TW202144407A - 結合cd47的抗原結合多肽及用途 - Google Patents
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Abstract
本發明公開了一種結合CD47的抗原結合多肽或其抗原結合部分及用途。具體地提供了結合CD47的抗原結合多肽及其抗原結合部分、編碼它們的核酸、包含該核酸的載體、包含該載體的細胞、包含它們的藥物組合物,還提供了其在減少腫瘤或抑制腫瘤細胞生長、治療癌症、促進巨噬細胞吞噬作用等方面的用途。
Description
本發明涉及抗原結合多肽,尤其涉及結合CD47的抗原結合多肽及其抗原結合部分,並且涉及使用這類抗原結合多肽及其抗原結合部分的方法。
CD47是一種廣泛表達於多個物種和各個組織之間的跨膜糖蛋白,也被稱為整合素相關蛋白,是免疫球蛋白超家族中的成員。CD47約50kD,其包含1個胞外類Ig可變結構域、5個高度疏水延伸的跨膜片段以及1個短選擇性拼接的羧基端胞質尾區。
抑制性受體信號調節蛋白α(SIRPα)是CD47的配體之一,CD47結合在SIRPα的NH2
末端IgV樣結構域。SIRPα主要表達於髓系來源的細胞,包括巨噬細胞、粒細胞、DC細胞、肥大細胞以及它們的前體,包括造血幹細胞。例如,CD47可以通過與巨噬細胞表面的蛋白SIRPα結合,抑制巨噬細胞的吞噬功能。有研究顯示,阻斷CD47介導的與吞噬細胞上的SIRPα結合,或在CD47剔除小鼠中的表達缺失,可引起活細胞和非老化紅血球的去除。對於其中還存在預吞噬信號的那些細胞來說,阻斷SIRPα還允許通常不被吞噬的靶標的吞入。
程序性細胞死亡(PCD)和吞噬細胞去除是生物體響應以便除去受損的、癌前或感染的細胞的常見方式。因此,在此生物體響應情况下存活的細胞(癌性細胞、長期感染的細胞等)存在用於逃避PCD和吞噬細胞去除的方式。CD47在各類患病細胞、癌細胞以及受感染細胞中組成性上調,從而允許這些細胞逃避吞噬作用。阻斷一種細胞(癌性細胞、長期感染的細胞等)上的CD47與另一種細胞(吞噬細胞)上的SIRPα之間的相互作用的抗CD47化合物,可抵消CD47表達的增加並且促進癌細胞和/或受感染細胞的吞噬作用。
CD47表達和/或活性已經牽涉許多疾病和病症。不同的研究表明,幾乎所有的腫瘤細胞和腫瘤組織都高表達CD47。腫瘤細胞表面高表達的CD47通過與巨噬細胞表面SIRPα結合,釋放“別吃我”(don’t eat me)的信號,從而導致腫瘤組織浸潤區的巨噬細胞不但同腫瘤細胞和諧相處,而且還會通過促進腫瘤內血管增殖,抑制效應T細胞發揮作用,促進腫瘤細胞擴增和生長。因而需要靶向CD47治療。
本發明提供了一種新的分離的與CD47結合的抗原結合多肽及其抗原結合部分,為靶向CD47的治療提供解決方案。
一方面,本發明提供了結合CD47的分離的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽包含以下互補決定區:
重鏈CDR1,其包含與選自SEQ ID NO:1、2、3、4或5的胺基酸序列具有至少80%同一性的胺基酸序列;
重鏈CDR2,其包含與選自SEQ ID NO:6、7、8、9或10的胺基酸序列具有至少80%同一性的胺基酸序列;
重鏈CDR3,其包含與選自SEQ ID NO:11、12、13、14或15的胺基酸序列具有至少80%同一性的胺基酸序列;
輕鏈CDR1,其包含與選自SEQ ID NO:16、17、18、19或20的胺基酸序列具有至少80%同一性的胺基酸序列;
輕鏈CDR2,其包含與選自SEQ ID NO:21、22、23、24或25的胺基酸序列具有至少80%同一性的胺基酸序列;和
輕鏈CDR3,其包含與選自SEQ ID NO:26、27、28、30或32的胺基酸序列具有至少80%同一性的胺基酸序列。
其中,SEQ ID NO:32所示序列為QQFSX2
STWT,X2
為D或E。
另一方面,本發明提供了結合CD47的分離的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽包含以下互補決定區:
重鏈CDR1,其包含選自SEQ ID NO:1、2、3、4或5或者其保守修飾形式的胺基酸序列;
重鏈CDR2,其包含選自SEQ ID NO:6、7、8、9或10或者其保守修飾形式的胺基酸序列;
重鏈CDR3,其包含選自SEQ ID NO:11、12、13、14或15或者其保守修飾形式的胺基酸序列;
輕鏈CDR1,其包含選自SEQ ID NO:16、17、18、19或20或者其保守修飾形式的胺基酸序列;
輕鏈CDR2,其包含選自SEQ ID NO:21、22、23、24或25或者其保守修飾形式的胺基酸序列;和
輕鏈CDR3,其包含選自SEQ ID NO:26、27、28、30或32或者其保守修飾形式的胺基酸序列。
另一方面,本發明提供了結合CD47的分離的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽包含重鏈可變區和輕鏈可變區,所述的重鏈可變區包含與選自SEQ ID NO:33、35、37、39、41、83、85或87的胺基酸序列具有至少80%同一性的胺基酸序列,所述的輕鏈可變區包含與選自SEQ ID NO:34、36、38、40、42、84、86或88的胺基酸序列具有至少80%同一性的胺基酸序列。
其中,SEQ ID NO:83所示序列為:
QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGEFIPGSDTTNYAQKFQGRVTITAX3
X4
STX5
TAYMELSSLRSEDTAVYYCARGGLRRMDYWGQGTLVTVSS,其中,X3
為D或E,X4
為I或E,X5
為S或N;
SEQ ID NO:84所示序列為:
DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLHWYQQKPGKAPKLX6
IYTTSTLASGVPSRFSGSGSGTX7
X8
TLTISSLQPEDFATYYCQQFSX2
STWTFGQGTKLEIK,其中,X6
為L或W,X7
為D或S,X8
為F或Y,X2
為D或E;
SEQ ID NO:85所示序列為:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLX9
WMGWINTNTGEPTYAQX10
LQGRVTMTX11
DTSTX12
TAYMELRSLRSDDTAVYYCX13
RFSHLRGPMDYWGQGTLVTVSS,其中,X9
為E或K,X10
為K或E,X11
為L或T,X12
為R或S,X13
為A或T;
SEQ ID NO:86所示序列為:
DX14
QMTQSPSSLSASVGDRVTITCRSSQSLVHSNGYTYLHWYQQKPGKAPKLLIYKVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCSQSTHVPPTFGQGTKLEIK,其中,X14
為I或A;
SEQ ID NO:87所示序列為:
QVQLVQSGAEVKKPGASVKVSCKX15
SGFNIEDDYIEWVRQAPGQGLEWMGRIDPANDKTKYAQKFQGRVTMTX16
DTSTX17
TVYMELSSLRSEDTAVYYCX18
RPGLRRYYSMDYWGQGTLVTVSS,其中,X15
為A或V,X16
為R或G,X17
為S或N,X18
為A或T;
SEQ ID NO:88所示序列為:
DIQMTQSPSSLSASVGDRVTITCKASENVVSYVSWYQQKPGKAPKLLIYGASNRYTGVPSRFX19
GSGSX20
TDFTLTISSLQPEDFATYYCGQSYSYPLTFGQGTKLEIK,其中,X19
為S或I,X20
為S或G。
另一方面,本發明提供了結合CD47的分離的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽或其抗原結合部分展現出下述性質中的一種或幾種的組合:
(a)以1.89E-08或更小(例如1.53E-08或更小)的KD
值與CD47結合;
(b)阻斷CD47與SIRPα的結合;
(c)促進巨噬細胞介導的對表達CD47細胞的吞噬作用;
(d)沒有明顯誘導CD4+T細胞的凋亡;
(e)不引起實質性的紅血球減少、貧血或紅血球凝集;和
(f)所述抗原結合多肽或其抗原結合部分的熔解溫度T≥62℃,聚合溫度Tagg≥61℃。
另一方面,本發明提供了分離的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽或其抗原結合部分與本文提供的任何示例性抗原結合多肽或其抗原結合部分結合CD47上的相同表位。
另一方面,本發明提供了分離的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽或其抗原結合部分與本文提供的任何示例性抗原結合多肽或其抗原結合部分競爭結合CD47,其中所述競爭通過ELISA、流式細胞術或表面電漿共振測定進行測量。
在本文中,所述抗原結合部分可選自Fab片段、Fab'片段、F(ab')2
片段、Fd片段、Fv片段、dAb片段、分離的互補決定區和奈米抗體,但不限於此。
另一方面,本發明提供了免疫偶聯物,其包含本文所述的結合CD47的抗原結合多肽或其抗原結合部分,以及與所述抗原結合多肽或其抗原結合部分連接或綴合(conjugated)的治療劑。
在本文中,所述抗原結合多肽或其抗原結合部分可通過接頭與所述治療劑連接。接頭可以是可裂解的或不可裂解的。
在本文中,所述治療劑可選自細胞毒性藥物、放射性同位素或免疫調節劑,例如化學治療劑、免疫抑制劑、免疫刺激劑、抗代謝物、烷化劑、抗生素、抗血管生成劑、抗有絲***劑、毒素、細胞凋亡劑等。
另一方面,本發明提供了組合物,其包含組分A以及以及藥學上可接受的載體,其中組分A為本文所述的結合CD47的抗原結合多肽或其抗原結合部分、或本文所述的免疫偶聯物。
另一方面,本發明提供了分離的融合瘤(hybridoma)細胞系,其選自由2B2、2H8、3F10、16E5和14A9組成的組。
另一方面,本發明提供了分離的核酸,其編碼本文所述的結合CD47的抗原結合多肽或其抗原結合部分。
另一方面,本發明提供了載體,其包含本文所述的分離的核酸。
另一方面,本發明提供了宿主細胞,其包含本文所述的載體或在其基因組中整合有本文所述的分離的核酸。優選地,所述載體為表達載體。
又一方面,本發明提供了製備結合CD47的抗原結合多肽或其抗原結合部分的方法,包括:在適於表達編碼本文所述的結合CD47的抗原結合多肽或其抗原結合部分的核酸的條件下培養本文所述的宿主細胞,分離所表達的所述抗原結合多肽或其抗原結合部分。
又一方面,本發明提供了用於在受試者中減少腫瘤或抑制腫瘤細胞生長的方法,其中所述方法包括向所述受試者施用治療有效量的本文所述的結合CD47的抗原結合多肽或其抗原結合部分、本文所述的免疫偶聯物、或所述的組合物。
又一方面,本發明提供了用於在有需要的受試者中治療癌症的方法,其中所述方法包括向所述受試者施用治療有效量的本文所述的結合CD47的抗原結合多肽或其抗原結合部分、本文所述的免疫偶聯物、或所述的組合物。
又一方面,本發明提供了促進受試者巨噬細胞的吞噬作用的方法,其中所述方法包括向所述受試者施用有效量的本文所述的結合CD47的抗原結合多肽或其抗原結合部分、本文所述的免疫偶聯物、或所述的組合物。
以下將對本申請的示例性的實施方式進行描述,但是本領域具有通常知識者將理解的是本申請的保護範圍並不限於此,而是可基於本申請的精神和構思進行各種修飾、修改或改變,這些修飾、修改或改變後的內容仍然落在本申請的範圍內。
術語
如本文所用,術語“抗原結合多肽”是指具有至少一個抗原結合結構域的多肽和蛋白,抗原結合多肽的實例包括但不限於單株抗體、多特異性抗體或融合蛋白。如本文所用,術語抗原結合多肽的“抗原結合部分”是指抗原結合多肽的一個或多個片段,其保留特異性結合抗原(例如CD47蛋白)的能力。已經顯示抗原結合多肽的抗原結合功能可以通過其片段來執行。抗原結合多肽的“抗原結合部分”所涵蓋的實例包括:(i)Fab片段,由VL
、VH
、CL
和CH1
結構域組成的單價片段;(ii)“Fab'片段”與Fab片段的不同之處在於在重鏈CH1
結構域的羧基末端添加了幾個殘基,包括來自抗體鉸鏈區的一個或多個半胱胺酸;(iii)F(ab')2
片段,包含通過鉸鏈區二硫橋連接的兩個Fab片段的二價片段;(iv)Fd片段,由VH
和CH1
結構域組成;(v)Fv片段,由抗體單臂的VL和VH結構域組成;(vi)dAb片段(Ward等人(1989)Nature 341:544-546),由VH
結構域組成;(vii)分離的互補決定區(CDR);和(viii)奈米抗體,包含單個可變域的重鏈可變區和兩個恆定域。此外,雖然Fv片段的兩個結構域,VL
和VH
由不同的基因編碼,但是可以使用重組方法通過合成的接頭將它們連接起來,從而使它們能夠製備成單個蛋白鏈,其中VL
和VH
區配對形成單價分子(稱為單鏈Fv(scFv);參見例如Bird等人,(1988)Science 242:423-426;和Huston等人(1988)Proc.Natl.Acad.USA 85:5879-5883)。此類單鏈抗體也意圖涵蓋在術語抗原結合多肽中。本文的抗原結合部分可使用本領域具有通常知識者公知的常規技術獲得,可以以與完整抗原結合多肽相同的方式對片段篩選功用。
術語“同種型”是指由重鏈恆定區基因編碼的抗體種類。本發明的結合CD47的抗原結合多肽和其抗原結合部分可以衍生自任何物種,其包括但不限於小鼠、大鼠、兔、非人靈長類動物(如黑猩猩、食蟹猴、蜘蛛猴、獼猴)、美洲駝和人。結合CD47的抗原結合多肽和其抗原結合部分可以是嵌合抗體、人源化抗體或完整的人抗體。在一些實施方案中,結合CD47的抗原結合多肽是由源自小鼠的融合瘤細胞系產生的抗體。因此,在一些實施方案中,結合CD47的抗原結合多肽是鼠類抗體。在另一些實施方案中,結合CD47的抗原結合多肽是嵌合抗體。在一些實施方案中,嵌合抗體是小鼠-人嵌合抗體。在另一些實施方案中,結合CD47的抗原結合多肽是人源化抗體。在另一些實施方案中,結合CD47的抗原結合多肽衍生自鼠類抗體並且是人源化的。
術語“嵌合抗體”是下述抗體:所述抗體具有衍生自一種物種的重鏈可變區的至少一部分和輕鏈可變區的至少一部分;以及衍生自另一物種的恆定區的至少一部分。例如,在一些實施方案中,嵌合抗體可以包含鼠類可變區和人恆定區。
“人源化抗體”是下述抗體:所述抗體含有衍生自非人抗體的互補決定區(CDR);和衍生自人抗體的框架區以及恆定區。例如,本文提供的結合CD47的人源化抗體可以包含衍生自一種或多種鼠類抗體的CDR以及人框架區和恆定區。因此,在一些實施方案中,本文提供的人源化抗體與所述抗體的CDR所衍生自的鼠類抗體結合CD47上的相同表位。本文提供了示例性人源化抗體。包含本文提供的重鏈CDR和輕鏈CDR的另外的結合CD47的人源化抗體或其變體可以使用任何人框架序列產生,並且也包括在本發明中。在一些實施方案中,適用於在本發明中使用的框架序列包括在結構上與本文提供的框架序列類似的那些框架序列。可以在框架區中進行另外修飾以改進本文提供的抗體的特性。此類另外的框架修飾可以包括化學修飾,點突變以降低免疫原性或去除T細胞表位,或使突變回復為原始種系序列中的殘基。在一些實施方案中,此類修飾包括對應於本文示例的突變的那些修飾,包括對種系序列的回復突變。例如,在一些實施方案中,本文提供的人源化抗體的VH和/或VL的人框架區中的一個或多個胺基酸被回復突變為親本鼠類抗體中對應的胺基酸。例如,對於人源化3F10、14A9和16E5的VH和VL,上述模板人抗體的框架胺基酸的幾個位點被回復突變為小鼠3F10、14A9和16E5抗體中對應的胺基酸序列。在一些實施方案中,輕鏈可變區的位置2處和/或33處和/或48處和/或63處和/或68處和/或71處和/或72處和/或94處的胺基酸被回復突變為在小鼠3F10、14A9或16E5輕鏈可變區中的所述位置處發現的對應的胺基酸。在另一些實施方案中,重鏈可變區的位置24處和/或46和/或63處和/或72處和/或73處和/或74處和/或77處和/或97處的胺基酸被回復突變為在小鼠3F10、14A9或16E5重鏈可變區中的所述位置處發現的對應的胺基酸。在一些實施方案中,人源化3F10抗體包含重鏈可變區,其突變類型選自如下位點中的一個或多個:在位置73處的胺基酸從Asp(D)突變為Glu(E);在位置74處的胺基酸從Glu(E)突變為Ile(I);以及在位置77處的胺基酸從Ser(S)突變為Asn(N),並且對於人源化3F10抗體包含輕鏈可變區,其突變類型選自如下位點中的一個或多個:在位置48處的胺基酸從Leu(L)突變為Trp(W);在位置71處的胺基酸從Asp(D)突變為Ser(S);在位置72處的胺基酸從Phe(F)突變為Tyr(Y);以及在位置94處的胺基酸從Asp(D)突變為Glu(E)。在一些實施方案中,人源化14A9抗體包含重鏈可變區,其突變類型選自如下位點中的一個或多個:在位置24處的胺基酸從Ala(A)突變為Val(V);在位置72處的胺基酸從Arg(R)突變為Gly(G);在位置77處的胺基酸從Ser(S)突變為Asn(N);以及在位置97處的胺基酸從Ala(A)突變為Thr(T),並且人源化14A9包含輕鏈可變區,其突變類型選自如下位點中的一個或多個:在位置63處的胺基酸從Ser(S)突變為Ile(I);在位置68處的胺基酸從Gly(G)突變為Ser(S)。在一些實施方案中,人源化16E5抗體包含重鏈可變區,其突變類型選自如下位點中的一個或多個:在位置46處的胺基酸從Glu(E)突變為Lys(K);在位置63處的胺基酸從Lys(K)突變為Glu(E);在位置72處的胺基酸從Thr(T)突變為Leu(L);在位置77處的胺基酸從Ser(S)突變為Arg(R);以及在位置97處的胺基酸從Ala(A)突變為Thr(T),並且人源化16E5抗體包含輕鏈可變區,其突變類型選自如下位點中的一個或多個:在位置2處的胺基酸從Ile(I)突變為Ala(A);以及在位置33處的胺基酸從Asn(N)突變為Gln(Q)。如無特殊說明,本文中突變位點序號的描述按照可變區第一個胺基酸開始依次計數。另外的或另選的回復突變可以在本文提供的人源化抗體的框架區中進行以改進抗體的特性。本發明還包括下述人源化抗體,所述人源化抗體結合CD47並且包含對應於本文所述的相對於任何合適的框架序列的示例性修飾的框架修飾,以及以其他方式改進抗體特性的其他框架修飾。
如本文所用,術語“衍生的”當用於指相對於參考抗體或其他結合蛋白的分子或多肽時,意指能夠與參考抗體或其他結合蛋白特異性地結合相同表位的分子或多肽。
術語“分離的”是指已經從其天然環境中分離的目標化合物(例如,抗體或核酸)。
如本文所用,術語“EC50”是指有效濃度,抗體的50%最大應答。如本文所用,術語“IC50”是指抑制濃度,抗體的50%最大應答。EC50和IC50兩者均可以通過ELISA或FACS分析或本領域已知的任何其他方法進行測量。
術語“KD
”在用於本文時指解離常數,以莫耳濃度(M)表示。抗體的KD
值可以使用本領域公知的方法測定。一種優選的測定抗體KD
的方法是使用表面電漿子共振(surface plasmon resonance),更優選使用生物感測器系統,例如Biacore系統。
術語“治療”是指為了以統計學顯著的方式治療、治癒、減輕、緩解、改變、補救、改善、改進或影響疾患(例如疾病)、疾患的症狀,或預防或延緩症狀、併發症、生化指標的發作,或以其他方式阻滯或抑制疾病、疾患或病症的進一步發展而使用的措施。
如本文所用,術語“治療有效量”是指向受試者提供治療性和/或預防性益處所必需的化合物或組合物的量。
如本文所用,術語“受試者”包括任何人類或非人動物。術語“非人動物”包括所有的脊椎動物,例如哺乳動物和非哺乳動物,諸如非人靈長類、綿羊、犬、貓、馬、牛、雞、兩棲動物、爬行動物等。優選地,根據本發明的受試者是人。除非標明,術語“患者”或“受試者”可以互換使用。
如本文所用,“約”表示在本領域普通具有通常知識者判定的對特定值可以接受的誤差範圍內,其部分取決於如何測量或測定該值,即測量系統的限制。例如,“約”按照本領域實踐可表示1倍或超過1倍標準偏差以內。或者,“約”可以表示多至±5%的範圍,例如在所給定的具體數值範圍±2%範圍內、±1%範圍內或±0.5%範圍內波動。當本申請或權利要求中給出特定值時,除非另有說明,“約”的含義應認為是在該特定值的可接受的誤差範圍內。在本文中,除非另有說明,步驟參數或條件的值默認均由“約”修飾。
術語“同一性(identity)”,也稱一致性。兩序列間的百分比同一性為序列共有的相同位置數的函數(即%同一性=相同位置數/位置總數×100),其中需考慮產生兩序列的最優比對需要引入的缺口數和每個缺口的長度。如下述非限制性實施例所示,可以使用數學算法完成序列的比較和兩序列間百分比同一性的測定。可以使用E.Meyers和W.Miller的算法(Comput.Appl.Biosci.,4:11-17(1988))測定兩胺基酸序列間的百分比同一性,該算法已收入到ALIGN程序(版本2.0)中,其使用PAM120殘基權重表,缺口長度罰分為12,缺口罰分為4。此外,可以使用Needleman和Wunsch的算法(J. Mol.Biol. 484-453(1970))測定兩胺基酸序列的百分比同一性,該算法已摻入到GCG軟件包(可在www.gcg.com獲得)中的GAP程序中,其使用Blossum 62矩陣或PAM250矩陣,缺口權重為16、14、12、10、8、6或4,長度權重為1、2、3、4、5或6。
術語“Xn”和“Xaa”等同,是指未指定的胺基酸(Unspecified Amino Acid),通過相關表述中的後續定義來指定其涵蓋的範圍。
術語“包括”、“含有”或“包含”及其變體應理解為“包括但不限於”,意味著除所列出的要素、組分和步驟外,還可涵蓋其它未指明的要素、組分和步驟。
在本文中,除非上下文另有明確規定,否則單數術語涵蓋複數指代物,反之亦然。
為了描述和公開的目的,以引用的方式將所有的專利、專利申請和其它已確定的出版物在此明確地併入本文。這些出版物僅因為它們的公開早於本申請的申請日而提供。所有關於這些文件的日期的聲明或這些文件的內容的表述是基於申請者可得的信息,並且不構成任何關於這些文件的日期或這些文件的內容的正確性的承認。而且,在任何國家,在本文中對這些出版物的任何引用並不構成關於該出版物成為本領域的公知常識的一部分的認可。本發明的各個方面將在下述部分中進一步詳細描述。
結合CD47的抗原結合多肽及其抗原結合部分
本文中,術語“CD47”、“整合素相關蛋白”、“IAP(Integrin-associated protein)”、“OA3”、“MER6”之間彼此可以互換的使用。術語“人CD47”和“hCD47”等在本文中可互換使用,並且是指人CD47和人CD47的變體或同種型。本文中,“結合CD47的抗體”與“抗CD47抗體”之間彼此可以互換的使用。
本發明提供了結合CD47的抗原結合多肽或其抗原結合部分,為靶向CD47的治療提供新的解決方案。除了與人CD47或/和食蟹猴CD47結合外,本文提供的抗原結合多肽還顯示了其他諸多用於靶向治療的期望的特徵。具體的,這些期望的特徵例如可以是1.53E-08或更小的KD
值與CD47結合、阻斷CD47與SIRPα的結合、促進巨噬細胞介導的對表達CD47細胞的吞噬作用、沒有明顯誘導CD4+T細胞的凋亡、不引起實質性的紅血球減少、貧血或紅血球凝集、所述抗原結合多肽或其抗原結合部分的熔解溫度T≥62℃,聚合溫度Tagg≥61℃等中的至少一個。在一些實施方案中,結合CD47的抗原結合多肽表現了更好的治療效果;在一些實施方案中,結合CD47的抗原結合多肽表現了降低的副作用。
一方面,本發明提供了包含特定序列的結合CD47的抗原結合多肽及其抗原結合部分。
在一些實施方案中,本文提供了包含選自由SEQ ID NOs:1~32組成的組的一個或多個CDR的分離的結合CD47的抗原結合多肽或其抗原結合部分。
在一些實施方案中,結合CD47的分離的抗原結合多肽或其抗原結合部分包含重鏈CDR1序列,所述重鏈CDR1包含與選自SEQ ID NO:1、2、3、4或5的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽或其抗原結合部分包含重鏈CDR2,所述重鏈CDR2包含與選自SEQ ID NO:6、7、8、9或10的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽或其抗原結合部分包含重鏈CDR3,所述重鏈CDR3包含與選自SEQ ID NO:11、12、13、14或15的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽或其抗原結合部分包含輕鏈CDR1,所述輕鏈CDR1包含與選自SEQ ID NO:16、17、18、19或20的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽或其抗原結合部分包含輕鏈CDR2,所述輕鏈CDR2包含與選自SEQ ID NO:21、22、23、24或25的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽或其抗原結合部分包含輕鏈CDR3,所述輕鏈CDR3包含與選自SEQ ID NO:26、27、28、30或32的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。
本領域具有通常知識者將理解,本文提供的抗原結合多肽的重鏈CDR和輕鏈CDR可以獨立地進行選擇或混合和匹配,以形成包含來自本文提供的抗原結合多肽的任何重鏈CDR1、CDR2和CDR3;以及任何輕鏈CDR1、CDR2和CDR3的抗原結合多肽或其抗原結合部分。因此,在一些實施方案中,本發明提供了結合CD47的分離的抗原結合多肽,包含三個重鏈CDR(重鏈CDR1、重鏈CDR2和重鏈CDR3)和三個輕鏈CDR(輕鏈CDR1、輕鏈CDR2、輕鏈CDR3),其中:
重鏈CDR1,其包含與選自SEQ ID NO:1、2、3、4或5的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列;
重鏈CDR2,其包含與選自SEQ ID NO:6、7、8、9或10的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列;
重鏈CDR3,其包含與選自SEQ ID NO:11、12、13、14或15的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列;
輕鏈CDR1,其包含與選自SEQ ID NO:16、17、18、19或20的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列;
輕鏈CDR2,其包含與選自SEQ ID NO:21、22、23、24或25的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列;和
輕鏈CDR3,其包含與選自SEQ ID NO:26、27、28、30或32的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽,包含以下互補決定區:重鏈CDR1,其包含選自SEQ ID NO:1、2、3、4或5的胺基酸序列;重鏈CDR2,其包含選自SEQ ID NO:6、7、8、9或10的胺基酸序列;重鏈CDR3,其包含選自SEQ ID NO:11、12、13、14或15的胺基酸序列;輕鏈CDR1,其包含選自SEQ ID NO:16、17、18、19或20的胺基酸序列;輕鏈CDR2,其包含選自SEQ ID NO:21、22、23、24或25的胺基酸序列;和輕鏈CDR3,其包含選自SEQ ID NO:26、27、28、30或32的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈CDR1、重鏈CDR2、重鏈CDR3、輕鏈CDR1、輕鏈CDR2和輕鏈CDR3,所述重鏈CDR1、重鏈CDR2和重鏈CDR3分別包含與如SEQ ID NOs:1、6和11所示的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列,所述輕鏈CDR1、輕鏈CDR2和輕鏈CDR3分別包含與如SEQ ID NOs:16、21和26所示的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。在一些實施方案中,結合CD47的分離的抗原結合多肽包含以下互補決定區:包含SEQ ID NO:1的胺基酸序列的重鏈CDR1;包含SEQ ID NO:6的胺基酸序列的重鏈CDR2;包含SEQ ID NO:11的胺基酸序列的重鏈CDR3;包含SEQ ID NO:16的胺基酸序列的輕鏈CDR1;包含SEQ ID NO:21的胺基酸序列的輕鏈CDR2;和包含SEQ ID NO:26的胺基酸序列的輕鏈CDR3。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈CDR1、重鏈CDR2、重鏈CDR3、輕鏈CDR1、輕鏈CDR2和輕鏈CDR3,所述重鏈CDR1、重鏈CDR2和重鏈CDR3分別包含與如SEQ ID NOs:2、7和12所示的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列,所述輕鏈CDR1、輕鏈CDR2和輕鏈CDR3分別包含與如SEQ ID NOs:17、22和27所示的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。在一些實施方案中,結合CD47的分離的抗原結合多肽包含以下互補決定區:包含SEQ ID NO:2的胺基酸序列的重鏈CDR1;包含SEQ ID NO:7的胺基酸序列的重鏈CDR2;包含SEQ ID NO:12的胺基酸序列的重鏈CDR3;包含SEQ ID NO:17的胺基酸序列的輕鏈CDR1;包含SEQ ID NO:22的胺基酸序列的輕鏈CDR2;和包含SEQ ID NO:27的胺基酸序列的輕鏈CDR3。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈CDR1、重鏈CDR2、重鏈CDR3、輕鏈CDR1、輕鏈CDR2和輕鏈CDR3,所述重鏈CDR1、重鏈CDR2和重鏈CDR3分別包含與如SEQ ID NOs:3、8和13所示的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列,所述輕鏈CDR1、輕鏈CDR2和輕鏈CDR3分別包含與如SEQ ID NOs:18、23和28所示的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。在一些實施方案中,結合CD47的分離的抗原結合多肽包含以下互補決定區:包含SEQ ID NO:3的胺基酸序列的重鏈CDR1;包含SEQ ID NO:8的胺基酸序列的重鏈CDR2;包含SEQ ID NO:13的胺基酸序列的重鏈CDR3;包含SEQ ID NO:18的胺基酸序列的輕鏈CDR1;包含SEQ ID NO:23的胺基酸序列的輕鏈CDR2;和包含SEQ ID NO:28的胺基酸序列的輕鏈CDR3。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈CDR1、重鏈CDR2、重鏈CDR3、輕鏈CDR1、輕鏈CDR2和輕鏈CDR3,所述重鏈CDR1、重鏈CDR2和重鏈CDR3分別包含與如SEQ ID NOs:4、9和14所示的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列,所述輕鏈CDR1、輕鏈CDR2和輕鏈CDR3分別包含與如SEQ ID NOs:19、24和32所示的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。在一些實施方案中,結合CD47的分離的抗原結合多肽包含以下互補決定區:包含SEQ ID NO:4的胺基酸序列的重鏈CDR1;包含SEQ ID NO:9的胺基酸序列的重鏈CDR2;包含SEQ ID NO:14的胺基酸序列的重鏈CDR3;包含SEQ ID NO:19的胺基酸序列的輕鏈CDR1;包含SEQ ID NO:24的胺基酸序列的輕鏈CDR2;和包含SEQ ID NO:32的胺基酸序列的輕鏈CDR3。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈CDR1、重鏈CDR2、重鏈CDR3、輕鏈CDR1、輕鏈CDR2和輕鏈CDR3,所述重鏈CDR1、重鏈CDR2和重鏈CDR3分別包含與如SEQ ID NOs:5、10和15所示的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列,所述輕鏈CDR1、輕鏈CDR2和輕鏈CDR3分別包含與如SEQ ID NOs:20、25和30所示的胺基酸序列具有至少80%同一性、至少81%同一性、至少82%同一性、至少83%同一性、至少84%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。在一些實施方案中,結合CD47的分離的抗原結合多肽包含以下互補決定區:包含SEQ ID NO:5的胺基酸序列的重鏈CDR1;包含SEQ ID NO:10的胺基酸序列的重鏈CDR2;包含SEQ ID NO:15的胺基酸序列的重鏈CDR3;包含SEQ ID NO:20的胺基酸序列的輕鏈CDR1;包含SEQ ID NO:25的胺基酸序列的輕鏈CDR2;和包含SEQ ID NO:30的胺基酸序列的輕鏈CDR3。
本發明還提供了保守修飾形式的抗原結合多肽及其抗原結合部分。本領域具有通常知識者將認識到,保守的胺基酸取代是用具有類似結構或化學特性(例如像類似的側鏈)的另一胺基酸取代一個胺基酸。示例性保守取代在本領域中例如,在Watson等,MolecularBiology of the Gene,The Bengamin/Cummings Publication Company,第4版(1987)中進行了描述。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含:重鏈CDR1,其包含選自SEQ ID NO:1、2、3、4或5或者其保守修飾形式的胺基酸序列;重鏈CDR2,其包含選自SEQ ID NO:6、7、8、9或10或者其保守修飾形式的胺基酸序列;重鏈CDR3,其包含選自SEQ ID NO:11、12、13、14或15或者其保守修飾形式的胺基酸序列;輕鏈CDR1,其包含選自SEQ ID NO:16、17、18、19或20或者其保守修飾形式的胺基酸序列;輕鏈CDR2,其包含選自SEQ ID NO:21、22、23、24或25或者其保守修飾形式的胺基酸序列;和輕鏈CDR3,其包含選自SEQ ID NO:26、27、28、30或32或者其保守修飾形式的胺基酸序列。保守修飾存在於任意一個或多個輕鏈CDR或重鏈CDR。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含:重鏈CDR1,其包含選自SEQ ID NO:3、4或5的胺基酸序列;重鏈CDR2,其包含選自SEQ ID NO:8、9或10的胺基酸序列;重鏈CDR3,其包含選自SEQ ID NO:13、14或15的胺基酸序列;輕鏈CDR1,其包含選自SEQ ID NO:18、19或20的胺基酸序列;輕鏈CDR2,其包含選自SEQ ID NO:23、24或25的胺基酸序列;和輕鏈CDR3,其包含選自SEQ ID NO:28、30或32的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈CDR1、重鏈CDR2、重鏈CDR3、輕鏈CDR1、輕鏈CDR2和輕鏈CDR3,所述重鏈CDR1包含SEQ ID NO:1或其保守修飾形式的胺基酸序列,所述重鏈CDR2包含SEQ ID NO:6或其保守修飾形式的胺基酸序列,所述重鏈CDR3包含SEQ ID NO:11或其保守修飾形式的胺基酸序列,所述輕鏈CDR1包含SEQ ID NO:16或其保守修飾形式的胺基酸序列,所述輕鏈CDR2包含SEQ ID NO:21或其保守修飾形式的胺基酸序列,所述輕鏈CDR3包含SEQ ID NO:26或其保守修飾形式的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈CDR1、重鏈CDR2、重鏈CDR3、輕鏈CDR1、輕鏈CDR2和輕鏈CDR3,所述重鏈CDR1包含SEQ ID NO:2或其保守修飾形式的胺基酸序列,所述重鏈CDR2包含SEQ ID NO:7或其保守修飾形式的胺基酸序列,所述重鏈CDR3包含SEQ ID NO:12或其保守修飾形式的胺基酸序列,所述輕鏈CDR1包含SEQ ID NO:17或其保守修飾形式的胺基酸序列,所述輕鏈CDR2包含SEQ ID NO:22或其保守修飾形式的胺基酸序列,所述輕鏈CDR3包含SEQ ID NO:27或其保守修飾形式的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈CDR1、重鏈CDR2、重鏈CDR3、輕鏈CDR1、輕鏈CDR2和輕鏈CDR3,所述重鏈CDR1包含SEQ ID NO:3或其保守修飾形式的胺基酸序列,所述重鏈CDR2包含SEQ ID NO:8或其保守修飾形式的胺基酸序列,所述重鏈CDR3包含SEQ ID NO:13或其保守修飾形式的胺基酸序列,所述輕鏈CDR1包含SEQ ID NO:18或其保守修飾形式的胺基酸序列,所述輕鏈CDR2包含SEQ ID NO:23或其保守修飾形式的胺基酸序列,所述輕鏈CDR3包含SEQ ID NO:28或其保守修飾形式的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈CDR1、重鏈CDR2、重鏈CDR3、輕鏈CDR1、輕鏈CDR2和輕鏈CDR3,所述重鏈CDR1包含SEQ ID NO:4或其保守修飾形式的胺基酸序列,所述重鏈CDR2包含SEQ ID NO:9或其保守修飾形式的胺基酸序列,所述重鏈CDR3包含SEQ ID NO:14或其保守修飾形式的胺基酸序列,所述輕鏈CDR1包含SEQ ID NO:19或其保守修飾形式的胺基酸序列,所述輕鏈CDR2包含SEQ ID NO:24或其保守修飾形式的胺基酸序列,所述輕鏈CDR3包含SEQ ID NO:32或其保守修飾形式的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈CDR1、重鏈CDR2、重鏈CDR3、輕鏈CDR1、輕鏈CDR2和輕鏈CDR3,所述重鏈CDR1包含SEQ ID NO:5或其保守修飾形式的胺基酸序列,所述重鏈CDR2包含SEQ ID NO:10或其保守修飾形式的胺基酸序列,所述重鏈CDR3包含SEQ ID NO:15或其保守修飾形式的胺基酸序列,所述輕鏈CDR1包含SEQ ID NO:20或其保守修飾形式的胺基酸序列,所述輕鏈CDR2包含SEQ ID NO:25或其保守修飾形式的胺基酸序列,所述輕鏈CDR3包含SEQ ID NO:30或其保守修飾形式的胺基酸序列。
在一些實施方案中,本文提供的結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,重鏈和輕鏈的可變區包含CDR區和框架區FR(包括FR1、FR2、FR3和FR4),形成次序為FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4的可變區序列。
因此,另一方面,本發明提供了結合CD47的分離的抗原結合多肽或其抗原結合部分,所述抗原結合多肽包含重鏈可變區和輕鏈可變區,所述的重鏈可變區包含與選自SEQ ID NO:33、35、37、39、41、83、85或87的胺基酸序列具有至少80%、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列,所述的輕鏈可變區包含與選自SEQ ID NO:34、36、38、40、42、84、86或88的胺基酸序列具有至少80%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。
其中,SEQ ID NO:83所示序列為:
QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE
WVRQAPGQGLEWMGEFIPGSDT
TNYAQKFQGRVTITAX3
X4
STX5
TAYMELSSLRSEDTAVYYCARGGLRRMDY
WGQGTLVTVSS,其中,X3
為D或E,X4
為I或E,X5
為S或N;
SEQ ID NO:84所示序列為:
DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH
WYQQKPGKAPKLX6
IYTTSTLAS
GVPSRFSGSGSGTX7
X8
TLTISSLQPEDFATYYCQQFSX2
STWT
FGQGTKLEIK,其中,X6
為L或W,X7
為D或S,X8
為F或Y,X2
為D或E;
SEQ ID NO:85所示序列為:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMN
WVRQAPGQGLX9
WMGWINTNTGEPT
YAQX10
LQGRVTMTX11DTSTX12
TAYMELRSLRSDDTAVYYCX13
RFSHLRGPMDY
WGQGTLVTVSS,其中,X9
為E或K,X10
為K或E,X11
為L或T,X12
為R或S,X13
為A或T;
SEQ ID NO:86所示序列為:
DX14
QMTQSPSSLSASVGDRVTITCRSSQSLVHSNGYTYLH
WYQQKPGKAPKLLIYKVSNRFS
GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCSQSTHVPPT
FGQGTKLEIK,其中,X14
為I或A;
SEQ ID NO:87所示序列為:
QVQLVQSGAEVKKPGASVKVSCKX15
SGFNIEDDYIE
WVRQAPGQGLEWMGRIDPANDKTK
YAQKFQGRVTMTX16
DTSTX17
TVYMELSSLRSEDTAVYYCX18
RPGLRRYYSMDY
WGQGTLVTVSS,其中,X15
為A或V,X16
為R或G,X17
為S或N,X18
為A或T;
SEQ ID NO:88所示序列為:
DIQMTQSPSSLSASVGDRVTITCKASENVVSYVS
WYQQKPGKAPKLLIYGASNRYT
GVPSRFX19
GSGSX20
TDFTLTISSLQPEDFATYYCGQSYSYPLT
FGQGTKLEIK,其中,X19
為S或I,X20
為S或G。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,所述的重鏈可變區包含以下序列或由以下序列組成:選自SEQ ID NO:33、35、37、39、41、83、85或87的胺基酸序列,所述的輕鏈可變區包含以下序列或由以下序列組成:選自SEQ ID NO:34、36、38、40、42、84、86或88的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,所述的重鏈可變區包含以下序列或由以下序列組成:選自SEQ ID NO:35、39、41、83、85或87的胺基酸序列,所述的輕鏈可變區包含以下序列或由以下序列組成:選自SEQ ID NO:36、40、42、84、86或88的胺基酸序列。在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,所述的重鏈可變區包含SEQ ID NO:79的胺基酸序列或由SEQ ID NO:79的胺基酸序列組成,所述的輕鏈可變區包含SEQ ID NO:80的胺基酸序列或由SEQ ID NO:80的胺基酸序列組成。在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,所述的重鏈可變區包含SEQ ID NO:81的胺基酸序列或由SEQ ID NO:81的胺基酸序列組成,所述的輕鏈可變區包含SEQ ID NO:82的胺基酸序列或由SEQ ID NO:82的胺基酸序列組成。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,所述的重鏈可變區包含與SEQ ID NO:33的胺基酸序列具有至少80%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列,所述的輕鏈可變區包含與SEQ ID NO:34的胺基酸序列具有至少80%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。在一些實施方案中,所述的結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,其中所述的重鏈可變區包含SEQ ID NO:33的胺基酸序列,所述的輕鏈可變區包含SEQ ID NO:34的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,所述的重鏈可變區包含與SEQ ID NO:35的胺基酸序列具有至少80%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列,所述的輕鏈可變區包含與SEQ ID NO:36的胺基酸序列具有至少80%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。在一些實施方案中,所述的結合抗CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,其中所述的重鏈可變區包含SEQ ID NO:35的胺基酸序列,所述的輕鏈可變區包含SEQ ID NO:36的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,所述的重鏈可變區包含與SEQ ID NO:37的胺基酸序列具有至少80%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列,所述的輕鏈可變區包含與SEQ ID NO:38的胺基酸序列具有至少80%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。在一些實施方案中,本文提供的結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,其中所述的重鏈可變區包含SEQ ID NO:37的胺基酸序列,所述的輕鏈可變區包含SEQ ID NO:38的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,所述的重鏈可變區包含與SEQ ID NO:39的胺基酸序列具有至少80%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列,所述的輕鏈可變區包含與SEQ ID NO:40的胺基酸序列具有至少80%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。在一些實施方案中,本文提供的結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,其中所述的重鏈可變區包含SEQ ID NO:39的胺基酸序列,所述的輕鏈可變區包含SEQ ID NO:40的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,所述的重鏈可變區包含與SEQ ID NO:41的胺基酸序列具有至少80%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列,所述的輕鏈可變區包含與SEQ ID NO:42的胺基酸序列具有至少80%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。在一些實施方案中,本文提供的結合CD47的分離的抗原結合多肽,其中所述的重鏈可變區包含SEQ ID NO:41的胺基酸序列,所述的輕鏈可變區包含SEQ ID NO:42的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,所述的重鏈可變區包含與SEQ ID NO:83的胺基酸序列具有至少80%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列,所述的輕鏈可變區包含與SEQ ID NO:84的胺基酸序列具有至少80%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,其中所述的重鏈可變區包含SEQ ID NO:83的胺基酸序列,所述的輕鏈可變區包含SEQ ID NO:84的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,所述的重鏈可變區包含與SEQ ID NO:85的胺基酸序列具有至少80%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列,所述的輕鏈可變區包含與SEQ ID NO:86的胺基酸序列具有至少80%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,其中所述的重鏈可變區包含SEQ ID NO:85的胺基酸序列,所述的輕鏈可變區包含SEQ ID NO:86的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,所述的重鏈可變區包含與SEQ ID NO:87的胺基酸序列具有至少80%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列,所述的輕鏈可變區包含與SEQ ID NO:88的胺基酸序列具有至少80%同一性、至少85%同一性、至少86%同一性、至少87%同一性、至少88%同一性、至少89%同一性、至少90%同一性、至少91%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。在一些實施方案中,結合CD47的分離的抗原結合多肽包含重鏈可變區和輕鏈可變區,其中所述的重鏈可變區包含SEQ ID NO:87的胺基酸序列,所述的輕鏈可變區包含SEQ ID NO:88的胺基酸序列。
