈 之胺基酸序列中之 輕鏈 可 變 區
※於表中,各胺基酸序列中之重鏈可變區及輕鏈可變區係由該區域之最初之胺基酸與最後之胺基酸所表示。例如,序列編號:14之胺基酸序列(H鏈、即重鏈)中之可變區係20Q至240R之221個胺基酸長度之區域。表6中以序列編號表示之胺基酸序列為重鏈整體及輕鏈整體之胺基酸序列(包含訊息序列),因此於本說明書中,「具有序列編號:n之胺基酸序列之重鏈可變區」意指具有序列編號:n之重鏈可變區之胺基酸序列之重鏈可變區,「具有序列編號:m之胺基酸序列之輕鏈可變區」意指具有序列編號:m之輕鏈可變區之胺基酸序列之輕鏈可變區。各可變區之末端之胺基酸序列之數個胺基酸可具有選自由附加、缺失、刪除、及置換所組成之群中之1個以上胺基酸突變。序列編號:53之重鏈可變區之胺基酸編號未確定,序列編號:123~125之CDR於序列表中由數個X表示但未推定,序列表中之X之個數與CDR之長度無關。
序列編號 | H鏈/L鏈 | 可變區 | 序列編號 | H鏈/L鏈 | 可變區 |
14 | H鏈 | 20Q-240R | 58 | L鏈 | 21D-288N |
15 | L鏈 | 21D-238K | 59 | H鏈 | 20E-239P |
16 | H鏈 | 20E-235R | 60 | L鏈 | 20D-210R |
17 | L鏈 | 21D-239K | 61 | H鏈 | 20D-236R |
39 | H鏈 | 20E-138S | 62 | L鏈 | 21D-237N |
40 | L鏈 | 25D-133A | 63 | H鏈 | 20E-234E |
41 | H鏈 | 20D-236R | 64 | L鏈 | 20D-235R |
42 | L鏈 | 21D-237N | 65 | H鏈 | 20E-234E |
43 | H鏈 | 20D-236R | 66 | L鏈 | 20D-235R |
44 | L鏈 | 21N-237N | 67 | H鏈 | 20E-238R |
45 | H鏈 | 20Q-234R | 68 | L鏈 | 25D-235R |
46 | L鏈 | 21D-239C | 69 | H鏈 | 29E-245R |
47 | H鏈 | 20E-236R | 70 | L鏈 | 21D-237N |
48 | L鏈 | 23D-283N | 71 | H鏈 | 20E-234V |
49 | H鏈 | 20Q-249I | 72 | L鏈 | 20D-235R |
50 | L鏈 | 21D-239C | 73 | H鏈 | 20Q-249I |
51 | H鏈 | 20E-238R | 74 | L鏈 | 21D-240C |
52 | L鏈 | 25D-210R | 75 | H鏈 | 20E-239R |
53 | H鏈 | N.D. | 76 | L鏈 | 20D-238C |
54 | L鏈 | 20D-286C | 77 | H鏈 | 20D-236R |
55 | H鏈 | 20D-236R | 78 | L鏈 | 21D-237N |
56 | L鏈 | 21D-237N | 79 | H鏈 | 20E-238R |
57 | H鏈 | 20D-236R | 80 | L鏈 | 25D-235R |
序列編號1:人c-erb-B-2(HER2)鹼基序列(Genebank寄存編號:X03363)
序列編號2:人c-erb-B-2(HER2)胺基酸序列(UniprotKB ID:P04626)
序列編號3:人c-erb-B-2(HER2)ec(胞外域分泌型)胺基酸序列(23-652aa)
序列編號4:引子(InF.HindIII-H2-214H)
序列編號5:引子(InF.HindIII-H2-250H)
序列編號6:引子(InFr.IgG1terNotI)
序列編號7:引子(InF.HindIII-H2-214L)
序列編號8:引子(InF.HindIII-H2-250L)
序列編號9:引子(InF.mIgCKterNotI)
序列編號10:編碼H
2Mab-214抗體之H鏈之DNA之鹼基序列
序列編號11:編碼H
2Mab-214抗體之L鏈之DNA之鹼基序列
序列編號12:編碼H
2Mab-250抗體之H鏈之DNA之鹼基序列
序列編號13:編碼H
2Mab-250抗體之L鏈之DNA之鹼基序列
序列編號14:H
2Mab-214抗體之H鏈胺基酸序列
序列編號15:H
2Mab-214抗體之L鏈胺基酸序列
序列編號16:H
2Mab-250抗體之H鏈胺基酸序列
序列編號17:H
2Mab-250抗體之L鏈胺基酸序列
序列編號18:H
2Mab-214抗體之H鏈CDR1之胺基酸序列
序列編號19:H
2Mab-214抗體之H鏈CDR2之胺基酸序列
序列編號20:H
2Mab-214抗體之H鏈CDR3之胺基酸序列
序列編號21:H
2Mab-214抗體之L鏈CDR1之胺基酸序列
序列編號22:H
2Mab-214抗體之L鏈CDR2之胺基酸序列
序列編號23:H
2Mab-214抗體之L鏈CDR3之胺基酸序列
序列編號24:H
2Mab-250抗體之H鏈CDR1之胺基酸序列
序列編號25:H
2Mab-250抗體之H鏈CDR2之胺基酸序列
序列編號26:H
2Mab-250抗體之H鏈CDR3之胺基酸序列
序列編號27:H
2Mab-250抗體之L鏈CDR1之胺基酸序列
序列編號28:H
2Mab-250抗體之L鏈CDR2之胺基酸序列
序列編號29:H
2Mab-250抗體之L鏈CDR3之胺基酸序列
序列編號30:序列編號2之人HER2之胺基酸編號600~652之胺基酸序列
序列編號31:序列編號2之人HER2之胺基酸編號603~622之胺基酸序列
序列編號32:序列編號2之人HER2之胺基酸編號613~632之胺基酸序列
序列編號33:序列編號2之人HER2之胺基酸編號613~622之胺基酸序列
序列編號34:序列編號2之人HER2之胺基酸編號611~618之胺基酸序列
序列編號35:序列編號2之人HER2之胺基酸編號612~618之胺基酸序列
序列編號36:序列編號2之人HER2之胺基酸編號613~619之胺基酸序列
序列編號37:HER2p604-622C之胺基酸序列
序列編號38:scFv所使用之連接子之一例
序列編號39:H
2Mab-279抗體之H鏈胺基酸序列
序列編號40:H
2Mab-279抗體之L鏈胺基酸序列
序列編號41:H
2Mab-280抗體之H鏈胺基酸序列
序列編號42:H
2Mab-280抗體之L鏈胺基酸序列
序列編號43:H
2Mab-281抗體之H鏈胺基酸序列
序列編號44:H
2Mab-281抗體之L鏈胺基酸序列
序列編號45:H
2Mab-282抗體之H鏈胺基酸序列
序列編號46:H
2Mab-282抗體之L鏈胺基酸序列
序列編號47:H
2Mab-283抗體之H鏈胺基酸序列
序列編號48:H
2Mab-283抗體之L鏈胺基酸序列
序列編號49:H
2Mab-284抗體之H鏈胺基酸序列
序列編號50:H
2Mab-284抗體之L鏈胺基酸序列
序列編號51:H
2Mab-285抗體之H鏈胺基酸序列
序列編號52:H
2Mab-285抗體之L鏈胺基酸序列
序列編號53:H
2Mab-286抗體之H鏈胺基酸序列
序列編號54:H
2Mab-286抗體之L鏈胺基酸序列
序列編號55:H
2Mab-287抗體之H鏈胺基酸序列
序列編號56:H
2Mab-287抗體之L鏈胺基酸序列
序列編號57:H
2Mab-288抗體之H鏈胺基酸序列
序列編號58:H
2Mab-288抗體之L鏈胺基酸序列
序列編號59:H
2Mab-289抗體之H鏈胺基酸序列
序列編號60:H
2Mab-289抗體之L鏈胺基酸序列
序列編號61:H
2Mab-290抗體之H鏈胺基酸序列
序列編號62:H
2Mab-290抗體之L鏈胺基酸序列
序列編號63:H
2Mab-291抗體之H鏈胺基酸序列
序列編號64:H
2Mab-291抗體之L鏈胺基酸序列
序列編號65:H
2Mab-292抗體之H鏈胺基酸序列
序列編號66:H
2Mab-292抗體之L鏈胺基酸序列
序列編號67:H
2Mab-293抗體之H鏈胺基酸序列
序列編號68:H
2Mab-293抗體之L鏈胺基酸序列
序列編號69:H
2Mab-294抗體之H鏈胺基酸序列
序列編號70:H
2Mab-294抗體之L鏈胺基酸序列
序列編號71:H
2Mab-295抗體之H鏈胺基酸序列
序列編號72:H
2Mab-295抗體之L鏈胺基酸序列
序列編號73:H
2Mab-296抗體之H鏈胺基酸序列
序列編號74:H
2Mab-296抗體之L鏈胺基酸序列
序列編號75:H
2Mab-297抗體之H鏈胺基酸序列
序列編號76:H
2Mab-297抗體之L鏈胺基酸序列
序列編號77:H
2Mab-298抗體之H鏈胺基酸序列
序列編號78:H
2Mab-298抗體之L鏈胺基酸序列
序列編號79:H
2Mab-299抗體之H鏈胺基酸序列
序列編號80:H
2Mab-299抗體之L鏈胺基酸序列
序列編號81:H
2Mab-279抗體之H鏈CDR1之胺基酸序列
序列編號82:H
2Mab-279抗體之H鏈CDR2之胺基酸序列
序列編號83:H
2Mab-279抗體之H鏈CDR3之胺基酸序列
序列編號84:H
2Mab-279抗體之L鏈CDR1之胺基酸序列
序列編號85:H
2Mab-279抗體之L鏈CDR2之胺基酸序列
序列編號86:H
2Mab-279抗體之L鏈CDR3之胺基酸序列
序列編號87:H
2Mab-280抗體之H鏈CDR1之胺基酸序列
序列編號88:H
2Mab-280抗體之H鏈CDR2之胺基酸序列
序列編號89:H
2Mab-280抗體之H鏈CDR3之胺基酸序列
序列編號90:H
2Mab-280抗體之L鏈CDR1之胺基酸序列
序列編號91:H
2Mab-280抗體之L鏈CDR2之胺基酸序列
序列編號92:H
2Mab-280抗體之L鏈CDR3之胺基酸序列
序列編號93:H
2Mab-281抗體之H鏈CDR1之胺基酸序列
序列編號94:H
2Mab-281抗體之H鏈CDR2之胺基酸序列
序列編號95:H
2Mab-281抗體之H鏈CDR3之胺基酸序列
序列編號96:H
2Mab-281抗體之L鏈CDR1之胺基酸序列
序列編號97:H
2Mab-281抗體之L鏈CDR2之胺基酸序列
序列編號98:H
2Mab-281抗體之L鏈CDR3之胺基酸序列
序列編號99:H
2Mab-282抗體之H鏈CDR1之胺基酸序列
序列編號100:H
2Mab-282抗體之H鏈CDR2之胺基酸序列
序列編號101:H
2Mab-282抗體之H鏈CDR3之胺基酸序列
序列編號102:H
2Mab-282抗體之L鏈CDR1之胺基酸序列
序列編號103:H
2Mab-282抗體之L鏈CDR2之胺基酸序列
序列編號104:H
2Mab-282抗體之L鏈CDR3之胺基酸序列
序列編號105:H
2Mab-283抗體之H鏈CDR1之胺基酸序列
序列編號106:H
2Mab-283抗體之H鏈CDR2之胺基酸序列
序列編號107:H
2Mab-283抗體之H鏈CDR3之胺基酸序列
序列編號108:H
2Mab-283抗體之L鏈CDR1之胺基酸序列
序列編號109:H
2Mab-283抗體之L鏈CDR2之胺基酸序列
序列編號110:H
2Mab-283抗體之L鏈CDR3之胺基酸序列
序列編號111:H
2Mab-284抗體之H鏈CDR1之胺基酸序列
序列編號112:H
2Mab-284抗體之H鏈CDR2之胺基酸序列
序列編號113:H
2Mab-284抗體之H鏈CDR3之胺基酸序列
序列編號114:H
2Mab-284抗體之L鏈CDR1之胺基酸序列
序列編號115:H
2Mab-284抗體之L鏈CDR2之胺基酸序列
序列編號116:H
2Mab-284抗體之L鏈CDR3之胺基酸序列
序列編號117:H
2Mab-285抗體之H鏈CDR1之胺基酸序列
序列編號118:H
2Mab-285抗體之H鏈CDR2之胺基酸序列
序列編號119:H
2Mab-285抗體之H鏈CDR3之胺基酸序列
序列編號120:H
2Mab-285抗體之L鏈CDR1之胺基酸序列
序列編號121:H
2Mab-285抗體之L鏈CDR2之胺基酸序列
序列編號122:H
2Mab-285抗體之L鏈CDR3之胺基酸序列
序列編號123:H
2Mab-286抗體之H鏈CDR1之胺基酸序列
序列編號124:H
2Mab-286抗體之H鏈CDR2之胺基酸序列
序列編號125:H
2Mab-286抗體之H鏈CDR3之胺基酸序列
序列編號126:H
2Mab-286抗體之L鏈CDR1之胺基酸序列
序列編號127:H
2Mab-286抗體之L鏈CDR2之胺基酸序列
序列編號128:H
2Mab-286抗體之L鏈CDR3之胺基酸序列
序列編號129:H
2Mab-287抗體之H鏈CDR1之胺基酸序列
序列編號130:H
2Mab-287抗體之H鏈CDR2之胺基酸序列
序列編號131:H
2Mab-287抗體之H鏈CDR3之胺基酸序列
序列編號132:H
2Mab-287抗體之L鏈CDR1之胺基酸序列
序列編號133:H
2Mab-287抗體之L鏈CDR2之胺基酸序列
序列編號134:H
2Mab-287抗體之L鏈CDR3之胺基酸序列
序列編號135:H
2Mab-288抗體之H鏈CDR1之胺基酸序列
序列編號136:H
2Mab-288抗體之H鏈CDR2之胺基酸序列
序列編號137:H
2Mab-288抗體之H鏈CDR3之胺基酸序列
序列編號138:H
2Mab-288抗體之L鏈CDR1之胺基酸序列
序列編號139:H
2Mab-288抗體之L鏈CDR2之胺基酸序列
序列編號140:H
2Mab-288抗體之L鏈CDR3之胺基酸序列
序列編號141:H
2Mab-289抗體之H鏈CDR1之胺基酸序列
序列編號142:H
2Mab-289抗體之H鏈CDR2之胺基酸序列
序列編號143:H
2Mab-289抗體之H鏈CDR3之胺基酸序列
序列編號144:H
2Mab-289抗體之L鏈CDR1之胺基酸序列
序列編號145:H
2Mab-289抗體之L鏈CDR2之胺基酸序列
序列編號146:H
2Mab-289抗體之L鏈CDR3之胺基酸序列
序列編號147:H
2Mab-290抗體之H鏈CDR1之胺基酸序列
序列編號148:H
2Mab-290抗體之H鏈CDR2之胺基酸序列
序列編號149:H
2Mab-290抗體之H鏈CDR3之胺基酸序列
序列編號150:H
2Mab-290抗體之L鏈CDR1之胺基酸序列
序列編號151:H
2Mab-290抗體之L鏈CDR2之胺基酸序列
序列編號152:H
2Mab-290抗體之L鏈CDR3之胺基酸序列
序列編號153:H
2Mab-291抗體之H鏈CDR1之胺基酸序列
序列編號154:H
2Mab-291抗體之H鏈CDR2之胺基酸序列
序列編號155:H
2Mab-291抗體之H鏈CDR3之胺基酸序列
序列編號156:H
2Mab-291抗體之L鏈CDR1之胺基酸序列
序列編號157:H
2Mab-291抗體之L鏈CDR2之胺基酸序列
序列編號158:H
2Mab-291抗體之L鏈CDR3之胺基酸序列
序列編號159:H
2Mab-292抗體之H鏈CDR1之胺基酸序列
序列編號160:H
2Mab-292抗體之H鏈CDR2之胺基酸序列
序列編號161:H
2Mab-292抗體之H鏈CDR3之胺基酸序列
序列編號162:H
2Mab-292抗體之L鏈CDR1之胺基酸序列
序列編號163:H
2Mab-292抗體之L鏈CDR2之胺基酸序列
序列編號164:H
2Mab-292抗體之L鏈CDR3之胺基酸序列
序列編號165:H
2Mab-293抗體之H鏈CDR1之胺基酸序列
序列編號166:H
2Mab-293抗體之H鏈CDR2之胺基酸序列
序列編號167:H
2Mab-293抗體之H鏈CDR3之胺基酸序列
序列編號168:H
2Mab-293抗體之L鏈CDR1之胺基酸序列
序列編號169:H
2Mab-293抗體之L鏈CDR2之胺基酸序列
序列編號170:H
2Mab-293抗體之L鏈CDR3之胺基酸序列
序列編號171:H
2Mab-294抗體之H鏈CDR1之胺基酸序列
序列編號172:H
2Mab-294抗體之H鏈CDR2之胺基酸序列
序列編號173:H
2Mab-294抗體之H鏈CDR3之胺基酸序列
序列編號174:H
2Mab-294抗體之L鏈CDR1之胺基酸序列
序列編號175:H
2Mab-294抗體之L鏈CDR2之胺基酸序列
序列編號176:H
2Mab-294抗體之L鏈CDR3之胺基酸序列
序列編號177:H
2Mab-295抗體之H鏈CDR1之胺基酸序列
序列編號178:H
2Mab-295抗體之H鏈CDR2之胺基酸序列
序列編號179:H
2Mab-295抗體之H鏈CDR3之胺基酸序列
序列編號180:H
2Mab-295抗體之L鏈CDR1之胺基酸序列
序列編號181:H
2Mab-295抗體之L鏈CDR2之胺基酸序列
序列編號182:H
2Mab-295抗體之L鏈CDR3之胺基酸序列
序列編號183:H
2Mab-296抗體之H鏈CDR1之胺基酸序列
序列編號184:H
2Mab-296抗體之H鏈CDR2之胺基酸序列
序列編號185:H
2Mab-296抗體之H鏈CDR3之胺基酸序列
序列編號186:H
2Mab-296抗體之L鏈CDR1之胺基酸序列
序列編號187:H
2Mab-296抗體之L鏈CDR2之胺基酸序列
序列編號188:H
2Mab-296抗體之L鏈CDR3之胺基酸序列
序列編號189:H
2Mab-297抗體之H鏈CDR1之胺基酸序列
序列編號190:H
2Mab-297抗體之H鏈CDR2之胺基酸序列
序列編號191:H
2Mab-297抗體之H鏈CDR3之胺基酸序列
序列編號192:H
2Mab-297抗體之L鏈CDR1之胺基酸序列
序列編號193:H
2Mab-297抗體之L鏈CDR2之胺基酸序列
序列編號194:H
2Mab-297抗體之L鏈CDR3之胺基酸序列
序列編號195:H
2Mab-298抗體之H鏈CDR1之胺基酸序列
序列編號196:H
2Mab-298抗體之H鏈CDR2之胺基酸序列
序列編號197:H
2Mab-298抗體之H鏈CDR3之胺基酸序列
序列編號198:H
2Mab-298抗體之L鏈CDR1之胺基酸序列
序列編號199:H
2Mab-298抗體之L鏈CDR2之胺基酸序列
序列編號200:H
2Mab-298抗體之L鏈CDR3之胺基酸序列
序列編號201:H
2Mab-299抗體之H鏈CDR1之胺基酸序列
序列編號202:H
2Mab-299抗體之H鏈CDR2之胺基酸序列
序列編號203:H
2Mab-299抗體之H鏈CDR3之胺基酸序列
序列編號204:H
2Mab-299抗體之L鏈CDR1之胺基酸序列
序列編號205:H
2Mab-299抗體之L鏈CDR2之胺基酸序列
序列編號206:H
2Mab-299抗體之L鏈CDR3之胺基酸序列
產業上之可利用性
本發明之抗體或其抗原結合性片段對於癌之檢測及/或處置而言有用。
圖1A係實施例中所使用之pCAG/PA-HER2-RAP-MAP之向量圖。
圖1B係實施例中所使用之pCAG/PA-HER2ec-RAP-MAP之向量圖。
圖2表示本發明之抗體之一例(H
2Mab-214及H
2Mab-250)結合於在乳癌細胞株(SK-BR-3細胞)上表現之HER2,另一方面,與於正常人類表皮角化細胞株(HaCaT細胞)上表現之HER2完全不反應。
圖3表示免疫組織化學染色(IHC)之結果,該免疫組織化學染色(IHC)之結果表示本發明之抗體之一例(H
2Mab-214及H
2Mab-250)將由調查癌細胞之HER2表現狀況之先前之診斷試劑診斷為HER2陰性的癌細胞染色。
圖4表示H
2Mab-214及H
2Mab-250與各種HER2之部分肽之結合性。
圖5表示使用使各種HER2之丙胺酸置換突變體(W614A、K615A、F616A)表現之CHO-K1細胞而分別對於PA標籤之抗體(NZ-1)、H
2Mab-214抗體、H
2Mab-250抗體、陽性對照抗體(曲妥珠單抗)之流式細胞分析(FACS)解析結果。最左使用使野生型HER2表現之CHO-K1細胞作為細胞之陽性對照。
圖6A~E表示實施例6中所獲得之抗體群之表位解析結果。
圖7A~G表示實施例6中所獲得之抗體群之流式細胞分析(FACS)解析結果。
圖8A~F表示實施例6中所獲得之抗體群之癌細胞與正常細胞中之免疫組織化學染色(IHC)之結果。
<![CDATA[<110> 日商小野藥品工業股份有限公司(ONO PHARMACEUTICAL CO., LTD.)]]> 國立大學法人東北大學(TOHOKU UNIVERSITY) <![CDATA[<120> HER2標靶藥物]]> <![CDATA[<130> PON-5001TW]]> <![CDATA[<150> JP 2020-198044]]> <![CDATA[<151> 2020-11-30]]> <![CDATA[<150> JP 2021-110912]]> <![CDATA[<151> 2021-07-02]]> <![CDATA[<160> 206 ]]> <![CDATA[<170> PatentIn第3.5版]]> <![CDATA[<210> 1]]> <![CDATA[<211> 4473]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 1]]> aaggggaggt aaccctggcc cctttggtcg gggccccggg cagccgcgcg ccccttccca 60 cggggccctt tactgcgccg cgcgcccggc ccccacccct cgcagcaccc cgcgccccgc 120 gccctcccag ccgggtccag ccggagccat ggggccggag ccgcagtgag caccatggag 180 ctggcggcct tgtgccgctg ggggctcctc ctcgccctct tgccccccgg agccgcgagc 240 acccaagtgt gcaccggcac agacatgaag ctgcggctcc ctgccagtcc cgagacccac 300 ctggacatgc tccgccacct ctaccagggc tgccaggtgg tgcagggaaa cctggaactc 360 acctacctgc ccaccaatgc cagcctgtcc ttcctgcagg atatccagga ggtgcagggc 420 tacgtgctca tcgctcacaa ccaagtgagg caggtcccac tgcagaggct gcggattgtg 480 cgaggcaccc agctctttga ggacaactat gccctggccg tgctagacaa tggagacccg 540 ctgaacaata ccacccctgt cacaggggcc tccccaggag gcctgcggga gctgcagctt 600 cgaagcctca cagagatctt gaaaggaggg gtcttgatcc agcggaaccc ccagctctgc 660 taccaggaca cgattttgtg gaaggacatc ttccacaaga acaaccagct ggctctcaca 720 ctgatagaca ccaaccgctc tcgggcctgc cacccctgtt ctccgatgtg taagggctcc 780 cgctgctggg gagagagttc tgaggattgt cagagcctga cgcgcactgt ctgtgccggt 840 ggctgtgccc gctgcaaggg gccactgccc actgactgct gccatgagca gtgtgctgcc 900 ggctgcacgg gccccaagca ctctgactgc ctggcctgcc tccacttcaa ccacagtggc 960 atctgtgagc tgcactgccc agccctggtc acctacaaca cagacacgtt tgagtccatg 1020 cccaatcccg agggccggta tacattcggc gccagctgtg tgactgcctg tccctacaac 1080 tacctttcta cggacgtggg atcctgcacc ctcgtctgcc ccctgcacaa ccaagaggtg 1140 acagcagagg atggaacaca gcggtgtgag aagtgcagca agccctgtgc ccgagtgtgc 1200 tatggtctgg gcatggagca cttgcgagag gtgagggcag ttaccagtgc caatatccag 1260 gagtttgctg gctgcaagaa gatctttggg agcctggcat ttctgccgga gagctttgat 1320 ggggacccag cctccaacac tgccccgctc cagccagagc agctccaagt gtttgagact 1380 ctggaagaga tcacaggtta cctatacatc tcagcatggc cggacagcct gcctgacctc 1440 agcgtcttcc agaacctgca agtaatccgg ggacgaattc tgcacaatgg cgcctactcg 1500 ctgaccctgc aagggctggg catcagctgg ctggggctgc gctcactgag ggaactgggc 1560 agtggactgg ccctcatcca ccataacacc cacctctgct tcgtgcacac ggtgccctgg 1620 gaccagctct ttcggaaccc gcaccaagct ctgctccaca ctgccaaccg gccagaggac 1680 gagtgtgtgg gcgagggcct ggcctgccac cagctgtgcg cccgagggca ctgctggggt 1740 ccagggccca cccagtgtgt caactgcagc cagttccttc ggggccagga gtgcgtggag 1800 gaatgccgag tactgcaggg gctccccagg gagtatgtga atgccaggca ctgtttgccg 1860 tgccaccctg agtgtcagcc ccagaatggc tcagtgacct gttttggacc ggaggctgac 1920 cagtgtgtgg cctgtgccca ctataaggac cctcccttct gcgtggcccg ctgccccagc 1980 ggtgtgaaac ctgacctctc ctacatgccc atctggaagt ttccagatga ggagggcgca 2040 tgccagcctt gccccatcaa ctgcacccac tcctgtgtgg acctggatga caagggctgc 2100 cccgccgagc agagagccag ccctctgacg tccatcatct ctgcggtggt tggcattctg 2160 ctggtcgtgg tcttgggggt ggtctttggg atcctcatca agcgacggca gcagaagatc 2220 cggaagtaca cgatgcggag actgctgcag gaaacggagc tggtggagcc gctgacacct 2280 agcggagcga tgcccaacca ggcgcagatg cggatcctga aagagacgga gctgaggaag 2340 gtgaaggtgc ttggatctgg cgcttttggc acagtctaca agggcatctg gatccctgat 2400 ggggagaatg tgaaaattcc agtggccatc aaagtgttga gggaaaacac atcccccaaa 2460 gccaacaaag aaatcttaga cgaagcatac gtgatggctg gtgtgggctc cccatatgtc 2520 tcccgccttc tgggcatctg cctgacatcc acggtgcagc tggtgacaca gcttatgccc 2580 tatggctgcc tcttagacca tgtccgggaa aaccgcggac gcctgggctc ccaggacctg 2640 ctgaactggt gtatgcagat tgccaagggg atgagctacc tggaggatgt gcggctcgta 2700 cacagggact tggccgctcg gaacgtgctg gtcaagagtc ccaaccatgt caaaattaca 2760 gacttcgggc tggctcggct gctggacatt gacgagacag agtaccatgc agatgggggc 2820 aaggtgccca tcaagtggat ggcgctggag tccattctcc gccggcggtt cacccaccag 2880 agtgatgtgt ggagttatgg tgtgactgtg tgggagctga tgacttttgg ggccaaacct 2940 tacgatggga tcccagcccg ggagatccct gacctgctgg aaaaggggga gcggctgccc 3000 cagcccccca tctgcaccat tgatgtctac atgatcatgg tcaaatgttg gatgattgac 3060 tctgaatgtc ggccaagatt ccgggagttg gtgtctgaat tctcccgcat ggccagggac 3120 ccccagcgct ttgtggtcat ccagaatgag gacttgggcc cagccagtcc cttggacagc 3180 accttctacc gctcactgct ggaggacgat gacatggggg acctggtgga tgctgaggag 3240 tatctggtac cccagcaggg cttcttctgt ccagaccctg ccccgggcgc tgggggcatg 3300 gtccaccaca ggcaccgcag ctcatctacc aggagtggcg gtggggacct gacactaggg 3360 ctggagccct ctgaagagga ggcccccagg tctccactgg caccctccga aggggctggc 3420 tccgatgtat ttgatggtga cctgggaatg ggggcagcca aggggctgca aagcctcccc 3480 acacatgacc ccagccctct acagcggtac agtgaggacc ccacagtacc cctgccctct 3540 gagactgatg gctacgttgc ccccctgacc tgcagccccc agcctgaata tgtgaaccag 3600 ccagatgttc ggccccagcc cccttcgccc cgagagggcc ctctgcctgc tgcccgacct 3660 gctggtgcca ctctggaaag gcccaagact ctctccccag ggaagaatgg ggtcgtcaaa 3720 gacgtttttg cctttggggg tgccgtggag aaccccgagt acttgacacc ccagggagga 3780 gctgcccctc agccccaccc tcctcctgcc ttcagcccag ccttcgacaa cctctattac 3840 tgggaccagg acccaccaga gcggggggct ccacccagca ccttcaaagg gacacctacg 3900 gcagagaacc cagagtacct gggtctggac gtgccagtgt gaaccagaag gccaagtccg 3960 cagaagccct gatgtgtcct cagggagcag ggaaggcctg acttctgctg gcatcaagag 4020 gtgggagggc cctccgacca cttccagggg aacctgccat gccaggaacc tgtcctaagg 4080 aaccttcctt cctgcttgag ttcccagatg gctggaaggg gtccagcctc gttggaagag 4140 gaacagcact ggggagtctt tgtggattct gaggccctgc ccaatgagac tctagggtcc 4200 agtggatgcc acagcccagc ttggcccttt ccttccagat cctgggtact gaaagcctta 4260 gggaagctgg cctgagaggg gaagcggccc taagggagtg tctaagaaca aaagcgaccc 4320 attcagagac tgtccctgaa acctagtact gccccccatg aggaaggaac agcaatggtg 4380 tcagtatcca ggctttgtac agagtgcttt tctgtttagt ttttactttt tttgttttgt 4440 ttttttaaag atgaaataaa gacccagggg gag 4473 <![CDATA[<210> 2]]> <![CDATA[<211> 1255]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<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 Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu 340 345 350 Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys 355 360 365 Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp 370 375 380 Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe 385 390 395 400 Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro 405 410 415 Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg 420 425 430 Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu 435 440 445 Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly 450 455 460 Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val 465 470 475 480 Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr 485 490 495 Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His 500 505 510 Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys 515 520 525 Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys 530 535 540 Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys 545 550 555 560 Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys 565 570 575 Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp 580 585 590 Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu 595 600 605 Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln 610 615 620 Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys 625 630 635 640 Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser 645 650 655 Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly 660 665 670 Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg 675 680 685 Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly 690 695 700 Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu 705 710 715 720 Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys 725 730 735 Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile 740 745 750 Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu 755 760 765 Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg 770 775 780 Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu 785 790 795 800 Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg 805 810 815 Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly 820 825 830 Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala 835 840 845 Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe 850 855 860 Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp 865 870 875 880 Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg 885 890 895 Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val 900 905 910 Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala 915 920 925 Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro 930 935 940 Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met 945 950 955 960 Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe 965 970 975 Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu 980 985 990 Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu 995 1000 1005 Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr 1010 1015 1020 Leu Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly 1025 1030 1035 Ala Gly Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg 1040 1045 1050 Ser Gly Gly Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu 1055 1060 1065 Glu Ala Pro Arg Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser 1070 1075 1080 Asp Val Phe Asp Gly Asp Leu Gly Met Gly Ala Ala Lys Gly Leu 1085 1090 1095 Gln Ser Leu Pro Thr His Asp Pro Ser Pro Leu Gln Arg Tyr Ser 1100 1105 1110 Glu Asp Pro Thr Val Pro Leu Pro Ser Glu Thr Asp Gly Tyr Val 1115 1120 1125 Ala Pro Leu Thr Cys Ser Pro Gln Pro Glu Tyr Val Asn Gln Pro 1130 1135 1140 Asp Val Arg Pro Gln Pro Pro Ser Pro Arg Glu Gly Pro Leu Pro 1145 1150 1155 Ala Ala Arg Pro Ala Gly Ala Thr Leu Glu Arg Pro Lys Thr Leu 1160 1165 1170 Ser Pro Gly Lys Asn Gly Val Val Lys Asp Val Phe Ala Phe Gly 1175 1180 1185 Gly Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln Gly Gly Ala 1190 1195 1200 Ala Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala Phe Asp 1205 1210 1215 Asn Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala Pro 1220 1225 1230 Pro Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr 1235 1240 1245 Leu Gly Leu Asp Val Pro Val 1250 1255 <![CDATA[<210> 3]]> <![CDATA[<211> 630]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> HER2ec]]> <![CDATA[<400> 3]]> Thr Gln Val Cys Thr Gly Thr Asp Met Lys Leu Arg Leu Pro Ala Ser 1 5 10 15 Pro Glu Thr His Leu Asp Met Leu Arg His Leu Tyr Gln Gly Cys Gln 20 25 30 Val Val Gln Gly Asn Leu Glu Leu Thr Tyr Leu Pro Thr Asn Ala Ser 35 40 45 Leu Ser Phe Leu Gln Asp Ile Gln Glu Val Gln Gly Tyr Val Leu Ile 50 55 60 Ala His Asn Gln Val Arg Gln Val Pro Leu Gln Arg Leu Arg Ile Val 65 70 75 80 Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr Ala Leu Ala Val Leu Asp 85 90 95 Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro Val Thr Gly Ala Ser Pro 100 105 110 Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser Leu Thr Glu Ile Leu Lys 115 120 125 Gly Gly Val Leu Ile Gln Arg Asn Pro Gln Leu Cys Tyr Gln Asp Thr 130 135 140 Ile Leu Trp Lys Asp Ile Phe His Lys Asn Asn Gln Leu Ala Leu Thr 145 150 155 160 Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys His Pro Cys Ser Pro Met 165 170 175 Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser Ser Glu Asp Cys Gln Ser 180 185 190 Leu Thr Arg Thr Val Cys Ala Gly Gly Cys Ala Arg Cys Lys Gly Pro 195 200 205 Leu Pro Thr Asp Cys Cys His Glu Gln Cys Ala Ala Gly Cys Thr Gly 210 215 220 Pro Lys His Ser Asp Cys Leu Ala Cys Leu His Phe Asn His Ser Gly 225 230 235 240 Ile Cys Glu Leu His Cys Pro Ala Leu Val Thr Tyr Asn Thr Asp Thr 245 250 255 Phe Glu Ser Met Pro Asn Pro Glu Gly Arg Tyr Thr Phe Gly Ala Ser 260 265 270 Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu Ser Thr Asp Val Gly Ser 275 280 285 Cys Thr Leu Val Cys Pro Leu His Asn Gln Glu Val Thr Ala Glu Asp 290 295 300 Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys Pro Cys Ala Arg Val Cys 305 310 315 320 Tyr Gly Leu Gly Met Glu His Leu Arg Glu Val Arg Ala Val Thr Ser 325 330 335 Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys Lys Ile Phe Gly Ser Leu 340 345 350 Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp Pro Ala Ser Asn Thr Ala 355 360 365 Pro Leu Gln Pro Glu Gln Leu Gln Val Phe Glu Thr Leu Glu Glu Ile 370 375 380 Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro Asp Ser Leu Pro Asp Leu 385 390 395 400 Ser Val Phe Gln Asn Leu Gln Val Ile Arg Gly Arg Ile Leu His Asn 405 410 415 Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu Gly Ile Ser Trp Leu Gly 420 425 430 Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly Leu Ala Leu Ile His His 435 440 445 Asn Thr His Leu Cys Phe Val His Thr Val Pro Trp Asp Gln Leu Phe 450 455 460 Arg Asn Pro His Gln Ala Leu Leu His Thr Ala Asn Arg Pro Glu Asp 465 470 475 480 Glu Cys Val Gly Glu Gly Leu Ala Cys His Gln Leu Cys Ala Arg Gly 485 490 495 His Cys Trp Gly Pro Gly Pro Thr Gln Cys Val Asn Cys Ser Gln Phe 500 505 510 Leu Arg Gly Gln Glu Cys Val Glu Glu Cys Arg Val Leu Gln Gly Leu 515 520 525 Pro Arg Glu Tyr Val Asn Ala Arg His Cys Leu Pro Cys His Pro Glu 530 535 540 Cys Gln Pro Gln Asn Gly Ser Val Thr Cys Phe Gly Pro Glu Ala Asp 545 550 555 560 Gln Cys Val Ala Cys Ala His Tyr Lys Asp Pro Pro Phe Cys Val Ala 565 570 575 Arg Cys Pro Ser Gly Val Lys Pro Asp Leu Ser Tyr Met Pro Ile Trp 580 585 590 Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln Pro Cys Pro Ile Asn Cys 595 600 605 Thr His Ser Cys Val Asp Leu Asp Asp Lys Gly Cys Pro Ala Glu Gln 610 615 620 Arg Ala Ser Pro Leu Thr 625 630 <![CDATA[<210> 4]]> <![CDATA[<211> 35]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> InF.HindIII-H2-214H]]> <![CDATA[<400> 4]]> cggtatcgat aagcttgata tggacaggct tactt 35 <![CDATA[<210> 5]]> <![CDATA[<211> 35]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> InF.HindIII-H2-250H]]> <![CDATA[<400> 5]]> cggtatcgat aagcttaaca tgaacttagg gctca 35 <![CDATA[<210> 6]]> <![CDATA[<211> 34]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> InFr.IgG1terNotI]]> <![CDATA[<400> 6]]> tctagagtcg cggccgctca tttaccagga gagt 34 <![CDATA[<210> 7]]> <![CDATA[<211> 34]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> InF.HindIII-H2-214L]]> <![CDATA[<400> 7]]> cggtatcgat aagcttgaga tggagtcaga caca 34 <![CDATA[<210> 8]]> <![CDATA[<211> 35]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> InF.HindIII-H2-250L]]> <![CDATA[<400> 8]]> cggtatcgat aagcttaaaa tgatgagtcc tgccc 35 <![CDATA[<210> 9]]> <![CDATA[<211> 34]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> InF.mIgCKterNotI]]> <![CDATA[<400> 9]]> tctagagtcg cggccgccta acactcattc ctgt 34 <![CDATA[<210> 10]]> <![CDATA[<211> 1395]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-214重鏈DNA]]> <![CDATA[<400> 10]]> atggacaggc ttacttcctc attcctgctg ctgattgtcc ctgcatatgt cctttcccag 60 gttactctga aagagtctgg ccctgggata ttgcagccct cccagaccct cagtctgact 120 tgttctttct ctgggttttc actgagcact tctggtatgg gtgtgagctg gattcgtcag 180 ccttcaggaa agggtctgga gtggctggca cacattttct gggatgatga caagcgctat 240 aacccatccc tgaagagccg gctcacaatc tccaaggata cctccagaaa taaggtattc 300 ctcaagatca ccagtgtgga cactgcagat actgccacat actactgtgc tcgaagggta 360 gtagctacag actggtactt cgatgtctgg ggcgcaggga ccacggtcac cgtctcctca 420 gccaaaacga cacccccatc tgtctatcca ctggcccctg gatctgctgc ccaaactaac 480 tccatggtga ccctgggatg cctggtcaag ggctatttcc ctgagccagt gacagtgacc 540 tggaactctg gatccctgtc cagcggtgtg cacaccttcc cagctgtcct gcagtctgac 600 ctctacactc tgagcagctc agtgactgtc ccctccagca cctggcccag cgagaccgtc 660 acctgcaacg ttgcccaccc ggccagcagc accaaggtgg acaagaaaat tgtgcccagg 720 gattgtggtt gtaagccttg catatgtaca gtcccagaag tatcatctgt cttcatcttc 780 cccccaaagc ccaaggatgt gctcaccatt actctgactc ctaaggtcac gtgtgttgtg 840 gtagacatca gcaaggatga tcccgaggtc cagttcagct ggtttgtaga tgatgtggag 900 gtgcacacag ctcagacgca accccgggag gagcagttca acagcacttt ccgctcagtc 960 agtgaacttc ccatcatgca ccaggactgg ctcaatggca aggagttcaa atgcagggtc 1020 aacagtgcag ctttccctgc ccccatcgag aaaaccatct ccaaaaccaa aggcagaccg 1080 aaggctccac aggtgtacac cattccacct cccaaggagc agatggccaa ggataaagtc 1140 agtctgacct gcatgataac agacttcttc cctgaagaca ttactgtgga gtggcagtgg 1200 aatgggcagc cagcggagaa ctacaagaac actcagccca tcatggacac agatggctct 1260 tacttcgtct acagcaagct caatgtgcag aagagcaact gggaggcagg aaatactttc 1320 acctgctctg tgttacatga gggcctgcac aaccaccata ctgagaagag cctctcccac 1380 tctcctggta aatga 1395 <![CDATA[<210> 11]]> <![CDATA[<211> 717]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-214輕鏈DNA]]> <![CDATA[<400> 11]]> atggagtcag acacactcct gctatgggtg ctgctgctct gggttccagg ctccactggt 60 gacattgtgc tcacccaatc tccagcttct ttggctgtgt ctctaggtca gagagccacc 120 atctcctgca gagccagtga aagtgttgaa tattatggca caactttaat gcagtggtac 180 caacagaaac caggacagcc acccaaactc ctcatctatg ctgcatccaa agtagaatct 240 ggggtccctg ccaggtttag tggcagtggg tctgggactg acttcagcct caacatccat 300 cctgtggagg aggatgatgt tgcaatgtat ttctgtcagc aaagtaggaa ggttccgctc 360 acgttcggtg ctgggaccaa gctggagctg aaacgggctg atgctgcacc aactgtatcc 420 atcttcccac catccagtga gcagttaaca tctggaggtg cctcagtcgt gtgcttcttg 480 aacaacttct accccaaaga catcaatgtc aagtggaaga ttgatggcag tgaacgacaa 540 aatggcgtcc tgaacagttg gactgatcag gacagcaaag acagcaccta cagcatgagc 600 agcaccctca cgttgaccaa ggacgagtat gaacgacata acagctatac ctgtgaggcc 660 actcacaaga catcaacttc acccattgtc aagagcttca acaggaatga gtgttag 717 <![CDATA[<210> 12]]> <![CDATA[<211> 1380]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-250重鏈DNA]]> <![CDATA[<400> 12]]> atgaacttag ggctcagctt cattttcctt gccctttttt taaaaggtgt ccggtgtgag 60 gtgcagctgg tggagtctgg gggaggctta gtgcagccag gagggtccct gaaactctcc 120 tgtgcagcct ctggattcac tttcagtaac tatggcatgt cttgggttcg ccagactcca 180 gacaggaggc tggagttggt cgcaaccatt aataataatg gtggtggtac ctattatcca 240 gacagtgtga agggccggtt caccatctcc agagacaatg ccaagaacac cctgtacctg 300 caaatgagca gtctgaagtc tgaggacaca gccatgtact actgcacaag ccccggccta 360 ctatgggatg cctggggcgc agggaccacg gtcaccgtct cctcagccaa aacgacaccc 420 ccatctgtct atccactggc ccctggatct gctgcccaaa ctaactccat ggtgaccctg 480 ggatgcctgg tcaagggcta tttccctgag ccagtgacag tgacctggaa ctctggatcc 540 ctgtccagcg gtgtgcacac cttcccagct gtcctgcagt ctgacctcta cactctgagc 600 agctcagtga ctgtcccctc cagcacctgg cccagcgaga ccgtcacctg caacgttgcc 660 cacccggcca gcagcaccaa ggtggacaag aaaattgtgc ccagggattg tggttgtaag 720 ccttgcatat gtacagtccc agaagtatca tctgtcttca tcttcccccc aaagcccaag 780 gatgtgctca ccattactct gactcctaag gtcacgtgtg ttgtggtaga catcagcaag 840 gatgatcccg aggtccagtt cagctggttt gtagatgatg tggaggtgca cacagctcag 900 acgcaacccc gggaggagca gttcaacagc actttccgct cagtcagtga acttcccatc 960 atgcaccagg actggctcaa tggcaaggag ttcaaatgca gggtcaacag tgcagctttc 1020 cctgccccca tcgagaaaac catctccaaa accaaaggca gaccgaaggc tccacaggtg 1080 tacaccattc cacctcccaa ggagcagatg gccaaggata aagtcagtct gacctgcatg 1140 ataacagact tcttccctga agacattact gtggagtggc agtggaatgg gcagccagcg 1200 gagaactaca agaacactca gcccatcatg gacacagatg gctcttactt cgtctacagc 1260 aagctcaatg tgcagaagag caactgggag gcaggaaata ctttcacctg ctctgtgtta 1320 catgagggcc tgcacaacca ccatactgag aagagcctct cccactctcc tggtaaatga 1380 <![CDATA[<210> 13]]> <![CDATA[<211> 720]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-250輕鏈DNA]]> <![CDATA[<400> 13]]> atgatgagtc ctgcccagtt cctgtttctg ttagtgctct ggattcggga aaccaacggt 60 gatgttgtga tgacccagac tccactcact ttgtcggtct ccattggaca accagcctcc 120 atctcttgca agtcaagtca gagcctctta gatagtgatg gaaggacata tttgaattgg 180 ttgttacaga ggccaggcca gtctccaaag cgcctaatct atctggtgtc taaactggac 240 tctggagccc ctgacaggtt cactggcagt ggatcaggga cagattttac actgaaaatc 300 agcagagtgg aggctgagga tttgggagtt tattattgct ggcaaggtac acattttcct 360 cagacgttcg gtggaggcac caagctggaa atcaaacggg ctgatgctgc accaactgta 420 tccatcttcc caccatccag tgagcagtta acatctggag gtgcctcagt cgtgtgcttc 480 ttgaacaact tctaccccaa agacatcaat gtcaagtgga agattgatgg cagtgaacga 540 caaaatggcg tcctgaacag ttggactgat caggacagca aagacagcac ctacagcatg 600 agcagcaccc tcacgttgac caaggacgag tatgaacgac ataacagcta tacctgtgag 660 gccactcaca agacatcaac ttcacccatt gtcaagagct tcaacaggaa tgagtgttag 720 <![CDATA[<210> 14]]> <![CDATA[<211> 464]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-214重鏈蛋白質]]> <![CDATA[<400> 14]]> Met Asp Arg Leu Thr Ser Ser Phe Leu Leu Leu Ile Val Pro Ala Tyr 1 5 10 15 Val Leu Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln 20 25 30 Pro Ser Gln Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu 35 40 45 Ser Thr Ser Gly Met Gly Val Ser Trp Ile Arg Gln Pro Ser Gly Lys 50 55 60 Gly Leu Glu Trp Leu Ala His Ile Phe Trp Asp Asp Asp Lys Arg Tyr 65 70 75 80 Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Arg 85 90 95 Asn Lys Val Phe Leu Lys Ile Thr Ser Val Asp Thr Ala Asp Thr Ala 100 105 110 Thr Tyr Tyr Cys Ala Arg Arg Val Val Ala Thr Asp Trp Tyr Phe Asp 115 120 125 Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr 130 135 140 Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn 145 150 155 160 Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val 195 200 205 Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val 210 215 220 Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg 225 230 235 240 Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser 245 250 255 Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu 260 265 270 Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro 275 280 285 Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala 290 295 300 Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val 305 310 315 320 Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe 325 330 335 Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr 340 345 350 Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile 355 360 365 Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys 370 375 380 Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp 385 390 395 400 Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp 405 410 415 Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser 420 425 430 Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly 435 440 445 Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 460 <![CDATA[<210> 15]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-214輕鏈蛋白質]]> <![CDATA[<400> 15]]> Met Glu Ser Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala 20 25 30 Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser 35 40 45 Val Glu Tyr Tyr Gly Thr Thr Leu Met Gln Trp Tyr Gln Gln Lys Pro 50 55 60 Gly Gln Pro Pro Lys Leu Leu Ile Tyr Ala Ala Ser Lys Val Glu Ser 65 70 75 80 Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser 85 90 95 Leu Asn Ile His Pro Val Glu Glu Asp Asp Val Ala Met Tyr Phe Cys 100 105 110 Gln Gln Ser Arg Lys Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu 115 120 125 Glu Leu Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 16]]> <![CDATA[<211> 459]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-250重鏈蛋白質]]> <![CDATA[<400> 16]]> Met Asn Leu Gly Leu Ser Phe Ile Phe Leu Ala Leu Phe Leu Lys Gly 1 5 10 15 Val Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Asn Tyr Gly Met Ser Trp Val Arg Gln Thr Pro Asp Arg Arg Leu 50 55 60 Glu Leu Val Ala Thr Ile Asn Asn Asn Gly Gly Gly Thr Tyr Tyr Pro 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met 100 105 110 Tyr Tyr Cys Thr Ser Pro Gly Leu Leu Trp Asp Ala Trp Gly Ala Gly 115 120 125 Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr 130 135 140 Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu 145 150 155 160 Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp 165 170 175 Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185 190 Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser 195 200 205 Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser 210 215 220 Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys 225 230 235 240 Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro 245 250 255 Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr 260 265 270 Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser 275 280 285 Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg 290 295 300 Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile 305 310 315 320 Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn 325 330 335 Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys 340 345 350 Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu 355 360 365 Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe 370 375 380 Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala 385 390 395 400 Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr 405 410 415 Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly 420 425 430 Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His 435 440 445 Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 <![CDATA[<210> 17]]> <![CDATA[<211> 239]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-250輕鏈蛋白質]]> <![CDATA[<400> 17]]> Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Arg 1 5 10 15 Glu Thr Asn Gly Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser 20 25 30 Val Ser Ile Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser 35 40 45 Leu Leu Asp Ser Asp Gly Arg Thr Tyr Leu Asn Trp Leu Leu Gln Arg 50 55 60 Pro Gly Gln Ser Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp 65 70 75 80 Ser Gly Ala Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe 85 90 95 Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr 100 105 110 Cys Trp Gln Gly Thr His Phe Pro Gln Thr Phe Gly Gly Gly Thr Lys 115 120 125 Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro 130 135 140 Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe 145 150 155 160 Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp 165 170 175 Gly Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp 180 185 190 Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys 195 200 205 Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys 210 215 220 Thr Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 18]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-214 HCDR1]]> <![CDATA[<400> 18]]> Thr Ser Gly Met Gly Val Ser 1 5 <![CDATA[<210> 19]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-214 HCDR2]]> <![CDATA[<400> 19]]> His Ile Phe Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <![CDATA[<210> 20]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-214 HCDR3]]> <![CDATA[<400> 20]]> Arg Val Val Ala Thr Asp Trp Tyr Phe Asp Val 1 5 10 <![CDATA[<210> 21]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-214 LCDR1]]> <![CDATA[<400> 21]]> Arg Ala Ser Glu Ser Val Glu Tyr Tyr Gly Thr Thr Leu Met Gln 1 5 10 15 <![CDATA[<210> 22]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-214 LCDR2]]> <![CDATA[<400> 22]]> Ala Ala Ser Lys Val Glu Ser 1 5 <![CDATA[<210> 23]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-214 LCDR3]]> <![CDATA[<400> 23]]> Gln Gln Ser Arg Lys Val Pro Leu Thr 1 5 <![CDATA[<210> 24]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-250 HCDR1]]> <![CDATA[<400> 24]]> Asn Tyr Gly Met Ser 1 5 <![CDATA[<210> 25]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-250 HCDR2]]> <![CDATA[<400> 25]]> Thr Ile Asn Asn Asn Gly Gly Gly Thr Tyr Tyr Pro Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 26]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-250 HCDR3]]> <![CDATA[<400> 26]]> Pro Gly Leu Leu Trp Asp Ala 1 5 <![CDATA[<210> 27]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-250 LCDR1]]> <![CDATA[<400> 27]]> Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Arg Thr Tyr Leu Asn 1 5 10 15 <![CDATA[<210> 28]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-250 LCDR2]]> <![CDATA[<400> 28]]> Leu Val Ser Lys Leu Asp Ser 1 5 <![CDATA[<210> 29]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2Mab-250 LCDR3]]> <![CDATA[<400> 29]]> Trp Gln Gly Thr His Phe Pro Gln Thr 1 5 <![CDATA[<210> 30]]> <![CDATA[<211> 53]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人HER2 600-652]]> <![CDATA[<400> 30]]> Cys Pro Ser Gly Val Lys Pro Asp Leu Ser Tyr Met Pro Ile Trp Lys 1 5 10 15 Phe Pro Asp Glu Glu Gly Ala Cys Gln Pro Cys Pro Ile Asn Cys Thr 20 25 30 His Ser Cys Val Asp Leu Asp Asp Lys Gly Cys Pro Ala Glu Gln Arg 35 40 45 Ala Ser Pro Leu Thr 50 <![CDATA[<210> 31]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人HER2 603-622]]> <![CDATA[<400> 31]]> Gly Val Lys Pro Asp Leu Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp 1 5 10 15 Glu Glu Gly Ala 20 <![CDATA[<210> 32]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人HER2 613-632]]> <![CDATA[<400> 32]]> Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln Pro Cys Pro Ile 1 5 10 15 Asn Cys Thr His 20 <![CDATA[<210> 33]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人HER2 613-622]]> <![CDATA[<400> 33]]> Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala 1 5 10 <![CDATA[<210> 34]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人HER2 611-618]]> <![CDATA[<400> 34]]> Met Pro Ile Trp Lys Phe Pro Asp 1 5 <![CDATA[<210> 35]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人HER2 612-618]]> <![CDATA[<400> 35]]> Pro Ile Trp Lys Phe Pro Asp 1 5 <![CDATA[<210> 36]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人HER2 613-619]]> <![CDATA[<400> 36]]> Ile Trp Lys Phe Pro Asp Glu 1 5 <![CDATA[<210> 37]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人HER2 p604-622C]]> <![CDATA[<400> 37]]> Val Lys Pro Asp Leu Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu 1 5 10 15 Glu Gly Ala Cys 20 <![CDATA[<210> 38]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 連接子]]> <![CDATA[<400> 38]]> Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Ser 20 <![CDATA[<210> 39]]> <![CDATA[<211> 463]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M279重鏈蛋白質]]> <![CDATA[<400> 39]]> Met Asn Leu Gly Leu Ser Phe Ile Phe Leu Ala Leu Ile Leu Lys Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe 35 40 45 Ser Ser Tyr Gly Ile Phe Trp Val Arg Gln Thr Pro Asp Lys Arg Leu 50 55 60 Glu Leu Val Ala Thr Ile Lys Ser Asn Gly Gly Arg Thr Tyr Tyr Pro 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Thr Leu His Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met 100 105 110 Tyr Tyr Cys Ala Arg Glu Gly Gly Asp Tyr Trp Gly Gln Gly Thr Ser 115 120 125 Val Thr Val Ser Ser Ala Thr Thr Thr Ala Pro Ser Val Tyr Pro Leu 130 135 140 Val Pro Gly Cys Ser Asp Thr Ser Gly Ser Ser Val Thr Leu Gly Cys 145 150 155 160 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Lys Trp Asn Tyr 165 170 175 Gly Ala Leu Ser Ser Gly Val Arg Thr Val Ser Ser Val Leu Gln Ser 180 185 190 Gly Phe Tyr Ser Leu Ser Ser Leu Val Thr Val Pro Ser Ser Thr Trp 195 200 205 Pro Ser Gln Thr Val Ile Cys Asn Val Ala His Pro Ala Ser Lys Thr 210 215 220 Glu Leu Ile Lys Arg Ile Glu Pro Arg Ile Pro Lys Pro Ser Thr Pro 225 230 235 240 Pro Gly Ser Ser Cys Pro Pro Gly Asn Ile Leu Gly Gly Pro Ser Val 245 250 255 Phe Ile Phe Pro Pro Lys Pro Lys Asp Ala Leu Met Ile Ser Leu Thr 260 265 270 Pro Lys Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp 275 280 285 Val His Val Ser Trp Phe Val Asp Asn Lys Glu Val His Thr Ala Trp 290 295 300 Thr Gln Pro Arg Glu Ala Gln Tyr Asn Ser Thr Phe Arg Val Val Ser 305 310 315 320 Ala Leu Pro Ile Gln His Gln Asp Trp Met Arg Gly Lys Glu Phe Lys 325 330 335 Cys Lys Val Asn Asn Lys Ala Leu Pro Ala Pro Ile Glu Arg Thr Ile 340 345 350 Ser Lys Pro Lys Gly Arg Ala Gln Thr Pro Gln Val Tyr Thr Ile Pro 355 360 365 Pro Pro Arg Glu Gln Met Ser Lys Lys Lys Val Ser Leu Thr Cys Leu 370 375 380 Val Thr Asn Phe Phe Ser Glu Ala Ile Ser Val Glu Trp Glu Arg Asn 385 390 395 400 Gly Glu Leu Glu Gln Asp Tyr Lys Asn Thr Pro Pro Ile Leu Asp Ser 405 410 415 Asp Gly Thr Tyr Phe Leu Tyr Ser Lys Leu Thr Val Asp Thr Asp Ser 420 425 430 Trp Leu Gln Gly Glu Ile Phe Thr Cys Ser Val Val His Glu Ala Leu 435 440 445 His Asn His His Thr Gln Lys Asn Leu Ser Arg Ser Pro Gly Lys 450 455 460 <![CDATA[<210> 40]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M279輕鏈蛋白質]]> <![CDATA[<400> 40]]> Met Gly Ile Lys Met Glu Thr His Ser Gln Val Phe Val Tyr Met Leu 1 5 10 15 Leu Trp Leu Ser Gly Ile Glu Gly Asp Ile Val Met Thr Gln Ser His 20 25 30 Lys Ile Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Ser Cys Lys 35 40 45 Ala Ser Gln Asp Val Gly Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro 50 55 60 Gly Gln Ser Pro Ile Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr 65 70 75 80 Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Thr Ile Ser Asn Val Gln Ser Glu Asp Leu Ala Asp Tyr Phe Cys 100 105 110 Gln Gln Tyr Lys Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu 115 120 125 Glu Leu Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 41]]> <![CDATA[<211> 457]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M280重鏈蛋白質]]> <![CDATA[<400> 41]]> Met Asn Phe Gly Leu Arg Leu Ile Phe Leu Val Leu Thr Leu Lys Gly 1 5 10 15 Val Gln Cys Asp Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Ser Tyr Ser Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu 50 55 60 Glu Trp Val Ala Ile Ile Ser Ser Gly Gly Ser Tyr Thr Phe Tyr Pro 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met 100 105 110 Tyr His Cys Thr Arg Glu Ala Gly Asp Tyr Trp Gly Gln Gly Thr Thr 115 120 125 Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu 130 135 140 Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys 145 150 155 160 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser 165 170 175 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 180 185 190 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp 195 200 205 Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 210 215 220 Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys 225 230 235 240 Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys 245 250 255 Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val 260 265 270 Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe 275 280 285 Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu 290 295 300 Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala 325 330 335 Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg 340 345 350 Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met 355 360 365 Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro 370 375 380 Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn 385 390 395 400 Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val 405 410 415 Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr 420 425 430 Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu 435 440 445 Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 <![CDATA[<210> 42]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M280輕鏈蛋白質]]> <![CDATA[<400> 42]]> Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Arg 1 5 10 15 Glu Thr Asn Gly Asp Ile Val Met Thr Gln Thr Pro Leu Thr Leu Ser 20 25 30 Val Thr Ile Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser 35 40 45 Leu Leu His Ser Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg 50 55 60 Pro Gly Gln Ser Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp 65 70 75 80 Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe 85 90 95 Thr Leu Lys Ile Ser Arg Val Glu Ala Asp Asp Leu Gly Ile Tyr Tyr 100 105 110 Cys Trp Gln Gly Thr His Phe Pro Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 43]]> <![CDATA[<211> 457]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M281重鏈蛋白質]]> <![CDATA[<400> 43]]> Met Asn Phe Gly Leu Arg Leu Ile Phe Leu Val Leu Thr Leu Lys Gly 1 5 10 15 Val Gln Cys Asp Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Ser Tyr Ser Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu 50 55 60 Glu Trp Val Ala Ile Ile Ser Ser Gly Gly Thr Tyr Thr Tyr Tyr Thr 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn 85 90 95 Thr Leu Asn Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met 100 105 110 Phe Tyr Cys Thr Arg Glu Ala Gly Asp Tyr Trp Gly Gln Gly Thr Thr 115 120 125 Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu 130 135 140 Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys 145 150 155 160 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser 165 170 175 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 180 185 190 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp 195 200 205 Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 210 215 220 Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys 225 230 235 240 Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys 245 250 255 Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val 260 265 270 Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe 275 280 285 Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu 290 295 300 Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala 325 330 335 Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg 340 345 350 Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met 