TW202241503A - 肌肉萎縮性側索硬化症之治療用醫藥組合物 - Google Patents
肌肉萎縮性側索硬化症之治療用醫藥組合物 Download PDFInfo
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Abstract
本發明提供一種包含抗EphA4抗體作為有效成分之用以治療ALS之新穎醫藥組合物,上述抗EphA4抗體能夠與EphA4結合,促進EphA4之切斷。本發明之醫藥組合物係包含抗EphA4抗體之用以治療ALS者,上述抗EphA4抗體包含如下重鏈及輕鏈,上述重鏈包括:由序列編號44所示之胺基酸序列所組成之重鏈CDR1、由序列編號27所示之胺基酸序列所組成之重鏈CDR2及由序列編號28所示之胺基酸序列所組成之重鏈CDR3,上述輕鏈包括:由序列編號29所示之胺基酸序列所組成之輕鏈CDR1、由序列編號30所示之胺基酸序列所組成之輕鏈CDR2及由序列編號31所示之胺基酸序列所組成之輕鏈CDR3。
Description
本發明係關於一種包含與EphA4結合之抗體之用以治療肌肉萎縮性側索硬化症(ALS)的醫藥組合物。
EphA4係受體型酪胺酸激酶家族之一個成員。已知A型肝配蛋白及B型肝配蛋白係EphA4之配體,當EphA4與作為其配體之肝配蛋白結合時,會誘導產生脫黏著訊息。EphA4於運動神經元中表現,在神經迴路形成期之脊髓中,藉由肝配蛋白在運動神經元之非投射區表現,而控制正確之軸突引導。已知EphA4取決於神經活動地被基質金屬蛋白酶(MMP)、ADAM(去整合素-金屬蛋白酶,a disintegrin and metalloproteinase)及γ分泌酶切斷。
根據先前之研究,提示抑制EphA4之功能係針對肌肉萎縮性側索硬化症(Amyotrophic lateral sclerosis,以下亦稱為「ALS」)或阿茲海默症等神經退化性疾病、脊髓損傷的有效治療手段。
據報告,EphA4係調整ALS之表現型之基因(專利文獻1、非專利文獻1)。揭示有EphA4之基因缺損、或由EphA4-Fc等產生之拮抗作用會促進小鼠/大鼠之脊髓損傷時之軸突伸長或功能恢復(非專利文獻2及非專利文獻3)。
作為現有之EphA4抑制藥,已知有KYL肽、化合物1(專利文獻1、非專利文獻1及非專利文獻2)。還已知具有抑制EphA4與其配體結合之活性的抗體(專利文獻2及專利文獻3),但迄今為止,尚無有關具有促進EphA4之切斷之活性之抗體的報告。
[先前技術文獻]
[專利文獻]
[專利文獻1] WO 2012/156351 A1
[專利文獻2] WO 2016/019280 A1
[專利文獻3] WO 2017/043466 A1
[非專利文獻]
[非專利文獻1] Van Hoecke et al., Nature Medicine, vol18: 1418-1422, 2012
[非專利文獻2] Goldshmit et al., PLoS one, vol6: e24636, 2011
[非專利文獻3] Spanevello et al., Journal of Neurotrauma, vol30: 1023-1034, 2013
[發明所欲解決之問題]
本發明之目的在於提供一種用以治療ALS之新穎醫藥組合物。
[解決問題之技術手段]
本發明人等為了解決上述課題而反覆進行了銳意研究,結果取得了對治療ALS有效之抗體,其可與EphA4結合,促進EphA4之切斷。
本發明包括以下之特徵。
(1)一種醫藥組合物,其係包含抗EphA4抗體之用以治療肌肉萎縮性側索硬化症(ALS)者,
上述抗EphA4抗體包含重鏈及輕鏈,上述重鏈包括:
(a)由序列編號44所示之胺基酸序列所組成之重鏈CDR1;
(b)由序列編號27所示之胺基酸序列所組成之重鏈CDR2;及
(c)由序列編號28所示之胺基酸序列所組成之重鏈CDR3;
上述輕鏈包括:
(d)由序列編號29所示之胺基酸序列所組成之輕鏈CDR1;
(e)由序列編號30所示之胺基酸序列所組成之輕鏈CDR2;及
(f)由序列編號31所示之胺基酸序列所組成之輕鏈CDR3。
(2)如(1)記載之醫藥組合物,其中
上述抗EphA4抗體被人源化。
(3)如(1)或(2)記載之醫藥組合物,其中
上述抗EphA4抗體與EphA4特異性地結合,促進EphA4之切斷。
(4)如(1)至(3)中任一項記載之醫藥組合物,其中
上述抗EphA4抗體與EphA4特異性地結合,抑制EphA4與肝配蛋白(ephrin)之結合。
(5)如(1)至(4)中任一項記載之醫藥組合物,其中
上述重鏈包括:由序列編號45所示之胺基酸序列所組成之可變區,
上述輕鏈包括:由序列編號46所示之胺基酸序列所組成之可變區。
(6)如(1)至(5)中任一項記載之醫藥組合物,其中
上述重鏈之恆定區及上述輕鏈之恆定區包含源自人類抗體之胺基酸序列。
(7)如(6)記載之醫藥組合物,其中
上述重鏈之恆定區係人類IgG之恆定區。
(8)如(7)記載之醫藥組合物,其中
上述人類IgG之恆定區係人類IgG
2之恆定區。
(9)如(8)記載之醫藥組合物,其中
上述人類IgG
2之恆定區包含序列編號47所示之胺基酸序列。
(10)如(6)至(9)中任一項記載之醫藥組合物,其中
上述輕鏈之恆定區係人類Igκ之恆定區。
(11)如(10)記載之醫藥組合物,其中
上述人類Igκ之恆定區包含序列編號48所示之胺基酸序列。
(12)一種醫藥組合物,其係包含抗EphA4抗體之用以治療肌肉萎縮性側索硬化症(ALS)者,
上述抗EphA4抗體包含重鏈及輕鏈,
上述重鏈包含序列編號59所示之胺基酸序列,
上述輕鏈包含序列編號60所示之胺基酸序列,
上述重鏈之C末端離胺酸可缺失。
(13)如(12)記載之醫藥組合物,其中
上述重鏈之C末端離胺酸缺失。
(14)一種醫藥組合物,其係包含抗EphA4抗體之用以治療肌肉萎縮性側索硬化症(ALS)者,
上述抗EphA4抗體包含重鏈及輕鏈,
上述重鏈包含序列編號59所示之胺基酸序列,
上述輕鏈包含序列編號60所示之胺基酸序列。
(15)一種醫藥組合物,其係包含抗EphA4抗體之用以治療肌肉萎縮性側索硬化症(ALS)者,
上述抗EphA4抗體包含重鏈及輕鏈,
上述重鏈包含序列編號59所示之胺基酸序列,
上述輕鏈包含序列編號60所示之胺基酸序列,
上述重鏈之C末端離胺酸缺失。
(16)如(1)至(15)中任一項記載之醫藥組合物,其進而包含
至少一種藥劑學上所容許之載體。
(17)一種抗EphA4抗體,上述抗EphA4抗體包含重鏈及輕鏈,
上述重鏈包括:
(a)由序列編號44所示之胺基酸序列所組成之重鏈CDR1;
(b)由序列編號27所示之胺基酸序列所組成之重鏈CDR2;及
(c)由序列編號28所示之胺基酸序列所組成之重鏈CDR3;
上述輕鏈包括:
(d)由序列編號29所示之胺基酸序列所組成之輕鏈CDR1;
(e)由序列編號30所示之胺基酸序列所組成之輕鏈CDR2;及
(f)由序列編號31所示之胺基酸序列所組成之輕鏈CDR3。
(18)如(17)記載之抗EphA4抗體,其中
上述抗EphA4抗體被人源化。
(19)如(17)或(18)記載之抗EphA4抗體,其中
上述抗EphA4抗體與EphA4特異性地結合,促進EphA4之切斷。
(20)如(17)至(19)中任一項記載之抗EphA4抗體,其中
上述抗EphA4抗體與EphA4特異性地結合,抑制EphA4與肝配蛋白之結合。
(21)如(17)至(20)中任一項記載之抗EphA4抗體,其中
上述重鏈包括:由序列編號45所示之胺基酸序列所組成之可變區,
上述輕鏈包括:由序列編號46所示之胺基酸序列所組成之可變區。
(22)如(17)至(21)中任一項記載之抗EphA4抗體,其中
上述重鏈之恆定區及上述輕鏈之恆定區包含源自人類抗體之胺基酸序列。
(23)如(22)記載之抗EphA4抗體,其中
上述重鏈之恆定區係人類IgG之恆定區。
(24)如(23)記載之抗EphA4抗體,其中
上述人類IgG之恆定區係人類IgG
2之恆定區。
(25)如(24)記載之抗EphA4抗體,其中
上述人類IgG
2之恆定區包含序列編號47所示之胺基酸序列。
(26)如(22)至(25)中任一項記載之抗EphA4抗體,其中
上述輕鏈之恆定區係人類Igκ之恆定區。
(27)如(26)記載之抗EphA4抗體,其中
上述人類Igκ之恆定區包含序列編號48所示之胺基酸序列。
(28)一種抗EphA4抗體,
上述抗EphA4抗體包含重鏈及輕鏈,
上述重鏈包含序列編號59所示之胺基酸序列,
上述輕鏈包含序列編號60所示之胺基酸序列,
上述重鏈之C末端離胺酸可缺失。
(29)如(28)記載之抗EphA4抗體,其中
上述重鏈之C末端離胺酸缺失。
(30)一種抗EphA4抗體,
上述抗EphA4抗體包含重鏈及輕鏈,
上述重鏈包含序列編號59所示之胺基酸序列,
上述輕鏈包含序列編號60所示之胺基酸序列。
(31)一種抗EphA4抗體,
上述抗EphA4抗體包含重鏈及輕鏈,
上述重鏈包含序列編號59所示之胺基酸序列,
上述輕鏈包含序列編號60所示之胺基酸序列,
上述重鏈之C末端離胺酸缺失。
(32)如(17)至(31)中任一項記載之抗EphA4抗體,其用以治療肌肉萎縮性側索硬化症(ALS)。
(33)一種肌肉萎縮性側索硬化症(ALS)之治療方法,其包括將治療有效量之如(17)至(31)中任一項記載之抗EphA4抗體投予至需要其之患者。
(34)一種如(17)至(31)中任一項記載之抗EphA4抗體之用途,其用以製造肌肉萎縮性側索硬化症(ALS)治療用之醫藥組合物。
(35)如(34)記載之抗EphA4抗體之用途,其中
上述醫藥組合物包含至少一種藥劑學上所容許之載體。
(36)一種肌肉萎縮性側索硬化症(ALS)之治療劑,其包含如(17)至(31)中任一項記載之抗EphA4抗體。
[發明之效果]
根據本發明,提供一種用以治療ALS之新穎醫藥組合物。上述醫藥組合物包含抗EphA4抗體作為有效成分,上述抗EphA4抗體可與EphA4結合,促進EphA4之切斷。
由本說明書中所使用之序列編號特定或編碼之區域如下所示:
SEQ No | 序列區域 | SEQ No | 序列區域 |
1 | 小鼠EphA4(胺基酸序列) | 34 | 人類EphA4之訊息序列(胺基酸序列) |
2 | 小鼠EphA4之胞外域(胺基酸序列) | 35 | 前胰蛋白酶之訊息序列(胺基酸序列) |
3 | 小鼠EphA4胞外域-SEAP-His蛋白質(胺基酸序列) | 36 | 人類EphA4之胞外域(胺基酸序列) |
4 | 小鼠EphA4之訊息序列(胺基酸序列) | 37 | 人類EphA4之配體結合域(胺基酸序列) |
5 | 人類EphA4(胺基酸序列) | 38 | 人類EphA4之纖維黏連蛋白III型域1(胺基酸序列) |
6 | 人類EphA4之胞外域(胺基酸序列) | 39 | 人類EphA4之纖維黏連蛋白III型域2(胺基酸序列) |
7 | 寡DNA ad29S(核酸序列) | 40 | 人類抗體之輕鏈FR IGKV1-17*01(胺基酸序列) |
8 | 寡DNA ad29AS(核酸序列) | 41 | 人類抗體之輕鏈FR JK4(胺基酸序列) |
9 | 5’正向引子(核酸序列) | 42 | 人類抗體之重鏈FR IGHV3-33*03(胺基酸序列) |
10 | 小鼠IgG重鏈用3’反向引子(核酸序列) | 43 | 人類抗體之重鏈FR JH6(胺基酸序列) |
11 | 小鼠Igκ輕鏈用3’反向引子(核酸序列) | 44 | 抗體B之重鏈CDR1(胺基酸序列) |
12 | 抗體A之重鏈訊息序列(胺基酸序列) | 45 | 抗體B之重鏈可變區HK2-42(胺基酸序列) |
13 | 抗體A之重鏈可變區(胺基酸序列) | 46 | 抗體B之輕鏈可變區L1-8(胺基酸序列) |
14 | 抗體A之輕鏈訊息序列(胺基酸序列) | 47 | 抗體B之人類IgG 2重鏈恆定區(胺基酸序列) |
15 | 抗體A之輕鏈可變區(胺基酸序列) | 48 | 抗體B之人類Igκ輕鏈恆定區(胺基酸序列) |
16 | 抗體A之重鏈訊息序列(核酸序列) | 49 | 抗體B之重鏈CDR1(核酸序列) |
17 | 抗體A之重鏈可變區(核酸序列) | 50 | 抗體B之重鏈CDR2(核酸序列) |
18 | 抗體A之輕鏈訊息序列(核酸序列) | 51 | 抗體B之重鏈CDR3(核酸序列) |
19 | 抗體A之輕鏈可變區(核酸序列) | 52 | 抗體B之輕鏈CDR1(核酸序列) |
20 | 抗體A重鏈用5’正向引子(核酸序列) | 53 | 抗體B之輕鏈CDR2(核酸序列) |
21 | 抗體A輕鏈用5’正向引子(核酸序列) | 54 | 抗體B之輕鏈CDR3(核酸序列) |
22 | 抗體A重鏈用3’反向引子(核酸序列) | 55 | 抗體B之重鏈可變區HK2-42(核酸序列) |
23 | 抗體A輕鏈用3’反向引子(核酸序列) | 56 | 抗體B之輕鏈可變區L1-8(核酸序列) |
24 | 抗體A之重鏈恆定區(胺基酸序列) | 57 | 抗體B之人類IgG 2重鏈恆定區(核酸序列) |
25 | 抗體A之輕鏈恆定區(胺基酸序列) | 58 | 抗體B之人類Igκ輕鏈恆定區(核酸序列) |
26 | 抗體A之重鏈CDR1(胺基酸序列) | 59 | 抗體B之重鏈全長序列(胺基酸序列) |
27 | 抗體A之重鏈CDR2(胺基酸序列) | 60 | 抗體B之輕鏈全長序列(胺基酸序列) |
28 | 抗體A之重鏈CDR3(胺基酸序列) | 61 | 抗體B之重鏈全長序列(核酸序列) |
29 | 抗體A之輕鏈CDR1(胺基酸序列) | 62 | 抗體B之輕鏈全長序列(核酸序列) |
30 | 抗體A之輕鏈CDR2(胺基酸序列) | 63 | 變異人類SOD1用引子(核酸序列) |
31 | 抗體A之輕鏈CDR3(胺基酸序列) | 64 | 變異人類SOD1用引子(核酸序列) |
32 | 猴EphA4(胺基酸序列) | 65 | 內部標準用引子(核酸序列) |
33 | 猴EphA4之胞外域(胺基酸序列) | 66 | 內部標準用引子(核酸序列) |
本發明之抗EphA4抗體係可識別並結合EphA4之抗體,如以下所述,該抗體可為完整之抗體,或者亦可為合成抗體(例如重組抗體、嵌合抗體、人源化抗體等),只要具有與EphA4之結合親和性即可。本說明書中,EphA4可理解為指源自人類、小鼠、大鼠及猴之EphA4。源自人類、小鼠、大鼠及猴之EphA4可自美國生物技術資訊中心提供之基因庫等登錄有序列資訊之公共數據庫中獲取,除此以外,還可藉由基於有近緣關係之動物種類之EphA4的鹼基序列資訊來設計引子,從所需動物種類提取RNA,由所提取之RNA進行選殖,從而獲取EphA4基因之序列資訊。例如,人類、小鼠、大鼠、猴之EphA4之鹼基序列資訊分別以基因庫登錄號NM_004438.5、NM_007936.3、NM_001162411.1、NM_001260870.1登錄在數據庫上。
於一態樣中,抗EphA4抗體係與EphA4特異性地結合之抗體。術語「特異性結合」係該技術領域從業者眾所周知之術語,用於確定抗體或其抗原結合片段對於抗原或表位之特異性結合的方法亦眾所周知。於一實施形態中,「特異性結合」可理解為:相較於與其他靶分子結合,抗EphA4抗體能夠以更大之結合親和性、結合活性並更迅速、及/或持續更長時間地藉由免疫學反應與EphA4結合。其並不意味著與EphA4特異性地結合之抗體不與其他靶分子結合。於另一實施形態中,「特異性結合」可由對EphA4具有至少約10
-7M、或至少約10
-8M、或至少約10
-9M、或其以下之KD的抗體顯示。又,於又一實施形態中,「特異性結合」可理解為藉由免疫學反應與EphA4結合,但與Eph受體之其他家族分子實質上未結合。
於一態樣中,抗EphA4抗體係與EphA4之胞外域結合之抗體。於一實施形態中,抗EphA4抗體係與EphA4之胞外域中之配體結合域(LBD)結合之抗體。
於一實施形態中,抗EphA4抗體可與EphA4特異性地結合,促進EphA4之切斷。於特定之實施形態中,抗EphA4抗體可與EphA4特異性地結合,促進利用基質金屬蛋白酶(MMP)或ADAM(去整合素-金屬蛋白酶)切斷EphA4胞外域。
於一實施形態中,抗EphA4抗體可與EphA4特異性地結合,抑制EphA4與作為其配體之肝配蛋白之結合。
於另一實施形態中,抗EphA4抗體可與EphA4特異性地結合,增加海馬神經元之樹突棘數量或使海馬神經元之樹突棘穩定。
於另一實施形態中,抗EphA4抗體可保護運動神經元以避免由SOD1基因異常引起之細胞死亡。
本發明於一實施形態中,包含可與人類EphA4、小鼠EphA4、大鼠EphA4、及猴EphA4中之至少一者特異性地結合,抑制與其配體之結合的抗EphA4抗體。本發明於另一實施形態中,包含可與人類EphA4、小鼠EphA4、大鼠EphA4、及猴EphA4中之兩者以上特異性地結合,抑制與其配體之結合的抗EphA4抗體。本發明於又一實施形態中,包含可與人類EphA4、小鼠EphA4、大鼠EphA4、及猴EphA4全部特異性地結合,抑制與其配體之結合的抗EphA4抗體。
測定抗EphA4抗體對於抗原之結合特性(例如,結合親和性及物種交叉反應性)的方法可使用該技術領域從業者所公知的方法。例如結合親和性可使用Biacore(註冊商標)生物感測器、KinExA生物感測器、閃爍親近測定法、ELISA、ORIGEN免疫測定法(IGEN公司)、流式細胞分析、螢光消光、螢光轉移、酵母展示、及/或免疫染色來進行測定,但並不限定於其等。抗EphA4抗體對於EphA4與其配體之結合的中和活性可使用Biacore(註冊商標)生物感測器、ELISA、及/或流式細胞分析進行測定,但並不限定於其等。
本發明之抗EphA4抗體可為單株抗體,只要與EphA4結合即可。
本發明之抗EphA4抗體可為IgG、IgA或IgM(或者其等之亞型)等任意類別,但並不限定於特定類別。根據重鏈(亦有時稱為H鏈)之恆定區之抗體胺基酸序列,免疫球蛋白被分為不同類別。5個主要之免疫球蛋白之類別為IgA、IgD、IgE、IgG及IgM,其中幾個類別可以進一步細分為例如IgG
1、IgG
2、IgG
3、IgG
4、IgA
1及IgA
2等亞型(同型)。不同類別之免疫球蛋白所對應之重鏈的恆定區分別稱為α、δ、ε、γ及μ。又,抗體之輕鏈(亦有時稱為L鏈)種類有λ鏈及κ鏈。本發明之抗EphA4抗體可以為IgG抗體,例如可以為IgG
1抗體或IgG
2抗體等。又,本發明之抗EphA4抗體根據情形不同,可以為單體、二聚體或多聚體之形態。
本發明之抗體之可變區可以意味著抗體輕鏈之可變區及/或抗體重鏈之可變區,抗體之恆定區可以意味著抗體輕鏈之恆定區及/或抗體重鏈之恆定區。重鏈及輕鏈之可變區分別由4個架構區(FR)所組成,上述4個架構區由亦作為互補決定區為人所知之3個CDR連結。各鏈中之CDR被FR保持得較為靠近,從而有助於與另一條鏈中之CDR一同形成抗體之抗原結合部位。作為用以確定CDR之技術,並無限定,例如可以例舉:(1)基於異質序列可變性之方法(例如,Kabat et al, Sequences of Proteins of Immunological Interest, 5th ed., 1991, National Institutes of Health, Bethesda MD);及(2)基於抗原-抗體複合體之結晶結構學研究之方法(Al-lazikani et al., 1997 J. Molec. Biol. 273: 927-948)。亦可將該等方法、其他方法組合來使用。
本說明書中,單株抗體可以意味著實質上自均一之抗體群體中獲得之抗體。即,該群體中所包含之各個抗體除若干有可能存在之天然突變體以外均相同。單株抗體對於單一抗原部位,具有高度特異性。進而,與以不同抗原、不同表位為靶向之典型多株抗體相比,各單株抗體係以抗原之單一表位為靶向。修飾語「單株」表示實質上自均一之抗體群體中獲得之抗體的特性,不應被限定性地理解為需要藉由特定方法來生產抗體。
本發明之抗EphA4抗體可以為小鼠抗體、嵌合抗體或人源化抗體。嵌合抗體例如為使非人類(例如小鼠或大鼠)抗體之可變區與人類抗體之恆定區融合而成之抗體,例如可以指可變區源自非人類抗體、恆定區源自人類抗體的抗體。人源化抗體例如為將非人類抗體之互補決定區(complementarity-determining region:CDR(亦有時稱為超可變區))導入人類抗體中所得之抗體,例如可以指CDR源自非人類抗體、此以外之抗體區域源自人類抗體的抗體。但是,嵌合抗體與人源化抗體之界限不一定必需明確,可以為可稱為嵌合抗體亦可稱為人源化抗體的狀態。又,於嵌合抗體或人源化抗體中,源自人類抗體之抗體區域(FR、恆定區)不一定必需全部由源自人類抗體之胺基酸所構成,亦可含有一個或多個源自非人類抗體之胺基酸,只要於人類對象中能夠正常使用即可。作為人源化抗體之一實施態樣,係CDR源自嚙齒類抗體、此以外之抗體區域源自人類抗體的抗體。作為人源化抗體之特定實施態樣,係CDR源自小鼠抗體、此以外之抗體區域源自人類抗體的抗體。於該等實施態樣中,CDR亦可以包含一個或多個源自非嚙齒類抗體之胺基酸、或者一個或多個源自非小鼠抗體之胺基酸,CDR以外之抗體區域亦可以包含一個或多個源自非人類抗體之胺基酸。此處,「多個」並不限定於此,為2個 ~ 20個、或者2個 ~ 15個、例如14個、13個、12個、11個、10個、9個、8個、7個、6個、5個、4個、3個或2個;或者為胺基酸序列中之胺基酸數之10%以內、9%以內、8%以內、7%以內、6%以內、5%以內、4%以內、3%以內、2%以內或1%以內。人源化可使用CDR移植法(Kontermann and Dubel, Antibody Engineering, Springer Lab Manual(2001)及Tsurushita et al., Methods 36: 69-83(2005))來進行,除此以外,還可以藉由如下方式來進行人源化,即,使用該技術領域中公知之方法(例如參照Jones et al., Nature 321: 522-525(1986);Riechmann et al., Nature 332: 323-327(1988);及Verhoeyen et al., Science 239: 1534-1536(1988)),將CDR序列置換為人類抗體所對應之序列。
為了減少抗原性,於製作人源化抗體時,在輕鏈及重鏈兩者中選擇使用人類可變區可能較為重要。根據「最佳匹配」法,針對全部已知之人類FR序列庫,篩選出嚙齒類抗體之可變區序列。繼而,最接近嚙齒類序列之人類序列被視為人源化抗體之人類FR。請參照例如Sims et al., J. Immunol. 151: 2296-2308(1993)及Chothia et al., J. Mol. Biol. 196: 901-917(1987)。於另一方法中,使用特定之架構,該特定之架構源自輕鏈或重鏈之特定亞群的所有人類抗體之共通序列。相同之架構可用於若干不同之人源化抗體。請參照例如Carter et al., Proc. Natl. Acad. Set USA 89: 4285-4289(1992)及Presta et al., J. Immunol. 151: 2623-2632(1993)。
進而,人源化抗體一般而言,較為理想的是保持對於抗原之較高結合親和性及其他較佳之生物學性質。為了達成該目標,根據一方法,藉由使用親本序列及人源化序列之三維模型來分析親本序列及各種概念性人源化產物的步驟而製備人源化抗體。一般而言,三維免疫球蛋白模型是可用的,且為從業者所知。可利用將選擇出之候選免疫球蛋白序列的所需三維立體結構模式化並進行顯示之電腦程式。藉由對其等之顯示進行研究,能夠分析候選免疫球蛋白序列之功能中殘基之可能作用,即能夠分析對候選免疫球蛋白與其抗原結合之能力造成影響的殘基。藉由該方法,可以自接收序列及導入序列中選擇FR殘基並加以組合,以達成所需之抗體特性,例如增大對於單個或多個靶抗原(例如EphA4或其片段)之結合親和性。
毋庸置疑,於本發明之抗EphA4抗體中,亦包括針對上述例示之嵌合抗體或人源化抗體,保持該抗體之功能不變(或者為了追加、提高該抗體之功能)而經適當改型(例如抗體之修飾、或者抗體之胺基酸序列之局部置換、附加及/或缺失)的抗體。更具體而言,本發明之範圍亦包括為了修飾抗體之效應物功能而對恆定區之胺基酸序列進行改型後所得之抗體,例如本發明之範圍亦包括:為了降低抗體依賴性細胞毒殺(ADCC)活性及/或抗體依賴性細胞吞噬作用(ADCP)活性,人類IgG
2抗體之Eu編號中之第234位之纈胺酸(Val)被置換為丙胺酸(Ala),第237位之甘胺酸(Gly)被置換為丙胺酸(Ala)的抗體等。進而,本發明之範圍亦包括:同時具有本發明之抗EphA4抗體之CDR序列之抗體結合部位、以及結合於不同抗原之抗原結合部位的雙重特異性抗體(Kontermann(2012), mAbs 4, 182-97)。
本發明之抗EphA4抗體亦可視需要進行修飾。抗EphA4抗體之修飾亦可為進行如下改變之修飾,即改變(a)修飾區域中胺基酸序列之三維結構,例如片狀或螺旋構形等;(b)靶部位之分子之電荷或疏水性之狀態;或者(c)對於維持側鏈容積之修飾效果,或者亦可以為不會明顯觀察到該等變化之修飾。
本發明之抗EphA4抗體之修飾例如可藉由構成之胺基酸殘基之置換、缺失、附加等來達成。
本說明書中,胺基酸以其最寬泛之含義使用,不僅包括天然胺基酸、例如絲胺酸(Ser)、天冬醯胺(Asn)、纈胺酸(Val)、白胺酸(Leu)、異白胺酸(Ile)、丙胺酸(Ala)、酪胺酸(Tyr)、甘胺酸(Gly)、離胺酸(Lys)、精胺酸(Arg)、組胺酸(His)、天冬胺酸(Asp)、麩胺酸(Glu)、麩醯胺(Gln)、蘇胺酸(Thr)、半胱胺酸(Cys)、甲硫胺酸(Met)、苯基丙胺酸(Phe)、色胺酸(Trp)、脯胺酸(Pro),還包括胺基酸變異體及衍生物等非天然胺基酸。從業者考慮這一寬泛之定義,當然理解本說明書中之胺基酸例如可例舉:L-胺基酸;D-胺基酸;胺基酸變異體、胺基酸衍生物等經化學修飾之胺基酸;甘白胺酸、β-丙胺酸、鳥胺酸等不會於生物體內成為蛋白質之構成材料的胺基酸;及從業者公知之具有胺基酸特性之化學合成之化合物等。作為非天然胺基酸之例,可例舉:α-甲基胺基酸(α-甲基丙胺酸等)、D-胺基酸(D-天冬胺酸、D-麩胺酸等)、類組胺酸之胺基酸(2-胺基-組胺酸、β-羥基-組胺酸、高組胺酸、α-氟甲基-組胺酸、α-甲基-組胺酸等)、側鏈具有多餘之亞甲基之胺基酸(「高」胺基酸)及側鏈中之羧酸官能基胺基酸被置換為磺酸基之胺基酸(半胱胺酸等)等。
天然存在之胺基酸殘基例如基於一般之側鏈特性,可分類為以下之群組:
(1)疏水性:Met、Ala、Val、Leu、Ile;
(2)中性親水性:Asn、Gln、Cys、Ser、Thr;
(3)酸性:Asp、Glu;
(4)鹼性:His、Lys、Arg;
(5)對鏈配向造成影響之殘基:Gly、Pro;及
(6)芳香族:Trp、Tyr、Phe。
構成抗體之胺基酸序列之非保守性置換可藉由將屬於其中一個群組之胺基酸更換為屬於其他群組之胺基酸而進行。更保守性之置換可藉由將屬於其中一個群組之胺基酸更換為同一群組之其他胺基酸而進行。同樣地,亦可適當進行胺基酸序列之缺失或置換。
作為構成抗體之胺基酸之修飾,例如可為利用糖之糖基化、乙醯化或磷酸化等轉譯後修飾。抗體可在其恆定區之保守位置上進行糖基化。抗體之糖基化通常為N-結合型或O-結合型之任一者。N-結合型意味著糖部分與天冬醯胺殘基之側鏈之結合。作為三肽序列之天冬醯胺-X-絲胺酸、天冬醯胺-X-蘇胺酸、及天冬醯胺-X-半胱胺酸(式中,X為脯胺酸以外之任意胺基酸)係用以將糖部分酶促附加到天冬醯胺側鏈之識別序列。藉由使該等三肽序列之任一者存在於抗體中,而存在潛在性糖基化部位。O-結合型糖基化可為N-乙醯基半乳胺糖、半乳糖、或木糖之任一者與羥基胺基酸(例如絲胺酸或蘇胺酸)的結合,根據情形不同,亦可為與5-羥基脯胺酸或5-羥基離胺酸之結合。從業者可根據目的適當選擇糖基化之條件(於使用生物學方法進行糖基化之情形時,例如有宿主細胞或細胞培養基之種類、pH等)。
對於本發明之抗EphA4抗體,可進而基於從業者公知之技術常識,藉由其他修飾方法,單獨地進行修飾或組合地進行修飾。
本發明之抗EphA4抗體可藉由從業者眾所周知之方法產生。例如,可將編碼本發明之抗EphA4抗體之核酸組入表現載體,將該表現載體導入宿主細胞,對該宿主細胞進行培養,藉此產生抗體。因此,本發明包括:編碼抗EphA4抗體之核酸、包含該核酸之載體、包含該載體之宿主細胞、及包括培養該宿主細胞之步驟之抗EphA4抗體之製作方法。
編碼本發明之抗EphA4抗體之核酸可具有編碼訊息序列之DNA,可在編碼重鏈可變區之DNA、及編碼輕鏈可變區之DNA之5´末端上具有編碼訊息序列之DNA。訊息序列係分泌蛋白或膜主體蛋白於核糖體上合成後穿過脂質雙層所必需的、存在於蛋白質N末端之胺基酸殘基,於本發明中,只要為具有該功能之序列,則無特別限定。作為本發明之抗EphA4抗體可能包含之訊息序列,可例舉源自人類、小鼠、大鼠、兔、驢、山羊、馬、雞、狗、貓、酵母等之訊息序列。本發明中,具體而言,作為關於重鏈之訊息序列,可例舉包含序列編號12或16所表示之胺基酸序列之肽,作為關於輕鏈之訊息序列,可例舉包含序列編號14或18所表示之胺基酸序列之肽。又,只要功能上同等,則亦可於序列編號12或16所表示之胺基酸序列、序列編號14或18所表示之胺基酸序列中具有1個或多個(例如2、3、4或5個)胺基酸之置換、附加及/或缺失。
本發明之抗EphA4抗體亦可為依據從業者公知之方法經過分離或純化者。