在一些實施方案中,本文所述的重鏈可變區和輕鏈可變區中含有本文所述的重鏈CDR1、重鏈CDR2、重鏈CDR3、輕鏈CDR1、輕鏈CDR2和輕鏈CDR3的序列特徵。
在一些實施方案中,本文提供的結合CD47的分離的抗原結合多肽包含重鏈和輕鏈,重鏈和輕鏈除了包含本文所述的重鏈可變區和輕鏈可變區外,還包括恆定區。在一些實施方案中,恆定區是人源化的。在一些實施方案中,恆定區與可變區的框架區FR都是人源化的。通過構建嵌合抗體(例如人源化的恆定區和非人源的可變區)或人源化抗體(例如人源化的恆定區和FR區)降低免疫原性。
在一些實施方案中,抗原結合多肽的輕鏈恆定區是人κ鏈恆定區。在一些實施方案中,抗原結合多肽的輕鏈恆定區是人λ鏈恆定區。
抗原結合多肽的重鏈恆定區可來自任何類型的恆定區,例如IgG、IgM、IgD、IgA和IgE;以及任何同種型,例如IgG1、IgG2、IgG3和IgG4。在一些實施方案中,結合CD47的分離的抗原結合多肽是IgG1同種型。在一些實施方案中,結合CD47的分離的抗原結合多肽是IgG4同種型。
在一些實施方案中,抗原結合多肽包含經修飾的恆定區。在一些實施方案中,對人IgG4恆定區內的鉸鏈區進行修飾以避免或減少鏈交換,例如IgG4型抗體具有根據EU編號索引的Ser228Pro(S228P)突變。
在一些實施方案中,結合CD47的分離的抗原結合多肽是嵌合抗體,其包含重鏈可變區和輕鏈可變區,所述的重鏈可變區包含以下序列或由以下序列組成:選自SEQ ID NO:33、35、37、39或41的胺基酸序列,所述的輕鏈可變區包含以下序列或由以下序列組成:選自SEQ ID NO:34、36、38、40或42的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽是嵌合抗體,其包含重鏈和輕鏈,所述重鏈具有與選自SEQ ID NO:89、93、97、101或105所示的胺基酸序列具有至少80%同一性、至少85%同一性、至少90%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列,所述輕鏈具有與選自SEQ ID NO:91、95、99、103或107所示的胺基酸序列具有至少80%同一性、至少85%同一性、至少90%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。在一個實施方案中,結合CD47的分離的抗原結合多肽是嵌合抗體,包含根據SEQ ID NO:89的重鏈和根據SEQ ID NO:91的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是嵌合抗體,包含根據SEQ ID NO:93的重鏈和根據SEQ ID NO:95的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是嵌合抗體,包含根據SEQ ID NO:97的重鏈和根據SEQ ID NO:99的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是嵌合抗體,包含根據SEQ ID NO:101的重鏈和根據SEQ ID NO:103的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是嵌合抗體,包含根據SEQ ID NO:105的重鏈和根據SEQ ID NO:107的輕鏈。
在一些實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,其包含重鏈可變區和輕鏈可變區,所述的重鏈可變區包含以下序列或由以下序列組成:選自SEQ ID NO:83、85或87的胺基酸序列,所述的輕鏈可變區包含以下序列或由以下序列組成:選自SEQ ID NO:84、86或88的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,所述重鏈具有與選自SEQ ID NO:109、113、117、121、125、129、133、137、141、145、149、153、157、161、165、169、173、177、181或185所示的胺基酸序列具有至少80%同一性、至少85%同一性、至少90%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列,所述輕鏈具有與選自SEQ ID NO:111、115、119、123、127、131、135、139、143、147、151、155、159、163、167、171、175、179、183和187所示的胺基酸序列具有至少80%同一性、至少85%同一性、至少90%同一性、至少92%同一性、至少93%同一性、至少94%同一性、至少95%同一性、至少96%同一性、至少97%同一性、至少98%同一性、至少99%同一性或100%同一性的胺基酸序列。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:109的重鏈和根據SEQ ID NO:111的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:113的重鏈和根據SEQ ID NO:115的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:117的重鏈和根據SEQ ID NO:119的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:121的重鏈和根據SEQ ID NO:123的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:125的重鏈和根據SEQ ID NO:127的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:129的重鏈和根據SEQ ID NO:131的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:133的重鏈和根據SEQ ID NO:135的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:137的重鏈和根據SEQ ID NO:139的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:141的重鏈和根據SEQ ID NO:143的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:145的重鏈和根據SEQ ID NO:147的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:149的重鏈和根據SEQ ID NO:151的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:153的重鏈和根據SEQ ID NO:155的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:157的重鏈和根據SEQ ID NO:159的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:161的重鏈和根據SEQ ID NO:163的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:165的重鏈和根據SEQ ID NO:167的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:169的重鏈和根據SEQ ID NO:171的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:173的重鏈和根據SEQ ID NO:175的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:177的重鏈和根據SEQ ID NO:179的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:181的重鏈和根據SEQ ID NO:183的輕鏈。在一個實施方案中,結合CD47的分離的抗原結合多肽是人源化抗體,包含根據SEQ ID NO:185的重鏈和根據SEQ ID NO:187的輕鏈。
在一個實施方案中,結合CD47的分離的抗原結合多肽包含重鏈和輕鏈,所述重鏈包含以下序列或由以下序列組成:選自SEQ ID NO:93、101、105、109、113、117、121、125、129、133、137、141、145、149、153、157、161、165、169、173、177、181或185的胺基酸序列;所述輕鏈包含以下序列或由以下序列組成:選自SEQ ID NO:95、103、107、111、115、119、123、127、131、135、139、143、147、151、155、159、163、167、171、175、179、183或187的胺基酸序列。
在一些實施方案中,結合CD47的分離的抗原結合多肽或/和其抗原結合部分以1.53E-08 M或更小的KD
值與CD47結合。在一些實施方案中,所述抗原結合多肽或/和其抗原結合部分結合人CD47。在另一些實施方案中,所述抗原結合多肽或/和其抗原結合部分結合食蟹猴CD47。在另一些實施方案中,所述抗原結合多肽或/和其抗原結合部分結合人CD47以及食蟹猴CD47。在一些實施方案中,所述抗原結合多肽或/和其抗原結合部分對人CD47具有下述結合親和力(KD
):在約1E-12 M至約1E-05 M、約1E-12 M至約1.89E-06 M、約1E-12 M至約1.89E-07 M、約1E-11 M至約1.89E-07 M、約9.46E-10 M至約1.89E-07 M、約9.46E-10 M至約1.89E-08 M、約2.04E-10 M至約1.53E-07 M或約2.04E-10 M至約1.89E-08 M的範圍內。在一些實施方案中,所述抗原結合多肽或/和其抗原結合部分對人CD47具有下述結合親和力(KD
):約1E-05 M或更小、約1.89E-06 M或更小、約1.89E-07 M或更小、約1.89E-08 M或更小、約1.53E-08 M或更小、約9.31E-08 M或更小、約9.31E-09 M或更小、約8.55E-09 M或更小、約2.35E-09 M或更小、或者約2.04E-010 M或更小。在一些實施方案中,所述抗原結合多肽或/和其抗原結合部分對人CD47具有下述結合親和力(KD
):約7.48E-09 M、約3.50E-10 M、約7.67E-10 M、約9.06E-09 M、約2.35E-09 M、約9.46E-10 M、約8.36E-10 M、約1.53E-09 M、約1.42E-09 M、約9.60E-10 M、約5.92E-10 M、約9.04E-10 M、約7.79E-10 M、約1.15E-09 M、約1.34E-09 M、約8.96E-10 M、約7.65E-10 M、約1.89E-08 M、約6.28E-09 M、約9.31E-09 M、約1.71E-08 M、約1.53E-08 M、約7.13E-09 M、約2.04E-10 M或約8.55E-09 M。在一些實施方案中,通過Biacore來測量本文提供的結合CD47的抗原結合多肽和其抗原結合部分的結合親和力KD
。
在一些實施方案中,結合CD47的抗原結合多肽或/和其抗原結合部分對人CD47具有約1 ng/mL至約2000 ng/mL、約1 ng/mL至約1500 ng/mL、約1 ng/mL至約1106 ng/mL、約1 ng/mL至約699 ng/mL、約1 ng/mL至約340 ng/mL、約30 ng/mL至約340 ng/mL、約50 ng/mL至約340 ng/mL或約100 ng/mL至約340 ng/mL的結合EC50。在一些實施方案中,結合CD47的抗原結合多肽或/和其抗原結合部分對人CD47具有約2000 ng/mL或更小、約1500 ng/mL或更小、約1106 ng/mL或更小、約699 ng/mL或更小、或約340 ng/mL或更小的結合EC50。在一些實施方案中,通過ELISA或FACS來測量本文提供的結合CD47的抗原結合多肽和其抗原結合部分的EC50。
在一些實施方案中,結合CD47的抗原結合多肽或/和其抗原結合部分阻斷CD47與SIRPα的結合。信號調節性蛋白α(SIRPα)是結合CD47的配體之一,SIRPα在包括巨噬細胞和樹突細胞在內的造血細胞上表達。CD47與巨噬細胞上的SIRPα的相互作用,將“別吃我”信號發送至巨噬細胞,在治療情况下,用結合CD47的抗原結合多肽或其抗原結合部分阻斷SIRPα與CD47的相互作用可以促進宿主免疫系統攝取並清除癌細胞。因此,阻斷CD47與SIRPα的相互作用從而使得巨噬細胞吞噬表達CD47的腫瘤細胞的能力是一些結合CD47抗原結合多肽的重要功能特徵。在一些實施方案中,基於Jurkat細胞及流式細胞術檢測,所述抗原結合多肽(一些示例例如嵌合抗體Xi2B2、Xi2H8、Xi3F10、Xi16E5、Xi14A9)或/和其抗原結合部分的阻斷IC50為約358.5 ng/mL至約26966 ng/mL、約358.5 ng/mL至約4861 ng/mL、約358.5 ng/mL至約631.2 ng/mL或約358.5 ng/mL至約1283 ng/mL。在一些實施方案中,所述抗原結合多肽或/和其抗原結合部分的阻斷IC50為約26966 ng/mL或更小、約15000 ng/mL或更小、約10000 ng/mL或更小、約8000 ng/mL或更小、約6000 ng/mL或更小、約4861 ng/mL或更小、約3000 ng/mL或更小、約2500 ng/mL或更小、約2000 ng/mL或更小、約1500ng/mL或更小、約1283 ng/mL或更小、約1000 ng/mL或更小、約800 ng/mL或更小、約500 ng/mL或更小、或約358.5 ng/mL或更小。
在一些實施方案中,基於ELISA分析,結合CD47的抗原結合多肽(一些示例例如嵌合抗體Xi2B2、Xi2H8、Xi3F10或其人源化抗體、Xi16E5或其人源化抗體、Xi14A9或其人源化抗體等)或/和其抗原結合部分的阻斷IC50為約4.682 ng/mL至約15246 ng/mL、約621.1 ng/mL至約15246 ng/mL、約621.1 ng/mL至約7910 ng/mL、約621.1 ng/mL至約2939 ng/mL、約621.1 ng/mL至約2500 ng/mL、約621.1 ng/mL至約2051 ng/mL、約621.1 ng/mL至約1738 ng/mL、約621.1 ng/mL至約1500 ng/mL、約621.1 ng/mL至約1400 ng/mL、約621.1 ng/mL至約1300 ng/mL、約621.1 ng/mL至約1200 ng/mL、約621.1 ng/mL至約1100 ng/mL、約621.1 ng/mL至約1000 ng/mL、約621.1 ng/mL至約900 ng/mL、約621.1 ng/mL至約800 ng/mL、或約621.1 ng/mL至約703.2 ng/mL。在一些實施方案中,基於ELISA分析,所述抗原結合多肽或/和其抗原結合部分的阻斷IC50為約15246 ng/mL或更小、約7910 ng/mL或更小、約2939 ng/mL或更小、約2500 ng/mL或更小、約2051 ng/mL或更小、約1738 ng/mL或更小、約1500 ng/mL或更小、約1400 ng/mL或更小、約1300 ng/mL或更小、約1200 ng/mL或更小、約1100 ng/mL或更小、約1000 ng/mL或更小、約900 ng/mL或更小、約800 ng/mL或更小、約703.2 ng/mL或更小、約621.1 ng/mL或更小、約450 ng/mL或更小、約350 ng/mL或更小、約250 ng/mL或更小、約150 ng/mL或更小、約100 ng/mL或更小、約50 ng/mL或更小、約40 ng/mL或更小、約30ng/mL或更小、約20 ng/mL或更小、約10 ng/mL或更小、或約4.682 ng/mL或更小。
在一些實施方案中,結合CD47的抗原結合多肽或/和其抗原結合部分促進巨噬細胞介導的對表達CD47細胞的吞噬作用。如前所述,通過結合CD47抗原結合多肽阻斷SIRPα與CD47的結合進而增加巨噬細胞對表達CD47細胞如癌細胞(具體的例子如HL60細胞等)的吞噬作用。在一些實施方案中,約1 μg/mL至約10 μg/mL結合CD47的抗原結合多肽濃度下,巨噬細胞吞噬率為約3.5%至約65.7%、約11.5%至約65.7%、約28.8%至約65.7%、或約44.67%至約65.7%。在一些實施方案中,在約1 μg/mL至約10 μg/mL抗原結合多肽濃度下,巨噬細胞吞噬率為約1.34%至約81.66%、約2%至約81.66%、約11.95%至約81.66%、約24.19%至約81.66%、或約71.48%至約81.66%。
在一些實施方案中,結合CD47的抗原結合多肽或/和其抗原結合部分沒有明顯誘導CD4+T細胞的凋亡。在一些實施方案中,凋亡檢測採用流式細胞術的測定方法。本文明顯的凋亡是指在可接受範圍內(例如對受試者無影響或在可控範圍內)或者與陰性對照相比在統計學意義上無顯著差異(P≤0.05),例如,一些實施方案中,與陰性對照IgG相比無顯著差異。
在一些實施方案中,結合CD47的抗原結合多肽或/和其抗原結合部分具有如下Tm(熔解溫度):約62℃或更高、約63℃或更高、約64℃或更高、約65℃或更高、約66℃或更高、約67℃或更高、約68℃或更高、約69℃或更高、或約70℃或更高。在一些實施方案中,所述抗體或/和其片段具有如下Tagg(聚集溫度):約61℃或更高、約62℃或更高、約63℃或更高、約64℃或更高、約65℃或更高、約66℃或更高、約67℃或更高、約68℃或更高、約69℃或更高、約70℃或更高、約71℃或更高、約72℃或更高、或約73℃或更高。在一些實施方案中,所述抗原結合多肽或/和其抗原結合部分的Tm為約62℃至約75℃、約63℃至約70.6℃、約64℃至約70.6℃、約65℃至約70.6℃、約67℃至約70.6℃、或約68℃至約70.6℃。在一些實施方案中,所述抗體或/和其片段的Tagg為約60℃至約73.81℃、約61℃至約73.81℃、約62℃至約73.81℃、約63℃至約73.81℃、約64℃至約73.81℃、約65℃至約73.81℃、約67℃至約73.81℃、或約68℃至約73.81℃。在一些實施方案中,Tm、Tagg通過nano DSF檢測。
在一些優選的實施方案中,結合CD47的抗原結合多肽或/和其抗原結合部分不引起實質性的紅血球減少、貧血或紅血球凝集。術語“血紅血球”和“紅血球”是同義詞並可互換使用。術語“凝集”表示細胞結塊。由於紅血球也表達CD47,某些結合CD47的抗原結合多肽會與紅血球結合,從而發生凝集現象,因此,避免或降低結合CD47抗原結合多肽對紅血球的傷害作用將有望降低治療副反應。
因此,另一方面,本發明提供了展現出下述性質中的一種或幾種組合的結合CD47的抗原結合多肽及其抗原結合部分:
(a)以1.89E-08(例如1.53E-08)或更小的KD
值與CD47結合;
(b)阻斷CD47與SIRPα的結合;
(c)促進巨噬細胞介導的對表達CD47細胞的吞噬作用;
(d)沒有明顯誘導CD4+T細胞的凋亡;
(e)不引起實質性的紅血球減少、貧血或紅血球凝集;和
(f)所述抗原結合多肽或其抗原結合部分的熔解溫度T≥62℃,聚集溫度Tagg≥61℃。
在一些實施方案中,結合CD47的抗原結合多肽或/和其抗原結合部分具有所述性質(a)~(f)中的一個、兩個、三個、四個、五個或六個。在一些實施方案中,所述抗原結合多肽或其抗原結合部分具有所述性質(a)、(b)和(c)。在一些實施方案中,所述抗原結合多肽或其抗原結合部分具有所述性質(a)、(b)和(e)。在一些實施方案中,所述抗原結合多肽或其抗原結合部分具有所述性質(a)、(c)和(e)。在一些實施方案中,所述抗原結合多肽或其抗原結合部分具有所述性質(a)、(b)、(c)和(d)。在一些實施方案中,所述抗原結合多肽或其抗原結合部分具有所述性質(a)、(b)、(c)和(e)。在一些實施方案中,所述抗原結合多肽或其抗原結合部分具有所述性質(a)、(b)、(c)和(f)。在一些實施方案中,所述抗原結合多肽或其抗原結合部分具有所述性質(a)、(b)、(c)、(d)和(f)。在一些實施方案中,所述抗原結合多肽或其抗原結合部分具有所述性質(a)、(b)、(c)、(d)、(e)和(f)。
在一些實施方案中,與CD47結合的抗原結合多肽及其抗原結合部分是抗CD47抗體或其抗原結合部分。
在一些實施方案中,本文提供的結合CD47的分離的抗原結合多肽是單株抗體。
在一些實施方案中,本文提供的結合CD47的分離的抗體是單特異性抗體。
在一些實施方案中,本文提供的結合CD47的分離的抗體是多特異性抗體。例如,雙特異抗體或者三特異性抗體等。
在一些實施方案中,本發明提供了與本文提供的任何示例性抗體結合CD47上的相同表位的結合CD47的抗原結合多肽或其抗原結合部分,例如與16E5的嵌合抗體或人源化抗體結合相同表位,例如與3F10的嵌合抗體或人源化抗體結合相同表位,例如與14A9的嵌合抗體或人源化抗體結合相同表位。在一些實施方案中,抗原結合多肽或其抗原結合部分與本文提供的用於結合CD47的任何示例性抗體競爭,例如與16E5的嵌合抗體或人源化抗體競爭結合CD47,例如與3F10的嵌合抗體或人源化抗體競爭結合CD47,例如與14A9的嵌合抗體或人源化抗體競爭結合CD47。可以通過ELISA、流式細胞術、表面電漿共振(SPR)測定或本領域已知的任何其他方法測量與CD47的結合。
本發明提供了一些示例性的結合CD47的單株抗體,包括2B2、2H8、3F10、16E5和14A9抗體的嵌合版本(Xi2B2、Xi2H8、Xi3F10、Xi16E5和Xi14A9)以及3F10、16E5、14A9的人源化變體。本文提供的示例性的結合CD47的抗體的重鏈CDR(重鏈CDR1、重鏈CDR2和重鏈CDR3)的胺基酸序列提供於下表S1中,輕鏈CDR(輕鏈CDR1、輕鏈CDR2和輕鏈CDR3)的胺基酸序列提供於下表S2中,可變區以及全長重鏈、輕鏈的胺基酸序列提供於下表S3、S4中。
表S1:抗CD47抗體的重鏈的CDR序列
抗體名稱 | 重鏈CDR1 | 重鏈CDR2 | 重鏈CDR3 |
Xi2H8 | GFSLTNYGVH (SEQ ID NO:1) | IIWAGGSTN (SEQ ID NO:6) | DDYASMDY (SEQ ID NO:11) |
Xi2B2 | GFTFSNYYMS (SEQ ID NO:2) | YISSGGGSTY (SEQ ID NO:7) | FAY (SEQ ID NO:12) |
Xi16E5 | GYTFTNYGMN (SEQ ID NO:3) | WINTNTGEPT (SEQ ID NO:8) | FSHLRGPMDY (SEQ ID NO:13) |
Xi3F10 | GYTFSRYWIE (SEQ ID NO:4) | EFIPGSDT (SEQ ID NO:9) | GGLRRMDY (SEQ ID NO:14) |
Xi14A9 | GFNIEDDYIE (SEQ ID NO:5) | RIDPANDKTK (SEQ ID NO:10) | PGLRRYYSMDY (SEQ ID NO:15) |
hz3F10-1.1 / 2.1 / 3.1 / 4.1 / 5.1 / 6.1 / 1.2 / 2.2 / 3.2 / 4.2 / 5.2 / 6.2 | GYTFSRYWIE (SEQ ID NO:4) | EFIPGSDT (SEQ ID NO:9) | GGLRRMDY (SEQ ID NO:14) |
hz16E5-1.1 / 1.3 / 1.2 / 3.2 / 3.1 / 3.3 | GYTFTNYGMN (SEQ ID NO:3) | WINTNTGEPT (SEQ ID NO:8) | FSHLRGPMDY (SEQ ID NO:13) |
hz14A9-2.3 / 2.4 | GFNIEDDYIE (SEQ ID NO:5) | RIDPANDKTK (SEQ ID NO:10) | PGLRRYYSMDY (SEQ ID NO:15) |
表S2:抗CD47抗體的輕鏈CDR序列
名稱 | 輕鏈CDR1 | 輕鏈CDR2 | 輕鏈CDR3 |
Xi2H8 | RSSQSLVHSNGNTYLH (SEQ ID NO:16) | KVSNRFS (SEQ ID NO:21) | SQSTHVPYT (SEQ ID NO:26) |
Xi2B2 | KSSQSLLDSDGKTYLN (SEQ ID NO:17) | LVSKLDS (SEQ ID NO:22) | GTHFPLT (SEQ ID NO:27) |
Xi16E5 | RSSQSLVHSNGYTYLH (SEQ ID NO:18) | KVSNRFS (SEQ ID NO:23) | SQSTHVPPT (SEQ ID NO:28) |
Xi3F10 | RASSSVSSTYLH (SEQ ID NO:19) | TTSTLAS (SEQ ID NO:24) | QQFSDSTWT (SEQ ID NO:29) |
Xi14A9 | KASENVVSYVS (SEQ ID NO:20) | GASNRYT (SEQ ID NO:25) | GQSYSYPLT (SEQ ID NO:30) |
hz3F10-1.1 / 3.1 / 5.1 / 1.2 / 3.2 / 5.2 | RASSSVSSTYLH (SEQ ID NO:19) | TTSTLAS (SEQ ID NO:24) | QQFSDSTWT (SEQ ID NO:29) |
hz3F10-2.1 / 4.1 / 6.1 / 2.2 / 4.2 / 6.2 | RASSSVSSTYLH (SEQ ID NO:19) | TTSTLAS (SEQ ID NO:24) | QQFSESTWT (SEQ ID NO:31) |
hz16E5-1.1 / 1.3 / 1.2 / 3.2 / 3.1 / 3.3 | RSSQSLVHSNGYTYLH (SEQ ID NO:18) | KVSNRFS (SEQ ID NO:23) | SQSTHVPPT (SEQ ID NO:28) |
hz14A9-2.3 / 2.4 | KASENVVSYVS (SEQ ID NO:20) | GASNRYT (SEQ ID NO:25) | GQSYSYPLT (SEQ ID NO:30) |
人源化3F10 (共同) | RASSSVSSTYLH (SEQ ID NO:19) | TTSTLAS (SEQ ID NO:24) | QQFSX2 STWT ,其中, X2 為 D 或 E (SEQ ID NO:32) |
表S3:抗CD47抗體的可變區序列
名稱 | 區 | 胺基酸序列 | SEQ ID NO: |
Xi2H8 | VH | QVQLKESGPGLVAPSQSLSITCTVSGFSLTNYGVH WVRQPPGKGLEWLGIIWAGGSTN YNSALMSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCARDDYASMDY WGQGTSVTVSS | 33 |
VL | DAFMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLH WYLQKPGQSPKLLIYKVSNRFS GVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYT LGGGTKLEIK | 34 | |
Xi16E5 | VH | EVQLQQSGPELKKPGETVKISCKASGYTFTNYGMN WVKQVPGKGLKWMGWINTNTGEPT YAEEFKGRFAFSLETSARTAFLQINNLKNEDTATYFCTRFSHLRGPMDY WGQGASVTVSS | 35 |
VL | DAVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGYTYLH WYLQKPGQSPKLLIYKVSNRFS GVPDRFSGSGSGTDFTLKISRLEAEDLGVYFCSQSTHVPPT FGGGTKLEIK | 36 | |
Xi2B2 | VH | EVMLVESGGGLVQPGGSLKLSCAASGFTFSNYYMS WVRQTPEKRLEWVAYISSGGGSTY YPDSVKGRFTISRDNAKNTLYLQMSSLKSEDTAMYYCAWFAY WGQGTLVTVSA | 37 |
VL | DAVVTQTPLTLSVTIGQPASISCKSSQSLLDSDGKTYLN WLLQRPGQSPKRLIYLVSKLDS GVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTHFPLT FGAGTKLELK | 38 | |
Xi3F10 | VH | EVQLQQSVAELMKPGASVKIYCKATGYTFSRYWIE WVKQRPGHGLEWIGEFIPGSDT TNFNEKFKGKATFTAEISSNTAYMQLSSLTSEDSAVYFCARGGLRRMDY WGQGTSVTVSS | 39 |
VL | DIVMTQTPAIMSASPGEKVTMTCRASSSVSSTYLH WYQQKSGASPKLWIYTTSTLAS GVPARFSGSGSGTSYSLTISSVEAEDAATYYCQQFSDSTWT FGGGTKLEIK | 40 | |
Xi14A9 | VH | EVQLQQSGAEVARPGASVKLSCTVSGFNIEDDYIE WVKQRPEQGLEWIGRIDPANDKTK YAPKFQDKATITGDTSSNTAYLQLSSLTSEDTAVYYCTRPGLRRYYSMDY WGQGTSVTVSS | 41 |
VL | NIVLTQSPKSMSMSVGERVTLSCKASENVVSYVS WYQQKPEQSPKLLIYGASNRYT GVPDRFIGSGSSTDFTLIISSFQPEDLADYHCGQSYSYPLT FGAGTKLELK | 42 | |
hz3F10-1.1 | VH | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITADISTSTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS | 43 |
VL | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLLIYTTSTLAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFSDSTWT FGQGTKLEIK | 44 | |
hz3F10-2.1 | VH | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITADISTSTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS | 45 |
VL | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLLIYTTSTLAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFSESTWT FGQGTKLEIK | 46 | |
hz3F10-3.1 | VH | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITADISTSTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS | 47 |
VL | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLLIYTTSTLAS GVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSDSTWT FGQGTKLEIK | 48 | |
hz3F10-4.1 | VH | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITADISTSTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS | 49 |
VL | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLLIYTTSTLAS GVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSESTWT FGQGTKLEIK | 50 | |
hz3F10-5.1 | VH | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITADISTSTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS | 51 |
VL | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLWIYTTSTLAS GVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSDSTWT FGQGTKLEIK | 52 | |
hz3F10-6.1 | VH | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITADISTSTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS | 53 |
VL | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLWIYTTSTLAS GVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSESTWT FGQGTKLEIK | 54 | |
hz3F10-1.2 | VH | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITAEISTNTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS | 55 |
VL | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLLIYTTSTLAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFSDSTWT FGQGTKLEIK | 56 | |
hz3F10-2.2 | VH | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITAEISTNTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS | 57 |
VL | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLLIYTTSTLAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFSESTWT FGQGTKLEIK | 58 | |
hz3F10-3.2 | VH | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITAEISTNTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS | 59 |
VL | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLLIYTTSTLAS GVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSDSTWT FGQGTKLEIK | 60 | |
hz3F10-4.2 | VH | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITAEISTNTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS | 61 |
VL | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLLIYTTSTLAS GVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSESTWT FGQGTKLEIK | 62 | |
hz3F10-5.2 | VH | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITAEISTNTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS | 63 |
VL | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLWIYTTSTLAS GVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSDSTWT FGQGTKLEIK | 64 | |
hz3F10-6.2 | VH | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITAEISTNTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS | 65 |
VL | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLWIYTTSTLAS GVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSESTWT FGQGTKLEIK | 66 | |
hz16E5-1.1 | VH | QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMN WVRQAPGQGLEWMGWINTNTGEPT YAQKLQGRVTMTLDTSTRTAYMELRSLRSDDTAVYYCARFSHLRGPMDY WGQGTLVTVSS | 67 |
VL | DIQMTQSPSSLSASVGDRVTITCRSSQSLVHSNGYTYLH WYQQKPGKAPKLLIYKVSNRFS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCSQSTHVPPT FGQGTKLEIK | 68 | |
hz16E5-1.3 | VH | QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMN WVRQAPGQGLKWMGWINTNTGEPT YAQELQGRVTMTLDTSTRTAYMELRSLRSDDTAVYYCTRFSHLRGPMDY WGQGTLVTVSS | 69 |
VL | DIQMTQSPSSLSASVGDRVTITCRSSQSLVHSNGYTYLH WYQQKPGKAPKLLIYKVSNRFS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCSQSTHVPPT FGQGTKLEIK | 70 | |
hz16E5-1.2 | VH | QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMN WVRQAPGQGLKWMGWINTNTGEPT YAQELQGRVTMTLDTSTRTAYMELRSLRSDDTAVYYCARFSHLRGPMDY WGQGTLVTVSS | 71 |
VL | DIQMTQSPSSLSASVGDRVTITCRSSQSLVHSNGYTYLH WYQQKPGKAPKLLIYKVSNRFS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCSQSTHVPPT FGQGTKLEIK | 72 | |
hz16E5-3.2 | VH | QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMN WVRQAPGQGLKWMGWINTNTGEPT YAQELQGRVTMTLDTSTRTAYMELRSLRSDDTAVYYCARFSHLRGPMDY WGQGTLVTVSS | 73 |
VL | DAQMTQSPSSLSASVGDRVTITCRSSQSLVHSNGYTYLH WYQQKPGKAPKLLIYKVSNRFS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCSQSTHVPPT FGQGTKLEIK | 74 | |
hz16E5-3.1 | VH | QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMN WVRQAPGQGLEWMGWINTNTGEPT YAQKLQGRVTMTLDTSTRTAYMELRSLRSDDTAVYYCARFSHLRGPMDY WGQGTLVTVSS | 75 |
VL | DAQMTQSPSSLSASVGDRVTITCRSSQSLVHSNGYTYLH WYQQKPGKAPKLLIYKVSNRFS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCSQSTHVPPT FGQGTKLEIK | 76 | |
hz16E5-3.3 | VH | QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMN WVRQAPGQGLKWMGWINTNTGEPT YAQELQGRVTMTLDTSTRTAYMELRSLRSDDTAVYYCTRFSHLRGPMDY WGQGTLVTVSS | 77 |
VL | DAQMTQSPSSLSASVGDRVTITCRSSQSLVHSNGYTYLH WYQQKPGKAPKLLIYKVSNRFS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCSQSTHVPPT FGQGTKLEIK | 78 | |
hz14A9-2.3 | VH | QVQLVQSGAEVKKPGASVKVSCKVSGFNIEDDYIE WVRQAPGQGLEWMGRIDPANDKTK YAQKFQGRVTMTGDTSTNTVYMELSSLRSEDTAVYYCARPGLRRYYSMDY WGQGTLVTVSS | 79 |
VL | DIQMTQSPSSLSASVGDRVTITCKASENVVSYVS WYQQKPGKAPKLLIYGASNRYT GVPSRFIGSGSSTDFTLTISSLQPEDFATYYCGQSYSYPLT FGQGTKLEIK | 80 | |
hz14A9-2.4 | VH | QVQLVQSGAEVKKPGASVKVSCKVSGFNIEDDYIE WVRQAPGQGLEWMGRIDPANDKTK YAQKFQGRVTMTGDTSTNTVYMELSSLRSEDTAVYYCT RPGLRRYYSMDY WGQGTLVTVSS | 81 |
VL | DIQMTQSPSSLSASVGDRVTITCKASENVVSYVS WYQQKPGKAPKLLIYGASNRYT GVPSRFIGSGSSTDFTLTISSLQPEDFATYYCGQSYSYPLT FGQGTKLEIK | 82 | |
人源化3F10 (共同) | VH | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITAX3 X4 STX5 TAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS 其中,X3 為D或E,X4 為I或E,X5 為S或N | 83 |
VL | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLX6 IYTTSTLAS GVPSRFSGSGSGTX7 X8 TLTISSLQPEDFATYYCQQFS X2 STWT FGQGTKLEIK 其中,X6 為L或W,X7 為D或S,X8 為F或Y,X2 為D或E | 84 | |
人源化16E5 (共同) | VH | QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMN WVRQAPGQGLX9 WMGWINTNTGEPT YAQX10 LQGRVTMTX11 DTSTX12 TAYMELRSLRSDDTAVYYC X13 RFSHLRGPMDY WGQGTLVTVSS 其中,X9 為E或K,X10 為K或E,X11 為L或T,X12 為R或S,X13 為A或T | 85 |
VL | DX14 QMTQSPSSLSASVGDRVTITCRSSQSLVHSNGYTYLH WYQQKPGKAPKLLIYKVSNRFS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCSQSTHVPPT FGQGTKLEIK 其中,X14 為I或A | 86 | |
人源化14A9 (共同) | VH | QVQLVQSGAEVKKPGASVKVSCKX15 SGFNIEDDYIE WVRQAPGQGLEWMGRIDPANDKTK YAQKFQGRVTMTX16 DTSTX17 TVYMELSSLRSEDTAVYYC X18 RPGLRRYYSMDY WGQGTLVTVSS 其中,X15 為A或V,X16 為R或G,X17 為S或N,X18 為A或T | 87 |
VL | DIQMTQSPSSLSASVGDRVTITCKASENVVSYVS WYQQKPGKAPKLLIYGASNRYT GVPSRFX19 GSGSX20 TDFTLTISSLQPEDFATYYCGQSYSYPLT FGQGTKLEIK 其中,X19 為S或I,X20 為S或G | 88 |
表S4:抗CD47抗體的全長重鏈和全長輕鏈的序列
名稱 | 區 | 胺基酸序列 | SEQ ID NO: |
Xi2H8 | 重鏈 | QVQLKESGPGLVAPSQSLSITCTVSGFSLTNYGVH WVRQPPGKGLEWLGIIWAGGSTN YNSALMSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCARDDYASMDYWGQGTSVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 89 |
輕鏈 | DAFMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLH WYLQKPGQSPKLLIYKVSNRFS GVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYT LGGGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 91 | |
Xi16E5 | 重鏈 | EVQLQQSGPELKKPGETVKISCKASGYTFTNYGMN WVKQVPGKGLKWMGWINTNTGEPT YAEEFKGRFAFSLETSARTAFLQINNLKNEDTATYFCTRFSHLRGPMDY WGQGASVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 93 |
輕鏈 | DAVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGYTYLH WYLQKPGQSPKLLIYKVSNRFS GVPDRFSGSGSGTDFTLKISRLEAEDLGVYFCSQSTHVPPT FGGGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 95 | |
Xi2B2 | 重鏈 | EVMLVESGGGLVQPGGSLKLSCAASGFTFSNYYMS WVRQTPEKRLEWVAYISSGGGSTY YPDSVKGRFTISRDNAKNTLYLQMSSLKSEDTAMYYCAWFAY WGQGTLVTVSA ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 97 |
輕鏈 | DAVVTQTPLTLSVTIGQPASISCKSSQSLLDSDGKTYLN WLLQRPGQSPKRLIYLVSKLDS GVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTHFPLT FGAGTKLELK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 99 | |
