TWI733685B - 靶向il-23a與b細胞活化因子(baff)之化合物及其用途 - Google Patents

靶向il-23a與b細胞活化因子(baff)之化合物及其用途 Download PDF

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TWI733685B
TWI733685B TW105123026A TW105123026A TWI733685B TW I733685 B TWI733685 B TW I733685B TW 105123026 A TW105123026 A TW 105123026A TW 105123026 A TW105123026 A TW 105123026A TW I733685 B TWI733685 B TW I733685B
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珊加雅 辛
潘琦
里查瑞貝卡 貝瑞特
雷斯里Ｓ 強森
潘卡吉 朱皮塔
莎拉 羅
海霞 吳
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德商包林格因蓋爾漢國際股份有限公司
美商總體遺傳因子公司
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Abstract

本揭示案係關於特異於IL23A及BAFF的化合物、包含此等化合物的組合物及其使用方法。亦揭示與此等化合物及組合物相關的核酸、細胞及產生方法。

Description

靶向IL-23A與B細胞活化因子(BAFF)之化合物及其用途
本發明係關於靶向IL-23A與B細胞活化因子(B-cell activating factor; BAFF)之化合物及其用途。
發炎涉及到對抗感染所需的先天及適應性免疫反應。然而，當發炎成為未加遏制的自體免疫疾病或自體炎性疾病時，可發展成神經退化性疾病且甚至癌症。眾所周知，諸如IL1、BAFF、TNF-α、IL6、IL12、IL17、IL18及IL23之促炎性細胞介素參與發炎及活化免疫細胞的特定路徑。然而，尚不清楚抑制此等細胞介素中的一者或更多者是否或如何可導致治療自體免疫疾病或自體炎性疾病。
介白素23(IL23)係一種由兩個亞單位p40與p19組成的異源二聚體細胞介素。p19亞單位亦稱為IL-23A。儘管p19亞單位為IL23獨有的，但p40亞單位與細胞介素IL12共享。IL23正在成為病原性Th17、γδT及先天淋巴樣細胞(innate lymphoid cell; ILC)的關鍵調節因子，此三種細胞驅使導致局部組織發炎及損傷的IL17、IL22及其他細胞介素的產生。IL23促進基質金屬蛋白酶MMP9的上調，增加血管生成，減少CD8+T細胞浸潤，並且牽連癌性腫瘤的發展。另外，結合IL6及TGFP1，IL23刺激初始CD4+T細胞(naive CD4+ T cell)分化成Th17細胞。接著，Th17細胞又產生IL17，IL17係一種促炎性細胞介素，其增強T細胞引動並刺激諸如IL1、IL6、TNF-α、NOS-2之促炎性細胞介素的產生，並且亦誘發導致發炎及發病機制的趨化介素之表現。IL23經由細胞表面受體發揮其作用，此細胞表面受體由與獨有IL23R亞單位搭檔的IL12受體之IL12β1亞單位構成。IL23R之表現受限於特定免疫細胞群，並且主要在T細胞之亞群（αβ與γδ TCR+）及NK細胞上被發現。
在小鼠中，IL23p19基因的基因切除導致IL23功能的選擇性喪失，伴隨著嚴重損害的T依賴性免疫反應，包括抗原特異性免疫球蛋白的產生減少及受損的遲發型超敏反應（Ghilardi N等人，(2004) J. Immunol. 172 (5): 2827-33）。在多發性硬化症、關節炎及炎性腸病之動物模型中，缺少IL23p40或IL23p19任一者或者缺少IL23受體之任一亞單位（IL23R與IL12p1）的基因敲除小鼠發展出不太嚴重的症狀。在EAE中使用特異於IL23p19的抗體已經獲得了類似結果，並且T細胞介導的結腸炎模型進一步證實了IL23在此等疾病設定中的作用（Chen Y.等人，(2006) J. Clin. Invet. 116(5):1317-26；Elson CO.等人，(2007) Gastroenterology 132(7): 2359-70）。此凸顯了IL23在慢性發炎中的重要性（Langowski等人，(2006) Nature 442 (7101): 461-5；Kikly K等人，(2006) Curr. Opin. Immunol. 18 (6): 670-5）。另外，提高的IL23產量已暗示了IL23是炎性關節炎及炎性自體免疫疾病中的主要因素（Adamopoulos等人，(2011) J. Immunol. 187: 593-594；及Langris等人，(2005) J. Exp. Med. 201:233-240）。已在過度表現IL23的小鼠模型系統中公開了IL23、其下游細胞介素IL22與骨形成之間的關聯（Sherlock等人，(2012) Nat. Med. 18: 1069-76）。
B細胞活化因子(B-cell activating factor; BAFF)係一種細胞介素，其屬於腫瘤壞死因子(tumor necrosis factor; TNF)配體超家族，並充當受體BAFF-R (BR3)、TACI（transmembrane activator and calcium modulator and cyclophilin ligand interactor；跨膜活化子與鈣調節子及親環素配體相互作用因子）及BCMA（B-cell maturation antigen；B細胞成熟抗原）的配體。BAFF與其受體之間的相互作用觸發對於形成並維持B細胞所必需的信號，此隨後又回應於外來物質入侵合成免疫球蛋白。患者體內的適當BAFF水平幫助維持正常免疫水平，而水平不足可導致免疫缺陷，且水平過量可導致異常高的抗體產量。當患者展示出自體免疫性時，其產生對抗自己身體之組織或器官的抗體。包括紅斑狼瘡及類風濕性關節炎的自體免疫疾病源自體內過量的BAFF水平。因此，重要的是調變BAFF之產生以便治療患有此等疾病的患者。
BAFF可以三種形式存在：膜結合(mbBAFF)、可溶性三聚體BAFF (sBAFF)及由60個BAFF單體(BAFF 60mer)組成的多聚體形式。尚未很好地理解正常與疾病生理學中各種形式之BAFF的相對重要性。如所指出的，BAFF結合至三種受體，BAFFR (BR3)、TACI及BCMA。增殖誘導配體(APRIL)係TNF受體配體家族中的一個相關成員，已展示出與TACI及BCMA的高親和性結合。與高親和性APRIL:BCMA相互作用相比，BAFF:BCMA相互作用具有低親和性(1-2μM)，並且據信在體內並未發揮重要作用（Bossen及Schneider，2006）。
在患有全身性紅斑狼瘡(systemic lupus erythematosus; SLE)的個體中及在發炎靶器官（諸如腎臟）中以高水平表現可溶性BAFF。可溶性BAFF充當B細胞穩態及存活的關鍵因素（Kalled等人，2005；Mackay等人，2003；Smith及Cancro，2003；Patke等人，2004）。藉由BAFF依賴性B細胞的自體抗體形成導致腎小球IC沉積，最初在近端小管上皮細胞(proximal tubular epithelial cell; PTEC)內的腎小球基底膜(glomerular basement membrane; GBM)、腎小球系膜及間質組織處。此等IC沉積導致補體固定及嗜中性白血球活化，從而造成局部腎臟損害。由受損腎細胞（MC、PTEC、腎成纖維細胞、內皮細胞）產生的發炎介體（例如，IL6、IL8、MCP-1）藉由增加免疫細胞浸潤（例如，B細胞、T細胞、樹突狀細胞、嗜中性白血球及巨噬細胞）加劇發炎週期。
抗BAFF單株抗體貝利木單抗(belimumab) (Benlysta® )已論證了減少自體抗體形成的能力，並已對患有全身性紅斑狼瘡(SLE)的患者提供了顯著益處。然而，貝利木單抗在SLE患者中的功效最多是適中的，並且存在相當大的改良餘地（Furie等人，2011）。因此，仍需要具有增加功效的新組合物用於治療及預防自體免疫疾病或炎性疾病。此外，對更有效治療的鑑別應允許減小劑量的投藥，以及降低與治療關聯的成本。
本文提供對特異於BAFF及IL23A的化合物、包含此類化合物的組合物以及此等化合物、組合物之使用及產生之方法。
本揭示案之態樣係關於一種包含第一多肽及第二多肽的化合物，其中： (A)  該第一多肽包含： (i)  特異於第一靶蛋白的第一免疫球蛋白(VL1)之輕鏈可變域； (ii) 特異於第二靶蛋白的第二免疫球蛋白(VH2)之重鏈可變域；以及 (iii) 鉸鏈區、重鏈恆定區2(CH2)及重鏈恆定區3 (CH3)；以及 (B)  該第二多肽包含： (i)  特異於該第二靶蛋白的第二免疫球蛋白(VL2)之輕鏈可變域； (ii) 特異於該第一靶蛋白的第一免疫球蛋白(VH1)之重鏈可變域； 其中： a) 該VL1與VH1締合以形成結合該第一靶蛋白的結合位點； b) 該VL2與VH2締合以形成結合該第二靶蛋白的結合位點； c) 該重鏈恆定區2 (CH2)包含根據Kabat中的EU索引編號的位置252處的酪胺酸、位置254處的蘇胺酸及位置256處的麩胺酸；以及 d) 該第一靶蛋白係BAFF且該第二靶蛋白係IL-23A或該第一靶蛋白係IL-23A且該第二靶蛋白係BAFF， 且其中： (i)  該VL1包含SEQ ID NO:2，該VH1包含SEQ ID NO:1，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:3；或 (ii) 該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:2，及該VH2包含SEQ ID NO:1；或 (iii) 該VL1包含SEQ ID NO:85，該VH1包含SEQ ID NO:84，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:4；或 (iv) 該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:85，及該VH2包含SEQ ID NO:84；或 (v)  該VL1包含SEQ ID NO:87，該VH1包含SEQ ID NO:86，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:3；或 (vi) 該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:87，及該VH2包含SEQ ID NO:86；或 (vii)   該VL1包含SEQ ID NO:89，該VH1包含SEQ ID NO:88，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:3；或 (viii)  該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:89，及該VH2包含SEQ ID NO:88；或 (ix) 該VL1包含SEQ ID NO:91，該VH1包含SEQ ID NO:90，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:3；或 (x)  該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:91，及該VH2包含SEQ ID NO:90。
在一些實施例中，該第一多肽進一步包含該VL1與該VH2之間的第一連接子且該第二多肽進一步包含該VL2與該VH1之間的第二連接子。在一些實施例中，該第一連接子或該第二連接子包含胺基酸序列GGGSGGGG (SEQ ID NO:69)。在一些實施例中，該第一連接子及該第二連接子包含胺基酸序列GGGSGGGG (SEQ ID NO:69)。在一些實施例中，該第一多肽進一步包含該VH2或該VL1與該鉸鏈區之間的第三連接子，且該第二多肽進一步包含該VH1之後（在VH1的C末端處）或該VL2之後（在VL2的C末端處）的第四連接子。在一些實施例中，該第一多肽之該第三連接子包含胺基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK (SEQ ID NO:82)，且該第二多肽之該第四連接子包含胺基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE (SEQ ID NO:83)。在其他實施例中，該第一多肽之該第三連接子包含胺基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE (SEQ ID NO:83)，且該第二多肽之該第四連接子包含胺基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK (SEQ ID NO:82)。在一些實施例中，該第一多肽之該第三連接子包含胺基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK (SEQ ID NO:82)或胺基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE (SEQ ID NO:83)。在其他實施例中，該第二多肽之該第四連接子包含胺基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK (SEQ ID NO:82)或胺基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE (SEQ ID NO:83)。在一些實施例中，該第三連接子包含胺基酸序列VEPKSC (SEQ ID NO:72)或胺基酸序列FNRGEC (SEQ ID NO:71)。在一些實施例中，該第四連接子包含胺基酸序列FNRGEC (SEQ ID NO:71)或胺基酸序列VEPKSC (SEQ ID NO:72)。在一些實施例中，該第三連接子包含胺基酸序列VEPKSC (SEQ ID NO:72)及該第四連接子包含胺基酸序列FNRGEC (SEQ ID NO:71)。
在一些實施例中，該第一多肽進一步包含該VH2或該VL1（取決於構型）與鉸鏈區之間的重鏈恆定區1域(CH1)且該第二多肽進一步包含該VH1或VL2（取決於構型）之C末端處的輕鏈恆定區域(CL)，其中該CL與該CH1經由二硫鍵締合在一起以形成C1域。在一些實施例中，該第一連接子（該VL1與該VH2之間）或該第二連接子（該VL2與該VH1之間）包含胺基酸序列GGGSGGGG (SEQ ID NO:69)。在一些實施例中，該第一連接子及該第二連接子包含胺基酸序列GGGSGGGG (SEQ ID NO:69)。在一些實施例中，該第一多肽進一步包含該VH2或該VL1（取決於構型）與該CH1之間的第三連接子，且該第二多肽進一步包含該VH1或該VL2（取決於構型）與該CL之間的第四連接子。在一些實施例中，該第三連接子或該第四連接子包含胺基酸序列LGGGSG (SEQ ID NO:70)。在一些實施例中，該第三連接子及該第四連接子包含胺基酸序列LGGGSG (SEQ ID NO:70)。在一些實施例中，該第三連接子及/或該第四連接子包含可選半胱胺酸殘基。在一些實施例中，該第三連接子及/或該第四連接子包含胺基酸序列GGCGGG (SEQ ID NO:135)或LGGCGGGS (SEQ ID NO:136)。
在一些實施例中，該重鏈恆定區2 (CH2)包含對於習知抗體根據Kabat中的EU索引編號的位置234處的丙胺酸及位置235處的丙胺酸。
在一些實施例中，該鉸鏈區、該重鏈恆定區2 (CH2)或該重鏈恆定區3 (CH3)之胺基酸序列源自於IgG1或源自於IgG4。在一些實施例中，該鉸鏈區包含胺基酸序列EPKSCDKTHTCPPCP (SEQ ID NO:76)。SEQ ID NO:76之鉸鏈區存在於例如SEQ ID NO:5多肽中。在其他實施例中，鉸鏈區包含胺基酸序列LEPKSSDKTHTCPPCP (SEQ ID NO:130)。SEQ ID NO:130之鉸鏈區存在於例如SEQ ID NO:9多肽中。在又其他實施例中，鉸鏈區包含胺基酸序列ESKYGPPCPPCP (SEQ ID NO:134)。SEQ ID NO:134之鉸鏈區存在於例如SEQ ID NO:13多肽中。
在一些實施例中，該化合物包含兩個該第一多肽及兩個該第二多肽，其中該兩個第一多肽經由至少一個二硫鍵締合在一起。在一些實施例中，該化合物包含兩個該第一多肽及兩個該第二多肽，其中該兩個第一多肽經由至少一個二硫鍵締合在一起且其中該等第一多肽之各者經由至少一個二硫鍵締合至一個該第二多肽。
在一些實施例中， (i)  該第一多肽包含SEQ ID NO:5之胺基酸序列及該第二多肽包含SEQ ID NO:6之胺基酸序列；或 (ii) 該第一多肽包含SEQ ID NO:7之胺基酸序列及該第二多肽包含SEQ ID NO:8之胺基酸序列；或 (iii) 該第一多肽包含SEQ ID NO:9之胺基酸序列及該第二多肽包含SEQ ID NO:10之胺基酸序列；或 (iv) 該第一多肽包含SEQ ID NO:11之胺基酸序列及該第二多肽包含SEQ ID NO:12之胺基酸序列；或 (v)  該第一多肽包含SEQ ID NO:13之胺基酸序列及該第二多肽包含SEQ ID NO:14之胺基酸序列；或 (vi) 該第一多肽包含SEQ ID NO:15之胺基酸序列及該第二多肽包含SEQ ID NO:16之胺基酸序列；或 (vii)   該第一多肽包含SEQ ID NO:17之胺基酸序列及該第二多肽包含SEQ ID NO:18之胺基酸序列；或 (viii)  該第一多肽包含SEQ ID NO:19之胺基酸序列及該第二多肽包含SEQ ID NO:20之胺基酸序列；或 (ix) 該第一多肽包含SEQ ID NO:21之胺基酸序列及該第二多肽包含SEQ ID NO:22之胺基酸序列；或 (x)  該第一多肽包含SEQ ID NO:23之胺基酸序列及該第二多肽包含SEQ ID NO:24之胺基酸序列；或 (xi) 該第一多肽包含SEQ ID NO:25之胺基酸序列及該第二多肽包含SEQ ID NO:26之胺基酸序列；或 (xii)   該第一多肽包含SEQ ID NO:27之胺基酸序列及該第二多肽包含SEQ ID NO:28之胺基酸序列；或 (xiii)  該第一多肽包含SEQ ID NO:29之胺基酸序列及該第二多肽包含SEQ ID NO:30之胺基酸序列；或 (xiv)  該第一多肽包含SEQ ID NO:31之胺基酸序列及該第二多肽包含SEQ ID NO:32之胺基酸序列；或 (xv) 該第一多肽包含SEQ ID NO:33之胺基酸序列及該第二多肽包含SEQ ID NO:34之胺基酸序列；或 (xvi)  該第一多肽包含SEQ ID NO:35之胺基酸序列及該第二多肽包含SEQ ID NO:36之胺基酸序列；或 (xvii) 該第一多肽包含SEQ ID NO:37之胺基酸序列及該第二多肽包含SEQ ID NO:38之胺基酸序列；或 (xviii) 該第一多肽包含SEQ ID NO:39之胺基酸序列及該第二多肽包含SEQ ID NO:40之胺基酸序列；或 (xix)  該第一多肽包含SEQ ID NO:41之胺基酸序列及該第二多肽包含SEQ ID NO:42之胺基酸序列；或 (xx) 該第一多肽包含SEQ ID NO:43之胺基酸序列及該第二多肽包含SEQ ID NO:44之胺基酸序列；或 (xxi)  該第一多肽包含SEQ ID NO:45之胺基酸序列及該第二多肽包含SEQ ID NO:46之胺基酸序列；或 (xxii) 該第一多肽包含SEQ ID NO:47之胺基酸序列及該第二多肽包含SEQ ID NO:48之胺基酸序列；或 (xxiii) 該第一多肽包含SEQ ID NO:49之胺基酸序列及該第二多肽包含SEQ ID NO:50之胺基酸序列；或 (xxiv) 該第一多肽包含SEQ ID NO:51之胺基酸序列及該第二多肽包含SEQ ID NO:52之胺基酸序列；或 (xxv)  該第一多肽包含SEQ ID NO:53之胺基酸序列及該第二多肽包含SEQ ID NO:54之胺基酸序列；或 (xxvi) 該第一多肽包含SEQ ID NO:55之胺基酸序列及該第二多肽包含SEQ ID NO:56之胺基酸序列；或 (xxvii)   該第一多肽包含SEQ ID NO:57之胺基酸序列及該第二多肽包含SEQ ID NO:58之胺基酸序列；或 (xxviii)  該第一多肽包含SEQ ID NO:59之胺基酸序列及該第二多肽包含SEQ ID NO:60之胺基酸序列；或 (xxix) 該第一多肽包含SEQ ID NO:61之胺基酸序列及該第二多肽包含SEQ ID NO:62之胺基酸序列；或 (xxx)  該第一多肽包含SEQ ID NO:63之胺基酸序列及該第二多肽包含SEQ ID NO:64之胺基酸序列；或 (xxxi) 該第一多肽包含SEQ ID NO:65之胺基酸序列及該第二多肽包含SEQ ID NO:66之胺基酸序列；或 (xxxii)   該第一多肽包含SEQ ID NO:67之胺基酸序列及該第二多肽包含SEQ ID NO:68之胺基酸序列。
在一些實施例中，其中該化合物包含兩個該第一多肽及兩個該第二多肽，其中該兩個第一多肽經由至少一個二硫鍵締合在一起。
在一些實施例中，該化合物包含兩個該第一多肽及兩個該第二多肽，且其中第一多肽之一者的鉸鏈、CH2及CH3與第一多肽之另一者的鉸鏈、CH2及CH3締合以形成四價分子。在一些實施例中，該化合物包含兩個該第一多肽及兩個該第二多肽，其中該等第一多肽之各者包含CH1、鉸鏈、CH2及CH3及該等第二多肽之各者包含CL，且其中第一多肽之一者的鉸鏈、CH2及CH3與第一多肽之另一者的鉸鏈、CH2及CH3締合且每個該第一多肽的CH1與一個該第二多肽的CL締合以形成四價分子（例如，實例部分中描述的單體、單體抗體）（例如，化合物E及V）。在一些實施例中，該化合物包含兩個該第一多肽及兩個該第二多肽，其中該等第一多肽之各者包含第三連接子、鉸鏈、CH2及CH3，及該等第二多肽之各者包含第四連接子，且其中第一多肽之一者的鉸鏈、CH2及CH3與第一多肽之另一者的鉸鏈、CH2及CH3締合且每個該第一多肽的第三連接子與一個該第二多肽的第四連接子締合以形成四價分子（例如，實例部分中描述的單體、單體抗體）（例如，化合物U及T）。
本揭示案之其他態樣係關於一種第一化合物，此第一化合物與第二化合物競爭結合至IL-23A及至BAFF，其中該第一化合物包含第三多肽及第四多肽，其中： (A)  該第三多肽包含： (i)  特異於第一靶蛋白的第一免疫球蛋白(VL1)之輕鏈可變域； (ii) 特異於第二靶蛋白的第二免疫球蛋白(VH2)之重鏈可變域；以及 (iii) 鉸鏈區、重鏈恆定區2 (CH2)及重鏈恆定區3 (CH3)；以及 (B)  該第四多肽包含： (i)  特異於該第二靶蛋白的第二免疫球蛋白(VL2)之輕鏈可變域； (ii) 特異於該第一靶蛋白的第一免疫球蛋白(VH1)之重鏈可變域； 且其中 (i)  該VL1與VH1締合以形成結合該第一靶蛋白的結合位點； (ii) 該VL2與VH2締合以形成結合該第二靶蛋白的結合位點；以及 (iii) 該第一靶蛋白係BAFF且該第二靶蛋白係IL-23A或該第一靶蛋白係IL-23A且該第二靶蛋白係BAFF， 且其中該第二化合物包含第一多肽及第二多肽，其中： (i)  該第一多肽包含SEQ ID NO:5之胺基酸序列及該第二多肽包含SEQ ID NO:6之胺基酸序列；或 (ii) 該第一多肽包含SEQ ID NO:7之胺基酸序列及該第二多肽包含SEQ ID NO:8之胺基酸序列；或 (iii) 該第一多肽包含SEQ ID NO:9之胺基酸序列及該第二多肽包含SEQ ID NO:10之胺基酸序列；或 (iv) 該第一多肽包含SEQ ID NO:11之胺基酸序列及該第二多肽包含SEQ ID NO:12之胺基酸序列；或 (v)  該第一多肽包含SEQ ID NO:13之胺基酸序列及該第二多肽包含SEQ ID NO:14之胺基酸序列；或 (vi) 該第一多肽包含SEQ ID NO:15之胺基酸序列及該第二多肽包含SEQ ID NO:16之胺基酸序列；或 (vii)   該第一多肽包含SEQ ID NO:17之胺基酸序列及該第二多肽包含SEQ ID NO:18之胺基酸序列；或 (viii)  該第一多肽包含SEQ ID NO:19之胺基酸序列及該第二多肽包含SEQ ID NO:20之胺基酸序列；或 (ix) 該第一多肽包含SEQ ID NO:21之胺基酸序列及該第二多肽包含SEQ ID NO:22之胺基酸序列；或 (x)  該第一多肽包含SEQ ID NO:23之胺基酸序列及該第二多肽包含SEQ ID NO:24之胺基酸序列；或 (xi) 該第一多肽包含SEQ ID NO:25之胺基酸序列及該第二多肽包含SEQ ID NO:26之胺基酸序列；或 (xii)   該第一多肽包含SEQ ID NO:27之胺基酸序列及該第二多肽包含SEQ ID NO:28之胺基酸序列；或 (xiii)  該第一多肽包含SEQ ID NO:29之胺基酸序列及該第二多肽包含SEQ ID NO:30之胺基酸序列；或 (xiv)  該第一多肽包含SEQ ID NO:31之胺基酸序列及該第二多肽包含SEQ ID NO:32之胺基酸序列；或 (xv) 該第一多肽包含SEQ ID NO:33之胺基酸序列及該第二多肽包含SEQ ID NO:34之胺基酸序列；或 (xvi)  該第一多肽包含SEQ ID NO:35之胺基酸序列及該第二多肽包含SEQ ID NO:36之胺基酸序列；或 (xvii) 該第一多肽包含SEQ ID NO:37之胺基酸序列及該第二多肽包含SEQ ID NO:38之胺基酸序列；或 (xviii) 該第一多肽包含SEQ ID NO:39之胺基酸序列及該第二多肽包含SEQ ID NO:40之胺基酸序列；或 (xix)  該第一多肽包含SEQ ID NO:41之胺基酸序列及該第二多肽包含SEQ ID NO:42之胺基酸序列；或 (xx) 該第一多肽包含SEQ ID NO:43之胺基酸序列及該第二多肽包含SEQ ID NO:44之胺基酸序列；或 (xxi)  該第一多肽包含SEQ ID NO:45之胺基酸序列及該第二多肽包含SEQ ID NO:46之胺基酸序列；或 (xxii) 該第一多肽包含SEQ ID NO:47之胺基酸序列及該第二多肽包含SEQ ID NO:48之胺基酸序列；或 (xxiii) 該第一多肽包含SEQ ID NO:49之胺基酸序列及該第二多肽包含SEQ ID NO:50之胺基酸序列；或 (xxiv) 該第一多肽包含SEQ ID NO:51之胺基酸序列及該第二多肽包含SEQ ID NO:52之胺基酸序列；或 (xxv)  該第一多肽包含SEQ ID NO:53之胺基酸序列及該第二多肽包含SEQ ID NO:54之胺基酸序列；或 (xxvi) 該第一多肽包含SEQ ID NO:55之胺基酸序列及該第二多肽包含SEQ ID NO:56之胺基酸序列；或 (xxvii)   該第一多肽包含SEQ ID NO:57之胺基酸序列及該第二多肽包含SEQ ID NO:58之胺基酸序列；或 (xxviii)  該第一多肽包含SEQ ID NO:59之胺基酸序列及該第二多肽包含SEQ ID NO:60之胺基酸序列；或 (xxix) 該第一多肽包含SEQ ID NO:61之胺基酸序列及該第二多肽包含SEQ ID NO:62之胺基酸序列；或 (xxx)  該第一多肽包含SEQ ID NO:63之胺基酸序列及該第二多肽包含SEQ ID NO:64之胺基酸序列；或 (xxxi) 該第一多肽包含SEQ ID NO:65之胺基酸序列及該第二多肽包含SEQ ID NO:66之胺基酸序列；或 (xxxii)   該第一多肽包含SEQ ID NO:67之胺基酸序列及該第二多肽包含SEQ ID NO:68之胺基酸序列。
本揭示案之其他態樣係關於一種包含兩個第一多肽及兩個第二多肽的化合物； 其中該兩個第一多肽經由至少一個二硫鍵締合在一起且其中該等第一多肽之各者經由至少一個二硫鍵締合至一個該第二多肽； 其中該等第一多肽之各者包含： (i)  特異於第一靶蛋白的第一免疫球蛋白(VL1)之輕鏈可變域； (ii) 特異於第二靶蛋白的第二免疫球蛋白(VH2)之重鏈可變域； (iii) 重鏈恆定區1 (CH1)、鉸鏈區、重鏈恆定區2 (CH2)及重鏈恆定區3 (CH3)；以及 其中該等第二多肽之各者包含： (i)  特異於該第二靶蛋白的第二免疫球蛋白(VL2)之輕鏈可變域； (ii) 特異於該第一靶蛋白的第一免疫球蛋白(VH1)之重鏈可變域； (iii) 輕鏈恆定區域(CL)； 其中第一多肽之一者的鉸鏈、CH2及CH3與第一多肽之另一者的鉸鏈、CH2及CH3締合且每一個該第一多肽的CH1與該每一第二多肽的CL締合以形成四價分子； 其中 a) 該VL1與VH1締合以形成結合該第一靶蛋白的結合位點； b) 該VL2與VH2締合以形成結合該第二靶蛋白的結合位點； c) 該重鏈恆定區2 (CH2)包含根據Kabat中的EU索引編號的位置252處的酪胺酸、位置254處的蘇胺酸及位置256處的麩胺酸；以及 d) 該第一靶蛋白係BAFF且該第二靶蛋白係IL-23A或該第一靶蛋白係IL-23A且該第二靶蛋白係BAFF， 且其中： (i)  該VL1包含SEQ ID NO:2，該VH1包含SEQ ID NO:1，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:3；或 (ii) 該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:2，及該VH2包含SEQ ID NO:1；或 (iii) 該VL1包含SEQ ID NO:85，該VH1包含SEQ ID NO:84，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:4；或 (iv) 該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:85，及該VH2包含SEQ ID NO:84；或 (v)  該VL1包含SEQ ID NO:87，該VH1包含SEQ ID NO:86，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:3；或 (vi) 該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:87，及該VH2包含SEQ ID NO:86；或 (vii)   該VL1包含SEQ ID NO:89，該VH1包含SEQ ID NO:88，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:3；或 (viii)  該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:89，及該VH2包含SEQ ID NO:88；或 (ix) 該VL1包含SEQ ID NO:91，該VH1包含SEQ ID NO:90，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:3；或 (x)  該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:91，及該VH2包含SEQ ID NO:90。
在關於上述態樣的一些實施例中，該等第一多肽之各者進一步包含該VL1與該VH2之間的第一連接子，及該等第二多肽之各者進一步包含該VL2與該VH1之間的第二連接子。在一些實施例中，該第一連接子或該第二連接子包含胺基酸序列GGGSGGGG (SEQ ID NO:69)。在一些實施例中，該第一連接子及該第二連接子包含胺基酸序列GGGSGGGG (SEQ ID NO:69)。在一些實施例中，該等第一多肽之各者進一步包含該VH2（或該VL1）與該CH1之間的第三連接子，及該等第二多肽之各者進一步包含該VH1（或該VL2）與該CL之間的第四連接子。在一些實施例中，該第三連接子或該第四連接子包含胺基酸序列LGGGSG (SEQ ID NO:70)。
在一些實施例中，該第三連接子及該第四連接子包含胺基酸序列LGGGSG (SEQ ID NO:70)。在一些實施例中，該第三連接子及/或該第四連接子包含可選半胱胺酸殘基。在一些實施例中，該第三連接子及/或該第四連接子包含胺基酸序列GGCGGG (SEQ ID NO:135)或LGGCGGGS (SEQ ID NO:136)。在一些實施例中，該重鏈恆定區2 (CH2)包含根據Kabat中的EU索引編號的位置234處的丙胺酸及位置235處的丙胺酸。在一些實施例中，該鉸鏈區、該重鏈恆定區2 (CH2)或該重鏈恆定區3 (CH3)之胺基酸序列源自於IgG1或源自於IgG4。在一些實施例中，該鉸鏈區包含胺基酸序列EPKSCDKTHTCPPCP (SEQ ID NO:76)、胺基酸序列LEPKSSDKTHTCPPCP (SEQ ID NO:130)或胺基酸序列ESKYGPPCPPCP (SEQ ID NO:134)。
在一些實施例中， (i)  該等第一多肽之各者包含SEQ ID NO:5之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:6之胺基酸序列；或 (ii) 該等第一多肽之各者包含SEQ ID NO:7之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:8之胺基酸序列；或 (iii) 該等第一多肽之各者包含SEQ ID NO:13之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:14之胺基酸序列；或 (iv) 該等第一多肽之各者包含SEQ ID NO:15之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:16之胺基酸序列；或 (v)  該等第一多肽之各者包含SEQ ID NO:21之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:22之胺基酸序列；或 (vi) 該等第一多肽之各者包含SEQ ID NO:25之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:26之胺基酸序列；或 (vii)   該等第一多肽之各者包含SEQ ID NO:29之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:30之胺基酸序列；或 (viii)  該等第一多肽之各者包含SEQ ID NO:33之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:34之胺基酸序列；或 (ix) 該等第一多肽之各者包含SEQ ID NO:37之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:38之胺基酸序列；或 (x)  該等第一多肽之各者包含SEQ ID NO:41之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:42之胺基酸序列；或 (xi) 該等第一多肽之各者包含SEQ ID NO:45之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:46之胺基酸序列；或 (xii)   該等第一多肽之各者包含SEQ ID NO:49之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:50之胺基酸序列；或 (xiii)  該等第一多肽之各者包含SEQ ID NO:53之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:54之胺基酸序列；或 (xiv)  該等第一多肽之各者包含SEQ ID NO:55之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:56之胺基酸序列；或 (xv) 該等第一多肽之各者包含SEQ ID NO:57之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:58之胺基酸序列；或 (xvi)  該等第一多肽之各者包含SEQ ID NO:59之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:60之胺基酸序列；或 (xvii) 該等第一多肽之各者包含SEQ ID NO:61之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:62之胺基酸序列；或 (xviii) 該等第一多肽之各者包含SEQ ID NO:63之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:64之胺基酸序列；或 (xix)  該等第一多肽之各者包含SEQ ID NO:65之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:66之胺基酸序列；或 (xx) 該等第一多肽之各者包含SEQ ID NO:67之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:68之胺基酸序列。
本揭示案之其他態樣係關於一種包含兩個第一多肽及兩個第二多肽的化合物；其中該兩個第一多肽經由至少一個二硫鍵締合在一起且其中該等第一多肽之各者經由至少一個二硫鍵締合至一個該第二多肽；且其中(i)該等第一多肽之各者包含SEQ ID NO:5之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:6之胺基酸序列；或 (ii) 該等第一多肽之各者包含SEQ ID NO:7之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:8之胺基酸序列；或 (iii) 該等第一多肽之各者包含SEQ ID NO:13之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:14之胺基酸序列；或 (iv) 該等第一多肽之各者包含SEQ ID NO:15之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:16之胺基酸序列；或 (v)  該等第一多肽之各者包含SEQ ID NO:21之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:22之胺基酸序列；或 (vi) 該等第一多肽之各者包含SEQ ID NO:25之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:26之胺基酸序列；或 (vii)   該等第一多肽之各者包含SEQ ID NO:29之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:30之胺基酸序列；或 (viii)  該等第一多肽之各者包含SEQ ID NO:33之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:34之胺基酸序列；或 (ix) 該等第一多肽之各者包含SEQ ID NO:37之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:38之胺基酸序列；或 (x)  該等第一多肽之各者包含SEQ ID NO:41之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:42之胺基酸序列；或 (xi) 該等第一多肽之各者包含SEQ ID NO:45之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:46之胺基酸序列；或 (xii)   該等第一多肽之各者包含SEQ ID NO:49之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:50之胺基酸序列；或 (xiii)  該等第一多肽之各者包含SEQ ID NO:53之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:54之胺基酸序列；或 (xiv)  該等第一多肽之各者包含SEQ ID NO:55之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:56之胺基酸序列；或 (xv) 該等第一多肽之各者包含SEQ ID NO:57之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:58之胺基酸序列；或 (xvi)  該等第一多肽之各者包含SEQ ID NO:59之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:60之胺基酸序列；或 (xvii) 該等第一多肽之各者包含SEQ ID NO:61之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:62之胺基酸序列；或 (xviii) 該等第一多肽之各者包含SEQ ID NO:63之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:64之胺基酸序列；或 (xix)  該等第一多肽之各者包含SEQ ID NO:65之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:66之胺基酸序列；或 (xx) 該等第一多肽之各者包含SEQ ID NO:67之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:68之胺基酸序列。
本揭示案之其他態樣係關於一種包含兩個第一多肽及兩個第二多肽的化合物； 其中該兩個第一多肽經由至少一個二硫鍵締合在一起且其中該等第一多肽之各者經由至少一個二硫鍵締合至一個該第二多肽； 其中該等第一多肽之各者包含： (iv) 特異於第一靶蛋白的第一免疫球蛋白(VL1)之輕鏈可變域； (v)  特異於第二靶蛋白的第二免疫球蛋白(VH2)之重鏈可變域； (vi) 鉸鏈區、重鏈恆定區2 (CH2)及重鏈恆定區3 (CH3)； 且其中該等第二多肽之各者包含： (i)  特異於該第二靶蛋白的第二免疫球蛋白(VL2)之輕鏈可變域；以及 (ii) 特異於該第一靶蛋白的第一免疫球蛋白(VH1)之重鏈可變域； 其中第一多肽之一者的鉸鏈、CH2及CH3與第一多肽之另一者的鉸鏈、CH2及CH3締合，且； 其中 e) 該VL1與VH1締合以形成結合該第一靶蛋白的結合位點； f) 該VL2與VH2締合以形成結合該第二靶蛋白的結合位點； g) 該重鏈恆定區2 (CH2)包含根據Kabat中的EU索引編號的位置252處的酪胺酸、位置254處的蘇胺酸及位置256處的麩胺酸；以及 h) 該第一靶蛋白係BAFF且該第二靶蛋白係IL-23A或該第一靶蛋白係IL-23A且該第二靶蛋白係BAFF， 且其中： (i)  該VL1包含SEQ ID NO:2，該VH1包含SEQ ID NO:1，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:3；或 (ii) 該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:2，及該VH2包含SEQ ID NO:1；或 (iii) 該VL1包含SEQ ID NO:85，該VH1包含SEQ ID NO:84，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:4；或 (iv) 該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:85，及該VH2包含SEQ ID NO:84；或 (v)  該VL1包含SEQ ID NO:87，該VH1包含SEQ ID NO:86，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:3；或 (vi) 該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:87，及該VH2包含SEQ ID NO:86；或 (vii)   該VL1包含SEQ ID NO:89，該VH1包含SEQ ID NO:88，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:3；或 (viii)  該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:89，及該VH2包含SEQ ID NO:88；或 (ix) 該VL1包含SEQ ID NO:91，該VH1包含SEQ ID NO:90，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:3；或 (x)  該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:91，及該VH2包含SEQ ID NO:90。
在關於上述態樣的一些實施例中，該等第一多肽之各者進一步包含該VL1與該VH2之間的第一連接子，及該等第二多肽之各者進一步包含該VL2與該VH1之間的第二連接子。在一些實施例中，該第一連接子或該第二連接子包含胺基酸序列GGGSGGGG (SEQ ID NO:69)。在一些實施例中，該第一連接子及該第二連接子包含胺基酸序列GGGSGGGG (SEQ ID NO:69)。在一些實施例中，該等第一多肽之各者進一步包含該VH2或該VL1與該鉸鏈區之間的第三連接子，及該等第二多肽之各者進一步包含該VH1或該VL2之C末端處的第四連接子。在一些實施例中，該第一多肽之該第三連接子包含胺基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK (SEQ ID NO:82)，及該第二多肽之該第四連接子包含胺基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE (SEQ ID NO:83)。在其他實施例中，該第一多肽之該第三連接子包含胺基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE (SEQ ID NO:83)，及該第二多肽之該第四連接子包含胺基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK (SEQ ID NO:82)。在一些實施例中，該第一多肽之該第三連接子包含胺基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK (SEQ ID NO:82)或胺基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE (SEQ ID NO:83)。在其他實施例中，該第二多肽之該第四連接子包含胺基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK (SEQ ID NO:82)或胺基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE (SEQ ID NO:83)。在一些實施例中，該第三連接子包含胺基酸序列VEPKSC (SEQ ID NO:72)或胺基酸序列FNRGEC (SEQ ID NO:71)。在一些實施例中，該第四連接子包含胺基酸序列FNRGEC (SEQ ID NO:71)或胺基酸序列VEPKSC (SEQ ID NO:72)。在一些實施例中，該第三連接子包含胺基酸序列VEPKSC (SEQ ID NO:72)及該第四連接子包含胺基酸序列FNRGEC (SEQ ID NO:71)。在一些實施例中，該重鏈恆定區2 (CH2)包含根據Kabat中的EU索引編號的位置234處的丙胺酸及位置235處的丙胺酸。在一些實施例中，該鉸鏈區、該重鏈恆定區2 (CH2)或該重鏈恆定區3 (CH3)之胺基酸序列源自於IgG1或源自於IgG4。在一些實施例中，該鉸鏈區包含胺基酸序列EPKSCDKTHTCPPCP (SEQ ID NO:76)、胺基酸序列LEPKSSDKTHTCPPCP (SEQ ID NO:130)或胺基酸序列ESKYGPPCPPCP (SEQ ID NO:134)。在一些實施例中，(i)該等第一多肽之各者包含SEQ ID NO:9之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:10之胺基酸序列；或 (ii) 該等第一多肽之各者包含SEQ ID NO:11之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:12之胺基酸序列；或 (iii) 該等第一多肽之各者包含SEQ ID NO:17之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:18之胺基酸序列；或 (iv) 該等第一多肽之各者包含SEQ ID NO:19之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:20之胺基酸序列；或 (v)  該等第一多肽之各者包含SEQ ID NO:23之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:24之胺基酸序列；或 (vi) 該等第一多肽之各者包含SEQ ID NO:27之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:28之胺基酸序列；或 (vii)   該等第一多肽之各者包含SEQ ID NO:31之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:32之胺基酸序列；或 (viii)  該等第一多肽之各者包含SEQ ID NO:35之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:36之胺基酸序列；或 (ix) 該等第一多肽之各者包含SEQ ID NO:39之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:40之胺基酸序列；或 (x)  該等第一多肽之各者包含SEQ ID NO:43之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:44之胺基酸序列；或 (xi) 該等第一多肽之各者包含SEQ ID NO:47之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:48之胺基酸序列；或 (xii)   該等第一多肽之各者包含SEQ ID NO:51之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:52之胺基酸序列。
本揭示案之又其他態樣係關於一種醫藥組合物，此醫藥組合物包含本文所描述之化合物（諸如上文所描述之化合物）。
本揭示案之其他態樣係關於一種治療自體免疫疾病或炎性疾病的方法，此方法包含向個體投予本文所描述之化合物（諸如上文所描述之化合物）或包含該化合物的醫藥組合物。
本揭示案之又其他態樣係關於一種供醫學中使用的本文所描述之化合物（諸如上文所描述之化合物）。在一些實施例中，該用途係自體免疫疾病或炎性疾病之治療。
本揭示案之又其他態樣係關於一種醫藥組合物，此醫藥組合物包含供醫學中使用的本文所描述之化合物（諸如上文所描述之化合物）。在一些實施例中，該用途係自體免疫疾病或炎性疾病之治療。
本揭示案之又其他態樣係關於一種核酸，此核酸包含編碼本文所描述之多肽（諸如上文所描述之多肽）的核苷酸序列。本揭示案之其他態樣係關於一種包含該核酸的載體。在一些實施例中，載體包含與該核酸可操作連接的啟動子。本揭示案之其他態樣係關於一種包含該核酸或該載體的細胞。
本揭示案之其他態樣係關於一種產生本文所描述之化合物或多肽（諸如上文描述之多肽）之方法，此方法包含：獲得本文所描述之細胞（諸如上文描述之細胞）；以及在該細胞中表現本文所描述之核酸。在一些實施例中，方法進一步包含分離及純化該多肽或化合物。
在下文描述中闡述本揭示案之一或更多個實施例之細節。本揭示案之其他特徵或優勢將自若干實施例之以下圖式及詳細描述以及亦自隨附申請專利範圍顯而易見。
本文描述結合至BAFF及IL-23A（亦稱為IL23p19或IL23A）兩者的化合物。目前為止，尚不存在靶向BAFF及IL23A兩者的獲批准化合物。在使用生物治療途徑同時中和兩個/更多個關鍵發炎介體方面存在的研究有限，並且此等研究未能展示出對於類風濕性關節炎(rheumatoid arthritis; RA)量測的臨床結果的改良。另外，此類組合可增加副作用，諸如感染風險（參見，例如，Genovese, M.C.、Cohen, S.、Moreland, L.、Lium, D.、Robbins, S.等人，(2004). Arth. Rheum. 50, 1412-9；Genovese, M.C.、Cohen, S.、Moreland, L.、Lium, D.、Robbins, S.等人，(2004). Arth. Rheum. 50, 1412-9；及Weinblatt, M.、Schiff, M.、Goldman, A. Kremer, J.、Luggen, M.等人，(2007). Ann.Rheum.Dis.66, 228-34）。此外，由於可溶性（例如，聚集）及穩定性（例如，不良的藥物動力）相關的問題，已經難以設計此類雙特異性化合物。
令人驚訝的是，已發現本文所描述之結合至BAFF及IL-23A的化合物中的一些具有與靶向IL-23A或BAFF任一者的個別抗體相比類似或改良的特性。亦發現一些化合物具有適宜的藥物動力及出於投藥目的在適宜範圍處可溶。此外，在一些實施例中，從個體治療之副作用角度來看，單次投藥比多次個別劑量投藥存在優勢，並具有較低劑量。另外，在一些實施例中，化合物之CMC特性展示出一些化合物具有高熔化溫度(Tm)及低聚集度。在一個態樣中，一種示例性化合物尤其展示出高濃度下的低聚集度。咸信本文所描述之化合物與標準抗體分子（例如，IgG分子或抗原結合片段（例如，Fab））相比具有一或更多個有利特性，例如減少的副作用、增加的投藥簡便性及安全性、增加的半衰期、增加的結合親和性或增加的抑制活性。
因此，本揭示案之態樣係關於特異於BAFF及IL-23A兩者的化合物，以及此類化合物之使用及產生方法。在一個態樣中，本發明技術係關於對治療及預防自體免疫疾病或炎性疾病具有增加效力的組合物，此等自體免疫疾病或炎性疾病諸如全身性紅斑狼瘡(systemic lupus erythematosus; SLE)、腎臟受累及的全身性紅斑狼瘡/狼瘡腎炎(Lupus Nephritis; LN)、ANCA關聯血管炎(ANCA-associated vasculitis; AAV)、原發性乾燥症候群(primary Sjogren’s syndrome; pSS)、慢性移植物抗宿主病(chronic graft versus host disease; cGVHD)、全身性硬化症(systemic sclerosis; SSc)、類風濕性關節炎(RA)、牛皮癬(Psoriasis; Ps)、強直性脊椎炎(Ankylosing Spondylitis; AS)及牛皮癬性關節炎(Psoriatic Arthritis; PA)。BAFF/IL23A雙重拮抗劑將抑制自體抗體/免疫複合體與IL23軸向介導的末梢器官損害兩者，並可實現與目前治療SLE及LN的護理標準相比對臨床反應優良的誘導與維持。與BAFF抗體及IL-23抗體之共同投藥以同時抑制兩個路徑相比，BAFF/IL23A雙重拮抗劑對患者更加便利，可產生改良的順應性及減小的疼痛感。BAFF/IL23A雙重拮抗劑應允許減小劑量的投藥，以及降低與治療關聯的成本。另外，BAFF/IL23A拮抗劑亦可有益於治療涉及異常調節的B細胞/自體抗體及IL23介導的組織損傷的疾病叢發，包括原發性乾燥症候群(primary Sjogren’s syndrome; pSS)、慢性移植物抗宿主病(chronic graft versus host disease; cGVHD)、全身性硬化症(systemic sclerosis; SSc)及ANCA關聯血管炎(ANCA-associated vasculitis; AAV)。
難以設計雙靶向治療分子，將兩個藥理學實體放在一起並維持每一組分之功能效力，同時具有適於大規模生產的生物物理學特性。活體外與活體內穩定性相關的許多問題，諸如活體內的不良表現、聚集度、有限的存放期、不良血清穩定性及不良藥物動力學特性(Demarest SJ, Glaser SM. (2008). Curr Opin Drug Discov Devel. 11, 675-87)已阻礙了雙靶向分子的發展。
此處，發明人揭示一種產生抑制BAFF及IL23兩種功能的雙靶向分子之方法。本發明技術之雙靶向分子具有有利且令人驚訝的特性，諸如高熔化溫度(Tm)、高濃度下的低聚集度及預測的人PK特性，此等特性允許每兩週一次或更小頻率的s.c.投藥。化合物
本揭示案之態樣係關於一種特異於BAFF及IL23A兩者的化合物。
下文展示BAFF的示例性蛋白序列及IL23A的示例性蛋白序列。
＞sp|Q9Y275|B細胞活化因子(BAFF) - TN13B_HUMAN腫瘤壞死因子配體超家族成員13B OS=智人 GN=TNFSF13B PE=1 SV=1
MDDSTEREQSRLTSCLKKREEMKLKECVSILPRKESPSVRSSKDGKLLAATLLLALLSCCLTVVSFYQVAALQGDLASLRAELQGHHAEKLPAGAGAPKAGLEEAPAVTAGLKIFEPPAPGEGNSSQNSRNKRAVQGPEETVTQDCLQLIADSETPTIQKGSYTFVPWLLSFKRGSALEEKENKILVKETGYFFIYGQVLYTDKTYAMGHLIQRKKVHVFGDELSLVTLFRCIQNMPETLPNNSCYSAGIAKLEEGDELQLAIPRENAQISLDGDVTFFGALKLL (SEQ ID NO:80)
＞NP_057668.1 - IL23A [智人]
MLGSRAVMLLLLLPWTAQGRAVPGGSSPAWTQCQQLSQKLCTLAWSAHPLVGHMDLREEGDEETTNDVPHIQCGDGCDPQGLRDNSQFCLQRIHQGLIFYEKLLGSDIFTGEPSLLPDSPVGQLHASLLGLSQLLQPEGHHWETQQIPSLSPSQPWQRLLLRFKILRSLQAFVAVAARVFAHGAATLSP （胺基酸1-19係預測信號序列）(SEQ ID NO:81)
在一些實施例中，化合物包含第一多肽及第二多肽。在一些實施例中，第一多肽包含：(i)特異於第一靶蛋白的第一免疫球蛋白(VL1)之輕鏈可變域，(ii)特異於第二靶蛋白的第二免疫球蛋白(VH2)之重鏈可變域；以及(iii)鉸鏈區、重鏈恆定區2 (CH2)及重鏈恆定區3 (CH3)。在一些實施例中，第一多肽進一步包含重鏈恆定區1 (CH1)。在一些實施例中，第二多肽包含：(i)特異於第二靶蛋白的第二免疫球蛋白(VL2)之輕鏈可變域；(ii)特異於第一靶蛋白的第一免疫球蛋白(VH1)之重鏈可變域。在一些實施例中，第二多肽進一步包含輕鏈恆定區(CL)。
應理解，第一多肽之可變域及恆定域/區可呈任何次序且第二多肽之可變域及恆定域/區（若有）可呈任何次序。在第一多肽及第二多肽上自N末端至C末端的域/區之多個示例性構型如下所示。
第一多肽構型1：N-VL1-VH2-鉸鏈-CH2-CH3-C
第一多肽構型2：N-VH2-VL1-鉸鏈-CH2-CH3-C
第一多肽構型3：N-VL1-VH2-CH1-鉸鏈-CH2-CH3-C
第一多肽構型4：N-VH2-VL1-CH1-鉸鏈-CH2-CH3-C
第二多肽構型1：N-VL2-VH1-C
第二多肽構型2：N-VH1-VL2-C
第二多肽構型3：N-VL2-VH1-CL-C
第二多肽構型4：N-VH1-VL2-CL-C
在第1A圖及第1B圖中圖示化合物之示例性構型。
在一些實施例中，第一多肽與第二多肽之可變區彼此締合以形成第一靶蛋白的結合位點及第二靶蛋白的結合位點。在一些實施例中，第一多肽之VL1與第二多肽之VH1締合以形成結合第一靶蛋白的結合位點，且第二多肽之VL2與第一多肽之VH2締合以形成結合第二靶蛋白的結合位點。在一些實施例中，第一靶蛋白係BAFF及第二靶蛋白係IL23A。在其他實施例中，第一靶蛋白係IL23A及第二靶蛋白係BAFF。應理解，術語「第一」與「第二」並不意在暗指任一靶蛋白的重要程度。
下文在表1及亦在實例1中的表2中提供VL1、VH1、VL2及VH2之各者的序列之示例性組合。
表1：VL1、VH1、VL2及VH2的序列之示例性組合。
Figure 105123026-A0304-0001
在一些實施例中，化合物包含VL1序列及VH1序列、VL2序列及VH2序列，VL1序列包含第一輕鏈CDR1、CDR2及CDR3，VH1序列包含第一重鏈CDR1、CDR2及CDR3，VL2序列包含第二輕鏈CDR1、CDR2及CDR3，VH2序列包含第二重鏈CDR1、CDR2及CDR3。在一些實施例中，CDR係表1中所提供之一或更多個VL1、VH1、VL2及VH2序列之CDR。表1中所提供之VL1、VH1、VL2及VH2的示例性輕鏈及重鏈CDR序列如下所示：
SEQ ID NO: 1 CDRs: GGTFNNNAIN (SEQ ID NO:92) (CDR1), GIIPMFGTAKYSQNFQG (SEQ ID NO:93) (CDR2), SRDLLLFPHHALSP (SEQ ID NO:94) (CDR3)
SEQ ID NO: 2 CDRs: QGDSLRSYYAS (SEQ ID NO:95) (CDR1), GKNNRPS (SEQ ID NO:96) (CDR2), SSRDSSGNHWV (SEQ ID NO:97) (CDR3)
SEQ ID NO: 3 CDRs: GYTFTDQTIH (SEQ ID NO:98) (CDR1), YIYPRDDSPKYNENFKG (SEQ ID NO:99) (CDR2), PDRSGYAWFIY (SEQ ID NO:100) (CDR3)
SEQ ID NO: 4 CDRs: KASRDVAIAVA (SEQ ID NO:101) (CDR1), WASTRHT (SEQ ID NO:102) (CDR2), HQYSSYPFT (SEQ ID NO:103) (CDR3)
SEQ ID NO: 84 CDRs: DHIFSIHWMQ (SEQ ID NO:104) (CDR1), EIFPGSGTTDYNEKFKG (SEQ ID NO:105) (CDR2), GAFDY (SEQ ID NO:106) (CDR3)
SEQ ID NO: 85 CDRs: RASQDIGNRLS (SEQ ID NO:107) (CDR1 ATSSLDS (SEQ ID NO:108) (CDR2), LQYASSPFT (SEQ ID NO:109) (CDR3)
SEQ ID NO: 86 CDRs: DHIFSIHWMQ (SEQ ID NO:110) (CDR1), EIFPGSGTTDYNEKFKG (SEQ ID NO:111) (CDR2), GAFDY (SEQ ID NO: 112) (CDR3)
SEQ ID NO: 87 CDRs: RASQDIGNRLN (SEQ ID NO:112) (CDR1 ATSSLDS (SEQ ID NO:113) (CDR2), LQYASSPFT (SEQ ID NO:114) (CDR3)
SEQ ID NO: 88 CDRs: GYSFSTFFIH (SEQ ID NO:115) (CDR1), RIDPNSGATKYNEKFES (SEQ ID NO:116) (CDR2), GEDLLIRTDALDY (SEQ ID NO:117) (CDR3)
SEQ ID NO: 89 CDRs: KASQNAGIDVA (SEQ ID NO:118) (CDR1), SKSNRYT (SEQ ID NO: 119) (CDR2), LQYRSYPRT (SEQ ID NO:120) (CDR3)
SEQ ID NO: 90 CDRs: GYSFSTFFIH (SEQ ID NO:121) (CDR1), GRIDPNSGATKYNEKFES (SEQ ID NO:122) (CDR2), GEDLLIRTDALDY (SEQ ID NO:123) (CDR3)
SEQ ID NO: 91 CDRs: KASQNAGIDVA (SEQ ID NO:124) (CDR1), SKSNRYT (SEQ ID NO:125) (CDR2), LQYRSYPRT (SEQ ID NO:126) (CDR3)
在一些實施例中，化合物包含VH1、VL1、VH2及/或VL2，VH1、VL1、VH2及/或VL2包含與表1中所描述之序列至少80%（例如，85%、90%、95%、96%、97%、98%或99%）相同（對於序列之整個長度的每單位殘基的殘基）的序列。使用Karlin and Altschul Proc. Natl. Acad. Sci. USA 87:2264-68, 1990（在Karlin and Altschul Proc. Natl. Acad. Sci. USA 90:5873-77, 1993中加以修改）之演算法判定兩個胺基酸序列之「一致性百分比」。將此演算法併入Altschul等人，J. Mol. Biol. 215:403-10, 1990之NBLAST與XBLAST程式（2.0版）。可利用XBLAST程式，得分=50，字長=3執行BLAST蛋白質搜尋以獲得與所關注的蛋白質分子相同的胺基酸序列。在兩個序列之間存在間隙的情況下，如Altschul等人在Nucleic Acids Res. 25(17):3389-3402, 1997中所描述的，可使用Gapped BLAST。當使用BLAST及Gapped BLAST程式時，可使用各別程式（例如，XBLAST及NBLAST）之預設參數。
在一些實施例中，化合物包含VH1、VL1、VH2及/或VL2，VH1、VL1、VH2及/或VL2包含在表1所描述之序列中包含一或更多個（例如，1、2、3、4、5、6、7、8、9、10或更多個）突變的序列。此類突變可為保守胺基酸取代。本文所使用之「保守胺基酸取代」係指不改變實行胺基酸取代的蛋白質之相對電荷或尺寸特徵的胺基酸取代。胺基酸之保守取代包括例如在以下群組內的胺基酸中實行的取代：(a) M、I、L、V；(b) F、Y、W；(c) K、R、H；(d) A、G；(e) S、T；(f) Q、N；及(g) E、D。
化合物之鉸鏈區、CH2及CH3（且視情況CH1及CL，若化合物含有此等區）之胺基酸序列可源自於任何適宜源，例如諸如IgG1、IgG2、IgG3或IgG4之抗體之恆定區。本技術領域中熟知抗體重鏈及輕鏈恆定區胺基酸序列，例如在IMGT資料庫(www.imgt.org)或在www.vbase2.org/vbstat.php.處提供的彼等，兩者以引用之方式併入本文。
此外，在一些表現系統中，可轉譯後移除CH3域之C末端離胺酸殘基。因此，CH3域之C末端離胺酸殘基為可選胺基酸殘基。由本發明特定提供的是，缺少CH3域之C末端離胺酸殘基的分子。亦由本發明特定包含的是，包含CH3域之C末端離胺酸殘基的此類構築體。在一些實施例中，CH2及CH3之胺基酸序列源自於IgG1（例如，SEQ ID NO:75）或IgG4（例如，SEQ ID NO:73）。在一些實施例中，CL包含κCL或λCL之胺基酸序列。在一些實施例中，鉸鏈區包含胺基酸序列EPKSCDKTHTCPPCP (SEQ ID NO: 76)。在例如SEQ ID NO:5多肽中存在SEQ ID NO:76之鉸鏈區。在其他實施例中，鉸鏈區包含胺基酸序列LEPKSSDKTHTCPPCP (SEQ ID NO:130)。在例如SEQ ID NO:9多肽中存在SEQ ID NO:130之鉸鏈區。SEQ ID NO:130之鉸鏈區亦存在於SEQ ID NO:129之Fc域之開始處。在又其他實施例中，鉸鏈區包含胺基酸序列ESKYGPPCPPCP (SEQ ID NO:134)。在例如SEQ ID NO:13多肽中存在SEQ ID NO:134之鉸鏈區。SEQ ID NO:134之鉸鏈區亦存在於SEQ ID NO:127之Fc域之開始處。
在一些實施例中，化合物之CH2及/或CH3（且視情況CH1及CL，若化合物含有此等區）可包含一或更多個胺基酸取代，此等胺基酸取代與野生型CH2或CH3不同，例如野生型IgG1 CH2或CH3中的一或更多個胺基酸取代或野生型IgG4 CH2或CH3中的一或更多個胺基酸取代（SEQ ID NO: 39提供示例性野生型IgG1）。本技術領域中已知此類取代（參見，例如，US7704497、US7083784、US6821505、US 8323962、US6737056及US7416727）。
在一些實施例中，CH2在對於習知抗體的根據Kabat中的EU索引編號的234、235、252、254及/或256處包含胺基酸取代（Kabat等人，Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, 1991，此將以引用之方式全部併入本文）。
應理解，本文所描述之所有胺基酸位置指示對於習知抗體的根據Kabat中的EU索引之編號。在一些實施例中，CH2包含位置252、254及/或256處的胺基酸取代。在一些實施例中，位置252處的胺基酸為酪胺酸、苯丙胺酸、絲胺酸、色胺酸或蘇胺酸。在一些實施例中，位置254處的胺基酸為蘇胺酸。在一些實施例中，位置254處的胺基酸為絲胺酸、精胺酸、麩醯胺酸、麩胺酸或天冬胺酸。在一些實施例中，CH2包含位置252處的酪胺酸、位置254處的蘇胺酸及位置256處的麩胺酸（本文稱為YTE突變體）。在一些實施例中，CH2包含位置234及/或235處的胺基酸取代。在一些實施例中，CH2包含位置234處的丙胺酸及位置235處的丙胺酸，本文亦稱為KO突變體。在一些實施例中，CH2包含位置252處的酪胺酸、位置254處的蘇胺酸、位置256處的麩胺酸、位置234處的丙胺酸及位置235處的丙胺酸，本文亦稱為KO-YTE突變體。
在一些實施例中，一或更多個連接子可用於在第一多肽及/或第二多肽上將域/區連接在一起。舉例而言，第一多肽可包含VL1與VH2之間的連接子。第一多肽進一步包含VL1或VH2（取決於上文所論述之構型）與鉸鏈之間的連接子（例如，-VL1-連接子-鉸鏈或-VH2-連接子-鉸鏈）。若第一多肽包含CH1，例如第一多肽可包含VL1或VH2（取決於上文所論述之構型）與CH1之間的連接子（例如，-VL1-連接子-CH1或-VH2-連接子-CH1）。在另一實例中，第二多肽可包含VL2與VH1之間的連接子。第二多肽可進一步包含在多肽鏈之C末端處的VL2或VH1後的連接子（取決於上文所論述之構型，例如-VL2-連接子或-VH1-連接子）。若第二多肽進一步包含CL，則第二多肽可進一步包含VL2或VH1（取決於上文所論述之構型）與CL之間的連接子（如在例如-VL2-連接子-CL或-VH1-連接子-CL）。應理解，可使用任何數目之連接子在第一多肽上將任何域或區連接至任何其他另一域或區及/或可使用任何數目之連接子在第二多肽上將任何域或區連接至任何其他另一域或區。
本文涵蓋本技術領域中已知的任何適宜連接子供使用。在一些實施例中，連接子為肽連接子。在一些實施例中，肽連接子包含至少兩個胺基酸，例如2、3、4、5、6、7、8、9、10個或更多個胺基酸。在一些實施例中，肽連接子在長度上至多50、40、30、25、20、19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3或2個胺基酸。在一些實施例中，肽連接子在長度上處於2與50、2與40、2與30、2與20、2與10、2與9、2與8、2與7或2與6個胺基酸之間。在一些實施例中，肽連接子包含胺基酸序列GGGSGGGG (SEQ ID NO:69)、LGGGSG (SEQ ID NO:70)、FNRGEC (SEQ ID NO:71)、VEPKSC (SEQ ID NO:72)、GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK (SEQ ID NO:82)、GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE (SEQ ID NO:83)或上述之組合。在一些實施例中，肽連接子可包含連接子序列之多個複本，例如序列GGGSGGGG (SEQ ID NO:69)、LGGGSG (SEQ ID NO:70)、FNRGEC (SEQ ID NO:71)、VEPKSC (SEQ ID NO:72)或上述之組合的多個複本。
在一些實施例中，第一多肽及第二多肽具有以下構型： 第一多肽構型1：N-VL1-VH2-鉸鏈-CH2-CH3-C， 第一多肽構型2：N-VH2-VL1-鉸鏈-CH2-CH3-C， 第二多肽構型1：N-VL2-VH1-C， 第二多肽構型2：N-VH1-VL2-C， 其中第一多肽之VL1與VH2之間的第一連接子或第二多肽之VL2與VH1之間的第二連接子包含胺基酸序列GGGSGGGG (SEQ ID NO:69)。在一些實施例中，該第一連接子及該第二連接子包含胺基酸序列GGGSGGGG (SEQ ID NO:69)。在一些實施例中，第一多肽進一步包含VH2或VL2與該鉸鏈區之間的第三連接子且第二多肽進一步包含該VH1或VL2後（C末端處）的第四連接子。在一些實施例中，該第一多肽之該第三連接子包含胺基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK (SEQ ID NO:82)，且該第二多肽之該第四連接子包含胺基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE (SEQ ID NO:83)。在其他實施例中，該第一多肽之該第三連接子包含胺基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE (SEQ ID NO:83)，且該第二多肽之該第四連接子包含胺基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK (SEQ ID NO:82)。在一些實施例中，該第一多肽之該第三連接子包含胺基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK (SEQ ID NO:82)或胺基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE (SEQ ID NO:83)。在其他實施例中，該第二多肽之該第四連接子包含胺基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK (SEQ ID NO:82)或胺基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE (SEQ ID NO:83)。在一些實施例中，該第三連接子包含胺基酸序列VEPKSC (SEQ ID NO:72)或胺基酸序列FNRGEC (SEQ ID NO:71)。在一些實施例中，該第四連接子包含胺基酸序列FNRGEC (SEQ ID NO:71)或胺基酸序列VEPKSC (SEQ ID NO:72)。在一些實施例中，該第三連接子包含胺基酸序列VEPKSC (SEQ ID NO:72)且該第四連接子包含胺基酸序列FNRGEC (SEQ ID NO:71)。胺基酸序列FNRGEC (SEQ ID NO:71)係CL域(SEQ ID NO:77)之最後六個胺基酸殘基且胺基酸VEPKSC (SEQ ID NO: 72)包括SEQ ID NO:76之CH1之最後一個胺基酸及鉸鏈區之最初五個胺基酸殘基（與在SEQ ID NO:5中一樣）。
在一些實施例中，第一多肽及第二多肽具有以下構型： 第一多肽構型3：N-VL1-VH2-CH1-鉸鏈-CH2-CH3-C， 第一多肽構型4：N-VH2-VL1-CH1-鉸鏈-CH2-CH3-C， 第二多肽構型3：N-VL2-VH 1-CL-C， 第二多肽構型4：N-VH 1-VL2-CL-C， 其中第一多肽之該VL1與該VH2之間的第一連接子或第二多肽之該VL2與該VH1之間的該第二連接子包含胺基酸序列GGGSGGGG (SEQ ID NO:69)。在一些實施例中，該第一連接子及該第二連接子包含胺基酸序列GGGSGGGG (SEQ ID NO:69)。在一些實施例中，該第一多肽進一步包含該VH2或VL1與該CH1之間的第三連接子且該第二多肽進一步包含該VH1或該VL2與該CL之間的第四連接子。在一些實施例中，該第三連接子或該第四連接子包含胺基酸序列LGGGSG (SEQ ID NO:70)。在一些實施例中，該第三連接子及該第四連接子包含胺基酸序列LGGGSG (SEQ ID NO:70)。在一些實施例中，該第三連接子及/或該第四連接子包含可選半胱胺酸殘基。在一些實施例中，該第三連接子及/或該第四連接子包含胺基酸序列GGCGGG (SEQ ID NO:135)或LGGCGGGS (SEQ ID NO:136)。
在一些實施例中，該重鏈恆定區2 (CH2)包含對於習知抗體的根據Kabat中的EU索引編號的位置234處的丙胺酸及位置235處的丙胺酸。
在一些實施例中，化合物包含兩個第一多肽及兩個第二多肽。在一些實施例中，第一多肽之一者之鉸鏈、CH2及CH3與第一多肽之另一者之鉸鏈、CH2及CH3締合以形成四價分子（例如，兩個第一多肽經由各別鉸鏈、CH2與CH3域之間的締合二聚化以形成四價分子，四價分子包含特異於第一靶蛋白的兩個結合位點及特異於第二靶蛋白的兩個結合位點），如實例部分中所描述之單體或單體抗體。若第一多肽進一步包含CH1域且第二多肽進一步包含CL域，則CH1及CL域亦可參與四價分子之形成（例如，兩個第一多肽經由各別鉸鏈、CH2與CH3域之間的締合二聚化且每一個該第一多肽之CH1與一個該第二多肽之CL締合以形成四價分子，四價分子包含第一靶蛋白的兩個結合位點及第二靶蛋白的兩個結合位點），如實例部分中所描述之單體或單體抗體。在一些實施例中，兩個第一多肽經由至少一個二硫鍵締合在一起。在一些實施例中，該化合物包含兩個該第一多肽及兩個該第二多肽，其中該等第一多肽之各者包含第三連接子、鉸鏈、CH2及CH3，且該等第二多肽之各者包含第四連接子，且其中第一多肽之一者的鉸鏈、CH2及CH3與第一多肽之另一者的鉸鏈、CH2及CH3締合且每一個該第一多肽的第三連接子與一個該第二多肽的第四連接子締合以形成四價分子（例如，實例部分中描述的單體、單體抗體）（例如，化合物U及T）。