本說明書中,「經分離」或「經純化」意味著從自然狀態經人工分離或純化。若分子或組合物為自然產生的,則當其產生了變化或自原本環境中被移除,或者兩者同時發生時,其即為「經分離」或「經純化」。作為分離或純化之方法之例,可以例舉電泳、分子生物學、免疫學或層析法等方法,具體而言,可以例舉離子交換層析法、疏水性層析法、逆相HPLC層析法、等電點電泳、或鹼萃取法等,但並不限定於其等。
於一實施形態中,抗EphA4抗體包含以下之CDR:
(a)由序列編號44所示之胺基酸序列所組成之重鏈CDR1;
(b)由序列編號27所示之胺基酸序列所組成之重鏈CDR2;
(c)由序列編號28所示之胺基酸序列所組成之重鏈CDR3;
(d)由序列編號29所示之胺基酸序列所組成之輕鏈CDR1;
(e)由序列編號30所示之胺基酸序列所組成之輕鏈CDR2;及
(f)由序列編號31所示之胺基酸序列所組成之輕鏈CDR3。
於一實施態樣中,上述抗EphA4抗體係人源化抗體或嵌合抗體,於特定之實施態樣中為人源化抗體。
於另一實施形態中,抗EphA4抗體包含重鏈及輕鏈,上述重鏈包含由序列編號45所示之胺基酸序列所組成之可變區,上述輕鏈包含由序列編號46所示之胺基酸序列所組成之可變區。再者,於該實施形態中,上述重鏈之可變區及/或上述輕鏈之可變區可包括:於序列編號45所示之胺基酸序列及/或序列編號46所示之胺基酸序列中置換、附加及/或缺失1個或多個胺基酸而成之胺基酸序列。此處,「多個」只要保持對於EphA4之結合親和性,促進EphA4之切斷即可,並無限定,為2個 ~ 15個、或2個 ~ 10個、例如9個、8個、7個、6個、5個、4個、3個或2個;或者為胺基酸序列中之胺基酸數之10%以內、例如9%以內、8%以內、7%以內、6%以內、5%以內、4%以內、3%以內、2%以內或1%以內。
於一實施形態中,抗EphA4抗體之重鏈包含人類IgG
2之恆定區。
於特定之實施形態中,人類IgG
2之恆定區包含序列編號47之胺基酸序列。
於一實施形態中,抗EphA4抗體之輕鏈包含人類Igκ之恆定區。
於特定之實施形態中,人類Igκ之恆定區包含序列編號48之胺基酸序列。
於一實施形態中,抗EphA4抗體包括包含序列編號59所示之胺基酸序列之重鏈及包含序列編號60所示之胺基酸序列之輕鏈。
於另一實施形態中,例如從減少藉由抗體產生細胞產生之抗體之不均一性等理由考慮(美國專利申請公開第2010/0297697號說明書或Liu H et al., MAbs. 2014 Sep-Oct; 6 (5): 1145-1154),抗EphA4抗體中,位於重鏈之C末端(羧基末端)之離胺酸缺失。本發明中,重鏈之C末端離胺酸缺失之抗EphA4抗體亦包括:藉由基因改造而使重鏈之C末端離胺酸缺失之抗EphA4抗體、或藉由羧肽酶等於轉譯後切斷重鏈之C末端離胺酸之抗EphA4抗體等。又,於本發明中,重鏈之C末端離胺酸缺失之抗EphA4抗體不僅包括於兩條重鏈中C末端離胺酸缺失之抗EphA4抗體,還包括僅於一條重鏈中C末端離胺酸缺失之抗EphA4抗體。
於一態樣中,本發明係關於一種編碼抗EphA4抗體且經分離之核酸。編碼抗EphA4抗體且經分離之核酸係指編碼抗EphA4抗體之重鏈及/或輕鏈之一個以上之核酸分子。於一實施形態中,本發明之核酸編碼抗EphA4抗體之重鏈。於另一實施形態中,本發明之核酸編碼抗EphA4抗體之輕鏈。於又一實施形態中,本發明之核酸編碼抗EphA4抗體之重鏈及輕鏈。本發明之核酸亦包括:編碼抗EphA4抗體之重鏈之第一核酸分子、及編碼抗EphA4抗體之輕鏈之第二核酸分子。
於另一態樣中,本發明係關於一種包含編碼抗EphA4抗體且經分離之核酸的載體。本發明之載體係指一種以上的包含編碼抗EphA4抗體且經分離之核酸的載體。於一實施形態中,本發明之載體包含:編碼抗EphA4抗體之重鏈之核酸及編碼抗EphA4抗體之輕鏈之核酸。於另一實施形態中,本發明之載體包含編碼抗EphA4抗體之重鏈及輕鏈之核酸。於又一實施形態中,本發明之載體包括:包含編碼抗EphA4抗體之重鏈之核酸之第一載體、及包含編碼抗EphA4抗體之輕鏈之核酸之第二載體。本發明之載體並不特別限定於其等,可以為質體、黏接質體、病毒、噬菌體等。例如本發明之載體還包括作為病毒載體之反轉錄病毒、慢病毒、腺病毒、腺相關病毒或疱疹單純型病毒載體等。
於又一態樣中,本發明亦包括:包含本發明之載體之宿主細胞、及包括對該宿主細胞進行培養之步驟的抗EphA4抗體之製作方法。本發明之宿主細胞並不特別限定於其等,可以為大腸桿菌細胞、猴COS細胞、中國倉鼠卵巢(CHO)細胞、NS0細胞等。於一實施形態中,抗EphA4抗體之製作方法包括:對宿主細胞進行培養之步驟;及自該宿主細胞(或宿主細胞之培養基)回收分泌出之抗EphA4抗體之步驟。
本發明之抗EphA4抗體係用以治療ALS。因此,本發明係關於一種包含本發明之抗EphA4抗體之用以治療ALS之醫藥組合物。又,本發明於另一態樣中,包括一種ALS之治療方法,其包括將治療有效量之抗EphA4抗體投予至罹患ALS之對象。
又,本發明於又一態樣中,包括一種抗EphA4抗體之用途,其係用以製造ALS之治療藥。
又,本發明於又一態樣中,包括一種抗EphA4抗體,其用以治療ALS。
本發明之抗EphA4抗體於治療法中可單獨使用、或者與其他藥劑或組合物一併使用。例如本發明之抗EphA4抗體可與其他藥劑同時投予或在不同時間投予。此種併用療法包括併用投予(於相同或不同之製劑中包含2種以上之藥劑)及分開投予(例如同時或連續地投予)。於分別投予2種以上之藥劑之情形時,本發明之抗EphA4抗體之投予可以在伴隨之治療法之前進行,或亦可在伴隨之治療法之後進行。
投予本發明之抗EphA4抗體之對象並無限定,例如可對於人類或非人類哺乳動物(猴、小鼠、大鼠、兔、牛、馬、山羊等)使用本發明。
將本發明之抗EphA4抗體投予至對象之方法(投予路徑、投予量、1天之投予次數、投予之時點等)並無特別限定,可以由從業者(例如醫生)根據對象之健康狀態、疾病之程度、所併用之藥劑之種類等來適當決定。
本發明之醫藥組合物包含上述本發明之抗EphA4抗體。本發明之醫藥組合物例如可以依據日本藥典(JP)、美國藥典(USP)或歐洲藥典(EP)中記載之方法等既知之方法進行製造。
從業者可以理解,只要技術上不存在衝突,則可以將本說明書中記載之所有態樣之任意一個或多個適當組合來實施本發明。進而從業者可以理解,只要技術上不存在衝突,則將本說明書中記載之較佳或有利之所有態樣適當組合來實施本發明為宜。
本說明書中所引用之文獻應視為其等之所有揭示均藉由參照被明確地引用至本說明書中,且從業者可以理解到,依據本說明書之上下文,在不脫離本發明之精神及範圍之情況下,將該等文獻中之相關揭示內容引用作本說明書之一部分。
本說明書中所引用之文獻僅僅是為了公開本申請之申請日之前的相關技術而提供,不應被解釋為,本發明人等承認因先前發明或任意其他理由而無權先進行此類公開。該等文獻之所有描述均基於本申請人可獲得之資訊,並不構成對該等描述內容準確之任何斷言。
本說明書中所使用之術語係用以說明特定之實施態樣,並不旨在限定發明。
關於本說明書中所使用之術語「包含(comprise)」,除非上下文清楚地需要不同之理解,否則旨在存在所記載之事項(構件、步驟、要素或數字等),且並不排除存在此以外之事項(構件、步驟、要素或數字等)。術語「由…所組成(consist of)」包括以術語「由…所組成(consist of)」及/或「實質上由…所組成(consist essentially of)」記載之態樣。
本說明書中所使用之術語「中和活性」意指抑制EphA4與其配體之結合的活性、及/或抑制EphA4藉由與其配體之結合在人活體內誘發之訊息傳遞、或者細胞之分子表現應答或功能性變化的活性。
除非另有定義,本文中使用之所有術語(包括技術術語及科學術語)具有與本發明所屬之技術從業者所廣泛理解相同之含義。關於此處所使用之術語,除非另有定義,均應理解為與本說明書及相關技術領域中之含義一致,而不應以理想化或過於形式之含義來解釋。
第1、第2等術語係用以表達各種要素,但可以理解為,該等要素不應受該等術語本身限定。該等術語僅用於將一個要素與另一個要素進行區別,例如在不脫離本發明之範圍之情況,能夠將第1要素記載為第2要素,同樣地,將第2要素記載為第1要素。
於本說明書中,除非另有說明,則用以表示成分含量、數值範圍等之數值應理解為由術語「約」來修飾。例如「4℃」除非另有說明,則可以理解為意指「約4℃」,當然從業者可以根據技術常識及本說明書之文意而合理地理解其程度。
可以理解到,除非在上下文清楚地表示其他含義,當在本說明書及申請專利範圍中使用時,以單數形式表示之各態樣亦可以為複數形式,只要在技術上沒有衝突即可,反之亦然。
於下文中,參考實施例對本發明更詳細地進行說明。然而,本發明可以藉由各種態樣來實現,不應被解釋為限於此處所記載之實施例。相關技術領域之從業者可以不變更本發明之精神或範圍,藉由各種改型、附加、缺失、置換等方式來實施本發明。
[實施例]
參考例1:抗EphA4單株抗體之製作
(A)小鼠抗EphA4單株抗體之製作
為了製作與小鼠EphA4(基因庫登錄號NP_031962.2、序列編號1)結合之單株抗體,藉由以下步驟製備於小鼠EphA4之胞外域(20 ~ 547位)(序列編號2)融合分泌型鹼性磷酸酶(SEAP)及組胺酸標籤而成之蛋白質(以下,稱為「小鼠EphA4胞外域-SEAP-His蛋白質」,序列編號3)。
首先,使用源自小鼠腦之總RNA,藉由RT-PCR對編碼小鼠EphA4之訊息序列(序列編號4)及胞外域(序列編號2)之DNA序列進行擴增,並選殖至具有編碼SEAP及組胺酸標籤之DNA序列之pENTR1A載體(美商英傑/生命技術公司)的SalI/NotI位點。繼而,藉由Gateway系統(美商英傑/生命技術公司)之LR反應,將編碼小鼠EphA4之訊息序列與胞外域、SEAP及組胺酸標籤之DNA序列轉移至pcDNA3.1_rfcB載體,構建pcDNA3.1-小鼠EphA4胞外域-SEAP-His表現載體。使用TransIT-LT1(日商寶生物技術公司),將所構建之pcDNA3.1-小鼠EphA4胞外域-SEAP-His表現載體轉染至HEK293EBNA細胞(美商英傑/生命技術公司)。培養6天(5% CO
2、37℃)後,回收培養上清液。使用Protino管柱(德商馬歇雷-納格爾),從所回收之培養上清液純化小鼠EphA4胞外域-SEAP-His蛋白質(序列編號3)。
將20 μg之小鼠EphA4胞外域-SEAP-His蛋白質與同量之TiterMax Gold佐劑(美商TiterMax公司)、或GERBU佐劑(德商格布生物技術股份有限公司)加以混合,並皮下注射至Balb/c小鼠之足底。其後,在第3天、第7天、及第10天同樣地投予小鼠EphA4胞外域-SEAP-His蛋白質。此時,僅在第10天使用TiterMax Gold佐劑(美商TiterMax公司),在第3天、第7天、及第10天使用GERBU佐劑(德商格布生物技術股份有限公司)。在第13天將小鼠處死(sacrificed),回收末梢淋巴結而製備淋巴結細胞。於GenomeONE-CF(日商石原產業股份有限公司)之存在下,將所製備之淋巴結細胞與P3U1骨髓瘤細胞(由日本京都大學提供)以5 : 1之比例融合。於96孔塑膠培養盤中培養上述融合細胞。培養7天(5% CO
2、37℃)後,回收培養上清液。
使用所獲得之培養上清液,挑取與小鼠、大鼠及人類EphA4具有反應性之孔。
關於與小鼠、大鼠及人類EphA4之反應性,使用使人類IgG
1之Fc區及組胺酸標籤與小鼠EphA4之胞外域、大鼠EphA4(基因庫登錄號NP_001155883.1)之胞外域(20 ~ 547位)或人類EphA4(基因庫登錄號NP_004429.1、序列編號5)之胞外域(20 ~ 547位)(序列編號6)融合而成之蛋白質(以下,分別稱為「小鼠EphA4胞外域-Fc-His蛋白質」、「大鼠EphA4胞外域-Fc-His蛋白質」或「人類EphA4胞外域-Fc-His蛋白質」)利用ELISA進行評價。
小鼠、大鼠或人類EphA4胞外域-Fc-His蛋白質係藉由以下步驟而製備。最初,構建pcDNA3.1-小鼠、大鼠或人類EphA4胞外域-Fc-His表現載體。首先,使用源自小鼠、大鼠或人類之腦之總RNA,藉由RT-PCR對編碼小鼠、大鼠或人類EphA4之訊息序列與胞外域之DNA序列進行擴增,並選殖至具有編碼Fc及組胺酸標籤之DNA序列之pENTR1A載體(美商英傑/生命技術公司)的SalI/NotI位點。繼而,藉由Gateway系統(美商英傑/生命技術公司)之LR反應,將編碼小鼠、大鼠或人類EphA4之訊息序列與胞外域、Fc及組胺酸標籤之DNA序列轉移至pcDNA3.1_rfcB載體,從而構建pcDNA3.1-小鼠、大鼠或人類EphA4胞外域-Fc-His表現載體。使用TransIT-LT1(日商寶生物技術公司),將所構建之該等表現載體轉染至HEK293EBNA細胞(美商英傑/生命技術公司)。培養6天(5% CO
2、37℃)後,回收培養上清液。
使用小鼠、大鼠或人類EphA4胞外域-Fc-His蛋白質之ELISA係依據以下步驟來進行。將抗人類IgG抗體(美商傑克遜免疫研究實驗室公司)塗抹在96孔培養盤(丹麥能肯公司)之孔上。於4℃下培養一夜後,藉由1 × Block Ace(大日本製藥),將孔在室溫下封閉1小時。利用0.02%吐溫20/磷酸鹽緩衝鹽水(日商半井公司)洗淨3次後,於各孔中添加包含小鼠、大鼠或人類EphA4胞外域-Fc-His蛋白質之培養上清液(最終濃度1 nM),並在室溫下培養1小時。洗淨3次後,於各孔中添加上述融合細胞之培養上清液。於室溫下培養1小時並洗淨3次後,添加辣根過氧化酶標記抗小鼠IgG抗體(美商傑克遜免疫研究實驗室公司),於室溫下培養1小時。洗淨3次後,於各孔中添加TMBZ(3,3’,5,5’-四甲基聯苯胺,美商西格瑪公司)溶液,於室溫下培養5 ~ 20分鐘。於各孔中添加等量之反應終止溶液(2N H
2SO
4,和光純藥),藉由微盤讀取器(美商鉑金埃爾默公司)讀取450 nm之吸光度。
藉由限制稀釋法,自經過上述步驟而挑取出之孔選殖雜交瘤,最終獲得表現對小鼠、大鼠及人類EphA4具有結合活性之小鼠抗EphA4抗體的雜交瘤純系。
對所獲得之雜交瘤純系進行培養,使用蛋白A(美商通用電氣醫療公司),自培養上清液純化小鼠抗EphA4單株抗體。
(B)EphA4切斷促進活性之評價
大鼠海馬神經元之製備係依據以下步驟來進行。自妊娠18天之大鼠(美商維通利華日本公司)中取出胎仔,切開頭部將腦取出。於立體顯微鏡下切出海馬區後,加入至消化溶液(137 mM NaCl(和光純藥),5 mM KCl(和光純藥),7 mM Na
2HPO
4(和光純藥),25 mM Hepes(DOJINDO)、0.5 mg/mL DNase(美商西格瑪公司)、0.25%胰蛋白酶(美商生命技術公司))中並於37℃下振盪10分鐘。除去溶液,添加20%胎牛血清/Hanks緩衝液(美商西格瑪公司)。除去溶液,利用Hanks緩衝液洗淨2次後,將海馬組織移液至Hanks緩衝液中而製作細胞懸浮液。將細胞接種至加入有培養液(Neurobasal培養基(美商生命技術公司)、1 × B-27補充劑(美商生命技術公司)、0.5 mM L-麩醯胺(美商生命技術公司))並塗抹有聚L離胺酸之96孔皿(美商Falcon公司)中。
使用海馬神經元之EphA4切斷促進活性評價係依據以下步驟來進行。用抗EphA4單株抗體(67 nM)及γ分泌酶抑制藥即化合物E(50 nM,瑞士恩佐生命科學公司)對接種至96孔皿(美商Falcon公司)之大鼠海馬神經元進行處置,於16小時後利用PBS(和光純藥)進行洗淨,添加SDS樣本緩衝液(Laemmli樣本緩衝液(美商伯樂公司)、5% 2-巰基乙醇(美商伯樂公司)),回收細胞並煮沸5分鐘。使用該樣本進行SDS-PAGE(Sodium dodecyl sulfate polyacrylamide gel electrophoresis,十二烷基硫酸鈉-聚丙烯醯胺凝膠電泳),使用抗EphA4單株抗體(亞諾法生技股份有限公司)進行西方墨點法,對條帶強度進行定量化,算出EphA4C末端片段/全長EphA4之值。
獲得具有促進EphA4之切斷之活性之小鼠抗EphA4單株抗體(抗體A)。抗體A之同型種係利用單株抗體分型套組(英商Serotec公司)來確定,對於重鏈而言為IgG
1,對於輕鏈而言為κ。
(C)抗體A之序列分析
藉由5’-RACE(5’-rapid amplification of cDNA ends,cDNA 5’末端快速擴增)法,對編碼抗體A之重鏈及輕鏈之訊息序列、及可變區的DNA序列進行擴增。使用RNeasy(德商凱傑公司),自上述雜交瘤製備總RNA,並利用DNase(deoxyribonuclease,去氧核糖核酸酶)(德商凱傑公司,無RNase之DNase套組)進行處理。使用cDNA合成套組(日商寶生物技術公司),由上述總RNA製備雙鏈cDNA。將藉由寡DNA ad29S(ACATCACTCCGT)(序列編號7)及寡DNAad29AS(ACGGAGTGATGTCCGTCGACGTATCTCTGCGTTGATAC TTCAGCGTAGCT)(序列編號8)之黏著(annealing)所獲得之5’接頭附加至上述cDNA。藉由5’正向引子(5’-PCR4引子、AGCTACGCTGAAGTATCAACGCAGAG)(序列編號9)及3’反向引子(小鼠IgG重鏈之擴增使用GCCAGTGGATAGACTGATGG(序列編號10),小鼠Igκ輕鏈之擴增使用GATGGATACAGTTGGTGCAGC(序列編號11)),對所獲得之cDNA進行擴增。將經擴增之cDNA插入至pCR2.1載體(美商英傑/生命技術公司)。使用ABI3130XL分析抗體A之基因序列。作為由藉由本分析所鑑定出之抗體A之基因序列所編碼的胺基酸序列,重鏈訊息序列為序列編號12所示之序列,重鏈可變區為序列編號13所示之序列,輕鏈訊息序列為序列編號14所示之序列,輕鏈可變區為序列編號15所示之序列。作為編碼抗體A之基因序列之核苷酸序列,重鏈訊息序列為序列編號16所示之序列,重鏈可變區為序列編號17所示之序列,輕鏈訊息序列為序列編號18所示之序列,輕鏈可變區為序列編號19所示之序列。
抗體A之重鏈及輕鏈之全長序列係藉由以下步驟取得。使用RNeasy(德商凱傑公司),自上述雜交瘤製備總RNA,並利用DNase(德商凱傑公司,無RNase之DNase套組)進行處理。使用RNA PCR套組(日商寶生物技術公司),由上述總RNA製備反轉錄產物。將所獲得之反轉錄產物用於模板,使用5’正向引子(重鏈之擴增使用GCGAAGCTTGCCGCCACCATGGCTGT CCTGGTGCTGCTCC(引子ID7455)(序列編號20),輕鏈之擴增使用GCGAAGCTTGCCGCCACCATGGACATGAGGGTTCCTGCTCACG(引子ID7453)(序列編號21))及3’反向引子(重鏈之擴增使用GCGGAATTCATCATTTACCAGGAGAGTGGGAGAGGC(引子ID7257)(序列編號22),輕鏈之擴增使用CGCGAATTCACTAACACTCATTCCT GTTGAAGCTCTTGAC(引子ID7249)(序列編號23)),利用PCR對編碼抗體A之重鏈及輕鏈之基因序列進行擴增,並分別選殖至pEE6.4及pEE12.4載體(瑞士龍沙公司)。使用ABI3130XL對基因序列進行分析。作為由藉由本分析所鑑定出之抗體A之基因序列所編碼之胺基酸序列,重鏈恆定區為序列編號24所示之序列,輕鏈恆定區為序列編號25所示之序列。
抗體A之CDR係藉由以下方法確定。依據Kabat之編號系統(Kabat numbering system),使用Abysis軟體(UCL)對抗體A之胺基酸序列進行編號。基於該編號,並依據用以鑑定CDR之Kabat之定義(Kabat definition)而確定CDR。將抗體A之CDR之胺基酸序列示於表1。
[表1]
抗體A之CDR之胺基酸序列 | |
名稱 | 序列 |
重鏈CDR1 | RYGVH(序列編號26) |
重鏈CDR2 | VIWRGGSTDYNAAFMS(序列編號27) |
重鏈CDR3 | ESLFGVYYDYGYYSMDY(序列編號28) |
輕鏈CDR1 | RASQEISGYLS(序列編號29) |
輕鏈CDR2 | AASTLDS(序列編號30) |
輕鏈CDR3 | LQYASYPLT(序列編號31) |
參考例2:抗EphA4單株抗體對於小鼠及人類EphA4之結合親和性
藉由使用Biacore T200(美商通用電氣醫療公司)之表面電漿子共振(SPR法)而確定抗體A對於小鼠及人類EphA4之結合親和性。首先,將抗His抗體(美商通用電氣醫療公司,28-9950-56)固定化至感測器晶片CM5。固定化係藉由使用N-羥基丁二醯亞胺(NHS)、及N-乙基-N’-(3-二甲胺基丙基)碳二醯亞胺鹽酸鹽(EDC)之胺偶合法來進行,封閉係使用乙醇胺(感測器晶片或固定化用試劑均為美商通用電氣醫療公司公司製造)。使用固定化用緩衝液(10 mM乙酸鈉,pH 4.5)稀釋至3.5 μg/mL,依據Biacore T200附帶之操作說明固定在感測器晶片上。使用運轉緩衝液HBS-EP(美商通用電氣醫療公司,BR-1001-88)將小鼠或人類EphA4胞外域-SEAP-His10加以稀釋,於流槽上進行120秒鐘送液而捕獲上述小鼠或人類EphA4胞外域-SEAP-His10(10RU左右之捕獲量)。繼而,將使用HBS-EP在100、50、25、12.5、6.3、3.2、1.6、0 nM之範圍內經連續稀釋後之抗體A添加至感測器晶片中120秒鐘,依序觀測添加時(結合相、120秒鐘)及添加結束後(解離相、600秒鐘)之結合反應曲線。在各觀測結束後,添加4M MgCl
2(60秒鐘,和光純藥)而再生感測器晶片。對於所獲得之結合反應曲線,使用系統附帶軟體即BIA evaluation軟體並利用1 : 1之結合模型來進行擬合分析,而算出對於小鼠及人類EphA4之結合親和性(KD = kd/ka)。
抗體A對於小鼠及人類EphA4之結合親和性(KD值)分別為1.32 × 10
-9M、1.19 × 10
-9M(圖1)。對於小鼠及人類EphA4之其他結合參數亦為大致相同程度。因此,認為抗體A對於小鼠及人類EphA4具有相同程度之結合親和性。
參考例3:抗EphA4單株抗體於海馬神經元中之EphA4切斷促進活性
針對抗體A,依據以下步驟來進行使用海馬神經元之EphA4切斷促進活性的評價。用抗體A(2.0、6.7、20 nM)及γ分泌酶抑制藥即化合物E(50 nM,瑞士恩佐生命科學公司)對接種至96孔皿(美商Falcon公司)之大鼠海馬神經元進行處理,於24小時後利用PBS(和光純藥)洗淨,添加SDS樣本緩衝液(Laemmli樣本緩衝液(美商伯樂公司)、5% 2-巰基乙醇(美商伯樂公司)),回收細胞並煮沸5分鐘。使用該樣本進行SDS-PAGE,使用抗EphA4單株抗體(亞諾法生技股份有限公司)進行西方墨點法,對條帶強度進行定量化,算出EphA4C末端片段/全長EphA4之值。
抗體A於海馬神經元中,濃度依賴性地促進EphA4切斷反應(圖2)。
參考例4:抗EphA4單株抗體之小鼠EphA4-小鼠配體結合抑制活性
針對抗體A,依據以下步驟來進行小鼠EphA4與小鼠配體之結合抑制活性的評價。將抗鹼性磷酸酶抗體(Thermo SCIENTIFIC)塗抹在96孔培養盤(丹麥能肯公司)之孔上。於4℃下培養一夜後,藉由1% Block Ace(日商DS製藥生物醫藥公司)將孔於室溫下封閉1小時。利用0.02%吐溫20/磷酸鹽緩衝鹽水(Thermo SCIENTIFIC)洗淨3次後,於孔中添加小鼠EphA4胞外域-SEAP-His蛋白質(最終濃度10 nM),於室溫下培養1小時。洗淨3次後,於孔中添加配體及抗體A(0、0.003、0.01、0.03、0.1、0.3、1、3、10、30、100、300、1000、3000 nM)。再者,配體使用生物素化小鼠肝配蛋白A1-Fc嵌合體(R & D Systems,最終濃度6 nM)及生物素化小鼠肝配蛋白B2-Fc嵌合體(R & D Systems,最終濃度2.5 nM)。於室溫下培養1小時並洗淨3次後,添加辣根過氧化酶標記抗生蛋白鏈菌素(美商通用電氣醫療公司),於室溫下培養1小時。洗淨3次後,於孔中添加TMBZ(3,3’,5,5’-四甲基聯苯胺,美商西格瑪公司)溶液,於室溫下培養2分鐘。於孔中添加等量之反應終止溶液(1N H
2SO
4,和光純藥),藉由微盤讀取器(美商鉑金埃爾默公司)讀取450 nm之吸光度。
抗體A濃度依賴性地抑制小鼠EphA4與小鼠配體之結合,對於小鼠肝配蛋白A1、肝配蛋白B2結合之IC
50值分別約為5.9 nM、3.1 nM(圖3)。因此示出,抗體A較強地抑制小鼠EphA4與小鼠配體之結合。
參考例5:抗EphA4單株抗體之人類EphA4-人類配體結合抑制活性
針對抗體A,依據以下步驟來進行人類EphA4與人類配體之結合抑制活性的評價。將抗鹼性磷酸酶抗體(Thermo SCIENTIFIC)塗抹在96孔培養盤(丹麥能肯公司)之孔上。於4℃下培養一夜後,藉由1% Block Ace(日商DS製藥生物醫藥公司)將孔於室溫下封閉1小時。利用0.05%吐溫20/磷酸鹽緩衝鹽水(Thermo SCIENTIFIC)洗淨3次後,於孔中添加人類EphA4胞外域-SEAP-His蛋白質(最終濃度10 nM),於室溫下培養1小時。洗淨3次後,於孔中添加配體及經連續稀釋之抗體A(0、0.003、0.01、0.03、0.1、0.3、1、3、10、30、100、300、1000、3000 nM)。再者,配體使用生物素化人類肝配蛋白A5-Fc嵌合體(R & D Systems,最終濃度0.7 nM)及生物素化人類肝配蛋白B3-Fc嵌合體(R & D Systems,最終濃度2.3 nM)。於室溫下培養1小時並洗淨3次後,添加辣根過氧化酶標記抗生蛋白鏈菌素(美商通用電氣醫療公司),於室溫下培養1小時。洗淨3次後,於孔中添加TMBZ(3,3’,5,5’-四甲基聯苯胺,美商西格瑪公司)溶液,於室溫下培養2~5分鐘。於孔中添加等量之反應終止溶液(1N H
2SO
4,和光純藥),藉由微盤讀取器(美商美谷分子公司或美商鉑金埃爾默公司)讀取450 nm之吸光度。
抗體A濃度依賴性地抑制人類EphA4與人類配體之結合,對於人類肝配蛋白A5、肝配蛋白B3結合之IC
50值分別約為2.8 nM、1.4 nM(圖4)。因此示出,抗體A較強地抑制人類EphA4與人類配體之結合。
參考例6:抗EphA4單株抗體對於人類Eph受體之選擇性
依據參考例1中記載之小鼠EphA4胞外域-SEAP-His蛋白質之製備方法,並使用源自組織之總RNA,藉由RT-PCR對編碼人類之各Eph受體(EphA1、EphA2、EphA3、EphA4、EphA5、EphA6、EphA7、EphA8、EphA10、EphB1、EphB2、EphB3、EphB4、EphB6)之訊息序列與胞外域的DNA序列進行擴增,選殖至具有編碼SEAP及組胺酸標籤之DNA序列之pENTR1A載體(美商英傑/生命技術公司)。繼而,藉由Gateway系統(美商英傑/生命技術公司)之LR反應,將編碼人類之各Eph受體之訊息序列與胞外域、SEAP及組胺酸標籤之DNA序列轉移至pcDNA3.1_rfcB載體,從而構建表現對人類之各Eph受體之胞外域融合SEAP及His標籤而成之蛋白質(稱為「Eph受體胞外域-SEAP-His蛋白質」)的載體(稱為「Eph受體胞外域-SEAP-His蛋白質表現載體」)。
繼而,使用Expi293表現系統(美商Gibco/賽默飛世爾公司),將人類之各Eph受體胞外域-SEAP-His蛋白質表現載體導入Expi293F細胞(美商Gibco/賽默飛世爾公司)。培養5天(5% CO
2、37℃、120 rpm)後,回收培養上清液,於室溫下以1500 rpm進行5分鐘離心。將離心上清液利用0.45 μm過濾器(美商密理博公司)進行過濾。
針對抗體A,依據以下步驟來進行人類Eph受體之結合活性之評價。
將兔抗6-His抗體(美商Bethyl實驗室公司)塗抹在96孔培養盤(丹麥能肯公司)之孔上。於4℃下培養一夜後,藉由1% Block Ace(日商DS製藥生物醫藥公司)將孔於室溫下封閉1小時。利用0.05%吐溫20/磷酸鹽緩衝鹽水(Thermo SCIENTIFIC)洗淨3次後,於各孔中接種人類之各Eph受體胞外域-SEAP-His蛋白質(最終濃度1 nM),於室溫下培養1小時。洗淨3次後,於孔中添加人類IgG溶液(100 μg/mL,三菱製藥)及抗體A(10 μg/mL),於室溫下培養1小時。添加辣根過氧化酶標記驢抗小鼠IgG抗體(美商傑克遜免疫研究實驗室公司),於室溫下培養1小時。洗淨3次後,於孔中添加TMBZ(3,3’,5,5’-四甲基聯苯胺,美商西格瑪公司)溶液,確認到適度之顯色後,於孔中添加等量之反應終止溶液(1N H
2SO
4,和光純藥),藉由微盤讀取器(美商鉑金埃爾默公司)讀取450 nm之吸光度。
抗體A於人類Eph受體家族間僅對人類EphA4具有特異性結合活性(圖5)。
參考例7:抗EphA4單株抗體對於小鼠Eph受體之選擇性
依據參考例1中記載之EphA4胞外域-Fc-His蛋白質之製備方法,並使用源自組織之總RNA,藉由RT-PCR對編碼小鼠之各Eph受體(EphA1、EphA3、EphA4、EphA5、EphA6、EphA7、EphA8、EphA10、EphB1、EphB2、EphB3、EphB4、EphB6)之訊息序列與胞外域之DNA序列進行擴增,選殖至具有編碼人類IgG