Xi3F10 | 重鏈 | EVQLQQSVAELMKPGASVKIYCKATGYTFSRYWIE WVKQRPGHGLEWIGEFIPGSDT TNFNEKFKGKATFTAEISSNTAYMQLSSLTSEDSAVYFCARGGLRRMDY WGQGTSVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 101 |
輕鏈 | DIVMTQTPAIMSASPGEKVTMTCRASSSVSSTYLH WYQQKSGASPKLWIYTTSTLAS GVPARFSGSGSGTSYSLTISSVEAEDAATYYCQQFSDSTWT FGGGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 103 | |
Xi14A9 | 重鏈 | EVQLQQSGAEVARPGASVKLSCTVSGFNIEDDYIE WVKQRPEQGLEWIGRIDPANDKTK YAPKFQDKATITGDTSSNTAYLQLSSLTSEDTAVYYCTRPGLRRYYSMDY WGQGTSVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 105 |
輕鏈 | NIVLTQSPKSMSMSVGERVTLSCKASENVVSYVS WYQQKPEQSPKLLIYGASNRYT GVPDRFIGSGSSTDFTLIISSFQPEDLADYHCGQSYSYPLT FGAGTKLELK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 107 | |
hz3F10-1.1 | 重鏈 | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITADISTSTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 109 |
輕鏈 | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLLIYTTSTLAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFSDSTWT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 111 | |
hz3F10-2.1 | 重鏈 | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITADISTSTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 113 |
輕鏈 | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLLIYTTSTLAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFSESTWTF GQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 115 | |
hz3F10-3.1 | 重鏈 | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITADISTSTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 117 |
輕鏈 | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLLIYTTSTLAS GVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSDSTWT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 119 | |
hz3F10-4.1 | 重鏈 | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITADISTSTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 121 |
輕鏈 | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLLIYTTSTLAS GVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSESTWT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 123 | |
hz3F10-5.1 | 重鏈 | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSD TTNYAQKFQGRVTITADISTSTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 125 |
輕鏈 | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLWIYTTSTLAS GVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSDSTWT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 127 | |
hz3F10-6.1 | 重鏈 | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITADISTSTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 129 |
輕鏈 | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLWIYTTSTLAS GVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSESTWT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 131 | |
hz3F10-1.2 | 重鏈 | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSD TTNYAQKFQGRVTITAEISTNTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 133 |
輕鏈 | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLLIYTTSTLAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFSDSTWT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 135 | |
hz3F10-2.2 | 重鏈 | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITAEISTNTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 137 |
輕鏈 | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLLIYTTSTLAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFSESTWT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 139 | |
hz3F10-3.2 | 重鏈 | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITAEISTNTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 141 |
輕鏈 | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLLIYTTSTLAS GVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSDSTWT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 143 | |
hz3F10-4.2 | 重鏈 | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITAEISTNTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 145 |
輕鏈 | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLLIYTTSTLAS GVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSESTWT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 147 | |
hz3F10-5.2 | 重鏈 | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITAEISTNTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 149 |
輕鏈 | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLWIYTTSTLAS GVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSDSTWT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 151 | |
hz3F10-6.2 | 重鏈 | QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIE WVRQAPGQGLEWMGEFIPGSDT TNYAQKFQGRVTITAEISTNTAYMELSSLRSEDTAVYYCARGGLRRMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 153 |
輕鏈 | DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLH WYQQKPGKAPKLWIYTTSTLAS GVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSESTWT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 155 | |
hz16E5-1.1 | 重鏈 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMN WVRQAPGQGLEWMGWINTNTGEPT YAQKLQGRVTMTLDTSTRTAYMELRSLRSDDTAVYYCARFSHLRGPMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 157 |
輕鏈 | DIQMTQSPSSLSASVGDRVTITCRSSQSLVHSNGYTYLH WYQQKPGKAPKLLIYKVSNRFS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCSQSTHVPPT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 159 | |
hz16E5-1.3 | 重鏈 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMN WVRQAPGQGLKWMGWINTNTGEPT YAQELQGRVTMTLDTSTRTAYMELRSLRSDDTAVYYCTRFSHLRGPMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 161 |
輕鏈 | DIQMTQSPSSLSASVGDRVTITCRSSQSLVHSNGYTYLH WYQQKPGKAPKLLIYKVSNRFS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCSQSTHVPPT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 163 | |
hz16E5-1.2 | 重鏈 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMN WVRQAPGQGLKWMGWINTNTGEPT YAQELQGRVTMTLDTSTRTAYMELRSLRSDDTAVYYCARFSHLRGPMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 165 |
輕鏈 | DIQMTQSPSSLSASVGDRVTITCRSSQSLVHSNGYTYLH WYQQKPGKAPKLLIYKVSNRFS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCSQSTHVPPT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 167 | |
hz16E5-3.2 | 重鏈 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMN WVRQAPGQGLKWMGWINTNTGEPT YAQELQGRVTMTLDTSTRTAYMELRSLRSDDTAVYYCARFSHLRGPMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 169 |
輕鏈 | DAQMTQSPSSLSASVGDRVTITCRSSQSLVHSNGYTYLH WYQQKPGKAPKLLIYKVSNRFS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCSQSTHVPPT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 171 | |
hz16E5-3.1 | 重鏈 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMN WVRQAPGQGLEWMGWINTNTGEPT YAQKLQGRVTMTLDTSTRTAYMELRSLRSDDTAVYYCARFSHLRGPMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 173 |
輕鏈 | DAQMTQSPSSLSASVGDRVTITCRSSQSLVHSNGYTYLH WYQQKPGKAPKLLIYKVSNRFS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCSQSTHVPPT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 175 | |
hz16E5-3.3 | 重鏈 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMN WVRQAPGQGLKWMGWINTNTGEPT YAQELQGRVTMTLDTSTRTAYMELRSLRSDDTAVYYCTRFSHLRGPMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 177 |
輕鏈 | DAQMTQSPSSLSASVGDRVTITCRSSQSLVHSNGYTYLH WYQQKPGKAPKLLIYKVSNRFS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCSQSTHVPPT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 179 | |
hz14A9-2.3 | 重鏈 | QVQLVQSGAEVKKPGASVKVSCKVSGFNIEDDYIE WVRQAPGQGLEWMGRIDPANDKTK YAQKFQGRVTMTGDTSTNTVYMELSSLRSEDTAVYYCARPGLRRYYSMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 181 |
輕鏈 | DIQMTQSPSSLSASVGDRVTITCKASENVVSYVS WYQQKPGKAPKLLIYGASNRYT GVPSRFIGSGSSTDFTLTISSLQPEDFATYYCGQSYSYPLT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 183 | |
hz14A9-2.4 | 重鏈 | QVQLVQSGAEVKKPGASVKVSCKVSGFNIEDDYIE WVRQAPGQGLEWMGRIDPANDKTK YAQKFQGRVTMTGDTSTNTVYMELSSLRSEDTAVYYCTRPGLRRYYSMDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 185 |
輕鏈 | DIQMTQSPSSLSASVGDRVTITCKASENVVSYVS WYQQKPGKAPKLLIYGASNRYT GVPSRFIGSGSSTDFTLTISSLQPEDFATYYCGQSYSYPLT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 187 |
免疫偶聯物
在一些實施方案中,本發明提供了結合CD47的抗原結合多肽或其抗原結合部分的免疫偶聯物。可以與結合CD47的抗原結合多肽或其抗原結合部分連接或綴合的治療劑可以包括但不限於細胞毒性藥物、放射性同位素、免疫調節劑或抗體。在一些實施方案中,結合CD47的抗原結合多肽或其抗原結合部分與治療劑直接綴合。在一些實施方案中,結合CD47的抗原結合多肽或其抗原結合部分通過接頭與治療劑綴合。
組合物
本發明提供了藥物組合物,所述藥物組合物包含分離的結合CD47的抗原結合多肽或其抗原結合部分,或編碼所述抗體或片段的核酸,或本文所述的免疫偶聯物,並且還包含一種或多種藥學上可接受的載體。在一些實施方案中,組合物包括2B2、2H8、3F10、16E5和14A9抗體的嵌合抗體及人源化抗體中的任一單株抗體,以及藥學上可接受的載體。藥學上可接受的載體包括,例如,賦形劑、稀釋劑、包封材料、填充劑、緩衝劑或其他試劑。
融合瘤
本發明提供了分離的融合瘤細胞系,其選自由2B2、2H8、3F10、16E5和14A9組成的組。融合瘤細胞系2B2、2H8、3F10、16E5和14A9分泌結合CD47的單株抗體。
分離的核酸
本發明提供了分離的核酸,其包含編碼本文所述結合CD47的抗原結合多肽或其抗原結合部分的序列,在一些實施方案中,所述核酸可以編碼包含本文所述抗原結合多肽重鏈可變區或/和輕鏈可變區的胺基酸序列。在另一些實施方案中,所述的核酸可以編碼包含本文所述的抗原結合多肽重鏈或/和抗原結合多肽輕鏈的胺基酸序列。序列表中示例性的列舉了一些可變區、抗原結合多肽重鏈和輕鏈的核苷酸序列。
載體
本發明提供了包含所述的分離的核酸的載體。在一些實施方案中,所述的載體為選殖載體;在另一些實施方案中,所述的載體為表達載體。
所述表達載體可選的能夠表達本文所述抗原結合多肽或其抗原結合部分的任意表達載體。
宿主細胞
在一些實施方案中,本發明提供包含所述載體的宿主細胞,宿主細胞為用於選殖或編碼結合CD47的抗原結合多肽或其抗原結合部分的適當宿主細胞。在一些實施方案中,宿主細胞為原核細胞。在另一些實施方案中,宿主細胞為真核細胞。在一些實施方案中,宿主細胞選自酵母細胞、哺乳細胞或適用於製備抗原結合多肽或其抗原結合部分的其他細胞。哺乳細胞例如為中國倉鼠(CHO)卵巢細胞。
製備結合CD47抗原結合多肽的方法
在一些實施方案中,本發明提供了製備結合CD47的分離的抗原結合多肽的方法,所述方法包括:在適合所述抗原結合多肽表達的條件下,培養包含編碼所述抗原結合多肽的核酸的宿主細胞,從所述宿主細胞或宿主細胞培養基中回收所述抗原結合多肽。為了產生結合CD47的抗原結合多肽,分離編碼所述抗體的核酸,並***一個或多個載體,用於在宿主細胞中進一步選殖或/和表達。所述核酸可以採用基因選殖、基因拼接、化學合成等多種本領域所熟知的方法獲取。
用途
本發明提供了結合CD47的分離的抗原結合多肽或其抗原結合部分的用途,一些實施方案中,向受試者施用治療有效量本文的分離的結合CD47的抗原結合多肽或其抗原結合部分,可以減少或抑制腫瘤細胞生長。一些實施方案中,向受試者施用治療有效量本文的分離的結合CD47的抗原結合多肽或其抗原結合部分,可以治療癌症。需要治療的受試者包括那些已經患有疾病或病狀的受試者,以及可能患疾病或病狀並且其目的是預防、延遲或減弱疾病或病狀的受試者。如本文所用,“癌症”是指哺乳動物中特徵通常在於不受調控的細胞生長的生理病狀。癌症的實例包括但不限於:白血病、淋巴瘤、卵巢癌、乳腺癌、子宮內膜癌、結腸癌、直腸癌、膀胱癌、尿路上皮癌、肺癌、支氣管癌、骨癌、***癌、胰腺癌、胃癌、肝細胞癌、膽囊癌、膽管癌、食道癌、腎細胞癌、甲狀腺癌、頭頸癌、睾丸癌、內分泌腺癌、腎上腺癌、腦下垂體癌、皮膚癌、軟組織癌、血管癌、腦癌、神經癌、眼癌、腦膜癌、口咽癌、下咽部癌、宮頸癌、以及子宮癌、膠質母細胞瘤(glioblastoma)、髓母細胞瘤(medulloblastoma)、星形細胞瘤、膠質瘤、腦膜瘤、胃泌素瘤、神經母細胞瘤(neuroblastoma)、黑色素瘤、急性髓系白血病、骨髓增生異常綜合症以及肉瘤。
一些實施方案中,向所述受試者施用有效量的本文結合CD47的分離的抗原結合多肽或其抗原結合部分,促進受試者巨噬細胞的吞噬作用。
儘管為了清楚理解的目的,已經通過舉例說明和實施例相當詳細地描述了前述發明,但是根據本發明的教義,本領域的普通具有通常知識者將顯而易見的是,可另外對本發明進行某些改變和修改而不背離所附申請專利範圍的精神和範圍。以下實施例僅以說明方式提供,而並不起限制作用。本領域的具有通常知識者將容易地識別多種非關鍵性參數,所述參數可發生改變或修改以產生基本上類似的結果。本文具體實施例中採用的陽性對照Hu5F9,其序列與美國專利US2015/0183874A1中的抗體“5F9”的序列相同,為人源化抗體。
除非特殊說明,否則本發明的實踐採用本領域熟知的並且在以下中描述的常規分子生物學、細胞生物學、生物化學和免疫學技術:例如,Methods in Molecular Biology,Humana Press;Molecular Cloning:A Laboratory Manual,第二版(Sambrook等,1989);Current Protocols in Immunology(J .E .Coligan等編,1991);Immunobiology(C .A.Janeway和P.Travers,1997);Antibodies(P.Finch,1997);Antibodies:a practical approach(D. Catty.編,IRL Press,1988-1989);Monoclonal antibodies:a practical approach(P. Shepherd和C. Dean編,Oxford University Press,2000);Phage display:a laboratory manual(C. Barbas III等Cold Spring Harbor Laboratory Press,2001);以及Using antibodies:a laboratory manual(E. Harlow and D. Lane(Cold Spring Harbor Laboratory Press,1999)等。
實施例1:抗CD47單株抗體的產生
使用CD47蛋白對小鼠的免疫:
為了產生針對CD47的抗體,使用等體積的弗氏完全佐劑(初次免疫)或弗氏不完全佐劑(加强免疫)乳化的重組體hCD47-His Tag蛋白(ACRObiosystems,目錄號:CD7-H5227)(50 μg/小鼠Balb/c)或hCD47-mFc(ACRObiosystems,目錄號:CD7-H52A5)每2周皮下免疫Balb/c小鼠,免疫三次持續6周。第四次免疫採用hCD47-mFc(ACRObiosystems,目錄號:CD7-H52A5)蛋白,20 μg/隻小鼠,肌肉注射(水相佐劑)。細胞融合前三天,通過靜脈內注射不含佐劑的抗原來加强小鼠免疫。使用聚乙二醇1500(Polyethylene Glycol 1500;Roche公司,目錄號:10783641001)將來自免疫小鼠的脾細胞(1×108
)與SP2/0骨髓瘤細胞(1.5×107
)融合。融合後,將細胞以0.1 ml/孔分配到96孔板中,並且在37℃、5% CO2
的培養箱中進行孵育。在第1天,通過向每孔添加另外的0.1 ml含有血清和補充有2×甲胺蝶呤的HAT培養基來飼養細胞。在第3天和第7天,用0.1 ml新鮮的HAT培養基替換來自每孔的0.1 ml培養基。通常在第9-14天之間進行篩選,並且通過ELISA針對與hCD47-His Tag(ACRObiosystems公司,目錄號:CD7-H5227)反應的抗體測試培養物上清液,篩選陽性孔。
融合瘤細胞選殖化採用有限稀釋法。將挑選出的陽性混合選殖進行有限稀釋,一株陽性混合選殖,鋪兩塊96孔板(100 cells/板、200 cells/板),將融合瘤細胞培養在含有10%胎牛血清的RPMI 1640(Hyclone公司,目錄號:SH30809.01)中。10天後,待有限稀釋後的亞選殖同樣經過ELISA試驗檢測培養物上清,挑取陽性亞選殖。選殖化的融合瘤細胞保種並用於cDNA的提取。
抗人CD47抗體的cDNA提取和可變區序列獲取:
使用RNA提取試劑盒(Takara,目錄號:9767)從篩選出的產生hCD47抗體的融合瘤細胞系中分離總RNA,以總RNA作為模板,根據製造商的說明書,用逆轉錄試劑盒(Thermo Fisher,目錄號:K1652)合成第一鏈cDNA。然後利用合成的cDNA,使用簡併小鼠IgG引物,通過PCR反應對抗體相關序列進行體外擴增。
將PCR擴增產物在1%瓊脂糖/Tris-醋酸鹽凝膠中進行電泳分離。從凝膠上切下具有預期大小(重鏈和輕鏈大約450 bp)的DNA片段並且對其純化。將3 μl純化的PCR產物選殖到pMD-19T載體(Takara,目錄號:6013)中,並且轉化到DH5α化學感受態大腸杆菌(Takara,目錄號:9057)中。每個連接反應中,隨機選擇10個陽性選殖,使用M13正向引物進行DNA測序。
從對應的融合瘤選殖(2B2、2H8、3F10、16E5、14A9)擴增、測序得到五個鼠源單株抗體(2B2、2H8、3F10、16E5、14A9抗體)的重鏈可變區(VH)序列和輕鏈可變區(VL)序列,序列信息如下:
抗體名稱 | VH(SEQ ID NO:) | VL(SEQ ID NO:) | ||
胺基酸序列 | 核苷酸序列 | 胺基酸序列 | 核苷酸序列 | |
2H8 | 33 | 189 | 34 | 190 |
16E5 | 35 | 191 | 36 | 192 |
2B2 | 37 | 193 | 38 | 194 |
3F10 | 39 | 195 | 40 | 196 |
14A9 | 41 | 197 | 42 | 198 |
嵌合抗體的構建和表達:
通過將小鼠抗體可變區的基因進行化學合成,將每種小鼠抗體的VL區分別連接到人κ鏈恆定區構建嵌合輕鏈,將小鼠VH區連接到人IgG4(EU編號S228P)恆定區構建嵌合重鏈。通過常規基因工程手段分別構建嵌合輕鏈的表達質體和嵌合重鏈的表達質體,將CHO細胞(200 mL體系,在106
個細胞/mL下)用100 μg的每種嵌合重鏈表達質體和嵌合輕鏈表達質體進行轉染並且將其培養6天。然後用蛋白A柱純化上清液中的嵌合抗體。
構建並表達得到五種嵌合抗體,其嵌合重鏈和嵌合輕鏈的全長序列及其編碼核酸如下:Xi2H8(嵌合重鏈及其編碼核酸:SEQ ID NOs:89~90;嵌合輕鏈及其編碼核酸:SEQ ID NOs:91~92)、Xi2B2(嵌合重鏈及其編碼核酸:SEQ ID NOs:97~98;嵌合輕鏈及其編碼核酸:SEQ ID NOs:99~100)、Xi3F10(嵌合重鏈及其編碼核酸:SEQ ID NOs:101~102;嵌合輕鏈及其編碼核酸:SEQ ID NOs:103~104)、Xi16E5(嵌合重鏈及其編碼核酸:SEQ ID NOs:93~94;嵌合輕鏈及其編碼核酸:SEQ ID NOs:95~96)、Xi14A9(嵌合重鏈及其編碼核酸:SEQ ID NOs:105~106;嵌合輕鏈及其編碼核酸:SEQ ID NOs:107~108)。
抗體人源化設計:
3F10、14A9和16E5的人鼠嵌合抗體使用CDR移植方法進行人源化(參見,例如,美國專利號5,225,539)。通過MOE(Molecular Operating Environment)對鼠源抗體3F10、14A9和16E5進行同源建模,產生Fv結構域的蛋白質結構模型。分別將鼠源3F10、14A9和16E5抗體的VH和VL胺基酸序列輸入到國際免疫遺傳信息系統相關工具網站(http://www.imgt.org/3Dstructure-DB/cgi/DomainGapAlign.cgi),從中篩選出與小鼠3F10、14A9和16E5抗體的可變區具有高度同源性的人胚系抗體序列。將鼠源3F10、14A9和16E5抗體的VH和VL中的互補決定區(CDR)嫁接模板人抗體。對於3F10,所選擇的模板人VH是IGHV1-69*01和IGHJ4*01的組合,所選擇的模板人VL是IGKV1-39*01和IGKJ2*01的組合。對於14A9,所選擇的模板人VH是IGHV1-46*01和IGHJ4*01的組合,所選擇的模板人VL是IGKV1-39*01和IGKJ2*01的組合。對於16E5,所選擇的模板人VH是IGHV1-18*01和IGHJ4*01的組合,所選擇的模板人VL是IGKV1-39*01和IGKJ2*01的組合。
上述模板人抗體的CDR胺基酸序列被融合瘤(小鼠)3F10、14A9和16E5抗體的CDR取代。用來自小鼠3F10、14A9和16E5抗體的VH和VL的必需胺基酸序列嫁接上述模板人胚系抗體VH和VL框架,以得到功能性人源化抗體。對於3F10、14A9和16E5抗體的VH和VL,上述模板人抗體的框架胺基酸的幾個位點被回復突變為小鼠3F10、14A9和16E5抗體中對應的胺基酸序列。個別的CDR區進行突變。
對於人源化3F10抗體的重鏈可變區,突變類型的選擇和搭配來自如下位點:在位置73處的胺基酸從Asp(D)突變為Glu(E);在位置74處的胺基酸從Glu(E)突變為Ile(I);在位置77處的胺基酸從Ser(S)突變為Asn(N),並且對於人源化3F10抗體的輕鏈可變區,突變類型的選擇和搭配來自如下位點:在位置48處的胺基酸從Leu(L)突變為Trp(W);在位置71處的胺基酸從Asp(D)突變為Ser(S);在位置72處的胺基酸從Phe(F)突變為Tyr(Y);在位置94處的胺基酸從Asp(D)突變為Glu(E)。對於人源化14A9的重鏈可變區,突變類型的選擇和搭配來自如下位點:在位置24處的胺基酸從Ala(A)突變為Val(V);在位置72處的胺基酸從Arg(R)突變為Gly(G);在位置77處的胺基酸從Ser(S)突變為Asn(N);在位置97處的胺基酸從Ala(A)突變為Thr(T),並且對於人源化14A9的輕鏈可變區,突變類型的選擇和搭配來自如下位點:在位置63處的胺基酸從Ser(S)突變為Ile(I);在位置68處的胺基酸從Gly(G)突變為Ser(S)。對於人源化16E5抗體的重鏈可變區,突變類型的選擇和搭配來自如下位點:在位置46處的胺基酸從Glu(E)突變為Lys(K);在位置63處的胺基酸從Lys(K)突變為Glu(E);在位置72處的胺基酸從Thr(T)突變為Leu(L);在位置77處的胺基酸從Ser(S)突變為Arg(R);在位置97處的胺基酸從Ala(A)突變為Thr(T),並且對於人源化16E5抗體的輕鏈可變區,突變類型的選擇和搭配來自如下位點:在位置2處的胺基酸從Ile(I)突變為Ala(A);在位置33處的胺基酸從Asn(N)突變為Gln(Q)。本段中突變位點序號的描述按照可變區第一個胺基酸開始依次計數,
人源化3F10、14A9和16E5抗體的序列及其編碼核酸如下:hz3F10-1.1(重鏈及其編碼核酸:SEQ ID NOs.109~110;輕鏈及其編碼核酸:SEQ ID NOs.111~112)、hz3F10-2.1(重鏈及其編碼核酸:SEQ ID NOs.113~114;輕鏈及其編碼核酸:SEQ ID NOs.115~116)、hz3F10-3.1(重鏈及其編碼核酸:SEQ ID NOs.117~118;輕鏈及其編碼核酸:SEQ ID NOs.119~120)、hz3F10-4.1(重鏈及其編碼核酸:SEQ ID NOs.121~122;輕鏈及其編碼核酸:SEQ ID NOs.123~124)、hz3F10-5.1(重鏈及其編碼核酸:SEQ ID NOs.125~126;輕鏈及其編碼核酸:SEQ ID NOs.127~128)、hz3F10-6.1(重鏈及其編碼核酸:SEQ ID NOs.129~130;輕鏈及其編碼核酸:SEQ ID NOs.131~132)、hz3F10-1.2(重鏈及其編碼核酸:SEQ ID NOs.133~134;輕鏈及其編碼核酸:SEQ ID NOs.135~136)、hz3F10-2.2(重鏈及其編碼核酸:SEQ ID NOs.137~138;輕鏈及其編碼核酸:SEQ ID NOs.139~140)、hz3F10-3.2(重鏈及其編碼核酸:SEQ ID NOs.141~142;輕鏈及其編碼核酸:SEQ ID NOs.143~144)、hz3F10-4.2(重鏈及其編碼核酸:SEQ ID NOs.145~146;輕鏈及其編碼核酸:SEQ ID NOs.147~148)、hz3F10-5.2(重鏈及其編碼核酸:SEQ ID NOs.149~150;輕鏈及其編碼核酸:SEQ ID NOs.151~152)、hz3F10-6.2(重鏈及其編碼核酸:SEQ ID NOs.153~154;輕鏈及其編碼核酸:SEQ ID NOs.155~156)、hz16E5-1.1(重鏈及其編碼核酸:SEQ ID NOs.157~158;輕鏈及其編碼核酸:SEQ ID NOs.159~160)、hz16E5-1.3(重鏈及其編碼核酸:SEQ ID NOs.161~162;輕鏈及其編碼核酸:SEQ ID NOs.163~164)、hz16E5-1.2(重鏈及其編碼核酸:SEQ ID NOs.165~166;輕鏈及其編碼核酸:SEQ ID NOs.167~168)、hz16E5-3.2(重鏈及其編碼核酸:SEQ ID NOs.169~170;輕鏈及其編碼核酸:SEQ ID NOs.171~172)、hz16E5-3.1(重鏈及其編碼核酸:SEQ ID NOs.173~174;輕鏈及其編碼核酸:SEQ ID NOs.175~176)、hz16E5-3.3(重鏈及其編碼核酸:SEQ ID NOs.177~178;輕鏈及其編碼核酸:SEQ ID NOs.179~180)、hz14A9-2.3(重鏈及其編碼核酸:SEQ ID NOs.181~182;輕鏈及其編碼核酸:SEQ ID NOs.183~184)、hz14A9-2.4(重鏈及其編碼核酸:SEQ ID NOs.185~186;輕鏈及其編碼核酸:SEQ ID NOs.187~188)。
人源化3F10、14A9和16E5抗體的構建和表達:
合成編碼人源化3F10、14A9和16E5抗體全長輕鏈和全長重鏈的DNA並且將所述DNA選殖到表達載體(包括例如CN107001463A披露的pcDNA3.1載體、CN109422811A披露的pCHO1.0載體等)。將CHO細胞(200ml體系,在106
個細胞/ml下)用100 μg的每種人源化抗體重鏈表達質體和輕鏈表達質體進行轉染並且將其用ExpiCHO培養基(Gibco;貨號:A29100-01)在37℃、5% CO2
的培養箱中培養6天。離心分離得到上清液後,然後用蛋白A柱純化上清液中的人源化抗體。
實施例2:抗CD47抗體的基於Biacore的親和力分析
通過Biacore分別測量人CD47蛋白(Human CD47 Protein, His Tag;ACRObiosystems公司,目錄號:CD7-H5227)和食蟹猴CD47蛋白(Cynomolgus /Rhesus macaque CD47 Protein, His Tag;ACRObiosystems公司,目錄號:CD7-C52H1)與抗CD47抗體(嵌合的或人源化的)之間的結合動力學,獲得平衡解離常數KD
(單位M);所述Biacore分析在25℃下進行並且以1Hz的數據收集速率進行記錄。
將多株兔抗小鼠IgG(GE,BR-1008-38)用10 mM pH 5.0的乙酸鈉進行稀釋,並且使用胺偶聯試劑盒(GE,BR10050)固定到CM5生物感測器晶片的參考流動池和實驗流動池上達到約15000 RΜ。在每個循環的開始,將稀釋的測試抗體(1.5 μg/mL)注射在實驗流動池上,持續1分鐘以被捕獲。這些數據表明,如通過Biacore測量的,抗CD47抗體(嵌合的和人源化的)結合CD47。
表1:抗CD47嵌合抗體與人CD47和食蟹猴CD47的結合親和力
抗體名稱 | Biacore:平衡解離常數KD (單位M) | |
人CD47蛋白 | 食蟹猴CD47蛋白 | |
Xi2B2 | 7.48E-09 | 1.20E-09 |
Xi2H8 | 3.50E-10 | 1.25E-09 |
Xi3F10 | 7.67E-10 | 1.04E-09 |
Xi16E5 | 9.06E-09 | 2.92E-09 |
Xi14A9 | 2.35E-09 | 1.58E-09 |
表2:抗CD47人源化抗體與人CD47和食蟹猴CD47的結合親和力
抗體名稱 | Biacore:平衡解離常數KD (單位M) | |
人CD47蛋白 | 食蟹猴CD47蛋白 | |
hz3F10-1.1 | 9.46E-10 | 1.31E-09 |
hz3F10-2.1 | 8.36E-10 | 1.17E-09 |
hz3F10-3.1 | 1.53E-09 | 1.92E-09 |
hz3F10-4.1 | 1.42E-09 | 1.62E-09 |
hz3F10-5.1 | 9.60E-10 | 1.30E-09 |
hz3F10-6.1 | 5.92E-10 | 2.47E-09 |
hz3F10-1.2 | 9.04E-10 | 1.33E-09 |
hz3F10-2.2 | 7.79E-10 | 1.14E-09 |
hz3F10-3.2 | 1.15E-09 | 1.47E-09 |
hz3F10-4.2 | 1.34E-09 | 1.86E-09 |
hz3F10-5.2 | 8.96E-10 | 1.40E-09 |
hz3F10-6.2 | 7.65E-10 | 1.15E-09 |
hz16E5-1.1 | 1.89E-08 | 4.77E-09 |
hz16E5-3.1 | 6.28E-09 | 3.28E-09 |
hz16E5-1.2 | 9.31E-09 | 2.26E-09 |
hz16E5-3.2 | 1.71E-08 | 3.10E-09 |
hz16E5-1.3 | 1.53E-08 | 2.73E-09 |
hz16E5-3.3 | 7.13E-09 | 1.87E-09 |
hz14A9-2.3 | 2.04E-10 | 3.07E-09 |
hz14A9-2.4 | 8.55E-09 | 2.00E-09 |
Hu5F9 | 8.33E-10 | 1.92E-09 |
實施例3:抗CD47抗體的基於ELISA的結合分析
ELISA結合分析基於人CD47蛋白與抗CD47嵌合抗體或抗CD47人源化抗體進行。將96孔板(Costar,目錄號:9018)在4℃下用100 μl/孔的2 μg/ml CD47-His(Human CD47 Protein, His Tag;ACRObiosystems公司,目錄號:CD7-H5227)的包被緩衝液PBS包被過夜。抽吸孔,並且通過添加100 μL/孔封閉液(具有1%(w/v)牛血清蛋白(BSA,Sigma公司,目錄號:B2064-100G)的PBS)並且在37℃下孵育1小時來封閉非特異性結合位點。用洗滌緩衝液(具有0.01%(w/v)吐溫20(Sigma公司,目錄號:P9416-100ML)的PBS)洗滌96孔板三次後,添加100 μl/孔的抗CD47抗體(嵌合抗體見表3,人源化抗體見表4)在封閉液中的1:4連續稀釋液(從30 μg/mL開始),並且在室溫下孵育2小時。洗滌96孔板,洗滌後再用第二抗體HRP-anti-Human IgG(BD公司,目錄號:555788)避光孵育20 min。洗滌96孔板後,添加100 μl/孔的底物溶液TMB(TIANGEN公司,目錄號:PA107-01)並將所述96孔板在室溫下溫育10min。添加100 μl/孔的停止溶液(1M H2SO4)以停止反應。產生比色信號並且使用多功能酶標儀(生產廠家:PerkinElmer;型號規格EnVision)在450 nm處讀取所述比色信號。使用GraphPad Prism5分析數據,並計算EC50。這些數據表明,通過ELISA測量,抗CD47抗體結合CD47,人源化抗體具有良好的表現。
表3:抗CD47嵌合抗體與人CD47蛋白基於ELISA的結合EC50
注:NA表示未達檢測限。
抗體名稱 | EC50(ng/mL) |
Xi2B2 | 349.5 |
Xi2H8 | NA |
Xi3F10 | 1106 |
Xi16E5 | 87.89 |
Xi14A9 | 273.4 |
表4:抗CD47人源化抗體與人CD47蛋白基於ELISA的結合EC50
抗體名稱 | EC50(ng/mL) | 抗體名稱 | EC50(ng/mL) |
hz3F10-1.1 | 70.02 | hz3F10-5.2 | 105.6 |
hz3F10-2.1 | 80.94 | hz3F10-6.2 | 129.3 |
hz3F10-3.1 | 126.9 | hz16E5-1.1 | 306 |
hz3F10-4.1 | 115.1 | hz16E5-3.1 | 139.7 |
hz3F10-5.1 | 99.33 | hz16E5-1.2 | 159.5 |
hz3F10-6.1 | 56.33 | hz16E5-3.2 | 215.1 |
hz3F10-1.2 | 124.8 | hz16E5-1.3 | 138.1 |
hz3F10-2.2 | 105.8 | hz16E5-3.3 | 240.9 |
hz3F10-3.2 | 165.9 | hz14A9-2.3 | 156.8 |
hz3F10-4.2 | 180.7 | hz14A9-2.4 | 339.3 |
實施例4:抗CD47抗體的基於細胞的結合分析
基於與穩定表達CD47的CHO-K1細胞系的結合進行抗CD47抗體(嵌合的或人源化的)的細胞結合分析。將CHO-K1-CD47細胞(表達人CD47蛋白的CHO-K1細胞)添加到96孔板(Eppendorf,目錄號:C030730.119)的各孔中,每孔1.2×104
個,並與抗CD47抗體(20 μg/ml,1:4的稀釋度,稀釋緩衝液為PBS)室溫孵育1-2h。然後將細胞用PBS緩衝液洗滌三次後,以100 μl/孔將二抗Alexa Fluor 488標記山羊抗人IgG(Jackson ImmunoResearch Inc,目錄號:109-545-088)按1:200用PBS稀釋後添加到細胞,並在室溫下孵育30min。將細胞用PBS緩衝液洗滌三次,細胞核染料Hoechst(Sigma公司,目錄號:B2261)用PBS緩衝液按稀釋比1:500稀釋後以100 μl/孔加入各孔中染色10min,PBS洗滌3次後通過高內涵篩選儀(High content Screening System,生產廠家:PerkinElmer,型號規格:Operetta)進行分析,結果見表5和6。這些數據表明,基於細胞的結合分析,抗CD47抗體結合CD47。
表5:抗CD47嵌合抗體與CD47基於細胞的結合EC50
注:NA表示未達檢測限。
抗體名稱 | EC50(ng/mL) |
Xi2B2 | 30790 |
Xi2H8 | NA |
Xi3F10 | 19803 |
Xi16E5 | 2026 |
Xi14A9 | 540.7 |
表6:抗CD47人源化抗體與CD47基於細胞的結合EC50
注:NA表示未達檢測限。
抗體名稱 | EC50(ng/mL) | 抗體名稱 | EC50(ng/mL) |
hz3F10-1.1 | 875.7 | hz3F10-6.2 | 1486 |
hz3F10-2.1 | 1068 | hz16E5-1.1 | 3866 |
hz3F10-3.1 | 1121 | hz16E5-3.1 | 5883 |
hz3F10-4.1 | 1162 | hz16E5-1.2 | NA |
hz3F10-5.1 | 1480 | hz16E5-3.2 | NA |
hz3F10-6.1 | 1184 | hz16E5-1.3 | 18845 |
hz3F10-1.2 | 1267 | Hz16E5-3.3 | 40479 |
hz3F10-2.2 | 1119 | hz14A9-2.3 | 498.6 |
hz3F10-3.2 | 1195 | hz14A9-2.4 | 470.7 |
hz3F10-4.2 | 1265 | Hu5F9 | 1076 |
hz3F10-5.2 | 1260 |
實施例5:抗CD47嵌合抗體基於細胞的抗體阻斷分析
基於流式細胞術的檢測,對抗CD47嵌合抗體對CD47與SIRPα結合的阻斷作用進行評價。
在96孔U型板中加入Jurkat細胞(中國科學院細胞庫,目錄號:TCHU123),每孔5×105
個細胞,每孔加100 μl濃度為1 μg/mL的CD47配體Human-SIRPα-mFC(Human SIRP alpha / CD172a Protein, Mouse IgG1 Fc Tag,ACRObiosystems公司,目錄號:SIA-H52A8)的PBS緩衝液稀釋液,室溫孵育1h。PBS緩衝液洗滌2次後,每孔加入100 μl抗CD47嵌合抗體(表7),起始濃度設置為20 μg/ml,以PBS緩衝液進行4倍稀釋,8個梯度,室溫孵育1-2h,PBS緩衝液洗滌3次後,以Alexa Fluor 488標記的山羊抗小鼠IgG(Alexa Fluor 488-Goat anti mouse IgG,Jackson ImmunoResearch Inc.,目錄號:115-545-062)作為檢測二抗,每孔加100 μl用PBS緩衝液以稀釋比1:200稀釋的檢測二抗,室溫1h,PBS緩衝液洗滌3次,通過流式細胞儀(BD公司,型號規格:C6)檢測抗CD47嵌合抗體對CD47與SIRPα結合的阻斷作用。結果見表7,抗CD47嵌合抗體能夠阻斷CD47與SIRPα結合,其中Xi3F10、Xi16E5、Xi14A9具有更好的阻斷效果。
表7:抗CD47嵌合抗體基於細胞的抗體阻斷分析
注:NA表示未達檢測限。
抗體名稱 | Xi2B2 | Xi2H8 | Xi3F10 | Xi16E5 | Xi14A9 |
IC50(ng/mL) | NA | 26966 | 358.5 | 4861 | 1283 |
實施例6:抗CD47抗體基於ELISA的抗體阻斷分析
基於ELISA的檢測,對抗CD47抗體對CD47與SIRPα結合的阻斷作用進行評價。
在酶標板96孔板(Costar,目錄號:9018)中,以CD47-His(Human CD47 Protein, His Tag;ACRObiosystems公司,目錄號:CD7-H5227)為捕獲抗原,每孔加入2 μg/mL的具有所述捕獲抗原的包被緩衝液PBS 100 μl,2-8℃過夜,抽吸孔以移除所述包被緩衝液,用100 μL/孔的封閉液(具有1%(w/v)牛血清蛋白(BSA,Sigma公司,目錄號:B2064-100G)的PBS)在37℃下孵育封閉1h。用洗滌緩衝液(具有0.01%(w/v)吐溫20(Sigma,目錄號:P9416-100ML)的PBS)洗滌96孔板。然後加入100 μl/孔的1 μg/ml CD47配體Human-SIRPα-mFC(Human SIRP alpha / CD172a Protein, Mouse IgG1 Fc Tag,ACRObiosystems公司,目錄號:SIA-H52A8),25±2℃溫育1.5h,PBS洗滌緩衝液洗滌96孔板後加入:抗CD47嵌合抗體或抗CD47人源化抗體(嵌合抗體見表8,人源化抗體見表9),起始濃度20 μg/mL,100 μL/孔,用PBS緩衝液4倍稀釋,8個梯度,室溫孵育1.5h。PBS緩衝液洗滌後加入100 μl/孔用PBS緩衝液按1:2000稀釋的HRP標記的山羊抗小鼠IgG(HRP Goatanti mouse IgG,BD公司,目錄號:554002),25±2℃溫育1h,PBS緩衝液洗滌96孔板後再加入100 μl/孔的底物溶液TMB(TIANGEN公司,目錄號:PA107-01)室溫溫育顯色10min,添加100 μl/孔的1M H2
SO4
終止反應。產生比色信號並且使用多功能酶標儀(生產廠家:PerkinElmer;型號規格EnVision)在450nm處讀取所述比色信號。使用GraphPad Prism5分析數據,並計算EC50。結果見表8、表9,基於ELISA檢測,14A9、16E5、3F10的嵌合抗體(Xi3F10、Xi16E5、Xi14A9)以及人源化抗體具有良好的阻斷效果。