在一些實施例中，本揭示案係關於一種包含兩個第一多肽及兩個第二多肽的化合物； 其中該兩個第一多肽經由至少一個二硫鍵締合在一起且其中該等第一多肽之各者經由至少一個二硫鍵締合至一個該第二多肽； 其中該等第一多肽之各者包含： (i)  特異於第一靶蛋白的第一免疫球蛋白(VL1)之輕鏈可變域； (ii) 特異於第二靶蛋白的第二免疫球蛋白(VH2)之重鏈可變域； (iii) 重鏈恆定區1 (CH1)、鉸鏈區、重鏈恆定區2 (CH2)及重鏈恆定區3 (CH3)；以及 其中該等第二多肽之各者包含： (i)  特異於該第二靶蛋白的第二免疫球蛋白(VL2)之輕鏈可變域； (ii) 特異於該第一靶蛋白的第一免疫球蛋白(VH1)之重鏈可變域； (iii) 輕鏈恆定區域(CL)； 其中第一多肽之一者的鉸鏈、CH2及CH3與第一多肽之另一者的鉸鏈、CH2及CH3締合且每一個該第一多肽的CH1與該每一第二多肽的CL締合以形成四價分子； 其中 a) 該VL1與VH1締合以形成結合該第一靶蛋白的結合位點； b) 該VL2與VH2締合以形成結合該第二靶蛋白的結合位點； c) 該重鏈恆定區2 (CH2)包含根據Kabat中的EU索引編號的位置252處的酪胺酸、位置254處的蘇胺酸及位置256處的麩胺酸；以及 d) 該第一靶蛋白係BAFF且該第二靶蛋白係IL-23A或該第一靶蛋白係IL-23A且該第二靶蛋白係BAFF， 且其中： (i)  該VL1包含SEQ ID NO:2，該VH1包含SEQ ID NO:1，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:3；或 (ii) 該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:2，及該VH2包含SEQ ID NO:1；或 (iii) 該VL1包含SEQ ID NO:85，該VH1包含SEQ ID NO:84，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:4；或 (iv) 該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:85，及該VH2包含SEQ ID NO:84；或 (v)  該VL1包含SEQ ID NO:87，該VH1包含SEQ ID NO:86，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:3；或 (vi) 該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:87，及該VH2包含SEQ ID NO:86；或 (vii)   該VL1包含SEQ ID NO:89，該VH1包含SEQ ID NO:88，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:3；或 (viii)  該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:89，及該VH2包含SEQ ID NO:88；或 (ix) 該VL1包含SEQ ID NO:91，該VH1包含SEQ ID NO:90，該VL2包含SEQ ID NO:4，及該VH2包含SEQ ID NO:3；或 (x)  該VL1包含SEQ ID NO:4，該VH1包含SEQ ID NO:3，該VL2包含SEQ ID NO:91，及該VH2包含SEQ ID NO:90。
在關於上述態樣的一些實施例中，該等第一多肽之各者進一步包含該VL1與該VH2之間的第一連接子，且該等第二多肽之各者進一步包含該VL2與該VH1之間的第二連接子。在一些實施例中，該第一連接子或該第二連接子包含胺基酸序列GGGSGGGG (SEQ ID NO:69)。在一些實施例中，該第一連接子及該第二連接子包含胺基酸序列GGGSGGGG (SEQ ID NO:69)。在一些實施例中，該等第一多肽之各者進一步包含該VH2或該VL1與該CH1之間的第三連接子，且該等第二多肽之各者進一步包含該VH1或該VL2與該CL之間的第四連接子。在一些實施例中，該第三連接子或該第四連接子包含胺基酸序列LGGGSG (SEQ ID NO:70)。在一些實施例中，該第三連接子及該第四連接子包含胺基酸序列LGGGSG (SEQ ID NO:70)。在一些實施例中，該第三連接子及/或該第四連接子包含可選半胱胺酸殘基。在一些實施例中，該第三連接子及/或該第四連接子包含胺基酸序列GGCGGG (SEQ ID NO:135)或LGGCGGGS (SEQ ID NO:136)。在一些實施例中，該重鏈恆定區2 (CH2)包含根據Kabat中的EU索引編號的位置234處的丙胺酸及位置235處的丙胺酸。在一些實施例中，該鉸鏈區、該重鏈恆定區2 (CH2)或該重鏈恆定區3 (CH3)之胺基酸序列源自於IgG1或源自於IgG4。在一些實施例中，該鉸鏈區包含胺基酸序列EPKSCDKTHTCPPCP (SEQ ID NO:76)、胺基酸序列LEPKSSDKTHTCPPCP (SEQ ID NO:130)或胺基酸序列ESKYGPPCPPCP (SEQ ID NO:134)。
在一些實施例中，(i)該等第一多肽之各者包含SEQ ID NO:5之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:6之胺基酸序列；或 (ii) 該等第一多肽之各者包含SEQ ID NO:7之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:8之胺基酸序列；或 (iii) 該等第一多肽之各者包含SEQ ID NO:13之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:14之胺基酸序列；或 (iv) 該等第一多肽之各者包含SEQ ID NO:15之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:16之胺基酸序列；或 (v)  該等第一多肽之各者包含SEQ ID NO:21之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:22之胺基酸序列；或 (vi) 該等第一多肽之各者包含SEQ ID NO:25之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:26之胺基酸序列；或 (vii)   該等第一多肽之各者包含SEQ ID NO:29之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:30之胺基酸序列；或 (viii)  該等第一多肽之各者包含SEQ ID NO:33之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:34之胺基酸序列；或 (ix) 該等第一多肽之各者包含SEQ ID NO:37之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:38之胺基酸序列；或 (x)  該等第一多肽之各者包含SEQ ID NO:41之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:42之胺基酸序列；或 (xi) 該等第一多肽之各者包含SEQ ID NO:45之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:46之胺基酸序列；或 (xii)   該等第一多肽之各者包含SEQ ID NO:49之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:50之胺基酸序列；或 (xiii)  該等第一多肽之各者包含SEQ ID NO:53之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:54之胺基酸序列；或 (xiv)  該等第一多肽之各者包含SEQ ID NO:55之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:56之胺基酸序列；或 (xv) 該等第一多肽之各者包含SEQ ID NO:57之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:58之胺基酸序列；或 (xvi)  該等第一多肽之各者包含SEQ ID NO:59之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:60之胺基酸序列；或 (xvii) 該等第一多肽之各者包含SEQ ID NO:61之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:62之胺基酸序列；或 (xviii) 該等第一多肽之各者包含SEQ ID NO:63之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:64之胺基酸序列；或 (xix)  該等第一多肽之各者包含SEQ ID NO:65之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:66之胺基酸序列；或 (xx) 該等第一多肽之各者包含SEQ ID NO:67之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:68之胺基酸序列。
本揭示案之其他態樣係關於一種包含兩個第一多肽及兩個第二多肽的化合物；其中該兩個第一多肽經由至少一個二硫鍵締合在一起且其中該等第一多肽之各者經由至少一個二硫鍵締合至一個該第二多肽；且其中(i)該等第一多肽之各者包含SEQ ID NO:5之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:6之胺基酸序列；或 (ii) 該等第一多肽之各者包含SEQ ID NO:7之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:8之胺基酸序列；或 (iii) 該等第一多肽之各者包含SEQ ID NO:13之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:14之胺基酸序列；或 (iv) 該等第一多肽之各者包含SEQ ID NO:15之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:16之胺基酸序列；或 (v)  該等第一多肽之各者包含SEQ ID NO:21之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:22之胺基酸序列；或 (vi) 該等第一多肽之各者包含SEQ ID NO:25之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:26之胺基酸序列；或 (vii)   該等第一多肽之各者包含SEQ ID NO:29之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:30之胺基酸序列；或 (viii)  該等第一多肽之各者包含SEQ ID NO:33之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:34之胺基酸序列；或 (ix) 該等第一多肽之各者包含SEQ ID NO:37之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:38之胺基酸序列；或 (x)  該等第一多肽之各者包含SEQ ID NO:41之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:42之胺基酸序列；或 (xi) 該等第一多肽之各者包含SEQ ID NO:45之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:46之胺基酸序列；或 (xii)   該等第一多肽之各者包含SEQ ID NO:49之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:50之胺基酸序列；或 (xiii)  該等第一多肽之各者包含SEQ ID NO:53之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:54之胺基酸序列；或 (xiv)  該等第一多肽之各者包含SEQ ID NO:55之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:56之胺基酸序列；或 (xv) 該等第一多肽之各者包含SEQ ID NO:57之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:58之胺基酸序列；或 (xvi)  該等第一多肽之各者包含SEQ ID NO:59之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:60之胺基酸序列；或 (xvii) 該等第一多肽之各者包含SEQ ID NO:61之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:62之胺基酸序列；或 (xviii) 該等第一多肽之各者包含SEQ ID NO:63之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:64之胺基酸序列；或 (xix)  該等第一多肽之各者包含SEQ ID NO:65之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:66之胺基酸序列；或 (xx) 該等第一多肽之各者包含SEQ ID NO:67之胺基酸序列及該等第二多肽之各者包含SEQ ID NO:68之胺基酸序列。
本文亦涵蓋與本文所描述之化合物競爭以結合的其他化合物，例如與本文所描述之化合物競爭以結合至BAFF及IL23A的測試化合物。在一些實施例中，測試化合物可具有與本文所描述之化合物相比至少80%、85%、90%、95%、96%、97%、98%或99%之序列一致性（在序列之整個長度上每單位胺基酸的胺基酸）。可使用本技術領域中已知的任何檢定（例如，平衡結合、ELISA、表面電漿共振或光譜法）判定競爭性結合。
在一些實施例中，本文所描述之化合物特異性結合至BAFF及IL23A兩者。對抗原或抗原決定部位「特異性結合」的化合物為本技術領域中較好理解的術語，且用以判定此特異性結合的方法亦為本技術領域中所熟知。據稱，若與處理替代靶相比分子更加頻繁、更加快速地反應或締合，具有更長持續時間及/或與特定靶抗原具有更大親和性，則分子展示出「特異性結合」。若與結合至其他物質相比化合物在具有更大親和性、活性、更容易及/或具有更長持續時間下結合，則化合物「特異性結合」至靶抗原或抗原決定部位。舉例而言，特異性（或優先）結合至抗原（例如，BAFF或IL23A）或抗原性抗原決定部位的化合物係與結合至其他抗原或相同抗原中的其他抗原決定部位相比在具有更大親和性、活性、更容易及/或具有更長持續時間下結合此靶抗原的化合物。藉由閱讀此定義亦應理解，例如，特異性結合至第一靶抗原的化合物可以或可不特異性或優先結合至第二靶抗原。因此，「特異性結合」或「優先結合」不一定需要（儘管可包括）排他性結合。大體而言，但並非必然，對結合之引用意指優先結合。在一些實例中，「特異性結合」至靶抗原或其抗原決定部位的化合物可並未結合至其他抗原或相同抗原中的其他抗原決定部位。在一些實施例中，本文所描述之化合物具有對於BAFF及IL23或其抗原性抗原決定部位的適宜結合親和性。本文所使用之「結合親和性」係指表觀締合常數或KA 。KA 為解離常數(KD )的倒數。本文所描述之化合物對於靶抗原或抗原性抗原決定部位之一者或兩者可具有至少10-5 、10-6 、10-7 、10-8 、10-9 、10-10 、10-11 、10-12 M或更低之結合親和性(KD )。增加的結合親和性對應於減小的KD 。在一些實施例中，本文所描述之化合物對於靶抗原或抗原性抗原決定部位之一者或兩者具有至少10-11 M或更低之結合親和性(KD )。化合物對於第一抗原及第二抗原相對於第三抗原的較高親和性結合可由與結合第三抗原的KA （或數值KD ）相比結合第一抗原及第二抗原的較高KA （或較小數值KD ）指示。在此類情況下，化合物具有第一抗原及第二抗原（例如，第一構造中的第一蛋白或其擬態及第一構造中的第二蛋白或其擬態）相對於第三抗原（例如，第二構造中的相同第一蛋白或第二蛋白或其擬態；或第三蛋白）的特異性。結合親和性中的差異（例如，對於特異性或其他比較）可為至少1.5、2、3、4、5、10、15、20、37.5、50、70、80、91、100、500、1000、10,000或105 倍。
結合親和性（或結合特異性）可藉由各種方法判定，包括平衡結合、ELISA、表面電漿共振或光譜法（例如，使用螢光檢定）。評估結合親和性的示例性條件為處於HBS-P緩衝液（10 mM HEPES pH 7.4，150 mM NaCl，0.005% (v/v)界面活性劑P20）中。此等技術可用於量測隨靶蛋白濃度變化的已結合的結合蛋白之濃度。藉由以下方程式使已結合的結合蛋白之濃度（[Bound]）與游離靶蛋白之濃度（[Free]）及靶上的結合蛋白之結合位點之濃度關聯，其中(N)為每單位靶分子的結合位點數目： [Bound] = [N][Free]/(Kd+[Free])
並不總是需要做出KA 之精確判定，然而，由於有時足以獲得親和性之定量量測（例如，使用諸如ELISA或FACS之方法判定），此與KA 成比例，且因此可用於比較，諸如判定較高親和性是否為例如2倍高，以獲得親和性之定性量測，或獲得親和性之推論（例如，藉由功能檢定（例如，活體外或活體內檢定）中的活性）。
在一些實施例中，化合物包含表2A中界定的第一多肽及第二多肽。在一些實施例中，化合物包含： (i)  該第一多肽包含SEQ ID NO:5之胺基酸序列及該第二多肽包含SEQ ID NO:6之胺基酸序列；或 (ii) 該第一多肽包含SEQ ID NO:7之胺基酸序列及該第二多肽包含SEQ ID NO:8之胺基酸序列；或 (iii) 該第一多肽包含SEQ ID NO:9之胺基酸序列及該第二多肽包含SEQ ID NO:10之胺基酸序列；或 (iv) 該第一多肽包含SEQ ID NO:11之胺基酸序列及該第二多肽包含SEQ ID NO:12之胺基酸序列；或 (v)  該第一多肽包含SEQ ID NO:13之胺基酸序列及該第二多肽包含SEQ ID NO:14之胺基酸序列；或 (vi) 該第一多肽包含SEQ ID NO:15之胺基酸序列及該第二多肽包含SEQ ID NO:16之胺基酸序列；或 (vii)   該第一多肽包含SEQ ID NO:17之胺基酸序列及該第二多肽包含SEQ ID NO:18之胺基酸序列；或 (viii)  該第一多肽包含SEQ ID NO:19之胺基酸序列及該第二多肽包含SEQ ID NO:20之胺基酸序列；或 (ix) 該第一多肽包含SEQ ID NO:21之胺基酸序列及該第二多肽包含SEQ ID NO:22之胺基酸序列；或 (x)  該第一多肽包含SEQ ID NO:23之胺基酸序列及該第二多肽包含SEQ ID NO:24之胺基酸序列；或 (xi) 該第一多肽包含SEQ ID NO:25之胺基酸序列及該第二多肽包含SEQ ID NO:26之胺基酸序列；或 (xii)   該第一多肽包含SEQ ID NO:27之胺基酸序列及該第二多肽包含SEQ ID NO:28之胺基酸序列；或 (xiii)  該第一多肽包含SEQ ID NO:29之胺基酸序列及該第二多肽包含SEQ ID NO:30之胺基酸序列；或 (xiv)  該第一多肽包含SEQ ID NO:31之胺基酸序列及該第二多肽包含SEQ ID NO:32之胺基酸序列；或 (xv) 該第一多肽包含SEQ ID NO:33之胺基酸序列及該第二多肽包含SEQ ID NO:34之胺基酸序列；或 (xvi)  該第一多肽包含SEQ ID NO:35之胺基酸序列及該第二多肽包含SEQ ID NO:36之胺基酸序列；或 (xvii) 該第一多肽包含SEQ ID NO:37之胺基酸序列及該第二多肽包含SEQ ID NO:38之胺基酸序列；或 (xviii) 該第一多肽包含SEQ ID NO:39之胺基酸序列及該第二多肽包含SEQ ID NO:40之胺基酸序列；或 (xix)  該第一多肽包含SEQ ID NO:41之胺基酸序列及該第二多肽包含SEQ ID NO:42之胺基酸序列；或 (xx) 該第一多肽包含SEQ ID NO:43之胺基酸序列及該第二多肽包含SEQ ID NO:44之胺基酸序列；或 (xxi)  該第一多肽包含SEQ ID NO:45之胺基酸序列及該第二多肽包含SEQ ID NO:46之胺基酸序列；或 (xxii) 該第一多肽包含SEQ ID NO:47之胺基酸序列及該第二多肽包含SEQ ID NO:48之胺基酸序列；或 (xxiii) 該第一多肽包含SEQ ID NO:49之胺基酸序列及該第二多肽包含SEQ ID NO:50之胺基酸序列；或 (xxiv) 該第一多肽包含SEQ ID NO:51之胺基酸序列及該第二多肽包含SEQ ID NO:52之胺基酸序列；或 (xxv)  該第一多肽包含SEQ ID NO:53之胺基酸序列及該第二多肽包含SEQ ID NO:54之胺基酸序列；或 (xxvi) 該第一多肽包含SEQ ID NO:55之胺基酸序列及該第二多肽包含SEQ ID NO:56之胺基酸序列；或 (xxvii)   該第一多肽包含SEQ ID NO:57之胺基酸序列及該第二多肽包含SEQ ID NO:58之胺基酸序列；或 (xxviii)  該第一多肽包含SEQ ID NO:59之胺基酸序列及該第二多肽包含SEQ ID NO:60之胺基酸序列；或 (xxix) 該第一多肽包含SEQ ID NO:61之胺基酸序列及該第二多肽包含SEQ ID NO:62之胺基酸序列；或 (xxx)  該第一多肽包含SEQ ID NO:63之胺基酸序列及該第二多肽包含SEQ ID NO:64之胺基酸序列；或 (xxxi) 該第一多肽包含SEQ ID NO:65之胺基酸序列及該第二多肽包含SEQ ID NO:66之胺基酸序列；或 (xxxii)   該第一多肽包含SEQ ID NO:67之胺基酸序列及該第二多肽包含SEQ ID NO:68之胺基酸序列。產生化合物、核酸、載體及細胞之方法
本揭示案之態樣亦包括編碼本文所描述之化合物或本文所描述之多肽（例如，本文所描述之第一多肽或第二多肽）的核酸，此等化合物或多肽可被一起編碼或單獨編碼。可獲得編碼本文所描述之化合物或本文所描述之多肽的聚核苷酸，且藉由本技術領域中已知的任何方法判定聚核苷酸之核苷酸序列。
在一些實施例中，核酸被包含在載體（諸如表現載體）內。在一些實施例中，載體包含可操作連接至核酸的啟動子。
多種啟動子可用於表現本文所描述之化合物或本文所描述之多肽，包括但不限於巨細胞病毒(cytomegalovirus; CMV)中間早期啟動子、病毒LTR（諸如Rous肉瘤病毒LTR、HIV-LTR、HTLV-1 LTR）、猿猴病毒40 (SV40)早期啟動子、大腸桿菌lac UV5啟動子以及單純性皰疹tk病毒啟動子。
亦可使用可調節啟動子。此類可調節啟動子包括使用自大腸桿菌的lac抑制子作為轉錄調節劑以自載運lac操縱子的哺乳動物細胞啟動子調節轉錄的彼等[Brown, M.等人，Cell, 49:603-612 (1987)]，使用四環素抑制子(tetR)的彼等[Gossen, M.與Bujard, H.，Proc. Natl. Acad. Sci. USA 89:5547-5551 (1992)；Yao, F.等人，Human Gene Therapy, 9:1939-1950 (1998)；Shockelt, P.等人，Proc. Natl. Acad. Sci. USA, 92:6522-6526 (1995)]。其他系統包括使用雌二醇、RU486、聯苯酚米樂甾酮或雷帕黴素的FK506二聚體、VP16或p65。誘導系統可購自Invitrogen、Clontech及Ariad。
可使用可調節啟動子，此等啟動子包括具有操縱子的抑制子。在一個實施例中，自大腸桿菌的lac抑制子可作用為轉錄調節劑以自載運lac操縱子的哺乳動物細胞啟動子調節轉錄[M. Brown等人，Cell, 49:603-612 (1987)]；Gossen與Bujard (1992)；[M. Gossen等人，Natl. Acad. Sci. USA, 89:5547-5551 (1992)]，將四環素抑制子(tetR)與轉錄活化子(VP 16)組合以產生tetR哺乳動物細胞轉錄活化子融合蛋白tTa (tetR-VP 16)，其中載運tetO的最小啟動子源自於人類巨細胞病毒(human cytomegalovirus; hCMV)主要立即早期啟動子以產生tetR-tet操縱子系統來控制哺乳動物細胞中的基因表現。在一個實施例中，使用四環素可誘導轉換（Yao等人，Human Gene Therapy；Gossen等人，Natl. Acad. Sci. USA, 89:5547-5551 (1992)；Shockett等人，Proc. Natl. Acad. Sci. USA, 92:6522-6526 (1995)）。
另外，載體可含有例如以下中的一些或全部：可選擇標記基因，諸如新黴素基因，用於在哺乳動物細胞中選擇穩定或暫態轉染子；自人CMV之立即早期基因的增進子/啟動子序列，用於高水平轉錄；自SV40的轉錄終止及RNA處理信號，用於mRNA穩定性；複製之SV40多瘤起源及ColE1，用於適當游離型複製；內部核糖體結合位點(IRESes)、通用多個選殖位點；及T7與SP6 RNA啟動子，用於有義與反義RNA之活體外轉錄。適宜載體及用於產生含有轉基因的載體之方法為本技術領域中所熟知並可用。
可藉由習知技術（例如，電穿孔、脂質體轉染及磷酸鈣沉澱）將包含核酸的表現載體移送至宿主細胞，並且隨後藉由習知技術培養轉染細胞以產生本文所描述之化合物。在一些實施例中，藉由構成型、可誘導型或組織特異性啟動子調節本文所描述之化合物之表現。
用於表現本文所描述之化合物或本文所描述之多肽的宿主細胞可為細菌細胞（諸如大腸桿菌）或較佳為真核細胞。特定而言，哺乳動物細胞（諸如中國倉鼠卵巢細胞(Chinese hamster ovary cells; CHO)）與諸如來自人類巨細胞病毒的主要中間早期基因啟動子元件之載體結合係免疫球蛋白的有效表現系統（Foecking等人，(1986) 「Powerful And Versatile Enhancer-Promoter Unit For Mammalian Expression Vectors」，Gene 45:101-106；Cockett等人，(1990) 「High Level Expression Of Tissue Inhibitor Of Metalloproteinases In Chinese Hamster Ovary Cells Using Glutamine Synthetase Gene Amplification」，Biotechnology 8:662-667）。
可使用各種宿主表現載體系統表現本文所描述之化合物或本文所描述之多肽。此類宿主表現系統表示媒劑，藉由此等媒劑可產生及隨後純化本文所描述之化合物或本文所描述之多肽之編碼序列，而且表示細胞，當用適宜核苷酸編碼序列轉化或轉染時，此等細胞可原位表現本文所描述之化合物。此等包括但不限於：微生物，例如用重組噬菌體DNA、質體DNA或含有本文所描述之化合物的編碼序列的黏質體DNA表現載體轉化的細菌（例如，大腸桿菌及枯草芽孢桿菌）；用含有編碼本文所描述之化合物的序列的重組酵母表現載體轉化的酵母（例如，釀酒畢赤酵母）；感染含有編碼本文所描述之化合物的序列的重組病毒表現載體（例如，桿狀病毒）的昆蟲細胞系統；感染重組病毒表現載體（例如，花椰菜花葉病毒(CaMV)及菸草鑲崁病毒(TMV)）或用含有編碼本文所描述之分子化合物的序列的重組質體表現載體（例如，Ti質體）轉化的植物細胞系統；或哺乳動物細胞系統（例如，COS、CHO、BHK、293、293T、3T3細胞、淋巴細胞（參見美國專利第5,807,715號），Per C.6細胞（由Crucell公司開發的人視網膜細胞）攜帶含有啟動子的重組表現構造，此等啟動子源自於哺乳動物細胞的基因組（例如，金屬硫蛋白啟動子）或源自於哺乳動物病毒（例如，腺病毒晚期啟動子；牛痘病毒7.5K啟動子）。
在細菌系統中，可取決於正表現的化合物所欲的用途有利地選擇眾多表現載體。舉例而言，當產生大量此蛋白質時，對於本文所描述之化合物之醫藥組合物的產生，可需要導引易於純化的高水平之融合蛋白產物之表現的載體。此類載體包括但不限於大腸桿菌表現載體pUR278（Ruther等人，(1983) 「Easy Identification Of cDNA Clones」，EMBO J. 2:1791-1794），其中可將編碼序列單獨接合至具有lac Z編碼區的方框中的載體，使得產生融合蛋白；pIN載體（Inouye等人，(1985) 「Up-Promoter Mutations In The lpp Gene Of Escherichia Coli」，Nucleic Acids Res. 13:3101-3110；Van Heeke等人，(1989) 「Expression Of Human Asparagine Synthetase In Escherichia Coli」，J. Biol. Chem. 24:5503-5509)；及類似者。pGEX載體亦可用於將外源多肽表現為具有麩胱甘肽S-轉移酶(glutathione S-transferase; GST)的融合蛋白。大體而言，此類融合蛋白為可溶的且可容易地自裂解細胞藉由吸附及結合至基質麩胱甘肽-瓊脂糖珠，繼之以在游離麩胱甘肽存在下溶離加以純化。pGEX載體經設計以包括凝血酶或Xa因子蛋白酶裂解位點使得可自GST部分釋放選殖的靶基因產物。
在昆蟲系統中，苜蓿銀紋夜蛾核型多角體病毒(Autographa californica nuclear polyhedrosis virus; AcNPV)用作載體以表現外源基因。此病毒生長在草地黏蟲細胞中。可將編碼序列單獨選殖至病毒之非基本區（例如，多角體蛋白基因），並置於AcNPV啟動子（例如，多角體蛋白啟動子）之控制下。
在哺乳動物宿主細胞中，可使用眾多基於病毒的表現系統。在將腺病毒用作表現載體的情況下，可將所關注的編碼序列接合至腺病毒轉錄/轉譯控制複合物（例如，晚期啟動子及三聯前導序列）。可隨後藉由活體外或活體內重組將此嵌合基因插入腺病毒基因組中。病毒基因組之非基本區中的插入（例如，區E1或E3）將產生重組病毒，重組病毒係可行的且能夠在受感染宿主中表現免疫球蛋白分子（例如，參見Logan等人，(1984) 「Adenovirus Tripartite Leader Sequence Enhances Translation Of mRNAs Late After Infection」，Proc. Natl. Acad. Sci. USA 81:3655-3659）。亦可需要特異性起始信號用於所插入抗體編碼序列之高效轉譯。此等信號包括ATG起始密碼子及相鄰序列。此外，起始密碼子必須與所需編碼序列之閱讀框同相以確保整個插入體的轉譯。此等外生轉譯控制信號及起始密碼子可具有天然與合成的各種起源。可藉由包含適宜轉錄增進子元件、轉錄終止子等來增進表現效率（參見Bitter等人，(1987) 「Expression And Secretion Vectors For Yeast」，Methods in Enzymol. 153:516-544）。
另外，可選擇宿主細胞株，此宿主細胞株調變所插入序列之表現，或以所需特異性方式修飾及處理基因產物。蛋白質產物之此類修飾（例如，醣基化作用）及處理（例如，裂解）可對蛋白質之功能很重要。舉例而言，在某些實施例中，可將本文所描述之化合物表現為單個基因產物（例如，單個多肽鏈，亦即多蛋白前驅物），需要藉由天然或重組細胞機制執行蛋白水解裂解以形成本文所描述之化合物之單獨多肽。因此，本揭示案包含設計核酸序列以編碼包含本文所描述之化合物之多肽的多蛋白前驅物分子，此核酸序列包括能夠導引該多蛋白前驅物之轉譯後裂解的編碼序列。多蛋白前驅物之轉譯後裂解產生本文所描述之化合物之多肽。包含本文所描述之化合物之多肽的前驅物分子之轉譯後裂解可發生在活體內（亦即，藉由天然或重組細胞系統/機制在宿主細胞內，例如在適宜位點處的弗林蛋白酶裂解）或可發生在活體外（例如，該多肽鏈在包含已知活性之蛋白酶或肽酶的組合物中或在包含已知促進所需蛋白水解作用的條件或試劑的組合物中的培養）。本技術領域中熟知重組蛋白之純化及修飾，使得多蛋白前驅物之設計可包括易於被熟練技術人員所理解的眾多實施例。本技術領域中已知的任何已知蛋白酶或肽酶可用於前驅物分子之所描述修飾，例如凝血酶或Xa因子（Nagai等人，(1985) 「Oxygen Binding Properties Of Human Mutant Hemoglobins Synthesized In Escherichia Coli」，Proc. Nat. Acad. Sci. USA 82:7252-7255，及在Jenny等人，(2003) 「A Critical Review Of The Methods For Cleavage Of Fusion Proteins With Thrombin And Factor Xa」，Protein Expr. Purif. 31:1-11中綜述，上述之各者以引用之方式全部併入本文）、腸激酶（Collins-Racie等人，(1995) 「Production Of Recombinant Bovine Enterokinase Catalytic Subunit In Escherichia Coli Using The Novel Secretory Fusion Partner DsbA」，Biotechnology 13:982-987，藉此以引用之方式全部併入本文）、弗林蛋白酶及AcTEV（Parks等人，(1994) 「Release Of Proteins And Peptides From Fusion Proteins Using A Recombinant Plant Virus Proteinase」，Anal. Biochem. 216:413-417，藉此以引用之方式全部併入本文）以及口蹄疫病毒蛋白酶C3。
不同宿主細胞對於蛋白質及基因產物之轉譯後處理及修飾具有特定及特異性機制。可選擇適宜細胞株或宿主系統以確保所表現之外源蛋白之正確修飾及處理。為此目的，可使用真核宿主細胞，此等真核宿主細胞具有細胞機制用於適當處理基因產物之初級轉錄、醣基化作用及磷酸化作用。此類哺乳動物宿主細胞包括但不限於CHO、VERY、BHK、HeLa、COS、MDCK、293、293T、3T3、WI38、BT483、Hs578T、HTB2、BT20與T47D、CRL7030及Hs578Bst。
對於長期、高產量的重組蛋白生產，穩定表現較佳。舉例而言，可設計穩定表現本文所描述之化合物的細胞株。可用由適宜表現控制元件（例如，啟動子、增進子、序列、轉錄終止子、聚腺苷酸化位點等）控制的DNA及可選擇標記轉化宿主細胞，而非使用含有複製之病毒起源的表現載體。在引入外源DNA之後，可允許經設計的細胞在富集培養基中生長1-2天，並且隨後轉換至選擇性培養基。重組質體中的可選擇標記向選擇賦予抗性，並允許細胞將質體穩定地整合到染色體中及生長以形成變異區，接著又可經選殖及擴增成細胞株。此方法可有利地用於設計表現本文所描述之化合物的細胞株。此類經設計的細胞株可特別用於篩選及評估與本文所描述之化合物直接或間接相互作用的化合物。
可使用眾多選擇系統，包括但不限於單純皰疹病毒胸苷激酶（Wigler等人，(1977) 「Transfer Of Purified Herpes Virus Thymidine Kinase Gene To Cultured Mouse Cells」，Cell 11: 223-232）、次黃嘌呤-鳥嘌呤磷酸核糖基轉移酶（Szybalska等人，(1992) 「Use Of The HPRT Gene And The HAT Selection Technique In DNA-Mediated Transformation Of Mammalian Cells First Steps Toward Developing Hybridoma Techniques And Gene Therapy」，Bioessays 14: 495-500）及腺嘌呤磷酸核糖基轉移酶（Lowy等人，(1980) 「Isolation Of Transforming DNA: Cloning The Hamster aprt Gene」，Cell 22: 817-823）基因可分別用於tk-、hgprt-或aprt-細胞。又，抗代謝物抗性可用作以下基因的選擇基礎：dhfr，向甲胺喋呤賦予抗性（Wigler等人，(1980) 「Transformation Of Mammalian Cells With An Amplifiable Dominant-Acting Gene」，Proc. Natl. Acad. Sci. USA 77:3567-3570；O'Hare等人，(1981) 「Transformation Of Mouse Fibroblasts To Methotrexate Resistance By A Recombinant Plasmid Expressing A Prokaryotic Dihydrofolate Reductase」，Proc. Natl. Acad. Sci. USA 78: 1527-1531）；gpt，向黴酚酸賦予抗性（Mulligan等人，(1981) 「Selection For Animal Cells That Express The Escherichia coli Gene Coding For Xanthine-Guanine Phosphoribosyltransferase」，Proc. Natl. Acad. Sci. USA 78: 2072-2076）；neo，向胺基糖苷G-418賦予抗性（Tolstoshev (1993) 「Gene Therapy, Concepts, Current Trials And Future Directions」，Ann. Rev. Pharmacol. Toxicol. 32:573-596；Mulligan (1993) 「The Basic Science Of Gene Therapy」，Science 260:926-932；及Morgan 等人，(1993) 「Human Gene Therapy」，Ann. Rev. Biochem. 62:191-217)及hygro，向潮黴素賦予抗性（Santerre等人，(1984) 「Expression Of Prokaryotic Genes For Hygromycin B And G418 Resistance As Dominant-Selection Markers In Mouse L Cells」，Gene 30:147-156）。在Ausubel等人（編），1993, Current Protocols in Molecular Biology, John Wiley & Sons, NY；Kriegler, 1990, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY中；及在第12章及第13章中，Dracopoli等人（編），1994, Current Protocols in Human Genetics, John Wiley & Sons, NY.；Colberre-Garapin等人，(1981) 「A New Dominant Hybrid Selective Marker For Higher Eukaryotic Cells」，J. Mol. Biol. 150:1-14描述可使用之重組DNA技術領域中通常已知的方法。
可藉由載體擴增增加本文所描述之化合物或本文所描述之多肽之表現水平（對於綜述，參見Bebbington與Hentschel，The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA cloning, 第3卷 (Academic Press, New York, 1987)）。當表現本文所描述之化合物的載體系統中的標記為可擴增的時，宿主細胞培養中存在的抑制子水平的增加將增加標記基因之複本數量。由於擴增區與本文所描述之化合物或本文所描述之多肽之核苷酸序列締合，多肽的產生亦將增加（Crouse等人，「Expression And Amplification Of Engineered Mouse Dihydrofolate Reductase Minigenes」，Mol. Cell. Biol. 3:257-266）。
可使宿主細胞與兩個表現載體共同轉染，第一載體編碼本文所描述之化合物之第一多肽，且第二載體編碼本文所描述之化合物之第二多肽。兩個載體可含有相同的可選擇標記，此等標記啟用兩個多肽之同等表現。或者，可使用單個載體，此載體編碼兩個多肽。本文所描述之化合物之多肽的編碼序列可包含cDNA或基因組DNA。
一旦已重組表現本文所描述之化合物或本文所描述之多肽，可藉由本技術領域中已知的任何方法純化此化合物或多肽以便多肽、多聚蛋白或抗體的純化（例如，類似於基於抗原選擇性的抗體純化方案），例如藉由層析法（例如，離子交換、親和性，尤其是藉由對於特異性抗原的親和性（視情況在蛋白質A選擇之後，在此處化合物包含Fc域（或Fc域的部分）），以及尺寸管柱層析法），離心作用，差異可溶性，或藉由任何其他標準技術以便多肽或抗體的純化。
本揭示案之其他態樣係關於一種包含本文所描述之核酸或本文所描述之載體的細胞。細胞可為原核或真核細胞。在一些實施例中，細胞為哺乳動物細胞。本文描述示例性細胞類型。
本揭示案之又其他態樣係關於一種產生本文所描述之化合物或本文所描述之多肽（例如，第一多肽或第二多肽）的方法，此方法包含：獲得本文所描述之細胞；及在該細胞中表現本文所描述之核酸。在一些實施例中，此方法進一步包含分離及純化本文所描述之化合物或本文所描述之多肽。治療方法及供醫學中使用的組合物
本揭示案之其他態樣係關於治療方法及供醫學中使用的組合物。供此類方法及組合物中使用的化合物之非限制性實例係包含以下的化合物： (i)  該第一多肽包含SEQ ID NO:5之胺基酸序列及該第二多肽包含SEQ ID NO:6之胺基酸序列；或 (ii) 該第一多肽包含SEQ ID NO:7之胺基酸序列及該第二多肽包含SEQ ID NO:8之胺基酸序列；或 (iii) 該第一多肽包含SEQ ID NO:9之胺基酸序列及該第二多肽包含SEQ ID NO:10之胺基酸序列；或 (iv) 該第一多肽包含SEQ ID NO:11之胺基酸序列及該第二多肽包含SEQ ID NO:12之胺基酸序列；或 (v)  該第一多肽包含SEQ ID NO:13之胺基酸序列及該第二多肽包含SEQ ID NO:14之胺基酸序列；或 (vi) 該第一多肽包含SEQ ID NO:15之胺基酸序列及該第二多肽包含SEQ ID NO:16之胺基酸序列；或 (vii)   該第一多肽包含SEQ ID NO:17之胺基酸序列及該第二多肽包含SEQ ID NO:18之胺基酸序列；或 (viii)  該第一多肽包含SEQ ID NO:19之胺基酸序列及該第二多肽包含SEQ ID NO:20之胺基酸序列；或 (ix) 該第一多肽包含SEQ ID NO:21之胺基酸序列及該第二多肽包含SEQ ID NO:22之胺基酸序列；或 (x)  該第一多肽包含SEQ ID NO:23之胺基酸序列及該第二多肽包含SEQ ID NO:24之胺基酸序列；或 (xi) 該第一多肽包含SEQ ID NO:25之胺基酸序列及該第二多肽包含SEQ ID NO:26之胺基酸序列；或 (xii)   該第一多肽包含SEQ ID NO:27之胺基酸序列及該第二多肽包含SEQ ID NO:28之胺基酸序列；或 (xiii)  該第一多肽包含SEQ ID NO:29之胺基酸序列及該第二多肽包含SEQ ID NO:30之胺基酸序列；或 (xiv)  該第一多肽包含SEQ ID NO:31之胺基酸序列及該第二多肽包含SEQ ID NO:32之胺基酸序列；或 (xv) 該第一多肽包含SEQ ID NO:33之胺基酸序列及該第二多肽包含SEQ ID NO:34之胺基酸序列；或 (xvi)  該第一多肽包含SEQ ID NO:35之胺基酸序列及該第二多肽包含SEQ ID NO:36之胺基酸序列；或 (xvii) 該第一多肽包含SEQ ID NO:37之胺基酸序列及該第二多肽包含SEQ ID NO:38之胺基酸序列；或 (xviii) 該第一多肽包含SEQ ID NO:39之胺基酸序列及該第二多肽包含SEQ ID NO:40之胺基酸序列；或 (xix)  該第一多肽包含SEQ ID NO:41之胺基酸序列及該第二多肽包含SEQ ID NO:42之胺基酸序列；或 (xx) 該第一多肽包含SEQ ID NO:43之胺基酸序列及該第二多肽包含SEQ ID NO:44之胺基酸序列；或 (xxi)  該第一多肽包含SEQ ID NO:45之胺基酸序列及該第二多肽包含SEQ ID NO:46之胺基酸序列；或 (xxii) 該第一多肽包含SEQ ID NO:47之胺基酸序列及該第二多肽包含SEQ ID NO:48之胺基酸序列；或 (xxiii) 該第一多肽包含SEQ ID NO:49之胺基酸序列及該第二多肽包含SEQ ID NO:50之胺基酸序列；或 (xxiv) 該第一多肽包含SEQ ID NO:51之胺基酸序列及該第二多肽包含SEQ ID NO:52之胺基酸序列；或 (xxv)  該第一多肽包含SEQ ID NO:53之胺基酸序列及該第二多肽包含SEQ ID NO:54之胺基酸序列；或 (xxvi) 該第一多肽包含SEQ ID NO:55之胺基酸序列及該第二多肽包含SEQ ID NO:56之胺基酸序列；或 (xxvii)   該第一多肽包含SEQ ID NO:57之胺基酸序列及該第二多肽包含SEQ ID NO:58之胺基酸序列；或 (xxviii)  該第一多肽包含SEQ ID NO:59之胺基酸序列及該第二多肽包含SEQ ID NO:60之胺基酸序列；或 (xxix) 該第一多肽包含SEQ ID NO:61之胺基酸序列及該第二多肽包含SEQ ID NO:62之胺基酸序列；或 (xxx)  該第一多肽包含SEQ ID NO:63之胺基酸序列及該第二多肽包含SEQ ID NO:64之胺基酸序列；或 (xxxi) 該第一多肽包含SEQ ID NO:65之胺基酸序列及該第二多肽包含SEQ ID NO:66之胺基酸序列；或 (xxxii)   該第一多肽包含SEQ ID NO:67之胺基酸序列及該第二多肽包含SEQ ID NO:68之胺基酸序列。
在一些實施例中，治療方法或用途係治療自體免疫疾病或炎性疾病之方法或此方法中的用途。在一些實施例中，此方法包含向個體（例如，患有自體免疫疾病或炎性疾病或處於罹患自體免疫疾病或炎性疾病風險中的個體）投予本文所描述之化合物或包含該化合物的醫藥組合物。
待由本文所描述之方法治療之個體可為哺乳動物，更佳為人類。哺乳動物包括但不限於農場動物、運動動物、寵物、靈長類動物、馬、犬、貓、小鼠及大鼠。需要治療的人類個體可為患有疾病、處於患病風險或懷疑患有疾病的人類個體。患有疾病的個體可藉由常規醫療檢查（例如，身體檢查、實驗室測試、器官功能測試、CT掃描或超音波）識別。懷疑患有任何此疾病的個體可展示出此疾病之一或更多個症狀。疾病（例如，自體免疫及炎性疾病）的體征及症狀為本技術領域中的一般技藝者所熟知。處於患病風險中的個體可為具有彼疾病之風險因數中的一或更多者的個體。
自體免疫疾病之非限制性實例包括狼瘡腎炎(lupus nephritis; LN)（腎臟受累及的全身性紅斑狼瘡(systemic lupus erythematosus; SLE)）、全身性紅斑狼瘡(systemic lupus erythematosus; SLE)、原發性乾燥症候群(primary Sjogren's syndrome; pSS)、休格倫氏病、移植物抗宿主病(graft versus host disease; GVHD)（例如，慢性移植物抗宿主病(chronic graft versus host disease; cGVHD)）、全身性硬化症(systemic sclerosis; SSc)、抗嗜中性白血球細胞質自體抗體(Anti-Neutrophil Cytoplasmic Autoantibody; ANCA)關聯血管炎(ANCA-associated vasculitis; AAV)、類風濕性關節炎、牛皮癬、1型糖尿病、全身性紅斑狼瘡、移植排斥、自體免疫性甲狀腺病（橋本氏病）、結節病、硬皮病、肉芽腫性血管炎、克羅恩氏病、潰瘍性結腸炎、休格倫氏病、強直性脊椎炎、牛皮癬性關節炎、多肌炎性皮肌炎、多發性結節性動脈炎、免疫介導的起泡皮膚病、Behcet氏症候群、多發性硬化症、古巴士德氏病或免疫介導的腎絲球性腎炎。
炎性疾病之非限制性實例包括類風濕性關節炎、全身性紅斑狼瘡、斑禿、強直性脊椎炎、抗磷脂症候群、自體免疫性阿狄森氏病、自體免疫性溶血性貧血、自體免疫性肝炎、自體免疫性內耳病、自體免疫性淋巴組織增生症候群(autoimmune lymphoproliferative syndrome; ALPS)、自體免疫性血小板減少性紫癜(autoimmune thrombocytopenic purpura; ATP)、Behcet氏病、大皰性類天皰瘡、心肌病、口炎性腹瀉-皮炎、慢性疲勞症候群免疫缺陷症候群(chronic fatigue syndrome immune deficiency syndrome; CFIDS)、慢性炎性脫髓鞘性多發性神經病、瘢痕性類天皰瘡、冷凝集素病、Crest症候群、克羅恩氏病、Dego氏病、皮肌炎、皮肌炎-青少年、盤狀狼瘡、原發性混合型冷球蛋白血症、纖維肌痛-纖維肌炎、格雷氏病、格巴二氏症候群、橋本氏甲狀腺炎、特發性肺纖維化、特發性血小板減少性紫癜(idiopathic thrombocytopenia purpura; ITP)、Iga腎病、胰島素依賴型糖尿病（I型）、青少年關節炎、梅尼埃病、混合結締組織病、多發性硬化症、重症肌無力、尋常天皰瘡、惡性貧血、多發性結節性動脈炎、多軟骨炎、多腺體症候群、風濕性多肌痛、多肌炎與皮肌炎、原發性無γ球蛋白血症、原發性膽汁性肝硬化、牛皮癬、Raynaud氏現象、Reiter氏症候群、風濕熱、結節病、硬皮症、乾燥症候群、全身肌強直症候群、Takayasu氏動脈炎、顳動脈炎/巨細胞動脈炎、潰瘍性結腸炎、葡萄膜炎、血管炎、白斑病及華格納氏肉芽病。在一些實施例中，自體免疫疾病或炎性疾病為克羅恩氏病、強直性脊椎炎或牛皮癬性關節炎。
為了實踐本文所揭示之方法，可向需要治療的個體（例如，人類）投予有效量的本文所描述之化合物或醫藥組合物。已知各種遞送系統及可使用此等遞送系統投予本發明技術之化合物。投藥方法包括但不限於：皮內、肌內、腹腔內、靜脈內、皮下、鼻內、硬膜外及口服路徑。可例如藉由輸注、快速推注或注射投予本發明技術之化合物，並且可與其他生物活性劑（諸如抗炎劑）一起投予此等化合物。投藥可為全身或局部。在較佳實施例中，投藥為藉由皮下注射。可在例如預填充式注射器中製備此類注射的調配物，可每隔一週投予一次。
本文所使用之「有效量」係指在單獨或與一或更多種其他化合物組合情況下對個體賦予治療效果所需的每一化合物的量。取決於正治療的特定病症、病症嚴重程度、個體個體參數（包括年齡、身體狀況、體型、性別及體重）、治療持續時間、並行治療（若有）的性質、投藥之特定路徑以及保健醫生知識與經驗範圍內的類似因素，有效量隨熟習此項技術者所認可的而不同。此等因數為本技術領域中的一般技藝者所熟知，且可在不超過常規的實驗中加以解決。通常較佳的是，使用個別組分或組分之組合的最大劑量，亦即根據合理醫學判斷的最高安全劑量。然而，本技術領域中的一般技藝者應理解，出於醫學原因、心理原因或出於實際上任何其他原因，個體可堅持較低劑量或可耐受劑量。
經驗考慮（諸如半衰期）通常將有助於劑量的判定。舉例而言，與人類免疫系統可相容的化合物（諸如包含來自人化抗體或完全人類抗體的區的化合物）可用以延長化合物之半衰期並防止化合物受到宿主免疫系統攻毒。可在治療過程中決定及調整投藥頻率，且大體上但非必然根據疾病之治療及/或抑制及/或改善及/或延緩。或者，化合物之持續連續釋放調配物可為適宜的。本技術領域中已知用於實現持續釋放的多種調配物及裝置。
在一些實施例中，劑量為每日、每隔一天、每三天、每四天、每五天或每六天。在一些實施例中，投藥頻率為每週、每2週、每4週、每5週、每6週、每7週、每8週、每9週或每10週一次；或每月、每2月或每3月或更久一次。此治療之進展易於藉由習知技術及檢定監測。投藥方案（包括所用化合物）可隨時間而變化。
在一些實施例中，對於正常重量的成人個體，可投予自約0.01至1000 mg/kg範圍內之劑量。在一些實施例中，劑量介於1至200 mg之間。特定劑量方案（亦即，劑量、定時及重複）將取決於特定個體及彼個體之病史，以及化合物之性質（諸如化合物之半衰期及本技術領域中熟知的其他考慮）。
出於本揭示案之目的，本文所描述之化合物之適宜劑量將取決於所採用的特定化合物（或化合物之組合物）、給藥之調配物及路徑、疾病之類型及嚴重程度、化合物是否投予用於預防或治療目的、先前治療、個體之臨床史及對拮抗劑的反應以及主治醫師的判斷。通常，臨床醫師將投予化合物，直至達到實現所欲結果的劑量。一或更多種化合物之投藥可為連續或間歇性，例如取決於受者之生理狀況、投藥目的是治療還是預防，及熟練實踐者已知的其他因數。化合物投藥可在預選定時段上基本連續，或可以一系列間隔劑量，例如在發展疾病之前、期間或之後。
本文所使用之術語「治療」係指向患病、具有疾病症狀或患病傾向的個體應用或投予化合物或包括化合物的組合物，目的是治療、治癒、減輕、緩解、改變、補救、改良、改善或影響疾病、疾病症狀或患病傾向。
減輕疾病包括延緩疾病之發展或進程，或降低疾病嚴重程度。減輕疾病不一定需要治癒結果。本文所使用之「延緩」疾病之發展係指延期、阻礙、減緩、延遲、穩定及/或推遲疾病之進程。此延緩可取決於病史及/或接受治療的個體而具有不同時間長度。「延緩」或減輕疾病發展或延緩疾病發病的方法係在與不使用此方法相比時在給定時間框內減小發展一或更多個疾病症狀的機率及/或在給定時間框內減輕症狀程度的方法。此類比較通常基於臨床研究，使用足以給出統計上顯著結果的眾多個體。
疾病之「發展」或「進程」意指疾病之最初表現及/或隨後進程。疾病之發展可為可偵測的且使用本技術領域中熟知的標準臨床技術加以評估。然而，發展亦指示可為不可偵測的進程。出於本揭示案之目的，發展或進程指示病症之生物學過程。「發展」包括發生、復發及發病。本文所使用之疾病之「發病」或「發生」包括最初發病及/或復發。
在一些實施例中，以一定量向需要治療的個體投予本文所描述之化合物，此量足以在活體內或活體外將BAFF或IL23A之一者或兩者之活性抑制至少20%（例如，30%、40%、50%、60%、70%、80%、90%或更大）。本技術領域中已知用於判定化合物之抑制能力的方法。在實例中提供示例性BAFF及IL23A抑制檢定。
醫學技術領域中的一般技藝者已知的習知方法可用於取決於待治療之疾病類型或疾病部位向個體投予化合物或醫藥組合物。亦可經由其他習知路徑（例如，口服、非經腸、藉由吸入噴霧、局部、直腸、經鼻、口腔、陰道或經由植入的儲藥器投予）投予此組合物。本文所使用之術語「非經腸」包括皮下、皮內、靜脈內、肌內、關節內、動脈內、滑膜內、胸骨內、鞘內、病灶內及顱內注射或輸注技術。另外，可經由投藥之可注射積存路徑（諸如使用1個月、3個月或6個月積存可注射或生物可降解材料及方法）向個體投予組合物。醫藥組合物
本揭示案之又其他態樣係關於包含本文描述之化合物的醫藥組合物。可向患有自體免疫疾病或炎性疾病或處於罹患自體免疫疾病或炎性疾病風險的患者投予包含本發明技術之化合物（例如，對於BAFF與IL23A兩者特異的化合物）的組合物。本發明技術進一步提供本發明技術之化合物在用於治療自體免疫疾病或炎性疾病的藥劑製造中的使用。在預防或治療自體免疫疾病或炎性疾病中單獨或與其他組合物組合投予化合物。供此類醫藥組合物中使用的本發明技術之化合物之非限制性實例係包含以下的化合物： (i)  該第一多肽包含SEQ ID NO:5之胺基酸序列及該第二多肽包含SEQ ID NO:6之胺基酸序列；或 (ii) 該第一多肽包含SEQ ID NO:7之胺基酸序列及該第二多肽包含SEQ ID NO:8之胺基酸序列；或 (iii) 該第一多肽包含SEQ ID NO:9之胺基酸序列及該第二多肽包含SEQ ID NO:10之胺基酸序列；或 (iv) 該第一多肽包含SEQ ID NO:11之胺基酸序列及該第二多肽包含SEQ ID NO:12之胺基酸序列；或 (v)  該第一多肽包含SEQ ID NO:13之胺基酸序列及該第二多肽包含SEQ ID NO:14之胺基酸序列；或 (vi) 該第一多肽包含SEQ ID NO:15之胺基酸序列及該第二多肽包含SEQ ID NO:16之胺基酸序列；或 (vii)   該第一多肽包含SEQ ID NO:17之胺基酸序列及該第二多肽包含SEQ ID NO:18之胺基酸序列；或 (viii)  該第一多肽包含SEQ ID NO:19之胺基酸序列及該第二多肽包含SEQ ID NO:20之胺基酸序列；或 (ix) 該第一多肽包含SEQ ID NO:21之胺基酸序列及該第二多肽包含SEQ ID NO:22之胺基酸序列；或 (x)  該第一多肽包含SEQ ID NO:23之胺基酸序列及該第二多肽包含SEQ ID NO:24之胺基酸序列；或 (xi) 該第一多肽包含SEQ ID NO:25之胺基酸序列及該第二多肽包含SEQ ID NO:26之胺基酸序列；或 (xii)   該第一多肽包含SEQ ID NO:27之胺基酸序列及該第二多肽包含SEQ ID NO:28之胺基酸序列；或 (xiii)  該第一多肽包含SEQ ID NO:29之胺基酸序列及該第二多肽包含SEQ ID NO:30之胺基酸序列；或 (xiv)  該第一多肽包含SEQ ID NO:31之胺基酸序列及該第二多肽包含SEQ ID NO:32之胺基酸序列；或 (xv) 該第一多肽包含SEQ ID NO:33之胺基酸序列及該第二多肽包含SEQ ID NO:34之胺基酸序列；或 (xvi)  該第一多肽包含SEQ ID NO:35之胺基酸序列及該第二多肽包含SEQ ID NO:36之胺基酸序列；或 (xvii) 該第一多肽包含SEQ ID NO:37之胺基酸序列及該第二多肽包含SEQ ID NO:38之胺基酸序列；或 (xviii) 該第一多肽包含SEQ ID NO:39之胺基酸序列及該第二多肽包含SEQ ID NO:40之胺基酸序列；或 (xix)  該第一多肽包含SEQ ID NO:41之胺基酸序列及該第二多肽包含SEQ ID NO:42之胺基酸序列；或 (xx) 該第一多肽包含SEQ ID NO:43之胺基酸序列及該第二多肽包含SEQ ID NO:44之胺基酸序列；或 (xxi)  該第一多肽包含SEQ ID NO:45之胺基酸序列及該第二多肽包含SEQ ID NO:46之胺基酸序列；或 (xxii) 該第一多肽包含SEQ ID NO:47之胺基酸序列及該第二多肽包含SEQ ID NO:48之胺基酸序列；或 (xxiii) 該第一多肽包含SEQ ID NO:49之胺基酸序列及該第二多肽包含SEQ ID NO:50之胺基酸序列；或 (xxiv) 該第一多肽包含SEQ ID NO:51之胺基酸序列及該第二多肽包含SEQ ID NO:52之胺基酸序列；或 (xxv)  該第一多肽包含SEQ ID NO:53之胺基酸序列及該第二多肽包含SEQ ID NO:54之胺基酸序列；或 (xxvi) 該第一多肽包含SEQ ID NO:55之胺基酸序列及該第二多肽包含SEQ ID NO:56之胺基酸序列；或 (xxvii)   該第一多肽包含SEQ ID NO:57之胺基酸序列及該第二多肽包含SEQ ID NO:58之胺基酸序列；或 (xxviii)  該第一多肽包含SEQ ID NO:59之胺基酸序列及該第二多肽包含SEQ ID NO:60之胺基酸序列；或 (xxix) 該第一多肽包含SEQ ID NO:61之胺基酸序列及該第二多肽包含SEQ ID NO:62之胺基酸序列；或 (xxx)  該第一多肽包含SEQ ID NO:63之胺基酸序列及該第二多肽包含SEQ ID NO:64之胺基酸序列；或 (xxxi) 該第一多肽包含SEQ ID NO:65之胺基酸序列及該第二多肽包含SEQ ID NO:66之胺基酸序列；或 (xxxii)   該第一多肽包含SEQ ID NO:67之胺基酸序列及該第二多肽包含SEQ ID NO:68之胺基酸序列。
本文所使用之術語「醫藥組合物」係指本文所描述之化合物與醫藥學上可接受之載體組合的調配物。醫藥組合物可進一步包含額外製劑（例如，用於特異性遞送、增加半衰期或其他治療化合物）。
本文所使用之術語「醫藥學上可接受之載體」意指涉及自身體之一個部位（例如，遞送點）攜帶或輸送化合物至另一部位（例如，身體之器官、組織或部分）的醫藥學上可接受之材料、組合物或媒劑，諸如液體或固體填充劑、稀釋劑、賦形劑、製造助劑（例如，潤滑劑、滑石硬脂酸鎂、硬脂酸鈣或硬脂酸鋅或硬脂酸），或溶劑封裝材料。醫藥學上可接受之載體係在與調配物之其他成分可相容且對個體之組織無損害的意義上「可接受」（例如，生理學上可相容、無菌、生理pH等）。
可充當醫藥學上可接受之載體的材料之一些實例包括：(1)糖，諸如乳糖、葡萄糖及蔗糖；(2)澱粉，諸如玉米澱粉及馬鈴薯澱粉；(3)纖維素及其衍生物，諸如羧甲基纖維素鈉鹽、甲基纖維素、乙基纖維素、微晶纖維素及醋酸纖維素；(4)粉末狀黃蓍膠；(5)麥芽；(6)明膠；(7)潤滑劑，諸如硬脂酸鎂、月桂基硫酸鈉及滑石；(8)賦形劑，諸如可可脂及栓劑蠟；(9)油劑，諸如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油及大豆油；(10)二醇，諸如丙二醇；(11)多元醇，諸如甘油、山梨糖醇、甘露醇及聚乙二醇(polyethylene glycol; PEG)；(12)酯，諸如油酸乙酯及月桂酸乙酯；(13)瓊脂；(14)緩衝劑，諸如氫氧化鎂及氫氧化鋁；(15)褐藻酸；(16)無熱原水；(17)等滲鹽水；(18)林格氏溶液；(19)乙醇；(20)pH緩衝溶液；(21)聚酯、聚碳酸酯及/或聚酐；(22)膨脹劑，諸如多肽及胺基酸(23)血清組分，諸如血清白蛋白、HDL及LDL；(22)C2-C12醇類，諸如乙醇；及(23)醫藥調配物中所採用的其他無毒可相容物質。
調配物中亦可存在濕潤劑、著色劑、釋放劑、包覆劑、甜味劑、調味劑、芳香劑、防腐劑及抗氧化劑。本文可互換使用諸如「賦形劑」、「載體」、「醫藥學上可接受之載體」等術語。
在一些實施例中，藉由注射、經由導管、經由栓劑或經由植入物投予組合物中的本發明技術之化合物，植入物具有多孔、無孔或凝膠狀材料，包括膜（諸如矽膠膜）或纖維。通常，當投予組合物時，使用本發明技術之化合物不吸收的材料。
在其他實施例中，在控制釋放系統中遞送本發明技術之化合物。在一個實施例中，可使用泵（參見，例如，Langer, 1990, Science 249:1527-1533；Sefton, 1989, CRC Crit. Ref. Biomed. Eng. 14:201；Buchwald等人，1980, Surgery 88:507；Saudek等人，1989, N. Engl. J. Med. 321:574）。在另一實施例中，可使用聚合材料。（參見，例如，Medical Applications of Controlled Release （Langer與Wise編，CRC Press, Boca Raton, Fla., 1974）；Controlled Drug Bioavailability, Drug Product Design and Performance（Smolen與Ball編，Wiley, New York, 1984）；Ranger與Peppas，1983, Macromol. Sci. Rev. Macromol. Chem. 23:61。亦參見Levy等人，1985, Science 228:190；During等人，1989, Ann. Neurol. 25:351；Howard等人，1989, J. Neurosurg. 71:105.）其他控制釋放系統論述於例如Langer(同上)中。
本發明技術之化合物可作為醫藥組合物投予，此等醫藥組合物包含治療有效量之結合劑及一或更多種醫藥學上可相容之成分。
在典型實施例中，根據常規程序將醫藥組合物調配為適於向個體（例如，人類）靜脈內注射或皮下投藥的醫藥組合物。通常，藉由注射投藥的組合物為無菌等滲水性緩衝液中的溶液。在必要情況下，藥物亦可包括增溶劑及局部麻醉劑（諸如利多卡因），以在注射部位處減輕疼痛。大體而言，單獨或以單位劑型混合在一起供應成分，例如作為在指示活性劑之量的密閉容器（諸如安瓿或藥囊）中的凍乾粉末或無水濃縮物。在藉由輸注投予藥物的情況下，可利用含有無菌醫藥級用水或鹽水的輸液瓶分配藥物。在藉由注射投予藥物時，可提供注射用無菌水或鹽水之安瓿，使得可在投藥前混合多種成分。
對於全身性投藥的醫藥組合物可為液體（例如，無菌鹽水、乳酸林格氏溶液或Hank's溶液）。另外，醫藥組合物可呈固體形式並在使用前不久再溶解或懸浮。亦涵蓋凍乾形式。
可在脂質顆粒或微脂粒（諸如脂質體或微晶）內含有醫藥組合物，此亦適於非經腸投藥。顆粒可具有任何適宜結構，諸如單層或多層，只要組合物含在其中。可在含有融合脂質二油醯基磷脂醯乙醇胺(dioleoylphosphatidylethanolamine; DOPE)、低水平（5莫耳%-10莫耳%）陽離子脂質的「穩定質體-脂質顆粒」(stabilized plasmid-lipid particle; SPLP)中截留化合物，並藉由聚乙二醇(polyethyleneglycol; PEG)塗層使得穩定（Zhang Y. P.等人，Gene Ther. 1999, 6:1438-47）。帶正電荷的脂質（諸如N-[1-(2,3-二油醯基氧)丙基]-N,N,N-三甲基-甲基硫酸銨））或「DOTAP」對於此類顆粒及微脂粒尤其較佳。熟知此類脂質顆粒之製備。參見，例如，美國專利第4,880,635號；第4,906,477號；第4,911,928號；第4,917,951號；第4,920,016號；及第4,921,757號。
舉例而言，可作為單位劑量投予或封裝本揭示案之醫藥組合物。當關於本揭示案之醫藥組合物使用時，術語「單位劑量」係指對於個體適合作為整體劑量的實體分立單元，每一單元含有預定量之活性材料，此量經計算以產生與所需稀釋劑（亦即，載體或媒劑）關聯的所需治療效果。
在一些實施例中，可將本文所描述之化合物共軛至治療部分（例如，抗炎劑）。熟知用於將此類治療部分共軛至多肽（包括例如Fc域）的技術；參見，例如，Amon等人，「Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy」，Monoclonal Antibodies And Cancer Therapy中，Reisfeld等人（編），1985，第243-56頁，Alan R. Liss, Inc.）；Hellstrom等人，「Antibodies For Drug Delivery」，Controlled Drug Delivery（第2版），Robinson等人（編），1987，第623-53頁，Marcel Dekker, Inc.）；Thorpe，「Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review」，Monoclonal Antibodies '84: Biological And Clinical Applications中，Pinchera等人（編），1985，第475-506頁）；「Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy」，Monoclonal Antibodies For Cancer Detection And Therapy中，Baldwin等人（編），1985，第303-16頁，Academic Press；及Thorpe等人(1982) 「The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates」，Immunol. Rev., 62:119-158。
此外，可將醫藥組合物提供為醫藥套組，此醫藥套組包含：(a)容器，含有呈凍乾形式的本發明技術之化合物；及(b)第二容器，含有用於注射的醫藥學上可接受之稀釋劑（例如，無菌水）。醫藥學上可接受之稀釋劑可用於本發明技術之凍乾化合物之重新構成或稀釋。與此類容器視情況關聯的可為以由監管醫藥或生物製品之製造、使用或銷售的政府機構規定的形式呈現的注意事項，此注意事項反映了此機構針對人類投藥在製造、使用或銷售方面的審批。
在另一態樣中，包括含有用於治療上文所描述之疾病的材料的製品。在一些實施例中，製品包含容器及標籤。適宜容器包括例如瓶、小瓶、注射器及試管。容器可由諸如玻璃或塑膠之各種材料形成。在一些實施例中，容器盛放有效用於治療本文所描述之疾病的組合物且可具有無菌出入口。舉例而言，容器可為靜脈內輸液袋或具有可由皮下注射針刺穿之擋止件的小瓶。組合物中的活性劑為本發明技術之化合物。在一些實施例中，容器上或與容器關聯的標籤指示組合物用於治療所選疾病。製品可進一步包含第二容器，第二容器包含醫藥學上可接受之緩衝劑，諸如磷酸鹽緩衝鹽水、林格氏溶液或右旋糖溶液。製品可進一步包括在商業及使用者立場上所需的其他材料，包括其他緩衝劑、稀釋劑、過濾器、針頭、注射器及具有使用說明書的包裝插頁。
在無進一步詳細說明的情況下，據信熟習此項技術者可基於上文描述利用本揭示案至最大程度。因此，將以下特定實施例視為僅具有說明性，而在任何情況下不以任何方式限制本揭示案之剩餘部分。出於本文所引用之目的或標的，以引用之方式合併本文所引用之所有專利公開案。 實例實例 1 ：靶向 IL23A 及 BAFF 的示例性化合物之構造
藉由技術領域中已知的重組方法產生本發明技術之化合物（參見，例如，PCT公開案WO 2006/113665、WO 2008/157379及WO 2010/080538，上述所有公開案之內容以引用之方式併入本文）。表2A提供結合至下文實例中使用之IL23A與BAFF兩者的示例性化合物。簡言之，使用FreeStyle MAX試劑(CHO)將編碼每一化合物之第一多肽及第二多肽的質體一起轉染至CHO-S細胞中。將細胞培養13-14天，並使用蛋白A層析法純化由細胞產生的化合物。使用尺寸排阻層析法進一步純化化合物。
表2A：示例性IL23A與BAFF結合化合物
Figure 105123026-A0304-0002
 VL=可變域輕鏈，VH=可變域重鏈，每一鏈在VL與VH之間包含連接子GGGSGGG (SEQ ID NO:69)。
亦出於比較目的使用對照抗體。對照組係靶向BAFF或IL23任一者的單株抗體。
表2B：對照抗體/拮抗劑
Figure 105123026-A0304-0003
 實例 2 ：化合物之熱穩定性 方法
在20℃至110℃下經由自動毛細管DSC（MicroCal，LLC，波士頓）以60℃/hr之掃描頻率監控化合物在磷酸鹽緩衝液中的2 mg/ml溶液之熱去折疊及聚集。執行利用相應緩衝液的兩次掃描以建立儀器熱歷史，並獲得每一樣本的儀器基線，其中自後續蛋白質溫譜圖減去此等掃描之平均值以獲得表觀熱容量。隨後用Origin 7.0分析正規化掃描。自每一所得熱容量溫譜圖減去轉變前基線，以給出隨溫度變化的所得過多熱容量(Cp,ex)。轉變溫度(Tm)之報告值表示由實驗溫譜圖之目視檢驗判定的峰最大值之位置。結果
表3中展示結果。資料展示，靶向IL23A及BAFF的示例性化合物具有第一峰(Tm1 )的轉變溫度範圍，處於自51.59℃至71.25℃範圍內。結果令人驚訝，因為示例性化合物全部皆具有相同整體結構並含有靶向IL-23A的相同VH及VL基因序列。具有較高轉變溫度的化合物更加穩定，並預計具有長存放期。
表3：化合物的熱去折疊轉變溫度
Figure 105123026-A0304-0004
 實例 3 ：示例性化合物之表面電漿共振 (Surface Plasma Resonance; SPR) 親和性
藉由SPR分析測試化合物以判定BAFF及IL23A的親和性。材料及方法：
在ProteOn XPR36儀器(Bio Rad)上執行SPR實驗。在垂直與水平方向上以30 μl/min之流動速率將0.5%之SDS、50 mM之NaOH及100 mM之HCl連續注射60秒來預處理GLM晶片。
隨後藉由在6個水平通道中以1:1之比率注射EDC (76.7 mg/ml)及磺基-NHS (21.7 mg/ml)混合物活化預處理GLM晶片。將10 mM、pH 5.0醋酸鈉緩衝液中的濃度為30 μg/ml之山羊抗人IgG (GAHA) Fcγ (Invitrogen)在6個水平通道中固定至活化GLM晶片上的8,000個共振單元。最後在6個水平通道中利用1 M乙醇胺HCl停用晶片。將所製備GAHA晶片旋轉至垂直方向以在5個垂直通道上捕集測試化合物，並且將最後一個通道用作管柱參照。
隨後將所捕集之晶片再次旋轉至水平方向以便結合。在以下流動緩衝液(Bio Rad)：磷酸鹽緩衝液鹽水(pH 7.4)，0.005% Tween 20中以40 μl/min之流動速率將五個濃度10.0 nM、5.00 nM、2.50 nM、1.25 nM及0.625 nM的經連接之人IL-23 (Boehringer Ingelheim Pharmaceuticals, Inc.)水平注射到測試化合物表面上10分鐘。允許解離2小時。在10分鐘締合及2小時解離後，在水平與垂直方向上以100 μl/min之流動速率使用短脈衝注射（18秒）0.85%之磷酸(Bio Rad)再生GAHA表面。再生GAHA準備用於另一結合週期。以類似方式實行化合物至食蟹獼猴IL23、人BAFF或食蟹獼猴BAFF之結合，但用於結合至人BAFF或食蟹獼猴BAFF的滴定濃度為6.25 nM、3.12 nM、1.56 nM、0.78 nM及0.39 nM。結果：
表4中的結果展示出所測試之兩種化合物能夠在皮莫耳範圍內的解離常數(KD)下結合BAFF及IL23。
表4：化合物結合至BAFF及IL23之親和性
Figure 105123026-A0304-0005
 實例 4 ： BAFFR-CHO 螢光素酶報導細胞中的人及食蟹獼猴 BAFF 三聚體誘導 NFkB 活化的抑制 材料 / 方法：
簡言之，在X-VIVO15（一種化學定義的無血清培養基(Lonza)）中(v/v) 1%青黴素/鏈黴素之檢定培養基(assay medium; AM)中以每毫升1.6×106 個細胞之濃度採集、洗滌、計數及再懸浮人BAFFR CHO NFkB螢光素酶報導細胞。在AM中以單一濃度(52 pM)製備重組人或食蟹獼猴BAFF三聚體(Boehringer Ingelheim Pharmaceuticals, Inc.)，並用AM單獨或用測試化合物之連續滴定在加濕培養箱中37℃、5% CO2 下預培養30分鐘。在預培養BAFF+測試化合物之後，將50 ul之混合物添加至50 ul之細胞，並在37℃（如所描述）下進一步培養測試板24小時。對照樣本接收AM（未刺激對照）或AM中稀釋的重組BAFF三聚體（刺激對照）任一者。在24小時培養後，遵循製造商說明書用100ul STEADY-Glo試劑(Promega)處理細胞懸浮液，並且檢定螢光素酶表現。繪製所得相對發光單元(Relative Luminesence Unit; RLU)對比測試化合物之Log10奈莫耳濃度之曲線圖，其中使用由Excel附加項Xlfit (ID Business Solutions Limited)支持的四參數對數模型計算IC50 與IC90 值。如上文所描述的計算測試化合物IC50 與IC90 值，並跨多個實驗計算幾何平均值，且展示於表5及表8中。結果：
測試化合物劑量依賴性地抑制了BAFFR-CHO螢光素酶報導細胞中的人及食蟹獼猴BAFF三聚體誘導NFkB活化。表5及表6中所示結果指出，測試化合物的IC50 與IC90 幾何平均值與對照BAFF拮抗劑相比為相當或更有效力。
表5：用於抑制BAFFR-CHO報導細胞中的人BAFF三聚體的IC50 及IC90 幾何平均值
Figure 105123026-A0304-0006
 表6：用於抑制BAFFR-CHO報導細胞中的食蟹獼猴BAFF三聚體的IC50 及IC90 幾何平均值
Figure 105123026-A0304-0007
 實例 5 ： TACI-CHO 螢光素酶報導細胞中的人 BAFF 三聚體誘導 NFkB 活化的抑制 材料 / 方法：
簡言之，在X-VIVO15（一種化學定義的無血清培養基）中(v/v) 1%青黴素/鏈黴素之檢定培養基(AM)中以每毫升1.6×106 個細胞之濃度採集、洗滌、計數及再懸浮人TACI CHO NFkB螢光素酶報導細胞。在AM中以單一濃度(222 pM)製備重組人BAFF三聚體(Boehringer Ingelheim Pharmaceuticals, Inc.)，並用AM單獨或用測試化合物之連續滴定在加濕培養箱中37℃、5% CO2 下預培養30分鐘。在預培養BAFF+測試化合物之後，將50 ul之混合物添加至50 ul之細胞，並在37℃（如所描述）下進一步培養測試板24小時。對照樣本接收AM（未刺激對照）或AM中稀釋的重組人BAFF三聚體（刺激對照）任一者。在24小時培養後，遵循製造商說明書用100 ul STEADY-Glo試劑(Promega)處理細胞懸浮液，並且檢定螢光素酶表現。繪製所得相對發光單元(Relative Luminesence Unit; RLU)對比測試化合物之Log10奈莫耳濃度之曲線圖，其中使用由Excel附加項Xlfit (ID Business Solutions Limited)支持的四參數對數模型計算IC50 與IC90 值。如上文所描述的計算測試化合物IC50 與IC90 值，並跨多個實驗計算幾何平均值，且展示於表7中。結果：
測試化合物劑量依賴性地抑制了TACI-CHO螢光素酶報導細胞中的人BAFF三聚體誘導NFkB活化。表7中所示結果指出，測試化合物的IC50 與IC90 幾何平均值與對照BAFF拮抗劑相比為相當或更有效力。
表7：用於抑制TACI-CHO報導細胞中的人BAFF三聚體的IC50 及IC90 幾何平均值
Figure 105123026-A0304-0008
 實例 6 ： BAFFR-CHO 螢光素酶報導細胞中的 BAFF 60mer 誘導 NFkB 活化的抑制 材料 / 方法：
簡言之，在X-VIVO15（一種化學定義的無血清培養基）中(v/v) 1%青黴素/鏈黴素之檢定培養基(AM)中以每毫升1.6×106 個細胞之濃度採集、洗滌、計數及再懸浮人BAFFR CHO NFkB螢光素酶報導細胞。在AM中以單一濃度(4.2 pM)製備重組人BAFF 60mer (Boehringer Ingelheim Pharmaceuticals, Inc.)，並用AM單獨或用測試化合物之連續滴定在加濕培養箱中37℃、5% CO2 下預培養30分鐘。在預培養BAFF+測試化合物之後，將50 ul之混合物添加至50 ul之細胞，並在37℃（如所描述）下進一步培養測試板24小時。
對照樣本接收AM（未刺激對照）或AM中稀釋的重組人BAFF 60mer（刺激對照）任一者。在24小時培養後，遵循製造商說明書用100 ul STEADY-Glo試劑(Promega)處理細胞懸浮液，並且檢定螢光素酶表現。繪製所得相對發光單元(Relative Luminesence Unit; RLU)對比測試化合物之Log10奈莫耳濃度之曲線圖，其中使用由Excel附加項Xlfit (ID Business Solutions Limited)支持的四參數對數模型計算IC50 與IC90 值。如上文所描述的計算測試化合物IC50 與IC90 值，並跨多個實驗計算幾何平均值，且展示於表8中。結果：
測試化合物劑量依賴性地抑制了BAFFR-CHO螢光素酶報導細胞中的人BAFF 60mer誘導NFkB活化。表8中所示的結果指出，測試化合物A、B、C、D、O、P、Q及R的IC50 與IC90 幾何平均值與所有三個對照BAFF拮抗劑相比更有效力。
表8：用於抑制BAFFR-CHO報導細胞中的人BAFF 60mer的IC50 及IC90 幾何平均值
Figure 105123026-A0304-0009
 實例 7 ： BAFFRCHO 螢光素酶報導細胞中的膜結合 BAFF 誘導 NFkB 活化的中和 材料 / 方法
計數表現人BAFF的CHO-K1細胞，並在標準生長培養基中以每毫升2×106 個細胞之濃度再懸浮。為了停止膜結合BAFF的裂解，用0.125%多聚甲醛(Electron Microscopy)處理細胞，並在室溫下培養一小時。隨後洗滌固定人BAFF CHO-K1細胞，並在標準生長培養基中以每毫升2×106 個細胞再懸浮，且在37℃、5% CO2 下培養隔夜。隨後採集固定人BAFF CHO-K1細胞，並在X-VIVO15中以每毫升3.2×106 個細胞之濃度再懸浮，X-VIVO15為含有1%青黴素/鏈黴素(v/v)的化學上定義的無血清(Lonza)檢定培養基(AM)。