1之Fc區及組胺酸標籤之DNA序列之pENTR1A載體(美商英傑/生命技術公司)。繼而,藉由Gateway系統(美商英傑/生命技術公司)之LR反應,將編碼小鼠之各Eph受體(EphA1、EphA3、EphA4、EphA5、EphA6、EphA7、EphA8、EphA10、EphB1、EphB2、EphB3、EphB4、EphB6)之訊息序列與胞外域、Fc及組胺酸標籤之DNA序列轉移到pcDNA3.1_rfcB載體,從而構建小鼠之各Eph受體之胞外域-Fc-His蛋白質表現載體。於小鼠EphA2之胞外域-Fc-His蛋白質表現載體之構建中,使用源自組織之總RNA,藉由RT-PCR對編碼小鼠EphA2之訊息序列與胞外域之DNA序列進行擴增,選殖至具有編碼Fc及組胺酸標籤之DNA序列之pcDNA3.1載體,從而構建小鼠EphA2胞外域-Fc-His蛋白質表現載體。
繼而,使用Expi293表現系統(美商Gibco/賽默飛世爾公司),將小鼠之各Eph受體胞外域-Fc-His蛋白質表現載體導入Expi293F細胞(美商Gibco/賽默飛世爾公司)。培養5天(5% CO
2、37℃、120 rpm)後,回收培養上清液,於室溫下以1500 rpm進行5分鐘離心。將離心上清液利用0.45 μm過濾器(美商密理博公司)進行過濾。
針對抗體A,依據以下步驟進行小鼠Eph受體之結合活性之評價。
將兔抗6-His抗體(美商Bethyl實驗室公司)塗抹在96孔培養盤(丹麥能肯公司)之孔上。於4℃下培養一夜後,藉由1% Block Ace(日商DS製藥生物醫藥公司)將孔於室溫下封閉1小時。利用0.05%吐溫20/磷酸鹽緩衝鹽水(Thermo SCIENTIFIC)洗淨3次後,於各孔中接種小鼠之各Eph受體胞外域-Fc-His蛋白質(最終濃度1 nM),於室溫下培養1小時。洗淨3次後,於孔中添加人類IgG溶液(100 μg/mL,美商西格瑪公司)及抗體A(10 μg/mL),於室溫下培養1小時。添加辣根過氧化酶標記驢抗小鼠IgG抗體(美商傑克遜免疫研究實驗室公司),於室溫下培養1小時。洗淨3次後,於孔中添加TMBZ(3,3’,5,5’-四甲基聯苯胺,美商西格瑪公司)溶液,確認到適度之顯色後,於孔中添加等量之反應終止溶液(1N H
2SO
4,和光純藥),藉由微盤讀取器(美商鉑金埃爾默公司)讀取450 nm之吸光度。
抗體A於小鼠Eph受體家族間僅對小鼠EphA4具有特異性結合活性(圖6)。
參考例8:抗EphA4單株抗體對於小鼠、大鼠、猴及人類EphA4之反應性
小鼠、大鼠、猴及人類EphA4胞外域-Fc-His蛋白質之製作係依據以下步來進行。首先,依據參考例1中所記載之EphA4胞外域-Fc-His蛋白質之製備方法,而構建猴EphA4胞外域-Fc-His蛋白質表現載體。將在載體構建中所利用之猴EphA4之胺基酸序列示於序列編號32,將其胞外域示於序列編號33。使用猴EphA4胞外域-Fc-His蛋白質表現載體、及參考例1中記載之小鼠、大鼠及人類EphA4胞外域-Fc-His蛋白質表現載體,製備各種EphA4胞外域-Fc-His蛋白質。
針對抗體A,依據以下步驟來進行與各種EphA4胞外域之結合活性之評價。
將驢抗人類IgG抗體(美商傑克遜免疫研究實驗室公司)塗抹在96孔培養盤(丹麥能肯公司)之孔上。於4℃下培養一夜後,藉由1% Block Ace(日商DS製藥生物醫藥公司)將孔於室溫下封閉1小時。利用0.05%吐溫20/磷酸鹽緩衝鹽水(Thermo SCIENTIFIC)洗淨3次後,於孔中接種小鼠、大鼠、猴及人類EphA4胞外域-Fc-His蛋白質(最終濃度1 nM),於室溫下培養1小時。洗淨3次後,於孔中添加人類IgG溶液(100 μg/mL,三菱製藥)及抗體A(0、0.00013、0.00064、0.0032、0.016、0.08、0.4、2、10、μg/mL),於室溫下培養1小時。添加辣根過氧化酶標記驢抗小鼠IgG抗體(美商傑克遜免疫研究實驗室公司),於室溫下培養1小時。洗淨3次後,於孔中添加TMBZ(3,3’,5,5’-四甲基聯苯胺,美商西格瑪公司)溶液,確認到適度之顯色後,於孔中添加等量之反應終止溶液(1N H
2SO
4,和光純藥),藉由微盤讀取器(美商鉑金埃爾默公司)讀取450 nm之吸光度。
抗體A對於小鼠、大鼠、猴及人類EphA4均具有同等之結合活性(圖7)。
參考例9:抗EphA4單株抗體對於人類EphA4胞外域、配體結合域、纖維黏連蛋白III型域1、纖維黏連蛋白III型域2之反應性
使人類EphA4之胞外域(ECD)、配體結合域(LBD)、纖維黏連蛋白III型域1(FN1)或纖維黏連蛋白III型域2(FN2)與麥芽糖結合蛋白質(MBP)及組胺酸標籤融合而成之蛋白質(以下,稱為「人類EphA4胞外域-MBP-His蛋白質」、「人類EphA4配體結合域-MBP-His蛋白質」、「人類EphA4纖維黏連蛋白III型域1-MBP-His蛋白質」、及「人類EphA4纖維黏連蛋白III型域2-MBP-His蛋白質」)之製作係依據以下步驟來進行。最開始,構建pcDNA3.4-人類EphA4胞外域、配體結合域、纖維黏連蛋白III型域1、或纖維黏連蛋白III型域2-MBP-His表現載體。首先,藉由PCR,對編碼人類EphA4之訊息序列(序列編號34)或前胰蛋白酶之訊息序列(序列編號35)及人類EphA4之各區域之DNA序列進行擴增,選殖至具有編碼MBP及組胺酸標籤之DNA序列之pcDNA3.4載體(美商英傑/生命技術公司),從而構建人類EphA4胞外域-MBP-His蛋白質、人類EphA4配體結合域-MBP-His蛋白質、人類EphA4纖維黏連蛋白III型域1-MBP-His蛋白質、及人類EphA4纖維黏連蛋白III型域2-MBP-His蛋白質之表現載體。在載體構建中所利用之人類EphA4之胺基酸序列示於序列編號5,其胞外域示於序列編號36,配體結合域示於序列編號37,纖維黏連蛋白III型域1示於序列編號38,纖維黏連蛋白III型域2示於序列編號39。使用Expi293表現系統(Thermo SCIENTIFIC),將上述表現載體轉染至Expi293F細胞(Thermo SCIENTIFIC)。於4天後回收培養上清液,並通過0.45 μm過濾器(美商密理博公司)。使用Amylose resin(美商紐英倫生物技術公司)進行粗純化,使用Zeba 旋轉除鹽管柱(Thermo SCIENTIFIC)將緩衝液置換為PBS(和光純藥)。藉由Superdex200 10/300(美商通用電氣醫療公司)對單體組分進行區分純化。
針對抗體A,依據以下之步驟來進行與各種人類EphA4內區域之結合活性之評價。
將兔抗6-His抗體(美商Bethyl實驗室公司)塗抹在96孔培養盤(丹麥能肯公司)之孔上。於4℃下培養一夜後,藉由1% Block Ace(日商DS製藥生物醫藥公司)將孔於室溫下封閉1小時。藉由0.02%吐溫20/磷酸鹽緩衝鹽水(日商半井公司)洗淨2次後,於孔中接種人類EphA4胞外域-MBP-His蛋白質、人類EphA4配體結合域-MBP-His蛋白質、人類EphA4纖維黏連蛋白III型域1-MBP-His蛋白質、及人類EphA4纖維黏連蛋白III型域2-MBP-His蛋白質(最終濃度10 nM),於室溫下培養1小時。洗淨3次後,於孔中添加抗體A(最終濃度10 nM),於室溫下培養1小時。添加辣根過氧化酶標記山羊抗小鼠IgG Fcγ片段抗體(美商傑克遜免疫研究實驗室公司),於室溫下培養1小時。洗淨5次後,於孔中添加TMB溶液(美商KPL公司),確認到適度之顯色後,於孔中添加等量之反應終止溶液(2N H
2SO
4,和光純藥),藉由微盤讀取器(美商鉑金埃爾默公司)讀取450 nm及650 nm之吸光度。
抗體A對於人類EphA4胞外域(ECD)及配體結合域(LBD)具有結合活性(圖8)。未與纖維黏連蛋白III型域1(FN1)及纖維黏連蛋白III型域2(FN2)反應。因此可知,抗體A與人類EphA4胞外域之配體結合域特異性地結合。
參考例10:抗EphA4單株抗體對於海馬神經元之樹突棘數量之增加效果
大鼠海馬神經元之製備係以上述參考例1之(B)中記載之方式進行。使用Nucleofector(瑞士龍沙公司)將EGFP基因導入大鼠海馬神經元,與未進行基因導入之大鼠海馬神經元混合,接種至裝有塗抹有聚L離胺酸之覆蓋玻璃(日商松浪硝子工業公司)之24孔培養盤(美商Falcon公司)。
使用海馬神經元之樹突棘之計數係依據以下步驟來進行。用對照抗體(小鼠IgG
1;BioLegend)或抗體A(6.7、20 nM)對接種至裝有塗抹有聚L離胺酸之覆蓋玻璃(日商松浪硝子工業公司)之24孔培養盤(美商Falcon公司)的在培養第13天導入EGFP的大鼠海馬神經元進行24小時處置。其後,將覆蓋玻璃移至2% PFA(和光純藥)/4%蔗糖(和光純藥)/PBS中,靜置20分鐘而固定細胞。除去固定液,利用PBS將細胞洗淨3次後,添加0.25%TritonX-100(和光純藥)/PBS,進行15分鐘細胞透過處理。除去液,將覆蓋玻璃移至2%BSA(美商西格瑪公司)/0.25%TritonX-100/Opti-MEM(美商GIBCO公司)中,實施1小時封閉後,使抗GFP抗體(日商半井公司)反應1小時30分鐘。除去第一抗體液,利用PBS洗淨3次後,使第二抗體反應1小時。除去第二抗體液,利用PBS洗淨3次後,添加Prolong Gold抗淬滅試劑(美商分子探針公司)並封入,利用LSM800(德商蔡司公司)進行觀察。實施上述實驗3次,每次實驗時,自2片覆蓋玻璃提取神經元,使用圖像解析軟體Imaris(註冊商標)(瑞士Bitplane公司),對存在於各樹狀突起中之樹突棘進行計數,算出各神經元中每10 μm之樹突棘數量。
抗體A係使海馬神經元之樹突棘數量增加(圖9)。本結果顯示,抗體A具有於海馬神經元中使樹突棘穩定化之活性。
參考例11:利用X射線結晶結構分析之EphA4-配體結合域(EphA4-LBD)之表位映射
抗體A-Fab之製備係依據以下步驟來進行。使抗體A 101.1 mg溶解於以15 mg/mL之濃度包含30 mM L-半胱胺酸及2 mM EDTA之0.1M磷酸鈉緩衝液(pH 7.0)中。於該抗體溶液中添加相對於抗體為1/200量之木瓜酶(美商西格瑪公司),並於37℃下進行18小時酶消化。用PBS對抗體A酶消化液進行透析後,藉由離心分離將沈澱去除(所產生之沈澱於PBS中再溶解,與離心分離上清液加以混合)。繼而,為了除去抗體A-Fab以外之雜質而進行以下之步驟。
1)利用蛋白A管柱進行純化
將該酶消化溶液應用於經PBS平衡化之2 mL之ProSep vA High Capacity(美商密理博公司),回收流穿液組分及經PBS洗淨之組分。
2)使用抗人類IgG Fcγ抗體之親和純化
於NHS-活化瓊脂糖凝膠4FF(美商通用電氣醫療公司)上共價結合有抗人類IgG Fcγ抗體(美商傑克遜免疫研究實驗室公司)之親和管柱係依據該Sepharose之指南來製備。向該親和管柱中加入上述1)中所回收之溶液,回收其流穿液溶液及經PBS洗淨之洗淨液。
3)利用凝膠過濾進行純化
使用超過濾膜將上述2)中所獲得之流穿液組分進行濃縮。將瓊脂糖凝膠12(美商通用電氣醫療公司)利用PBS進行平衡化,應用經過濃縮之樣品進行分離純化。利用SDS-PAGE對經分離純化之一部分組分進行分析,回收並收集含有高純度抗體A-Fab之組分。將如此純化後所得之樣品作為抗體A-Fab。
為了製作抗體A-Fab與作為抗原之EphA4-LBD之複合體,而製備EphA4-LBD(Qin H. et al., J. Biol. Chem., 283: 29473-29484 (2008))。以EphA4-LBD相對於抗體A-Fab成為約1.5倍之莫耳比之方式將0.68 μmol(200 μM、3.4 mL)之EphA4-LBD與0.45 μmol(300 μM、1.5 mL)之抗體A-Fab加以混合。繼而將混合液應用於HILOAD 26/60 Superdex 75 prep grade(美商通用電氣醫療公司),利用層析用緩衝液(25 mM Tris/HCl(pH 7.5)、100 mM NaCl)進行溶出。利用SDS PAGE對包含複合體之組分進行分析,採集高純度之組分並濃縮至約40.8 mg/mL,將其用於結晶化。
複合體之結晶化係藉由使用自動結晶化裝置Hydra II Plus One系統(美商矩陣科技股份有限公司)之坐滴蒸氣擴散法來進行。培養盤使用MRC-2(美商Molecular Dimensions公司)。貯液器溶液之組成為100 mM HEPES(pH 7.5)、10%聚乙二醇8000、8%乙二醇,以該貯液器溶液與上述複合體溶液之體積比成為1 : 1之方式加以混合而製作結晶化微滴。所製作之結晶化培養盤係於20℃下靜置。
於上述條件下進行結晶化,結果獲得了空間群P212121、晶格常數a = 71.0Å、b = 84.5Å、c = 116.1Å之結晶。使放射光X射線(1.0Å)入射至所獲得之結晶而取得1.79Å之繞射數據。藉由HKL2000(美商HKL研究公司)對繞射數據進行處理,藉由分子置換法來確定相位。分子置換法係使用CCP4軟體套件(協同計算項目編號4,[CCP4]第6.5.0版,Acta Cryst. D 67: 235-242(2011))所包含之程式PHASER(第2.5.0版,McCoy A. J. et al., J. Appl. Cryst. 40: 658-674(2007))。作為分子置換法之搜索模型,使用EphA4-LBD之結晶結構(PDBID:3CKH)及IgG之Fab區域之結晶結構(PDBID:2VXT(L鏈)與1FGN(H鏈))。以與自所確定之相位獲得之電子密度匹配的方式,使用程式COOT(Emsley P. et al., Acta Cryst. D 60: 2126-2132n(2004))來構建分子模型,並使用程式REFMAC(Murshudov G.N., Acta Cryst. D 53: 240-255(1997))進行結構精密化。
藉由以上之結構計算而獲得2.0Å解析度之複合體結晶結構(R = 0.212、Rfree = 0.258)。
使用計算化學系統MOE 2018.0101(加拿大化學計算集團公司)所搭載之相互作用檢測工具對所獲得之抗體A-Fab/EphA4-LBD複合體的結晶結構進行分析,鑑定與抗體A-Fab直接接觸之EphA4-LBD上之胺基酸殘基(圖10A)。鑑定出之胺基酸殘基係Glu51、Gly52、Ile59、Gln71、Cys73、Asn74、Val75、Met76、Glu77、Thr104、Arg106、Leu111、Pro112、Met115、Arg162、Met164、Cys191、Ala193、Val195。圖10B中表示由Maestro(第11.0版,Schrodinger,LLC)所製作之EphA4-LBD之表面結構。該結果為,本發明人等得出了如下結論:存在該等胺基酸殘基之區域係EphA4-LBD中之抗體A-Fab結合域。
實施例1:抗體A之人源化抗體之製作
人源化抗EphA4抗體之製備
設計人源化抗體之可變區。基於抗體A之架構區(FR)之較高同源性,自人類抗體之FR中,關於重鏈,選擇IGHV3-33*03(序列編號42)、及JH6(序列編號43)作為人源化抗體之FR,關於輕鏈,選擇IGKV1-17*01(序列編號40)、及JK4(序列編號41)作為人源化抗體之FR。其後,使用小鼠抗體A之3D結構預測模型,預測會與CDR之胺基酸相互作用之FR中之胺基酸,與重鏈之CDR1具有Y32F之變異之抗體A之CDR(序列編號44、27、28、及29-31)一起移植,設計出HK2-42(序列編號45)作為人源化抗體之重鏈可變區,設計出L1-8(序列編號46)作為人源化抗體之輕鏈可變區。將所移植之CDR之胺基酸序列示於表2,將核酸序列示於表3。
作為重鏈恆定區,使用人類IgG
2之恆定區(序列編號47)。作為輕鏈恆定區,使用人類Igκ(序列編號48)。使用Expi293表現系統(美商Gibco/賽默飛世爾公司),將包含編碼人源化抗體之胺基酸序列之基因序列的表現載體(pcDNA3.4)轉染至Expi293F細胞(美商Gibco/賽默飛世爾公司)。作為編碼人源化抗體之胺基酸序列之基因序列,分別為:重鏈可變區使用序列編號55所示之核酸序列,輕鏈可變區使用序列編號56所示之核酸序列,重鏈恆定區使用序列編號57所示之核酸序列,輕鏈恆定區使用序列編號58所示之核酸序列。人源化抗體之重鏈全長(不包括訊息序列)之胺基酸序列係序列編號59所示之胺基酸序列,輕鏈全長(不包括訊息序列)之胺基酸序列係序列編號60所示之胺基酸序列。編碼人源化抗體之重鏈全長之核酸序列係序列編號61所示之核酸序列,編碼輕鏈全長之核酸序列係序列編號62所示之核酸序列。回收上清液,使用MabSelectSuRe(美商通用電氣醫療公司)純化抗體A之人源化抗體(抗體B)。
[表2]
[表3]
抗體B之CDR之胺基酸序列 | |
名稱 | 序列 |
重鏈CDR1 | RFGVH(序列編號44) |
重鏈CDR2 | VIWRGGSTDYNAAFMS(序列編號27) |
重鏈CDR3 | ESLFGVYYDYGYYSMDY(序列編號28) |
輕鏈CDR1 | RASQEISGYLS(序列編號29) |
輕鏈CDR2 | AASTLDS(序列編號30) |
輕鏈CDR3 | LQYASYPLT(序列編號31) |
抗體B之CDR之核酸序列 | |
名稱 | 序列 |
重鏈CDR1 | AGATTTGGAGTGCAT(序列編號49) |
重鏈CDR2 | GTGATCTGGAGGGGAGGATCCACCGACTACAACGCTGCTTTTATGAGC(序列編號50) |
重鏈CDR3 | GAGAGCCTGTTCGGCGTGTACTATGACTACGGCTACTATTCTATGGATTAT(序列編號51) |
輕鏈CDR1 | CGCGCCTCCCAGGAGATCTCTGGCTACCTGTCC(序列編號52) |
輕鏈CDR2 | GCTGCCTCCACCCTGGACTCT(序列編號53) |
輕鏈CDR3 | CTGCAGTACGCTTCCTATCCACTGACC(序列編號54) |
實施例2:人源化抗EphA4單株抗體對於人類EphA4之親和性
藉由使用Biacore T200(美商通用電氣醫療公司)之表面電漿子共振(SPR法)而確定實施例1中所獲得之抗體B對於人類EphA4之結合親和性。首先,將抗His抗體(美商通用電氣醫療公司,28-9950-56)固定化至感測器晶片CM5。固定化係藉由使用N-羥基丁二醯亞胺(NHS)、及N-乙基-N’-(3-二甲胺基丙基)碳二醯亞胺鹽酸鹽(EDC)之胺偶合法來進行,封閉係使用乙醇胺(感測器晶片或固定化用試劑均為美商通用電氣醫療公司公司製造)。使用固定化用緩衝液(10 mM乙酸鈉,pH 4.5)稀釋至3.5 μg/mL,依據Biacore T200附帶之操作說明固定在感測器晶片上。使用運轉緩衝液HBS-EP(美商通用電氣醫療公司,BR-1001-88)將人類EphA4胞外域-SEAP-His10加以稀釋,於流槽上進行120秒鐘送液而捕獲上述人類EphA4胞外域-SEAP-His10(10RU左右之捕獲量)。繼而,將使用HBS-EP在100、50、25、12.5、6.3、3.2、1.6、0 nM之範圍內進行連續稀釋後之抗體B添加至感測器晶片中120秒鐘,依序觀察添加時(結合相,120秒鐘)、及添加結束後(解離相、600秒鐘)之結合反應曲線。在各觀察結束後,添加4M MgCl
2(60秒鐘,和光純藥)而再生感測器晶片。對於所獲得之結合反應曲線,使用系統附帶軟體即BIA evaluation軟體並利用1 : 1之結合模型來進行擬合分析,而算出對於人類EphA4之親和性(KD = kd/ka)。
抗體B對於人類EphA4之結合親和性(KD值)係1.34 × 10
-9M(圖11)。可知抗體B顯示與進行人源化之前之抗體A大致同等的親和性。
實施例3:人源化抗EphA4單株抗體於海馬神經元中之EphA4切斷促進活性
針對實施例1中所獲得之抗體B,依據以下步驟進行使用海馬神經元之EphA4切斷促進活性的評價。
用抗體B(2.0、6.7、20 nM)及γ分泌酶抑制藥即化合物E(50 nM、瑞士恩佐生命科學公司)對接種至96孔皿(美商Falcon公司)之大鼠海馬神經元進行處理,於24小時後利用PBS(和光純藥)洗淨,添加SDS樣本緩衝液(Laemmli樣本緩衝液(美商伯樂公司)、5% 2-巰基乙醇(美商伯樂公司)),回收細胞並煮沸5分鐘。使用該樣本進行SDS-PAGE,使用抗EphA4單株抗體(亞諾法生技股份有限公司)進行西方墨點法,對條帶強度進行定量化,算出EphA4C末端片段/全長EphA4之值。
抗體B於海馬神經元中,濃度依賴性地促進EphA4切斷反應(圖12)
實施例4:人源化抗EphA4單株抗體之人類EphA4-人類配體結合抑制活性
針對實施例1中所獲得之抗體B,依據以下步驟來進行人類EphA4與人類配體之結合抑制活性的評價。將抗鹼性磷酸酶抗體(Thermo SCIENTIFIC)塗抹在96孔培養盤(丹麥能肯公司)之孔上。於4℃下培養一夜後,藉由1% Block Ace(日商DS製藥生物醫藥公司)將孔於室溫下封閉1小時。利用0.05%吐溫20/磷酸鹽緩衝鹽水(Thermo SCIENTIFIC)洗淨3次後,於孔中接種人類EphA4胞外域-SEAP-His蛋白質(最終濃度10 nM),於室溫下培養1小時。洗淨3次後,於孔中添加配體及經連續稀釋之抗體B(0、0.003、0.01、0.03、0.1、0.3、1、3、10、30、100、300、1000、3000 nM)。再者,配體使用生物素化人類肝配蛋白A5-Fc嵌合體(R & D Systems,最終濃度0.7 nM)及生物素化人類肝配蛋白B3-Fc嵌合體(R & D Systems,最終濃度2.3 nM)。於室溫下培養1小時並洗淨3次後,添加辣根過氧化酶標記抗生蛋白鏈菌素(美商通用電氣醫療公司),於室溫下培養1小時。洗淨3次後,於孔中添加TMBZ(3,3’,5,5’-四甲基聯苯胺,美商西格瑪公司)溶液,於室溫下培養2 ~ 5分鐘。於孔中添加等量之反應終止溶液(1N H
2SO
4,和光純藥),藉由微盤讀取器(美商美谷分子公司或美商鉑金埃爾默公司)讀取450 nm之吸光度。
抗體B濃度依賴性地抑制人類EphA4與人類配體之結合,對於人類肝配蛋白A5、肝配蛋白B3結合之IC
50值分別約為4.9 nM、1.6 nM。因此可知,抗體B較強地抑制人類EphA4與人類配體之結合,示出與進行人源化之前之抗體A大致同等的抑制活性(圖13)。
實施例5:人源化抗EphA4單株抗體之小鼠EphA4-小鼠配體結合抑制活性
針對實施例1中所獲得之抗體B,依據以下步驟來進行小鼠EphA4與小鼠配體之結合抑制活性的評價。將抗鹼性磷酸酶抗體(Thermo SCIENTIFIC)塗抹在96孔培養盤(丹麥能肯公司)之孔上。於4℃下培養一夜後,藉由1% Block Ace(日商DS製藥生物醫藥公司)將孔於室溫下封閉1小時。藉由0.02%吐溫20/磷酸鹽緩衝鹽水(Thermo SCIENTIFIC)洗淨3次後,於孔中添加小鼠EphA4胞外域-SEAP-His蛋白質(最終濃度10 nM),於室溫下培養1小時。洗淨3次後,於孔中添加配體及經連續稀釋之抗體B(0、0.003、0.01、0.03、0.1、0.3、1、3、10、30、100、300、1000、3000 nM)。再者,配體使用生物素化小鼠肝配蛋白A1-Fc嵌合體(R & D Systems,最終濃度6 nM)及生物素化小鼠肝配蛋白B2-Fc嵌合體(R & D Systems,最終濃度2.5 nM)。於室溫下培養1小時並洗淨3次後,添加辣根過氧化酶標記抗生蛋白鏈菌素(美商通用電氣醫療公司),於室溫下培養1小時。洗淨3次後,於孔中添加TMBZ(3,3’,5,5’-四甲基聯苯胺,美商西格瑪公司)溶液,於室溫下培養2分鐘。於孔中添加等量之反應終止溶液(1N H
2SO
4,和光純藥),藉由微盤讀取器(美商美谷分子公司或美商鉑金埃爾默公司)讀取450 nm之吸光度。
抗體B濃度依賴性地抑制小鼠EphA4與小鼠配體之結合,對於小鼠肝配蛋白A1、肝配蛋白B2結合之IC
50值分別約為8.7 nM、4.2 nM。因此可知,抗體B較強地抑制小鼠EphA4與小鼠配體之結合,示出與進行人源化之前之抗體A大致同等之抑制活性(圖14)。
實施例6:人源化抗EphA4單株抗體對於人類Eph受體之選擇性
與參考例1中記載之小鼠EphA4胞外域-SEAP-His蛋白質之製備方法同樣地,使用源自組織之總RNA,藉由RT-PCR對編碼人類之各Eph受體(EphA1、EphA2、EphA3、EphA4、EphA5、EphA6、EphA7、EphA8、EphA10、EphB1、EphB2、EphB3、EphB4、EphB6)之訊息序列與胞外域的DNA序列進行擴增,選殖至具有編碼SEAP蛋白質及組胺酸標籤之DNA序列之pENTR1A載體(美商英傑/生命技術公司)。繼而,藉由Gateway系統(美商英傑/生命技術公司)之LR反應,將編碼人類之各Eph受體之訊息序列與胞外域、SEAP蛋白質及組胺酸標籤之DNA序列轉移至pcDNA3.1_rfcB載體,從而構建表現對人類之各Eph受體之胞外域融合SEAP蛋白質及His標籤而成之蛋白質(稱為「Eph受體胞外域-SEAP-His蛋白質」)的載體(稱為「Eph受體胞外域-SEAP-His蛋白質表現載體」)。
繼而,使用Expi293表現系統(美商Gibco/賽默飛世爾公司),將人類之各Eph受體胞外域-SEAP-His蛋白質表現載體導入Expi293F細胞(美商Gibco/賽默飛世爾公司)。培養5天(5%CO
2、37℃)後,回收培養上清液,於室溫下以1500 rpm進行5分鐘離心。將離心上清液利用0.45 μm過濾器(美商密理博公司)進行過濾。
針對實施例1中所獲得之抗體B,依據以下步驟進行人類Eph受體之結合活性的評價。
將兔抗6-His抗體(美商Bethyl實驗室公司)塗抹在96孔培養盤(丹麥能肯公司)之孔上。於4℃下培養一夜後,藉由1% Block Ace(日商DS製藥生物醫藥公司)將孔於室溫下封閉1小時。藉由0.05%吐溫20/磷酸鹽緩衝鹽水(Thermo SCIENTIFIC)洗淨3次後,於各孔中接種人類之各Eph受體胞外域-SEAP-His蛋白質(最終濃度1 nM),於室溫下培養1小時。洗淨3次後,於孔中添加人類IgG溶液(100 μg/mL,三菱製藥)及抗體B(10 μg/mL),於室溫下培養1小時。添加辣根過氧化酶標記驢抗人類IgG抗體(美商傑克遜免疫研究實驗室公司),於室溫下培養1小時。洗淨3次後,於孔中添加TMBZ(3,3’,5,5’-四甲基聯苯胺,美商西格瑪公司)溶液,確認到適度之顯色後,於孔中添加等量之反應終止溶液(1N H
2SO
4,和光純藥),藉由微盤讀取器(美商鉑金埃爾默公司)讀取450 nm之吸光度。
抗體B與進行人源化之前之抗體A同樣地,於人類Eph受體家族間與人類EphA4特異性地結合(圖15)。
實施例7:人源化抗EphA4單株抗體對於小鼠Eph受體之選擇性
依據參考例1中記載之EphA4胞外域-Fc-His蛋白質之製備方法,使用源自組織之總RNA,藉由RT-PCR對編碼小鼠之各Eph受體(EphA1、EphA3、EphA4、EphA5、EphA6、EphA7、EphA8、EphA10、EphB1、EphB2、EphB3、EphB4、EphB6)之訊息序列與胞外域之DNA序列進行擴增,選殖至具有編碼人類IgG
1之Fc區及組胺酸標籤之DNA序列的pENTR1A載體(美商英傑/生命技術公司)。繼而,藉由Gateway系統(美商英傑/生命技術公司)之LR反應,將編碼小鼠之各Eph受體(EphA1、EphA3、EphA4、EphA5、EphA6、EphA7、EphA8、EphA10、EphB1、EphB2、EphB3、EphB4、EphB6)之訊息序列與胞外域、Fc及組胺酸標籤之DNA序列轉移至pcDNA3.1_rfcB載體,從而構建小鼠之各Eph受體之胞外域-Fc-His蛋白質表現載體。於小鼠EphA2之胞外域-Fc-His蛋白質表現載體之構建中,使用源自組織之總RNA,藉由RT-PCR對編碼小鼠EphA2之訊息序列與胞外域之DNA序列進行擴增,選殖至具有編碼Fc及組胺酸標籤之DNA序列之pcDNA3.1載體,從而構建小鼠EphA2胞外域-Fc-His蛋白質表現載體。
繼而,使用Expi293表現系統(美商Gibco/賽默飛世爾公司),將小鼠之各Eph受體胞外域-Fc-His蛋白質表現載體導入Expi293F細胞(美商Gibco/賽默飛世爾公司)。培養5天(5% CO
2、37℃、120 rpm)後,回收培養上清液,於室溫下以1500 rpm進行5分鐘離心。將離心上清液利用0.45 μm過濾器(美商密理博公司)進行過濾。
針對抗體B,依據以下步驟來進行小鼠Eph受體之結合活性的評價。
將兔抗6-His抗體(美商Bethyl實驗室公司)塗抹至96孔培養盤(丹麥能肯公司)之孔上。於4℃下培養一夜後,藉由1% Block Ace(日商DS製藥生物醫藥公司)將孔於室溫下封閉1小時。利用0.05%吐溫20/磷酸鹽緩衝鹽水(Thermo SCIENTIFIC)洗淨3次後,於各孔中接種小鼠之各Eph受體胞外域‐Fc-His蛋白質(最終濃度1 nM),於室溫下培養1小時。洗淨3次後,於孔中添加人類IgG溶液(100 μg/mL,美商西格瑪公司)及抗體B(10 μg/mL),於室溫下培養1小時。添加辣根過氧化酶標記山羊抗人類Kappa輕鏈抗體(IBL),於室溫下培養1小時。洗淨3次後,於孔中添加TMBZ(3,3’,5,5’-四甲基聯苯胺,美商西格瑪公司)溶液,確認適度之顯色後,於孔中添加等量之反應終止溶液(1N H