表8:抗CD47嵌合抗體基於ELISA的抗體阻斷分析
注:NA表示未達檢測限。
抗體名稱 | IC50(ng/mL) |
Xi2B2 | NA |
Xi2H8 | 4.682 |
Xi3F10 | 7910 |
Xi16E5 | 946.1 |
Xi14A9 | 444.4 |
表9:抗CD47人源化抗體基於ELISA的抗體阻斷分析
注:NA表示未達檢測限。
抗體名稱 | IC50(ng/mL) | 抗體名稱 | IC50(ng/mL) |
hz3F10-1.1 | 1534 | hz3F10-6.2 | 1839 |
hz3F10-2.1 | 1612 | hz16E5-1.1 | NA |
hz3F10-3.1 | 1678 | hz16E5-3.1 | 15246 |
hz3F10-4.1 | 1952 | hz16E5-1.2 | 2939 |
hz3F10-5.1 | 1701 | hz16E5-3.2 | 2051 |
hz3F10-6.1 | 1768 | hz16E5-1.3 | 2323 |
hz3F10-1.2 | 1689 | hz16E5-3.3 | 1998 |
hz3F10-2.2 | 1725 | hz14A9-2.3 | 703.2 |
hz3F10-3.2 | 1741 | hz14A9-2.4 | 621.1 |
hz3F10-4.2 | 1738 | Hu5F9 | 2398 |
hz3F10-5.2 | 1824 |
實施例7:抗CD47抗體基於促使巨噬細胞吞噬作用的分析
基於流式細胞術測定抗CD47抗體促使細胞表面含有SIRPα的巨噬細胞吞噬腫瘤細胞的能力。
使用單核細胞分離試劑盒(STEMCELL,目錄號:19058)從人的外周血單個核細胞(PBMC,賽笠生物,目錄號:190056)中分離出單核細胞,鋪入24孔板(Greiner bio-one,目錄號:662-160)中,每孔5×105
個細胞,並在100 ng/mL刺激因子M-CSF(R&D Systems公司,目錄號:216-MC-010)的環境誘導7天,從而誘導成巨噬細胞。將1×106
個靶細胞HL60(上海細胞所,目錄號:TCHu23)懸浮於5 μmol /L CFSE(BD公司,目錄號:565082)熒光染料(熒光染料用PBS緩衝液稀釋到所需濃度)中,37℃水浴鍋避光孵育15 min,PBS緩衝液洗滌細胞,製備成CFSE標記的HL60細胞;將CFSE標記的HL60細胞分別與10 μg/mL、1 μg/mL抗CD47抗體(嵌合的抗體見表10,人源化的抗體見表11)於37℃、5% CO2
培養箱中孵育1-2 h。PBS緩衝液洗滌三次孵育後的HL60細胞,加入到巨噬細胞中,37℃、5% CO2
培養箱中作用2-4 h,PBS緩衝液洗滌三次後,每孔加入260 μl PBS、20μl抗APC-CD14(APC Mouse Anti-Human CD14,BD公司,目錄號:555399)和20 μl PE-CD11b(PE Mouse Anti-Human CD11b/Mac-1,BD公司,目錄號:555388)抗體的混合液,4℃避光孵育30 min,PBS緩衝液洗滌三次,胰酶(Gibco,目錄號:12604-013)消化下來用流式細胞儀(BD公司,型號規格:C6)檢測巨噬細胞的吞噬率(%)。
抗CD47嵌合抗體和抗CD47人源化抗體對巨噬細胞吞噬作用的影響參見表10和表11,其中嵌合抗體Xi3F10、Xi16E5、Xi14A9以及抗CD47人源化抗體具有良好的促吞噬作用,人源化抗體hz14A9-2.3、hz14A9-2.4表現更優異。
表10:抗CD47嵌合抗體基於促使巨噬細胞吞噬作用的分析(吞噬率,%)
抗體名稱 | 10 μg/mL | 1 μg/mL |
Xi2B2 | 4.1 | 7.3 |
Xi2H8 | 3.5 | 7.1 |
Xi3F10 | 59.8 | 65.7 |
Xi16E5 | 28.8 | 11.5 |
Xi14A9 | 44.67 | 54.17 |
表11:抗CD47人源化抗體基於促使巨噬細胞吞噬作用的分析(吞噬率,%)
抗體名稱 | 10 μg/mL | 1 μg/mL | 抗體名稱 | 10 μg/mL | 1 μg/mL |
hz3F10-1.1 | 43.10 | 41.25 | hz3F10-6.2 | 44.19 | 49.32 |
hz3F10-2.1 | 55.23 | 47.24 | hz16E5-1.1 | 4.02 | 14.79 |
hz3F10-3.1 | 58.72 | 50.60 | hz16E5-3.1 | 24.19 | 6.37 |
hz3F10-4.1 | 58.26 | 50.26 | hz16E5-1.2 | 17.83 | 5.1 |
hz3F10-5.1 | 58.46 | 50.45 | hz16E5-3.2 | 2.03 | 3.02 |
hz3F10-6.1 | 60.91 | 47.57 | hz16E5-1.3 | 4.33 | 3.03 |
hz3F10-1.2 | 38.86 | 55.52 | hz16E5-3.3 | 4.7 | 11.62 |
hz3F10-2.2 | 34.72 | 44.19 | hz14A9-2.3 | 74.93 | 71.48 |
hz3F10-3.2 | 37.09 | 47.04 | hz14A9-2.4 | 81.66 | 81.65 |
hz3F10-4.2 | 31.67 | 46.24 | Hu5F9 | 72.35 | 67.5 |
hz3F10-5.2 | 29.6 | 47.06 |
實施例8:抗CD47抗體對CD4+T細胞的影響
基於流式細胞術的測定方法,測定抗CD47抗體對CD4+T細胞的影響。
使用T細胞分離試劑盒(Miltenyi Biotech,目錄號:130-094-131)從人的外周血單個核細胞(PBMC,賽笠生物,目錄號:190056)中分離出CD4+T細胞,鋪入24孔板(Greiner bio-one,目錄號:662106),每孔5×105
個細胞,同時分別加入抗CD47抗體(嵌合的抗體見表12,人源化的抗體見表13)使終濃度分別為10 μg/mL和1 μg/mL,加入1640完全培養基,37℃、5% CO2
培養箱中培養20 h,使用凋亡試劑盒(STEMCELL,目錄號:556547)室溫染色15min,流式儀(BD,型號規格:C6)檢測細胞凋亡率(%),以早期凋亡和晚期凋亡總和計算凋亡率。結果表明抗CD47抗體(嵌合的抗體見表12和人源化的抗體見表13)對T細胞凋亡沒有明顯影響。
表12:抗CD47嵌合抗體對CD4+T細胞的影響(凋亡率%)
抗體名稱 | 10 μg/mL | 1 μg/mL |
Xi2B2 | 10.3 | 12.1 |
Xi2H8 | 10.5 | 12.1 |
Xi3F10 | 13.6 | 12.6 |
Xi16E5 | 23.1 | 0.4 |
Xi14A9 | 1.34 | 1.42 |
表13:抗CD47人源化抗體對CD4+T細胞的影響(凋亡率%)
抗體名稱 | 10 μg/mL | 1 μg/mL | 抗體名稱 | 10 μg/mL | 1 μg/mL |
hz3F10-1.1 | 1.94 | 1.82 | hz3F10-6.2 | 1.68 | 2.18 |
hz3F10-2.1 | 1.7 | 1.38 | hz16E5-1.1 | 1.88 | 1.62 |
hz3F10-3.1 | 1.88 | 2 | hz16E5-3.1 | 2.04 | 1.8 |
hz3F10-4.1 | 1.86 | 1.94 | hz16E5-1.2 | 1.66 | 1.08 |
hz3F10-5.1 | 1.74 | 1.94 | hz16E5-3.2 | 1.8 | 1.52 |
hz3F10-6.1 | 2.12 | 1.34 | hz16E5-1.3 | 1.28 | 1.38 |
hz3F10-1.2 | 1.74 | 1.7 | hz16E5-3.3 | 1.54 | 1.54 |
hz3F10-2.2 | 1.82 | 1.94 | hz14A9-2.3 | 1.56 | 1.59 |
hz3F10-3.2 | 1.84 | 1.66 | hz14A9-2.4 | 1.89 | 1.38 |
hz3F10-4.2 | 1.84 | 1.78 | Hu5F9 | 1.35 | 1.58 |
hz3F10-5.2 | 1.94 | 1.78 | IgG4 | 1.72 | 1.81 |
實施例9:基於nano DSF檢測抗CD47抗體的熱穩定性
高通量蛋白穩定性分析儀Prometheus NT.48是得到蛋白分子結構穩定性、聚集穩定性、膠體分散穩定性等多種類型數據的設備。利用該設備檢測抗CD47嵌合抗體以及抗CD47人源化抗體的熔解溫度(Tm)和聚合溫度(Tagg),結果見表14和表15,表明抗CD47抗體具有良好的熱穩定性。
表14:抗CD47嵌合抗體熱穩定性
抗體名稱 | Tm(℃) | Tagg(℃) |
Xi2B2 | 62.99 | 61.34 |
Xi2H8 | 69.77 | 68.57 |
Xi3F10 | 70.51 | 70.59 |
Xi16E5 | 69.89 | 73.39 |
Xi14A9 | 66.73 | 75.75 |
表15:抗CD47人源化抗體熱穩定性
抗體名稱 | Tm(℃) | Tagg(℃) | 抗體名稱 | Tm(℃) | Tagg(℃) |
hz3F10-1.1 | 68.44 | 72.68 | hz14A9-2.4 | 68.3 | 68.3 |
hz3F10-2.1 | 68.44 | 72.68 | hz3F10-4.2 | 68.48 | 61.13 |
hz3F10-3.1 | 68.15 | 61.53 | hz3F10-5.2 | 68.69 | 62.67 |
hz3F10-4.1 | 68.35 | 62.54 | hz3F10-6.2 | 68.64 | 61.91 |
hz3F10-5.1 | 68.05 | 62.12 | hz16E5-1.1 | 68.21 | 61.87 |
hz3F10-6.1 | 68.6 | 68.6 | hz16E5-3.1 | 69.20 | 61.84 |
hz3F10-1.2 | 68.71 | 61.92 | hz16E5-1.2 | 69.54 | 61.90 |
hz3F10-2.2 | 68.92 | 62.40 | hz16E5-3.2 | 69.10 | 61.44 |
hz3F10-3.2 | 68.30 | 61.80 | hz16E5-1.3 | 68.90 | 73.77 |
hz14A9-2.3 | 68.10 | 73.42 | hz16E5-3.3 | 68.72 | 73.81 |
實施例10:抗CD47抗體對紅血球凝集的影響
某些公開的研究表明,紅血球表面含有一定量的CD47蛋白,這導致在加入某些抗CD47抗體後會與紅血球結合,從而可能引起紅血球的凝集現象。因此,測試抗CD47抗體對紅血球凝集的影響。
取抗凝血,加等量生理鹽水,混勻,2000 rpm/min離心5min,去上清。使用無鈣離子、鎂離子Hank’s平衡鹽溶液(Thermo Fisher Scientific,目錄號:14175-095)將紅血球洗滌3次,前2次2000 rpm/min離心5min,末次2000 rpm/min離心10min,去上清。使用PBS緩衝液將紅血球稀釋10倍,製成10%的紅血球懸液,100 μl/孔放入96孔U型板(eppendorf,目錄號:003073119)中。加入100 μl/孔不同濃度的抗CD47抗體,所述抗體的起始濃度設置為10 μg/ml,以PBS緩衝液3倍稀釋,8個濃度梯度,於37℃中孵育2~6小時。觀察拍照,紅血球全部凝集,沉於底部,平鋪成網狀,即為凝集;不凝集者紅血球沉於孔底呈點狀。
抗CD47嵌合抗體對紅血球凝集的影響見圖1。抗CD47人源化抗體對紅血球凝集的影響見圖2、圖3,嵌合抗體Xi3F10、Xi16E5以及Hu5F9均有凝血現象,其中Xi3F10從1111.1 ng/ml開始凝血,Xi16E5和Hu5F9從123.46 ng/ml開始凝血,嵌合抗體Xi2B2、Xi2H8、Xi14A9在測試的所有濃度下均無凝血現象。人源化抗體hz3F10-3.1、hz3F10-4.1、hz3F10-3.2、hz3F10-4.2從3.3μg/ml開始發生凝血現象,hz16E5-1.1、hz16E5-3.1、hz16E5-1.2、hz16E5-3.2、hz16E5-1.3、hz16E5-3.3從3.3μg/ml開始發生凝血現象,其它人源化抗體在測試的所有濃度下均無凝血現象。
實施例11:抗CD47抗體與紅血球的結合分析
基於紅血球表面一定量的CD47,可能會與某些抗CD47抗體結合,因此檢測抗CD47抗體與紅血球的結合情况。
取抗凝血,加等量生理鹽水,混勻,2000 rpm/min離心5min,去上清。使用無鈣離子、鎂離子Hank’s平衡鹽溶液(Thermo Fisher Scientific,目錄號:14175-095)將紅血球洗滌3次,前2次2000 rpm/min離心5min,末次2000 rpm/min離心10min,去上清。將分離後紅血球用4%多聚甲醛(生工生物工程上海公司,目錄號:E672002-0500)固定過夜,次日與10 μg/ml或1 μg/ml抗CD47抗體室溫孵育1-2h,PBS緩衝液清洗後,用PBS緩衝液按1:200稀釋的二抗Alexa Fluor 488標記山羊抗人IgG(Jackson ImmunoResearch Inc,目錄號:109-545-088)室溫孵育1h,PBS緩衝液清洗後用流式細胞儀(BD公司,型號規格:C6)檢測,以平均熒光强度(MFI)反映紅血球與抗CD47嵌合抗體(見表16)或人源化抗體(見表17)的結合情况。
表16:抗CD47嵌合抗體與紅血球的結合分析(MFI)
抗體名稱 | 10 μg/mL | 1 μg/mL |
Xi2B2 | 608 | 656 |
Xi2H8 | 5303 | 952 |
Xi3F10 | 61821 | 36114 |
Xi16E5 | 3318 | 1309 |
Xi14A9 | 32831 | 26477 |
表17:抗CD47人源化抗體與紅血球的結合分析(MFI)
抗體名稱 | 10 μg/mL | 1 μg/mL | 抗體名稱 | 10 μg/mL | 1 μg/mL |
hz3F10-1.1 | 50,463 | 4,449 | hz3F10-6.2 | 55,886 | 3,435 |
hz3F10-2.1 | 53,218 | 8,454 | hz16E5-1.1 | 6,461 | 945 |
hz3F10-3.1 | 41,362 | 6,703 | hz16E5-3.1 | 5,145 | 945 |
hz3F10-4.1 | 41,900 | 5,976 | hz16E5-1.2 | 4,729 | 913 |
hz3F10-5.1 | 50,634 | 7,403 | hz16E5-3.2 | 4,204 | 860 |
hz3F10-6.1 | 53,048 | 7,583 | hz16E5-1.3 | 4,885 | 894 |
hz3F10-1.2 | 56,720 | 6,247 | hz16E5-3.3 | 3,874 | 848 |
hz3F10-2.2 | 56,086 | 5,612 | hz14A9-2.3 | 10,979 | 2,506 |
hz3F10-3.2 | 45,305 | 5,096 | hz14A9-2.4 | 14,954 | 5,237 |
hz3F10-4.2 | 45,616 | 4,814 | IgG4 | 484 | 449 |
hz3F10-5.2 | 53,329 | 5,134 |
實施例12:抗CD47抗體在淋巴瘤Raji細胞小鼠血液瘤模型中的藥效活性
使用血液瘤Raji細胞建立小鼠血液瘤模型,並在該模型上應用抗CD47抗體,評價該抗體的藥效活性。
PBS緩衝液配製的Raji細胞懸液濃度5×106
個/mL,0.1mL/每隻小鼠通過尾靜脈注射到雌性NOD/SCID小鼠中。7天後隨機分成4組,每組10隻,其中,組1:IgG4組,組2:Hu5F9組,組3:hz3F10-6.1,組4:hz14A9-2.3,腹腔注射給藥,給藥劑量為10 mg/kg,連續給藥21天。觀察動物生存期。
如圖4,在Raji血液瘤模型中,抗CD47抗體hz14A9-2.3和hz3F10-6.1具有抗腫瘤活性。小鼠的生存率數據顯示:IgG4組第17天全組動物死亡,中位生存期為13.5天;Hu5F9組第30天全組動物死亡,中位生存期為18.5天;hz14A9-2.3組第34天全組動物死亡,中位生存期為28.5天;hz3F10-6.1組第21天全組動物死亡,中位生存期為17.5天。這些數據表明抗體hz14A9-2.3在延長動物生存期方面的藥效優於其他組別,抗體hz3F10-6.1 和Hu5F9的效果基本持平。
實施例13:抗CD47抗體單次給藥的毒性檢測
由於CD47在紅血球上表達並在清除老化紅血球方面發揮作用,因此對抗CD47抗體在B-hCD47小鼠中的毒性作用進行比較。
將B-hCD47小鼠隨機分成3組:Hu5F9組3隻,hz14A9-2.3組4隻、hz3F10-6.1組3隻。通過單次尾靜脈注射給予B-hCD47小鼠一定劑量的Hu5F9抗體、hz14A9-2.3抗體或hz3F10-6.1抗體,給藥劑量為10mg/kg,檢測給藥後2天、4天、7天、10天、14天紅血球計數(RBC)、血紅蛋白(HGB)量、體重的變化。
表18:給藥後小鼠體重變化率(vs 給藥前)
給藥後天數 | Hu5F9 10mpk | hz14A9-2.3 10mpk | hz3F10-6.1 10mpk |
0 | 0.0% | 0.0% | 0.0% |
2 | -7.0% | 2.3% | -13.0% |
4 | -3.2% | 6.3% | -15.8% |
7 | -5.1% | 2.0% | -2.5% |
10 | 4.8% | 5.9% | -8.4% |
14 | 5.6% | 8.6% | 8.2% |
表19:給藥後小鼠RBC變化率(vs 給藥前)
給藥後天數 | Hu5F9 10mpk | hz14A9-2.3 10mpk | hz3F10-6.1 10mpk |
0 | 0.0% | 0.0% | 0.0% |
2 | -52.8% | -13.6% | -56.7% |
4 | -61.8% | -16.7% | -75.6% |
7 | -22.2% | -9.8% | -38.7% |
10 | -21.6% | -8.5% | -6.6% |
14 | -7.4% | -2.2% | -2.0% |
表20:給藥後小鼠HGB變化率(vs 給藥前)
給藥後天數 | Hu5F9 10mpk | hz14A9-2.3 10mpk | hz3F10-6.1 10mpk |
0 | 0.0% | 0.0% | 0.0% |
2 | -52.7% | -13.3% | -57.1% |
4 | -57.8% | -18.5% | -74.7% |
7 | -16.5% | -9.9% | -39.2% |
10 | -12.8% | -10.0% | -6.0% |
14 | -1.2% | -3.9% | -3.0% |
如表18、圖5和圖6所示,只有hz14A9-2.3組小鼠體重是持續增加的,Hu5F9和hz3F10-6.1兩組小鼠在給藥後體重先下降,後上升;hz3F10-6.1組下降幅度高於Hu5F9組。如表19-表20、圖7-圖10所示,給藥後三組動物的RBC和HGB均出現下降,給藥後4天達最低,隨後開始上升。hz14A9-2.3組給藥後7天RBC和HGB基本恢復正常,另外兩組至少於給藥後10天基本恢復正常。給藥後4天RBC和HGB的下降幅度,由高到低依次為:hz3F10-6.1>Hu5F9>hz14A9-2.3。可知,抗體hz14A9-2.3沒有顯著的毒性,優於陽性抗體Hu5F9。
實施例14
使用人急性髓系白血病細胞MOLM-16細胞小鼠模型檢測抗體的抗腫瘤活性。每隻NOD-SCID小鼠皮下接種MOLM-16細胞,待腫瘤長到80-150 mm3
後,將動物隨機分成5組:①模型組(陰性對照組,給予5 mg/kg人IgG4),n=10隻;②hz14A9-2.3 0.5 mg/kg組,n=6隻;③hz14A9-2.3 1.5 mg/kg組,n=6隻;④hz14A9-2.3 5 mg/kg組,n=6隻;⑤Hu5F9 5 mg/kg組,n=6隻。在第0天(D0)小鼠分組,靜脈注射給藥,每3天給藥1次,共給藥2次,每周二次測量腫瘤直徑,根據腫瘤體積判斷療效。
腫瘤體積(V)計算公式為:V=(a×b2
)/2,其中a、b分別表示長、寬。
T/C(%)=(T-T0
)/(C-C0
)*100,其中T、C分別為治療組、陰性對照組實驗結束時的平均腫瘤體積;T0
、C0
分別為治療組、陰性對照組實驗開始時的平均腫瘤體積。
抑瘤率(TGI)(%)=100%-T/C(%)。
結果見表21和表11。抗體hz14A9-2.3在1.5mg/kg劑量下可以有效抑制腫瘤生長,第17天(D17)的腫瘤生長抑制率(或抑瘤率)達到93%。5mg/kg劑量下,抗體hz14A9-2.3的腫瘤生長抑制率達到125%。
表21
。
分組 | 給藥 | 途徑 | 平均腫瘤體積(mm3 ) D0 | 標準誤(SEM) D0 | 平均腫瘤體積(mm3 ) D17 | 標準誤(SEM) D17 | T/C(%) D17 | 腫瘤生長抑制率(%) D17 | P值D17 | 部分消退 | 實驗開始每組動物數(隻) | 實驗結束每組動物數(隻) |
hIgG4 5mg/kg | D0,3 | IV | 107.8 | ±1.1 | 3732.0 | ±272.8 | - | - | - | 0 | 10 | 10 |
hz14A9-2.3 0.5mg/kg | D0,3 | IV | 111.2 | ±2.5 | 4298.1 | ±291.1 | 116 | -16 | 0.200 | 0 | 6 | 6 |
hz14A9-2.3 1.5mg/kg | D0,3 | IV | 110.6 | ±1.8 | 377.5 | ±244.7 | 7 | 93 | 0.000 | 3 | 6 | 6 |
hz14A9-2.3 5mg/kg | D0,3 | IV | 111.8 | ±2.0 | 84.2 | ±2.8 | -25 | 125 | 0.000 | 6 | 6 | 6 |
Hu5F9 5mg/kg | D0,3 | IV | 110.8 | ±1.3 | 91.4 | ±2.4 | -18 | 118 | 0.000 | 6 | 6 | 6 |
無。
序列表
<110> 大陸商正大天晴藥業集團股份有限公司(CHIA TAI TIANQING PHARMACEUTICAL GROUP CO., LTD.)
<120> 結合CD47的抗原結合多肽及用途
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<170> SIPOSequenceListing 1.0
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<213> 小鼠(Mus musculus)
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Gly Phe Ser Leu Thr Asn Tyr Gly Val His
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<210> 2
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<212> PRT
<213> 小鼠(Mus musculus)
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Gly Phe Thr Phe Ser Asn Tyr Tyr Met Ser
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<213> 小鼠(Mus musculus)
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Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn
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Gly Tyr Thr Phe Ser Arg Tyr Trp Ile Glu
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<213> 小鼠(Mus musculus)
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Gly Phe Asn Ile Glu Asp Asp Tyr Ile Glu
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<213> 小鼠(Mus musculus)
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Ile Ile Trp Ala Gly Gly Ser Thr Asn
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<213> 小鼠(Mus musculus)
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Tyr Ile Ser Ser Gly Gly Gly Ser Thr Tyr
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<213> 小鼠(Mus musculus)
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Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr
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<213> 小鼠(Mus musculus)
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Glu Phe Ile Pro Gly Ser Asp Thr
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<213> 小鼠(Mus musculus)
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Arg Ile Asp Pro Ala Asn Asp Lys Thr Lys
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<213> 小鼠(Mus musculus)
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Asp Asp Tyr Ala Ser Met Asp Tyr
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<212> PRT
<213> 小鼠(Mus musculus)
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Phe Ala Tyr
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Phe Ser His Leu Arg Gly Pro Met Asp Tyr
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<213> 小鼠(Mus musculus)
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Gly Gly Leu Arg Arg Met Asp Tyr
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Pro Gly Leu Arg Arg Tyr Tyr Ser Met Asp Tyr
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<213> 小鼠(Mus musculus)
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Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His
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<213> 小鼠(Mus musculus)
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Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu Asn
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<213> 小鼠(Mus musculus)
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Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Tyr Thr Tyr Leu His
1 5 10 15
<210> 19
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<213> 小鼠(Mus musculus)
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Arg Ala Ser Ser Ser Val Ser Ser Thr Tyr Leu His
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<213> 小鼠(Mus musculus)
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Lys Ala Ser Glu Asn Val Val Ser Tyr Val Ser
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<210> 21
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<213> 小鼠(Mus musculus)
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Lys Val Ser Asn Arg Phe Ser
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<213> 小鼠(Mus musculus)
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Leu Val Ser Lys Leu Asp Ser
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<213> 小鼠(Mus musculus)
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Lys Val Ser Asn Arg Phe Ser
1 5
<210> 24
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<213> 小鼠(Mus musculus)
<400> 24
Thr Thr Ser Thr Leu Ala Ser
1 5
<210> 25
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<213> 小鼠(Mus musculus)
<400> 25
Gly Ala Ser Asn Arg Tyr Thr
1 5
<210> 26
<211> 9
<212> PRT
<213> 小鼠(Mus musculus)
<400> 26
Ser Gln Ser Thr His Val Pro Tyr Thr
1 5
<210> 27
<211> 7
<212> PRT
<213> 小鼠(Mus musculus)
<400> 27
Gly Thr His Phe Pro Leu Thr
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<210> 28
<211> 9
<212> PRT
<213> 小鼠(Mus musculus)
<400> 28
Ser Gln Ser Thr His Val Pro Pro Thr
1 5
<210> 29
<211> 9
<212> PRT
<213> 小鼠(Mus musculus)
<400> 29
Gln Gln Phe Ser Asp Ser Thr Trp Thr
1 5
<210> 30
<211> 9
<212> PRT
<213> 小鼠(Mus musculus)
<400> 30
Gly Gln Ser Tyr Ser Tyr Pro Leu Thr
1 5
<210> 31
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 31
Gln Gln Phe Ser Glu Ser Thr Trp Thr
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<210> 32
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<222> (5)
<223> Xaa is D or E
<400> 32
Gln Gln Phe Ser Xaa Ser Thr Trp Thr
1 5
<210> 33
<211> 116
<212> PRT
<213> 小鼠(Mus musculus)
<400> 33
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Ile Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Asp Asp Tyr Ala Ser Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
100 105 110
Thr Val Ser Ser
115
<210> 34
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 34
Asp Ala Phe Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Tyr Thr Leu Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 35
<211> 119
<212> PRT
<213> 小鼠(Mus musculus)
<400> 35
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Val Pro Gly Lys Gly Leu Lys Trp Met
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Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Glu Glu Phe
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Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Arg Thr Ala Phe
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Thr Arg Phe Ser His Leu Arg Gly Pro Met Asp Tyr Trp Gly Gln Gly
100 105 110
Ala Ser Val Thr Val Ser Ser
115
<210> 36
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 36
Asp Ala Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
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Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Tyr Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
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Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
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Ser Arg Leu Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 37
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 37
Glu Val Met Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
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Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
100 105 110
<210> 38
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 38
Asp Ala Val Val Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 39
<211> 117
<212> PRT
<213> 小鼠(Mus musculus)
<400> 39
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Met Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Tyr Cys Lys Ala Thr Gly Tyr Thr Phe Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Phe Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Phe Thr Ala Glu Ile Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 40
<211> 108
<212> PRT
<213> 小鼠(Mus musculus)
<400> 40
Asp Ile Val Met Thr Gln Thr Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Ser Gly Ala Ser Pro Lys Leu Trp
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu
65 70 75 80
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Asp Ser Thr
85 90 95
Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 41
<211> 120
<212> PRT
<213> 小鼠(Mus musculus)
<400> 41
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Val Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Val Ser Gly Phe Asn Ile Glu Asp Asp
20 25 30
Tyr Ile Glu Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Asn Asp Lys Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Asp Lys Ala Thr Ile Thr Gly Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
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Thr Arg Pro Gly Leu Arg Arg Tyr Tyr Ser Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 42
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 42
Asn Ile Val Leu Thr Gln Ser Pro Lys Ser Met Ser Met Ser Val Gly
1 5 10 15
Glu Arg Val Thr Leu Ser Cys Lys Ala Ser Glu Asn Val Val Ser Tyr
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Glu Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Ile Gly
50 55 60
Ser Gly Ser Ser Thr Asp Phe Thr Leu Ile Ile Ser Ser Phe Gln Pro
65 70 75 80
Glu Asp Leu Ala Asp Tyr His Cys Gly Gln Ser Tyr Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 43
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 43
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
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Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Ile 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 44
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<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 Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Asp Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 45
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 45
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Ile 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 46
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 46
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Glu Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 47
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 47
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Ile 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 48
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<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 Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Asp Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 49
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 49
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Ile 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 50
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<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 Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Glu Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 51
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 51
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Ile 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 52
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<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 Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Asp Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 53
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 53
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Ile 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 54
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<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 Arg Ala Ser Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Glu Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 55
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 55
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Glu Ile Ser Thr Asn 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 56
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<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 Arg Ala Ser Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Asp Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 57
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 57
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Glu Ile Ser Thr Asn 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 58