在檢定培養基中以每毫升1.6×106 個細胞之濃度採集、洗滌及再懸浮人BAFFR CHO NFkB螢光素酶報導細胞。隨後將在AM中以每毫升3.2×106 個細胞製備且用測試化合物之連續滴定預培養的固定人BAFF CHO-K1細胞添加至50 ul之人BAFFR CHO NFkB螢光素酶報導細胞中且在37℃下進一步培養24小時。對照報導細胞接收僅AM（未刺激對照）或AM中稀釋的固定人BAFF CHO-K1細胞（刺激對照）任一者。在24小時培養後，用100 ul STEADY-Glo試劑(Promega)處理樣本，並檢定螢光素酶表現。繪製相對發光單元(Relative Luminesence Unit; RLU)對比測試化合物之Log10奈莫耳濃度之曲線圖，其中使用由Excel附加項Xlfit (ID Business Solutions Limited)支持的四參數對數模型計算IC50 與IC90 值。如上文所描述的計算測試化合物IC50 與IC90 值，並跨多個實驗計算幾何平均值，且展示於表9中。結果
測試化合物劑量依賴性地抑制了BAFFR-CHO螢光素酶報導細胞中的膜結合人BAFF誘導NFkB活化。表9中所示結果指出，測試化合物的IC50 與IC90 值與所有三個對照BAFF拮抗劑相比更有效力。
表9：用於抑制BAFFR-CHO報導細胞中的mbBAFF的IC50 及IC90 幾何平均值
Figure 105123026-A0304-0010
 實例 8 ：具有 STAT3 螢光素酶報導體的淋巴母細胞 B 細胞（ DB 細胞）中的人 IL-23 活性的抑制 材料 / 方法
用慢病毒STAT-3/螢光素酶報導基因(Qiagen)穩定轉導淋巴母細胞B細胞（DB細胞；ATCC目錄號#CRL-2289）。在使用嘌呤黴素(Life Technologies)的選擇下保持轉導的細胞。完整培養基為補充有10% FBS (Hyclone)及2 μg/mL嘌呤黴素(Life Technologies)的RPMI-1640培養基(Life Technologies)。檢定培養基為補充有10% FBS (Hyclone)的RPMI-1640培養基(Life Technologies)。
在白色平底96孔板中以20,000個細胞/孔在檢定培養基中以80 μL/孔接種經設計的DB-STAT3細胞。在聚丙烯圓底96孔板中的檢定培養基中製備測試化合物(10x)，且因此稀釋以產生自1 μg/mL至10 pg/mL之劑量範圍。向每一孔一式三份添加10 μL之稀釋測試分子或檢定培養基（對於對照孔）。向每一孔添加10 μL之10x人IL-23（至每板75 ng/mL之最終濃度）。或者，向對照孔添加10 μL之培養基。供檢定中使用選定的IL-23劑量表示DB設計細胞的人IL-23之EC60刺激劑量，如先前研究中所判定的。在37℃下的5% CO2 中培養板隔夜。製備ONE-GloTM 螢光素酶檢定試劑(Promega)，且向每一孔添加100 μL並混合。在Envision板閱讀器上量測發光，並隨後繪製（y軸）對比抗體濃度（x軸）的曲線圖。藉由使用GraphPad Prism 6軟體應用資料至4參數S形劑量-反應函數來判定化合物之IC50 值。藉由具有GraphPad Prism 6軟體的Find ECanything計算資料來判定IC90 值。跨多個實驗計算幾何平均值，並展示於表10中。結果
結果展示，所測試化合物能夠抑制具有STAT3螢光素酶報導體的DB細胞中的人IL-23活性。
表10：用於抑制淋巴母細胞B細胞中的人IL-23的IC50 及IC90 幾何平均值
Figure 105123026-A0304-0011
 實例 9 ：小鼠脾細胞中的人及食蟹獼猴 IL-23 活性的抑制 材料及方法
將來自小鼠脾臟（雌性，C57BL/6，年齡小於13週；Jackson Laboratories）的單核細胞分離、洗滌、計數及再懸浮至標準T細胞培養基(T cell media; TCM)中4×106 個細胞/ml。將一百微升之mIL-2/脾細胞懸浮液添加至96孔微量滴定板。在TCM中稀釋重組人IL-23 (Boehringer Ingelheim Pharmaceuticals, Inc.)或重組食蟹獼猴IL-23 (Boehringer Ingelheim Pharmaceuticals, Inc.)，並在37℃下預培養2小時，其中僅使用TCM或使用測試樣本之滴定。在測試樣本+IL-23的預培養之後，將100 ul之混合物添加至細胞，並在37℃下用5% CO2 加濕空氣培養測試板48小時。對照樣本接收TCM（未刺激對照）或TCM中稀釋的重組IL-23（刺激對照）任一者。在培養之後，根據製造商說明書(R&D Systems)使用Quantikine® 小鼠IL-17免疫檢定自上清液判定小鼠IL-17水平。針對每一樣本判定內插mIL-17 pg/ml值，並轉換成對照百分比(percent of control; POC)。繪製測試樣本之POC對比濃度曲線圖，並使用由Excel附加項XLfit (Activity Base軟體，ID Business Solutions, Ltd.）啟動的四參數對數模型計算IC90 值。關於上文所描述之IC50 及IC90 分析測試化合物，且跨多個實驗針對每一測試化合物計算幾何平均值，並展示於表11中。結果
結果展示，所測試化合物能夠抑制小鼠IL-17之人與食蟹獼猴-IL23誘導的小鼠脾細胞釋放。
表11：用於抑制小鼠脾細胞中的人及食蟹獼猴IL-23的IC50 及IC90 幾何平均值
Figure 105123026-A0304-0012
 實例 10 ：化合物在食蟹獼猴中的藥物動力學 材料及方法：
在雄性食蟹獼猴中實施對於測試化合物A、B、C及D的單靜脈內(intravenous; IV)劑量PK研究（每分子n=2）。劑量為慢速1 mg/kg IV快速推注注射投予。在給藥前、給藥當天給藥後0.25小時、2小時及6小時，以及給藥後1天、2天、3天、4天、7天、10天、14天、21天及28天收集全血樣本。藉由基於MSD的配體結合檢定調節投藥分子之血清濃度。
在100%匯集的食蟹獼猴血清中製備校準標準曲線及品質控制(quality control; QC)樣本。每一標準曲線由七個非零點組成，起始於512 ng/mL，隨後連續稀釋三倍。亦包括空白樣本（無分析物的矩陣）。製備低、中及高範圍的五個QC樣本，起始於256 ng/mL，隨後連續稀釋四倍至8 ng/mL，隨後使用2倍稀釋製備4 ng/mL的最低QC。在每次分析執行期間，一式兩份包括標準曲線及QC樣本。將量化的下限及上限定義為最低及最高QC點，具有可再生反算濃度不超過標稱濃度的30%。對於標準曲線點的驗收標準為標稱濃度的30%。
為了量測血清樣本中的活性藥物濃度，製備主混合物，在結合緩衝液（1x PBS中5% BSA，具有0.05% Tween 20）中將0.5 μg/mL之生物素化重組人BAFF與0.5 μg/mL磺基標記的山羊抗人IgG偵測組合。向96孔非結合且擋光板以每孔50 μL添加主混合物。向含有主混合物的非結合板每孔一式兩份添加25 μL之標準及QC（在結合緩衝液中1:20稀釋儲備）。在結合緩衝液中1:20稀釋及在含有5%血清的結合緩衝液中1:400稀釋未知血清樣本。向含有主混合物的非結合板每孔添加25 μL之稀釋樣本。在室溫下在板振盪器上（500 rpm，1.5 h）培養非結合板。並行地，使用150 μL阻斷緩衝液（具有1X PBS的5% BSA，具有0.05% Tween 20）阻斷MSD抗生蛋白鏈菌素金板，並在板振盪器上（500 rpm，1.5 h）在室溫下培養。在培養之後，用每孔300μL之洗滌緩衝液（1XPBS中0.05% Tween 20）洗滌MSD板三次。向MSD板添加來自非結合板的50 μL之樣本，並在室溫下培養（1.5 h，600 rpm）。在培養之後，用洗滌緩衝液洗滌板三次，並向每孔添加150 μL之2x Read Buffer T，及在MSD Sector Imager 2400上立即讀取。使用MSD Discovery Workbench軟體將標準曲線擬合至四參數對數方程式。在Phoenix WinNonlin 6.3（Certara，MD，美國）中使用非分區分析計算藥物動力學參數。結果：
第2圖圖示測試化合物的平均(SD)血清濃度對比時間輪廓。表2中匯總測試化合物的平均(SD)藥物動力參數。顯示出隨時間變化藥物濃度急劇下降的血清樣本已證實為積極抗藥抗體，排除在藥物動力參數計算之外。
表12：在單次1 mg/kg靜脈內劑量後雄性食蟹獼猴體內的測試化合物之平均(SD)藥物動力參數
Figure 105123026-A0304-0013
 實例 11 ：預測示例性化合物的人 PK 及人劑量
使用基本Dedrick尺度將化合物B之平均猴血清濃度縮放至人，對於分佈體積使用1.0之異速生長指數，對於清除率使用0.85。將預測人i.v.血清濃度-時間輪廓擬合至線性兩個分區模型。藉由將自兩個分區i.v.模型的參數與對於市售治療mAbs遵循的平均s.c.吸收率及生物利用率組合來預測人s.c.血清濃度-時間輪廓。預測健康人類的清除率及末端半衰期分別為0.34 L/d及9.9 d。在每兩週一次投予100 mg s.c.劑量之後，在第3圖中圖示化合物B之預測人血清濃度-時間輪廓。
預測人有效劑量為每兩週一次s.c.遞送1 mg/kg。此劑量方案預計維持Cmin≧30 nM (6 μg/mL)，雙週或較不頻繁s.c.投藥。預測有效劑量可基於對於SLE及RA患者體內貝利木單抗(Benlysta® )、塔巴木單抗(tabalumab)及blisibimod遵循的濃度-PD生物標記反應。在此等研究中，BAFF相關生物標記之最大抑制與30-40 nM穩態Cmin關聯。中和IL23所需的濃度比中和BAFF所需的濃度低得多，且因此不影響對於雙重拮抗劑的整體所需Cmin。實例 12 ：化合物純化 方法：
使用Mab Select SuRe作為親和性純化步驟純化化合物。使用醋酸鈉緩衝液pH 3.5執行溶離。在Mab Select SuRe純化之後，中和樣本，並應用於Poros 50 HS樹脂，及使用檸檬酸鈉緩衝液中的氯化鈉梯度溶離。單體峰值在20 mM檸檬酸鈉及120 mM NaCl pH 6.0下溶離。在離子交換層析法之後，樣本為一致＞95%單體。
使用經由分析超速離心(Analytical ultracentrifugation; AUC)的沉降速度(Sedimentation velocity; SV)實驗提供關於樣本純度及團聚狀態的資訊。在20℃下使用以40,000 rpm運轉的An60Ti四孔轉子在最佳XL-I (Beckman Coulter, Fullerton, CA)中離心處理樣本。藉由280 nm處紫外光吸收，使用相應稀釋緩衝液作為參考緩衝液監測沉澱過程。使用XL-I作業軟體收集超速離心細胞中隨時間的濃度分佈變化，並使用SEDFIT軟體（14.1版）中的連續c(S)分佈模型加以分析以給出沉澱係數之分佈。基於積分峰值區域計算單體百分比。結果：
在表13中展示化合物之純化結果。資料展示，化合物具有高純度及均質性，從而指示良好的穩定性。
表13
Figure 105123026-A0304-0014
 實例 13 ：化合物之質譜分析輪廓 方法：
天然樣本
此程序得到化合物或蛋白質的完整質量。將0.15ul樣本注射在Agilent PoroShell 300SB-C3管柱，5um，(30x1.0mm)上。管柱溫度為80℃且流動速率為150 ul/min。用0分鐘時10%B至6分鐘時85%B的梯度將化合物或蛋白質溶離管柱。移動相A為水/乙腈/甲酸/乙酸銨(99/1/0.1/2mM)並移動相B為正丙醇/乙腈/水/甲酸(70/20/10/0.1)。將流出物導引至Agilent 6224 T0F質譜儀，此質譜儀自質量600至質量3200加以掃描。用程式MassHunter對原始資料去卷積。
簡化樣本
此程序得到蛋白質或輕鏈的質量及重鏈的質量。向5 uL之8M Guanadine HCL:TCEP之20:1混合物添加5 ul之樣本，並在室溫下培養15分鐘。如上文注射0.15 ul之此樣本，其中具有以下差異：用自0分鐘時5%B至6分鐘時85%B的梯度將化合物或蛋白質溶離管柱，管柱溫度為60℃，且質量範圍為600-2000。
去醣基化樣本
此程序得到蛋白質或輕鏈及重鏈的去醣基化質量。向3.2 uL之400 mM碳酸氫銨：PNGase F之20:1混合物添加7.5 ul之樣本，並在37℃下培養3小時。隨後，向樣本添加10 ul之8M Guanadine HCL:TCEP之20:1混合物，並在室溫下培養15分鐘。如上文針對簡化樣本注射此樣本。
藉由質譜分析法的肽圖
將樣本稀釋成由6M GdHCl、250 mM Tris-HCL pH 7.5及10 mM DTT組成的變性緩衝液，並隨後在37℃下培養30分鐘。隨後用碘乙醯胺烷基化樣本，並在室溫下黑暗中培養30分鐘。使用Sephadex G-25 Superfine濾筒將反應混合物純化並緩衝交換成100mM Tris-HCL pH 7.5。隨後在37℃下的4小時培養期間用胰蛋白酶消化樣本。接著藉由添加TFA中止所消化的反應混合物。
經由Dionex Ultimate 3000 HPLC之自動取樣器將所獲得之胰蛋白酶消化物注射到Phenomenex Jupiter C18反相管柱上。使用由溶劑A：0.1%甲酸/99%水/1%乙腈及溶劑B：0.1%甲酸/5%水/95%乙腈組成的梯度溶劑系統。溶劑B之百分比經由140分鐘自0%增加至38%。在室溫下以100 μl/min之流動速率發生層析分離。自動取樣器中的樣本儲存處於4℃下。在層析分離後，樣本進入以正電噴霧電離模式操作的Thermo Scientific Orbitrap Fusion質譜儀中。所採用的方法包括CID的活化類型，使用30,000之解析度、10,000之最小信號、1.0之分離寬度及35.0V之正規化碰撞能。將S透鏡RF水平設定為20%。資料收集類型對於全MS掃描為輪廓且對於CID MS/MS資料為質心。在250-2000 Da之質量範圍內以1光譜/秒之獲得速率收集資料。
利用Proteome Discover 1.4 (Thermo Scientific)針對給定序列分析自酶消化物的所收集原始LC MS及LC-MS/MS片段資料。隨後藉由對於醣基化肽人工提取EIC分析含有N-X-S/T (X不為P)之一致性的識別肽。使用跨EIC的醣基化肽之MS強度估計醣形之總豐度的百分比。結果：
表14中展示結果。資料指出，已在無意外異質性的情況下表現及恢復了所欲胺基酸序列及結構。醣基化模式為CHO細胞中表現的習知抗體之典型，並且未展示任何非典型結構。
表14：
Figure 105123026-A0304-0015
 實例 14 ：高濃度下的單體含量
此製程描述之目的為藉由估計在增加的濃度下聚集來評估化合物B之固有特性。在無調配評估的情況下使用20 mM檸檬酸鈉120 mM NaCl pH 6之標準緩衝液，以理解分子聚集的傾向。方法：
使用Amicon Ultra離心過濾器在50,000道爾頓之截止分子量(Millipore，Billerica)下將化合物B逐漸濃縮至儘可能高的濃度，而經觀察無沉澱。經濃縮之蛋白質溶液隨後經歷分析sec分析以提供關於樣本純度及聚集狀態的資訊。使用Agilent 1200系列HPLC系統執行層析法。以1.0 ml/min執行此系統23分鐘。將約30 ug之材料注射到Tosoh Biosciences TSKgel G3000SWXL管柱(5 um 7.8×30 cm)中，並在280 nm處讀出結果。所使用之流動緩衝液為50 mM磷酸鈉、0.2 M L-精胺酸pH 6.8。結果：
表15及第4圖中列出在濃縮製程期間的化合物B之分析SEC資料之匯總。呈現展示出增加濃度下的聚集度及樣本純度的資料，此論證了化合物B不具有在增加的濃度下聚集的傾向。
表15：在濃縮製程期間的化合物B之分析SEC資料之匯總
Figure 105123026-A0304-0016
 M=單體，A=聚集體實例 15 ：化合物之價數 方法：
使用分析膜約束電泳量測化合物之價數，此等化合物已經預先隔夜透析成10 mM醋酸鹽50 mM KCl pH 5.0緩衝液。在實驗設置中，將20 μL之樣本以1 mg/mL裝入2×2×4 mm3 石英比色皿中，藉由10 MWCO半滲透再生纖維素生物技術級膜密封兩端。此等膜截留巨分子，同時允許水及溶劑組分穿過。隨後施加1 mA電流穿過比色皿，沿比色皿長度建立電場，其中在新鮮緩衝液之連續流動下帶電巨分子在電場中移動。使用線性光電二極體陣列(linear photodiode array; LPDA)偵測實時移動濃度分界線，從而提供沿比色皿間隔的強度讀數。使用密度分界線之速度計算電泳遷移率及隨後計算有效價數。隨後使用諸如斯托克半徑（自AUC中流動的沉降速度獲得）、相對離子半徑（對於氯離子為0.122 nm）、緩衝液電導率(6.35 mS)及離子強度(0.05 M)之額外資訊顯露巨分子之基礎價數。結果：
價數資料（參看表16）指示化合物在溶液中的膠態穩定性（亦即，溶液中的蛋白質與蛋白質之網格相互作用）。具有價數大於15的化合物具有強網格排斥相互作用及具有很大潛在可能是在高濃度下加以調配。
表16：化合物之價數資料
Figure 105123026-A0304-0017
 實例 16 ：化合物之全血穩定性 方法
在Octet RED96上發展全血干擾檢定，以偵測在全血(whole blood; WB)存在下化合物之非特異性結合或偏離靶結合之效應。在37℃溫度下將全血及1x動態流動緩衝液(1xkb)中的化合物溶液培養48小時。利用配備有抗生蛋白鏈菌素(streptavidin; SA)生物感測器尖端(ForteBio, Menlo Park, CA)在27℃下執行所培養化合物樣本的動態量測。報告緩衝液及全血中的速率上/結合信號之比率。比率＜2視為展示出無干擾。結果
表17中展示結果。對於測試化合物經觀察無全血干擾。
表17：化合物之全血結合結果
Figure 105123026-A0304-0018
 實例 17 ：電腦模擬 (in silico ) 免疫原性預測 方法
利用由EpiVax, Inc. (Providence RI)開發的計算工具EpiMatrix在電腦中預測蛋白質治療劑之免疫原性。EpiMatrix合併T輔助抗原決定部位以及T-reg抗原決定部位的預測，其中前者將刺激免疫反應，而後者則為抑制性。簡言之，首先將蛋白質序列解析成重疊9-mer肽框，此已被證明為II類HLA結合的核心。基於實驗資料或計算預測評估9-mer肽至八個共同II類HLA對偶基因之各者的結合潛力。產生得分以反映9-mer肽至每一HLA對偶基因的結合潛力，並且執行正常化以使得跨多個HLA對偶基因比較任何9-mer及在全域尺度上啟用免疫原性預報成為可能。最後，程式產生總「免疫原性得分」tReg調整Epx得分，化合物可能將激發活體內的免疫反應。結果
表18中展示結果。測試化合物的總免疫原性得分很低，且預測此等化合物不可能引發活體內的強烈免疫反應。
表18：EpiVax得分
Figure 105123026-A0304-0019
 實例 18 ：在原生人 B 細胞增殖檢定中人 BAFF 的抑制 材料及方法
此研究中所用的正常健康血液樣本（n=3個供體）購自美國賓夕法尼亞州費城的Biological Specialty Corporation。完整培養基為補充有10% FBS (Life Technologies)加Pen/Strep (Life Technologies)的IMDM (Life Technologies)。B細胞分離緩衝液由無菌Mg++ 及Ca++ 游離DPBS (Life Technologies)加2% FBS加2 mM EDTA (Life Technologies)組成。
自健康人全血分離人B細胞
將四百毫升肝素化全血移送到1000 mL無菌聚苯乙烯瓶中，並添加等體積的DPBS。將三十五(35)毫升PBS稀釋的血液置於50 mL聚苯乙烯圓底管中梯度預裝的15 mL Ficoll-PaqueTM Plus(GE Healthcare)之頂部上。在室溫下以2000 rpm離心處理試管20分鐘而不制動。接著，吸出頂部上清液的三分之二，並將含有周圍血液單核細胞(peripheral blood mononuclear cell; PBMC)的中間灰層移送至50 mL錐形管。添加DPBS（Ca++ 及Mg++ 游離）+2% FBS，直到50 mL之體積。以1200 rpm旋轉沉降試管10分鐘。用DPBS（Ca++ 及Mg++ 游離）+2% FBS（洗滌緩衝液）再懸浮所得細胞小球，並重複離心步驟（1200 rpm長達10分鐘）。在洗滌緩衝液中再次再懸浮細胞小球，直到50 mL。在此點處量測細胞活力及細胞濃度。
隨後以1200 rpm旋轉沉降試管10分鐘，並拋棄上清液。用完整培養基再懸浮細胞小球，並將細胞濃度調節至5×106 個細胞/mL。將懸浮細胞置於75 cm組織培養燒瓶中，並在5% CO2 培養箱（在37℃下）培養隔夜。隨後藉由根據製造商協定使用Dynabeads® UntouchedTM 人B細胞套組(Life Technologies)分離B細胞。在量測細胞濃度及活力之後，將細胞濃度調節至適合於下游程序。
使用3H-胸苷合併檢定評估B細胞增殖
在Falcon組織培養96孔圓底板（每孔1×105 個細胞/100 μL培養基）中接種B細胞。隨後，利用完整培養基，在範圍自0.028至20 nM之4x連續濃度下製備測試物品及在4x濃度下B細胞刺激（抗IgM抗體及人BAFF）。向各別孔添加50 μL之預稀釋測試物品（最終濃度0.007至5 nM）。隨後，向相應孔添加50 μL之預稀釋山羊抗人IgM（最終濃度2 μg/mL）及hBAFF（最終濃度5 ng/mL或98 pM）（參看第6圖）。在5% CO2 37℃加濕培養箱中培養B細胞72小時。在培養結束前十八小時處，向每一孔添加20 μL之1 μCi 3H胸苷(Pelkin Elmer)。使用細胞採集器將3H-胸苷合併DNA/孔移送至微纖維玻璃過濾板，其中在風乾此板至少4小時後向孔添加30 μL之閃爍增強劑。使用MicroBeta Topcount量測每一孔之每分鐘計數(counts per minute; cpm)值，並繪製cpm值（y軸）對比測試樣本濃度（x軸）曲線圖。
統計分析
藉由使用GraphPad Prism 6軟體使曲線擬合資料至4參數S形劑量-反應函數來判定IC50 及IC90 。跨三個實驗計算幾何平均值，並展示於表19中。結果
結果展示，當比較IC50 及IC90 值時，化合物B與對照抗體3相比似乎具有約2倍效力。
表19:在原生人B細胞增殖檢定中對於抑制人BAFF的IC50 及IC90 幾何平均值
Figure 105123026-A0304-0020
 實例 19 ： B10.RIII 小鼠中由人 BAFF 過度表現誘導的 B220+ B 細胞數目的抑制 材料及方法
簡言之，在第1天，將B10.RIII雌性小鼠（6-8週大，Jackson Laboratory）隨機分為10個群組，10只動物/群組，並且分別以1.3、0.4及0.13 mg/kg對比1、3及0.1 mg/kg之當量莫耳劑量給予檸檬酸鹽緩衝液（20 mM檸檬酸鈉，115 mM NaCl，pH 6.0）或測試化合物之100 μl腹腔內注射。首次接受試驗的未處理小鼠為額外對照。在治療第1天後緊接著，將單個3 mg劑量(1.5 mg/mL)之人BAFF微環DNA (System Biosciences)經由流體動力注射投予小鼠對比空載體(empty vector; EV)對照群組。在第3天、第6天、第9天及第12天，每72小時重複檸檬酸鹽緩衝液或測試化合物的腹腔內治療。
在第14天，經由異氟烷(Butler Schein)麻醉小鼠，並經由頸部脫位犧牲小鼠。移去脾臟，並針對B220+ B細胞藉由流式細胞儀分析細胞懸浮液。使用單向ANOVA繼之以Dunnett多重比較測試判定每一治療群組的平均數及計算與對照組相比的顯著性。在第5圖中圖示結果。結果
結果展示，使用化合物B治療14天能夠明顯抑制由人BAFF微環DNA誘導的B220+ B細胞之擴增。實例 20 ： C57/B16 小鼠中人 IL23 誘導小鼠 IL17A 及 IL22 釋放的抑制 材料及方法
簡言之，將C57BL/6雌性小鼠（7-10週大，Charles River）隨機分為8個群組，8只動物/群組，並且分別以1.3、0.4及0.13 mg/kg對比1、3及0.1 mg/kg之當量莫耳劑量給予檸檬酸鹽緩衝液（20 mM檸檬酸鈉，115 mM NaCl，pH 6.0）或測試化合物之100 μl腹腔內注射。
在測試化合物投藥後一小時，經由異氟烷(Butler Schein)麻醉小鼠，並對雙耳給予0.1%BSA (Sigma)對照或鹽水(Invitrogen)中稀釋的15 μg/ml (0.3μg) rhIL23（內部產生）之20 μl皮內注射。連續2天每日重複皮內攻毒。在第二次攻毒後二十四小時處，經由頸部脫位犧牲小鼠，並移去兩隻耳朵。在1 ml之勻漿緩衝液（HBSS (Gibco)；0.4% Triton X-100 (Sigma)；SigmaFast蛋白酶抑制劑(Sigma)）中使用MP Biomedicals Fast-Prep 24均質器均質化耳組織。在4C下將均質化樣本離心分離10分鐘，並收集上清液。根據製造商說明書(R&D Systems)使用Quantikine® 小鼠IL-17及小鼠IL-22免疫檢定針對小鼠IL17A及IL22的存在檢定上清液。針對每一樣本判定內插細胞介素pg/ml值。使用單向ANOVA繼之以Dunnett多重比較測試判定每一治療群組的平均pg/ml水平及計算與對照組相比的顯著性。結果
第6圖中的結果展示，使用單個腹腔內劑量之化合物B的治療能夠顯著抑制由兩次每日連續皮內注射重組人IL23誘導的皮膚內的小鼠IL17及IL22之釋放。序列
Figure 105123026-A0304-0021
 其他實施例
可以任何組合組合本說明書中所揭示之所有特徵。可藉由用於相同、等效或相似目的的替代特徵替換本說明書中所揭示之每一特徵。因此，除非另有明確陳述，否則所揭示之每一特徵僅為一般系列之等效或相似特徵之實例。
自上文描述，熟習此項技術者可容易確定本揭示案之基本特徵，且在不脫離本揭示案之精神及範疇的情況下，可實行本揭示案之各種變化及修改以使其適用於各種用途及條件。因此，其他實施例亦屬於申請專利範圍內。
無
以下圖式形成本說明書的一部分且經包括以進一步論證本揭示案之某些態樣，此等態樣可結合本文所呈現之特定實施例之詳細描述並藉由參照此等圖式之一或更多者更好地加以理解。
第1A圖係對BAFF及IL23A特異的示例性化合物之示意圖。第一多肽鏈含有CH3、CH2、VH2 (VHII )及VL1 (VLI )域。第二多肽鏈含有VH1 (VHI )及VL2 (VLII )域。VL1 及VH1 係特異於第一靶蛋白（BAFF或IL23A任一者），並且VL2 及VH2 係特異於第二靶蛋白（IL23A或BAFF任一者）。上部圖單獨圖示每一多肽鏈。下部圖圖示經由一個第一多肽之CH2及CH3域與另一第一多肽之CH2及CH3域之締合形成的四價化合物（例如，實例部分中所描述之單體、單體抗體）。分別經由VH1 與VL1 之締合及經由VH2 與VL2 之締合形成第一靶蛋白及第二靶蛋白的結合域。
第1B圖係特異於BAFF及IL23A的另一示例性化合物之示意圖。第一多肽鏈含有CH3、CH2、CH1、VH2 (VHII )及VL1 (VLI )域。第二多肽鏈含有CL、VH1 (VHI )及VL2 (VLII )域。VL1 及VH1 係特異於第一靶蛋白（BAFF或IL23A任一者），並且VL2 及VH2 係特異於第二靶蛋白（IL23A或BAFF任一者）。上部圖單獨圖示每一多肽鏈。下部圖圖示經由一個第一多肽之CH2及CH3域與另一第一多肽之CH2及CH3域之締合形成的四價化合物（例如，實例部分中所描述之單體、單體抗體）。分別經由VH1 與VL1 之締合及經由VH2 與VL2 之締合形成第一靶蛋白及第二靶蛋白的結合域。經由CL與CH1域之間的相互作用進一步締合化合物。
第2圖係圖示如實例10中所描述的在雄性食蟹獼猴體內單次1 mg/kg靜脈內劑量後的化合物A（實心正方形）、化合物B（空心正方形）、化合物C（實心三角形）及化合物D（空心三角形）之血清濃度（平均值±SD）的曲線圖。
第3圖圖示如實例11中所描述的在每兩週一次投予100 mg s.c.劑量後的化合物B之預測的人血清濃度-時間輪廓。虛線表示靶向Cmin (30 nM)。
第4圖圖示如實例14中所描述的化合物B之單體百分比對比濃度之圖形匯總。
第5圖圖示化合物B對比抗BAFF維持活體內的功能效力。用抗BAFF或化合物B任一者對小鼠等莫耳投藥，並用人BAFF微環攻毒(challenged)以誘導B細胞擴增。在第14天時，收集脾，並藉由流式細胞儀對小鼠B220+ B細胞加以分析，作為BAFF之功能阻斷的量度。
第6圖圖示化合物B對比抗IL23維持活體內的功能效力。在IL23誘導細胞介素檢定中評估化合物B。用抗IL23或化合物B任一者對小鼠等莫耳投藥，並用人IL23攻毒兩次以誘發耳部發炎。在最後注射的二十四小時後，收集耳朵，並對小鼠IL17A及小鼠IL22加以分析，作為IL23之功能阻斷的量度。
國內寄存資訊 (請依寄存機構、日期、號碼順序註記) 無
國外寄存資訊 (請依寄存國家、機構、日期、號碼順序註記) 無
<110> 德商‧包林格因蓋爾漢國際股份有限公司(Boehringer Ingelheim International GmbH) 美商‧總體遺傳因子公司(MacroGenics,Inc.)
<120> 靶向IL-23A與B細胞活化因子(BAFF)之化合物及其用途
<140> 尚未指定
<141> 同時
<150> US 62/196,170
<151> 2015-07-23
<150> US 62/201,067
<151> 2015-08-04
<150> US 62/355,302
<151> 2016-06-27
<160> 136
<170> PatentIn 3.5版
<210> 1
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 1
Figure 105123026-A0305-02-0161-1
Gly Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser Gln Asn Phe     50                  55                  60                      Gln Gly Arg Val Ala Ile Thr Ala Asp Glu Ser Thr Gly Thr Ala Ser 65                  70                  75                  80      Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys                 85                  90                  95          Ala Arg Ser Arg Asp Leu Leu Leu Phe Pro His His Ala Leu Ser Pro             100                 105                 110             Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser         115                 120                 ＜210＞  2 ＜211＞  108 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  2   Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1               5                   10                  15          Thr Val Arg Val Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala             20                  25                  30              Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr         35                  40                  45                   Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser     50                  55                  60                      Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65                  70                  75                  80      Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Arg Asp Ser Ser Gly Asn His                 85                  90                  95          Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu             100                 105                 ＜210＞  3 ＜211＞  120 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  3   Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1               5                   10                  15          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Gln             20                  25                  30              Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile         35                  40                  45                  Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn Glu Asn Phe     50                  55                  60                      Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65                  70                  75                  80      Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys                 85                  90                  95          Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr Trp Gly Gln             100                 105                 110              Gly Thr Leu Val Thr Val Ser Ser         115                 120     ＜210＞  4 ＜211＞  107 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  4   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys             100                 105             ＜210＞  5 ＜211＞  571 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  5   Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1               5                   10                  15          Thr Val Arg Val Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala             20                  25                  30              Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr         35                  40                  45                   Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser     50                  55                  60                      Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65                  70                  75                  80      Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Arg Asp Ser Ser Gly Asn His                 85                  90                  95          Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu Gly Gly Gly Ser             100                 105                 110             Gly Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys         115                 120                 125                 Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr     130                 135                 140                     Phe Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly 145                 150                 155                 160     Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr                 165                 170                 175         Asn Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr             180                 185                 190             Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala         195                 200                 205                 Val Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile     210                 215                 220                      Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly 225                 230                 235                 240     Ser Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser                 245                 250                 255         Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys             260                 265                 270             Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu         275                 280                 285                 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu     290                 295                 300                     Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 305                 310                 315                 320     Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val                 325                 330                 335         Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro             340                 345                 350             Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe         355                 360                 365                 Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val     370                 375                 380                     Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 385                 390                 395                 400     Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro                 405                 410                 415         Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr             420                 425                 430              Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val         435                 440                 445                 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala     450                 455                 460                      Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 465                 470                 475                 480     Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly                 485                 490                 495         Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro             500                 505                 510             Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser         515                 520                 525                 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln     530                 535                 540                     Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 545                 550                 555                 560     Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly                 565                 570         ＜210＞  6 ＜211＞  351 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  6   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30               Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                       Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Arg Val Ser Cys Lys Ala Ser Gly Gly Thr Phe     130                 135                 140                     Asn Asn Asn Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser                 165                 170                 175         Gln Asn Phe Gln Gly Arg Val Ala Ile Thr Ala Asp Glu Ser Thr Gly             180                 185                 190             Thr Ala Ser Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Ser Arg Asp Leu Leu Leu Phe Pro His His Ala     210                 215                 220                     Leu Ser Pro Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser Leu Gly 225                 230                 235                 240     Gly Gly Ser Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro                 245                 250                 255         Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu             260                 265                 270             Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp         275                 280                 285                 Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp     290                 295                 300                     Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys 305                 310                 315                 320     Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln                 325                 330                 335         Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             340                 345                 350         ＜210＞  7 ＜211＞  573 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  7   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Arg Val Ser Cys Lys Ala Ser Gly Gly Thr Phe     130                 135                 140                     Asn Asn Asn Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser                 165                 170                 175         Gln Asn Phe Gln Gly Arg Val Ala Ile Thr Ala Asp Glu Ser Thr Gly             180                 185                 190             Thr Ala Ser Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Ser Arg Asp Leu Leu Leu Phe Pro His His Ala     210                 215                 220                     Leu Ser Pro Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser Leu Gly 225                 230                 235                 240     Gly Gly Ser Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala                 245                 250                 255         Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu             260                 265                 270             Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly         275                 280                 285                 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser     290                 295                 300                     Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 305                 310                 315                 320     Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr                 325                 330                 335         Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr             340                 345                 350             Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe         355                 360                 365                 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro     370                 375                 380                     Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 385                 390                 395                 400     Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr                 405                 410                 415         Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val             420                 425                 430             Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys         435                 440                 445                 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser     450                 455                 460                     Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 465                 470                 475                 480     Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val                 485                 490                 495         Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly             500                 505                 510             Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp         515                 520                 525                 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp     530                 535                 540                     Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 545                 550                 555                 560     Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly                 565                 570                 ＜210＞  8 ＜211＞  349 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  8   Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1               5                   10                  15          Thr Val Arg Val Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala             20                  25                  30              Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr         35                  40                  45                  Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser     50                  55                  60                      Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65                  70                  75                  80      Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Arg Asp Ser Ser Gly Asn His                 85                  90                  95           Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu Gly Gly Gly Ser             100                 105                 110             Gly Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys         115                 120                 125                 Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr     130                 135                 140                     Phe Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly 145                 150                 155                 160     Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr                 165                 170                 175         Asn Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr             180                 185                 190             Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala         195                 200                 205                 Val Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile     210                 215                 220                     Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly 225                 230                 235                 240     Ser Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser                 245                 250                 255         Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn             260                 265                 270             Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala         275                 280                 285                 Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys     290                 295                 300                     Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp 305                 310                 315                 320     Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu                 325                 330                 335         Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             340                 345                     ＜210＞  9 ＜211＞  502 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  9   Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1               5                   10                  15          Thr Val Arg Val Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala             20                  25                  30              Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr         35                  40                  45                  Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser     50                  55                  60                      Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65                  70                  75                  80      Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Arg Asp Ser Ser Gly Asn His                 85                  90                  95          Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu Gly Gly Gly Ser             100                 105                 110             Gly Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys         115                 120                 125                 Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr     130                 135                 140                     Phe Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly 145                 150                 155                 160     Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr                 165                 170                 175         Asn Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr             180                 185                 190             Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala         195                 200                 205                 Val Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile     210                 215                 220                     Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly 225                 230                 235                 240     Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala Ala Leu Glu Lys                 245                 250                 255         Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys Leu Glu             260                 265                 270             Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro         275                 280                 285                 Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys     290                 295                 300                     Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val 305                 310                 315                 320     Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp                 325                 330                 335         Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr             340                 345                 350             Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp         355                 360                 365                  Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu     370                 375                 380                     Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 385                 390                 395                 400     Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys                 405                 410                 415         Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp             420                 425                 430             Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys         435                 440                 445                 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser     450                 455                 460                     Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 465                 470                 475                 480     Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser                 485                 490                 495         Leu Ser Leu Ser Pro Gly             500             ＜210＞  10 ＜211＞  272 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  10   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30               Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                       Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Arg Val Ser Cys Lys Ala Ser Gly Gly Thr Phe     130                 135                 140                     Asn Asn Asn Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser                 165                 170                 175         Gln Asn Phe Gln Gly Arg Val Ala Ile Thr Ala Asp Glu Ser Thr Gly             180                 185                 190             Thr Ala Ser Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Ser Arg Asp Leu Leu Leu Phe Pro His His Ala     210                 215                 220                     Leu Ser Pro Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser Gly Gly 225                 230                 235                 240     Cys Gly Gly Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu                 245                 250                 255         Lys Glu Lys Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu             260                 265                 270             ＜210＞  11 ＜211＞  504 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  11   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                   Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Arg Val Ser Cys Lys Ala Ser Gly Gly Thr Phe     130                 135                 140                     Asn Asn Asn Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser                 165                 170                 175         Gln Asn Phe Gln Gly Arg Val Ala Ile Thr Ala Asp Glu Ser Thr Gly             180                 185                 190             Thr Ala Ser Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Ser Arg Asp Leu Leu Leu Phe Pro His His Ala     210                 215                 220                     Leu Ser Pro Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser Gly Gly 225                 230                 235                 240     Cys