2SO
4,和光純藥),藉由微盤讀取器(美商鉑金埃爾默公司)讀取450 nm之吸光度。
抗體B於小鼠Eph受體家族間僅對小鼠EphA4具有特異性之結合活性(圖16)。
實施例8:人源化抗EphA4單株抗體對於小鼠、大鼠、猴及人類EphA4之反應性
針對抗體B,依據以下步驟來進行與各種EphA4之結合活性之評價。
將抗鹼性磷酸酶抗體(Thermo SCIENTIFIC)塗抹在96孔培養盤(丹麥能肯公司)之孔上。於4℃下培養一夜後,藉由1% Block Ace(日商DS製藥生物醫藥公司)將孔於室溫下封閉1小時。利用0.05%吐溫20/磷酸鹽緩衝鹽水(Thermo SCIENTIFIC)洗淨3次後,於孔中接種小鼠、大鼠、猴及人類EphA4胞外域-SEAP-His蛋白質(最終濃度1 nM),於室溫下培養1小時。洗淨3次後,於孔中添加人類IgG溶液(100 μg/mL,三菱製藥)及抗體B(0、0.00013、0.00064、0.0032、0.016、0.08、0.4、2、10 μg/mL),於室溫下培養1小時。添加辣根過氧化酶標記驢抗人類IgG抗體(美商傑克遜免疫研究實驗室公司),於室溫下培養1小時。洗淨3次後,於孔中添加TMBZ(3,3’,5,5’-四甲基聯苯胺,美商西格瑪公司)溶液,確認適度之顯色後,於孔中添加等量之反應終止溶液(1N H
2SO
4,和光純藥),藉由微盤讀取器(美商鉑金埃爾默公司)讀取450 nm之吸光度。
抗體B對於小鼠、大鼠、猴及人類EphA4均具有同等之結合活性(圖17)。
實施例9:人源化抗EphA4單株抗體對於人類EphA4胞外域、配體結合域、纖維黏連蛋白III型域1、纖維黏連蛋白III型域2之反應性
針對實施例1中所獲得之抗體B,依據以下步驟來進行與各種人類EphA4內區域之結合活性之評價。
將兔抗6-His抗體(美商Bethyl實驗室公司)塗抹在96孔培養盤(丹麥能肯公司)之孔上。於4℃下培養一夜後,藉由1% Block Ace(日商DS製藥生物醫藥公司)將孔於室溫下封閉1小時。利用0.02%吐溫20/磷酸鹽緩衝鹽水(日商半井公司)洗淨2次後,於孔中接種人類EphA4胞外域-MBP-His蛋白質、人類EphA4配體結合域-MBP-His蛋白質、人類EphA4纖維黏連蛋白III型域1-MBP-His蛋白質、及人類EphA4纖維黏連蛋白III型域2-MBP-His蛋白質(最終濃度10 nM),於室溫下培養1小時。洗淨3次後,於孔中添加抗體B(最終濃度10 nM),於室溫下培養1小時。添加辣根過氧化酶標記兔抗人類IgG Fcγ片段抗體(美商傑克遜免疫研究實驗室公司),於室溫下培養1小時。洗淨5次後,於孔中添加TMB(美商KPL公司)溶液,確認適度之顯色後,於孔中添加等量之反應終止溶液(2N H
2SO
4,和光純藥),藉由微盤讀取器(美商鉑金埃爾默公司)讀取450 nm及650 nm之吸光度。
抗體B對於人類EphA4胞外域(ECD)及配體結合域(LBD)具有結合活性(圖18)。未與纖維黏連蛋白III型域1(FN1)及纖維黏連蛋白III型域2(FN2)反應。因此可知,抗體B與人類EphA4胞外域之配體結合域特異性地結合。
實施例10:人源化抗EphA4單株抗體對於海馬神經元之樹突棘數量之增加效果
大鼠海馬神經元之製備係以參考例1之(B)中記載之方式進行。使用Nucleofector(瑞士龍沙公司)將EGFP基因導入大鼠海馬神經元,接種至裝有塗抹有聚L離胺酸之覆蓋玻璃(日商松浪硝子工業公司)的24孔培養盤(美商Falcon公司)。
使用海馬神經元之樹突棘之計數係依據以下之步驟來進行。用對照抗體(人類IgG
2;美商西格瑪公司)或抗體B(6.7、20 nM)對接種至裝有塗抹有聚L離胺酸之覆蓋玻璃(日商松浪硝子工業公司)之24孔培養盤(美商Falcon公司)中的培養第13天的EGFP導入大鼠海馬神經元進行24小時處置。其後,將覆蓋玻璃移至2%PFA(和光純藥)/4%蔗糖(和光純藥)/PBS中,靜置20分鐘而固定細胞。除去固定液,利用PBS將細胞洗淨3次後,添加0.25%TritonX-100(和光純藥)/PBS,進行15分鐘細胞透過處理。除去液體,將覆蓋玻璃移至2%BSA(美商西格瑪公司)/0.25%TritonX-100/OPTI-MEM(美商GIBCO公司)中,實施1小時封閉後,使抗GFP抗體(日商半井公司)反應1小時30分鐘。除去第一抗體液,利用PBS洗淨3次後,使第二抗體反應1小時。除去第二抗體液,利用PBS洗淨3次後,添加Prolong Gold抗淬滅試劑(美商分子探針公司)並封入,利用LSM800(德商蔡司公司)進行觀察。實施上述實驗3次,每次實驗時,自2片覆蓋玻璃提取神經元,使用圖像解析軟體Imaris(註冊商標)(瑞士Bitplane公司),對存在於各樹狀突起中之樹突棘進行計數,算出各神經元中每10 μm之樹突棘數量。
抗體B係使海馬神經元之樹突棘數量增加(圖19)。本結果顯示,抗體B具有於海馬神經元中使樹突棘穩定化之活性。
實施例11:人源化抗EphA4單株抗體之人類EphA4切斷促進活性
針對實施例1中獲得之抗體B,依據以下步驟來進行對於人類EphA4之切斷促進活性的評價。
大鼠海馬神經元之製備係以參考例1之(B)中記載之方式進行。使用Nucleofector(瑞士龍沙公司)將人類EphA4-HA蛋白質表現載體導入大鼠海馬神經元,接種至塗抹有聚L離胺酸之96孔皿(美商Falcon公司)。用抗體B(6.7、20、67 nM)及γ分泌酶抑制藥即化合物E(50 nM、瑞士恩佐生命科學公司)對所接種之大鼠海馬神經元進行處置,於約24小時後利用PBS(和光純藥)洗淨,添加SDS樣本緩衝液(Laemmli樣本緩衝液(美商伯樂公司),5% 2-巰基乙醇(美商伯樂公司)),回收細胞並煮沸5分鐘。使用該樣本進行SDS-PAGE,使用大鼠抗HA單株抗體(瑞士羅氏公司)進行西方墨點法,對條帶強度進行定量化,算出EphA4C末端片段/全長EphA4之值。
抗體B於海馬神經元中促進人類EphA4切斷反應(圖20)。
實施例12:MMP及ADAM與人源化抗EphA4單株抗體之海馬神經元之樹突棘數量增加效果的相關性
大鼠海馬神經元之製備係以參考例1之(B)中記載之方式進行。使用Nucleofector(瑞士龍沙公司)將EGFP基因導入一部分大鼠海馬神經元,接種至裝有塗抹有聚L離胺酸之覆蓋玻璃(日商松浪硝子工業公司)之24孔培養盤(美商Falcon公司)。
使用海馬神經元之樹突棘之計數係依據以下步驟來進行。用對照抗體(人類IgG
2;美商西格瑪公司)或抗體B(20 nM)、及DMSO(美商西格瑪公司)或MMP及ADAM之抑制劑即GM6001(2.5 μM,MedChemExpress)對接種至裝有塗抹有聚L離胺酸之覆蓋玻璃(日商松浪硝子工業公司)之24孔培養盤(美商Falcon公司)中的培養第13天的導入有EGFP之大鼠海馬神經元進行24小時處置。其後,將覆蓋玻璃移至2%PFA(和光純藥)/4%蔗糖(和光純藥)/PBS,靜置20分鐘而固定細胞。除去固定液,利用PBS將細胞洗淨3次後,添加0.25%TritonX-100(和光純藥)/PBS,進行15分鐘細胞透過處理。除去0.25%TritonX-100/PBS,將覆蓋玻璃移至2%BSA(美商西格瑪公司)/0.25%TritonX-100/OPTI-MEM(美商GIBCO公司)中,實施1小時封閉後,使抗GFP抗體(日商半井公司)反應1小時30分鐘。除去一次抗體液,利用PBS洗淨3次後,使第二抗體反應1小時。除去第二抗體液,利用PBS洗淨3次後,添加Prolong Gold抗淬滅試劑(美商分子探針公司)並封入,利用LSM800(德商蔡司公司)進行觀察。實施上述實驗3次,每次實驗時,自2片覆蓋玻璃提取神經元,使用圖像解析軟體Imaris(註冊商標)(瑞士Bitplane公司),對存在於各樹狀突起中之樹突棘進行計數,算出各神經元中每10 μm之樹突棘數量。
藉由對GM6001同時處理,利用抗體B之海馬神經元之樹突棘數量增加受到抑制(圖21)。本結果顯示,抗體B於海馬神經元中具有由MMP及ADAM介導之樹突棘穩定化活性。
實施例13:人源化抗EphA4單株抗體於試管內ALS模型中之源自人類iPS細胞的運動神經元保護效果
(A)人類iPS細胞之維持培養
人類iPS細胞之維持培養係依據以下步驟來進行。將在液態氮中以幹細胞凍存液(Stem cell banker)(日商寶生物技術公司)冷凍保存之人類iPS細胞(201B7)自液態氮層中取出,懸浮於預先加溫至37℃之人類iPS細胞培養基(Essential 8,美商賽默飛世爾科技公司)5 mL中並進行融解。將細胞懸浮液回收至15 mL錐形管(美商賽默飛世爾科技公司)中,於1000 rpm、5分鐘、室溫之條件下進行離心後,去除上清液,懸浮於新的培養基中後,接種至預先塗抹有0.3 μg/cm
2iMatrix-511(日商Nippi公司)的φ 60 mm細胞培養皿(Corning),添加10 μM Y-27632(WAKO)後,於CO
2培養箱內(37℃、5%CO
2)中進行培養。毎天更換培養基,於達到亞融合之時點進行繼代培養,藉此進行人類iPS細胞之維持培養。繼代培養係以如下方式來實施。抽吸亞融合狀態之人類iPS細胞之培養基,利用2 mL之PBS(WAKO)洗淨後,添加細胞消化液(日商半井公司)1 mL,於CO
2培養箱內(37℃、5%CO
2)中培養5分鐘。於包含10 μM Y-27632之4 mL之人類iPS細胞培養基中進行懸浮,藉此使人類iPS細胞分離成單細胞,其後回收至15 mL之錐形管中。於1000 rpm、5分鐘、室溫之條件下進行離心,抽吸上清液後,使人類iPS細胞懸浮於包含10 μM Y-27632之1 mL之人類iPS細胞培養基中。計測細胞數,使2 × 10
5個之人類iPS細胞懸浮於4 mL之人類iPS細胞培養基中後,接種至塗抹有0.3 μg/cm
2iMatrix-511之φ 60 mm細胞培養皿,於CO
2培養箱內(37℃、5%CO
2)進行培養。實驗中使用實施過1次以上之繼代培養的人類iPS細胞。
(B)星狀細胞之建立及維持培養
來自新生小鼠之星狀細胞之建立及維持培養係依據以下步驟來進行。將出生後2天齡之野生型新生小鼠(C57BL/6JJmsSlc(日商SLC公司))及野生型小鼠與變異人類SOD1(G93A)Tg-(B6.Cg-Tg(SOD1 G93A)1Gur/J(美商傑克遜免疫研究實驗室公司))小鼠的雜交新生小鼠於異氟醚(Interpets)吸入麻醉下藉由斷頭而安樂死後,分離大腦皮質,利用0.25%胰蛋白酶‐EDTA(美商賽默飛世爾科技公司)以37℃進行15分鐘處理而進行分散。酶處理後,藉由包含10%FBS(美商賽默飛世爾科技公司)及1%青黴素-鏈黴素(日商半井公司)之杜爾貝科改良伊格爾培養基(美商賽默飛世爾科技公司)(10%FBS-DMEM)4 mL進行稀釋,而使酶消化停止。其後,藉由細胞濾器(Corning)將單一細胞以外的雜質進行過濾,並以1500 rpm進行5分鐘離心。抽吸上清液,將細胞稀釋至新的10%FBS-DMEM 4 mL,每個個體均接種至φ 60 mm細胞培養皿,並於37℃下培養。接種2天後,抽吸培養基,將新的10% FBS-DMEM 4 mL添加至細胞中,並進行培養基更換。於達到融合後,實施繼代培養。源自新生小鼠之星狀細胞之繼代培養係以如下方式來實施。於φ 60 mm細胞培養皿上抽吸達到融合之星狀細胞之10%FBS-DMEM後,利用PBS(WAKO)2 mL進行洗淨,添加0.25%胰蛋白酶-EDTA 1 mL,於CO
2培養箱內(37℃、5%CO
2)進行3分鐘培養。藉由懸浮於10%FBS-DMEM 3 mL中而將星狀細胞解離成單細胞,其後回收至15 mL錐形管。於1500 rpm、3分鐘、室溫之條件下進行離心,抽吸上清液後,向細胞添加新的10%FBS-DMEM 8 mL,接種至φ 100 mm細胞培養皿(繼代1)。繼代培養係於細胞達到融合時藉由與上述相同之方法來實施。再者,於在φ 100 mm細胞培養皿中經過培養之星狀細胞之繼代培養時,使用4 mL之PBS、及2 mL之0.25%胰蛋白酶-EDTA。又,於繼代培養時回收細胞懸浮液之一部分,供於變異人類SOD1(G93A)之基因分型。將實施合計3次繼代培養後之星狀細胞稀釋至Cell banker(日本全藥工業)中,於-80℃下冷凍保存直至供於試驗。供於試驗時,使冷凍保存之細胞懸浮液分別於恆溫槽內融解後,利用預先加溫至37℃之10%FBS-DMEM進行稀釋。將各細胞懸浮液離心後(1500 rpm、3分鐘、室溫),去除上清液,懸浮於新的培養基中後,接種至8孔腔室(美商易必迪公司),於CO
2培養箱內(37℃、5%CO
2)進行維持培養。
變異人類SOD1(G93A)之基因分型係使用REDExtract-N-Amp™ Tissue PCR套組(美商西格瑪公司)來進行。將於星狀細胞之繼代培養時回收之細胞懸浮液移至1.5 mL管中,以1500 rpm進行3分鐘離心。離心後,抽吸上清液,將PBS 1 mL添加於細胞中並進行洗淨,於再次離心後進行抽吸。將純化溶液50 μL及組織製備溶液12.5 μL加以混合並添加至樣本中。混合後,移至聚合酶鏈反應(PCR)管中,於GeneAmp(註冊商標)PCR系統9700(Applied biosystems(註冊商標))中於55℃下反應10分鐘,於95℃下反應3分鐘,其後,添加套組附帶之中和溶液50 μL而製備基因組DNA。
使用所提取之基因組DNA,以表4所示之組成進行染色體組PCR。PCR中所使用之引子序列示於表5。PCR後以1%瓊脂糖凝膠/100V/20分鐘進行電泳。將檢測到內部標準324 bp、及變異人類SOD1(G93A)236 bp之2個條帶者鑑定為表現變異人類SOD1(G93A)之星狀細胞。
[表4]
Red mix = RED Extract-N-Amp PCR反應混合物
染色體組PCR混合物 | |
試藥名 | 液量 |
模板: | 1 μL |
Red mix: | 5 μL |
引子1(100 μmol/L): | 0.05 μL |
引子2(100 μmol/L): | 0.05 μL |
引子3(100 μmol/L): | 0.05 μL |
引子4(100 μmol/L): | 0.05 μL |
蒸餾水: | 3.8 μL |
總量: | 10 μL |
[表5]
引子之核苷酸序列 | ||
引子1 | 變異人類 SOD1(G93A) | CATCAGCCCTAATCCATCTGA(序列編號63) |
引子2 | 變異人類 SOD1(G93A) | CGCGACTAACAATCAAAGTGA(序列編號64) |
引子3 | 內部標準 | CTAGGCCACAGAATTGAAAGATCT(序列編號65) |
引子4 | 內部標準 | GTAGGTGGAAATTCTAGCATCATCC(序列編號66) |
(C)試管內ALS模型中之源自人類iPS細胞之運動神經元保護效果的評價
試管內ALS模型中之源自人類iPS細胞之運動神經元保護效果的評價係依據以下步驟來進行。藉由與上述(A)之繼代培養相同之方法獲得人類iPS細胞之單細胞懸浮液後,於1000 rpm、5分鐘、室溫之條件下進行離心,抽吸上清液。使人類iPS細胞懸浮於DFK20培養基(包含20%Knockout血清替代物(KSR,美商賽默飛世爾科技公司)、1%非必要胺基酸(NEAA,美商賽默飛世爾科技公司)、1%GlutaMAX-I Supplement(美商賽默飛世爾科技公司)、100 units/mL青黴素-100 μg/mL鏈黴素(日商半井公司)、100 μM β-巰基乙醇(美商賽默飛世爾科技公司)之DMEM/F12(美商賽默飛世爾科技公司))中後,對細胞數進行計測。使3 × 10
5個人類iPS細胞懸浮於包含10 μM SB431542(美商西格瑪公司)、100 nM LDN193189(美商西格瑪公司)、3 μM CHIR99021(美商開曼化學公司)、10 μM Y-27632之DFK20培養基2 mL中,接種至低黏著性6孔細胞培養盤(Corning)之1孔中,並於CO
2培養箱內(37℃、5%CO
2)進行培養。於培養第3天,將人類iPS細胞分化細胞塊(SFEBs)連同培養基一起回收至15 mL錐形管中,於300 rpm、2分鐘、常溫之條件下進行離心,藉此使細胞塊沈澱。抽吸該上清液,使SFEBs緩慢地懸浮於包含10 μM SB431542、100 nM LDN193189、3 μM CHIR99021(美商開曼化學公司)、5 μM Y-27632、1 μM 視黃酸(美商西格瑪公司)之DFK20培養基中,返回至原本之孔中,藉此進行培養基更換。於培養第5天亦藉由同樣之方法實施培養基更換。其中,使Y-27632之濃度為2.5 μM而實施培養基更換(其他化合物與培養第3天相同)。於培養第7天,將SFEBs連同培養基一起回收至15 mL錐形管中,於常溫下靜置10分鐘,藉此使SFEBs沈澱。抽吸該上清液,使SFEBs 懸浮於包含1 μM視黃酸、1 μM 9-環己基-N-[4-(4-嗎啉基)苯基]-2-(1-萘氧基)-9H-嘌呤-6-胺(Purmorphamine)(德商美天旎生物技術公司)之3 mL之DFK5培養基(包含5%KSR、1%NEAA、1%GlutaMAX-I Supplement、100 units/mL 青黴素-100 μg/mL鏈黴素、100 μM β-巰基乙醇之DMEM/F12)中,返回至原本之孔中,於CO
2培養箱內(37℃、5%CO
2)中進行培養。其後,每2至3天,藉由與培養第7天相同之步驟進行培養基更換,使人類iPS細胞分化誘導為運動神經元。於培養第33天,將SFEBs連同培養基一起回收至15 mL錐形管中,於常溫下靜置5分鐘,藉此使SFEBs沈澱。抽吸上清液,添加包含10 μM Y-27632之2 mL之細胞消化液,並於37℃恆溫水槽中培養10分鐘。其後,利用P1000移液管進行30次移液,使細胞塊分散後,於包含10 μM Y-27632之10 mL之DFK5培養基中使酶反應停止。將細胞懸浮液回收至新的15 mL錐形管中,於1000 rpm、5分鐘、室溫之條件下進行離心,抽吸上清液。使細胞再懸浮於包含10 μM Y-27632之DFK5培養基後,藉由細胞濾器(Corning)進行過濾,其後計測細胞數。於共培養培養基(包含2%B27 Supplement(美商賽默飛世爾科技公司)、10 μM Y-27632、1%GlutaMax-I Supplement、100 units/mL 青黴素-100 μg/mL 鏈黴素之神經基礎培養基(美商賽默飛世爾科技公司)中製備成細胞為5 × 10
5個/mL之懸浮液,分為對照組、媒劑添加組及藥物處置組。藥物之稀釋係使用共培養培養基。將媒劑(共培養培養基)及作為薬物之抗體B添加至各群中後,以200 μL/孔接種至預先以8 × 10
4個/孔接種有源自小鼠之野生型星狀細胞或表現變異人類SOD1(G93A)之星狀細胞的8孔腔室中,以星狀細胞與運動神經元之共培養細胞之形式用於評價。將在野生型星狀細胞與運動神經元之共培養中所觀察到之運動神經元數作為對照。於媒劑添加組及藥物處置組中,進行表現變異人類SOD1(G93A)之星狀細胞與運動神經元之共培養,將條件設為媒劑添加(1%共培養培養基)、抗體B(10、30、100 nmol/L)。於各條件下在CO
2培養箱內(37℃、5% CO
2)培養2天後,使用抗ISL1抗體(英商艾博抗公司)及抗人類核抗原(HNA)抗體(美商密理博公司),以免疫細胞化學方式對運動神經細胞進行染色。將每孔之ISL1/HNA共陽性細胞以存活運動神經元來計數,運動神經元存活率以相對於對照之%而算出。再者,圖22顯示表示評價系統之步驟的簡單模式圖。
於表現變異人類SOD1(G93A)之星狀細胞/源自人類iPS細胞之運動神經元共培養(試管內ALS模型)中,運動神經元存活率顯著地降低。抗體B濃度依賴性地抑制由表現變異人類SOD1(G93A)之星狀細胞誘發之源自人類iPS細胞的運動神經元死亡(圖23)。本結果表示,抗體B於試管內ALS模型中促進運動神經元之存活。
[圖1]表示抗EphA4單株抗體(抗體A)對於小鼠及人類EphA4之結合親和性。
[圖2]表示使用海馬神經元之抗EphA4單株抗體(抗體A)之EphA4切斷促進活性。
[圖3]表示抗EphA4單株抗體(抗體A)之小鼠EphA4-小鼠配體結合抑制活性。
[圖4]表示抗EphA4單株抗體(抗體A)之人類EphA4-人類配體結合抑制活性。
[圖5]表示抗EphA4單株抗體(抗體A)對於各人類Eph受體之選擇性。
[圖6]表示抗EphA4單株抗體(抗體A)對於各小鼠Eph受體之選擇性。
[圖7]表示抗EphA4單株抗體(抗體A)對於小鼠、大鼠、猴及人類EphA4之反應性。
[圖8]表示抗EphA4單株抗體(抗體A)對於人類EphA4胞外域(ECD)、配體結合域(LBD)、纖維黏連蛋白III型域1(FN1)、及纖維黏連蛋白III型域2(FN2)之反應性。
[圖9]表示抗EphA4單株抗體(抗體A)對於海馬神經元之樹突棘數量的增加效果。
[圖10A]中,橫軸表示EphA4-配體結合域(EphA4-LBD)之胺基酸,縱軸表示抗體A-Fab之結構區域。黑色小塊表示存在相互作用之組合的交點。
[圖10B]表示EphA4-配體結合域(EphA4-LBD)之表面結構。圖10B中,在相應位置顯示結合域所包含之胺基酸名及殘基編號,並以帶狀模型顯示所結合之抗體A-Fab之H鏈及L鏈之CDR。
[圖11]表示人源化抗EphA4單株抗體(抗體B)對於人類EphA4之親和性。
[圖12]表示人源化抗EphA4單株抗體(抗體B)於海馬神經元中之EphA4切斷促進活性。
[圖13]表示人源化抗EphA4單株抗體(抗體B)之人類EphA4-人類配體結合抑制活性。
[圖14]表示人源化抗EphA4單株抗體(抗體B)之小鼠EphA4-小鼠配體結合抑制活性。
[圖15]表示人源化抗EphA4單株抗體(抗體B)對於人類Eph受體之選擇性。
[圖16]表示人源化抗EphA4單株抗體(抗體B)對於小鼠Eph受體之選擇性。
[圖17]表示人源化抗EphA4單株抗體(抗體B)對於小鼠、大鼠、猴子及人EphA4之反應性。
[圖18]表示人源化抗EphA4單株抗體(抗體B)對於人類EphA4胞外域(ECD)、配體結合域(LBD)、纖維黏連蛋白III型域1(FN1)、及纖維黏連蛋白III型域2(FN2)的反應性。
[圖19]表示人源化抗EphA4單株抗體(抗體B)對於海馬神經元之樹突棘數量的增加效果。
[圖20]表示人源化抗EphA4單株抗體(抗體B)於海馬神經元中之人類EphA4切斷促進活性。
[圖21]表示人源化抗EphA4單株抗體(抗體B)由MMP及ADAM介導之對於海馬神經元之樹突棘數量的增加效果。
[圖22]表示實施例13中所實施之評價體系的模式圖。
[圖23]表示人源化抗EphA4單株抗體(抗體B)對於由表現變異人類SOD1(superoxide dismutase 1,超氧化物歧化酶1)(G93A)之星狀細胞誘發之源自人類iPS細胞之運動神經元死亡的效果。
<![CDATA[<110> 日商衛材R&D企管股份有限公司(EISAI R&D MANAGEMENT CO., LTD.)]]> <![CDATA[<120> 肌肉萎縮性側索硬化症之治療用醫藥組合物]]> <![CDATA[<130> ESAP2001]]> <![CDATA[<160> 66 ]]> <![CDATA[<170> PatentIn第3.5版]]> <![CDATA[<210> 1]]> <![CDATA[<211> 986]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 1]]> Met Ala Gly Ile Phe Tyr Phe Ile Leu Phe Ser Phe Leu Phe Gly Ile 1 5 10 15 Cys Asp Ala Val Thr Gly Ser Arg Val Tyr Pro Ala Asn Glu Val Thr 20 25 30 Leu Leu Asp Ser Arg Ser Val Gln Gly Glu Leu Gly Trp Ile Ala Ser 35 40 45 Pro Leu Glu Gly Gly Trp Glu Glu Val Ser Ile Met Asp Glu Lys Asn 50 55 60 Thr Pro Ile Arg Thr Tyr Gln Val Cys Asn Val Met Glu Ala Ser Gln 65 70 75 80 Asn Asn Trp Leu Arg Thr Asp Trp Ile Thr Arg Glu Gly Ala Gln Arg 85 90 95 Val Tyr Ile Glu Ile Lys Phe Thr Leu Arg Asp Cys Asn Ser Leu Pro 100 105 110 Gly Val Met Gly Thr Cys Lys Glu Thr Phe Asn Leu Tyr Tyr Tyr Glu 115 120 125 Ser Asp Asn Asp Lys Glu Arg Phe Ile Arg Glu Ser Gln Phe Gly Lys 130 135 140 Ile Asp Thr Ile Ala Ala Asp Glu Ser Phe Thr Gln Val Asp Ile Gly 145 150 155 160 Asp Arg Ile Met Lys Leu Asn Thr Glu Ile Arg Asp Val Gly Pro Leu 165 170 175 Ser Lys Lys Gly Phe Tyr Leu Ala Phe Gln Asp Val Gly Ala Cys Ile 180 185 190 Ala Leu Val Ser Val Arg Val Phe Tyr Lys Lys Cys Pro Leu Thr Val 195 200 205 Arg Asn Leu Ala Gln Phe Pro Asp Thr Ile Thr Gly Ala Asp Thr Ser 210 215 220 Ser Leu Val Glu Val Arg Gly Ser Cys Val Asn Asn Ser Glu Glu Lys 225 230 235 240 Asp Val Pro Lys Met Tyr Cys Gly Ala Asp Gly Glu Trp Leu Val Pro 245 250 255 Ile Gly Asn Cys Leu Cys Asn Ala Gly His Glu Glu Gln Asn Gly Glu 260 265 270 Cys Gln Ala Cys Lys Ile Gly Tyr Tyr Lys Ala Leu Ser Thr Asp Ala 275 280 285 Ser Cys Ala Lys Cys Pro Pro His Ser Tyr Ser Val Trp Glu Gly Ala 290 295 300 Thr Ser Cys Thr Cys Asp Arg Gly Phe Phe Arg Ala Asp Asn Asp Ala 305 310 315 320 Ala Ser Met Pro Cys Thr Arg Pro Pro Ser Ala Pro Leu Asn Leu Ile 325 330 335 Ser Asn Val Asn Glu Thr Ser Val Asn Leu Glu Trp Ser Ser Pro Gln 340 345 350 Asn Thr Gly Gly Arg Gln Asp Ile Ser Tyr Asn Val Val Cys Lys Lys 355 360 365 Cys Gly Ala Gly Asp Pro Ser Lys Cys Arg Pro Cys Gly Ser Gly Val 370 375 380 His Tyr Thr Pro Gln Gln Asn Gly Leu Lys Thr Thr Arg Val Ser Ile 385 390 395 400 Thr Asp Leu Leu Ala His Thr Asn Tyr Thr Phe Glu Ile Trp Ala Val 405 410 415 Asn Gly Val Ser Lys Tyr Asn Pro Ser Pro Asp Gln Ser Val Ser Val 420 425 430 Thr Val Thr Thr Asn Gln Ala Ala Pro Ser Ser Ile Ala Leu Val Gln 435 440 445 Ala Lys Glu Val Thr Arg Tyr Ser Val Ala Leu Ala Trp Leu Glu Pro 450 455 460 Asp Arg Pro Asn Gly Val Ile Leu Glu Tyr Glu Val Lys Tyr Tyr Glu 465 470 475 480 Lys Asp Gln Asn Glu Arg Ser Tyr Arg Ile Val Arg Thr Ala Ala Arg 485 490 495 Asn Thr Asp Ile Lys Gly Leu Asn Pro Leu Thr Ser Tyr Val Phe His 500 505 510 Val Arg Ala Arg Thr Ala Ala Gly Tyr Gly Asp Phe Ser Glu Pro Leu 515 520 525 Glu Val Thr Thr Asn Thr Val Pro Ser Arg Ile Ile Gly