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<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 Arg Ala Ser Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Glu Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 59
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 59
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Glu Ile Ser Thr Asn 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 60
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 60
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Asp Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 61
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 61
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Glu Ile Ser Thr Asn 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 62
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<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 Arg Ala Ser Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Glu Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 63
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 63
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Glu Ile Ser Thr Asn 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 64
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<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 Arg Ala Ser Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Asp Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 65
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 65
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Glu Ile Ser Thr Asn 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 66
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<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 Arg Ala Ser Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Glu Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 67
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 67
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 Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Leu Asp Thr Ser Thr Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Phe Ser His Leu Arg Gly Pro Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 68
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<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 Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Tyr Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 69
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 69
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 Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Gln Glu Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Leu Asp Thr Ser Thr Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Phe Ser His Leu Arg Gly Pro Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 70
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 70
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 Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Tyr Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 71
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 71
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 Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Gln Glu Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Leu Asp Thr Ser Thr Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Phe Ser His Leu Arg Gly Pro Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 72
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 72
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 Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Tyr Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 73
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 73
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 Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Gln Glu Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Leu Asp Thr Ser Thr Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Phe Ser His Leu Arg Gly Pro Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 74
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 74
Asp Ala 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 Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Tyr Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 75
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 75
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 Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Leu Asp Thr Ser Thr Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Phe Ser His Leu Arg Gly Pro Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 76
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 76
Asp Ala 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 Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Tyr Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 77
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 77
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 Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Gln Glu Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Leu Asp Thr Ser Thr Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Phe Ser His Leu Arg Gly Pro Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 78
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 78
Asp Ala 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 Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Tyr Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 79
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 79
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 Val Ser Gly Phe Asn Ile Glu Asp Asp
20 25 30
Tyr Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asn Asp Lys Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Asn Thr Val 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 Arg Pro Gly Leu Arg Arg Tyr Tyr Ser Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 80
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 80
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 Glu Asn Val Val Ser Tyr
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ile Gly
50 55 60
Ser Gly Ser Ser Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gln Ser Tyr Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 81
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 81
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 Val Ser Gly Phe Asn Ile Glu Asp Asp
20 25 30
Tyr Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asn Asp Lys Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Asn Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Pro Gly Leu Arg Arg Tyr Tyr Ser Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 82
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 82
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 Glu Asn Val Val Ser Tyr
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ile Gly
50 55 60
Ser Gly Ser Ser Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gln Ser Tyr Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 83
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<222> (73)
<223> Xaa is D or E
<220>
<221> UNSURE
<222> (74)
<223> Xaa is I or E
<220>
<221> UNSURE
<222> (77)
<223> Xaa is S or N
<400> 83
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Xaa Xaa Ser Thr Xaa 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 84
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<222> (48)
<223> Xaa is L or W
<220>
<221> UNSURE
<222> (71)
<223> Xaa is D or S
<220>
<221> UNSURE
<222> (72)
<223> Xaa is F or Y
<220>
<221> UNSURE
<222> (94)
<223> Xaa is D or E
<400> 84
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 Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Xaa
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Xaa Xaa Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Xaa Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 85
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<222> (46)
<223> Xaa is E or K
<220>
<221> UNSURE
<222> (63)
<223> Xaa is E or K
<220>
<221> UNSURE
<222> (72)
<223> Xaa is L or T
<220>
<221> UNSURE
<222> (77)
<223> Xaa is R or S
<220>
<221> UNSURE
<222> (97)
<223> Xaa is A or T
<400> 85
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 Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Xaa Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Gln Xaa Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Xaa Asp Thr Ser Thr Xaa Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Xaa Arg Phe Ser His Leu Arg Gly Pro Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 86
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<222> (2)
<223> Xaa is I or A
<400> 86
Asp Xaa 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 Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Tyr Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 87
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<222> (24)
<223> Xaa is A or V
<220>
<221> UNSURE
<222> (72)
<223> Xaa is R or G
<220>
<221> UNSURE
<222> (77)
<223> Xaa is S or N
<220>
<221> UNSURE
<222> (97)
<223> Xaa is A or T
<400> 87
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 Xaa Ser Gly Phe Asn Ile Glu Asp Asp
20 25 30
Tyr Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asn Asp Lys Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Xaa Asp Thr Ser Thr Xaa Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Xaa Arg Pro Gly Leu Arg Arg Tyr Tyr Ser Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 88
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<222> (63)
<223> Xaa is S or I
<220>
<221> UNSURE
<222> (68)
<223> Xaa is S or G
<400> 88
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 Glu Asn Val Val Ser Tyr
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Xaa Gly
50 55 60
Ser Gly Ser Xaa Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gln Ser Tyr Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 89
<211> 443
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 89
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Ile Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Asp Asp Tyr Ala Ser Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 90
<211> 1332
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 90
caggtgcagc tgaaggagtc tggaccagga ctggtggctc catctcagtc cctgagcatc 60
acctgcacag tgtccggctt cagcctgacc aactacggag tgcactgggt gaggcagcca 120
cctggcaagg gactggagtg gctgggcatc atctgggctg gcggctccac aaactataat 180
tctgccctga tgtcccggct gtctatctcc aaggacaaca gcaagtctca ggtgtttctg 240
aagatgaata gcctgcagac cgacgataca gccatgtact attgtgctag ggacgattac 300
gccagcatgg attattgggg ccagggcacc tctgtgacag tgtccagcgc ctctacaaag 360
ggcccttccg tgttcccact ggctccctgc tccagaagca catctgagtc caccgccgct 420
ctgggctgtc tggtgaagga ctacttccct gagccagtga ccgtgtcctg gaacagcggc 480
gccctgacat ctggcgtgca cacctttcca gctgtgctgc agtccagcgg cctgtactcc 540
ctgtcttccg tggtgacagt gcccagctct tccctgggca ccaagacata tacctgcaac 600
gtggaccata agccttccaa taccaaggtg gataagaggg tggagagcaa gtacggacca 660
ccttgcccac catgtccagc tcctgagttt ctgggaggac catccgtgtt cctgtttcct 720
ccaaagccta aggacaccct gatgatcagc cggacacctg aggtgacctg cgtggtggtg 780
gacgtgtctc aggaggatcc agaggtgcag ttcaactggt acgtggatgg cgtggaggtg 840
cacaatgcta agaccaagcc aagagaggag cagtttaatt ccacataccg cgtggtgagc 900
gtgctgaccg tgctgcatca ggattggctg aacggcaagg agtataagtg caaggtgtcc 960
aataagggcc tgcccagctc tatcgagaag acaatcagca aggctaaggg acagcctagg 1020
gagccacagg tgtacaccct gcccccttct caggaggaga tgacaaagaa ccaggtgtcc 1080
ctgacctgtc tggtgaaggg cttctatcca agcgacatcg ctgtggagtg ggagtctaat 1140
ggccagcccg agaacaatta caagaccaca ccacccgtgc tggactctga tggctccttc 1200
tttctgtatt ctaggctgac agtggataag tcccggtggc aggagggcaa cgtgtttagc 1260
tgctctgtga tgcacgaggc cctgcacaat cattataccc agaagtccct gagcctgtct 1320
ctgggcaagt ga 1332
<210> 91
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 91
Asp Ala Phe Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Tyr Thr Leu Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 92
<211> 660
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 92
gacgccttca tgacccagac accactgtcc ctgcctgtga gcctgggcga tcaggcttct 60
atctcctgca gatccagcca gtctctggtg cactccaacg gcaatacata cctgcattgg 120
tatctgcaga agccaggcca gtcccccaag ctgctgatct acaaggtgag caacaggttc 180
tctggcgtgc ctgaccggtt tagcggctct ggctccggca ccgatttcac actgaagatc 240
tccagggtgg aggctgagga cctgggcgtg tacttttgta gccagtctac ccacgtgcca 300
tatacactgg gcggcggcac caagctggag atcaagcgta cggtggccgc tcccagcgtg 360
ttcatctttc ccccttctga cgagcagctg aagtctggca ccgcttccgt ggtgtgcctg 420
ctgaacaatt tctaccccag agaggccaag gtgcagtgga aggtggataa cgctctgcag 480
tccggcaata gccaggagtc tgtgaccgag caggactcca aggatagcac atattctctg 540
tcttccaccc tgacactgtc taaggccgac tacgagaagc acaaggtgta tgcttgcgag 600
gtgacccatc agggcctgag ctctcctgtg acaaagtcct ttaatcgcgg cgagtgttga 660
<210> 93
<211> 446
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 93
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Val Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Glu Glu Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Arg Thr Ala Phe
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Thr Arg Phe Ser His Leu Arg Gly Pro Met Asp Tyr Trp Gly Gln Gly
100 105 110
Ala Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 94
<211> 1341
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 94
gaggtgcagc tgcagcagtc tggccccgag ctgaagaagc ctggcgagac cgtgaagatc 60
tcttgcaagg cctccggcta caccttcaca aactatggca tgaattgggt gaagcaggtg 120
ccaggcaagg gcctgaagtg gatgggctgg atcaacacca atacaggcga gcccacatac 180
gccgaggagt tcaagggcag attcgctttt agcctggaga cctctgcccg cacagctttt 240
ctgcagatca acaatctgaa gaacgaggac accgccacat acttctgtac caggttttcc 300
cacctgcggg gccccatgga ttattggggc cagggcgcta gcgtgacagt gtccagcgcc 360
tctacaaagg gcccttccgt gttcccactg gctccctgct ccagaagcac atctgagtcc 420
accgccgctc tgggctgtct ggtgaaggac tacttccctg agccagtgac cgtgtcctgg 480
aacagcggcg ccctgacatc tggcgtgcac acctttccag ctgtgctgca gtccagcggc 540
ctgtactccc tgtcttccgt ggtgacagtg cccagctctt ccctgggcac caagacatat 600
acctgcaacg tggaccataa gccttccaat accaaggtgg ataagagggt ggagagcaag 660
tacggaccac cttgcccacc atgtccagct cctgagtttc tgggaggacc atccgtgttc 720
ctgtttcctc caaagcctaa ggacaccctg atgatcagcc ggacacctga ggtgacctgc 780
gtggtggtgg acgtgtctca ggaggatcca gaggtgcagt tcaactggta cgtggatggc 840
gtggaggtgc acaatgctaa gaccaagcca agagaggagc agtttaattc cacataccgc 900
gtggtgagcg tgctgaccgt gctgcatcag gattggctga acggcaagga gtataagtgc 960
aaggtgtcca ataagggcct gcccagctct atcgagaaga caatcagcaa ggctaaggga 1020
cagcctaggg agccacaggt gtacaccctg cccccttctc aggaggagat gacaaagaac 1080
caggtgtccc tgacctgtct ggtgaagggc ttctatccaa gcgacatcgc tgtggagtgg 1140
gagtctaatg gccagcccga gaacaattac aagaccacac cacccgtgct ggactctgat 1200
ggctccttct ttctgtattc taggctgaca gtggataagt cccggtggca ggagggcaac 1260
gtgtttagct gctctgtgat gcacgaggcc ctgcacaatc attataccca gaagtccctg 1320
agcctgtctc tgggcaagtg a 1341
<210> 95
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 95
Asp Ala Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Tyr Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Leu Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 96
<211> 660
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 96
gacgccgtga tgacccagac accactgtcc ctgcccgtga gcctgggcga tcaggcttct 60
atctcctgca gatccagcca gtctctggtg cactccaacg gctacacata tctgcattgg 120
tacctgcaga agcctggcca gtccccaaag ctgctgatct ataaggtgag caataggttc 180
tctggagtgc cagaccggtt tagcggatct ggatccggca ccgatttcac actgaagatc 240
tccaggctgg aggctgagga cctgggcgtg tacttctgta gccagtctac ccacgtgccc 300
cctacatttg gcggcggcac caagctggag atcaagcgta cggtggccgc tcccagcgtg 360
ttcatctttc ccccttctga cgagcagctg aagtctggca ccgcttccgt ggtgtgcctg 420
ctgaacaatt tctaccccag agaggccaag gtgcagtgga aggtggataa cgctctgcag 480
tccggcaata gccaggagtc tgtgaccgag caggactcca aggatagcac atattctctg 540
tcttccaccc tgacactgtc taaggccgac tacgagaagc acaaggtgta tgcttgcgag 600
gtgacccatc agggcctgag ctctcctgtg acaaagtcct ttaatcgcgg cgagtgttga 660
<210> 97
<211> 439
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 97
Glu Val Met Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
100 105 110
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
115 120 125
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
130 135 140
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
145 150 155 160
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
165 170 175
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
180 185 190
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
195 200 205
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
210 215 220
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
225 230 235 240
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
245 250 255
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
260 265 270
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
275 280 285
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
290 295 300
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
305 310 315 320
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
325 330 335
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
340 345 350
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
355 360 365
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
370 375 380
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
385 390 395 400
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
405 410 415
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
420 425 430
Leu Ser Leu Ser Leu Gly Lys
435
<210> 98
<211> 1320
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 98
gaagtgatgc tggtggagag cggaggagga ctggtgcagc caggaggcag cctgaagctg 60
tcttgcgccg cttccggctt cacctttagc aactactata tgtcttgggt gagacagaca 120
cccgagaagc gcctggagtg ggtggcttac atctccagcg gaggaggatc cacctactat 180
cctgacagcg tgaagggcag gttcaccatc tctcgggata acgccaagaa tacactgtac 240
ctgcagatgt cttccctgaa gtccgaggac acagctatgt actattgtgc ctggtttgct 300
tattggggcc agggcaccct ggtgacagtg tctgctgcct ctacaaaggg cccttccgtg 360
ttcccactgg ctccctgctc cagaagcaca tctgagtcca ccgccgctct gggctgtctg 420
gtgaaggact acttccctga gccagtgacc gtgtcctgga acagcggcgc cctgacatct 480
ggcgtgcaca cctttccagc tgtgctgcag tccagcggcc tgtactccct gtcttccgtg 540
gtgacagtgc ccagctcttc cctgggcacc aagacatata cctgcaacgt ggaccataag 600
ccttccaata ccaaggtgga taagagggtg gagagcaagt acggaccacc ttgcccacca 660
tgtccagctc ctgagtttct gggaggacca tccgtgttcc tgtttcctcc aaagcctaag 720
gacaccctga tgatcagccg gacacctgag gtgacctgcg tggtggtgga cgtgtctcag 780
gaggatccag aggtgcagtt caactggtac gtggatggcg tggaggtgca caatgctaag 840
accaagccaa gagaggagca gtttaattcc acataccgcg tggtgagcgt gctgaccgtg 900
ctgcatcagg attggctgaa cggcaaggag tataagtgca aggtgtccaa taagggcctg 960
cccagctcta tcgagaagac aatcagcaag gctaagggac agcctaggga gccacaggtg 1020
tacaccctgc ccccttctca ggaggagatg acaaagaacc aggtgtccct gacctgtctg 1080
gtgaagggct tctatccaag cgacatcgct gtggagtggg agtctaatgg ccagcccgag 1140
aacaattaca agaccacacc acccgtgctg gactctgatg gctccttctt tctgtattct 1200
aggctgacag tggataagtc ccggtggcag gagggcaacg tgtttagctg ctctgtgatg 1260
cacgaggccc tgcacaatca ttatacccag aagtccctga gcctgtctct gggcaagtga 1320
<210> 99
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 99
Asp Ala Val Val Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 100
<211> 660
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 100
gacgccgtgg tgacccagac accactgacc ctgtccgtga caatcggcca gcccgcttct 60
atctcctgca agtccagcca gtccctgctg gacagcgatg gcaagacata cctgaactgg 120
ctgctgcaga ggccaggaca gagccctaag cggctgatct atctggtgtc taagctggac 180
tccggcgtgc ctgatagatt caccggcagc ggctctggca ccgactttac actgaagatc 240
tctcgcgtgg aggccgagga tctgggcgtg tactattgtt ggcagggcac ccacttccca 300
ctgacatttg gcgctggcac caagctggag ctgaagcgta cggtggccgc tcccagcgtg 360
ttcatctttc ccccttctga cgagcagctg aagtctggca ccgcttccgt ggtgtgcctg 420
ctgaacaatt tctaccccag agaggccaag gtgcagtgga aggtggataa cgctctgcag 480
tccggcaata gccaggagtc tgtgaccgag caggactcca aggatagcac atattctctg 540
tcttccaccc tgacactgtc taaggccgac tacgagaagc acaaggtgta tgcttgcgag 600
gtgacccatc agggcctgag ctctcctgtg acaaagtcct ttaatcgcgg cgagtgttga 660
<210> 101
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 101
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Met Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Tyr Cys Lys Ala Thr Gly Tyr Thr Phe Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Phe Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Phe Thr Ala Glu Ile Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 102
<211> 1335
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 102
gaggtgcagc tgcagcagtc tgtggccgag ctgatgaagc caggcgcttc cgtgaagatc 60
tactgcaagg ccaccggcta cacattcagc agatattgga tcgagtgggt gaagcagagg 120
ccaggacacg gactggagtg gatcggcgag ttcatccctg gctctgacac cacaaacttc 180
aatgagaagt ttaagggcaa ggccaccttt acagctgaga tctccagcaa caccgcttat 240
atgcagctgt cttccctgac atccgaggac agcgccgtgt acttttgtgc taggggcggc 300
ctgaggcgga tggattattg gggccagggc acctccgtga cagtgagctc tgcctctaca 360
aagggccctt ccgtgttccc actggctccc tgctccagaa gcacatctga gtccaccgcc 420
gctctgggct gtctggtgaa ggactacttc cctgagccag tgaccgtgtc ctggaacagc 480
ggcgccctga catctggcgt gcacaccttt ccagctgtgc tgcagtccag cggcctgtac 540
tccctgtctt ccgtggtgac agtgcccagc tcttccctgg gcaccaagac atatacctgc 600
aacgtggacc ataagccttc caataccaag gtggataaga gggtggagag caagtacgga 660
ccaccttgcc caccatgtcc agctcctgag tttctgggag gaccatccgt gttcctgttt 720
cctccaaagc ctaaggacac cctgatgatc agccggacac ctgaggtgac ctgcgtggtg 780
gtggacgtgt ctcaggagga tccagaggtg cagttcaact ggtacgtgga tggcgtggag 840
gtgcacaatg ctaagaccaa gccaagagag gagcagttta attccacata ccgcgtggtg 900
agcgtgctga ccgtgctgca tcaggattgg ctgaacggca aggagtataa gtgcaaggtg 960
tccaataagg gcctgcccag ctctatcgag aagacaatca gcaaggctaa gggacagcct 1020
agggagccac aggtgtacac cctgccccct tctcaggagg agatgacaaa gaaccaggtg 1080
tccctgacct gtctggtgaa gggcttctat ccaagcgaca tcgctgtgga gtgggagtct 1140