Gly Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala Ala Leu                 245                 250                 255         Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys             260                 265                 270             Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro         275                 280                 285                 Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys     290                 295                 300                     Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val 305                 310                 315                 320     Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr                 325                 330                 335         Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu             340                 345                 350             Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His         355                 360                 365                 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys     370                 375                 380                     Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 385                 390                 395                 400     Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met                 405                 410                 415         Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro             420                 425                 430             Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn         435                 440                 445                 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu     450                 455                 460                      Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 465                 470                 475                 480     Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln                 485                 490                 495         Lys Ser Leu Ser Leu Ser Pro Gly             500                     ＜210＞  12 ＜211＞  270 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  12   Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1               5                   10                  15          Thr Val Arg Val Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala             20                  25                  30              Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr         35                  40                  45                  Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser     50                  55                  60                      Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65                  70                  75                  80      Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Arg Asp Ser Ser Gly Asn His                 85                  90                  95          Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu Gly Gly Gly Ser             100                 105                 110             Gly Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys         115                 120                 125                  Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr     130                 135                 140                     Phe Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly 145                 150                 155                 160     Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr                 165                 170                 175         Asn Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr             180                 185                 190             Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala         195                 200                 205                 Val Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile     210                 215                 220                     Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly 225                 230                 235                 240     Gly Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu                 245                 250                 255         Lys Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu             260                 265                 270     ＜210＞  13 ＜211＞  568 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  13   Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1               5                   10                  15          Thr Val Arg Val Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala             20                  25                  30              Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr         35                  40                  45                  Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser     50                  55                  60                      Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65                  70                  75                  80      Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Arg Asp Ser Ser Gly Asn His                 85                  90                  95          Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu Gly Gly Gly Ser             100                 105                 110             Gly Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys         115                 120                 125                 Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr     130                 135                 140                      Phe Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly 145                 150                 155                 160     Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr                 165                 170                 175         Asn Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr             180                 185                 190             Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala         195                 200                 205                 Val Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile     210                 215                 220                     Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly 225                 230                 235                 240     Ser Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys                 245                 250                 255         Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys             260                 265                 270             Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu         275                 280                 285                 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu     290                 295                 300                     Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 305                 310                 315                 320     Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val                 325                 330                 335         Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro             340                 345                 350              Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys         355                 360                 365                 Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val     370                 375                 380                      Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 385                 390                 395                 400     Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu                 405                 410                 415         Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His             420                 425                 430             Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys         435                 440                 445                 Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln     450                 455                 460                     Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met 465                 470                 475                 480     Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro                 485                 490                 495         Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn             500                 505                 510             Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu         515                 520                 525                 Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val     530                 535                 540                     Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 545                 550                 555                 560     Lys Ser Leu Ser Leu Ser Leu Gly                 565                 ＜210＞  14 ＜211＞  351 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  14   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Arg Val Ser Cys Lys Ala Ser Gly Gly Thr Phe     130                 135                 140                     Asn Asn Asn Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser                 165                 170                 175         Gln Asn Phe Gln Gly Arg Val Ala Ile Thr Ala Asp Glu Ser Thr Gly             180                 185                 190             Thr Ala Ser Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Ser Arg Asp Leu Leu Leu Phe Pro His His Ala     210                 215                 220                     Leu Ser Pro Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser Leu Gly 225                 230                 235                 240     Gly Gly Ser Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro                 245                 250                 255         Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu             260                 265                 270             Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp         275                 280                 285                  Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp     290                 295                 300                     Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys 305                 310                 315                 320     Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln                 325                 330                 335         Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             340                 345                 350         ＜210＞  15 ＜211＞  570 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  15   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                   Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Arg Val Ser Cys Lys Ala Ser Gly Gly Thr Phe     130                 135                 140                     Asn Asn Asn Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser                 165                 170                 175         Gln Asn Phe Gln Gly Arg Val Ala Ile Thr Ala Asp Glu Ser Thr Gly             180                 185                 190             Thr Ala Ser Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Ser Arg Asp Leu Leu Leu Phe Pro His His Ala     210                 215                 220                      Leu Ser Pro Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser Leu Gly 225                 230                 235                 240     Gly Gly Ser Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala                 245                 250                 255         Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu             260                 265                 270             Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly         275                 280                 285                 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser     290                 295                 300                     Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 305                 310                 315                 320     Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr                 325                 330                 335         Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro             340                 345                 350             Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro         355                 360                 365                 Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr     370                 375                 380                     Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 385                 390                 395                 400     Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg                 405                 410                 415         Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val             420                 425                 430              Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser         435                 440                 445                 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys     450                 455                 460                      Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 465                 470                 475                 480     Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe                 485                 490                 495         Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu             500                 505                 510             Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe         515                 520                 525                 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly     530                 535                 540                     Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 545                 550                 555                 560     Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly                 565                 570     ＜210＞  16 ＜211＞  349 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  16   Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1               5                   10                  15          Thr Val Arg Val Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala             20                  25                  30               Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr         35                  40                  45                  Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser     50                  55                  60                       Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65                  70                  75                  80      Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Arg Asp Ser Ser Gly Asn His                 85                  90                  95          Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu Gly Gly Gly Ser             100                 105                 110             Gly Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys         115                 120                 125                 Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr     130                 135                 140                     Phe Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly 145                 150                 155                 160     Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr                 165                 170                 175         Asn Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr             180                 185                 190             Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala         195                 200                 205                 Val Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile     210                 215                 220                     Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly 225                 230                 235                 240     Ser Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser                 245                 250                 255         Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn             260                 265                 270             Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala         275                 280                 285                 Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys     290                 295                 300                     Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp 305                 310                 315                 320     Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu                 325                 330                 335         Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             340                 345                     ＜210＞  17 ＜211＞  498 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  17   Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1               5                   10                  15          Thr Val Arg Val Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala             20                  25                  30               Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr         35                  40                  45                  Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser     50                  55                  60                      Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65                  70                  75                  80      Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Arg Asp Ser Ser Gly Asn His                 85                  90                  95          Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu Gly Gly Gly Ser             100                 105                 110             Gly Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys         115                 120                 125                 Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr     130                 135                 140                     Phe Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly 145                 150                 155                 160     Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr                 165                 170                 175         Asn Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr             180                 185                 190             Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala         195                 200                 205                 Val Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile     210                 215                 220                     Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly 225                 230                 235                 240     Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala Ala Leu Glu Lys                 245                 250                 255         Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Ser             260                 265                 270             Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly         275                 280                 285                 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr     290                 295                 300                     Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 305                 310                 315                 320     Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val                 325                 330                 335         His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr             340                 345                 350             Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly         355                 360                 365                 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile     370                 375                 380                     Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 385                 390                 395                 400     Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser                 405                 410                 415         Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu             420                 425                 430             Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro         435                 440                 445                 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val     450                 455                 460                     Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 465                 470                 475                 480     His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser                 485                 490                 495         Leu Gly             ＜210＞  18 ＜211＞  272 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  18   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Arg Val Ser Cys Lys Ala Ser Gly Gly Thr Phe     130                 135                 140                     Asn Asn Asn Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser                 165                 170                 175         Gln Asn Phe Gln Gly Arg Val Ala Ile Thr Ala Asp Glu Ser Thr Gly             180                 185                 190             Thr Ala Ser Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Ser Arg Asp Leu Leu Leu Phe Pro His His Ala     210                 215                 220                     Leu Ser Pro Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser Gly Gly 225                 230                 235                 240     Cys Gly Gly Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu                 245                 250                 255         Lys Glu Lys Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu             260                 265                 270             ＜210＞  19 ＜211＞  500 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  19   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Arg Val Ser Cys Lys Ala Ser Gly Gly Thr Phe     130                 135                 140                     Asn Asn Asn Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser                 165                 170                 175         Gln Asn Phe Gln Gly Arg Val Ala Ile Thr Ala Asp Glu Ser Thr Gly             180                 185                 190              Thr Ala Ser Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Ser Arg Asp Leu Leu Leu Phe Pro His His Ala     210                 215                 220                      Leu Ser Pro Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser Gly Gly 225                 230                 235                 240     Cys Gly Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala Ala Leu                 245                 250                 255         Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys             260                 265                 270             Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe         275                 280                 285                 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr     290                 295                 300                     Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val 305                 310                 315                 320     Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val                 325                 330                 335         Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser             340                 345                 350             Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu         355                 360                 365                 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser     370                 375                 380                     Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 385                 390                 395                 400     Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln                 405                 410                 415         Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala             420                 425                 430             Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr         435                 440                 445                 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu     450                 455                 460                     Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser 465                 470                 475                 480     Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser                 485                 490                 495         Leu Ser Leu Gly             500     ＜210＞  20 ＜211＞  270 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  20   Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1               5                   10                  15          Thr Val Arg Val Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala             20                  25                  30              Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr         35                  40                  45                  Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser     50                  55                  60                      Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65                  70                  75                  80      Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Arg Asp Ser Ser Gly Asn His                 85                  90                  95          Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu Gly Gly Gly Ser             100                 105                 110             Gly Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys         115                 120                 125                 Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr     130                 135                 140                     Phe Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly 145                 150                 155                 160     Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr                 165                 170                 175         Asn Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr             180                 185                 190             Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala         195                 200                 205                 Val Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile     210                 215                 220                     Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly 225                 230                 235                 240     Gly Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu                 245                 250                 255         Lys Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu             260                 265                 270     ＜210＞  21 ＜211＞  564 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  21   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30               Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe     130                 135                 140                     Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn                 165                 170                 175         Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr     210                 215                 220                     Val Thr Val Ser Ser Leu Gly Gly Gly Ser Gly Ala Ser Thr Lys Gly 225                 230                 235                 240     Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly                 245                 250                 255         Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val             260                 265                 270             Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe         275                 280                 285                 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val     290                 295                 300                     Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 305                 310                 315                 320     Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys                 325                 330                 335         Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala             340                 345                 350             Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr         355                 360                 365                 Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val     370                 375                 380                     Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 385                 390                 395                 400     Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser                 405                 410                 415         Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu             420                 425                 430             Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala         435                 440                 445                 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro     450                 455                 460                     Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 465                 470                 475                 480     Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala                 485                 490                 495         Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr             500                 505                 510             Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu         515                 520                 525                 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser     530                 535                 540                     Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 545                 550                 555                 560     Leu Ser Pro Gly                     ＜210＞  22 ＜211＞  348 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  22   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 Asp Ile Gly Asn Arg             20                  25                  30              Leu Ser Trp Leu Gln Gln Glu Pro Gly Lys Ala Pro Lys Arg Leu Ile         35                  40                  45                  Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110              Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                      Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser 225                 230                 235                 240     Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp                 245                 250                 255         Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn             260                 265                 270             Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu         275                 280                 285                 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp     290                 295                 300                     Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 305                 310                 315                 320     Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser                 325                 330                 335         Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             340                 345                 ＜210＞  23 ＜211＞  495 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  23   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe     130                 135                 140                      Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn                 165                 170                 175         Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr     210                 215                 220                     Val Thr Val Ser Ser Gly Gly Cys Gly Gly Gly Glu Val Ala Ala Cys 225                 230                 235                 240     Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys                 245                 250                 255         Glu Val Ala Ala Leu Glu Lys Leu Glu Pro Lys Ser Ser Asp Lys Thr             260                 265                 270             His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser         275                 280                 285                 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg     290                 295                 300                     Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 305                 310                 315                 320     Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala                 325                 330                 335         Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val             340                 345                 350              Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr         355                 360                 365                 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr     370                 375                 380                      Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 385                 390                 395                 400     Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys                 405                 410                 415         Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser             420                 425                 430             Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp         435                 440                 445                 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser     450                 455                 460                     Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 465                 470                 475                 480     Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly                 485                 490                 495     ＜210＞  24 ＜211＞  269 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  24   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 Asp Ile Gly Asn Arg             20                  25                  30              Leu Ser Trp Leu Gln Gln Glu Pro Gly Lys Ala Pro Lys Arg Leu Ile         35                  40                  45                  Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                      Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly Gly 225                 