Asp Gly Ala 530 535 540 Asn Ser Thr Val Leu Leu Val Ser Val Ser Gly Ser Val Val Leu Val 545 550 555 560 Val Ile Leu Ile Ala Ala Phe Val Ile Ser Arg Arg Arg Ser Lys Tyr 565 570 575 Ser Lys Ala Lys Gln Glu Ala Asp Glu Glu Lys His Leu Asn Gln Gly 580 585 590 Val Arg Thr Tyr Val Asp Pro Phe Thr Tyr Glu Asp Pro Asn Gln Ala 595 600 605 Val Arg Glu Phe Ala Lys Glu Ile Asp Ala Ser Cys Ile Lys Ile Glu 610 615 620 Lys Val Ile Gly Val Gly Glu Phe Gly Glu Val Cys Ser Gly Arg Leu 625 630 635 640 Lys Val Pro Gly Lys Arg Glu Ile Cys Val Ala Ile Lys Thr Leu Lys 645 650 655 Ala Gly Tyr Thr Asp Lys Gln Arg Arg Asp Phe Leu Ser Glu Ala Ser 660 665 670 Ile Met Gly Gln Phe Asp His Pro Asn Ile Ile His Leu Glu Gly Val 675 680 685 Val Thr Lys Cys Lys Pro Val Met Ile Ile Thr Glu Tyr Met Glu Asn 690 695 700 Gly Ser Leu Asp Ala Phe Leu Arg Lys Asn Asp Gly Arg Phe Thr Val 705 710 715 720 Ile Gln Leu Val Gly Met Leu Arg Gly Ile Gly Ser Gly Met Lys Tyr 725 730 735 Leu Ser Asp Met Ser Tyr Val His Arg Asp Leu Ala Ala Arg Asn Ile 740 745 750 Leu Val Asn Ser Asn Leu Val Cys Lys Val Ser Asp Phe Gly Met Ser 755 760 765 Arg Val Leu Glu Asp Asp Pro Glu Ala Ala Tyr Thr Thr Arg Gly Gly 770 775 780 Lys Ile Pro Ile Arg Trp Thr Ala Pro Glu Ala Ile Ala Tyr Arg Lys 785 790 795 800 Phe Thr Ser Ala Ser Asp Val Trp Ser Tyr Gly Ile Val Met Trp Glu 805 810 815 Val Met Ser Tyr Gly Glu Arg Pro Tyr Trp Asp Met Ser Asn Gln Asp 820 825 830 Val Ile Lys Ala Ile Glu Glu Gly Tyr Arg Leu Pro Pro Pro Met Asp 835 840 845 Cys Pro Ile Ala Leu His Gln Leu Met Leu Asp Cys Trp Gln Lys Glu 850 855 860 Arg Ser Asp Arg Pro Lys Phe Gly Gln Ile Val Asn Met Leu Asp Lys 865 870 875 880 Leu Ile Arg Asn Pro Asn Ser Leu Lys Arg Thr Gly Ser Glu Ser Ser 885 890 895 Arg Pro Asn Thr Ala Leu Leu Asp Pro Ser Ser Pro Glu Phe Ser Ala 900 905 910 Val Val Ser Val Gly Asp Trp Leu Gln Ala Ile Lys Met Asp Arg Tyr 915 920 925 Lys Asp Asn Phe Thr Ala Ala Gly Tyr Thr Thr Leu Glu Ala Val Val 930 935 940 His Met Ser Gln Asp Asp Leu Ala Arg Ile Gly Ile Thr Ala Ile Thr 945 950 955 960 His Gln Asn Lys Ile Leu Ser Ser Val Gln Ala Met Arg Thr Gln Met 965 970 975 Gln Gln Met His Gly Arg Met Val Pro Val 980 985 <![CDATA[<210> 2]]> <![CDATA[<211> 528]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 2]]> Val Thr Gly Ser Arg Val Tyr Pro Ala Asn Glu Val Thr Leu Leu Asp 1 5 10 15 Ser Arg Ser Val Gln Gly Glu Leu Gly Trp Ile Ala Ser Pro Leu Glu 20 25 30 Gly Gly Trp Glu Glu Val Ser Ile Met Asp Glu Lys Asn Thr Pro Ile 35 40 45 Arg Thr Tyr Gln Val Cys Asn Val Met Glu Ala Ser Gln Asn Asn Trp 50 55 60 Leu Arg Thr Asp Trp Ile Thr Arg Glu Gly Ala Gln Arg Val Tyr Ile 65 70 75 80 Glu Ile Lys Phe Thr Leu Arg Asp Cys Asn Ser Leu Pro Gly Val Met 85 90 95 Gly Thr Cys Lys Glu Thr Phe Asn Leu Tyr Tyr Tyr Glu Ser Asp Asn 100 105 110 Asp Lys Glu Arg Phe Ile Arg Glu Ser Gln Phe Gly Lys Ile Asp Thr 115 120 125 Ile Ala Ala Asp Glu Ser Phe Thr Gln Val Asp Ile Gly Asp Arg Ile 130 135 140 Met Lys Leu Asn Thr Glu Ile Arg Asp Val Gly Pro Leu Ser Lys Lys 145 150 155 160 Gly Phe Tyr Leu Ala Phe Gln Asp Val Gly Ala Cys Ile Ala Leu Val 165 170 175 Ser Val Arg Val Phe Tyr Lys Lys Cys Pro Leu Thr Val Arg Asn Leu 180 185 190 Ala Gln Phe Pro Asp Thr Ile Thr Gly Ala Asp Thr Ser Ser Leu Val 195 200 205 Glu Val Arg Gly Ser Cys Val Asn Asn Ser Glu Glu Lys Asp Val Pro 210 215 220 Lys Met Tyr Cys Gly Ala Asp Gly Glu Trp Leu Val Pro Ile Gly Asn 225 230 235 240 Cys Leu Cys Asn Ala Gly His Glu Glu Gln Asn Gly Glu Cys Gln Ala 245 250 255 Cys Lys Ile Gly Tyr Tyr Lys Ala Leu Ser Thr Asp Ala Ser Cys Ala 260 265 270 Lys Cys Pro Pro His Ser Tyr Ser Val Trp Glu Gly Ala Thr Ser Cys 275 280 285 Thr Cys Asp Arg Gly Phe Phe Arg Ala Asp Asn Asp Ala Ala Ser Met 290 295 300 Pro Cys Thr Arg Pro Pro Ser Ala Pro Leu Asn Leu Ile Ser Asn Val 305 310 315 320 Asn Glu Thr Ser Val Asn Leu Glu Trp Ser Ser Pro Gln Asn Thr Gly 325 330 335 Gly Arg Gln Asp Ile Ser Tyr Asn Val Val Cys Lys Lys Cys Gly Ala 340 345 350 Gly Asp Pro Ser Lys Cys Arg Pro Cys Gly Ser Gly Val His Tyr Thr 355 360 365 Pro Gln Gln Asn Gly Leu Lys Thr Thr Arg Val Ser Ile Thr Asp Leu 370 375 380 Leu Ala His Thr Asn Tyr Thr Phe Glu Ile Trp Ala Val Asn Gly Val 385 390 395 400 Ser Lys Tyr Asn Pro Ser Pro Asp Gln Ser Val Ser Val Thr Val Thr 405 410 415 Thr Asn Gln Ala Ala Pro Ser Ser Ile Ala Leu Val Gln Ala Lys Glu 420 425 430 Val Thr Arg Tyr Ser Val Ala Leu Ala Trp Leu Glu Pro Asp Arg Pro 435 440 445 Asn Gly Val Ile Leu Glu Tyr Glu Val Lys Tyr Tyr Glu Lys Asp Gln 450 455 460 Asn Glu Arg Ser Tyr Arg Ile Val Arg Thr Ala Ala Arg Asn Thr Asp 465 470 475 480 Ile Lys Gly Leu Asn Pro Leu Thr Ser Tyr Val Phe His Val Arg Ala 485 490 495 Arg Thr Ala Ala Gly Tyr Gly Asp Phe Ser Glu Pro Leu Glu Val Thr 500 505 510 Thr Asn Thr Val Pro Ser Arg Ile Ile Gly Asp Gly Ala Asn Ser Thr 515 520 525 <![CDATA[<210> 3]]> <![CDATA[<211> 1030]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多肽]]> <![CDATA[<400> 3]]> Val Thr Gly Ser Arg Val Tyr Pro Ala Asn Glu Val Thr Leu Leu Asp 1 5 10 15 Ser Arg Ser Val Gln Gly Glu Leu Gly Trp Ile Ala Ser Pro Leu Glu 20 25 30 Gly Gly Trp Glu Glu Val Ser Ile Met Asp Glu Lys Asn Thr Pro Ile 35 40 45 Arg Thr Tyr Gln Val Cys Asn Val Met Glu Ala Ser Gln Asn Asn Trp 50 55 60 Leu Arg Thr Asp Trp Ile Thr Arg Glu Gly Ala Gln Arg Val Tyr Ile 65 70 75 80 Glu Ile Lys Phe Thr Leu Arg Asp Cys Asn Ser Leu Pro Gly Val Met 85 90 95 Gly Thr Cys Lys Glu Thr Phe Asn Leu Tyr Tyr Tyr Glu Ser Asp Asn 100 105 110 Asp Lys Glu Arg Phe Ile Arg Glu Ser Gln Phe Gly Lys Ile Asp Thr 115 120 125 Ile Ala Ala Asp Glu Ser Phe Thr Gln Val Asp Ile Gly Asp Arg Ile 130 135 140 Met Lys Leu Asn Thr Glu Ile Arg Asp Val Gly Pro Leu Ser Lys Lys 145 150 155 160 Gly Phe Tyr Leu Ala Phe Gln Asp Val Gly Ala Cys Ile Ala Leu Val 165 170 175 Ser Val Arg Val Phe Tyr Lys Lys Cys Pro Leu Thr Val Arg Asn Leu 180 185 190 Ala Gln Phe Pro Asp Thr Ile Thr Gly Ala Asp Thr Ser Ser Leu Val 195 200 205 Glu Val Arg Gly Ser Cys Val Asn Asn Ser Glu Glu Lys Asp Val Pro 210 215 220 Lys Met Tyr Cys Gly Ala Asp Gly Glu Trp Leu Val Pro Ile Gly Asn 225 230 235 240 Cys Leu Cys Asn Ala Gly His Glu Glu Gln Asn Gly Glu Cys Gln Ala 245 250 255 Cys Lys Ile Gly Tyr Tyr Lys Ala Leu Ser Thr Asp Ala Ser Cys Ala 260 265 270 Lys Cys Pro Pro His Ser Tyr Ser Val Trp Glu Gly Ala Thr Ser Cys 275 280 285 Thr Cys Asp Arg Gly Phe Phe Arg Ala Asp Asn Asp Ala Ala Ser Met 290 295 300 Pro Cys Thr Arg Pro Pro Ser Ala Pro Leu Asn Leu Ile Ser Asn Val 305 310 315 320 Asn Glu Thr Ser Val Asn Leu Glu Trp Ser Ser Pro Gln Asn Thr Gly 325 330 335 Gly Arg Gln Asp Ile Ser Tyr Asn Val Val Cys Lys Lys Cys Gly Ala 340 345 350 Gly Asp Pro Ser Lys Cys Arg Pro Cys Gly Ser Gly Val His Tyr Thr 355 360 365 Pro Gln Gln Asn Gly Leu Lys Thr Thr Arg Val Ser Ile Thr Asp Leu 370 375 380 Leu Ala His Thr Asn Tyr Thr Phe Glu Ile Trp Ala Val Asn Gly Val 385 390 395 400 Ser Lys Tyr Asn Pro Ser Pro Asp Gln Ser Val Ser Val Thr Val Thr 405 410 415 Thr Asn Gln Ala Ala Pro Ser Ser Ile Ala Leu Val Gln Ala Lys Glu 420 425 430 Val Thr Arg Tyr Ser Val Ala Leu Ala Trp Leu Glu Pro Asp Arg Pro 435 440 445 Asn Gly Val Ile Leu Glu Tyr Glu Val Lys Tyr Tyr Glu Lys Asp Gln 450 455 460 Asn Glu Arg Ser Tyr Arg Ile Val Arg Thr Ala Ala Arg Asn Thr Asp 465 470 475 480 Ile Lys Gly Leu Asn Pro Leu Thr Ser Tyr Val Phe His Val Arg Ala 485 490 495 Arg Thr Ala Ala Gly Tyr Gly Asp Phe Ser Glu Pro Leu Glu Val Thr 500 505 510 Thr Asn Thr Val Pro Ser Arg Ile Ile Gly Asp Gly Ala Asn Ser Thr 515 520 525 Ala Ala Ala Ile Ile Pro Val Glu Glu Glu Asn Pro Asp Phe Trp Asn 530 535 540 Arg Glu Ala Ala Glu Ala Leu Gly Ala Ala Lys Lys Leu Gln Pro Ala 545 550 555 560 Gln Thr Ala Ala Lys Asn Leu Ile Ile Phe Leu Gly Asp Gly Met Gly 565 570 575 Val Ser Thr Val Thr Ala Ala Arg Ile Leu Lys Gly Gln Lys Lys Asp 580 585 590 Lys Leu Gly Pro Glu Ile Pro Leu Ala Met Asp Arg Phe Pro Tyr Val 595 600 605 Ala Leu Ser Lys Thr Tyr Asn Val Asp Lys His Val Pro Asp Ser Gly 610 615 620 Ala Thr Ala Thr Ala Tyr Leu Cys Gly Val Lys Gly Asn Phe Gln Thr 625 630 635 640 Ile Gly Leu Ser Ala Ala Ala Arg Phe Asn Gln Cys Asn Thr Thr Arg 645 650 655 Gly Asn Glu Val Ile Ser Val Met Asn Arg Ala Lys Lys Ala Gly Lys 660 665 670 Ser Val Gly Val Val Thr Thr Thr Arg Val Gln His Ala Ser Pro Ala 675 680 685 Gly Thr Tyr Ala His Thr Val Asn Arg Asn Trp Tyr Ser Asp Ala Asp 690 695 700 Val Pro Ala Ser Ala Arg Gln Glu Gly Cys Gln Asp Ile Ala Thr Gln 705 710 715 720 Leu Ile Ser Asn Met Asp Ile Asp Val Ile Leu Gly Gly Gly Arg Lys 725 730 735 Tyr Met Phe Arg Met Gly Thr Pro Asp Pro Glu Tyr Pro Asp Asp Tyr 740 745 750 Ser Gln Gly Gly Thr Arg Leu Asp Gly Lys Asn Leu Val Gln Glu Trp 755 760 765 Leu Ala Lys Arg Gln Gly Ala Arg Tyr Val Trp Asn Arg Thr Glu Leu 770 775 780 Met Gln Ala Ser Leu Asp Pro Ser Val Thr His Leu Met Gly Leu Phe 785 790 795 800 Glu Pro Gly Asp Met Lys Tyr Glu Ile His Arg Asp Ser Thr Leu Asp 805 810 815 Pro Ser Leu Met Glu Met Thr Glu Ala Ala Leu Arg Leu Leu Ser Arg 820 825 830 Asn Pro Arg Gly Phe Phe Leu Phe Val Glu Gly Gly Arg Ile Asp His 835 840 845 Gly His His Glu Ser Arg Ala Tyr Arg Ala Leu Thr Glu Thr Ile Met 850 855 860 Phe Asp Asp Ala Ile Glu Arg Ala Gly Gln Leu Thr Ser Glu Glu Asp 865 870 875 880 Thr Leu Ser Leu Val Thr Ala Asp His Ser His Val Phe Ser Phe Gly 885 890 895 Gly Tyr Pro Leu Arg Gly Ser Ser Ile Phe Gly Leu Ala Pro Gly Lys 900 905 910 Ala Arg Asp Arg Lys Ala Tyr Thr Val Leu Leu Tyr Gly Asn Gly Pro 915 920 925 Gly Tyr Val Leu Lys Asp Gly Ala Arg Pro Asp Val Thr Glu Ser Glu 930 935 940 Ser Gly Ser Pro Glu Tyr Arg Gln Gln Ser Ala Val Pro Leu Asp Glu 945 950 955 960 Glu Thr His Ala Gly Glu Asp Val Ala Val Phe Ala Arg Gly Pro Gln 965 970 975 Ala His Leu Val His Gly Val Gln Glu Gln Thr Phe Ile Ala His Val 980 985 990 Met Ala Phe Ala Ala Cys Leu Glu Pro Tyr Thr Ala Cys Asp Leu Ala 995 1000 1005 Pro Pro Ala Gly Thr Thr Asp Ala Ala His Pro Gly His His His 1010 1015 1020 His His His His His His His 1025 1030 <![CDATA[<210> 4]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 4]]> Met Ala Gly Ile Phe Tyr Phe Ile Leu Phe Ser Phe Leu Phe Gly Ile 1 5 10 15 Cys Asp Ala <![CDATA[<210> 5]]> <![CDATA[<211> 986]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 5]]> Met Ala Gly Ile Phe Tyr Phe Ala Leu Phe Ser Cys Leu Phe Gly Ile 1 5 10 15 Cys Asp Ala Val Thr Gly Ser Arg Val Tyr Pro Ala Asn Glu Val Thr 20 25 30 Leu Leu Asp Ser Arg Ser Val Gln Gly Glu Leu Gly Trp Ile Ala Ser 35 40 45 Pro Leu Glu Gly Gly Trp Glu Glu Val Ser Ile Met Asp Glu Lys Asn 50 55 60 Thr Pro Ile Arg Thr Tyr Gln Val Cys Asn Val Met Glu Pro Ser Gln 65 70 75 80 Asn Asn Trp Leu Arg Thr Asp Trp Ile Thr Arg Glu Gly Ala Gln Arg 85 90 95 Val Tyr Ile Glu Ile Lys Phe Thr Leu Arg Asp Cys Asn Ser Leu Pro 100 105 110 Gly Val Met Gly Thr Cys Lys Glu Thr Phe Asn Leu Tyr Tyr Tyr Glu 115 120 125 Ser Asp Asn Asp Lys Glu Arg Phe Ile Arg Glu Asn Gln Phe Val Lys 130 135 140 Ile Asp Thr Ile Ala Ala Asp Glu Ser Phe Thr Gln Val Asp Ile Gly 145 150 155 160 Asp Arg Ile Met Lys Leu Asn Thr Glu Ile Arg Asp Val Gly Pro Leu 165 170 175 Ser Lys Lys Gly Phe Tyr Leu Ala Phe Gln Asp Val Gly Ala Cys Ile 180 185 190 Ala Leu Val Ser Val Arg Val Phe Tyr Lys Lys Cys Pro Leu Thr Val 195 200 205 Arg Asn Leu Ala Gln Phe Pro Asp Thr Ile Thr Gly Ala Asp Thr Ser 210 215 220 Ser Leu Val Glu Val Arg Gly Ser Cys Val Asn Asn Ser Glu Glu Lys 225 230 235 240 Asp Val Pro Lys Met Tyr Cys Gly Ala Asp Gly Glu Trp Leu Val Pro 245 250 255 Ile Gly Asn Cys Leu Cys Asn Ala Gly His Glu Glu Arg Ser Gly Glu 260 265 270 Cys Gln Ala Cys Lys Ile Gly Tyr Tyr Lys Ala Leu Ser Thr Asp Ala 275 280 285 Thr Cys Ala Lys Cys Pro Pro His Ser Tyr Ser Val Trp Glu Gly Ala 290 295 300 Thr Ser Cys Thr Cys Asp Arg Gly Phe Phe Arg Ala Asp Asn Asp Ala 305 310 315 320 Ala Ser Met Pro Cys Thr Arg Pro Pro Ser Ala Pro Leu Asn Leu Ile 325 330 335 Ser Asn Val Asn Glu Thr Ser Val Asn Leu Glu Trp Ser Ser Pro Gln 340 345 350 Asn Thr Gly Gly Arg Gln Asp Ile Ser Tyr Asn Val Val Cys Lys Lys 355 360 365 Cys Gly Ala Gly Asp Pro Ser Lys Cys Arg Pro Cys Gly Ser Gly Val 370 375 380 His Tyr Thr Pro Gln Gln Asn Gly Leu Lys Thr Thr Lys Val Ser Ile 385 390 395 400 Thr Asp Leu Leu Ala His Thr Asn Tyr Thr Phe Glu Ile Trp Ala Val 405 410 415 Asn Gly Val Ser Lys Tyr Asn Pro Asn Pro Asp Gln Ser Val Ser Val 420 425 430 Thr Val Thr Thr Asn Gln Ala Ala Pro Ser Ser Ile Ala Leu Val Gln 435 440 445 Ala Lys Glu Val Thr Arg Tyr Ser Val Ala Leu Ala Trp Leu Glu Pro 450 455 460 Asp Arg Pro Asn Gly Val Ile Leu Glu Tyr Glu Val Lys Tyr Tyr Glu 465 470 475 480 Lys Asp Gln Asn Glu Arg Ser Tyr Arg Ile Val Arg Thr Ala Ala Arg 485 490 495 Asn Thr Asp Ile Lys Gly Leu Asn Pro Leu Thr Ser Tyr Val Phe His 500 505 510 Val Arg Ala Arg Thr Ala Ala Gly Tyr Gly Asp Phe Ser Glu Pro Leu 515 520 525 Glu Val Thr Thr Asn Thr Val Pro Ser Arg Ile Ile Gly Asp Gly Ala 530 535 540 Asn Ser Thr Val Leu Leu Val Ser Val Ser