aatggccagc ccgagaacaa ttacaagacc acaccacccg tgctggactc tgatggctcc 1200
ttctttctgt attctaggct gacagtggat aagtcccggt ggcaggaggg caacgtgttt 1260
agctgctctg tgatgcacga ggccctgcac aatcattata cccagaagtc cctgagcctg 1320
tctctgggca agtga 1335
<210> 103
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 103
Asp Ile Val Met Thr Gln Thr Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Ser Gly Ala Ser Pro Lys Leu Trp
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu
65 70 75 80
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Asp Ser Thr
85 90 95
Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 104
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 104
gacatcgtga tgacccagac acccgccatc atgtccgcct ctcctggcga gaaggtgacc 60
atgacatgca gggcctccag ctccgtgtcc agcacctacc tgcactggta tcagcagaag 120
agcggcgctt ctccaaagct gtggatctac accacatcca cactggctag cggagtgcca 180
gctcggttct ccggaagcgg atctggcacc tcctatagcc tgacaatctc ttccgtggag 240
gccgaggacg ccgctaccta ctattgtcag cagttctctg attccacctg gacatttggc 300
ggcggcacaa agctggagat caagcgtacg gtggccgctc ccagcgtgtt catctttccc 360
ccttctgacg agcagctgaa gtctggcacc gcttccgtgg tgtgcctgct gaacaatttc 420
taccccagag aggccaaggt gcagtggaag gtggataacg ctctgcagtc cggcaatagc 480
caggagtctg tgaccgagca ggactccaag gatagcacat attctctgtc ttccaccctg 540
acactgtcta aggccgacta cgagaagcac aaggtgtatg cttgcgaggt gacccatcag 600
ggcctgagct ctcctgtgac aaagtccttt aatcgcggcg agtgttga 648
<210> 105
<211> 447
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 105
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Val Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Val Ser Gly Phe Asn Ile Glu Asp Asp
20 25 30
Tyr Ile Glu Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Asn Asp Lys Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Asp Lys Ala Thr Ile Thr Gly Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Pro Gly Leu Arg Arg Tyr Tyr Ser Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 106
<211> 1344
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 106
gaggtgcagc tgcagcagtc tggagctgag gtggctaggc caggagcttc cgtgaagctg 60
agctgcaccg tgtctggctt caacatcgag gacgattaca tcgagtgggt gaagcagaga 120
ccagagcagg gactggagtg gatcggaagg atcgaccccg ccaacgataa gacaaagtac 180
gctcctaagt ttcaggacaa ggccaccatc acaggcgata cctccagcaa tacagcttat 240
ctgcagctgt cttccctgac ctccgaggac acagccgtgt actattgtac cagacccggc 300
ctgaggcggt actattccat ggattattgg ggccagggca ccagcgtgac agtgagctct 360
gcctctacaa agggcccttc cgtgttccca ctggctccct gctccagaag cacatctgag 420
tccaccgccg ctctgggctg tctggtgaag gactacttcc ctgagccagt gaccgtgtcc 480
tggaacagcg gcgccctgac atctggcgtg cacacctttc cagctgtgct gcagtccagc 540
ggcctgtact ccctgtcttc cgtggtgaca gtgcccagct cttccctggg caccaagaca 600
tatacctgca acgtggacca taagccttcc aataccaagg tggataagag ggtggagagc 660
aagtacggac caccttgccc accatgtcca gctcctgagt ttctgggagg accatccgtg 720
ttcctgtttc ctccaaagcc taaggacacc ctgatgatca gccggacacc tgaggtgacc 780
tgcgtggtgg tggacgtgtc tcaggaggat ccagaggtgc agttcaactg gtacgtggat 840
ggcgtggagg tgcacaatgc taagaccaag ccaagagagg agcagtttaa ttccacatac 900
cgcgtggtga gcgtgctgac cgtgctgcat caggattggc tgaacggcaa ggagtataag 960
tgcaaggtgt ccaataaggg cctgcccagc tctatcgaga agacaatcag caaggctaag 1020
ggacagccta gggagccaca ggtgtacacc ctgccccctt ctcaggagga gatgacaaag 1080
aaccaggtgt ccctgacctg tctggtgaag ggcttctatc caagcgacat cgctgtggag 1140
tgggagtcta atggccagcc cgagaacaat tacaagacca caccacccgt gctggactct 1200
gatggctcct tctttctgta ttctaggctg acagtggata agtcccggtg gcaggagggc 1260
aacgtgttta gctgctctgt gatgcacgag gccctgcaca atcattatac ccagaagtcc 1320
ctgagcctgt ctctgggcaa gtga 1344
<210> 107
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 107
Asn Ile Val Leu Thr Gln Ser Pro Lys Ser Met Ser Met Ser Val Gly
1 5 10 15
Glu Arg Val Thr Leu Ser Cys Lys Ala Ser Glu Asn Val Val Ser Tyr
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Glu Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Ile Gly
50 55 60
Ser Gly Ser Ser Thr Asp Phe Thr Leu Ile Ile Ser Ser Phe Gln Pro
65 70 75 80
Glu Asp Leu Ala Asp Tyr His Cys Gly Gln Ser Tyr Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 108
<211> 645
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 108
aacatcgtgc tgacccagtc ccctaagagc atgtctatgt ccgtgggcga gagggtgaca 60
ctgtcttgca aggcctccga gaacgtggtg tcctacgtga gctggtatca gcagaagccc 120
gagcagagcc ctaagctgct gatctacggc gcttctaata ggtataccgg agtgccagac 180
cggttcatcg gatccggctc cagcaccgat ttcacactga tcatctcttc ctttcagcca 240
gaggacctgg ccgattacca ctgtggccag agctactctt atcccctgac ctttggcgct 300
ggcacaaagc tggagctgaa gcgtacggtg gccgctccca gcgtgttcat ctttccccct 360
tctgacgagc agctgaagtc tggcaccgct tccgtggtgt gcctgctgaa caatttctac 420
cccagagagg ccaaggtgca gtggaaggtg gataacgctc tgcagtccgg caatagccag 480
gagtctgtga ccgagcagga ctccaaggat agcacatatt ctctgtcttc caccctgaca 540
ctgtctaagg ccgactacga gaagcacaag gtgtatgctt gcgaggtgac ccatcagggc 600
ctgagctctc ctgtgacaaa gtcctttaat cgcggcgagt gttga 645
<210> 109
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 109
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Ile 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 110
<211> 1335
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 110
caggtgcagc tggtgcagag cggagctgag gtgaagaagc caggctccag cgtgaaggtg 60
tcttgcaagg cttccggcta caccttctct agatattgga tcgagtgggt gcgccaggct 120
ccaggacagg gactggagtg gatgggcgag ttcatccctg gctccgacac cacaaactac 180
gctcagaagt ttcagggcag ggtgaccatc acagccgata tctccaccag cacagcttat 240
atggagctgt cttccctgag gagcgaggac acagccgtgt actattgtgc tagaggcggc 300
ctgaggcgga tggattactg gggccagggc accctggtga cagtgagctc tgcctctaca 360
aagggccctt ccgtgttccc actggctccc tgctccagaa gcacatctga gtccaccgcc 420
gctctgggct gtctggtgaa ggactacttc cctgagccag tgaccgtgtc ctggaacagc 480
ggcgccctga catctggcgt gcacaccttt ccagctgtgc tgcagtccag cggcctgtac 540
tccctgtctt ccgtggtgac agtgcccagc tcttccctgg gcaccaagac atatacctgc 600
aacgtggacc ataagccttc caataccaag gtggataaga gggtggagag caagtacgga 660
ccaccttgcc caccatgtcc agctcctgag tttctgggag gaccatccgt gttcctgttt 720
cctccaaagc ctaaggacac cctgatgatc agccggacac ctgaggtgac ctgcgtggtg 780
gtggacgtgt ctcaggagga tccagaggtg cagttcaact ggtacgtgga tggcgtggag 840
gtgcacaatg ctaagaccaa gccaagagag gagcagttta attccacata ccgcgtggtg 900
agcgtgctga ccgtgctgca tcaggattgg ctgaacggca aggagtataa gtgcaaggtg 960
tccaataagg gcctgcccag ctctatcgag aagacaatca gcaaggctaa gggacagcct 1020
agggagccac aggtgtacac cctgccccct tctcaggagg agatgacaaa gaaccaggtg 1080
tccctgacct gtctggtgaa gggcttctat ccaagcgaca tcgctgtgga gtgggagtct 1140
aatggccagc ccgagaacaa ttacaagacc acaccacccg tgctggactc tgatggctcc 1200
ttctttctgt attctaggct gacagtggat aagtcccggt ggcaggaggg caacgtgttt 1260
agctgctctg tgatgcacga ggccctgcac aatcattata cccagaagtc cctgagcctg 1320
tctctgggca agtga 1335
<210> 111
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 111
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 Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Asp Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 112
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 112
gacatccaga tgacacagag cccatccagc ctgtccgcca gcgtgggcga tagggtgacc 60
atcacatgcc gggcttcttc cagcgtgtct tccacctacc tgcactggta tcagcagaag 120
cccggcaagg cccctaagct gctgatctac accacaagca ccctggcttc tggcgtgcca 180
tccaggttct ctggctccgg cagcggcaca gactttaccc tgacaatcag ctctctgcag 240
cccgaggact tcgccaccta ctattgtcag cagttctctg attccacctg gacatttggc 300
cagggcacaa agctggagat caagcgtacg gtggccgctc ccagcgtgtt catctttccc 360
ccttctgacg agcagctgaa gtctggcacc gcttccgtgg tgtgcctgct gaacaatttc 420
taccccagag aggccaaggt gcagtggaag gtggataacg ctctgcagtc cggcaatagc 480
caggagtctg tgaccgagca ggactccaag gatagcacat attctctgtc ttccaccctg 540
acactgtcta aggccgacta cgagaagcac aaggtgtatg cttgcgaggt gacccatcag 600
ggcctgagct ctcctgtgac aaagtccttt aatcgcggcg agtgttga 648
<210> 113
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 113
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Ile 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 114
<211> 1335
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 114
caggtgcagc tggtgcagag cggagctgag gtgaagaagc caggctccag cgtgaaggtg 60
tcttgcaagg cttccggcta caccttctct agatattgga tcgagtgggt gcgccaggct 120
ccaggacagg gactggagtg gatgggcgag ttcatccctg gctccgacac cacaaactac 180
gctcagaagt ttcagggcag ggtgaccatc acagccgata tctccaccag cacagcttat 240
atggagctgt cttccctgag gagcgaggac acagccgtgt actattgtgc tagaggcggc 300
ctgaggcgga tggattactg gggccagggc accctggtga cagtgagctc tgcctctaca 360
aagggccctt ccgtgttccc actggctccc tgctccagaa gcacatctga gtccaccgcc 420
gctctgggct gtctggtgaa ggactacttc cctgagccag tgaccgtgtc ctggaacagc 480
ggcgccctga catctggcgt gcacaccttt ccagctgtgc tgcagtccag cggcctgtac 540
tccctgtctt ccgtggtgac agtgcccagc tcttccctgg gcaccaagac atatacctgc 600
aacgtggacc ataagccttc caataccaag gtggataaga gggtggagag caagtacgga 660
ccaccttgcc caccatgtcc agctcctgag tttctgggag gaccatccgt gttcctgttt 720
cctccaaagc ctaaggacac cctgatgatc agccggacac ctgaggtgac ctgcgtggtg 780
gtggacgtgt ctcaggagga tccagaggtg cagttcaact ggtacgtgga tggcgtggag 840
gtgcacaatg ctaagaccaa gccaagagag gagcagttta attccacata ccgcgtggtg 900
agcgtgctga ccgtgctgca tcaggattgg ctgaacggca aggagtataa gtgcaaggtg 960
tccaataagg gcctgcccag ctctatcgag aagacaatca gcaaggctaa gggacagcct 1020
agggagccac aggtgtacac cctgccccct tctcaggagg agatgacaaa gaaccaggtg 1080
tccctgacct gtctggtgaa gggcttctat ccaagcgaca tcgctgtgga gtgggagtct 1140
aatggccagc ccgagaacaa ttacaagacc acaccacccg tgctggactc tgatggctcc 1200
ttctttctgt attctaggct gacagtggat aagtcccggt ggcaggaggg caacgtgttt 1260
agctgctctg tgatgcacga ggccctgcac aatcattata cccagaagtc cctgagcctg 1320
tctctgggca agtga 1335
<210> 115
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 115
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 Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Glu Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 116
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 116
gacatccaga tgacacagag cccatccagc ctgtccgcca gcgtgggcga tagggtgacc 60
atcacatgcc gggcttcttc cagcgtgtct tccacctacc tgcactggta tcagcagaag 120
cccggcaagg cccctaagct gctgatctac accacaagca ccctggcttc tggcgtgcca 180
tccaggttct ctggctccgg cagcggcaca gactttaccc tgacaatcag ctctctgcag 240
cccgaggatt tcgccaccta ctattgtcag cagttctctg agtccacctg gacatttggc 300
cagggcacaa agctggagat caagcgtacg gtggccgctc ccagcgtgtt catctttccc 360
ccttctgacg agcagctgaa gtctggcacc gcttccgtgg tgtgcctgct gaacaatttc 420
taccccagag aggccaaggt gcagtggaag gtggataacg ctctgcagtc cggcaatagc 480
caggagtctg tgaccgagca ggactccaag gatagcacat attctctgtc ttccaccctg 540
acactgtcta aggccgacta cgagaagcac aaggtgtatg cttgcgaggt gacccatcag 600
ggcctgagct ctcctgtgac aaagtccttt aatcgcggcg agtgttga 648
<210> 117
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 117
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Ile 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 118
<211> 1335
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 118
caggtgcagc tggtgcagag cggagctgag gtgaagaagc caggctccag cgtgaaggtg 60
tcttgcaagg cttccggcta caccttctct agatattgga tcgagtgggt gcgccaggct 120
ccaggacagg gactggagtg gatgggcgag ttcatccctg gctccgacac cacaaactac 180
gctcagaagt ttcagggcag ggtgaccatc acagccgata tctccaccag cacagcttat 240
atggagctgt cttccctgag gagcgaggac acagccgtgt actattgtgc tagaggcggc 300
ctgaggcgga tggattactg gggccagggc accctggtga cagtgagctc tgcctctaca 360
aagggccctt ccgtgttccc actggctccc tgctccagaa gcacatctga gtccaccgcc 420
gctctgggct gtctggtgaa ggactacttc cctgagccag tgaccgtgtc ctggaacagc 480
ggcgccctga catctggcgt gcacaccttt ccagctgtgc tgcagtccag cggcctgtac 540
tccctgtctt ccgtggtgac agtgcccagc tcttccctgg gcaccaagac atatacctgc 600
aacgtggacc ataagccttc caataccaag gtggataaga gggtggagag caagtacgga 660
ccaccttgcc caccatgtcc agctcctgag tttctgggag gaccatccgt gttcctgttt 720
cctccaaagc ctaaggacac cctgatgatc agccggacac ctgaggtgac ctgcgtggtg 780
gtggacgtgt ctcaggagga tccagaggtg cagttcaact ggtacgtgga tggcgtggag 840
gtgcacaatg ctaagaccaa gccaagagag gagcagttta attccacata ccgcgtggtg 900
agcgtgctga ccgtgctgca tcaggattgg ctgaacggca aggagtataa gtgcaaggtg 960
tccaataagg gcctgcccag ctctatcgag aagacaatca gcaaggctaa gggacagcct 1020
agggagccac aggtgtacac cctgccccct tctcaggagg agatgacaaa gaaccaggtg 1080
tccctgacct gtctggtgaa gggcttctat ccaagcgaca tcgctgtgga gtgggagtct 1140
aatggccagc ccgagaacaa ttacaagacc acaccacccg tgctggactc tgatggctcc 1200
ttctttctgt attctaggct gacagtggat aagtcccggt ggcaggaggg caacgtgttt 1260
agctgctctg tgatgcacga ggccctgcac aatcattata cccagaagtc cctgagcctg 1320
tctctgggca agtga 1335
<210> 119
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 119
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 Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Asp Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 120
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 120
gacatccaga tgacacagag cccatccagc ctgtccgcca gcgtgggcga tagggtgacc 60
atcacatgcc gggcttcttc cagcgtgtct tccacctacc tgcactggta tcagcagaag 120
cccggcaagg cccctaagct gctgatctac accacaagca ccctggcttc tggcgtgcca 180
tccaggttct ctggctccgg cagcggcaca tcttataccc tgacaatcag ctctctgcag 240
cccgaggact ttgccaccta ctattgtcag cagttctctg attccacctg gacatttggc 300
cagggcacaa agctggagat caagcgtacg gtggccgctc ccagcgtgtt catctttccc 360
ccttctgacg agcagctgaa gtctggcacc gcttccgtgg tgtgcctgct gaacaatttc 420
taccccagag aggccaaggt gcagtggaag gtggataacg ctctgcagtc cggcaatagc 480
caggagtctg tgaccgagca ggactccaag gatagcacat attctctgtc ttccaccctg 540
acactgtcta aggccgacta cgagaagcac aaggtgtatg cttgcgaggt gacccatcag 600
ggcctgagct ctcctgtgac aaagtccttt aatcgcggcg agtgttga 648
<210> 121
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 121
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Ile 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 122
<211> 1335
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 122
caggtgcagc tggtgcagag cggagctgag gtgaagaagc caggctccag cgtgaaggtg 60
tcttgcaagg cttccggcta caccttctct agatattgga tcgagtgggt gcgccaggct 120
ccaggacagg gactggagtg gatgggcgag ttcatccctg gctccgacac cacaaactac 180
gctcagaagt ttcagggcag ggtgaccatc acagccgata tctccaccag cacagcttat 240
atggagctgt cttccctgag gagcgaggac acagccgtgt actattgtgc tagaggcggc 300
ctgaggcgga tggattactg gggccagggc accctggtga cagtgagctc tgcctctaca 360
aagggccctt ccgtgttccc actggctccc tgctccagaa gcacatctga gtccaccgcc 420
gctctgggct gtctggtgaa ggactacttc cctgagccag tgaccgtgtc ctggaacagc 480
ggcgccctga catctggcgt gcacaccttt ccagctgtgc tgcagtccag cggcctgtac 540
tccctgtctt ccgtggtgac agtgcccagc tcttccctgg gcaccaagac atatacctgc 600
aacgtggacc ataagccttc caataccaag gtggataaga gggtggagag caagtacgga 660
ccaccttgcc caccatgtcc agctcctgag tttctgggag gaccatccgt gttcctgttt 720
cctccaaagc ctaaggacac cctgatgatc agccggacac ctgaggtgac ctgcgtggtg 780
gtggacgtgt ctcaggagga tccagaggtg cagttcaact ggtacgtgga tggcgtggag 840
gtgcacaatg ctaagaccaa gccaagagag gagcagttta attccacata ccgcgtggtg 900
agcgtgctga ccgtgctgca tcaggattgg ctgaacggca aggagtataa gtgcaaggtg 960
tccaataagg gcctgcccag ctctatcgag aagacaatca gcaaggctaa gggacagcct 1020
agggagccac aggtgtacac cctgccccct tctcaggagg agatgacaaa gaaccaggtg 1080
tccctgacct gtctggtgaa gggcttctat ccaagcgaca tcgctgtgga gtgggagtct 1140
aatggccagc ccgagaacaa ttacaagacc acaccacccg tgctggactc tgatggctcc 1200
ttctttctgt attctaggct gacagtggat aagtcccggt ggcaggaggg caacgtgttt 1260
agctgctctg tgatgcacga ggccctgcac aatcattata cccagaagtc cctgagcctg 1320
tctctgggca agtga 1335
<210> 123
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 123
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 Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Glu Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 124
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 124
gacatccaga tgacacagag cccatccagc ctgtccgcca gcgtgggcga tagggtgacc 60
atcacatgcc gggcttcttc cagcgtgtct tccacctacc tgcactggta tcagcagaag 120
cccggcaagg cccctaagct gctgatctac accacaagca ccctggcttc tggcgtgcca 180
tccaggttct ctggctccgg cagcggcaca tcttataccc tgacaatcag ctctctgcag 240
cccgaggact ttgccaccta ctattgtcag cagttctctg agtccacctg gacatttggc 300
cagggcacaa agctggagat caagcgtacg gtggccgctc ccagcgtgtt catctttccc 360
ccttctgacg agcagctgaa gtctggcacc gcttccgtgg tgtgcctgct gaacaatttc 420
taccccagag aggccaaggt gcagtggaag gtggataacg ctctgcagtc cggcaatagc 480
caggagtctg tgaccgagca ggactccaag gatagcacat attctctgtc ttccaccctg 540
acactgtcta aggccgacta cgagaagcac aaggtgtatg cttgcgaggt gacccatcag 600
ggcctgagct ctcctgtgac aaagtccttt aatcgcggcg agtgttga 648
<210> 125
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 125
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Ile 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 126
<211> 1335
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 126
caggtgcagc tggtgcagag cggagctgag gtgaagaagc caggctccag cgtgaaggtg 60
tcttgcaagg cttccggcta caccttctct agatattgga tcgagtgggt gcgccaggct 120
ccaggacagg gactggagtg gatgggcgag ttcatccctg gctccgacac cacaaactac 180
gctcagaagt ttcagggcag ggtgaccatc acagccgata tctccaccag cacagcttat 240
atggagctgt cttccctgag gagcgaggac acagccgtgt actattgtgc tagaggcggc 300
ctgaggcgga tggattactg gggccagggc accctggtga cagtgagctc tgcctctaca 360
aagggccctt ccgtgttccc actggctccc tgctccagaa gcacatctga gtccaccgcc 420
gctctgggct gtctggtgaa ggactacttc cctgagccag tgaccgtgtc ctggaacagc 480
ggcgccctga catctggcgt gcacaccttt ccagctgtgc tgcagtccag cggcctgtac 540
tccctgtctt ccgtggtgac agtgcccagc tcttccctgg gcaccaagac atatacctgc 600
aacgtggacc ataagccttc caataccaag gtggataaga gggtggagag caagtacgga 660
ccaccttgcc caccatgtcc agctcctgag tttctgggag gaccatccgt gttcctgttt 720
cctccaaagc ctaaggacac cctgatgatc agccggacac ctgaggtgac ctgcgtggtg 780
gtggacgtgt ctcaggagga tccagaggtg cagttcaact ggtacgtgga tggcgtggag 840
gtgcacaatg ctaagaccaa gccaagagag gagcagttta attccacata ccgcgtggtg 900
agcgtgctga ccgtgctgca tcaggattgg ctgaacggca aggagtataa gtgcaaggtg 960
tccaataagg gcctgcccag ctctatcgag aagacaatca gcaaggctaa gggacagcct 1020
agggagccac aggtgtacac cctgccccct tctcaggagg agatgacaaa gaaccaggtg 1080
tccctgacct gtctggtgaa gggcttctat ccaagcgaca tcgctgtgga gtgggagtct 1140
aatggccagc ccgagaacaa ttacaagacc acaccacccg tgctggactc tgatggctcc 1200
ttctttctgt attctaggct gacagtggat aagtcccggt ggcaggaggg caacgtgttt 1260
agctgctctg tgatgcacga ggccctgcac aatcattata cccagaagtc cctgagcctg 1320
tctctgggca agtga 1335
<210> 127
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 127
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 Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Asp Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 128
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 128
gacatccaga tgacacagag cccatccagc ctgtccgcca gcgtgggcga tagggtgacc 60
atcacatgcc gggcttcttc cagcgtgtct tccacctacc tgcactggta tcagcagaag 120
cccggcaagg cccctaagct gtggatctac accacaagca ccctggcttc tggcgtgcca 180
tccaggttct ctggctccgg cagcggcaca tcttataccc tgacaatcag ctctctgcag 240
cccgaggact ttgccaccta ctattgtcag cagttctctg attccacctg gacatttggc 300
cagggcacaa agctggagat caagcgtacg gtggccgctc ccagcgtgtt catctttccc 360
ccttctgacg agcagctgaa gtctggcacc gcttccgtgg tgtgcctgct gaacaatttc 420
taccccagag aggccaaggt gcagtggaag gtggataacg ctctgcagtc cggcaatagc 480
caggagtctg tgaccgagca ggactccaag gatagcacat attctctgtc ttccaccctg 540
acactgtcta aggccgacta cgagaagcac aaggtgtatg cttgcgaggt gacccatcag 600
ggcctgagct ctcctgtgac aaagtccttt aatcgcggcg agtgttga 648
<210> 129
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 129
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Ile 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 130
<211> 1335
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 130
caggtgcagc tggtgcagag cggagctgag gtgaagaagc caggctccag cgtgaaggtg 60
tcttgcaagg cttccggcta caccttctct agatattgga tcgagtgggt gcgccaggct 120
ccaggacagg gactggagtg gatgggcgag ttcatccctg gctccgacac cacaaactac 180
gctcagaagt ttcagggcag ggtgaccatc acagccgata tctccaccag cacagcttat 240
atggagctgt cttccctgag gagcgaggac acagccgtgt actattgtgc tagaggcggc 300
ctgaggcgga tggattactg gggccagggc accctggtga cagtgagctc tgcctctaca 360
aagggccctt ccgtgttccc actggctccc tgctccagaa gcacatctga gtccaccgcc 420
gctctgggct gtctggtgaa ggactacttc cctgagccag tgaccgtgtc ctggaacagc 480
ggcgccctga catctggcgt gcacaccttt ccagctgtgc tgcagtccag cggcctgtac 540
tccctgtctt ccgtggtgac agtgcccagc tcttccctgg gcaccaagac atatacctgc 600
aacgtggacc ataagccttc caataccaag gtggataaga gggtggagag caagtacgga 660
ccaccttgcc caccatgtcc agctcctgag tttctgggag gaccatccgt gttcctgttt 720
cctccaaagc ctaaggacac cctgatgatc agccggacac ctgaggtgac ctgcgtggtg 780
gtggacgtgt ctcaggagga tccagaggtg cagttcaact ggtacgtgga tggcgtggag 840
gtgcacaatg ctaagaccaa gccaagagag gagcagttta attccacata ccgcgtggtg 900
agcgtgctga ccgtgctgca tcaggattgg ctgaacggca aggagtataa gtgcaaggtg 960
tccaataagg gcctgcccag ctctatcgag aagacaatca gcaaggctaa gggacagcct 1020
agggagccac aggtgtacac cctgccccct tctcaggagg agatgacaaa gaaccaggtg 1080
tccctgacct gtctggtgaa gggcttctat ccaagcgaca tcgctgtgga gtgggagtct 1140
aatggccagc ccgagaacaa ttacaagacc acaccacccg tgctggactc tgatggctcc 1200
ttctttctgt attctaggct gacagtggat aagtcccggt ggcaggaggg caacgtgttt 1260
agctgctctg tgatgcacga ggccctgcac aatcattata cccagaagtc cctgagcctg 1320
tctctgggca agtga 1335
<210> 131
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 131
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 Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Glu Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 132
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 132
gacatccaga tgacacagag cccatccagc ctgtccgcca gcgtgggcga tagggtgacc 60
atcacatgcc gggcttcttc cagcgtgtct tccacctacc tgcactggta tcagcagaag 120
cccggcaagg cccctaagct gtggatctac accacaagca ccctggcttc tggcgtgcca 180
tccaggttct ctggctccgg cagcggcaca tcttataccc tgacaatcag ctctctgcag 240
cccgaggact ttgccaccta ctattgtcag cagttctctg agtccacctg gacatttggc 300