230                 235                 240     Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu Lys                 245                 250                 255         Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu             260                 265                     ＜210＞  25 ＜211＞  561 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  25   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe     130                 135                 140                     Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn                 165                 170                 175         Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr     210                 215                 220                     Val Thr Val Ser Ser Leu Gly Gly Gly Ser Gly Ala Ser Thr Lys Gly 225                 230                 235                 240     Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser                 245                 250                 255         Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val             260                 265                 270             Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe         275                 280                 285                 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val     290                 295                 300                     Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 305                 310                 315                 320     Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys                 325                 330                 335         Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly             340                 345                 350             Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile         355                 360                 365                  Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu     370                 375                 380                     Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 385                 390                 395                 400     Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg                 405                 410                 415         Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys             420                 425                 430             Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu         435                 440                 445                 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr     450                 455                 460                     Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 465                 470                 475                 480     Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp                 485                 490                 495         Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val             500                 505                 510             Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp         515                 520                 525                 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His     530                 535                 540                     Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 545                 550                 555                 560     Gly         ＜210＞  26 ＜211＞  348 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  26   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 Asp Ile Gly Asn Arg             20                  25                  30              Leu Ser Trp Leu Gln Gln Glu Pro Gly Lys Ala Pro Lys Arg Leu Ile         35                  40                  45                  Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe                 85                  90                  95           Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser 225                 230                 235                 240     Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp                 245                 250                 255         Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn             260                 265                 270             Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu         275                 280                 285                 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp     290                 295                 300                      Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 305                 310                 315                 320     Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser                 325                 330                 335         Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             340                 345                 ＜210＞  27 ＜211＞  491 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  27   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                  Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe     130                 135                 140                     Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn                 165                 170                 175         Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr     210                 215                 220                     Val Thr Val Ser Ser Gly Gly Cys Gly Gly Gly Glu Val Ala Ala Cys 225                 230                 235                 240     Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys                 245                 250                 255         Glu Val Ala Ala Leu Glu Lys Glu Ser Lys Tyr Gly Pro Pro Cys Pro             260                 265                 270             Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe         275                 280                 285                 Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val     290                 295                 300                     Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 305                 310                 315                 320     Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro                 325                 330                 335         Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr             340                 345                 350             Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val         355                 360                 365                 Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala     370                 375                 380                     Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 385                 390                 395                 400     Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly                 405                 410                 415         Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro             420                 425                 430             Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser         435                 440                 445                 Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu     450                 455                 460                     Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 465                 470                 475                 480     Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly                 485                 490         ＜210＞  28 ＜211＞  269 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  28   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 Asp Ile Gly Asn Arg             20                  25                  30              Leu Ser Trp Leu Gln Gln Glu Pro Gly Lys Ala Pro Lys Arg Leu Ile         35                  40                  45                   Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly Gly 225                 230                 235                 240     Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu Lys                 245                 250                 255         Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu             260                 265                     ＜210＞  29 ＜211＞  564 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  29   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe     130                 135                 140                     Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn                 165                 170                 175         Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr     210                 215                 220                     Val Thr Val Ser Ser Leu Gly Gly Gly Ser Gly Ala Ser Thr Lys Gly 225                 230                 235                 240     Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly                 245                 250                 255         Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val             260                 265                 270             Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe         275                 280                 285                 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val     290                 295                 300                     Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 305                 310                 315                 320     Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys                 325                 330                 335         Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala             340                 345                 350             Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr         355                 360                 365                  Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val     370                 375                 380                     Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 385                 390                 395                 400     Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser                 405                 410                 415         Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu             420                 425                 430             Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala         435                 440                 445                 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro     450                 455                 460                     Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 465                 470                 475                 480     Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala                 485                 490                 495         Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr             500                 505                 510             Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu         515                 520                 525                 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser     530                 535                 540                     Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 545                 550                 555                 560     Leu Ser Pro Gly                     ＜210＞  30 ＜211＞  348 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  30   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 Asp Ile Gly Asn Arg             20                  25                  30              Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile         35                  40                  45                  Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                       Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser 225                 230                 235                 240     Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp                 245                 250                 255         Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn             260                 265                 270              Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu         275                 280                 285                 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp     290                 295                 300                      Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 305                 310                 315                 320     Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser                 325                 330                 335         Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             340                 345                 ＜210＞  31 ＜211＞  495 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  31   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30               Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                       Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe     130                 135                 140                     Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn                 165                 170                 175         Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                  Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr     210                 215                 220                     Val Thr Val Ser Ser Gly Gly Cys Gly Gly Gly Glu Val Ala Ala Cys 225                 230                 235                 240     Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys                 245                 250                 255         Glu Val Ala Ala Leu Glu Lys Leu Glu Pro Lys Ser Ser Asp Lys Thr             260                 265                 270             His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser         275                 280                 285                 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg     290                 295                 300                     Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 305                 310                 315                 320     Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala                 325                 330                 335         Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val             340                 345                 350             Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr         355                 360                 365                 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr     370                 375                 380                     Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 385                 390                 395                 400     Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys                 405                 410                 415         Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser             420                 425                 430             Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp         435                 440                 445                  Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser     450                 455                 460                     Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 465                 470                 475                 480     Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly                 485                 490                 495     ＜210＞  32 ＜211＞  269 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  32   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 Asp Ile Gly Asn Arg             20                  25                  30               Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile         35                  40                  45                  Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                       Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                  Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly Gly 225                 230                 235                 240     Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu Lys                 245                 250                 255         Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu             260                 265                     ＜210＞  33 ＜211＞  561 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  33   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                   Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe     130                 135                 140                     Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn                 165                 170                 175         Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr     210                 215                 220                      Val Thr Val Ser Ser Leu Gly Gly Gly Ser Gly Ala Ser Thr Lys Gly 225                 230                 235                 240     Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser                 245                 250                 255         Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val             260                 265                 270             Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe         275                 280                 285                 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val     290                 295                 300                     Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 305                 310                 315                 320     Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys                 325                 330                 335         Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly             340                 345                 350             Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile         355                 360                 365                 Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu     370                 375                 380                     Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 385                 390                 395                 400     Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg                 405                 410                 415         Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys             420                 425                 430             Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu         435                 440                 445                 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr     450                 455                 460                      Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 465                 470                 475                 480     Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp                 485                 490                 495         Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val             500                 505                 510             Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp         515                 520                 525                 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His     530                 535                 540                     Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 545                 550                 555                 560     Gly         ＜210＞  34 ＜211＞  348 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  34   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 Asp Ile Gly Asn Arg             20                  25                  30              Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile         35                  40                  45                  Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser 225                 230                 235                 240     Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp                 245                 250                 255         Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn             260                 265                 270             Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu         275                 280                 285                 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp     290                 295                 300                     Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 305                 310                 315                 320     Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser                 325                 330                 335         Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             340                 345                 ＜210＞  35 ＜211＞  491 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  35   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe     130                 135                 140                     Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn                 165                 170                 175         Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser             180                 185                 190              Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr     210                 215                 220                      Val Thr Val Ser Ser Gly Gly Cys Gly Gly Gly Glu Val Ala Ala Cys 225                 230                 235                 240     Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys                 245                 250                 255         Glu Val Ala Ala Leu Glu Lys Glu Ser Lys Tyr Gly Pro Pro Cys Pro             260                 265                 270             Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe         275                 280                 285                 Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val     290                 295                 300                     Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 305                 310                 315                 320     Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro                 325                 330                 335         Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr             340                 345                 350             Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val         355                 360                 365                 Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala     370                 375                 380                     Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 385                 390                 395                 400     Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly                 405                 410                 415         Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro             420                 425                 430             Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser         435                 440                 445                 Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu     450                 455                 460                     Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 465                 470                 475                 480     Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly                 485                 490         ＜210＞  36 ＜211＞  269 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  36   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 Asp Ile Gly Asn Arg             20                  25                  30              Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile         35                  40                  45                  Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly Gly 225                 230                 235                 240     Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu Lys                 245                 250                 255         Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu             260                 265                     ＜210＞  37 ＜211＞  572 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  37   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95           Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe     130                 135                 140                     Ser Thr Phe Phe Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn                 165                 170                 175         Glu Lys Phe Glu Ser Lys Val Thr Leu Thr Arg Asp Thr Ser Ile Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu     210                 215                 220                     Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Leu Gly Gly 225                 230                 235                 240     Gly Ser Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro                 245                 250                 255         Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val             260                 265                 270             Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala         275                 280                 285                 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly     290                 295                 300                     Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 305                 310                 315                 320     Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys                 325                 330                 335         Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys             340                 345                 350             Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu         355                 360                 365                 Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu     370                 375                 380                     Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 385                 390                 395                 400     Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys                 405                 410                 415         Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu             420                 425                 430             Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys         435                 440                 445                 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys     450                 455                 460                     Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 465                 470                 475                 480     Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys                 485                 490                 495         Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln             500                 505                 510             Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly         515                 520                 525                 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln     530                 535                 540                      Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 545                 550                 555                 560     His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly                 565                 570             ＜210＞  38 ＜211＞  348 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  38   Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1               5                   10                  15          Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp             20                  25                  30              Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Ser Lys Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Ala Asp Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg                 85                  90                  95          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                      Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser 225                 230                 235                 240     Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp                 245                 250                 255         Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn             260                 265                 270             Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu         275                 280                 285                 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp     290                 295                 300                     Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 305                 310                 315                 320     Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser                 325                 330                 335         Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             340                 345                 ＜210＞  39 ＜211＞  503 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  39   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe     130                 135                 140                     Ser Thr Phe Phe Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn                 165                 170                 175         Glu Lys Phe Glu Ser Lys Val Thr Leu Thr Arg Asp Thr Ser Ile Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu     210                 215                 220                     Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Cys 225                 230                 235                 240     Gly Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala Ala Leu Glu                 245                 250                 255         Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys Leu             260                 265                 270             Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala         275                 280                 285                 Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro     290                 295                 300                     Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val 305                 310                 315                 320     Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val                 325                 330                 335         Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln             340                 345                 350             Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln         355                 360                 365                 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala     370                 375                 380                      Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 385                 390                 395                 400     Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr                 405                 410                 415         Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser             420                 425                 430             Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr         435                 440                 445                 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr     450                 455                 460                     Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 465                 470                 475                 480     Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys                 485                 490                 495         Ser Leu Ser Leu Ser Pro Gly             500                 ＜210＞  40 ＜211＞  269 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜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 Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp             20                  25                  30              Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35                  40                  45                   Tyr Ser Lys Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Ala Asp Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg                 85                  90                  95          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly Gly 225                 230                 235                 240     Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu Lys                 245                 250                 255         Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu             260                 265                     ＜210＞  41 ＜211＞  569 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  41   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe     130                 135                 140                     Ser Thr Phe Phe Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn                 165                 170                 175         Glu Lys Phe Glu Ser Lys Val Thr Leu Thr Arg Asp Thr Ser Ile Ser             180                 185                 190              Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu     210                 215                 220                      Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Leu Gly Gly 225                 230                 235                 240     Gly Ser Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro                 245                 250                 255         Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val             260                 265                 270             Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala         275                 280                 285                 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly     290                 295                 300                     Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 305                 310                 315                 320     Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys                 325                 330                 335         Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys             340                 345                 350             Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro         355                 360                 365                 Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys     370                 375                 380                     Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp 385                 390                 395                 400     Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 405                 410                 415         Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             420                 