Gly Ser Val Val Leu Val 545 550 555 560 Val Ile Leu Ile Ala Ala Phe Val Ile Ser Arg Arg Arg Ser Lys Tyr 565 570 575 Ser Lys Ala Lys Gln Glu Ala Asp Glu Glu Lys His Leu Asn Gln Gly 580 585 590 Val Arg Thr Tyr Val Asp Pro Phe Thr Tyr Glu Asp Pro Asn Gln Ala 595 600 605 Val Arg Glu Phe Ala Lys Glu Ile Asp Ala Ser Cys Ile Lys Ile Glu 610 615 620 Lys Val Ile Gly Val Gly Glu Phe Gly Glu Val Cys Ser Gly Arg Leu 625 630 635 640 Lys Val Pro Gly Lys Arg Glu Ile Cys Val Ala Ile Lys Thr Leu Lys 645 650 655 Ala Gly Tyr Thr Asp Lys Gln Arg Arg Asp Phe Leu Ser Glu Ala Ser 660 665 670 Ile Met Gly Gln Phe Asp His Pro Asn Ile Ile His Leu Glu Gly Val 675 680 685 Val Thr Lys Cys Lys Pro Val Met Ile Ile Thr Glu Tyr Met Glu Asn 690 695 700 Gly Ser Leu Asp Ala Phe Leu Arg Lys Asn Asp Gly Arg Phe Thr Val 705 710 715 720 Ile Gln Leu Val Gly Met Leu Arg Gly Ile Gly Ser Gly Met Lys Tyr 725 730 735 Leu Ser Asp Met Ser Tyr Val His Arg Asp Leu Ala Ala Arg Asn Ile 740 745 750 Leu Val Asn Ser Asn Leu Val Cys Lys Val Ser Asp Phe Gly Met Ser 755 760 765 Arg Val Leu Glu Asp Asp Pro Glu Ala Ala Tyr Thr Thr Arg Gly Gly 770 775 780 Lys Ile Pro Ile Arg Trp Thr Ala Pro Glu Ala Ile Ala Tyr Arg Lys 785 790 795 800 Phe Thr Ser Ala Ser Asp Val Trp Ser Tyr Gly Ile Val Met Trp Glu 805 810 815 Val Met Ser Tyr Gly Glu Arg Pro Tyr Trp Asp Met Ser Asn Gln Asp 820 825 830 Val Ile Lys Ala Ile Glu Glu Gly Tyr Arg Leu Pro Pro Pro Met Asp 835 840 845 Cys Pro Ile Ala Leu His Gln Leu Met Leu Asp Cys Trp Gln Lys Glu 850 855 860 Arg Ser Asp Arg Pro Lys Phe Gly Gln Ile Val Asn Met Leu Asp Lys 865 870 875 880 Leu Ile Arg Asn Pro Asn Ser Leu Lys Arg Thr Gly Thr Glu Ser Ser 885 890 895 Arg Pro Asn Thr Ala Leu Leu Asp Pro Ser Ser Pro Glu Phe Ser Ala 900 905 910 Val Val Ser Val Gly Asp Trp Leu Gln Ala Ile Lys Met Asp Arg Tyr 915 920 925 Lys Asp Asn Phe Thr Ala Ala Gly Tyr Thr Thr Leu Glu Ala Val Val 930 935 940 His Val Asn Gln Glu Asp Leu Ala Arg Ile Gly Ile Thr Ala Ile Thr 945 950 955 960 His Gln Asn Lys Ile Leu Ser Ser Val Gln Ala Met Arg Thr Gln Met 965 970 975 Gln Gln Met His Gly Arg Met Val Pro Val 980 985 <![CDATA[<210> 6]]> <![CDATA[<211> 528]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 6]]> Val Thr Gly Ser Arg Val Tyr Pro Ala Asn Glu Val Thr Leu Leu Asp 1 5 10 15 Ser Arg Ser Val Gln Gly Glu Leu Gly Trp Ile Ala Ser Pro Leu Glu 20 25 30 Gly Gly Trp Glu Glu Val Ser Ile Met Asp Glu Lys Asn Thr Pro Ile 35 40 45 Arg Thr Tyr Gln Val Cys Asn Val Met Glu Pro Ser Gln Asn Asn Trp 50 55 60 Leu Arg Thr Asp Trp Ile Thr Arg Glu Gly Ala Gln Arg Val Tyr Ile 65 70 75 80 Glu Ile Lys Phe Thr Leu Arg Asp Cys Asn Ser Leu Pro Gly Val Met 85 90 95 Gly Thr Cys Lys Glu Thr Phe Asn Leu Tyr Tyr Tyr Glu Ser Asp Asn 100 105 110 Asp Lys Glu Arg Phe Ile Arg Glu Asn Gln Phe Val Lys Ile Asp Thr 115 120 125 Ile Ala Ala Asp Glu Ser Phe Thr Gln Val Asp Ile Gly Asp Arg Ile 130 135 140 Met Lys Leu Asn Thr Glu Ile Arg Asp Val Gly Pro Leu Ser Lys Lys 145 150 155 160 Gly Phe Tyr Leu Ala Phe Gln Asp Val Gly Ala Cys Ile Ala Leu Val 165 170 175 Ser Val Arg Val Phe Tyr Lys Lys Cys Pro Leu Thr Val Arg Asn Leu 180 185 190 Ala Gln Phe Pro Asp Thr Ile Thr Gly Ala Asp Thr Ser Ser Leu Val 195 200 205 Glu Val Arg Gly Ser Cys Val Asn Asn Ser Glu Glu Lys Asp Val Pro 210 215 220 Lys Met Tyr Cys Gly Ala Asp Gly Glu Trp Leu Val Pro Ile Gly Asn 225 230 235 240 Cys Leu Cys Asn Ala Gly His Glu Glu Arg Ser Gly Glu Cys Gln Ala 245 250 255 Cys Lys Ile Gly Tyr Tyr Lys Ala Leu Ser Thr Asp Ala Thr Cys Ala 260 265 270 Lys Cys Pro Pro His Ser Tyr Ser Val Trp Glu Gly Ala Thr Ser Cys 275 280 285 Thr Cys Asp Arg Gly Phe Phe Arg Ala Asp Asn Asp Ala Ala Ser Met 290 295 300 Pro Cys Thr Arg Pro Pro Ser Ala Pro Leu Asn Leu Ile Ser Asn Val 305 310 315 320 Asn Glu Thr Ser Val Asn Leu Glu Trp Ser Ser Pro Gln Asn Thr Gly 325 330 335 Gly Arg Gln Asp Ile Ser Tyr Asn Val Val Cys Lys Lys Cys Gly Ala 340 345 350 Gly Asp Pro Ser Lys Cys Arg Pro Cys Gly Ser Gly Val His Tyr Thr 355 360 365 Pro Gln Gln Asn Gly Leu Lys Thr Thr Lys Val Ser Ile Thr Asp Leu 370 375 380 Leu Ala His Thr Asn Tyr Thr Phe Glu Ile Trp Ala Val Asn Gly Val 385 390 395 400 Ser Lys Tyr Asn Pro Asn Pro Asp Gln Ser Val Ser Val Thr Val Thr 405 410 415 Thr Asn Gln Ala Ala Pro Ser Ser Ile Ala Leu Val Gln Ala Lys Glu 420 425 430 Val Thr Arg Tyr Ser Val Ala Leu Ala Trp Leu Glu Pro Asp Arg Pro 435 440 445 Asn Gly Val Ile Leu Glu Tyr Glu Val Lys Tyr Tyr Glu Lys Asp Gln 450 455 460 Asn Glu Arg Ser Tyr Arg Ile Val Arg Thr Ala Ala Arg Asn Thr Asp 465 470 475 480 Ile Lys Gly Leu Asn Pro Leu Thr Ser Tyr Val Phe His Val Arg Ala 485 490 495 Arg Thr Ala Ala Gly Tyr Gly Asp Phe Ser Glu Pro Leu Glu Val Thr 500 505 510 Thr Asn Thr Val Pro Ser Arg Ile Ile Gly Asp Gly Ala Asn Ser Thr 515 520 525 <![CDATA[<210> 7]]> <![CDATA[<211> 12]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> ad29S]]> <![CDATA[<400> 7]]> acatcactcc gt 12 <![CDATA[<210> 8]]> <![CDATA[<211> 50]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> ad29AS]]> <![CDATA[<400> 8]]> acggagtgat gtccgtcgac gtatctctgc gttgatactt cagcgtagct 50 <![CDATA[<210> 9]]> <![CDATA[<211> 26]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成引子]]> <![CDATA[<400> 9]]> agctacgctg aagtatcaac gcagag 26 <![CDATA[<210> 10]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成引子]]> <![CDATA[<400> 10]]> gccagtggat agactgatgg 20 <![CDATA[<210> 11]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成引子]]> <![CDATA[<400> 11]]> gatggataca gttggtgcag c 21 <![CDATA[<210> 12]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多肽]]> <![CDATA[<400> 12]]> Met Ala Val Leu Val Leu Leu Leu Cys Leu Val Thr Phe Pro Ser Cys 1 5 10 15 Val Leu Ser <![CDATA[<210> 13]]> <![CDATA[<211> 125]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多肽]]> <![CDATA[<400> 13]]> Gln Val Gln Leu Lys Gln Ser Gly Pro Ser Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Arg Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Met 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ala Asp Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Lys Glu Ser Leu Phe Gly Val Tyr Tyr Asp Tyr Gly Tyr Tyr Ser Met 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 14]]> <![CDATA[<211> 22]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多肽]]> <![CDATA[<400> 14]]> Met Asp Met Arg Val Pro Ala His Val Phe Gly Phe Leu Leu Leu Trp 1 5 10 15 Phe Pro Gly Thr Arg Cys 20 <![CDATA[<210> 15]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多肽]]> <![CDATA[<400> 15]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Glu Arg Val Ser Leu Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Leu Gln Gln Lys Pro Asp Gly Thr Ile Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Lys Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Glu Asp Phe Ala Asp Tyr Tyr Cys Leu Gln Tyr Ala Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <![CDATA[<210> 16]]> <![CDATA[<211> 57]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 16]]> atggctgtcc tggtgctgct cctctgcctg gtgacattcc caagctgtgt cctgtcc 57 <![CDATA[<210> 17]]> <![CDATA[<211> 375]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 17]]> caggtgcagc tgaagcagtc aggacctagc ctagtgcagc cctcacagag cctgtccata 60 acctgcacag tctctggttt ctcattaact aggtatggtg tacactgggt tcgccagtct 120 ccaggaaagg gtctggagtg gctgggagtg atttggagag gtggaagcac agactacaat 180 gcagctttca tgtccagact gagcatcacc aaggacaact ccaagagcca agttttcttt 240 aaaatgaaca gtctgcaagc tgatgacact gccatatact actgtgccaa agaaagccta 300 tttggggtct actatgatta cgggtactat tctatggact actggggtca aggaacctca 360 gtcaccgtct cctca 375 <![CDATA[<210> 18]]> <![CDATA[<211> 66]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 18]]> atggacatga gggttcctgc tcacgttttt ggcttcttgt tgctctggtt tccaggtacc 60 agatgt 66 <![CDATA[<210> 19]]> <![CDATA[<211> 321]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 19]]> gacatccaaa tgacccagtc tccatcctcc ttatctgcct ctctgggaga aagagtcagt 60 ctcacttgtc gggcaagtca ggaaattagt ggttacttaa gctggcttca gcagaaacca 120 gatggaacta ttaaacgcct gatctacgcc gcatccactt tagattctgg tgtcccaaaa 180 aggttcagtg gcagtaggtc tgggtcagat tattctctca ccatcagcag ccttgagtct 240 gaagattttg cagactatta ctgtctacaa tatgctagtt atccgctcac gttcggtgct 300 gggaccaagc tggagctgaa a 321 <![CDATA[<210> 20]]> <![CDATA[<211> 40]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成引子]]> <![CDATA[<400> 20]]> gcgaagcttg ccgccaccat ggctgtcctg gtgctgctcc 40 <![CDATA[<210> 21]]> <![CDATA[<211> 43]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成引子]]> <![CDATA[<400> 21]]> gcgaagcttg ccgccaccat ggacatgagg gttcctgctc acg 43 <![CDATA[<210> 22]]> <![CDATA[<211> 36]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成引子]]> <![CDATA[<400> 22]]> gcggaattca tcatttacca ggagagtggg agaggc 36 <![CDATA[<210> 23]]> <![CDATA[<211> 40]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成引子]]> <![CDATA[<400> 23]]> cgcgaattca ctaacactca ttcctgttga agctcttgac 40 <![CDATA[<210> 24]]> <![CDATA[<211> 324]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多肽]]> <![CDATA[<400> 24]]> Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala 1 5 10 15 Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu 50 55 60 Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val 65 70 75 80 Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys 85 90 95 Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro 100 105 110 Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu 115 120 125 Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser 130 135 140 Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu 145 150 155 160 Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr 165 170 175 Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn 180 185 190 Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro 195 200 205 Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln 210 215 220 Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val 225 230 235 240 Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val 245 250 255 Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln 260 265 270 Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn 275 280 285 Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val 290 295 300 Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His 305 310 315 320 Ser Pro Gly Lys <![CDATA[<210> 25]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多肽]]> <![CDATA[<400> 25]]> Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu 1 5 10 15 Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe 20 25 30 Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg 35 40 45 Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu 65 70 75 80 Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser 85 90 95 Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 100 105 <![CDATA[<210> 26]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 26]]> Arg Tyr Gly Val His 1 5 <![CDATA[<210> 27]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 27]]> Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Met Ser 1 5 10 15 <![CDATA[<210> 28]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 28]]> Glu Ser Leu Phe Gly Val Tyr Tyr Asp Tyr Gly Tyr Tyr Ser Met Asp 1 5 10 15 Tyr <![CDATA[<210> 29]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 29]]> Arg Ala Ser Gln Glu Ile Ser Gly Tyr Leu Ser 1 5 10 <![CDATA[<210> 30]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 30]]> Ala Ala Ser Thr Leu Asp Ser 1 5 <![CDATA[<210> 31]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 31]]> Leu Gln Tyr Ala Ser Tyr Pro Leu Thr 1 5 <![CDATA[<210> 32]]> <![CDATA[<211> 986]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 恆河獼猴]]> <![CDATA[<400> 32]]> Met Ala Gly Ile Phe Tyr Phe Ala Leu Phe Ser Cys Leu Phe Gly Ile 1 5 10 15 Cys Asp Ala Val Thr Gly Ser Arg Val Tyr Pro Ala Asn Glu Val Thr 20 25 30 Leu Leu Asp Ser Arg Ser Val Gln Gly Glu Leu Gly Trp Ile Ala Ser 35 40 45 Pro Leu Glu Gly Gly Trp Glu Glu Val Ser Ile Met Asp Glu Lys Asn 50 55 60 Thr Pro Ile Arg Thr Tyr Gln Val Cys Asn Val Met Glu Pro Ser Gln 65 70 75 80 Asn Asn Trp Leu Arg Thr Asp Trp Ile Thr Arg Glu Gly Ala Gln Arg 85 90 95 Val Tyr Ile Glu Ile Lys Phe Thr Leu Arg Asp Cys Asn Ser Leu Pro 100 105 110 Gly Val Met Gly Thr Cys Lys Glu Thr Phe Asn Leu Tyr Tyr Tyr Glu 115 120 125 Ser Asp Asn Asp Lys Glu Arg Phe Ile Arg Glu Asn Gln Phe Val Lys 130 135 140 Ile Asp Thr Ile Ala Ala Asp Glu Ser Phe Thr Gln Val Asp Ile Gly 145 150 155 160 Asp Arg Ile Met Lys Leu Asn Thr Glu Ile Arg Asp Val Gly Pro Leu 165 170 175 Ser Lys Lys Gly Phe Tyr Leu Ala Phe Gln Asp Val Gly Ala Cys Ile 180 185 190 Ala Leu Val Ser Val Arg Val Phe Tyr Lys Lys Cys Pro Leu Thr Val 195 200 205 Arg Asn Leu Ala Gln Phe Pro Asp Thr Ile Thr Gly Ala Asp Thr Ser 210 215 220 Ser Leu Val Glu Val Arg Gly Ser Cys Val Asn Asn Ser Glu Glu Lys 225 230 235 240 Asp Val Pro Lys Met Tyr Cys Gly