cagggcacaa agctggagat caagcgtacg gtggccgctc ccagcgtgtt catctttccc 360
ccttctgacg agcagctgaa gtctggcacc gcttccgtgg tgtgcctgct gaacaatttc 420
taccccagag aggccaaggt gcagtggaag gtggataacg ctctgcagtc cggcaatagc 480
caggagtctg tgaccgagca ggactccaag gatagcacat attctctgtc ttccaccctg 540
acactgtcta aggccgacta cgagaagcac aaggtgtatg cttgcgaggt gacccatcag 600
ggcctgagct ctcctgtgac aaagtccttt aatcgcggcg agtgttga 648
<210> 133
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 133
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Glu Ile Ser Thr Asn 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 134
<211> 1335
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 134
caggtgcagc tggtgcagag cggagctgag gtgaagaagc caggctccag cgtgaaggtg 60
tcctgcaagg ctagcggcta caccttctct agatattgga tcgagtgggt gcgccaggct 120
ccaggacagg gactggagtg gatgggcgag ttcatccctg gctccgacac cacaaactac 180
gctcagaagt ttcagggcag ggtgaccatc acagccgaga tctctaccaa tacagcttat 240
atggagctgt cttccctgag gtccgaggac acagccgtgt actattgtgc tagaggcggc 300
ctgaggcgga tggattactg gggccagggc accctggtga cagtgagctc tgcctctaca 360
aagggccctt ccgtgttccc actggctccc tgctccagaa gcacatctga gtccaccgcc 420
gctctgggct gtctggtgaa ggactacttc cctgagccag tgaccgtgtc ctggaacagc 480
ggcgccctga catctggcgt gcacaccttt ccagctgtgc tgcagtccag cggcctgtac 540
tccctgtctt ccgtggtgac agtgcccagc tcttccctgg gcaccaagac atatacctgc 600
aacgtggacc ataagccttc caataccaag gtggataaga gggtggagag caagtacgga 660
ccaccttgcc caccatgtcc agctcctgag tttctgggag gaccatccgt gttcctgttt 720
cctccaaagc ctaaggacac cctgatgatc agccggacac ctgaggtgac ctgcgtggtg 780
gtggacgtgt ctcaggagga tccagaggtg cagttcaact ggtacgtgga tggcgtggag 840
gtgcacaatg ctaagaccaa gccaagagag gagcagttta attccacata ccgcgtggtg 900
agcgtgctga ccgtgctgca tcaggattgg ctgaacggca aggagtataa gtgcaaggtg 960
tccaataagg gcctgcccag ctctatcgag aagacaatca gcaaggctaa gggacagcct 1020
agggagccac aggtgtacac cctgccccct tctcaggagg agatgacaaa gaaccaggtg 1080
tccctgacct gtctggtgaa gggcttctat ccaagcgaca tcgctgtgga gtgggagtct 1140
aatggccagc ccgagaacaa ttacaagacc acaccacccg tgctggactc tgatggctcc 1200
ttctttctgt attctaggct gacagtggat aagtcccggt ggcaggaggg caacgtgttt 1260
agctgctctg tgatgcacga ggccctgcac aatcattata cccagaagtc cctgagcctg 1320
tctctgggca agtga 1335
<210> 135
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 135
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 Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Asp Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 136
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 136
gacatccaga tgacacagag cccatccagc ctgtccgcca gcgtgggcga tagggtgacc 60
atcacatgcc gggcttcttc cagcgtgtct tccacctacc tgcactggta tcagcagaag 120
cccggcaagg cccctaagct gctgatctac accacaagca ccctggcttc tggcgtgcca 180
tccaggttct ctggctccgg cagcggcaca gactttaccc tgacaatcag ctctctgcag 240
cccgaggact tcgccaccta ctattgtcag cagttctctg attccacctg gacatttggc 300
cagggcacaa agctggagat caagcgtacg gtggccgctc ccagcgtgtt catctttccc 360
ccttctgacg agcagctgaa gtctggcacc gcttccgtgg tgtgcctgct gaacaatttc 420
taccccagag aggccaaggt gcagtggaag gtggataacg ctctgcagtc cggcaatagc 480
caggagtctg tgaccgagca ggactccaag gatagcacat attctctgtc ttccaccctg 540
acactgtcta aggccgacta cgagaagcac aaggtgtatg cttgcgaggt gacccatcag 600
ggcctgagct ctcctgtgac aaagtccttt aatcgcggcg agtgttga 648
<210> 137
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 137
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Glu Ile Ser Thr Asn 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 138
<211> 1335
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 138
caggtgcagc tggtgcagag cggagctgag gtgaagaagc caggctccag cgtgaaggtg 60
tcctgcaagg ctagcggcta caccttctct agatattgga tcgagtgggt gcgccaggct 120
ccaggacagg gactggagtg gatgggcgag ttcatccctg gctccgacac cacaaactac 180
gctcagaagt ttcagggcag ggtgaccatc acagccgaga tctctaccaa tacagcttat 240
atggagctgt cttccctgag gtccgaggac acagccgtgt actattgtgc tagaggcggc 300
ctgaggcgga tggattactg gggccagggc accctggtga cagtgagctc tgcctctaca 360
aagggccctt ccgtgttccc actggctccc tgctccagaa gcacatctga gtccaccgcc 420
gctctgggct gtctggtgaa ggactacttc cctgagccag tgaccgtgtc ctggaacagc 480
ggcgccctga catctggcgt gcacaccttt ccagctgtgc tgcagtccag cggcctgtac 540
tccctgtctt ccgtggtgac agtgcccagc tcttccctgg gcaccaagac atatacctgc 600
aacgtggacc ataagccttc caataccaag gtggataaga gggtggagag caagtacgga 660
ccaccttgcc caccatgtcc agctcctgag tttctgggag gaccatccgt gttcctgttt 720
cctccaaagc ctaaggacac cctgatgatc agccggacac ctgaggtgac ctgcgtggtg 780
gtggacgtgt ctcaggagga tccagaggtg cagttcaact ggtacgtgga tggcgtggag 840
gtgcacaatg ctaagaccaa gccaagagag gagcagttta attccacata ccgcgtggtg 900
agcgtgctga ccgtgctgca tcaggattgg ctgaacggca aggagtataa gtgcaaggtg 960
tccaataagg gcctgcccag ctctatcgag aagacaatca gcaaggctaa gggacagcct 1020
agggagccac aggtgtacac cctgccccct tctcaggagg agatgacaaa gaaccaggtg 1080
tccctgacct gtctggtgaa gggcttctat ccaagcgaca tcgctgtgga gtgggagtct 1140
aatggccagc ccgagaacaa ttacaagacc acaccacccg tgctggactc tgatggctcc 1200
ttctttctgt attctaggct gacagtggat aagtcccggt ggcaggaggg caacgtgttt 1260
agctgctctg tgatgcacga ggccctgcac aatcattata cccagaagtc cctgagcctg 1320
tctctgggca agtga 1335
<210> 139
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 139
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 Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Glu Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 140
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 140
gacatccaga tgacacagag cccatccagc ctgtccgcca gcgtgggcga tagggtgacc 60
atcacatgcc gggcttcttc cagcgtgtct tccacctacc tgcactggta tcagcagaag 120
cccggcaagg cccctaagct gctgatctac accacaagca ccctggcttc tggcgtgcca 180
tccaggttct ctggctccgg cagcggcaca gactttaccc tgacaatcag ctctctgcag 240
cccgaggatt tcgccaccta ctattgtcag cagttctctg agtccacctg gacatttggc 300
cagggcacaa agctggagat caagcgtacg gtggccgctc ccagcgtgtt catctttccc 360
ccttctgacg agcagctgaa gtctggcacc gcttccgtgg tgtgcctgct gaacaatttc 420
taccccagag aggccaaggt gcagtggaag gtggataacg ctctgcagtc cggcaatagc 480
caggagtctg tgaccgagca ggactccaag gatagcacat attctctgtc ttccaccctg 540
acactgtcta aggccgacta cgagaagcac aaggtgtatg cttgcgaggt gacccatcag 600
ggcctgagct ctcctgtgac aaagtccttt aatcgcggcg agtgttga 648
<210> 141
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 141
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Glu Ile Ser Thr Asn 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 142
<211> 1335
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 142
caggtgcagc tggtgcagag cggagctgag gtgaagaagc caggctccag cgtgaaggtg 60
tcctgcaagg ctagcggcta caccttctct agatattgga tcgagtgggt gcgccaggct 120
ccaggacagg gactggagtg gatgggcgag ttcatccctg gctccgacac cacaaactac 180
gctcagaagt ttcagggcag ggtgaccatc acagccgaga tctctaccaa tacagcttat 240
atggagctgt cttccctgag gtccgaggac acagccgtgt actattgtgc tagaggcggc 300
ctgaggcgga tggattactg gggccagggc accctggtga cagtgagctc tgcctctaca 360
aagggccctt ccgtgttccc actggctccc tgctccagaa gcacatctga gtccaccgcc 420
gctctgggct gtctggtgaa ggactacttc cctgagccag tgaccgtgtc ctggaacagc 480
ggcgccctga catctggcgt gcacaccttt ccagctgtgc tgcagtccag cggcctgtac 540
tccctgtctt ccgtggtgac agtgcccagc tcttccctgg gcaccaagac atatacctgc 600
aacgtggacc ataagccttc caataccaag gtggataaga gggtggagag caagtacgga 660
ccaccttgcc caccatgtcc agctcctgag tttctgggag gaccatccgt gttcctgttt 720
cctccaaagc ctaaggacac cctgatgatc agccggacac ctgaggtgac ctgcgtggtg 780
gtggacgtgt ctcaggagga tccagaggtg cagttcaact ggtacgtgga tggcgtggag 840
gtgcacaatg ctaagaccaa gccaagagag gagcagttta attccacata ccgcgtggtg 900
agcgtgctga ccgtgctgca tcaggattgg ctgaacggca aggagtataa gtgcaaggtg 960
tccaataagg gcctgcccag ctctatcgag aagacaatca gcaaggctaa gggacagcct 1020
agggagccac aggtgtacac cctgccccct tctcaggagg agatgacaaa gaaccaggtg 1080
tccctgacct gtctggtgaa gggcttctat ccaagcgaca tcgctgtgga gtgggagtct 1140
aatggccagc ccgagaacaa ttacaagacc acaccacccg tgctggactc tgatggctcc 1200
ttctttctgt attctaggct gacagtggat aagtcccggt ggcaggaggg caacgtgttt 1260
agctgctctg tgatgcacga ggccctgcac aatcattata cccagaagtc cctgagcctg 1320
tctctgggca agtga 1335
<210> 143
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 143
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 Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Asp Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 144
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 144
gacatccaga tgacacagag cccatccagc ctgtccgcca gcgtgggcga tagggtgacc 60
atcacatgcc gggcttcttc cagcgtgtct tccacctacc tgcactggta tcagcagaag 120
cccggcaagg cccctaagct gctgatctac accacaagca ccctggcttc tggcgtgcca 180
tccaggttct ctggctccgg cagcggcaca tcttataccc tgacaatcag ctctctgcag 240
cccgaggact ttgccaccta ctattgtcag cagttctctg attccacctg gacatttggc 300
cagggcacaa agctggagat caagcgtacg gtggccgctc ccagcgtgtt catctttccc 360
ccttctgacg agcagctgaa gtctggcacc gcttccgtgg tgtgcctgct gaacaatttc 420
taccccagag aggccaaggt gcagtggaag gtggataacg ctctgcagtc cggcaatagc 480
caggagtctg tgaccgagca ggactccaag gatagcacat attctctgtc ttccaccctg 540
acactgtcta aggccgacta cgagaagcac aaggtgtatg cttgcgaggt gacccatcag 600
ggcctgagct ctcctgtgac aaagtccttt aatcgcggcg agtgttga 648
<210> 145
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 145
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Glu Ile Ser Thr Asn 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 146
<211> 1335
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 146
caggtgcagc tggtgcagag cggagctgag gtgaagaagc caggctccag cgtgaaggtg 60
tcctgcaagg ctagcggcta caccttctct agatattgga tcgagtgggt gcgccaggct 120
ccaggacagg gactggagtg gatgggcgag ttcatccctg gctccgacac cacaaactac 180
gctcagaagt ttcagggcag ggtgaccatc acagccgaga tctctaccaa tacagcttat 240
atggagctgt cttccctgag gtccgaggac acagccgtgt actattgtgc tagaggcggc 300
ctgaggcgga tggattactg gggccagggc accctggtga cagtgagctc tgcctctaca 360
aagggccctt ccgtgttccc actggctccc tgctccagaa gcacatctga gtccaccgcc 420
gctctgggct gtctggtgaa ggactacttc cctgagccag tgaccgtgtc ctggaacagc 480
ggcgccctga catctggcgt gcacaccttt ccagctgtgc tgcagtccag cggcctgtac 540
tccctgtctt ccgtggtgac agtgcccagc tcttccctgg gcaccaagac atatacctgc 600
aacgtggacc ataagccttc caataccaag gtggataaga gggtggagag caagtacgga 660
ccaccttgcc caccatgtcc agctcctgag tttctgggag gaccatccgt gttcctgttt 720
cctccaaagc ctaaggacac cctgatgatc agccggacac ctgaggtgac ctgcgtggtg 780
gtggacgtgt ctcaggagga tccagaggtg cagttcaact ggtacgtgga tggcgtggag 840
gtgcacaatg ctaagaccaa gccaagagag gagcagttta attccacata ccgcgtggtg 900
agcgtgctga ccgtgctgca tcaggattgg ctgaacggca aggagtataa gtgcaaggtg 960
tccaataagg gcctgcccag ctctatcgag aagacaatca gcaaggctaa gggacagcct 1020
agggagccac aggtgtacac cctgccccct tctcaggagg agatgacaaa gaaccaggtg 1080
tccctgacct gtctggtgaa gggcttctat ccaagcgaca tcgctgtgga gtgggagtct 1140
aatggccagc ccgagaacaa ttacaagacc acaccacccg tgctggactc tgatggctcc 1200
ttctttctgt attctaggct gacagtggat aagtcccggt ggcaggaggg caacgtgttt 1260
agctgctctg tgatgcacga ggccctgcac aatcattata cccagaagtc cctgagcctg 1320
tctctgggca agtga 1335
<210> 147
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 147
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 Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Glu Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 148
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 148
gacatccaga tgacacagag cccatccagc ctgtccgcca gcgtgggcga tagggtgacc 60
atcacatgcc gggcttcttc cagcgtgtct tccacctacc tgcactggta tcagcagaag 120
cccggcaagg cccctaagct gctgatctac accacaagca ccctggcttc tggcgtgcca 180
tccaggttct ctggctccgg cagcggcaca tcttataccc tgacaatcag ctctctgcag 240
cccgaggact ttgccaccta ctattgtcag cagttctctg agtccacctg gacatttggc 300
cagggcacaa agctggagat caagcgtacg gtggccgctc ccagcgtgtt catctttccc 360
ccttctgacg agcagctgaa gtctggcacc gcttccgtgg tgtgcctgct gaacaatttc 420
taccccagag aggccaaggt gcagtggaag gtggataacg ctctgcagtc cggcaatagc 480
caggagtctg tgaccgagca ggactccaag gatagcacat attctctgtc ttccaccctg 540
acactgtcta aggccgacta cgagaagcac aaggtgtatg cttgcgaggt gacccatcag 600
ggcctgagct ctcctgtgac aaagtccttt aatcgcggcg agtgttga 648
<210> 149
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 149
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Glu Ile Ser Thr Asn 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 150
<211> 1335
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 150
caggtgcagc tggtgcagag cggagctgag gtgaagaagc caggctccag cgtgaaggtg 60
tcctgcaagg ctagcggcta caccttctct agatattgga tcgagtgggt gcgccaggct 120
ccaggacagg gactggagtg gatgggcgag ttcatccctg gctccgacac cacaaactac 180
gctcagaagt ttcagggcag ggtgaccatc acagccgaga tctctaccaa tacagcttat 240
atggagctgt cttccctgag gtccgaggac acagccgtgt actattgtgc tagaggcggc 300
ctgaggcgga tggattactg gggccagggc accctggtga cagtgagctc tgcctctaca 360
aagggccctt ccgtgttccc actggctccc tgctccagaa gcacatctga gtccaccgcc 420
gctctgggct gtctggtgaa ggactacttc cctgagccag tgaccgtgtc ctggaacagc 480
ggcgccctga catctggcgt gcacaccttt ccagctgtgc tgcagtccag cggcctgtac 540
tccctgtctt ccgtggtgac agtgcccagc tcttccctgg gcaccaagac atatacctgc 600
aacgtggacc ataagccttc caataccaag gtggataaga gggtggagag caagtacgga 660
ccaccttgcc caccatgtcc agctcctgag tttctgggag gaccatccgt gttcctgttt 720
cctccaaagc ctaaggacac cctgatgatc agccggacac ctgaggtgac ctgcgtggtg 780
gtggacgtgt ctcaggagga tccagaggtg cagttcaact ggtacgtgga tggcgtggag 840
gtgcacaatg ctaagaccaa gccaagagag gagcagttta attccacata ccgcgtggtg 900
agcgtgctga ccgtgctgca tcaggattgg ctgaacggca aggagtataa gtgcaaggtg 960
tccaataagg gcctgcccag ctctatcgag aagacaatca gcaaggctaa gggacagcct 1020
agggagccac aggtgtacac cctgccccct tctcaggagg agatgacaaa gaaccaggtg 1080
tccctgacct gtctggtgaa gggcttctat ccaagcgaca tcgctgtgga gtgggagtct 1140
aatggccagc ccgagaacaa ttacaagacc acaccacccg tgctggactc tgatggctcc 1200
ttctttctgt attctaggct gacagtggat aagtcccggt ggcaggaggg caacgtgttt 1260
agctgctctg tgatgcacga ggccctgcac aatcattata cccagaagtc cctgagcctg 1320
tctctgggca agtga 1335
<210> 151
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 151
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 Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Asp Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 152
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 152
gacatccaga tgacacagag cccatccagc ctgtccgcca gcgtgggcga tagggtgacc 60
atcacatgcc gggcttcttc cagcgtgtct tccacctacc tgcactggta tcagcagaag 120
cccggcaagg cccctaagct gtggatctac accacaagca ccctggcttc tggcgtgcca 180
tccaggttct ctggctccgg cagcggcaca tcttataccc tgacaatcag ctctctgcag 240
cccgaggact ttgccaccta ctattgtcag cagttctctg attccacctg gacatttggc 300
cagggcacaa agctggagat caagcgtacg gtggccgctc ccagcgtgtt catctttccc 360
ccttctgacg agcagctgaa gtctggcacc gcttccgtgg tgtgcctgct gaacaatttc 420
taccccagag aggccaaggt gcagtggaag gtggataacg ctctgcagtc cggcaatagc 480
caggagtctg tgaccgagca ggactccaag gatagcacat attctctgtc ttccaccctg 540
acactgtcta aggccgacta cgagaagcac aaggtgtatg cttgcgaggt gacccatcag 600
ggcctgagct ctcctgtgac aaagtccttt aatcgcggcg agtgttga 648
<210> 153
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 153
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Phe Ile Pro Gly Ser Asp Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Glu Ile Ser Thr Asn 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 Arg Gly Gly Leu Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 154
<211> 1335
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 154
caggtgcagc tggtgcagag cggagctgag gtgaagaagc caggctccag cgtgaaggtg 60
tcctgcaagg ctagcggcta caccttctct agatattgga tcgagtgggt gcgccaggct 120
ccaggacagg gactggagtg gatgggcgag ttcatccctg gctccgacac cacaaactac 180
gctcagaagt ttcagggcag ggtgaccatc acagccgaga tctctaccaa tacagcttat 240
atggagctgt cttccctgag gtccgaggac acagccgtgt actattgtgc tagaggcggc 300
ctgaggcgga tggattactg gggccagggc accctggtga cagtgagctc tgcctctaca 360
aagggccctt ccgtgttccc actggctccc tgctccagaa gcacatctga gtccaccgcc 420
gctctgggct gtctggtgaa ggactacttc cctgagccag tgaccgtgtc ctggaacagc 480
ggcgccctga catctggcgt gcacaccttt ccagctgtgc tgcagtccag cggcctgtac 540
tccctgtctt ccgtggtgac agtgcccagc tcttccctgg gcaccaagac atatacctgc 600
aacgtggacc ataagccttc caataccaag gtggataaga gggtggagag caagtacgga 660
ccaccttgcc caccatgtcc agctcctgag tttctgggag gaccatccgt gttcctgttt 720
cctccaaagc ctaaggacac cctgatgatc agccggacac ctgaggtgac ctgcgtggtg 780
gtggacgtgt ctcaggagga tccagaggtg cagttcaact ggtacgtgga tggcgtggag 840
gtgcacaatg ctaagaccaa gccaagagag gagcagttta attccacata ccgcgtggtg 900
agcgtgctga ccgtgctgca tcaggattgg ctgaacggca aggagtataa gtgcaaggtg 960
tccaataagg gcctgcccag ctctatcgag aagacaatca gcaaggctaa gggacagcct 1020
agggagccac aggtgtacac cctgccccct tctcaggagg agatgacaaa gaaccaggtg 1080
tccctgacct gtctggtgaa gggcttctat ccaagcgaca tcgctgtgga gtgggagtct 1140
aatggccagc ccgagaacaa ttacaagacc acaccacccg tgctggactc tgatggctcc 1200
ttctttctgt attctaggct gacagtggat aagtcccggt ggcaggaggg caacgtgttt 1260
agctgctctg tgatgcacga ggccctgcac aatcattata cccagaagtc cctgagcctg 1320
tctctgggca agtga 1335
<210> 155
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 155
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 Ser Ser Val Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp
35 40 45
Ile Tyr Thr Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Glu Ser Thr
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 156
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 156
gacatccaga tgacacagag cccatccagc ctgtccgcca gcgtgggcga tagggtgacc 60
atcacatgcc gggcttcttc cagcgtgtct tccacctacc tgcactggta tcagcagaag 120
cccggcaagg cccctaagct gtggatctac accacaagca ccctggcttc tggcgtgcca 180
tccaggttct ctggctccgg cagcggcaca tcttataccc tgacaatcag ctctctgcag 240
cccgaggact ttgccaccta ctattgtcag cagttctctg agtccacctg gacatttggc 300
cagggcacaa agctggagat caagcgtacg gtggccgctc ccagcgtgtt catctttccc 360
ccttctgacg agcagctgaa gtctggcacc gcttccgtgg tgtgcctgct gaacaatttc 420
taccccagag aggccaaggt gcagtggaag gtggataacg ctctgcagtc cggcaatagc 480
caggagtctg tgaccgagca ggactccaag gatagcacat attctctgtc ttccaccctg 540
acactgtcta aggccgacta cgagaagcac aaggtgtatg cttgcgaggt gacccatcag 600
ggcctgagct ctcctgtgac aaagtccttt aatcgcggcg agtgttga 648
<210> 157
<211> 446
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 157
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 Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Leu Asp Thr Ser Thr Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Phe Ser His Leu Arg Gly Pro Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 158
<211> 1341
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 158
caggtgcagc tggtgcagtc cggagctgag gtgaagaagc caggagctag cgtgaaggtg 60
tcttgcaagg cctccggcta caccttcaca aactatggca tgaattgggt gaggcaggct 120
ccaggacagg gactggagtg gatgggctgg atcaacacca atacaggcga gcctacatac 180
gcccagaagc tgcagggcag ggtgaccatg acactggaca ccagcacaag aaccgcttat 240
atggagctga ggtctctgcg gtccgacgat accgccgtgt actattgtgc tagattttct 300
cacctgaggg gaccaatgga ttactgggga cagggcacac tggtgaccgt gtccagcgcc 360
tctacaaagg gcccttccgt gttcccactg gctccctgct ccagaagcac atctgagtcc 420
accgccgctc tgggctgtct ggtgaaggac tacttccctg agccagtgac cgtgtcctgg 480
aacagcggcg ccctgacatc tggcgtgcac acctttccag ctgtgctgca gtccagcggc 540
ctgtactccc tgtcttccgt ggtgacagtg cccagctctt ccctgggcac caagacatat 600
acctgcaacg tggaccataa gccttccaat accaaggtgg ataagagggt ggagagcaag 660
tacggaccac cttgcccacc atgtccagct cctgagtttc tgggaggacc atccgtgttc 720
ctgtttcctc caaagcctaa ggacaccctg atgatcagcc ggacacctga ggtgacctgc 780
gtggtggtgg acgtgtctca ggaggatcca gaggtgcagt tcaactggta cgtggatggc 840
gtggaggtgc acaatgctaa gaccaagcca agagaggagc agtttaattc cacataccgc 900
gtggtgagcg tgctgaccgt gctgcatcag gattggctga acggcaagga gtataagtgc 960
aaggtgtcca ataagggcct gcccagctct atcgagaaga caatcagcaa ggctaaggga 1020
cagcctaggg agccacaggt gtacaccctg cccccttctc aggaggagat gacaaagaac 1080
caggtgtccc tgacctgtct ggtgaagggc ttctatccaa gcgacatcgc tgtggagtgg 1140
gagtctaatg gccagcccga gaacaattac aagaccacac cacccgtgct ggactctgat 1200
ggctccttct ttctgtattc taggctgaca gtggataagt cccggtggca ggagggcaac 1260
gtgtttagct gctctgtgat gcacgaggcc ctgcacaatc attataccca gaagtccctg 1320
agcctgtctc tgggcaagtg a 1341
<210> 159
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 159
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 Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Tyr Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 160
<211> 660
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 160
gacatccaga tgacacagtc cccatccagc ctgtccgcca gcgtgggcga tagggtgacc 60
atcacatgcc ggtcttccca gagcctggtg cactctaacg gctacaccta tctgcattgg 120
taccagcaga agccaggcaa ggctcccaag ctgctgatct ataaggtgtc caatagattc 180
agcggcgtgc cttctcgctt ttctggctcc ggcagcggca cagacttcac cctgacaatc 240
agctctctgc agccagagga ttttgccacc tactattgtt ctcagtccac ccacgtgccc 300
cctacattcg gccagggcac caagctggag atcaagcgta cggtggccgc tcccagcgtg 360
ttcatctttc ccccttctga cgagcagctg aagtctggca ccgcttccgt ggtgtgcctg 420
ctgaacaatt tctaccccag agaggccaag gtgcagtgga aggtggataa cgctctgcag 480
tccggcaata gccaggagtc tgtgaccgag caggactcca aggatagcac atattctctg 540
tcttccaccc tgacactgtc taaggccgac tacgagaagc acaaggtgta tgcttgcgag 600
gtgacccatc agggcctgag ctctcctgtg acaaagtcct ttaatcgcgg cgagtgttga 660
<210> 161
<211> 446
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 161
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 Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Gln Glu Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Leu Asp Thr Ser Thr Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Phe Ser His Leu Arg Gly Pro Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 162
<211> 1341
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 162
caggtgcagc tggtgcagtc cggagctgag gtgaagaagc caggagctag cgtgaaggtg 60
tcttgcaagg cctccggcta caccttcaca aactatggca tgaattgggt gaggcaggct 120
ccaggacagg gcctgaagtg gatgggatgg atcaacacca atacaggcga gcctacatac 180
gcccaggagc tgcagggcag ggtgaccatg acactggaca ccagcacaag aaccgcctat 240