425                 430             His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         435                 440                 445                 Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     450                 455                 460                     Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu 465                 470                 475                 480     Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 485                 490                 495         Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             500                 505                 510             Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         515                 520                 525                 Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn     530                 535                 540                     Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 545                 550                 555                 560     Gln Lys Ser Leu Ser Leu Ser Leu Gly                 565                     ＜210＞  42 ＜211＞  348 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  42   Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1               5                   10                  15          Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp             20                  25                  30               Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Ser Lys Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                       Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Ala Asp Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg                 85                  90                  95          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                  Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser 225                 230                 235                 240     Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp                 245                 250                 255         Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn             260                 265                 270             Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu         275                 280                 285                 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp     290                 295                 300                     Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 305                 310                 315                 320     Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser                 325                 330                 335         Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             340                 345                 ＜210＞  43 ＜211＞  499 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  43   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30               Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                       Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe     130                 135                 140                     Ser Thr Phe Phe Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn                 165                 170                 175         Glu Lys Phe Glu Ser Lys Val Thr Leu Thr Arg Asp Thr Ser Ile Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu     210                 215                 220                     Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Cys 225                 230                 235                 240     Gly Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala Ala Leu Glu                 245                 250                 255         Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys Glu             260                 265                 270             Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu         275                 280                 285                 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu     290                 295                 300                     Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser 305                 310                 315                 320     Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu                 325                 330                 335         Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr             340                 345                 350             Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn         355                 360                 365                 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser     370                 375                 380                     Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 385                 390                 395                 400     Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val                 405                 410                 415         Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val             420                 425                 430             Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro         435                 440                 445                 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr     450                 455                 460                     Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 465                 470                 475                 480     Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu                 485                 490                 495         Ser Leu Gly                 ＜210＞  44 ＜211＞  269 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  44   Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1               5                   10                  15          Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp             20                  25                  30               Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Ser Lys Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                       Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Ala Asp Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg                 85                  90                  95          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly Gly 225                 230                 235                 240     Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu Lys                 245                 250                 255         Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu             260                 265                     ＜210＞  45 ＜211＞  572 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  45   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                   Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe     130                 135                 140                     Ser Thr Phe Phe Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn                 165                 170                 175         Glu Lys Phe Glu Ser Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu     210                 215                 220                     Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Leu Gly Gly 225                 230                 235                 240     Gly Ser Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro                 245                 250                 255         Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val             260                 265                 270             Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala         275                 280                 285                 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly     290                 295                 300                     Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 305                 310                 315                 320     Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys                 325                 330                 335         Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys             340                 345                 350             Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu         355                 360                 365                 Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu     370                 375                 380                     Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 385                 390                 395                 400     Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys                 405                 410                 415         Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu             420                 425                 430             Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys         435                 440                 445                 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys     450                 455                 460                      Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 465                 470                 475                 480     Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys                 485                 490                 495         Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln             500                 505                 510             Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly         515                 520                 525                 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln     530                 535                 540                     Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 545                 550                 555                 560     His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly                 565                 570             ＜210＞  46 ＜211＞  348 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜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 Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp             20                  25                  30              Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Ser Lys Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                       Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser 225                 230                 235                 240     Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp                 245                 250                 255         Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn             260                 265                 270              Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu         275                 280                 285                 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp     290                 295                 300                      Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 305                 310                 315                 320     Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser                 325                 330                 335         Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             340                 345                 ＜210＞  47 ＜211＞  503 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  47   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30               Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                       Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe     130                 135                 140                     Ser Thr Phe Phe Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn                 165                 170                 175         Glu Lys Phe Glu Ser Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val         195                 200                 205                  Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu     210                 215                 220                     Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Cys 225                 230                 235                 240     Gly Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala Ala Leu Glu                 245                 250                 255         Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys Leu             260                 265                 270             Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala         275                 280                 285                 Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro     290                 295                 300                     Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val 305                 310                 315                 320     Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val                 325                 330                 335         Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln             340                 345                 350             Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln         355                 360                 365                 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala     370                 375                 380                     Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 385                 390                 395                 400     Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr                 405                 410                 415         Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser             420                 425                 430             Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr         435                 440                 445                 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr     450                 455                 460                     Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 465                 470                 475                 480     Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys                 485                 490                 495         Ser Leu Ser Leu Ser Pro Gly             500                 ＜210＞  48 ＜211＞  269 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  48   Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1               5                   10                  15          Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp             20                  25                  30              Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Ser Lys Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                  Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly Gly 225                 230                 235                 240     Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu Lys                 245                 250                 255         Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu             260                 265                     ＜210＞  49 ＜211＞  569 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  49   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110              Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe     130                 135                 140                      Ser Thr Phe Phe Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn                 165                 170                 175         Glu Lys Phe Glu Ser Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu     210                 215                 220                     Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Leu Gly Gly 225                 230                 235                 240     Gly Ser Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro                 245                 250                 255         Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val             260                 265                 270             Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala         275                 280                 285                 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly     290                 295                 300                     Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 305                 310                 315                 320     Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys                 325                 330                 335         Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys             340                 345                 350             Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro         355                 360                 365                 Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys     370                 375                 380                     Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp 385                 390                 395                 400     Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 405                 410                 415         Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             420                 425                 430             His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         435                 440                 445                 Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     450                 455                 460                     Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu 465                 470                 475                 480     Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 485                 490                 495         Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             500                 505                 510             Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         515                 520                 525                  Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn     530                 535                 540                     Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 545                 550                 555                 560     Gln Lys Ser Leu Ser Leu Ser Leu Gly                 565                     ＜210＞  50 ＜211＞  348 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  50   Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1               5                   10                  15          Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp             20                  25                  30              Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Ser Lys Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                  Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser 225                 230                 235                 240     Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp                 245                 250                 255         Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn             260                 265                 270             Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu         275                 280                 285                 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp     290                 295                 300                     Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 305                 310                 315                 320     Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser                 325                 330                 335         Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             340                 345                 ＜210＞  51 ＜211＞  499 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  51   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe     130                 135                 140                     Ser Thr Phe Phe Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn                 165                 170                 175         Glu Lys Phe Glu Ser Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser             180                 185                 190              Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu     210                 215                 220                      Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Cys 225                 230                 235                 240     Gly Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala Ala Leu Glu                 245                 250                 255         Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys Glu             260                 265                 270             Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu         275                 280                 285                 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu     290                 295                 300                     Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser 305                 310                 315                 320     Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu                 325                 330                 335         Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr             340                 345                 350             Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn         355                 360                 365                 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser     370                 375                 380                     Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 385                 390                 395                 400     Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val                 405                 410                 415         Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val             420                 425                 430             Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro         435                 440                 445                 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr     450                 455                 460                     Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 465                 470                 475                 480     Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu                 485                 490                 495         Ser Leu Gly                 ＜210＞  52 ＜211＞  269 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  52   Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1               5                   10                  15          Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp             20                  25                  30              Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Ser Lys Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly Gly 225                 230                 235                 240     Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu Lys                 245                 250                 255         Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu             260                 265                     ＜210＞  53 ＜211＞  570 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  53   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 Asp Ile Gly Asn Arg             20                  25                  30              Leu Ser Trp Leu Gln Gln Glu Pro Gly Lys Ala Pro Lys Arg Leu Ile         35                  40                  45                  Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                       Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser 225                 230                 235                 240     Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser                 245                 250                 255         Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp             260                 265                 270              Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr         275                 280                 285                 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr     290                 295                 300                      Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 305                 310                 315                 320     Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp                 325                 330                 335         Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro             340                 345                 350             Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro         355                 360                 365                 Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr     370                 375                 380                     Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 385                 390                 395                 400     Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg                 405                 410                 415         Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val             420                 425                 430             Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser         435                 440                 445                 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys     450                 455                 460                     Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu 465                 470                 475                 480     Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe                 485                 490                 495         Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu             500                 505                 510              Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe         515                 520                 525                 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly     530                 535                 540                      Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 545                 550                 555                 560     Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly                 565                 570     ＜210＞  54 ＜211＞  342 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  54   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110              Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe     130                 135                 140                      Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn                 165                 170                 175         Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr     210                 215                 220                     Val Thr Val Ser Ser Leu Gly Gly Gly Ser Gly Arg Thr Val Ala Ala 225                 230                 235                 240     Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly                 245                 250                 255         Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala             260                 265                 270             Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln         275                 280                 285                 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser     290                 295                 300                     Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 305                 310                 315                 320     Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser                 325                 330                 335         Phe Asn Arg Gly Glu Cys             340             ＜210＞  55 ＜211＞  567 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  55   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 Asp Ile Gly Asn Arg             20                  25                  30              Leu Ser Trp Leu Gln Gln Glu Pro Gly Lys Ala Pro Lys Arg Leu Ile         35                  40                  45                  Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser 225                 230                 235                 240     Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser                 245                 250                 255         Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp             260                 265                 270             Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr         275                 280                 285                 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr     290                 295                 300                     Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys 305                 310                 315                 320     Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp                 325                 330                 335         Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala             340                 345                 350             Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro         355                 360                 365                 Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val     370                 375                 380                     Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 385                 390                 395                 400     Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln                 405                 410                 415         Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln             420                 425                 430             Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly         435                 440                 445                 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro     450                 455                 460                     Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr 465                 470                 475                 480     Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser                 485                 490                 495         Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr             500                 505                 510             Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr         515                 520                 525                 Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe     530                 535                 540                     Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 545                 550                 555                 560     Ser Leu Ser Leu Ser Leu Gly                 565             ＜210＞  56 ＜211＞  342 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  56   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe     130                 135                 140                     Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn                 165                 170                 175         Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr     210                 215                 220                     Val Thr Val Ser Ser Leu Gly Gly Gly Ser Gly Arg Thr Val Ala Ala 225                 230                 235                 240     Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly                 245                 250                 255         Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala             260                 265                 270             Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln         275                 280                 285                  Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser     290                 295                 300                     Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 305                 310                 315                 320     Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser                 325                 330                 335         Phe Asn Arg Gly Glu Cys             340             ＜210＞  57 ＜211＞  570 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  57   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 Asp Ile Gly Asn Arg             20                  25                  30              Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile         35                  40                  45                  Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                  Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser 225                 230                 235                 240     Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser                 245                 250                 255         Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp             260                 265                 270             Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr         275                 280                 285                 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr     290                 295                 300                     Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 305                 310                 315                 320     Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp                 325                 330                 335         Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro             340                 345                 350             Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro         355                 360                 365                 Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr     370                 375                 380                     Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 385                 390                 395                 400     Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg                 405                 410                 415         Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val             420                 425                 430             Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser         435                 440                 445                 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys     450                 455                 460                     Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu 465                 470                 475                 480     Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe                 485                 490                 495         Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu             500                 505                 510             Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe         515                 520                 525                 