Ala Asp Gly Glu Trp Leu Val Pro 245 250 255 Ile Gly Asn Cys Leu Cys Asn Ala Gly His Glu Glu Arg Ser Gly Glu 260 265 270 Cys Gln Ala Cys Lys Ile Gly Tyr Tyr Lys Ala Leu Ser Thr Asp Ala 275 280 285 Thr Cys Ala Lys Cys Pro Pro His Ser Tyr Ser Val Trp Glu Gly Ala 290 295 300 Thr Ser Cys Thr Cys Asp Arg Gly Phe Phe Arg Ala Asp Asn Asp Ala 305 310 315 320 Ala Ser Met Pro Cys Thr Arg Pro Pro Ser Ala Pro Leu Asn Leu Ile 325 330 335 Ser Asn Val Asn Glu Thr Ser Val Asn Leu Glu Trp Ser Ser Pro Gln 340 345 350 Asn Thr Gly Gly Arg Gln Asp Ile Ser Tyr Asn Val Val Cys Lys Lys 355 360 365 Cys Gly Ala Gly Asp Pro Ser Lys Cys Arg Pro Cys Gly Ser Gly Val 370 375 380 His Tyr Thr Pro Gln Gln Asn Gly Leu Lys Thr Thr Lys Val Ser Ile 385 390 395 400 Thr Asp Leu Leu Ala His Thr Asn Tyr Thr Phe Glu Ile Trp Ala Val 405 410 415 Asn Gly Val Ser Lys Tyr Asn Pro Ser Pro Asp Gln Ser Val Ser Val 420 425 430 Thr Val Thr Thr Asn Gln Ala Ala Pro Ser Ser Ile Ala Leu Val Gln 435 440 445 Ala Lys Glu Val Thr Arg Tyr Ser Val Ala Leu Ala Trp Leu Glu Pro 450 455 460 Asp Arg Pro Asn Gly Val Ile Leu Glu Tyr Glu Val Lys Tyr Tyr Glu 465 470 475 480 Lys Asp Gln Asn Glu Arg Ser Tyr Arg Ile Val Arg Thr Ala Ala Arg 485 490 495 Asn Thr Asp Ile Lys Gly Leu Asn Pro Leu Thr Ser Tyr Val Phe His 500 505 510 Val Arg Ala Arg Thr Ala Ala Gly Tyr Gly Asp Phe Ser Glu Pro Leu 515 520 525 Glu Val Thr Thr Asn Thr Val Pro Ser Arg Ile Ile Gly Asp Gly Ala 530 535 540 Asn Ser Thr Val Leu Leu Val Ser Val Ser Gly Ser Val Val Leu Val 545 550 555 560 Val Ile Leu Ile Ala Ala Phe Val Ile Ser Arg Arg Arg Ser Lys Tyr 565 570 575 Ser Lys Ala Lys Gln Glu Ala Asp Glu Glu Lys His Leu Asn Gln Gly 580 585 590 Val Arg Thr Tyr Val Asp Pro Phe Thr Tyr Glu Asp Pro Asn Gln Ala 595 600 605 Val Arg Glu Phe Ala Lys Glu Ile Asp Ala Ser Cys Ile Lys Ile Glu 610 615 620 Lys Val Ile Gly Val Gly Glu Phe Gly Glu Val Cys Ser Gly Arg Leu 625 630 635 640 Lys Val Pro Gly Lys Arg Glu Ile Cys Val Ala Ile Lys Thr Leu Lys 645 650 655 Ala Gly Tyr Thr Asp Lys Gln Arg Arg Asp Phe Leu Ser Glu Ala Ser 660 665 670 Ile Met Gly Gln Phe Asp His Pro Asn Ile Ile His Leu Glu Gly Val 675 680 685 Val Thr Lys Cys Lys Pro Val Met Ile Ile Thr Glu Tyr Met Glu Asn 690 695 700 Gly Ser Leu Asp Ala Phe Leu Arg Lys Asn Asp Gly Arg Phe Thr Val 705 710 715 720 Ile Gln Leu Val Gly Met Leu Arg Gly Ile Gly Ser Gly Met Lys Tyr 725 730 735 Leu Ser Asp Met Ser Tyr Val His Arg Asp Leu Ala Ala Arg Asn Ile 740 745 750 Leu Val Asn Ser Asn Leu Val Cys Lys Val Ser Asp Phe Gly Met Ser 755 760 765 Arg Val Leu Glu Asp Asp Pro Glu Ala Ala Tyr Thr Thr Arg Gly Gly 770 775 780 Lys Ile Pro Ile Arg Trp Thr Ala Pro Glu Ala Ile Ala Tyr Arg Lys 785 790 795 800 Phe Thr Ser Ala Ser Asp Val Trp Ser Tyr Gly Ile Val Met Trp Glu 805 810 815 Val Met Ser Tyr Gly Glu Arg Pro Tyr Trp Asp Met Ser Asn Gln Asp 820 825 830 Val Ile Lys Ala Ile Glu Glu Gly Tyr Arg Leu Pro Pro Pro Met Asp 835 840 845 Cys Pro Ile Ala Leu His Gln Leu Met Leu Asp Cys Trp Gln Lys Glu 850 855 860 Arg Ser Asp Arg Pro Lys Phe Gly Gln Ile Val Asn Met Leu Asp Lys 865 870 875 880 Leu Ile Arg Asn Pro Asn Ser Leu Lys Arg Thr Gly Thr Glu Ser Ser 885 890 895 Arg Pro Asn Thr Ala Leu Leu Asp Pro Ser Ser Pro Glu Phe Ser Ala 900 905 910 Val Val Ser Val Gly Asp Trp Leu Gln Ala Ile Lys Met Asp Arg Tyr 915 920 925 Lys Asp Asn Phe Thr Ala Ala Gly Tyr Thr Thr Leu Glu Ala Val Val 930 935 940 His Val Asn Gln Glu Asp Leu Ala Arg Ile Gly Ile Thr Ala Ile Thr 945 950 955 960 His Gln Asn Lys Ile Leu Ser Ser Val Gln Ala Met Arg Thr Gln Met 965 970 975 Gln Gln Met His Gly Arg Met Val Pro Val 980 985 <![CDATA[<210> 33]]> <![CDATA[<211> 528]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 恆河獼猴]]> <![CDATA[<400> 33]]> Val Thr Gly Ser Arg Val Tyr Pro Ala Asn Glu Val Thr Leu Leu Asp 1 5 10 15 Ser Arg Ser Val Gln Gly Glu Leu Gly Trp Ile Ala Ser Pro Leu Glu 20 25 30 Gly Gly Trp Glu Glu Val Ser Ile Met Asp Glu Lys Asn Thr Pro Ile 35 40 45 Arg Thr Tyr Gln Val Cys Asn Val Met Glu Pro Ser Gln Asn Asn Trp 50 55 60 Leu Arg Thr Asp Trp Ile Thr Arg Glu Gly Ala Gln Arg Val Tyr Ile 65 70 75 80 Glu Ile Lys Phe Thr Leu Arg Asp Cys Asn Ser Leu Pro Gly Val Met 85 90 95 Gly Thr Cys Lys Glu Thr Phe Asn Leu Tyr Tyr Tyr Glu Ser Asp Asn 100 105 110 Asp Lys Glu Arg Phe Ile Arg Glu Asn Gln Phe Val Lys Ile Asp Thr 115 120 125 Ile Ala Ala Asp Glu Ser Phe Thr Gln Val Asp Ile Gly Asp Arg Ile 130 135 140 Met Lys Leu Asn Thr Glu Ile Arg Asp Val Gly Pro Leu Ser Lys Lys 145 150 155 160 Gly Phe Tyr Leu Ala Phe Gln Asp Val Gly Ala Cys Ile Ala Leu Val 165 170 175 Ser Val Arg Val Phe Tyr Lys Lys Cys Pro Leu Thr Val Arg Asn Leu 180 185 190 Ala Gln Phe Pro Asp Thr Ile Thr Gly Ala Asp Thr Ser Ser Leu Val 195 200 205 Glu Val Arg Gly Ser Cys Val Asn Asn Ser Glu Glu Lys Asp Val Pro 210 215 220 Lys Met Tyr Cys Gly Ala Asp Gly Glu Trp Leu Val Pro Ile Gly Asn 225 230 235 240 Cys Leu Cys Asn Ala Gly His Glu Glu Arg Ser Gly Glu Cys Gln Ala 245 250 255 Cys Lys Ile Gly Tyr Tyr Lys Ala Leu Ser Thr Asp Ala Thr Cys Ala 260 265 270 Lys Cys Pro Pro His Ser Tyr Ser Val Trp Glu Gly Ala Thr Ser Cys 275 280 285 Thr Cys Asp Arg Gly Phe Phe Arg Ala Asp Asn Asp Ala Ala Ser Met 290 295 300 Pro Cys Thr Arg Pro Pro Ser Ala Pro Leu Asn Leu Ile Ser Asn Val 305 310 315 320 Asn Glu Thr Ser Val Asn Leu Glu Trp Ser Ser Pro Gln Asn Thr Gly 325 330 335 Gly Arg Gln Asp Ile Ser Tyr Asn Val Val Cys Lys Lys Cys Gly Ala 340 345 350 Gly Asp Pro Ser Lys Cys Arg Pro Cys Gly Ser Gly Val His Tyr Thr 355 360 365 Pro Gln Gln Asn Gly Leu Lys Thr Thr Lys Val Ser Ile Thr Asp Leu 370 375 380 Leu Ala His Thr Asn Tyr Thr Phe Glu Ile Trp Ala Val Asn Gly Val 385 390 395 400 Ser Lys Tyr Asn Pro Ser Pro Asp Gln Ser Val Ser Val Thr Val Thr 405 410 415 Thr Asn Gln Ala Ala Pro Ser Ser Ile Ala Leu Val Gln Ala Lys Glu 420 425 430 Val Thr Arg Tyr Ser Val Ala Leu Ala Trp Leu Glu Pro Asp Arg Pro 435 440 445 Asn Gly Val Ile Leu Glu Tyr Glu Val Lys Tyr Tyr Glu Lys Asp Gln 450 455 460 Asn Glu Arg Ser Tyr Arg Ile Val Arg Thr Ala Ala Arg Asn Thr Asp 465 470 475 480 Ile Lys Gly Leu Asn Pro Leu Thr Ser Tyr Val Phe His Val Arg Ala 485 490 495 Arg Thr Ala Ala Gly Tyr Gly Asp Phe Ser Glu Pro Leu Glu Val Thr 500 505 510 Thr Asn Thr Val Pro Ser Arg Ile Ile Gly Asp Gly Ala Asn Ser Thr 515 520 525 <![CDATA[<210> 34]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 34]]> Met Ala Gly Ile Phe Tyr Phe Ala Leu Phe Ser Cys Leu Phe Gly Ile 1 5 10 15 Cys Asp Ala <![CDATA[<210> 35]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 35]]> Met Ser Ala Leu Leu Ile Leu Ala Leu Val Gly Ala Ala Val Ala 1 5 10 15 <![CDATA[<210> 36]]> <![CDATA[<211> 547]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 36]]> Met Ala Gly Ile Phe Tyr Phe Ala Leu Phe Ser Cys Leu Phe Gly Ile 1 5 10 15 Cys Asp Ala Val Thr Gly Ser Arg Val Tyr Pro Ala Asn Glu Val Thr 20 25 30 Leu Leu Asp Ser Arg Ser Val Gln Gly Glu Leu Gly Trp Ile Ala Ser 35 40 45 Pro Leu Glu Gly Gly Trp Glu Glu Val Ser Ile Met Asp Glu Lys Asn 50 55 60 Thr Pro Ile Arg Thr Tyr Gln Val Cys Asn Val Met Glu Pro Ser Gln 65 70 75 80 Asn Asn Trp Leu Arg Thr Asp Trp Ile Thr Arg Glu Gly Ala Gln Arg 85 90 95 Val Tyr Ile Glu Ile Lys Phe Thr Leu Arg Asp Cys Asn Ser Leu Pro 100 105 110 Gly Val Met Gly Thr Cys Lys Glu Thr Phe Asn Leu Tyr Tyr Tyr Glu 115 120 125 Ser Asp Asn Asp Lys Glu Arg Phe Ile Arg Glu Asn Gln Phe Val Lys 130 135 140 Ile Asp Thr Ile Ala Ala Asp Glu Ser Phe Thr Gln Val Asp Ile Gly 145 150 155 160 Asp Arg Ile Met Lys Leu Asn Thr Glu Ile Arg Asp Val Gly Pro Leu 165 170 175 Ser Lys Lys Gly Phe Tyr Leu Ala Phe Gln Asp Val Gly Ala Cys Ile 180 185 190 Ala Leu Val Ser Val Arg Val Phe Tyr Lys Lys Cys Pro Leu Thr Val 195 200 205 Arg Asn Leu Ala Gln Phe Pro Asp Thr Ile Thr Gly Ala Asp Thr Ser 210 215 220 Ser Leu Val Glu Val Arg Gly Ser Cys Val Asn Asn Ser Glu Glu Lys 225 230 235 240 Asp Val Pro Lys Met Tyr Cys Gly Ala Asp Gly Glu Trp Leu Val Pro 245 250 255 Ile Gly Asn Cys Leu Cys Asn Ala Gly His Glu Glu Arg Ser Gly Glu 260 265 270 Cys Gln Ala Cys Lys Ile Gly Tyr Tyr Lys Ala Leu Ser Thr Asp Ala 275 280 285 Thr Cys Ala Lys Cys Pro Pro His Ser Tyr Ser Val Trp Glu Gly Ala 290 295 300 Thr Ser Cys Thr Cys Asp Arg Gly Phe Phe Arg Ala Asp Asn Asp Ala 305 310 315 320 Ala Ser Met Pro Cys Thr Arg Pro Pro Ser Ala Pro Leu Asn Leu Ile 325 330 335 Ser Asn Val Asn Glu Thr Ser Val Asn Leu Glu Trp Ser Ser Pro Gln 340 345 350 Asn Thr Gly Gly Arg Gln Asp Ile Ser Tyr Asn Val Val Cys Lys Lys 355 360 365 Cys Gly Ala Gly Asp Pro Ser Lys Cys Arg Pro Cys Gly Ser Gly Val 370 375 380 His Tyr Thr Pro Gln Gln Asn Gly Leu Lys Thr Thr Lys Val Ser Ile 385 390 395 400 Thr Asp Leu Leu Ala His Thr Asn Tyr Thr Phe Glu Ile Trp Ala Val 405 410 415 Asn Gly Val Ser Lys Tyr Asn Pro Asn Pro Asp Gln Ser Val Ser Val 420 425 430 Thr Val Thr Thr Asn Gln Ala Ala Pro Ser Ser Ile Ala Leu Val Gln 435 440 445 Ala Lys Glu Val Thr Arg Tyr Ser Val Ala Leu Ala Trp Leu Glu Pro 450 455 460 Asp Arg Pro Asn Gly Val Ile Leu Glu Tyr Glu Val Lys Tyr Tyr Glu 465 470 475 480 Lys Asp Gln Asn Glu Arg Ser Tyr Arg Ile Val Arg Thr Ala Ala Arg 485 490 495 Asn Thr Asp Ile Lys Gly Leu Asn Pro Leu Thr Ser Tyr Val Phe His 500 505 510 Val Arg Ala Arg Thr Ala Ala Gly Tyr Gly Asp Phe Ser Glu Pro Leu 515 520 525 Glu Val Thr Thr Asn Thr Val Pro Ser Arg Ile Ile Gly Asp Gly Ala 530 535 540 Asn Ser Thr 545 <![CDATA[<210> 37]]> <![CDATA[<211> 328]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 37]]> Met Ala Gly Ile Phe Tyr Phe Ala Leu Phe Ser Cys Leu Phe Gly Ile 1 5 10 15 Cys Asp Ala Val Thr Gly Ser Arg Val Tyr Pro Ala Asn Glu Val Thr 20 25 30 Leu Leu Asp Ser Arg Ser Val Gln Gly Glu Leu Gly Trp Ile Ala Ser 35 40 45 Pro Leu Glu Gly Gly Trp Glu Glu Val Ser Ile Met Asp Glu Lys Asn 50 55 60 Thr Pro Ile Arg Thr Tyr Gln Val Cys Asn Val Met Glu Pro Ser Gln 65 70 75 80 Asn Asn Trp Leu Arg Thr Asp Trp Ile Thr Arg Glu Gly Ala Gln Arg 85 90 95 Val Tyr Ile Glu Ile Lys Phe Thr Leu Arg Asp Cys Asn Ser Leu Pro 100 105 110 Gly Val Met Gly Thr Cys Lys Glu Thr Phe Asn Leu Tyr Tyr Tyr Glu 115 120 125 Ser Asp Asn Asp Lys Glu Arg Phe Ile Arg Glu Asn Gln Phe Val Lys 130 135 140 Ile Asp Thr Ile Ala Ala Asp Glu Ser Phe Thr Gln Val Asp Ile Gly 145 150 155 160 Asp Arg Ile Met Lys Leu Asn Thr Glu Ile Arg Asp Val Gly Pro Leu 165 170 175 Ser Lys Lys Gly Phe Tyr Leu Ala Phe Gln Asp Val Gly Ala Cys Ile 180 185 190 Ala Leu Val Ser Val Arg Val Phe Tyr Lys Lys Cys Pro Leu Thr Val 195 200 205 Arg Asn Leu Ala Gln Phe Pro Asp Thr Ile Thr Gly Ala Asp Thr Ser 210 215 220 Ser Leu Val Glu Val Arg Gly Ser Cys Val Asn Asn Ser Glu Glu Lys 225 230 235 240 Asp Val Pro Lys Met Tyr Cys Gly Ala Asp Gly Glu Trp Leu Val Pro 245 250 255 Ile Gly Asn Cys Leu Cys Asn Ala Gly His Glu Glu Arg Ser Gly Glu 260 265 270 Cys Gln Ala Cys Lys Ile Gly Tyr Tyr Lys Ala Leu Ser Thr Asp Ala 275 280 285 Thr Cys Ala Lys Cys Pro Pro His Ser Tyr Ser Val Trp Glu Gly Ala 290 295 300 Thr Ser Cys Thr Cys Asp Arg Gly Phe Phe Arg Ala Asp Asn Asp Ala 305 310 315 320 Ala Ser Met Pro Cys Thr Arg Pro 325 <![CDATA[<210> 38]]> <![CDATA[<211> 236]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 38]]> Pro Leu Thr Val Arg Asn Leu Ala Gln Phe Pro Asp Thr Ile Thr Gly 1 5 10 15 Ala Asp Thr Ser Ser Leu Val Glu Val Arg Gly Ser Cys Val Asn Asn 20 25 30 Ser Glu Glu Lys Asp Val Pro Lys Met Tyr Cys Gly Ala Asp Gly Glu 35 40 45 Trp Leu Val Pro Ile Gly Asn Cys Leu Cys Asn Ala Gly His Glu Glu 50 55 60 Arg Ser Gly Glu Cys Gln Ala Cys Lys Ile Gly Tyr Tyr Lys Ala Leu 65 70 75 80 Ser Thr Asp Ala Thr Cys Ala Lys Cys Pro Pro His Ser Tyr Ser Val 85 90 95 Trp Glu Gly Ala Thr Ser Cys Thr Cys Asp Arg Gly Phe Phe Arg Ala 100 105 110 Asp Asn Asp Ala Ala Ser Met Pro Cys Thr Arg Pro Pro Ser Ala Pro 115 120 125 Leu Asn Leu Ile Ser Asn Val Asn Glu Thr Ser Val Asn Leu Glu Trp 130 135 140 Ser Ser Pro Gln Asn Thr Gly Gly Arg Gln Asp Ile Ser Tyr Asn Val 145 150 155 160 Val Cys Lys Lys Cys Gly Ala Gly Asp Pro Ser Lys Cys Arg Pro Cys 165 170 175 Gly Ser Gly Val His Tyr Thr Pro Gln Gln Asn Gly Leu Lys Thr Thr 180 185 190 Lys Val Ser Ile Thr Asp Leu Leu Ala His Thr Asn Tyr Thr Phe Glu 195 200 205 Ile Trp Ala Val Asn Gly Val Ser Lys Tyr Asn Pro Asn Pro Asp Gln 210 215 220 Ser Val Ser Val Thr Val Thr Thr Asn Gln Ala Ala 225 230 235 <![CDATA[<210> 39]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 39]]> Thr Asn Gln Ala Ala Pro Ser Ser Ile Ala Leu Val Gln Ala Lys Glu 1 5 10 15 Val Thr Arg Tyr Ser Val Ala Leu Ala Trp Leu Glu Pro Asp Arg Pro 20 25 30 Asn Gly Val Ile Leu Glu Tyr Glu Val Lys Tyr Tyr Glu Lys Asp Gln 35 40 45 Asn Glu Arg Ser Tyr Arg Ile Val Arg Thr Ala Ala Arg Asn Thr Asp 50 55 60 Ile Lys Gly Leu Asn Pro Leu Thr Ser Tyr Val Phe His Val Arg Ala 65 70 75 80 Arg Thr Ala Ala Gly Tyr Gly Asp Phe Ser Glu Pro Leu Glu Val Thr 85 90 95 Thr Asn Thr Val Pro Ser Arg Ile Ile Gly Asp Gly Ala Asn Ser Thr 100 105 110 <![CDATA[<210> 40]]> <![CDATA[<211> 