355 360 365 Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro 370 375 380 Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn 385 390 395 400 Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val 405 410 415 Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr 420 425 430 Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu 435 440 445 Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 <![CDATA[<210> 44]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M281輕鏈蛋白質]]> <![CDATA[<400> 44]]> Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Arg 1 5 10 15 Glu Thr Asn Gly Asn Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser 20 25 30 Val Thr Ile Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser 35 40 45 Leu Leu Tyr Ser Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg 50 55 60 Pro Gly Gln Ser Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp 65 70 75 80 Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe 85 90 95 Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr 100 105 110 Cys Trp Gln Gly Thr His Phe Pro Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 45]]> <![CDATA[<211> 464]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M282重鏈蛋白質]]> <![CDATA[<400> 45]]> Met Glu Arg His Trp Ile Phe Leu Leu Leu Leu Ser Val Thr Ala Gly 1 5 10 15 Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ser Arg 20 25 30 Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ala Gly Tyr Thr Phe 35 40 45 Ser Ser Tyr Met Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu 50 55 60 Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Ser Asn Tyr Asn 65 70 75 80 Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser 85 90 95 Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Tyr Cys Ala Phe Tyr Asp Tyr Asp Gly Asp Trp Gly Gln Gly Thr 115 120 125 Leu Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro 130 135 140 Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly 145 150 155 160 Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn 165 170 175 Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185 190 Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr 195 200 205 Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser 210 215 220 Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro 225 230 235 240 Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser 245 250 255 Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu 260 265 270 Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro 275 280 285 Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala 290 295 300 Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val 305 310 315 320 Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe 325 330 335 Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr 340 345 350 Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu 355 360 365 Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys 370 375 380 Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn 385 390 395 400 Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp 405 410 415 Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys 420 425 430 Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly 435 440 445 Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 450 455 460 <![CDATA[<210> 46]]> <![CDATA[<211> 239]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M282輕鏈蛋白質]]> <![CDATA[<400> 46]]> Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Arg 1 5 10 15 Asp Thr Asn Gly Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser 20 25 30 Val Thr Ile Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser 35 40 45 Leu Phe His Ser Asp Gly Arg Thr Phe Leu Asn Trp Leu Leu Gln Arg 50 55 60 Pro Gly Gln Ser Pro Lys Arg Leu Ile Tyr Lys Val Ser Lys Leu Asp 65 70 75 80 Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe 85 90 95 Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr 100 105 110 Cys Trp Gln Gly Thr His Phe Pro Trp Thr Phe Gly Gly Gly Thr Lys 115 120 125 Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro 130 135 140 Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe 145 150 155 160 Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp 165 170 175 Gly Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp 180 185 190 Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys 195 200 205 Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys 210 215 220 Thr Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 47]]> <![CDATA[<211> 459]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M283重鏈蛋白質]]> <![CDATA[<400> 47]]> Met Asn Leu Gly Leu Ser Phe Ile Phe Leu Ala Leu Ile Leu Lys Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Ser Tyr Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu 50 55 60 Glu Leu Val Ala Thr Ile Asn Ser Asn Gly Gly Ser Thr Phe Tyr Pro 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Thr Leu Tyr Leu His Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Ile 100 105 110 Tyr Tyr Cys Val Ser Pro Gly Ser Trp Phe Pro Tyr Trp Gly Arg Gly 115 120 125 Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro Ser Val Tyr 130 135 140 Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu 145 150 155 160 Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp 165 170 175 Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185 190 Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser 195 200 205 Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser 210 215 220 Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys 225 230 235 240 Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro 245 250 255 Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr 260 265 270 Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser 275 280 285 Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg 290 295 300 Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile 305 310 315 320 Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn 325 330 335 Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys 340 345 350 Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu 355 360 365 Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe 370 375 380 Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala 385 390 395 400 Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr 405 410 415 Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly 420 425 430 Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His 435 440 445 Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 <![CDATA[<210> 48]]> <![CDATA[<211> 241]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M283輕鏈蛋白質]]> <![CDATA[<400> 48]]> Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Arg 1 5 10 15 Val Ser Glu Thr Asn Gly Asp Val Val Met Thr Gln Thr Pro Leu Thr 20 25 30 Leu Ser Val Thr Ile Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser 35 40 45 Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu His Trp Leu Leu 50 55 60 Gln Arg Pro Gly Gln Ser Pro Lys Arg Leu Ile Tyr Leu Val Ser His 65 70 75 80 Leu Asp Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr 85 90 95 Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val 100 105 110 Tyr Tyr Cys Trp Gln Gly Thr His Phe Pro Gln Thr Phe Gly Gly Gly 115 120 125 Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile 130 135 140 Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val 145 150 155 160 Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys 165 170 175 Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp 180 185 190 Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu 195 200 205 Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr 210 215 220 His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu 225 230 235 240 Cys <![CDATA[<210> 49]]> <![CDATA[<211> 462]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M284重鏈蛋白質]]> <![CDATA[<400> 49]]> Met Gly Arg Leu Thr Ser Ser Phe Leu Leu Leu Ile Val Pro Ala Tyr 1 5 10 15 Val Leu Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln 20 25 30 Pro Ser Gln Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu 35 40 45 Ser Thr Ser Gly Val Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys 50 55 60 Gly Leu Glu Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Asn Tyr 65 70 75 80 Asn Pro Ala Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Thr 85 90 95 Asn Gln Gly Phe Leu Lys Ile Ala Ser Val Asp Thr Ala Asp Thr Ala 100 105 110 Thr Tyr Phe Cys Ala Arg Ile Glu Gly Gln Lys Gly Phe Ala Tyr Trp 115 120 125 Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro 130 135 140 Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met 145 150 155 160 Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr 165 170 175 Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro 180 185 190 Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val 195 200 205 Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His 210 215 220 Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys 225 230 235 240 Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe 245 250 255 Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro 260 265 270 Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val 275 280 285 Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr 290 295 300 Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu 305 310 315 320 Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys 325 330 335 Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser 340 345 350 Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro 355 360 365 Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile 370 375 380 Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly 385 390 395 400 Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp 405 410 415 Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp 420 425 430 Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His 435 440 445 Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 460 <![CDATA[<210> 50]]> <![CDATA[<211> 240]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M284輕鏈蛋白質]]> <![CDATA[<400> 50]]> Met Asp Ser Gln Ala Gln Val Leu Met Leu Leu Leu Leu Trp Val Ser 1 5 10 15 Gly Thr Cys Gly Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala 20 25 30 Val Ser Val Gly Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser 35 40 45 Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln 50 55 60 Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg 65 70 75 80 Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp 85 90 95 Phe Thr Leu Thr Ile Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr 100 105 110 Tyr Cys Gln Gln Tyr Tyr Ser Ser Pro Tyr Thr Phe Gly Gly Gly Thr 115 120 125 Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe 130 135 140 Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys 145 150 155 160 Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile 165 170 175 Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln 180 185 190 Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr 195 200 205 Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His 210 215 220 Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 240 <![CDATA[<210> 51]]> <![CDATA[<211> 463]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M285重鏈蛋白質]]> <![CDATA[<400> 51]]> Met Asn Leu Gly Leu Ser Phe Ile Phe Leu Val Leu Ile Leu Lys Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Asn Tyr Gly Ile Phe Trp Val Arg Gln Thr Pro Asp Lys Arg Leu 50 55 60 Glu Leu Val Ala Thr Val Lys Ser Asn Gly Gly Ser Thr Tyr Tyr Pro 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys 85 90 95 Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met 100 105 110 Tyr Tyr Cys Ala Arg Glu Gly Gly Asp Tyr Trp Gly Gln Gly Thr Ser 115 120 125 Val Thr Val Ser Ser Ala Thr Thr Thr Ala Pro Ser Val Tyr Pro Leu 130 135 140 Val Pro Gly Cys Ser Asp Thr Ser Gly Ser Ser Val Thr Leu Gly Cys 145 150 155 160 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Lys Trp Asn Tyr 165 170 175 Gly Ala Leu Ser Ser Gly Val Arg Thr Val Ser Ser Val Leu Gln Ser 180 185 190 Gly Phe Tyr Ser Leu Ser Ser Leu Val Thr Val Pro Ser Ser Thr Trp 195 200 205 Pro Ser Gln Thr Val Ile Cys Asn Val Ala His Pro Ala Ser Lys Thr 210 215 220 Glu Leu Ile Lys Arg Ile Glu Pro Arg Ile Pro Lys Pro Ser Thr Pro 225 230 235 240 Pro Gly Ser Ser Cys Pro Pro Gly Asn Ile Leu Gly Gly Pro Ser Val 245 250 255 Phe Ile Phe Pro Pro Lys Pro Lys Asp Ala Leu Met Ile Ser Leu Thr 260 265 270 Pro Lys Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp 275 280 285 Val His Val Ser Trp Phe Val Asp Asn Lys Glu Val His Thr Ala Trp 290 295 300 Thr Gln Pro Arg Glu Ala Gln Tyr Asn Ser Thr Phe Arg Val Val Ser 305 310 315 320 Ala Leu Pro Ile Gln His Gln Asp Trp Met Arg Gly Lys Glu Phe Lys 325 330 335 Cys Lys Val Asn Asn Lys Ala Leu Pro Ala Pro Ile Glu Arg Thr Ile 340 345 350 Ser Lys Pro Lys Gly Arg Ala Gln Thr Pro Gln Val Tyr Thr Ile Pro 355 360 365 Pro Pro Arg Glu Gln Met Ser Lys Lys Lys Val Ser Leu Thr Cys Leu 370 375 380 Val Thr Asn Phe Phe Ser Glu Ala Ile Ser Val Glu Trp Glu Arg Asn 385 390 395 400 Gly Glu Leu Glu Gln Asp Tyr Lys Asn Thr Pro Pro Ile Leu Asp Ser 405 410 415 Asp Gly Thr Tyr Phe Leu Tyr Ser Lys Leu Thr Val Asp Thr Asp Ser 420 425 430 Trp Leu Gln Gly Glu Ile Phe Thr Cys Ser Val Val His Glu Ala Leu 435 440 445 His Asn His His Thr Gln Lys Asn Leu Ser Arg Ser Pro Gly Lys 450 455 460 <![CDATA[<210> 52]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M285輕鏈蛋白質]]> <![CDATA[<400> 52]]> Met Gly Ile Lys Met Glu Thr His Ser Gln Val Phe Val Tyr Met Leu 1 5 10 15 Leu Trp Leu Ser Gly Val Glu Gly Asp Ile Val Met Thr Gln Ser His 20 25 30 Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr Cys Lys 35 40 45 Ala Ser Gln Asp Val Gly Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg His Thr 65 70 75 80 Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Thr Ile Arg Asn Val Gln Ser Glu Asp Leu Ala Asp Tyr Phe Cys 100 105 110 Gln Gln Tyr Asn Arg Asn Pro Leu Thr Phe Gly Ala Gly Thr Arg Leu 115 120 125 Glu Leu Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 53]]> <![CDATA[<211> 455]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M286重鏈蛋白質]]> <![CDATA[<400> 53]]> Met Arg Val Leu Ile Leu Leu Trp Leu Phe Thr Ala Phe Pro Gly Ile 1 5 10 15 Leu Ser Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro 20 25 30 Ser Gln Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr 35 40 45 Ser Asp Tyr Gly Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu 50 55 60 Glu Trp Met Gly Tyr Ile Arg Tyr Ser Gly Ile Thr Ser Tyr Asn Pro 65 70 75 80 Ser Leu Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln 85 90 95 Phe Phe Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr 100 105 110 Tyr Cys Thr Arg Glu Val Leu Ser Trp Gly Gln Gly Thr Thr Leu Thr 115 120 125 Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro 130 135 140 Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val 145 150 155 160 Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser 165 170 175 Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu 180 185 190 Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser 195 200 205 Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val 210 215 220 Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys 225 230 235 240 Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys 245 250 255 Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val 260 265 270 Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp 275 280 285 Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe 290 295 300 Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp 305 310 315 320 Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe 325 330 335 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys 340 345 350 Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys 355 360 365 Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp 370 375 380 Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys 385 390 395 400 Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser 405 410 415 Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr 420 425 430 Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser 435 440 445 Leu Ser His Ser Pro Gly Lys 450 455 <![CDATA[<210> 54]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M286輕鏈蛋白質]]> <![CDATA[<400> 54]]> Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala 1 5 10 15 Ser Ser Ser Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val 20 25 30 Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu 35 40 45 Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Phe Leu Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser 65 70 75 80 Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys 100 105 110 Ser Gln Ser Thr His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 55]]> <![CDATA[<211> 457]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M287重鏈蛋白質]]> <![CDATA[<400> 55]]> Met Asn Phe Gly Leu Arg Leu Ile Phe Leu Val Leu Thr Leu Lys Gly 1 5 10 15 Val Gln Cys Asp Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Ser Tyr Ser Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu 50 55 60 Glu Trp Val Ala Ile Ile Ser Ser Gly Gly Ser Tyr Ile Phe Tyr Pro 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met 100 105 110 Tyr Tyr Cys Thr Arg Glu Ala Gly Asp Tyr Trp Gly Gln Gly Thr Thr 115 120 125 Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu 130 135 140 Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys 145 150 155 160 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser 165 170 175 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 180 185 190 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp 195 200 205 Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 210 215 220 Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys 225 230 235 240 Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys 245 250 255 Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val 260 265 270 Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe 275 280 285 Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu 290 295 300 Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala 325 330 335 Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg 340 345 350 Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met 355 360 365 Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro 370 375 380 Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn 385 390 395 400 Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val 405 410 415 Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr 420 425 430 Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu 435 440 445 Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 <![CDATA[<210> 56]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M287輕鏈蛋白質]]> <![CDATA[<400> 56]]> Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Arg 1 5 10 15 Glu Thr Asn Gly Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser 20 25 30 Val Thr Ile Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser 35 40 45 Leu Leu His Ser Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg 50 55 60 Pro Gly Gln Ser Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp 65 70 75 80 Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe 85 90 95 Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr 100 105 110 Cys Trp Gln Gly Thr His Phe Pro Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 57]]> <![CDATA[<211> 457]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M288重鏈蛋白質]]> <![CDATA[<400> 57]]> Met Asn Phe Gly Leu Arg Leu Ile Phe Leu Val Leu Thr Leu Lys Gly 1 5 10 15 Val Gln Cys Asp Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Arg Tyr Ser Leu Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu 50 55 60 Glu Trp Val Ala Val Ile Ser Ser Gly Gly Arg Tyr Thr Phe Tyr Pro 65 70 75 80 Asp Gly Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met 100 105 110 Tyr Phe Cys Thr Arg Glu Ala Gly Asp Tyr Trp Gly Gln Gly Thr Pro 115 120 125 Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu 130 135 140 Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys 145 150 155 160 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser 165 170 175 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 180 185 190 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp 195 200 205 Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 210 215 220 Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys 225 230 235 240 Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys 245 250 255 Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val 260 265 270 Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe 275 280 285 Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu 290 295 300 Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala 325 330 335 Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg 340 345 350 Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met 355 360 365 Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro 370 375 380 Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn 385 390 395 400 Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val 405 410 415 Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr 420 425 430 Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu 435 440 445 Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 <![CDATA[<210> 58]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M288輕鏈蛋白質]]> <![CDATA[<400> 58]]> Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Arg 1 5 10 15 Glu Thr Asn Gly Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser 20 25 30 Val Thr Ile Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser 35 40 45 Leu Leu His Ser Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg 50 55 60 Pro Gly Gln Ser Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp 65 70 75 80 Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe 85 90 95 Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr 100 105 110 Cys Trp Gln Gly Thr His Phe Pro Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 59]]> <![CDATA[<211> 464]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M289重鏈蛋白質]]> <![CDATA[<400> 59]]> Met Gly Trp Ser Trp Ile Phe Leu Ser Leu Leu Ser Val Thr Ala Gly 1 5 10 15 Val Phe Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys 20 25 30 Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe 35 40 45 Thr Gly Phe Phe Met Asn Trp Val Met Gln Ser His Gly Lys Ser Leu 50 55 60 Glu Trp Ile Gly Arg Ile Asn Pro Tyr Asn Gly Asp Thr Phe Tyr Asn 65 70 75 80 Gln Lys Phe Asn Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Arg 85 90 95 Thr Ala His Met Asp Leu Arg Asn Leu Ala Ser Glu Asp Ser Ala Val 100 105 110 Tyr Tyr Cys Ala Thr Ile Ser Gly Asn Tyr Arg Gly Tyr Ala Met Asp 115 120 125 Asn Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr 130 135 140 Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn 145 150 155 160 Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val 195 200 205 Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val 210 215 220 Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg 225 230 235 240 Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser 245 250 255 Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu 260 265 270 Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro 275 280 285 Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala 290 295 300 Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val 305 310 315 320 Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe 325 330 335 Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr 340 345 350 Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile 355 360 365 Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys 370 375 380 Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp 385 390 395 400 Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp 405 410 415 Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser 420 425 430 Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly 435 440 445 Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 460 <![CDATA[<210> 60]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M289輕鏈蛋白質]]> <![CDATA[<400> 60]]> Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala 1 5 10 15 Ser Ser Ser Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val 20 25 30 Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Ile 35 40 45 Leu His Thr Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser 65 70 75 80 Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys 100 105 110 Phe Gln Gly Ser Arg Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 61]]> <![CDATA[<211> 457]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M290重鏈蛋白質]]> <![CDATA[<400> 61]]> Met Asn Phe Gly Leu Arg Leu Ile Phe Leu Val Leu Thr Leu Lys Gly 1 5 10 15 Val Gln Cys Asp Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Ser Tyr Ser Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu 50 55 60 Glu Trp Val Ala Ile Ile Ser Ser Gly Gly Ser Tyr Ile Phe Tyr Pro 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met 100 105 110 Tyr Tyr Cys Thr Arg Glu Ala Gly Asp Tyr Trp Gly Gln Gly Thr Thr 115 120 125 Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu 130 135 140 Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys 145 150 155 160 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser 165 170 175 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 180 185 190 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp 195 200 205 Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 210 215 220 Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys 225 230 235 240 Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys 245 250 255 Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val 260 265 270 Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe 275 280 285 Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu 290 295 300 Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala 325 330 335 Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg 340 345 350 Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met 355 360 365 Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro 370 375 380 Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn 385 390 395 400 Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val 405 410 415 Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr 420 425 430 Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu 435 440 445 Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 <![CDATA[<210> 62]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M290輕鏈蛋白質]]> <![CDATA[<400> 62]]> Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Arg 1 5 10 15 Glu Thr Asn Gly Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser 20 25 30 Val Thr Ile Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser 35 40 45 Leu Leu His Ser Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg 50 55 60 Pro Gly Gln Ser Pro Lys Arg Leu Leu Tyr Leu Val Ser Asn Leu Asp 65 70 75 80 Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe 85 90 95 Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Ile Tyr Tyr 100 105 110 Cys Trp Gln Gly Thr His Phe Pro Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 63]]> <![CDATA[<211> 463]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M291重鏈蛋白質]]> <![CDATA[<400> 63]]> Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly 1 5 10 15 Val His Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys 20 25 30 Pro Gly Ala Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe 35 40 45 Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu 50 55 60 Glu Trp Ile Gly Leu Ile Asn Pro Tyr Asn Gly Asn Thr Arg Tyr Asn 65 70 75 80 Gln Lys Phe Gln Asp Lys Ala Thr Leu Thr Val Asp Arg Ser Ser Ser 85 90 95 Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Tyr Cys Val Lys Glu Pro Ser Asp Tyr Trp Gly Gln Gly Thr Thr 115 120 125 Leu Thr Val Ser Ser Ala Thr Thr Thr Ala Pro Ser Val Tyr Pro Leu 130 135 140 Val Pro Gly Cys Ser Asp Thr Ser Gly Ser Ser Val Thr Leu Gly Cys 145 150 155 160 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Lys Trp Asn Tyr 165 170 175 Gly Ala Leu Ser Ser Gly Val Arg Thr Val Ser Ser Val Leu Gln Ser 180 185 190 Gly Phe Tyr Ser Leu Ser Ser Leu Val Thr Val Pro Ser Ser Thr Trp 195 200 205 Pro Ser Gln Thr Val Ile Cys Asn Val Ala His Pro Ala Ser Lys Thr 210 215 220 Glu Leu Ile Lys Arg Ile Glu Pro Arg Ile Pro Lys Pro Ser Thr Pro 225 230 235 240 Pro Gly Ser Ser Cys Pro Pro Gly Asn Ile Leu Gly Gly Pro Ser Val 245 250 255 Phe Ile Phe Pro Pro Lys Pro Lys Asp Ala Leu Met Ile Ser Leu Thr 260 265 270 Pro Lys Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp 275 280 285 Val His Val Ser Trp Phe Val Asp Asn Lys Glu Val His Thr Ala Trp 290 295 300 Thr Gln Pro Arg Glu Ala Gln Tyr Asn Ser Thr Phe Arg Val Val Ser 305 310 315 320 Ala Leu Pro Ile Gln His Gln Asp Trp Met Arg Gly Lys Glu Phe Lys 325 330 335 Cys Lys Val Asn Asn Lys Ala Leu Pro Ala Pro Ile Glu Arg Thr Ile 340 345 350 Ser Lys Pro Lys Gly Arg Ala Gln Thr Pro Gln Val Tyr Thr Ile Pro 355 360 365 Pro Pro Arg Glu Gln Met Ser Lys Lys Lys Val Ser Leu Thr Cys Leu 370 375 380 Val Thr Asn Phe Phe Ser Glu Ala Ile Ser Val Glu Trp Glu Arg Asn 385 390 395 400 Gly Glu Leu Glu Gln Asp Tyr Lys Asn Thr Pro Pro Ile Leu Asp Ser 405 410 415 Asp Gly Thr Tyr Phe Leu Tyr Ser Lys Leu Thr Val Asp Thr Asp Ser 420 425 430 Trp Leu Gln Gly Glu Ile Phe Thr Cys Ser Val Val His Glu Ala Leu 435 440 445 His Asn His His Thr Gln Lys Asn Leu Ser Arg Ser Pro Gly Lys 450 455 460 <![CDATA[<210> 64]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M291輕鏈蛋白質]]> <![CDATA[<400> 64]]> Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala 1 5 10 15 Ser Ser Ser Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val 20 25 30 Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu 35 40 45 Val His Ile Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Lys Arg Phe Ser 65 70 75 80 Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Lys Ile Ser Arg Val Glu Ala Ala Asp Leu Gly Val Tyr Phe Cys 100 105 110 Ser Gln Ser Thr His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 65]]> <![CDATA[<211> 463]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M292重鏈蛋白質]]> <![CDATA[<400> 65]]> Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly 1 5 10 15 Val His Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys 20 25 30 Pro Gly Ala Ser Arg Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe 35 40 45 Thr Gly Tyr Thr Met Asn Trp Val Lys Lys Ser His Gly Lys Asn Leu 50 55 60 Glu Trp Ile Gly Leu Ile Asn Pro Ser Asn Gly Gly Thr Arg Tyr Asn 65 70 75 80 Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser 85 90 95 Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Tyr Cys Val Lys Glu Pro Ser Asp Tyr Trp Gly Gln Gly Thr Thr 115 120 125 Leu Thr Val Ser Ser Ala Thr Thr Thr Ala Pro Ser Val Tyr Pro Leu 130 135 140 Val Pro Gly Cys Ser Asp Thr Ser Gly Ser Ser Val Thr Leu Gly Cys 145 150 155 160 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Lys Trp Asn Tyr 165 170 175 Gly Ala Leu Ser Ser Gly Val Arg Thr Val Ser Ser Val Leu Gln Ser 180 185 190 Gly Phe Tyr Ser Leu Ser Ser Leu Val Thr Val Pro Ser Ser Thr Trp 195 200 205 Pro Ser Gln Thr Val Ile Cys Asn Val Ala His Pro Ala Ser Lys Thr 210 215 220 Glu Leu Ile Lys Arg Ile Glu Pro Arg Ile Pro Lys Pro Ser Thr Pro 225 230 235 240 Pro Gly Ser Ser Cys Pro Pro Gly Asn Ile Leu Gly Gly Pro Ser Val 245 250 255 Phe Ile Phe Pro Pro Lys Pro Lys Asp Ala Leu Met Ile Ser Leu Thr 260 265 270 Pro Lys Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp 275 280 285 Val His Val Ser Trp Phe Val Asp Asn Lys Glu Val His Thr Ala Trp 290 295 300 Thr Gln Pro Arg Glu Ala Gln Tyr Asn Ser Thr Phe Arg Val Val Ser 305 310 315 320 Ala Leu Pro Ile Gln His Gln Asp Trp Met Arg Gly Lys Glu Phe Lys 325 330 335 Cys Lys Val Asn Asn Lys Ala Leu Pro Ala Pro Ile Glu Arg Thr Ile 340 345 350 Ser Lys Pro Lys Gly Arg Ala Gln Thr Pro Gln Val Tyr Thr Ile Pro 355 360 365 Pro Pro Arg Glu Gln Met Ser Lys Lys Lys Val Ser Leu Thr Cys Leu 370 375 380 Val Thr Asn Phe Phe Ser Glu Ala Ile Ser Val Glu Trp Glu Arg Asn 385 390 395 400 Gly Glu Leu Glu Gln Asp Tyr Lys Asn Thr Pro Pro Ile Leu Asp Ser 405 410 415 Asp Gly Thr Tyr Phe Leu Tyr Ser Lys Leu Thr Val Asp Thr Asp Ser 420 425 430 Trp Leu Gln Gly Glu Ile Phe Thr Cys Ser Val Val His Glu Ala Leu 435 440 445 His Asn His His Thr Gln Lys Asn Leu Ser Arg Ser Pro Gly Lys 450 455 460 <![CDATA[<210> 66]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M292輕鏈蛋白質]]> <![CDATA[<400> 66]]> Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala 1 5 10 15 Ser Ser Ser Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val 20 25 30 Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu 35 40 45 Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser 65 70 75 80 Gly Val Pro Asp Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Ile Tyr Phe Cys 100 105 110 Ser Gln Ser Thr His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 67]]> <![CDATA[<211> 463]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M293重鏈蛋白質]]> <![CDATA[<400> 67]]> Met Asn Leu Gly Leu Ser Phe Ile Phe Leu Ala Leu Ile Leu Lys Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Asn Tyr Gly Ile Phe Trp Val Arg Gln Thr Pro Asp Lys Arg Leu 50 55 60 Glu Leu Val Ala Thr Val Lys Ser Asn Gly Gly Ser Thr Tyr Tyr Pro 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys 85 90 95 Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met 100 105 110 Tyr Tyr Cys Ala Arg Glu Gly Gly Asp Tyr Trp Gly Gln Gly Thr Ser 115 120 125 Val Thr Val Ser Ser Ala Thr Thr Thr Ala Pro Ser Val Tyr Pro Leu 130 135 140 Val Pro Gly Cys Ser Asp Thr Ser Gly Ser Ser Val Thr Leu Gly Cys 145 150 155 160 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Lys Trp Asn Tyr 165 170 175 Gly Ala Leu Ser Ser Gly Val Arg Thr Val Ser Ser Val Leu Gln Ser 180 185 190 Gly Phe Tyr Ser Leu Ser Ser Leu Val Thr Val Pro Ser Ser Thr Trp 195 200 205 Pro Ser Gln Thr Val Ile Cys Asn Val Ala His Pro Ala Ser Lys Thr 210 215 220 Glu Leu Ile Lys Arg Ile Glu Pro Arg Ile Pro Lys Pro Ser Thr Pro 225 230 235 240 Pro Gly Ser Ser Cys Pro Pro Gly Asn Ile Leu Gly Gly Pro Ser Val 245 250 255 Phe Ile Phe Pro Pro Lys Pro Lys Asp Ala Leu Met Ile Ser Leu Thr 260 265 270 Pro Lys Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp 275 280 285 Val His Val Ser Trp Phe Val Asp Asn Lys Glu Val His Thr Ala Trp 290 295 300 Thr Gln Pro Arg Glu Ala Gln Tyr Asn Ser Thr Phe Arg Val Val Ser 305 310 315 320 Ala Leu Pro Ile Gln His Gln Asp Trp Met Arg Gly Lys Glu Phe Lys 325 330 335 Cys Lys Val Asn Asn Lys Ala Leu Pro Ala Pro Ile Glu Arg Thr Ile 340 345 350 Ser Lys Pro Lys Gly Arg Ala Gln Thr Pro Gln Val Tyr Thr Ile Pro 355 360 365 Pro Pro Arg Glu Gln Met Ser Lys Lys Lys Val Ser Leu Thr Cys Leu 370 375 380 Val Thr Asn Phe Phe Ser Glu Ala Ile Ser Val Glu Trp Glu Arg Asn 385 390 395 400 Gly Glu Leu Glu Gln Asp Tyr Lys Asn Thr Pro Pro Ile Leu Asp Ser 405 410 415 Asp Gly Thr Tyr Phe Leu Tyr Ser Lys Leu Thr Val Asp Thr Asp Ser 420 425 430 Trp Leu Gln Gly Glu Ile Phe Thr Cys Ser Val Val His Glu Ala Leu 435 440 445 His Asn His His Thr Gln Lys Asn Leu Ser Arg Ser Pro Gly Lys 450 455 460 <![CDATA[<210> 68]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M293輕鏈蛋白質]]> <![CDATA[<400> 68]]> Met Gly Ile Lys Met Glu Thr His Ser Gln Val Phe Val Tyr Met Leu 1 5 10 15 Leu Trp Leu Ser Gly Val Glu Gly Asp Ile Val Met Thr Gln Ser His 20 25 30 Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr Cys Lys 35 40 45 Ala Ser Gln Asp Val Gly Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg His Ile 65 70 75 80 Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Thr Ile Arg Asn Val Gln Ser Glu Asp Leu Ala Asn Tyr Phe Cys 100 105 110 Gln Gln Tyr Ser Lys Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu 115 120 125 Glu Leu Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 69]]> <![CDATA[<211> 468]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M294重鏈蛋白質]]> <![CDATA[<400> 69]]> Met Ser Thr Glu His Arg Pro Leu Ser Val Asn Leu Gly Leu Ser Phe 1 5 10 15 Ile Phe Leu Ala Leu Ile Leu Lys Gly Val Gln Cys Glu Val Gln Leu 20 25 30 Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu 35 40 45 Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly Met Ser Trp 50 55 60 Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Leu Val Ala Thr Ile Asn 65 70 75 80 Ser Asn Gly Gly Gly Thr Tyr Tyr Pro Asp Ser Val Lys Gly Arg Phe 85 90 95 Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Ser 100 105 110 Ser Leu Lys Ser Glu Asp Thr Ala Ile Tyr Tyr Cys Ala Ser Pro Gly 115 120 125 Ser Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 130 135 140 Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala 145 150 155 160 Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr 165 170 175 Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser 180 185 190 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu 195 200 205 Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val 210 215 220 Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys 225 230 235 240 Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro 245 250 255 Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu 260 265 270 Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser 275 280 285 Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu 290 295 300 Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr 305 310 315 320 Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn 325 330 335 Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro 340 345 350 Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln 355 360 365 Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val 370 375 380 Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val 385 390 395 400 Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln 405 410 415 Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn 420 425 430 Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val 435 440 445 Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His 450 455 460 Ser Pro Gly Lys 465 <![CDATA[<210> 70]]> <![CDATA[<211> 239]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M294輕鏈蛋白質]]> <![CDATA[<400> 70]]> Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Arg 1 5 10 15 Glu Thr Asn Gly Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser 20 25 30 Val Thr Ile Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser 35 40 45 Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu His Trp Leu Leu Gln Arg 50 55 60 Pro Gly Gln Ser Pro Arg Arg Leu Ile Phe Leu Val Ser Lys Leu Asp 65 70 75 80 Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe 85 90 95 Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr 100 105 110 Cys Trp Gln Gly Thr His Phe Pro Gln Thr Phe Gly Gly Gly Thr Lys 115 120 125 Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro 130 135 140 Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe 145 150 155 160 Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp 165 170 175 Gly Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp 180 185 190 Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys 195 200 205 Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys 210 215 220 Thr Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 71]]> <![CDATA[<211> 457]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M295重鏈蛋白質]]> <![CDATA[<400> 71]]> Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly 1 5 10 15 Val His Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys 20 25 30 Pro Gly Ala Ser Arg Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe 35 40 45 Thr Gly Tyr Thr Met Asn Trp Val Lys Lys Ser His Gly Lys Asn Leu 50 55 60 Glu Trp Ile Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Arg Tyr Asn 65 70 75 80 Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser 85 90 95 Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Tyr Cys Val Lys Glu Pro Ser Asp Tyr Trp Gly Gln Gly Thr Thr 115 120 125 Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu 130 135 140 Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys 145 150 155 160 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser 165 170 175 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 180 185 190 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp 195 200 205 Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 210 215 220 Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys 225 230 235 240 Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys 245 250 255 Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val 260 265 270 Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe 275 280 285 Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu 290 295 300 Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala 325 330 335 Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg 340 345 350 Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met 355 360 365 Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro 370 375 380 Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn 385 390 395 400 Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val 405 410 415 Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr 420 425 430 Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu 435 440 445 Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 <![CDATA[<210> 72]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M295輕鏈蛋白質]]> <![CDATA[<400> 72]]> Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala 1 5 10 15 Ser Ser Ser Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val 20 25 30 Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu 35 40 45 Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Lys Arg Phe Ser 65 70 75 80 Gly Val Pro Asp Arg Phe Ser Gly Cys Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Lys Ile Ser Arg Leu Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys 100 105 110 Ser Gln Ser Ser His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 73]]> <![CDATA[<211> 462]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M296重鏈蛋白質]]> <![CDATA[<400> 73]]> Met Gly Arg Leu Thr Ser Ser Phe Leu Leu Leu Ile Val Pro Ala Tyr 1 5 10 15 Val Leu Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln 20 25 30 Pro Ser Gln Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu 35 40 45 Ser Thr Ser Gly Met Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys 50 55 60 Gly Leu Glu Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Arg Tyr 65 70 75 80 Asn Pro Ala Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Ser 85 90 95 Asn Gln Val Phe Leu Lys Ile Ala Asn Val Asp Thr Ser Asp Thr Ala 100 105 110 Thr Tyr Tyr Cys Ser Arg Ile Glu Gly Gln Arg Gly Phe Ala Tyr Trp 115 120 125 Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro 130 135 140 Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met 145 150 155 160 Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr 165 170 175 Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro 180 185 190 Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val 195 200 205 Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His 210 215 220 Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys 225 230 235 240 Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe 245 250 255 Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro 260 265 270 Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val 275 280 285 Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr 290 295 300 Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu 305 310 315 320 Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys 325 330 335 Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser 340 345 350 Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro 355 360 365 Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile 370 375 380 Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly 385 390 395 400 Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp 405 410 415 Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp 420 425 430 Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His 435 440 445 Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 460 <![CDATA[<210> 74]]> <![CDATA[<211> 240]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M296輕鏈蛋白質]]> <![CDATA[<400> 74]]> Met Asp Ser Gln Ala Gln Val Leu Met Leu Leu Leu Leu Trp Val Ser 1 5 10 15 Gly Thr Cys Gly Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala 20 25 30 Val Ser Val Gly Glu Met Ile Thr Met Thr Cys Lys Ser Ser Gln Ser 35 40 45 Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln 50 55 60 Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg 65 70 75 80 Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp 85 90 95 Phe Thr Leu Thr Ile Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr 100 105 110 Tyr Cys Gln Gln Tyr Tyr Ser Gln Pro Tyr Thr Phe Gly Gly Gly Thr 115 120 125 Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe 130 135 140 Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys 145 150 155 160 Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile 165 170 175 Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln 180 185 190 Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr 195 200 205 Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His 210 215 220 Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 240 <![CDATA[<210> 75]]> <![CDATA[<211> 463]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M297重鏈蛋白質]]> <![CDATA[<400> 75]]> Met Asn Leu Gly Leu Ser Phe Ile Phe Leu Ala Leu Ile Leu Lys Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe 35 40 45 Ser Ser Tyr Gly Ile Phe