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly     530                 535                 540                     Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 545                 550                 555                 560     Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly                 565                 570     ＜210＞  58 ＜211＞  342 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  58   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                   Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe     130                 135                 140                     Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn                 165                 170                 175         Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr     210                 215                 220                     Val Thr Val Ser Ser Leu Gly Gly Gly Ser Gly Arg Thr Val Ala Ala 225                 230                 235                 240     Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly                 245                 250                 255         Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala             260                 265                 270             Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln         275                 280                 285                 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser     290                 295                 300                     Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 305                 310                 315                 320     Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser                 325                 330                 335         Phe Asn Arg Gly Glu Cys             340             ＜210＞  59 ＜211＞  567 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  59   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 Asp Ile Gly Asn Arg             20                  25                  30              Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile         35                  40                  45                  Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser 225                 230                 235                 240     Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser                 245                 250                 255         Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp             260                 265                 270             Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr         275                 280                 285                  Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr     290                 295                 300                     Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys 305                 310                 315                 320     Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp                 325                 330                 335         Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala             340                 345                 350             Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro         355                 360                 365                 Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val     370                 375                 380                     Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 385                 390                 395                 400     Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln                 405                 410                 415         Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln             420                 425                 430             Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly         435                 440                 445                 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro     450                 455                 460                     Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr 465                 470                 475                 480     Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser                 485                 490                 495         Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr             500                 505                 510             Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr         515                 520                 525                 Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe     530                 535                 540                     Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 545                 550                 555                 560     Ser Leu Ser Leu Ser Leu Gly                 565             ＜210＞  60 ＜211＞  342 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95           Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe     130                 135                 140                     Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn                 165                 170                 175         Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr     210                 215                 220                     Val Thr Val Ser Ser Leu Gly Gly Gly Ser Gly Arg Thr Val Ala Ala 225                 230                 235                 240     Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly                 245                 250                 255         Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala             260                 265                 270             Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln         275                 280                 285                 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser     290                 295                 300                      Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 305                 310                 315                 320     Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser                 325                 330                 335         Phe Asn Arg Gly Glu Cys             340             ＜210＞  61 ＜211＞  570 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  61   Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1               5                   10                  15          Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp             20                  25                  30              Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Ser Lys Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Ala Asp Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg                 85                  90                  95          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                  Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser 225                 230                 235                 240     Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser                 245                 250                 255         Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp             260                 265                 270             Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr         275                 280                 285                 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr     290                 295                 300                     Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 305                 310                 315                 320     Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp                 325                 330                 335         Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro             340                 345                 350             Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro         355                 360                 365                  Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr     370                 375                 380                     Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 385                 390                 395                 400     Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg                 405                 410                 415         Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val             420                 425                 430             Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser         435                 440                 445                 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys     450                 455                 460                     Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu 465                 470                 475                 480     Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe                 485                 490                 495         Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu             500                 505                 510             Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe         515                 520                 525                 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly     530                 535                 540                     Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 545                 550                 555                 560     Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly                 565                 570     ＜210＞  62 ＜211＞  350 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  62   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe     130                 135                 140                     Ser Thr Phe Phe Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn                 165                 170                 175         Glu Lys Phe Glu Ser Lys Val Thr Leu Thr Arg Asp Thr Ser Ile Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu     210                 215                 220                     Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Leu Gly Gly 225                 230                 235                 240     Gly Ser Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro                 245                 250                 255         Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu             260                 265                 270             Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn         275                 280                 285                 Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser     290                 295                 300                     Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala 305                 310                 315                 320     Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly                 325                 330                 335         Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             340                 345                 350     ＜210＞  63 ＜211＞  567 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  63   Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1               5                   10                  15          Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp             20                  25                  30              Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Ser Lys Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Ala Asp Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg                 85                  90                  95          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                  Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser 225                 230                 235                 240     Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser                 245                 250                 255         Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp             260                 265                 270             Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr         275                 280                 285                 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr     290                 295                 300                     Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys 305                 310                 315                 320     Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp                 325                 330                 335         Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala             340                 345                 350             Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro         355                 360                 365                 Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val     370                 375                 380                     Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 385                 390                 395                 400     Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln                 405                 410                 415         Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln             420                 425                 430             Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly         435                 440                 445                 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro     450                 455                 460                     Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr 465                 470                 475                 480     Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser                 485                 490                 495         Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr             500                 505                 510             Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr         515                 520                 525                 Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe     530                 535                 540                     Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 545                 550                 555                 560     Ser Leu Ser Leu Ser Leu Gly                 565              ＜210＞  64 ＜211＞  350 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  64   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                   Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe     130                 135                 140                     Ser Thr Phe Phe Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn                 165                 170                 175         Glu Lys Phe Glu Ser Lys Val Thr Leu Thr Arg Asp Thr Ser Ile Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu     210                 215                 220                     Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Leu Gly Gly 225                 230                 235                 240     Gly Ser Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro                 245                 250                 255         Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu             260                 265                 270             Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn         275                 280                 285                 Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser     290                 295                 300                     Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala 305                 310                 315                 320     Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly                 325                 330                 335         Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             340                 345                 350     ＜210＞  65 ＜211＞  570 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  65   Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1               5                   10                  15          Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp             20                  25                  30              Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Ser Lys Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190              Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                      Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser 225                 230                 235                 240     Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser                 245                 250                 255         Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp             260                 265                 270             Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr         275                 280                 285                 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr     290                 295                 300                     Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 305                 310                 315                 320     Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp                 325                 330                 335         Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro             340                 345                 350             Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro         355                 360                 365                 Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr     370                 375                 380                     Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 385                 390                 395                 400     Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg                 405                 410                 415         Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val             420                 425                 430             Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser         435                 440                 445                 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys     450                 455                 460                     Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu 465                 470                 475                 480     Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe                 485                 490                 495         Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu             500                 505                 510             Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe         515                 520                 525                 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly     530                 535                 540                     Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 545                 550                 555                 560     Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly                 565                 570     ＜210＞  66 ＜211＞  350 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  66   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30               Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                       Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe     130                 135                 140                     Ser Thr Phe Phe Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn                 165                 170                 175         Glu Lys Phe Glu Ser Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val         195                 200                 205                  Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu     210                 215                 220                     Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Leu Gly Gly 225                 230                 235                 240     Gly Ser Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro                 245                 250                 255         Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu             260                 265                 270             Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn         275                 280                 285                 Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser     290                 295                 300                     Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala 305                 310                 315                 320     Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly                 325                 330                 335         Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             340                 345                 350     ＜210＞  67 ＜211＞  567 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  67   Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1               5                   10                  15          Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp             20                  25                  30              Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Ser Lys Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe     130                 135                 140                     Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn                 165                 170                 175         Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr     210                 215                 220                     Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser 225                 230                 235                 240     Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser                 245                 250                 255         Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp             260                 265                 270             Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr         275                 280                 285                 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr     290                 295                 300                     Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys 305                 310                 315                 320     Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp                 325                 330                 335         Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala             340                 345                 350             Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro         355                 360                 365                 Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val     370                 375                 380                     Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 385                 390                 395                 400     Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln                 405                 410                 415         Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln             420                 425                 430             Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly         435                 440                 445                 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro     450                 455                 460                     Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr 465                 470                 475                 480     Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser                 485                 490                 495         Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr             500                 505                 510             Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr         515                 520                 525                 Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe     530                 535                 540                     Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 545                 550                 555                 560     Ser Leu Ser Leu Ser Leu Gly                 565             ＜210＞  68 ＜211＞  350 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  68   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 Lys Ala Ser Arg Asp Val Ala Ile Ala             20                  25                  30              Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe                 85                  90                  95          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly             100                 105                 110             Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys         115                 120                 125                 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe     130                 135                 140                     Ser Thr Phe Phe Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 145                 150                 155                 160     Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn                 165                 170                 175         Glu Lys Phe Glu Ser Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser             180                 185                 190             Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val         195                 200                 205                 Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu     210                 215                 220                     Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Leu Gly Gly 225                 230                 235                 240     Gly Ser Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro                 245                 250                 255         Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu             260                 265                 270             Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn         275                 280                 285                  Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser     290                 295                 300                     Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala 305                 310                 315                 320     Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly                 325                 330                 335         Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             340                 345                 350     ＜210＞  69 ＜211＞  8 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  69   Gly Gly Gly Ser Gly Gly Gly Gly 1               5                   ＜210＞  70 ＜211＞  6 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  70   Leu Gly Gly Gly Ser Gly 1               5           ＜210＞  71 ＜211＞  6 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  71   Phe Asn Arg Gly Glu Cys 1               5           ＜210＞  72 ＜211＞  6 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  72   Val Glu Pro Lys Ser Cys 1               5           ＜210＞  73 ＜211＞  326 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  73   Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys 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 Ser Leu Gly Thr Lys Thr 65                  70                  75                  80      Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85                  90                  95          Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro             100                 105                 110              Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys         115                 120                 125                 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val     130                 135                 140                      Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145                 150                 155                 160     Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe                 165                 170                 175         Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp             180                 185                 190             Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu         195                 200                 205                 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg     210                 215                 220                     Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 225                 230                 235                 240     Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp                 245                 250                 255         Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys             260                 265                 270             Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser         275                 280                 285                 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser     290                 295                 300                     Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 305                 310                 315                 320     Leu Ser Leu Ser Leu Gly                 325         ＜210＞  74 ＜211＞  326 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  74   Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys 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 Ser Leu Gly Thr Lys Thr 65                  70                  75                  80      Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85                  90                  95          Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro             100                 105                 110             Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys         115                 120                 125                 Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val     130                 135                 140                     Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145                 150                 155                 160     Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe                 165                 170                 175         Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp             180                 185                 190             Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu         195                 200                 205                 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg     210                 215                 220                     Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 225                 230                 235                 240     Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp                 245                 250                 255         Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys             260                 265                 270             Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser         275                 280                 285                 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser     290                 295                 300                     Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 305                 310                 315                 320     Leu Ser Leu Ser Leu Gly                 325         ＜210＞  75 ＜211＞  329 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  75   Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1               5                   10                  15          Ser Thr Ser Gly Gly 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 Ser Leu Gly Thr Gln Thr 65                  70                  75                  80      Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85                  90                  95          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100                 105                 110             Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro         115                 120                 125                 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130                 135                 140                     Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145                 150                 155                 160     Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165                 170                 175         Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180                 185                 190             His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195                 200                 205                  Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210                 215                 220                     Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225                 230                 235                 240     Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245                 250                 255         Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260                 265                 270             Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275                 280                 285                 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290                 295                 300                     Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305                 310                 315                 320     Gln Lys Ser Leu Ser Leu Ser Pro Gly                 325                      ＜210＞  76 ＜211＞  15 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  76   Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 1               5                   10                  15      ＜210＞  77 ＜211＞  107 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  77   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             ＜210＞  78 ＜211＞  330 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  78   Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1               5                   10                  15          Ser Thr Ser Gly Gly 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 Ser Leu Gly Thr Gln Thr 65                  70                  75                  80      Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85                  90                  95          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100                 105                 110             Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro         115                 120                 125                 Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys     130                 135                 140                     Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145                 150                 155                 160     Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165                 170                 175         Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180                 185                 190             His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195                 200                 205                 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210                 215                 220                     Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225                 230                 235                 240     Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245                 250                 255         Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260                 265                 270             Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275                 280                 285                 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290                 295                 300                     Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305                 310                 315                 320     Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys                 325                 330     ＜210＞  79 ＜211＞  329 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  79   Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1               5                   10                  15          Ser Thr Ser Gly Gly 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 Ser Leu Gly Thr Gln Thr 65                  70                  75                  80      Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85                  90                  95          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100                 105                 110             Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro         115                 120                 125                 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130                 135                 140                     Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145                 150                 155                 160     Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165                 170                 175         Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180                 185                 190             His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195                 200                 205                 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210                 215                 220                      Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225                 230                 235                 240     Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245                 250                 255         Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260                 265                 270             Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275                 280                 285                 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290                 295                 300                     Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305                 310                 315                 320     Gln Lys Ser Leu Ser Leu Ser Pro Gly                 325                     ＜210＞  80 ＜211＞  285 ＜212＞  PRT ＜213＞  智人   ＜400＞  80   Met Asp Asp Ser Thr Glu Arg Glu Gln Ser Arg Leu Thr Ser Cys Leu 1               5                   10                  15          Lys Lys Arg Glu Glu Met Lys Leu Lys Glu Cys Val Ser Ile Leu Pro             20                  25                  30              Arg Lys Glu Ser Pro Ser Val Arg Ser Ser Lys Asp Gly Lys Leu Leu         35                  40                  45                  Ala Ala Thr Leu Leu Leu Ala Leu Leu Ser Cys Cys Leu Thr Val Val     50                  55                  60                       Ser Phe Tyr Gln Val Ala Ala Leu Gln Gly Asp Leu Ala Ser Leu Arg 65                  70                  75                  80      Ala Glu Leu Gln Gly His His Ala Glu Lys Leu Pro Ala Gly Ala Gly                 85                  90                  95          Ala Pro Lys Ala Gly Leu Glu Glu Ala Pro Ala Val Thr Ala Gly Leu             100                 105                 110             Lys Ile Phe Glu Pro Pro Ala Pro Gly Glu Gly Asn Ser Ser Gln Asn         115                 120                 125                 Ser Arg Asn Lys Arg Ala Val Gln Gly Pro Glu Glu Thr Val Thr Gln     130                 135                 140                     Asp Cys Leu Gln Leu Ile Ala Asp Ser Glu Thr Pro Thr Ile Gln Lys 145                 150                 155                 160     Gly Ser Tyr Thr Phe Val Pro Trp Leu Leu Ser Phe Lys Arg Gly Ser                 165                 170                 175         Ala Leu Glu Glu Lys Glu Asn Lys Ile Leu Val Lys Glu Thr Gly Tyr             180                 185                 190             Phe Phe Ile Tyr Gly Gln Val Leu Tyr Thr Asp Lys Thr Tyr Ala Met         195                 200                 205                 Gly His Leu Ile Gln Arg Lys Lys Val His Val Phe Gly Asp Glu Leu     210                 215                 220                     Ser Leu Val Thr Leu Phe Arg Cys Ile Gln Asn Met Pro Glu Thr Leu 225                 230                 235                 240     Pro Asn Asn Ser Cys Tyr Ser Ala Gly Ile Ala Lys Leu Glu Glu Gly                 245                 250                 255         Asp Glu Leu Gln Leu Ala Ile Pro Arg Glu Asn Ala Gln Ile Ser Leu             260                 265                 270             Asp Gly Asp Val Thr Phe Phe Gly Ala Leu Lys Leu Leu         275                 280                 285     ＜210＞  81 ＜211＞  189 ＜212＞  PRT ＜213＞  智人   ＜400＞  81   Met Leu Gly Ser Arg Ala Val Met Leu Leu Leu Leu Leu Pro Trp Thr 1               5                   10                  15          Ala Gln Gly Arg Ala Val Pro Gly Gly Ser Ser Pro Ala Trp Thr Gln             20                  25                  30              Cys Gln Gln Leu Ser Gln Lys Leu Cys Thr Leu Ala Trp Ser Ala His         35                  40                  45                  Pro Leu Val Gly His Met Asp Leu Arg Glu Glu Gly Asp Glu Glu Thr     50                  55                  60                      Thr Asn Asp Val Pro His Ile Gln Cys Gly Asp Gly Cys Asp Pro Gln 65                  70                  75                  80      Gly Leu Arg Asp Asn Ser Gln Phe Cys Leu Gln Arg Ile His Gln Gly                 85                  90                  95          Leu Ile Phe Tyr Glu Lys Leu Leu Gly Ser Asp Ile Phe Thr Gly Glu             100                 105                 110             Pro Ser Leu Leu Pro Asp Ser Pro Val Gly Gln Leu His Ala Ser Leu         115                 120                 125                 Leu Gly Leu Ser Gln Leu Leu Gln Pro Glu Gly His His Trp Glu Thr     130                 135                 140                     Gln Gln Ile Pro Ser Leu Ser Pro Ser Gln Pro Trp Gln Arg Leu Leu 145                 150                 155                 160     Leu Arg Phe Lys Ile Leu Arg Ser Leu Gln Ala Phe Val Ala Val Ala                 165                 170                 175         Ala Arg Val Phe Ala His Gly Ala Ala Thr Leu Ser Pro             180                 185                     ＜210＞  82 ＜211＞  34 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  82   Gly Gly Cys Gly Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala 1               5                   10                  15          Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu             20                  25                  30              Glu Lys             ＜210＞  83 ＜211＞  34 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  83   Gly Gly Cys Gly Gly Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala 1               5                   10                  15          Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu             20                  25                  30              Lys Glu             ＜210＞  84 ＜211＞  114 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  84   Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1               5                   10                  15          Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe Ser Ile His             20                  25                  30              Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met         35                  40                  45                  Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn Glu Lys Phe     50                  55                  60                      Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr 65                  70                  75                  80      Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys                 85                  90                  95          Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val             100                 105                 110             Ser Ser             ＜210＞  85 ＜211＞  107 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  85   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 Asp Ile Gly Asn Arg             20                  25                  30              Leu Ser Trp Leu Gln Gln Glu Pro Gly Lys Ala Pro Lys Arg Leu Ile         35                  40                  45                  Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys             100                 105             ＜210＞  86 ＜211＞  114 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  86   Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1               5                   10                  15          Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe Ser Ile His             20                  25                  30               Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met         35                  40                  45                  Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn Glu Lys Phe     50                  55                  60                       Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr 65                  70                  75                  80      Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys                 85                  90                  95          Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val             100                 105                 110             Ser Ser             ＜210＞  87 ＜211＞  107 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  87   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 Asp Ile Gly Asn Arg             20                  25                  30              Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile         35                  40                  45                  Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys             100                 105             ＜210＞  88 ＜211＞  122 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  88   Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1               5                   10                  15          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Ser Thr Phe             20                  25                  30               Phe Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile         35                  40                  45                  Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn Glu Lys Phe     50                  55                  60                       Glu Ser Lys Val Thr Leu Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65                  70                  75                  80      Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys                 85                  90                  95          Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu Asp Tyr Trp             100                 105                 110             Gly Gln Gly Thr Ser Val Thr Val Ser Ser         115                 120             ＜210＞  89 ＜211＞  107 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  89   Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1               5                   10                  15          Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp             20                  25                  30              Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35                  40                  45                   Tyr Ser Lys Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Ala Asp Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg                 85                  90                  95          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys             100                 105             ＜210＞  90 ＜211＞  122 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  90   Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1               5                   10                  15          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Ser Thr Phe             20                  25                  30              Phe Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile         35                  40                  45                  Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn Glu Lys Phe     50                  55                  60                      Glu Ser Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65                  70                  75                  80      Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys                 85                  90                  95          Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu Asp Tyr Trp             100                 105                 110              Gly Gln Gly Thr Ser Val Thr Val Ser Ser         115                 120             ＜210＞  91 ＜211＞  107 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  91   Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1               5                   10                  15          Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp             20                  25                  30              Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35                  40                  45                  Tyr Ser Lys Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65                  70                  75                  80      Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys             100                 105             ＜210＞  92 ＜211＞  10 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  92   Gly Gly Thr Phe Asn Asn Asn Ala Ile Asn 1               5                   10      ＜210＞  93 ＜211＞  17 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  93   Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser Gln Asn Phe Gln 1               5                   10                  15          Gly         ＜210＞  94 ＜211＞  14 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  94   Ser Arg Asp Leu Leu Leu Phe Pro His His Ala Leu Ser Pro 1               5                   10                      ＜210＞  95 ＜211＞  11 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  95   Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser 1               5                   10          ＜210＞  96 ＜211＞  7 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  96   Gly Lys Asn Asn Arg Pro Ser 1               5               ＜210＞  97 ＜211＞  11 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  97   Ser Ser Arg Asp Ser Ser Gly Asn His Trp Val 1               5                   10          ＜210＞  98 ＜211＞  10 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  98   Gly Tyr Thr Phe Thr Asp Gln Thr Ile His 1               5                   10      ＜210＞  99 ＜211＞  17 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  99   Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn Glu Asn Phe Lys 1               5                   10                  15          Gly         ＜210＞  100 ＜211＞  11 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  100   Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr 1               5                   10          ＜210＞  101 ＜211＞  11 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  101   Lys Ala Ser Arg Asp Val Ala Ile Ala Val Ala 1               5                   10          ＜210＞  102 ＜211＞  7 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  102   Trp Ala Ser Thr Arg His Thr 1               5               ＜210＞  103 ＜211＞  9 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  103   His Gln Tyr Ser Ser Tyr Pro Phe Thr 1               5                       ＜210＞  104 ＜211＞  10 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  104   Asp His Ile Phe Ser Ile His Trp Met Gln 1               5                   10      ＜210＞  105 ＜211＞  17 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  105   Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn Glu Lys Phe Lys 1               5                   10                  15          Gly         ＜210＞  106 ＜211＞  5 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  106   Gly Ala Phe Asp Tyr 1               5       ＜210＞  107 ＜211＞  11 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  107   Arg Ala Ser Gln Asp Ile Gly Asn Arg Leu Ser 1               5                   10          ＜210＞  108 ＜211＞  7 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  108   Ala Thr Ser Ser Leu Asp Ser 1               5               ＜210＞  109 ＜211＞  9 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  109   Leu Gln Tyr Ala Ser Ser Pro Phe Thr 1               5                       ＜210＞  110 ＜211＞  10 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  110   Asp His Ile Phe Ser Ile His Trp Met Gln 1               5                   10      ＜210＞  111 ＜211＞  17 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  111   Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn Glu Lys Phe Lys 1               5                   10                  15          Gly         ＜210＞  112 ＜211＞  5 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  112   Gly Ala Phe Asp Tyr 1               5       ＜210＞  113 ＜211＞  11 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  113   Arg Ala Ser Gln Asp Ile Gly Asn Arg Leu Asn 1               5                   10          ＜210＞  114 ＜211＞  7 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  114   Ala Thr Ser Ser Leu Asp Ser 1               5               ＜210＞  115 ＜211＞  10 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  115   Gly Tyr Ser Phe Ser Thr Phe Phe Ile His 1               5                   10      ＜210＞  116 ＜211＞  17 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  116   Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn Glu Lys Phe Glu 1               5                   10                  15          Ser         ＜210＞  117 ＜211＞  13 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  117   Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu Asp Tyr 1               5                   10                  ＜210＞  118 ＜211＞  11 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  118   Lys Ala Ser Gln Asn Ala Gly Ile Asp Val Ala 1               5                   10          ＜210＞  119 ＜211＞  7 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  119   Ser Lys Ser Asn Arg Tyr Thr 1               5               ＜210＞  120 ＜211＞  9 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  120   Leu Gln Tyr Arg Ser Tyr Pro Arg Thr 1               5                       ＜210＞  121 ＜211＞  10 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  121   Gly Tyr Ser Phe Ser Thr Phe Phe Ile His 1               5                   10      ＜210＞  122 ＜211＞  18 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  122   Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn Glu Lys Phe 1               5                   10                  15          Glu Ser             ＜210＞  123 ＜211＞  13 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  123   Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu Asp Tyr 1               5                   10                  ＜210＞  124 ＜211＞  11 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  124   Lys Ala Ser Gln Asn Ala Gly Ile Asp Val Ala 1               5                   10          ＜210＞  125 ＜211＞  7 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  125   Ser Lys Ser Asn Arg Tyr Thr 1               5               ＜210＞  126 ＜211＞  9 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  126   Leu Gln Tyr Arg Ser Tyr Pro Arg Thr 1               5                       ＜210＞  127 ＜211＞  228 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  127   Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 1               5                   10                  15          Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr             20                  25                  30               Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val         35                  40                  45                  Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val     50                  55                  60                       Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser 65                  70                  75                  80      Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu                 85                  90                  95          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser             100                 105                 110             Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro         115                 120                 125                 Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln     130                 135                 140                     Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 145                 150                 155                 160     Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr                 165                 170                 175         Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu             180                 185                 190             Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser         195                 200                 205                 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser     210                 215                 220                     Leu Ser Leu Gly 225                 ＜210＞  128 ＜211＞  329 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  128   Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1               5                   10                  15          Ser Thr Ser Gly Gly 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 Ser Leu Gly Thr Gln Thr 65                  70                  75                  80      Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85                  90                  95          Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100                 105                 110             Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro         115                 120                 125                 Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys     130                 135                 140                     Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145                 150                 155                 160     Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165                 170                 175         Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180                 185                 190             His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195                 200                 205                 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210                 215                 220                     Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225                 230                 235                 240     Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245                 250                 255         Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260                 265                 270              Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275                 280                 285                 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290                 295                 300                      Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305                 310                 315                 320     Gln Lys Ser Leu Ser Leu Ser Pro Gly                 325                     ＜210＞  129 ＜211＞  232 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  129   Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro 1               5                   10                  15          Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys             20                  25                  30              Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val         35                  40                  45                  Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr     50                  55                  60                      Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 65                  70                  75                  80      Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His                 85                  90                  95          Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys             100                 105                 110              Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln         115                 120                 125                 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met     130                 135                 140                      Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 145                 150                 155                 160     Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn                 165                 170                 175         Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu             180                 185                 190             Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val         195                 200                 205                 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln     210                 215                 220                     Lys Ser Leu Ser Leu Ser Pro Gly 225                 230              ＜210＞  130 ＜211＞  16 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  130   Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro 1               5                   10                  15          ＜210＞  131 ＜211＞  290 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  131   Gly Cys Lys Trp Asp Leu Leu Ile Lys Gln Trp Val Cys Asp Pro Leu 1               5                   10                  15          Gly Ser Gly Ser Ala Thr Gly Gly Ser Gly Ser Thr Ala Ser Ser Gly             20                  25                  30              Ser Gly Ser Ala Thr His Met Leu Pro Gly Cys Lys Trp Asp Leu Leu         35                  40                  45                  Ile Lys Gln Trp Val Cys Asp Pro Leu Gly Gly Gly Gly Gly Val Asp     50                  55                  60                      Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 65                  70                  75                  80      Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile                 85                  90                  95          Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu             100                 105                 110             Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His         115                 120                 125                 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg     130                 135                 140                     Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 145                 150                 155                 160     Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu                 165                 170                 175         Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr             180                 185                 190             Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu         195                 200                 205                  Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp     210                 215                 220                     Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 225                 230                 235                 240     Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp                 245                 250                 255         Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His             260                 265                 270             Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro         275                 280                 285                 Gly Lys     290     ＜210＞  132 ＜211＞  123 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  132   Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 1               5                   10                  15          Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr             20                  25                  30               Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile         35                  40                  45                  Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys     50                  55                  60                      Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65                  70                  75                  80      Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala                 85                  90                  95          Arg Gly Tyr Tyr Asp Ile Leu Thr Gly Tyr Tyr Tyr Tyr Phe Asp Tyr             100                 105                 110             Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser         115                 120                 ＜210＞  133 ＜211＞  107 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  133   Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1               5                   10                  15          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Tyr             20                  25                  30              Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile         35                  40                  45                   Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly     50                  55                  60                      Ser Gly Ser Gly Thr Asp Ser Thr Leu Thr Ile Ser Ser Leu Glu Pro 65                  70                  75                  80      Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Arg                 85                  90                  95          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100                 105             ＜210＞  134 ＜211＞  12 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  134   Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro 1               5                   10              ＜210＞  135 ＜211＞  6 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  135   Gly Gly Cys Gly Gly Gly 1               5           ＜210＞  136 ＜211＞  8 ＜212＞  PRT ＜213＞  人工序列   ＜220＞ ＜223＞  合成多肽   ＜400＞  136   Leu Gly Gly Cys Gly Gly Gly Ser 1               5

Claims (14)

  1. 一種化合物，包含一第一多肽及一第二多肽，其中：(A)在自N末端至C末端的方向上，該第一多肽包含：(i)對介白素23p19亞單位(IL-23A)具特異性之一第一免疫球蛋白的一輕鏈可變域(VL1)，該VL1包含SEQ ID NO：4的胺基酸序列；(ii)一第一連接子；(iii)對B細胞活化因子(BAFF)具特異性之一第二免疫球蛋白的一重鏈可變域(VH2)，該VH2包含SEQ ID NO：90的胺基酸序列；(iv)一第三連接子；(v)一重鏈恆定區1(CH1)；(vi)一鉸鏈區；(vii)一重鏈恆定區2(CH2)，包含根據Kabat中的EU索引編號的位置252處的酪胺酸、位置254處的蘇胺酸及位置256處的麩胺酸；以及(viii)一重鏈恆定區3(CH3)；以及(B)在自N末端至C末端的方向上，該第二多肽包含：(i)對BAFF具特異性之該第二免疫球蛋白的一 輕鏈可變域(VL2)，該VL2包含SEQ ID NO：91的胺基酸序列；(ii)一第二連接子；(iii)對IL-23A具特異性之該第一免疫球蛋白的一重鏈可變域(VH1)，該VH1包含SEQ ID NO：3的胺基酸序列；(iv)一第四連接子；以及(v)一輕鏈恆定區(CL)，且其中：a)該VL1與VH1締合以形成結合IL-23A之一結合位點；b)該VL2與VH2締合以形成結合BAFF之一結合位點；c)該CL與該CH1形成一C1域；以及d)該CH1、該鉸鏈區、該CH2與該CH3形成源自IgG1或源自IgG4之一恆定區。
  2. 一種如請求項1所述之化合物，其特徵在於：(i)該第一連接子或該第二連接子包含胺基酸序列GGGSGGGG(SEQ ID NO：69)；(ii)該第一連接子及該第二連接子包含胺基酸序列GGGSGGGG(SEQ ID NO：69)；(iii)該第三連接子或該第四連接子包含胺基酸序 列LGGGSG(SEQ ID NO：70)；(iv)該第三連接子及該第四連接子包含胺基酸序列LGGGSG(SEQ ID NO：70)；或(v)該鉸鏈區包含胺基酸序列EPKSCDKTHTCPPCP(SEQ ID NO：76)、胺基酸序列LEPKSSDKTHTCPPCP(SEQ ID NO：130)或胺基酸序列ESKYGPPCPPCP(SEQ ID NO：134)。
  3. 一種如請求項1或2所述之化合物，其特徵在於：該化合物包含兩個該第一多肽及兩個該第二多肽，其中該兩個第一多肽經由至少一個二硫鍵締合在一起。
  4. 一種如請求項1、2或3所述之化合物，其特徵在於：(i)該第一多肽包含SEQ ID NO：45之胺基酸序列，且該第二多肽包含SEQ ID NO：46之胺基酸序列；或(ii)該第一多肽包含SEQ ID NO：49之胺基酸序列，且該第二多肽包含SEQ ID NO：50之胺基酸序列。
  5. 一種如請求項1所述之化合物，其中該第一 多肽包含SEQ ID NO：49之胺基酸序列，且該第二多肽包含SEQ ID NO：50之胺基酸序列。
  6. 一種如請求項1所述之化合物，其中該化合物包含兩個該第一多肽及兩個該第二多肽，其中該等第一多肽之各者經由至少一個二硫鍵締合至一個該第二多肽，且該兩個第一多肽經由至少一個二硫鍵締合在一起，以形成一四價分子。
  7. 一種醫藥組合物，該醫藥組合物包含如請求項1至6中任一項所述之化合物。
  8. 一種如請求項1至6中任一項所述之化合物用於製備一藥劑之用途，該藥劑用於治療一自體免疫疾病。
  9. 如請求項8所述之用途，其中該藥劑係用於治療一炎性疾病。
  10. 一種核酸，選自：(i)包含一核苷酸序列之核酸，該核苷酸序列編碼如請求項1至6中任一項所界定之一多肽；(ii)包含(i)中界定之一核酸之一載體；或(iii)包含(i)中界定之一核酸之一載體，進一步包含可操作連接至該核酸的一啟動子。
  11. 一種細胞，包含如請求項10所界定之一核酸或一載體。
  12. 一種產生如請求項1至6中任一項所述之一多肽的方法，該方法包含以下步驟：獲得如請求項11所述之一細胞；以及在該細胞中表現該核酸。
  13. 如請求項12所述之方法，進一步包含以下步驟：分離及純化該多肽。
  14. 如請求項9所述之用途，其中該自體免疫疾病或一炎性疾病包含全身性紅斑狼瘡(SLE)、腎臟受累的全身性紅斑狼瘡、狼瘡腎炎(LN)、ANCA關聯血管炎(AAV)、原發性乾燥症候群(pSS)、慢性移植物抗宿主病(cGVHD)、全身性硬化症(SSc)、類風濕性關節炎(RA)、牛皮癬(Ps)、強直性脊椎炎(AS)或牛皮癬性關節炎(PA)。
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TW202144411A (zh) 2021-12-01
SA518390788B1 (ar) 2021-12-26
CN108135976A (zh) 2018-06-08
US11884744B2 (en) 2024-01-30
JP6866345B2 (ja) 2021-04-28
US10280231B2 (en) 2019-05-07
WO2017015433A3 (en) 2017-03-09
KR20180028522A (ko) 2018-03-16
MX2018000959A (es) 2018-06-06
US10844138B2 (en) 2020-11-24
CA2993329A1 (en) 2017-01-26
PH12018500151A1 (en) 2018-07-30
IL256665A (en) 2018-02-28
SG10201912593VA (en) 2020-02-27
EA201890360A1 (ru) 2018-06-29
KR102644875B1 (ko) 2024-03-06
JP2018527323A (ja) 2018-09-20
CL2018000182A1 (es) 2018-08-31
TW201712030A (zh) 2017-04-01
IL256665B1 (en) 2023-06-01
AU2016297575B2 (en) 2021-05-27
UA125433C2 (uk) 2022-03-09
US20190241678A1 (en) 2019-08-08
EP3322436A2 (en) 2018-05-23
EP3322436A4 (en) 2019-03-27
PE20180774A1 (es) 2018-05-07
BR112018001255A2 (pt) 2018-09-11
CO2018001264A2 (es) 2018-05-10
IL256665B2 (en) 2023-10-01
WO2017015433A2 (en) 2017-01-26
US20210107998A1 (en) 2021-04-15
MY191081A (en) 2022-05-30
AU2016297575A1 (en) 2018-02-15
CN108135976B (zh) 2022-10-18

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