96]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多肽]]> <![CDATA[<400> 40]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Pro 85 90 95 <![CDATA[<210> 41]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多肽]]> <![CDATA[<400> 41]]> Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 1 5 10 <![CDATA[<210> 42]]> <![CDATA[<211> 98]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多肽]]> <![CDATA[<400> 42]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys <![CDATA[<210> 43]]> <![CDATA[<211> 18]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多肽]]> <![CDATA[<400> 43]]> Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr 1 5 10 15 Val Ser <![CDATA[<210> 44]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多肽]]> <![CDATA[<400> 44]]> Arg Phe Gly Val His 1 5 <![CDATA[<210> 45]]> <![CDATA[<211> 125]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多肽]]> <![CDATA[<400> 45]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Thr Arg Phe 20 25 30 Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Met 50 55 60 Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Lys Glu Ser Leu Phe Gly Val Tyr Tyr Asp Tyr Gly Tyr Tyr Ser Met 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 46]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多肽]]> <![CDATA[<400> 46]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Leu Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 47]]> <![CDATA[<211> 326]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 47]]> Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Thr Val Glu Arg Lys Ser Cys Val Glu Cys Pro Pro Cys Pro Ala Pro 100 105 110 Pro Ala Ala Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120 125 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 130 135 140 Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 145 150 155 160 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 165 170 175 Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp 180 185 190 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 195 200 205 Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu 210 215 220 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 245 250 255 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 260 265 270 Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 275 280 285 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 290 295 300 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 305 310 315 320 Ser Leu Ser Pro Gly Lys 325 <![CDATA[<210> 48]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 48]]> Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <![CDATA[<210> 49]]> <![CDATA[<211> 15]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 49]]> agatttggag tgcat 15 <![CDATA[<210> 50]]> <![CDATA[<211> 48]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 50]]> gtgatctgga ggggaggatc caccgactac aacgctgctt ttatgagc 48 <![CDATA[<210> 51]]> <![CDATA[<211> 51]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 51]]> gagagcctgt tcggcgtgta ctatgactac ggctactatt ctatggatta t 51 <![CDATA[<210> 52]]> <![CDATA[<211> 33]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 52]]> cgcgcctccc aggagatctc tggctacctg tcc 33 <![CDATA[<210> 53]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 53]]> gctgcctcca ccctggactc t 21 <![CDATA[<210> 54]]> <![CDATA[<211> 27]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 54]]> ctgcagtacg cttcctatcc actgacc 27 <![CDATA[<210> 55]]> <![CDATA[<211> 375]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 55]]> caggtgcagc tggtggagag cggaggagga gtggtgcagc ctggcaggtc cctgaggctg 60 agctgtgccg tgtccggctt cagcctgaca agatttggag tgcattgggt gcgccaggct 120 ccaggcaagg gactggagtg ggtggccgtg atctggaggg gaggatccac cgactacaac 180 gctgctttta tgagccggct gacaatctct aaggataact ccaagaatac cgtgtatctg 240 cagatgaact ccctgagggc tgaggacacc gccgtgtact attgcgccaa ggagagcctg 300 ttcggcgtgt actatgacta cggctactat tctatggatt attggggcca gggcaccaca 360 gtgacagtgt cctcc 375 <![CDATA[<210> 56]]> <![CDATA[<211> 321]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 56]]> gatatccaga tgacacagtc cccttccagc ctgtctgcct ccgtgggcga cagagtgacc 60 atcacatgtc gcgcctccca ggagatctct ggctacctgt cctggctgca gcagaagcca 120 ggcaaggctc ccaagcgcct gatctatgct gcctccaccc tggactctgg agtgccttcc 180 aggttcagcg gctctcggtc cggcacagag tacaccctga caatctcttc cctgcagcct 240 gaggatttcg ccacctacta ttgcctgcag tacgcttcct atccactgac ctttggcggc 300 ggcacaaagg tggagatcaa g 321 <![CDATA[<210> 57]]> <![CDATA[<211> 978]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 57]]> gcctccacca agggaccatc cgtgttccca ctggccccat cttcccggag cacatctgag 60 tccaccgccg ctctgggctg tctggtgaag gattacttcc ctgagccagt gacagtgtct 120 tggaactccg gcgctctgac atccggcgtg cacacctttc ctgccgtgct gcagagctct 180 ggcctgtaca gcctgtccag cgtggtgacc gtgccctctt ccaatttcgg cacccagaca 240 tatacctgca acgtggacca taagccttcc aatacaaagg tggataagac cgtggagaga 300 aagagctgcg tggagtgtcc accttgccca gctccaccag ccgctgcccc tagcgtgttc 360 ctgtttcctc caaagccaaa ggacacactg atgatctctc gcacacccga ggtgacctgc 420 gtggtggtgg acgtgtccca cgaggatcca gaggtgcagt ttaactggta cgtggatggc 480 gtggaggtgc ataatgctaa gaccaagccc agggaggagc agttcaactc cacatttcgg 540 gtggtgagcg tgctgaccgt ggtgcaccag gactggctga acggcaagga gtataagtgt 600 aaggtgagca ataagggcct gcccgcccct atcgagaaga caatctctaa gaccaagggc 660 cagcctagag agccacaggt gtacaccctg cccccttctc gcgaggagat gacaaagaac 720 caggtgtccc tgacctgcct ggtgaagggc ttctatccta gcgacatcgc tgtggagtgg 780 gagtctaatg gccagccaga gaacaattac aagaccacac cacccatgct ggacagcgat 840 ggctctttct ttctgtattc taagctgaca gtggataagt ccaggtggca gcagggcaac 900 gtgtttagct gctctgtgat gcatgaggcc ctgcacaatc attacaccca gaagtccctg 960 agcctgtctc caggcaag 978 <![CDATA[<210> 58]]> <![CDATA[<211> 321]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 58]]> aggacagtgg ccgctccatc cgtgttcatc tttcccccta gcgacgagca gctgaagagc 60 ggcaccgcct ctgtggtgtg cctgctgaac aatttctacc ccagggaggc caaggtgcag 120 tggaaggtgg ataacgctct gcagagcggc aattctcagg agtccgtgac cgagcaggac 180 agcaaggatt ctacatattc cctgagctct accctgacac tgagcaaggc cgattacgag 240 aagcacaagg tgtatgcttg cgaggtgacc catcagggcc tgtccagccc agtgacaaag 300 tcttttaaca ggggcgagtg t 321 <![CDATA[<210> 59]]> <![CDATA[<211> 451]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多肽]]> <![CDATA[<400> 59]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Thr Arg Phe 20 25 30 Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Met 50 55 60 Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Lys Glu Ser Leu Phe Gly Val Tyr Tyr Asp Tyr Gly Tyr Tyr Ser Met 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Arg Ser Thr Ser 130 135 140 Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys 195 200 205 Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu 210 215 220 Arg Lys Ser Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Ala Ala 225 230 235 240 Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe 290 295 300 Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <![CDATA[<210> 60]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多肽]]> <![CDATA[<400> 60]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Leu Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[<210> 61]]> <![CDATA[<211> 1353]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 61]]> caggtgcagc tggtggagag cggaggagga gtggtgcagc ctggcaggtc cctgaggctg 60 agctgtgccg tgtccggctt cagcctgaca agatttggag tgcattgggt gcgccaggct 120 ccaggcaagg gactggagtg ggtggccgtg atctggaggg gaggatccac cgactacaac 180 gctgctttta tgagccggct gacaatctct aaggataact ccaagaatac cgtgtatctg 240 cagatgaact ccctgagggc tgaggacacc gccgtgtact attgcgccaa ggagagcctg 300 ttcggcgtgt actatgacta cggctactat tctatggatt attggggcca gggcaccaca 360 gtgacagtgt cctccgcctc caccaaggga ccatccgtgt tcccactggc cccatcttcc 420 cggagcacat ctgagtccac cgccgctctg ggctgtctgg tgaaggatta cttccctgag 480 ccagtgacag tgtcttggaa ctccggcgct ctgacatccg gcgtgcacac ctttcctgcc 540 gtgctgcaga gctctggcct gtacagcctg tccagcgtgg tgaccgtgcc ctcttccaat 600 ttcggcaccc agacatatac ctgcaacgtg gaccataagc cttccaatac aaaggtggat 660 aagaccgtgg agagaaagag ctgcgtggag tgtccacctt gcccagctcc accagccgct 720 gcccctagcg tgttcctgtt tcctccaaag ccaaaggaca cactgatgat ctctcgcaca 780 cccgaggtga cctgcgtggt ggtggacgtg tcccacgagg atccagaggt gcagtttaac 840 tggtacgtgg atggcgtgga ggtgcataat gctaagacca agcccaggga ggagcagttc 900 aactccacat ttcgggtggt gagcgtgctg accgtggtgc accaggactg gctgaacggc 960 aaggagtata agtgtaaggt gagcaataag ggcctgcccg cccctatcga gaagacaatc 1020 tctaagacca agggccagcc tagagagcca caggtgtaca ccctgccccc ttctcgcgag 1080 gagatgacaa agaaccaggt gtccctgacc tgcctggtga agggcttcta tcctagcgac 1140 atcgctgtgg agtgggagtc taatggccag ccagagaaca attacaagac cacaccaccc 1200 atgctggaca gcgatggctc tttctttctg tattctaagc tgacagtgga taagtccagg 1260 tggcagcagg gcaacgtgtt tagctgctct gtgatgcatg aggccctgca caatcattac 1320 acccagaagt ccctgagcct gtctccaggc aag 1353 <![CDATA[<210> 62]]> <![CDATA[<211> 642]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 62]]> gatatccaga tgacacagtc cccttccagc ctgtctgcct ccgtgggcga cagagtgacc 60 atcacatgtc gcgcctccca ggagatctct ggctacctgt cctggctgca gcagaagcca 120 ggcaaggctc ccaagcgcct gatctatgct gcctccaccc tggactctgg agtgccttcc 180 aggttcagcg gctctcggtc cggcacagag tacaccctga caatctcttc cctgcagcct 240 gaggatttcg ccacctacta ttgcctgcag tacgcttcct atccactgac ctttggcggc 300 ggcacaaagg tggagatcaa gaggacagtg gccgctccat ccgtgttcat ctttccccct 360 agcgacgagc agctgaagag cggcaccgcc tctgtggtgt gcctgctgaa caatttctac 420 cccagggagg ccaaggtgca gtggaaggtg gataacgctc tgcagagcgg caattctcag 480 gagtccgtga ccgagcagga cagcaaggat tctacatatt ccctgagctc taccctgaca 540 ctgagcaagg ccgattacga gaagcacaag gtgtatgctt gcgaggtgac ccatcagggc 600 ctgtccagcc cagtgacaaa gtcttttaac aggggcgagt gt 642 <![CDATA[<210> 63]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 63]]> catcagccct aatccatctg a 21 <![CDATA[<210> 64]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 64]]> cgcgactaac aatcaaagtg a 21 <![CDATA[<210> 65]]> <![CDATA[<211> 24]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 65]]> ctaggccaca gaattgaaag atct 24 <![CDATA[<210> 66]]> <![CDATA[<211> 25]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成多核苷酸]]> <![CDATA[<400> 66]]> gtaggtggaa attctagcat catcc 25
Claims (15)
- 一種醫藥組合物,其係包含抗EphA4抗體之用以治療肌肉萎縮性側索硬化症(ALS)者, 上述抗EphA4抗體包含重鏈及輕鏈,上述重鏈包括: (a)由序列編號44所示之胺基酸序列所組成之重鏈CDR1; (b)由序列編號27所示之胺基酸序列所組成之重鏈CDR2;及 (c)由序列編號28所示之胺基酸序列所組成之重鏈CDR3; 上述輕鏈包括: (d)由序列編號29所示之胺基酸序列所組成之輕鏈CDR1; (e)由序列編號30所示之胺基酸序列所組成之輕鏈CDR2;及 (f)由序列編號31所示之胺基酸序列所組成之輕鏈CDR3。
- 如請求項1之醫藥組合物,其中 上述抗EphA4抗體被人源化。
- 如請求項1或2之醫藥組合物,其中 上述抗EphA4抗體與EphA4特異性地結合,促進EphA4之切斷。
- 如請求項1或2之醫藥組合物,其中 上述抗EphA4抗體與EphA4特異性地結合,抑制EphA4與肝配蛋白(ephrin)之結合。
- 如請求項1或2之醫藥組合物,其中 上述重鏈包括:由序列編號45所示之胺基酸序列所組成之可變區, 上述輕鏈包括:由序列編號46所示之胺基酸序列所組成之可變區。
- 如請求項1或2之醫藥組合物,其中 上述重鏈之恆定區及上述輕鏈之恆定區包含源自人類抗體之胺基酸序列。
- 如請求項6之醫藥組合物,其中 上述重鏈之恆定區為人類IgG之恆定區。
- 如請求項7之醫藥組合物,其中 上述人類IgG之恆定區為人類IgG 2之恆定區。
- 如請求項8之醫藥組合物,其中 上述人類IgG 2之恆定區包含序列編號47所示之胺基酸序列。
- 如請求項6之醫藥組合物,其中 上述輕鏈之恆定區為人類Igκ之恆定區。
- 如請求項10之醫藥組合物,其中 上述人類Igκ之恆定區包含序列編號48所示之胺基酸序列。
- 一種醫藥組合物,其係包含抗EphA4抗體之用以治療肌肉萎縮性側索硬化症(ALS)者, 上述抗EphA4抗體包含重鏈及輕鏈, 上述重鏈包含序列編號59所示之胺基酸序列, 上述輕鏈包含序列編號60所示之胺基酸序列, 上述重鏈之C末端離胺酸可缺失。
- 如請求項12之醫藥組合物,其中 上述重鏈之C末端離胺酸缺失。
- 一種抗EphA4抗體之用途,其係用於製造肌肉萎縮性側索硬化症(ALS)治療用之醫藥組合物, 上述抗EphA4抗體包含重鏈及輕鏈,上述重鏈包括: (a)由序列編號44所示之胺基酸序列所組成之重鏈CDR1; (b)由序列編號27所示之胺基酸序列所組成之重鏈CDR2;及 (c)由序列編號28所示之胺基酸序列所組成之重鏈CDR3; 上述輕鏈包括: (d)由序列編號29所示之胺基酸序列所組成之輕鏈CDR1; (e)由序列編號30所示之胺基酸序列所組成之輕鏈CDR2;及 (f)由序列編號31所示之胺基酸序列所組成之輕鏈CDR3。
- 如請求項14之抗EphA4抗體之用途,其中 上述重鏈包括:由序列編號45所示之胺基酸序列所組成之可變區, 上述輕鏈包括:由序列編號46所示之胺基酸序列所組成之可變區。
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US (1) | US20240010735A1 (zh) |
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ATE546543T1 (de) * | 2007-06-08 | 2012-03-15 | Eisai R&D Man Co Ltd | Screening-verfahren mit verwendung des neuen substrats epha4 für gamma-sekretase |
EP2031064A1 (de) | 2007-08-29 | 2009-03-04 | Boehringer Ingelheim Pharma GmbH & Co. KG | Verfahren zur Steigerung von Proteintitern |
JP6059017B2 (ja) * | 2010-12-17 | 2017-01-11 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | ゼラチナーゼによるEphA4の切断反応を指標としたスクリーニング方法 |
GB201107996D0 (en) | 2011-05-13 | 2011-06-29 | Vib Vzw | EphA4 is a diease modifier in motor neuron disease |
ES2925224T3 (es) | 2014-07-31 | 2022-10-14 | Us Gov Health & Human Services | Anticuerpos monoclonales humanos contra EphA4 y su uso |
US10428140B2 (en) | 2015-09-08 | 2019-10-01 | Eisai R&D Management Co., Ltd. | Anti-EphA4 antibody |
SG11202112433VA (en) * | 2019-07-01 | 2021-12-30 | Eisai R&D Man Co Ltd | ANTI-EphA4 ANTIBODY |
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KR20230124547A (ko) | 2023-08-25 |
CA3195085A1 (en) | 2022-06-30 |
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CN116710133A (zh) | 2023-09-05 |
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