Trp Val Arg Gln Thr Pro Asp Lys Arg Leu 50 55 60 Glu Leu Val Ala Thr Ile Lys Ser Asn Gly Gly Arg Thr Tyr Tyr Pro 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Thr Leu His Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met 100 105 110 Tyr Tyr Cys Ala Arg Glu Gly Gly Asp Tyr Trp Gly Gln Gly Thr Ser 115 120 125 Val Thr Val Ser Ser Ala Thr Thr Thr Ala Pro Ser Val Tyr Pro Leu 130 135 140 Val Pro Gly Cys Ser Asp Thr Ser Gly Ser Ser Val Thr Leu Gly Cys 145 150 155 160 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Lys Trp Asn Tyr 165 170 175 Gly Ala Leu Ser Ser Gly Val Arg Thr Val Ser Ser Val Leu Gln Ser 180 185 190 Gly Phe Tyr Ser Leu Ser Ser Leu Val Thr Val Pro Ser Ser Thr Trp 195 200 205 Pro Ser Gln Thr Val Ile Cys Asn Val Ala His Pro Ala Ser Lys Thr 210 215 220 Glu Leu Ile Lys Arg Ile Glu Pro Arg Ile Pro Lys Pro Ser Thr Pro 225 230 235 240 Pro Gly Ser Ser Cys Pro Pro Gly Asn Ile Leu Gly Gly Pro Ser Val 245 250 255 Phe Ile Phe Pro Pro Lys Pro Lys Asp Ala Leu Met Ile Ser Leu Thr 260 265 270 Pro Lys Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp 275 280 285 Val His Val Ser Trp Phe Val Asp Asn Lys Glu Val His Thr Ala Trp 290 295 300 Thr Gln Pro Arg Glu Ala Gln Tyr Asn Ser Thr Phe Arg Val Val Ser 305 310 315 320 Ala Leu Pro Ile Gln His Gln Asp Trp Met Arg Gly Lys Glu Phe Lys 325 330 335 Cys Lys Val Asn Asn Lys Ala Leu Pro Ala Pro Ile Glu Arg Thr Ile 340 345 350 Ser Lys Pro Lys Gly Arg Ala Gln Thr Pro Gln Val Tyr Thr Ile Pro 355 360 365 Pro Pro Arg Glu Gln Met Ser Lys Lys Lys Val Ser Leu Thr Cys Leu 370 375 380 Val Thr Asn Phe Phe Ser Glu Ala Ile Ser Val Glu Trp Glu Arg Asn 385 390 395 400 Gly Glu Leu Glu Gln Asp Tyr Lys Asn Thr Pro Pro Ile Leu Asp Ser 405 410 415 Asp Gly Thr Tyr Phe Leu Tyr Ser Lys Leu Thr Val Asp Thr Asp Ser 420 425 430 Trp Leu Gln Gly Glu Ile Phe Thr Cys Ser Val Val His Glu Ala Leu 435 440 445 His Asn His His Thr Gln Lys Asn Leu Ser Arg Ser Pro Gly Lys 450 455 460 <![CDATA[<210> 76]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M297輕鏈蛋白質]]> <![CDATA[<400> 76]]> Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala 1 5 10 15 Ser Ser Ser Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val 20 25 30 Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Val 35 40 45 Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser 65 70 75 80 Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Ile Tyr Tyr Cys 100 105 110 Phe Gln Gly Ser Arg Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Asn Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 77]]> <![CDATA[<211> 457]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M298重鏈蛋白質]]> <![CDATA[<400> 77]]> Met Asn Phe Gly Leu Arg Leu Ile Phe Leu Val Leu Thr Leu Lys Gly 1 5 10 15 Val Gln Cys Asp Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Arg Tyr Ser Met Ser Trp Val Arg Gln Thr Pro Glu Lys Lys Leu 50 55 60 Glu Trp Val Ala Ile Ile Ser Thr Gly Gly Ser Tyr Met Phe Tyr Pro 65 70 75 80 Asp Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met 100 105 110 Tyr Tyr Cys Thr Arg Glu Ala Gly Asp Tyr Trp Gly Gln Gly Thr Thr 115 120 125 Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu 130 135 140 Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys 145 150 155 160 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser 165 170 175 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 180 185 190 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp 195 200 205 Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 210 215 220 Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys 225 230 235 240 Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys 245 250 255 Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val 260 265 270 Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe 275 280 285 Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu 290 295 300 Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala 325 330 335 Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg 340 345 350 Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met 355 360 365 Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro 370 375 380 Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn 385 390 395 400 Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val 405 410 415 Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr 420 425 430 Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu 435 440 445 Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 <![CDATA[<210> 78]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M298輕鏈蛋白質]]> <![CDATA[<400> 78]]> Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Arg 1 5 10 15 Glu Thr Asn Gly Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser 20 25 30 Val Thr Ile Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser 35 40 45 Leu Leu His Ser Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg 50 55 60 Pro Gly Gln Ser Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp 65 70 75 80 Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe 85 90 95 Thr Leu Lys Ile Ser Arg Val Glu Ser Glu Asp Leu Gly Val Tyr Tyr 100 105 110 Cys Trp Gln Gly Thr His Phe Pro Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 79]]> <![CDATA[<211> 457]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M299重鏈蛋白質]]> <![CDATA[<400> 79]]> Met Asn Leu Gly Leu Ser Phe Ile Phe Leu Ala Leu Ile Leu Lys Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Asn Ile Tyr Gly Ile Phe Trp Val Arg Gln Thr Pro Asp Lys Arg Leu 50 55 60 Glu Leu Val Ala Thr Ile His Ser Asn Gly Gly Arg Ile Tyr Tyr Pro 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met 100 105 110 Tyr Tyr Cys Ala Arg Glu Gly Gly Asp Tyr Trp Gly Gln Gly Thr Ser 115 120 125 Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu 130 135 140 Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys 145 150 155 160 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser 165 170 175 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 180 185 190 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp 195 200 205 Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 210 215 220 Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys 225 230 235 240 Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys 245 250 255 Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val 260 265 270 Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe 275 280 285 Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu 290 295 300 Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala 325 330 335 Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg 340 345 350 Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met 355 360 365 Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro 370 375 380 Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn 385 390 395 400 Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val 405 410 415 Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr 420 425 430 Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu 435 440 445 Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 <![CDATA[<210> 80]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M299輕鏈蛋白質]]> <![CDATA[<400> 80]]> Met Gly Ile Lys Met Glu Thr His Ser Gln Val Phe Val Tyr Met Leu 1 5 10 15 Leu Trp Leu Ser Gly Val Glu Gly Asp Ile Val Met Thr Gln Ser His 20 25 30 Lys Val Met Ala Thr Ser Val Gly Asp Arg Val Ser Ile Thr Cys Lys 35 40 45 Ala Ser Gln Asp Val Gly Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr 65 70 75 80 Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Thr Ile Asn Asn Val Leu Ser Glu Asp Leu Val Asp Tyr Phe Cys 100 105 110 Gln Gln Tyr Arg Arg Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu 115 120 125 Glu Leu Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <![CDATA[<210> 81]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M279H-CDR1]]> <![CDATA[<400> 81]]> Ser Tyr Gly Ile Phe 1 5 <![CDATA[<210> 82]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M279H-CDR2]]> <![CDATA[<400> 82]]> Thr Ile Lys Ser Asn Gly Gly Arg Thr Tyr Tyr Pro Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 83]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M279H-CDR3]]> <![CDATA[<400> 83]]> Glu Gly Gly Asp Tyr 1 5 <![CDATA[<210> 84]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M279L-CDR1]]> <![CDATA[<400> 84]]> Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala 1 5 10 <![CDATA[<210> 85]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M279L-CDR2]]> <![CDATA[<400> 85]]> Trp Ala Ser Thr Arg His Thr 1 5 <![CDATA[<210> 86]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M279L-CDR3]]> <![CDATA[<400> 86]]> Gln Gln Tyr Lys Ser Asn Pro Leu Thr 1 5 <![CDATA[<210> 87]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M280H-CDR1]]> <![CDATA[<400> 87]]> Ser Tyr Ser Met Ser 1 5 <![CDATA[<210> 88]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M280H-CDR2]]> <![CDATA[<400> 88]]> Ile Ile Ser Ser Gly Gly Ser Tyr Thr Phe Tyr Pro Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 89]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M280H-CDR3]]> <![CDATA[<400> 89]]> Glu Ala Gly Asp Tyr 1 5 <![CDATA[<210> 90]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M280L-CDR1]]> <![CDATA[<400> 90]]> Lys Ser Ser Gln Ser Leu Leu His Ser Asp Gly Lys Thr Tyr Leu Asn 1 5 10 15 <![CDATA[<210> 91]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M280L-CDR2]]> <![CDATA[<400> 91]]> Leu Val Ser Lys Leu Asp Ser 1 5 <![CDATA[<210> 92]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M280L-CDR3]]> <![CDATA[<400> 92]]> Trp Gln Gly Thr His Phe Pro Thr 1 5 <![CDATA[<210> 93]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M281H-CDR1]]> <![CDATA[<400> 93]]> Ser Tyr Ser Met Ser 1 5 <![CDATA[<210> 94]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M281H-CDR2]]> <![CDATA[<400> 94]]> Ile Ile Ser Ser Gly Gly Thr Tyr Thr Tyr Tyr Thr Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 95]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M281H-CDR3]]> <![CDATA[<400> 95]]> Glu Ala Gly Asp Tyr 1 5 <![CDATA[<210> 96]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M281L-CDR1]]> <![CDATA[<400> 96]]> Lys Ser Ser Gln Ser Leu Leu Tyr Ser Asp Gly Lys Thr Tyr Leu Asn 1 5 10 15 <![CDATA[<210> 97]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M281L-CDR2]]> <![CDATA[<400> 97]]> Leu Val Ser Lys Leu Asp Ser 1 5 <![CDATA[<210> 98]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M281L-CDR3]]> <![CDATA[<400> 98]]> Trp Gln Gly Thr His Phe Pro Thr 1 5 <![CDATA[<210> 99]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M282H-CDR1]]> <![CDATA[<400> 99]]> Ser Tyr Met Ile His 1 5 <![CDATA[<210> 100]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M282H-CDR2]]> <![CDATA[<400> 100]]> Tyr Ile Asn Pro Ser Ser Gly Tyr Ser Asn Tyr Asn Gln Lys Phe Lys 1 5 10 15 Asp <![CDATA[<210> 101]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M282H-CDR3]]> <![CDATA[<400> 101]]> Tyr Asp Tyr Asp Gly Asp 1 5 <![CDATA[<210> 102]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M282L-CDR1]]> <![CDATA[<400> 102]]> Lys Ser Ser Gln Ser Leu Phe His Ser Asp Gly Arg Thr Phe Leu Asn 1 5 10 15 <![CDATA[<210> 103]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M282L-CDR2]]> <![CDATA[<400> 103]]> Lys Val Ser Lys Leu Asp Ser 1 5 <![CDATA[<210> 104]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M282L-CDR3]]> <![CDATA[<400> 104]]> Trp Gln Gly Thr His Phe Pro Trp Thr 1 5 <![CDATA[<210> 105]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M283H-CDR1]]> <![CDATA[<400> 105]]> Ser Tyr Gly Met Ser 1 5 <![CDATA[<210> 106]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M283H-CDR2]]> <![CDATA[<400> 106]]> Thr Ile Asn Ser Asn Gly Gly Ser Thr Phe Tyr Pro Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 107]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M283H-CDR3]]> <![CDATA[<400> 107]]> Pro Gly Ser Trp Phe Pro Tyr 1 5 <![CDATA[<210> 108]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M283L-CDR1]]> <![CDATA[<400> 108]]> Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu His 1 5 10 15 <![CDATA[<210> 109]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M283L-CDR2]]> <![CDATA[<400> 109]]> Leu Val Ser His Leu Asp Ser 1 5 <![CDATA[<210> 110]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M283L-CDR3]]> <![CDATA[<400> 110]]> Trp Gln Gly Thr His Phe Pro Gln Thr 1 5 <![CDATA[<210> 111]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M284H-CDR1]]> <![CDATA[<400> 111]]> Thr Ser Gly Val Gly Val Gly 1 5 <![CDATA[<210> 112]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M284H-CDR2]]> <![CDATA[<400> 112]]> His Ile Trp Trp Asp Asp Asp Lys Asn Tyr Asn Pro Ala Leu Lys Ser 1 5 10 15 <![CDATA[<210> 113]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M284H-CDR3]]> <![CDATA[<400> 113]]> Ile Glu Gly Gln Lys Gly Phe Ala Tyr 1 5 <![CDATA[<210> 114]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M284L-CDR1]]> <![CDATA[<400> 114]]> Lys Ser Ser Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu 1 5 10 15 Ala <![CDATA[<210> 115]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M284L-CDR2]]> <![CDATA[<400> 115]]> Trp Ala Ser Thr Arg Glu Ser 1 5 <![CDATA[<210> 116]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M284L-CDR3]]> <![CDATA[<400> 116]]> Gln Gln Tyr Tyr Ser Ser Pro Tyr Thr 1 5 <![CDATA[<210> 117]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M285H-CDR1]]> <![CDATA[<400> 117]]> Asn Tyr Gly Ile Phe 1 5 <![CDATA[<210> 118]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M285H-CDR2]]> <![CDATA[<400> 118]]> Thr Val Lys Ser Asn Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 119]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M285H-CDR3]]> <![CDATA[<400> 119]]> Glu Gly Gly Asp Tyr 1 5 <![CDATA[<210> 120]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M285L-CDR1]]> <![CDATA[<400> 120]]> Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala 1 5 10 <![CDATA[<210> 121]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M285L-CDR2]]> <![CDATA[<400> 121]]> Trp Thr Ser Thr Arg His Thr 1 5 <![CDATA[<210> 122]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M285L-CDR3]]> <![CDATA[<400> 122]]> Gln Gln Tyr Asn Arg Asn Pro Leu Thr 1 5 <![CDATA[<210> 123]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M286H-CDR1]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<222> (1)..(5)]]> <![CDATA[<223> CDR1尚未確定]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<222> (1)..(5)]]> <![CDATA[<223> CDR1尚未確定。本序列長度並不等於實際CDR1之長度。 ]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<222> (6)..(6)]]> <![CDATA[<223> Xaa可為任意天然存在之胺基酸]]> <![CDATA[<400> 123]]> Xaa Xaa Xaa Xaa Xaa Xaa 1 5 <![CDATA[<210> 124]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M286H-CDR2]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<222> (1)..(10)]]> <![CDATA[<223> CDR2尚未確定。本序列長度並不等於實際CDR2之長度。 ]]> <![CDATA[<400> 124]]> Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 <![CDATA[<210> 125]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M286H-CDR3]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<222> (1)..(5)]]> <![CDATA[<223> CDR3尚未確定。本序列長度並不等於實際CDR3之長度。]]> <![CDATA[<400> 125]]> Xaa Xaa Xaa Xaa Xaa 1 5 <![CDATA[<210> 126]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M286L-CDR1]]> <![CDATA[<400> 126]]> Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His 1 5 10 15 <![CDATA[<210> 127]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M286L-CDR2]]> <![CDATA[<400> 127]]> Lys Val Ser Asn Arg Phe Ser 1 5 <![CDATA[<210> 128]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M286L-CDR3]]> <![CDATA[<400> 128]]> Ser Gln Ser Thr His Val Pro Pro Thr 1 5 <![CDATA[<210> 129]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M287H-CDR1]]> <![CDATA[<400> 129]]> Ser Tyr Ser Met Ser 1 5 <![CDATA[<210> 130]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M287H-CDR2]]> <![CDATA[<400> 130]]> Ile Ile Ser Ser Gly Gly Ser Tyr Ile Phe Tyr Pro Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 131]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M287H-CDR3]]> <![CDATA[<400> 131]]> Glu Ala Gly Asp Tyr 1 5 <![CDATA[<210> 132]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M287L-CDR1]]> <![CDATA[<400> 132]]> Lys Ser Ser Gln Ser Leu Leu His Ser Asp Gly Lys Thr Tyr Leu Asn 1 5 10 15 <![CDATA[<210> 133]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M287L-CDR2]]> <![CDATA[<400> 133]]> Leu Val Ser Lys Leu Asp Ser 1 5 <![CDATA[<210> 134]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M287L-CDR3]]> <![CDATA[<400> 134]]> Trp Gln Gly Thr His Phe Pro Thr 1 5 <![CDATA[<210> 135]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M288H-CDR1]]> <![CDATA[<400> 135]]> Arg Tyr Ser Leu Ser 1 5 <![CDATA[<210> 136]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M288H-CDR2]]> <![CDATA[<400> 136]]> Val Ile Ser Ser Gly Gly Arg Tyr Thr Phe Tyr Pro Asp Gly Val Lys 1 5 10 15 Gly <![CDATA[<210> 137]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M288H-CDR3]]> <![CDATA[<400> 137]]> Glu Ala Gly Asp Tyr 1 5 <![CDATA[<210> 138]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M288L-CDR1]]> <![CDATA[<400> 138]]> Lys Ser Ser Gln Ser Leu Leu His Ser Asp Gly Lys Thr Tyr Leu Asn 1 5 10 15 <![CDATA[<210> 139]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M288L-CDR2]]> <![CDATA[<400> 139]]> Leu Val Ser Lys Leu Asp Ser 1 5 <![CDATA[<210> 140]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M288L-CDR3]]> <![CDATA[<400> 140]]> Trp Gln Gly Thr His Phe Pro Thr 1 5 <![CDATA[<210> 141]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M289H-CDR1]]> <![CDATA[<400> 141]]> Gly Phe Phe Met Asn 1 5 <![CDATA[<210> 142]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M289H-CDR2]]> <![CDATA[<400> 142]]> Arg Ile Asn Pro Tyr Asn Gly Asp Thr Phe Tyr Asn Gln Lys Phe Asn 1 5 10 15 Asp <![CDATA[<210> 143]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M289H-CDR3]]> <![CDATA[<400> 143]]> Ile Ser Gly Asn Tyr Arg Gly Tyr Ala Met Asp Asn 1 5 10 <![CDATA[<210> 144]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M289L-CDR1]]> <![CDATA[<400> 144]]> Arg Ser Ser Gln Thr Ile Leu His Thr Asn Gly Asn Thr Tyr Leu Glu 1 5 10 15 <![CDATA[<210> 145]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M289L-CDR2]]> <![CDATA[<400> 145]]> Lys Val Ser Asn Arg Phe Ser 1 5 <![CDATA[<210> 146]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M289L-CDR3]]> <![CDATA[<400> 146]]> Phe Gln Gly Ser Arg Val Pro Pro Thr 1 5 <![CDATA[<210> 147]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M290H-CDR1]]> <![CDATA[<400> 147]]> Ser Tyr Ser Met Ser 1 5 <![CDATA[<210> 148]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M290H-CDR2]]> <![CDATA[<400> 148]]> Ile Ile Ser Ser Gly Gly Ser Tyr Ile Phe Tyr Pro Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 149]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M290H-CDR3]]> <![CDATA[<400> 149]]> Glu Ala Gly Asp Tyr 1 5 <![CDATA[<210> 150]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M290L-CDR1]]> <![CDATA[<400> 150]]> Lys Ser Ser Gln Ser Leu Leu His Ser Asp Gly Lys Thr Tyr Leu Asn 1 5 10 15 <![CDATA[<210> 151]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M290L-CDR2]]> <![CDATA[<400> 151]]> Leu Val Ser Asn Leu Asp Ser 1 5 <![CDATA[<210> 152]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M290L-CDR3]]> <![CDATA[<400> 152]]> Trp Gln Gly Thr His Phe Pro Thr 1 5 <![CDATA[<210> 153]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M291H-CDR1]]> <![CDATA[<400> 153]]> Gly Tyr Thr Met Asn 1 5 <![CDATA[<210> 154]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M291H-CDR2]]> <![CDATA[<400> 154]]> Leu Ile Asn Pro Tyr Asn Gly Asn Thr Arg Tyr Asn Gln Lys Phe Gln 1 5 10 15 Asp <![CDATA[<210> 155]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M291H-CDR3]]> <![CDATA[<400> 155]]> Glu Pro Ser Asp Tyr 1 5 <![CDATA[<210> 156]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M291L-CDR1]]> <![CDATA[<400> 156]]> Arg Ser Ser Gln Ser Leu Val His Ile Asn Gly Asn Thr Tyr Leu His 1 5 10 15 <![CDATA[<210> 157]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M291L-CDR2]]> <![CDATA[<400> 157]]> Lys Val Ser Lys Arg Phe Ser 1 5 <![CDATA[<210> 158]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M291L-CDR3]]> <![CDATA[<400> 158]]> Ser Gln Ser Thr His Val Pro Pro Thr 1 5 <![CDATA[<210> 159]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M292H-CDR1]]> <![CDATA[<400> 159]]> Gly Tyr Thr Met Asn 1 5 <![CDATA[<210> 160]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M292H-CDR2]]> <![CDATA[<400> 160]]> Leu Ile Asn Pro Ser Asn Gly Gly Thr Arg Tyr Asn Gln Lys Phe Lys 1 5 10 15 Asp <![CDATA[<210> 161]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M292H-CDR3]]> <![CDATA[<400> 161]]> Glu Pro Ser Asp Tyr 1 5 <![CDATA[<210> 162]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M292L-CDR1]]> <![CDATA[<400> 162]]> Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His 1 5 10 15 <![CDATA[<210> 163]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M292L-CDR2]]> <![CDATA[<400> 163]]> Lys Val Ser Asn Arg Phe Ser 1 5 <![CDATA[<210> 164]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M292L-CDR3]]> <![CDATA[<400> 164]]> Ser Gln Ser Thr His Val Pro Pro Thr 1 5 <![CDATA[<210> 165]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M293H-CDR1]]> <![CDATA[<400> 165]]> Asn Tyr Gly Ile Phe 1 5 <![CDATA[<210> 166]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M293H-CDR2]]> <![CDATA[<400> 166]]> Thr Val Lys Ser Asn Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 167]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M293H-CDR3]]> <![CDATA[<400> 167]]> Glu Gly Gly Asp Tyr 1 5 <![CDATA[<210> 168]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M293L-CDR1]]> <![CDATA[<400> 168]]> Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala 1 5 10 <![CDATA[<210> 169]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M293L-CDR2]]> <![CDATA[<400> 169]]> Trp Thr Ser Thr Arg His Ile 1 5 <![CDATA[<210> 170]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M293L-CDR3]]> <![CDATA[<400> 170]]> Gln Gln Tyr Ser Lys Asn Pro Leu Thr 1 5 <![CDATA[<210> 171]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M294H-CDR1]]> <![CDATA[<400> 171]]> Ser Tyr Gly Met Ser 1 5 <![CDATA[<210> 172]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M294H-CDR2]]> <![CDATA[<400> 172]]> Thr Ile Asn Ser Asn Gly Gly Gly Thr Tyr Tyr Pro Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 173]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M294H-CDR3]]> <![CDATA[<400> 173]]> Pro Gly Ser Trp Phe Pro Tyr 1 5 <![CDATA[<210> 174]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M294L-CDR1]]> <![CDATA[<400> 174]]> Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu His 1 5 10 15 <![CDATA[<210> 175]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M294L-CDR2]]> <![CDATA[<400> 175]]> Leu Val Ser Lys Leu Asp Ser 1 5 <![CDATA[<210> 176]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M294L-CDR3]]> <![CDATA[<400> 176]]> Trp Gln Gly Thr His Phe Pro Gln Thr 1 5 <![CDATA[<210> 177]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M295H-CDR1]]> <![CDATA[<400> 177]]> Gly Tyr Thr Met Asn 1 5 <![CDATA[<210> 178]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M295H-CDR2]]> <![CDATA[<400> 178]]> Leu Ile Asn Pro Tyr Asn Gly Gly Thr Arg Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <![CDATA[<210> 179]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M295H-CDR3]]> <![CDATA[<400> 179]]> Glu Pro Ser Asp Tyr 1 5 <![CDATA[<210> 180]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M295L-CDR1]]> <![CDATA[<400> 180]]> Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His 1 5 10 15 <![CDATA[<210> 181]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M295L-CDR2]]> <![CDATA[<400> 181]]> Lys Val Ser Lys Arg Phe Ser 1 5 <![CDATA[<210> 182]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M295L-CDR3]]> <![CDATA[<400> 182]]> Ser Gln Ser Ser His Val Pro Pro Thr 1 5 <![CDATA[<210> 183]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M296H-CDR1]]> <![CDATA[<400> 183]]> Thr Ser Gly Met Gly Val Gly 1 5 <![CDATA[<210> 184]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M296H-CDR2]]> <![CDATA[<400> 184]]> His Ile Trp Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ala Leu Lys Ser 1 5 10 15 <![CDATA[<210> 185]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M296H-CDR3]]> <![CDATA[<400> 185]]> Ile Glu Gly Gln Arg Gly Phe Ala Tyr 1 5 <![CDATA[<210> 186]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M296L-CDR1]]> <![CDATA[<400> 186]]> Lys Ser Ser Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu 1 5 10 15 Ala <![CDATA[<210> 187]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M296L-CDR2]]> <![CDATA[<400> 187]]> Trp Ala Ser Thr Arg Glu Ser 1 5 <![CDATA[<210> 188]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M296L-CDR3]]> <![CDATA[<400> 188]]> Gln Gln Tyr Tyr Ser Gln Pro Tyr Thr 1 5 <![CDATA[<210> 189]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M297H-CDR1]]> <![CDATA[<400> 189]]> Ser Tyr Gly Ile Phe 1 5 <![CDATA[<210> 190]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M297H-CDR2]]> <![CDATA[<400> 190]]> Thr Ile Lys Ser Asn Gly Gly Arg Thr Tyr Tyr Pro Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 191]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M297H-CDR3]]> <![CDATA[<400> 191]]> Glu Gly Gly Asp Tyr 1 5 <![CDATA[<210> 192]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M297L-CDR1]]> <![CDATA[<400> 192]]> Arg Ser Ser Gln Ser Val Val His Ser Asn Gly Asn Thr Tyr Leu Glu 1 5 10 15 <![CDATA[<210> 193]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M297L-CDR2]]> <![CDATA[<400> 193]]> Lys Val Ser Asn Arg Phe Ser 1 5 <![CDATA[<210> 194]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M297L-CDR3]]> <![CDATA[<400> 194]]> Phe Gln Gly Ser Arg Val Pro Pro Thr 1 5 <![CDATA[<210> 195]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M298H-CDR1]]> <![CDATA[<400> 195]]> Arg Tyr Ser Met Ser 1 5 <![CDATA[<210> 196]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M298H-CDR2]]> <![CDATA[<400> 196]]> Ile Ile Ser Thr Gly Gly Ser Tyr Met Phe Tyr Pro Asp Ser Ala Lys 1 5 10 15 Gly <![CDATA[<210> 197]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M298H-CDR3]]> <![CDATA[<400> 197]]> Glu Ala Gly Asp Tyr 1 5 <![CDATA[<210> 198]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M298L-CDR1]]> <![CDATA[<400> 198]]> Lys Ser Ser Gln Ser Leu Leu His Ser Asp Gly Lys Thr Tyr Leu Asn 1 5 10 15 <![CDATA[<210> 199]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M298L-CDR2]]> <![CDATA[<400> 199]]> Leu Val Ser Lys Leu Asp Ser 1 5 <![CDATA[<210> 200]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M298L-CDR3]]> <![CDATA[<400> 200]]> Trp Gln Gly Thr His Phe Pro Thr 1 5 <![CDATA[<210> 201]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M299H-CDR1]]> <![CDATA[<400> 201]]> Ile Tyr Gly Ile Phe 1 5 <![CDATA[<210> 202]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M299H-CDR2]]> <![CDATA[<400> 202]]> Thr Ile His Ser Asn Gly Gly Arg Ile Tyr Tyr Pro Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 203]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M299H-CDR3]]> <![CDATA[<400> 203]]> Glu Gly Gly Asp Tyr 1 5 <![CDATA[<210> 204]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M299L-CDR1]]> <![CDATA[<400> 204]]> Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala 1 5 10 <![CDATA[<210> 205]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M299L-CDR2]]> <![CDATA[<400> 205]]> Trp Ala Ser Thr Arg His Thr 1 5 <![CDATA[<210> 206]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> H2M299L-CDR3]]> <![CDATA[<400> 206]]> Gln Gln Tyr Arg Arg Tyr Pro Leu Thr 1 5
Claims (18)
- 一種經單離之抗體或抗體之抗原結合性片段,其相較於對於在非癌細胞上表現之HER2,對於在癌細胞上表現之HER2具有更強之結合反應性。
- 如請求項1之抗體或其抗原結合性片段,其(i)結合於包含選自由序列編號:31~37之胺基酸序列所組成之群中之任一胺基酸序列之肽。
- 如請求項1或2之抗體或其抗原結合性片段,其(ii)相較於對於在包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有選自由W614A、K615A、及F616A所組成之群中之1種以上胺基酸突變的HER2之胞外域之突變體,對於包含序列編號:3所記載之HER2之胞外域之肽具有更強之結合親和性(或反應性)。
- 如請求項1至3中任一項之抗體或其抗原結合性片段,其(iii)包含重鏈可變區及輕鏈可變區,上述重鏈可變區包含 具有序列編號:18之胺基酸序列之重鏈CDR1、 具有序列編號:19之胺基酸序列之重鏈CDR2、及 具有序列編號:20之胺基酸序列之重鏈CDR3, 上述輕鏈可變區包含 具有序列編號:21之胺基酸序列之輕鏈CDR1、 具有序列編號:22之胺基酸序列之輕鏈CDR2、及 具有序列編號:23之胺基酸序列之輕鏈CDR3; (iv)包含重鏈可變區及輕鏈可變區,上述重鏈可變區包含 具有序列編號:24之胺基酸序列之重鏈CDR1、 具有序列編號:25之胺基酸序列之重鏈CDR2、及 具有序列編號:26之胺基酸序列之重鏈CDR3, 上述輕鏈可變區包含 具有序列編號:27之胺基酸序列之輕鏈CDR1、 具有序列編號:28之胺基酸序列之輕鏈CDR2、及 具有序列編號:29之胺基酸序列之輕鏈CDR3;或者 於上述(iii)或(iv)之一個以上之CDR中具有至少1個置換、附加或缺失。
- 如請求項1至4中任一項之抗體或其抗原結合性片段,其(vii)包含具有序列編號:14之胺基酸序列之重鏈可變區、及 具有序列編號:15之胺基酸序列之輕鏈可變區; (viii)包含具有序列編號:16之胺基酸序列之重鏈可變區、及 具有序列編號:17之胺基酸序列之輕鏈可變區;或者 於上述(vii)或(viii)之各可變區中具有至少1個置換、附加或缺失。
- 如請求項1至5中任一項之抗體或其抗原結合性片段,其與由神經膠母細胞瘤細胞株之LN229細胞所產生且包含序列編號:3所記載之HER2之胞外域之肽結合。
- 如請求項1至6中任一項之抗體或其抗原結合性片段,其中癌細胞為乳癌細胞株之SK-BR-3細胞,非癌細胞為正常人類表皮角化細胞株之HaCaT細胞。
- 一種醫藥組合物,其含有包含如請求項1至7中任一項之抗體或其抗原結合性片段之HER2標靶藥物作為有效成分。
- 如請求項1至7中任一項之抗體或其抗原結合性片段,其複合有細胞毒殺劑。
- 一種醫藥組合物,其包含如請求項9之抗體或其抗原結合性片段作為有效成分。
- 如請求項8或10之醫藥組合物,其係用於處置癌。
- 一種癌之處置劑,其包含如請求項1至7中任一項之抗體或其抗原結合性片段作為有效成分。
- 一種核酸分子,其編碼如請求項2至5中任一項之抗體或其抗原結合性片段。
- 一種製造、選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括 自結合於HER2或其片段之抗體群或抗體之抗原結合性片段群中製造、選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而可與在癌細胞上表現之HER2特異性地反應的抗體或抗體之抗原結合性片段。
- 一種製造、選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括 自結合於HER2或其片段之抗體群或抗體之抗原結合性片段群中製造、選擇或鑑定滿足選自由下述(i)~(iii)所組成之群中之至少一者之抗體或抗體之抗原結合性片段, (i)結合於包含選自由序列編號:31~37之胺基酸序列所組成之群中之任一胺基酸序列之肽;及 (ii)相較於對於在包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有選自由W614A、K615A、及F616A所組成之群中之1種以上胺基酸突變之肽,對於包含序列編號:3所記載之HER2之胞外域之肽具有更強之反應性;以及 (iii)相較於對於在非癌細胞上表現之HER2,對於在癌細胞上表現之HER2具有更強之結合反應性。
- 一種製造、選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括 自滿足選自由下述(i)~(ii)所組成之群中之至少一者之抗體群或抗體之抗原結合性片段群中製造、選擇或鑑定結合於HER2或其片段之抗體或其抗原結合性片段, (i)結合於包含選自由序列編號:31~37之胺基酸序列所組成之群中之任一胺基酸序列之肽;及 (ii)相較於對於在包含序列編號:2所記載之HER2之胞外域之一部分(胺基酸編號603~622之區域)的肽中具有選自由W614A、K615A、及F616A所組成之群中之1種以上胺基酸突變之肽,對於包含序列編號:3所記載之HER2之胞外域之肽具有更強之反應性。
- 如請求項15或16之方法,其進而包括自所獲得之抗體或抗體之抗原結合性片段群中製造、選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而可與在癌細胞上表現之HER2特異性地反應的抗體或抗體之抗原結合性片段。
- 一種製造、選擇或鑑定抗體或抗體之抗原結合性片段之方法,其包括 自(iii)或(iv)之任意且至少一個CDR中具有選自由置換、附加、插入、及缺失所組成之群中之至少1個以上胺基酸之變異的抗體群或抗體之抗原結合性片段群中製造、選擇或鑑定不會與在非癌細胞上表現之HER2顯著地反應而可與在癌細胞上表現之HER2特異性地反應的抗體或抗體之抗原結合性片段。
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