atggagctga ggtctctgcg gtccgacgat acagccgtgt actattgtac cagattttct 300
cacctgaggg gaccaatgga ttactgggga cagggcacac tggtgaccgt gtccagcgcc 360
tctacaaagg gcccttccgt gttcccactg gctccctgct ccagaagcac atctgagtcc 420
accgccgctc tgggctgtct ggtgaaggac tacttccctg agccagtgac cgtgtcctgg 480
aacagcggcg ccctgacatc tggcgtgcac acctttccag ctgtgctgca gtccagcggc 540
ctgtactccc tgtcttccgt ggtgacagtg cccagctctt ccctgggcac caagacatat 600
acctgcaacg tggaccataa gccttccaat accaaggtgg ataagagggt ggagagcaag 660
tacggaccac cttgcccacc atgtccagct cctgagtttc tgggaggacc atccgtgttc 720
ctgtttcctc caaagcctaa ggacaccctg atgatcagcc ggacacctga ggtgacctgc 780
gtggtggtgg acgtgtctca ggaggatcca gaggtgcagt tcaactggta cgtggatggc 840
gtggaggtgc acaatgctaa gaccaagcca agagaggagc agtttaattc cacataccgc 900
gtggtgagcg tgctgaccgt gctgcatcag gattggctga acggcaagga gtataagtgc 960
aaggtgtcca ataagggcct gcccagctct atcgagaaga caatcagcaa ggctaaggga 1020
cagcctaggg agccacaggt gtacaccctg cccccttctc aggaggagat gacaaagaac 1080
caggtgtccc tgacctgtct ggtgaagggc ttctatccaa gcgacatcgc tgtggagtgg 1140
gagtctaatg gccagcccga gaacaattac aagaccacac cacccgtgct ggactctgat 1200
ggctccttct ttctgtattc taggctgaca gtggataagt cccggtggca ggagggcaac 1260
gtgtttagct gctctgtgat gcacgaggcc ctgcacaatc attataccca gaagtccctg 1320
agcctgtctc tgggcaagtg a 1341
<210> 163
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 163
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 Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Tyr Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 164
<211> 660
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 164
gacatccaga tgacacagtc cccatccagc ctgtccgcca gcgtgggcga tagggtgacc 60
atcacatgcc ggtcttccca gagcctggtg cactctaacg gctacaccta tctgcattgg 120
taccagcaga agccaggcaa ggctcccaag ctgctgatct ataaggtgtc caatagattc 180
agcggcgtgc cttctcgctt ttctggctcc ggcagcggca cagacttcac cctgacaatc 240
agctctctgc agccagagga ttttgccacc tactattgtt ctcagtccac ccacgtgccc 300
cctacattcg gccagggcac caagctggag atcaagcgta cggtggccgc tcccagcgtg 360
ttcatctttc ccccttctga cgagcagctg aagtctggca ccgcttccgt ggtgtgcctg 420
ctgaacaatt tctaccccag agaggccaag gtgcagtgga aggtggataa cgctctgcag 480
tccggcaata gccaggagtc tgtgaccgag caggactcca aggatagcac atattctctg 540
tcttccaccc tgacactgtc taaggccgac tacgagaagc acaaggtgta tgcttgcgag 600
gtgacccatc agggcctgag ctctcctgtg acaaagtcct ttaatcgcgg cgagtgttga 660
<210> 165
<211> 446
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 165
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 Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Gln Glu Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Leu Asp Thr Ser Thr Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Phe Ser His Leu Arg Gly Pro Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 166
<211> 1341
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 166
caggtgcagc tggtgcagtc cggagctgag gtgaagaagc caggagctag cgtgaaggtg 60
tcttgcaagg cctccggcta caccttcaca aactatggca tgaattgggt gaggcaggct 120
ccaggacagg gcctgaagtg gatgggatgg atcaacacca atacaggcga gcctacatac 180
gcccaggagc tgcagggcag ggtgaccatg acactggaca ccagcacaag aaccgcttat 240
atggagctga ggtctctgcg gtccgacgat accgccgtgt actattgtgc tagattttct 300
cacctgaggg gaccaatgga ttactgggga cagggcacac tggtgaccgt gtccagcgcc 360
tctacaaagg gcccttccgt gttcccactg gctccctgct ccagaagcac atctgagtcc 420
accgccgctc tgggctgtct ggtgaaggac tacttccctg agccagtgac cgtgtcctgg 480
aacagcggcg ccctgacatc tggcgtgcac acctttccag ctgtgctgca gtccagcggc 540
ctgtactccc tgtcttccgt ggtgacagtg cccagctctt ccctgggcac caagacatat 600
acctgcaacg tggaccataa gccttccaat accaaggtgg ataagagggt ggagagcaag 660
tacggaccac cttgcccacc atgtccagct cctgagtttc tgggaggacc atccgtgttc 720
ctgtttcctc caaagcctaa ggacaccctg atgatcagcc ggacacctga ggtgacctgc 780
gtggtggtgg acgtgtctca ggaggatcca gaggtgcagt tcaactggta cgtggatggc 840
gtggaggtgc acaatgctaa gaccaagcca agagaggagc agtttaattc cacataccgc 900
gtggtgagcg tgctgaccgt gctgcatcag gattggctga acggcaagga gtataagtgc 960
aaggtgtcca ataagggcct gcccagctct atcgagaaga caatcagcaa ggctaaggga 1020
cagcctaggg agccacaggt gtacaccctg cccccttctc aggaggagat gacaaagaac 1080
caggtgtccc tgacctgtct ggtgaagggc ttctatccaa gcgacatcgc tgtggagtgg 1140
gagtctaatg gccagcccga gaacaattac aagaccacac cacccgtgct ggactctgat 1200
ggctccttct ttctgtattc taggctgaca gtggataagt cccggtggca ggagggcaac 1260
gtgtttagct gctctgtgat gcacgaggcc ctgcacaatc attataccca gaagtccctg 1320
agcctgtctc tgggcaagtg a 1341
<210> 167
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 167
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 Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Tyr Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 168
<211> 660
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 168
gacatccaga tgacacagtc cccatccagc ctgtccgcca gcgtgggcga tagggtgacc 60
atcacatgcc ggtcttccca gagcctggtg cactctaacg gctacaccta tctgcattgg 120
taccagcaga agccaggcaa ggctcccaag ctgctgatct ataaggtgtc caatagattc 180
agcggcgtgc cttctcgctt ttctggctcc ggcagcggca cagacttcac cctgacaatc 240
agctctctgc agccagagga ttttgccacc tactattgtt ctcagtccac ccacgtgccc 300
cctacattcg gccagggcac caagctggag atcaagcgta cggtggccgc tcccagcgtg 360
ttcatctttc ccccttctga cgagcagctg aagtctggca ccgcttccgt ggtgtgcctg 420
ctgaacaatt tctaccccag agaggccaag gtgcagtgga aggtggataa cgctctgcag 480
tccggcaata gccaggagtc tgtgaccgag caggactcca aggatagcac atattctctg 540
tcttccaccc tgacactgtc taaggccgac tacgagaagc acaaggtgta tgcttgcgag 600
gtgacccatc agggcctgag ctctcctgtg acaaagtcct ttaatcgcgg cgagtgttga 660
<210> 169
<211> 446
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 169
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 Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Gln Glu Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Leu Asp Thr Ser Thr Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Phe Ser His Leu Arg Gly Pro Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 170
<211> 1341
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 170
caggtgcagc tggtgcagtc cggagctgag gtgaagaagc caggagctag cgtgaaggtg 60
tcttgcaagg cctccggcta caccttcaca aactatggca tgaattgggt gaggcaggct 120
ccaggacagg gcctgaagtg gatgggatgg atcaacacca atacaggcga gcctacatac 180
gcccaggagc tgcagggcag ggtgaccatg acactggaca ccagcacaag aaccgcttat 240
atggagctga ggtctctgcg gtccgacgat accgccgtgt actattgtgc tagattttct 300
cacctgaggg gaccaatgga ttactgggga cagggcacac tggtgaccgt gtccagcgcc 360
tctacaaagg gcccttccgt gttcccactg gctccctgct ccagaagcac atctgagtcc 420
accgccgctc tgggctgtct ggtgaaggac tacttccctg agccagtgac cgtgtcctgg 480
aacagcggcg ccctgacatc tggcgtgcac acctttccag ctgtgctgca gtccagcggc 540
ctgtactccc tgtcttccgt ggtgacagtg cccagctctt ccctgggcac caagacatat 600
acctgcaacg tggaccataa gccttccaat accaaggtgg ataagagggt ggagagcaag 660
tacggaccac cttgcccacc atgtccagct cctgagtttc tgggaggacc atccgtgttc 720
ctgtttcctc caaagcctaa ggacaccctg atgatcagcc ggacacctga ggtgacctgc 780
gtggtggtgg acgtgtctca ggaggatcca gaggtgcagt tcaactggta cgtggatggc 840
gtggaggtgc acaatgctaa gaccaagcca agagaggagc agtttaattc cacataccgc 900
gtggtgagcg tgctgaccgt gctgcatcag gattggctga acggcaagga gtataagtgc 960
aaggtgtcca ataagggcct gcccagctct atcgagaaga caatcagcaa ggctaaggga 1020
cagcctaggg agccacaggt gtacaccctg cccccttctc aggaggagat gacaaagaac 1080
caggtgtccc tgacctgtct ggtgaagggc ttctatccaa gcgacatcgc tgtggagtgg 1140
gagtctaatg gccagcccga gaacaattac aagaccacac cacccgtgct ggactctgat 1200
ggctccttct ttctgtattc taggctgaca gtggataagt cccggtggca ggagggcaac 1260
gtgtttagct gctctgtgat gcacgaggcc ctgcacaatc attataccca gaagtccctg 1320
agcctgtctc tgggcaagtg a 1341
<210> 171
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 171
Asp Ala 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 Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Tyr Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 172
<211> 660
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 172
gacgcccaga tgacacagtc cccatccagc ctgtccgcta gcgtgggcga tagggtgacc 60
atcacatgcc ggtcttccca gagcctggtg cactctaacg gctacaccta tctgcattgg 120
taccagcaga agccaggcaa ggcccccaag ctgctgatct ataaggtgtc caatagattc 180
agcggcgtgc cttctcgctt ttctggctcc ggcagcggca cagacttcac cctgacaatc 240
agctctctgc agccagagga ttttgctacc tactattgtt ctcagtccac ccacgtgccc 300
cctacattcg gccagggcac caagctggag atcaagcgta cggtggccgc tcccagcgtg 360
ttcatctttc ccccttctga cgagcagctg aagtctggca ccgcttccgt ggtgtgcctg 420
ctgaacaatt tctaccccag agaggccaag gtgcagtgga aggtggataa cgctctgcag 480
tccggcaata gccaggagtc tgtgaccgag caggactcca aggatagcac atattctctg 540
tcttccaccc tgacactgtc taaggccgac tacgagaagc acaaggtgta tgcttgcgag 600
gtgacccatc agggcctgag ctctcctgtg acaaagtcct ttaatcgcgg cgagtgttga 660
<210> 173
<211> 446
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 173
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 Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Leu Asp Thr Ser Thr Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Phe Ser His Leu Arg Gly Pro Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 174
<211> 1341
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 174
caggtgcagc tggtgcagtc cggagctgag gtgaagaagc caggagctag cgtgaaggtg 60
tcttgcaagg cctccggcta caccttcaca aactatggca tgaattgggt gaggcaggct 120
ccaggacagg gactggagtg gatgggctgg atcaacacca atacaggcga gcctacatac 180
gcccagaagc tgcagggcag ggtgaccatg acactggaca ccagcacaag aaccgcttat 240
atggagctga ggtctctgcg gtccgacgat accgccgtgt actattgtgc tagattttct 300
cacctgaggg gaccaatgga ttactgggga cagggcacac tggtgaccgt gtccagcgcc 360
tctacaaagg gcccttccgt gttcccactg gctccctgct ccagaagcac atctgagtcc 420
accgccgctc tgggctgtct ggtgaaggac tacttccctg agccagtgac cgtgtcctgg 480
aacagcggcg ccctgacatc tggcgtgcac acctttccag ctgtgctgca gtccagcggc 540
ctgtactccc tgtcttccgt ggtgacagtg cccagctctt ccctgggcac caagacatat 600
acctgcaacg tggaccataa gccttccaat accaaggtgg ataagagggt ggagagcaag 660
tacggaccac cttgcccacc atgtccagct cctgagtttc tgggaggacc atccgtgttc 720
ctgtttcctc caaagcctaa ggacaccctg atgatcagcc ggacacctga ggtgacctgc 780
gtggtggtgg acgtgtctca ggaggatcca gaggtgcagt tcaactggta cgtggatggc 840
gtggaggtgc acaatgctaa gaccaagcca agagaggagc agtttaattc cacataccgc 900
gtggtgagcg tgctgaccgt gctgcatcag gattggctga acggcaagga gtataagtgc 960
aaggtgtcca ataagggcct gcccagctct atcgagaaga caatcagcaa ggctaaggga 1020
cagcctaggg agccacaggt gtacaccctg cccccttctc aggaggagat gacaaagaac 1080
caggtgtccc tgacctgtct ggtgaagggc ttctatccaa gcgacatcgc tgtggagtgg 1140
gagtctaatg gccagcccga gaacaattac aagaccacac cacccgtgct ggactctgat 1200
ggctccttct ttctgtattc taggctgaca gtggataagt cccggtggca ggagggcaac 1260
gtgtttagct gctctgtgat gcacgaggcc ctgcacaatc attataccca gaagtccctg 1320
agcctgtctc tgggcaagtg a 1341
<210> 175
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 175
Asp Ala 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 Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Tyr Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 176
<211> 660
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 176
gacgcccaga tgacacagtc cccatccagc ctgtccgcta gcgtgggcga tagggtgacc 60
atcacatgcc ggtcttccca gagcctggtg cactctaacg gctacaccta tctgcattgg 120
taccagcaga agccaggcaa ggcccccaag ctgctgatct ataaggtgtc caatagattc 180
agcggcgtgc cttctcgctt ttctggctcc ggcagcggca cagacttcac cctgacaatc 240
agctctctgc agccagagga ttttgctacc tactattgtt ctcagtccac ccacgtgccc 300
cctacattcg gccagggcac caagctggag atcaagcgta cggtggccgc tcccagcgtg 360
ttcatctttc ccccttctga cgagcagctg aagtctggca ccgcttccgt ggtgtgcctg 420
ctgaacaatt tctaccccag agaggccaag gtgcagtgga aggtggataa cgctctgcag 480
tccggcaata gccaggagtc tgtgaccgag caggactcca aggatagcac atattctctg 540
tcttccaccc tgacactgtc taaggccgac tacgagaagc acaaggtgta tgcttgcgag 600
gtgacccatc agggcctgag ctctcctgtg acaaagtcct ttaatcgcgg cgagtgttga 660
<210> 177
<211> 446
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 177
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 Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Gln Glu Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Leu Asp Thr Ser Thr Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Phe Ser His Leu Arg Gly Pro Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 178
<211> 1341
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 178
caggtgcagc tggtgcagtc cggagctgag gtgaagaagc caggagctag cgtgaaggtg 60
tcttgcaagg cctccggcta caccttcaca aactatggca tgaattgggt gaggcaggct 120
ccaggacagg gcctgaagtg gatgggatgg atcaacacca atacaggcga gcctacatac 180
gcccaggagc tgcagggcag ggtgaccatg acactggaca ccagcacaag aaccgcctat 240
atggagctga ggtctctgcg gtccgacgat acagccgtgt actattgtac cagattttct 300
cacctgaggg gaccaatgga ttactgggga cagggcacac tggtgaccgt gtccagcgcc 360
tctacaaagg gcccttccgt gttcccactg gctccctgct ccagaagcac atctgagtcc 420
accgccgctc tgggctgtct ggtgaaggac tacttccctg agccagtgac cgtgtcctgg 480
aacagcggcg ccctgacatc tggcgtgcac acctttccag ctgtgctgca gtccagcggc 540
ctgtactccc tgtcttccgt ggtgacagtg cccagctctt ccctgggcac caagacatat 600
acctgcaacg tggaccataa gccttccaat accaaggtgg ataagagggt ggagagcaag 660
tacggaccac cttgcccacc atgtccagct cctgagtttc tgggaggacc atccgtgttc 720
ctgtttcctc caaagcctaa ggacaccctg atgatcagcc ggacacctga ggtgacctgc 780
gtggtggtgg acgtgtctca ggaggatcca gaggtgcagt tcaactggta cgtggatggc 840
gtggaggtgc acaatgctaa gaccaagcca agagaggagc agtttaattc cacataccgc 900
gtggtgagcg tgctgaccgt gctgcatcag gattggctga acggcaagga gtataagtgc 960
aaggtgtcca ataagggcct gcccagctct atcgagaaga caatcagcaa ggctaaggga 1020
cagcctaggg agccacaggt gtacaccctg cccccttctc aggaggagat gacaaagaac 1080
caggtgtccc tgacctgtct ggtgaagggc ttctatccaa gcgacatcgc tgtggagtgg 1140
gagtctaatg gccagcccga gaacaattac aagaccacac cacccgtgct ggactctgat 1200
ggctccttct ttctgtattc taggctgaca gtggataagt cccggtggca ggagggcaac 1260
gtgtttagct gctctgtgat gcacgaggcc ctgcacaatc attataccca gaagtccctg 1320
agcctgtctc tgggcaagtg a 1341
<210> 179
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 179
Asp Ala 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 Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Tyr Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 180
<211> 660
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 180
gacgcccaga tgacacagtc cccatccagc ctgtccgcta gcgtgggcga tagggtgacc 60
atcacatgcc ggtcttccca gagcctggtg cactctaacg gctacaccta tctgcattgg 120
taccagcaga agccaggcaa ggcccccaag ctgctgatct ataaggtgtc caatagattc 180
agcggcgtgc cttctcgctt ttctggctcc ggcagcggca cagacttcac cctgacaatc 240
agctctctgc agccagagga ttttgctacc tactattgtt ctcagtccac ccacgtgccc 300
cctacattcg gccagggcac caagctggag atcaagcgta cggtggccgc tcccagcgtg 360
ttcatctttc ccccttctga cgagcagctg aagtctggca ccgcttccgt ggtgtgcctg 420
ctgaacaatt tctaccccag agaggccaag gtgcagtgga aggtggataa cgctctgcag 480
tccggcaata gccaggagtc tgtgaccgag caggactcca aggatagcac atattctctg 540
tcttccaccc tgacactgtc taaggccgac tacgagaagc acaaggtgta tgcttgcgag 600
gtgacccatc agggcctgag ctctcctgtg acaaagtcct ttaatcgcgg cgagtgttga 660
<210> 181
<211> 447
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 181
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 Val Ser Gly Phe Asn Ile Glu Asp Asp
20 25 30
Tyr Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asn Asp Lys Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Asn Thr Val 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 Arg Pro Gly Leu Arg Arg Tyr Tyr Ser Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 182
<211> 1344
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 182
caggtgcagc tggtgcagtc cggagctgag gtgaagaagc caggagctag cgtgaaggtg 60
tcttgcaagg tgtccggctt caacatcgag gacgattaca tcgagtgggt gaggcaggct 120
ccaggacagg gactggagtg gatgggaagg atcgaccctg ccaacgataa gacaaagtac 180
gctcagaagt ttcagggcag agtgaccatg acaggcgaca ccagcacaaa taccgtgtat 240
atggagctgt ccagcctgcg ctctgaggat accgccgtgt actattgtgc taggcccggc 300
ctgagacgct actattccat ggactattgg ggccagggca cactggtgac cgtgtcttcc 360
gcctctacaa agggcccttc cgtgttccca ctggctccct gctccagaag cacatctgag 420
tccaccgccg ctctgggctg tctggtgaag gactacttcc ctgagccagt gaccgtgtcc 480
tggaacagcg gcgccctgac atctggcgtg cacacctttc cagctgtgct gcagtccagc 540
ggcctgtact ccctgtcttc cgtggtgaca gtgcccagct cttccctggg caccaagaca 600
tatacctgca acgtggacca taagccttcc aataccaagg tggataagag ggtggagagc 660
aagtacggac caccttgccc accatgtcca gctcctgagt ttctgggagg accatccgtg 720
ttcctgtttc ctccaaagcc taaggacacc ctgatgatca gccggacacc tgaggtgacc 780
tgcgtggtgg tggacgtgtc tcaggaggat ccagaggtgc agttcaactg gtacgtggat 840
ggcgtggagg tgcacaatgc taagaccaag ccaagagagg agcagtttaa ttccacatac 900
cgcgtggtga gcgtgctgac cgtgctgcat caggattggc tgaacggcaa ggagtataag 960
tgcaaggtgt ccaataaggg cctgcccagc tctatcgaga agacaatcag caaggctaag 1020
ggacagccta gggagccaca ggtgtacacc ctgccccctt ctcaggagga gatgacaaag 1080
aaccaggtgt ccctgacctg tctggtgaag ggcttctatc caagcgacat cgctgtggag 1140
tgggagtcta atggccagcc cgagaacaat tacaagacca caccacccgt gctggactct 1200
gatggctcct tctttctgta ttctaggctg acagtggata agtcccggtg gcaggagggc 1260
aacgtgttta gctgctctgt gatgcacgag gccctgcaca atcattatac ccagaagtcc 1320
ctgagcctgt ctctgggcaa gtga 1344
<210> 183
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 183
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 Glu Asn Val Val Ser Tyr
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ile Gly
50 55 60
Ser Gly Ser Ser Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gln Ser Tyr Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 184
<211> 645
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 184
gacatccaga tgacccagag cccttccagc ctgtccgcca gcgtgggcga tagggtgacc 60
atcacatgca aggcttctga gaacgtggtg tcctacgtga gctggtatca gcagaagccc 120
ggcaaggccc ctaagctgct gatctacggc gcttctaata ggtataccgg agtgccatcc 180
cggttcatcg gatccggctc ttccacagac tttaccctga caatcagctc tctgcagcca 240
gaggatttcg ccacatacta ttgtggccag agctactctt atcccctgac ctttggccag 300
ggcacaaagc tggagatcaa gcgtacggtg gccgctccca gcgtgttcat ctttccccct 360
tctgacgagc agctgaagtc tggcaccgct tccgtggtgt gcctgctgaa caatttctac 420
cccagagagg ccaaggtgca gtggaaggtg gataacgctc tgcagtccgg caatagccag 480
gagtctgtga ccgagcagga ctccaaggat agcacatatt ctctgtcttc caccctgaca 540
ctgtctaagg ccgactacga gaagcacaag gtgtatgctt gcgaggtgac ccatcagggc 600
ctgagctctc ctgtgacaaa gtcctttaat cgcggcgagt gttga 645
<210> 185
<211> 447
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 185
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 Val Ser Gly Phe Asn Ile Glu Asp Asp
20 25 30
Tyr Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asn Asp Lys Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Asn Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Pro Gly Leu Arg Arg Tyr Tyr Ser Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 186
<211> 1344
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 186
caggtgcagc tggtgcagtc cggagctgag gtgaagaagc caggagctag cgtgaaggtg 60
tcttgcaagg tgtccggctt caacatcgag gacgattaca tcgagtgggt gaggcaggct 120
ccaggacagg gactggagtg gatgggaagg atcgaccctg ccaacgataa gacaaagtac 180
gctcagaagt ttcagggcag agtgaccatg acaggcgaca ccagcacaaa taccgtgtat 240
atggagctgt ccagcctgcg ctctgaggat acagccgtgt actattgtac caggcccggc 300
ctgagacgct actattccat ggactattgg ggccagggca cactggtgac cgtgtcttcc 360
gcctctacaa agggcccttc cgtgttccca ctggctccct gctccagaag cacatctgag 420
tccaccgccg ctctgggctg tctggtgaag gactacttcc ctgagccagt gaccgtgtcc 480
tggaacagcg gcgccctgac atctggcgtg cacacctttc cagctgtgct gcagtccagc 540
ggcctgtact ccctgtcttc cgtggtgaca gtgcccagct cttccctggg caccaagaca 600
tatacctgca acgtggacca taagccttcc aataccaagg tggataagag ggtggagagc 660
aagtacggac caccttgccc accatgtcca gctcctgagt ttctgggagg accatccgtg 720
ttcctgtttc ctccaaagcc taaggacacc ctgatgatca gccggacacc tgaggtgacc 780
tgcgtggtgg tggacgtgtc tcaggaggat ccagaggtgc agttcaactg gtacgtggat 840
ggcgtggagg tgcacaatgc taagaccaag ccaagagagg agcagtttaa ttccacatac 900
cgcgtggtga gcgtgctgac cgtgctgcat caggattggc tgaacggcaa ggagtataag 960
tgcaaggtgt ccaataaggg cctgcccagc tctatcgaga agacaatcag caaggctaag 1020
ggacagccta gggagccaca ggtgtacacc ctgccccctt ctcaggagga gatgacaaag 1080
aaccaggtgt ccctgacctg tctggtgaag ggcttctatc caagcgacat cgctgtggag 1140
tgggagtcta atggccagcc cgagaacaat tacaagacca caccacccgt gctggactct 1200
gatggctcct tctttctgta ttctaggctg acagtggata agtcccggtg gcaggagggc 1260
aacgtgttta gctgctctgt gatgcacgag gccctgcaca atcattatac ccagaagtcc 1320
ctgagcctgt ctctgggcaa gtga 1344
<210> 187
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 187
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 Glu Asn Val Val Ser Tyr
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ile Gly
50 55 60
Ser Gly Ser Ser Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gln Ser Tyr Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 188
<211> 645
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 188
gacatccaga tgacccagag cccttccagc ctgtccgcca gcgtgggcga tagggtgacc 60
atcacatgca aggcttctga gaacgtggtg tcctacgtga gctggtatca gcagaagccc 120
ggcaaggccc ctaagctgct gatctacggc gcttctaata ggtataccgg agtgccatcc 180
cggttcatcg gatccggctc ttccacagac tttaccctga caatcagctc tctgcagcca 240
gaggatttcg ccacatacta ttgtggccag agctactctt atcccctgac ctttggccag 300
ggcacaaagc tggagatcaa gcgtacggtg gccgctccca gcgtgttcat ctttccccct 360
tctgacgagc agctgaagtc tggcaccgct tccgtggtgt gcctgctgaa caatttctac 420
cccagagagg ccaaggtgca gtggaaggtg gataacgctc tgcagtccgg caatagccag 480
gagtctgtga ccgagcagga ctccaaggat agcacatatt ctctgtcttc caccctgaca 540
ctgtctaagg ccgactacga gaagcacaag gtgtatgctt gcgaggtgac ccatcagggc 600
ctgagctctc ctgtgacaaa gtcctttaat cgcggcgagt gttga 645
<210> 189
<211> 348
<212> DNA
<213> 小鼠(Mus musculus)
<400> 189
caggtgcagc tgaaggagtc tggaccagga ctggtggctc catctcagtc cctgagcatc 60
acctgcacag tgtccggctt cagcctgacc aactacggag tgcactgggt gaggcagcca 120
cctggcaagg gactggagtg gctgggcatc atctgggctg gcggctccac aaactataat 180
tctgccctga tgtcccggct gtctatctcc aaggacaaca gcaagtctca ggtgtttctg 240
aagatgaata gcctgcagac cgacgataca gccatgtact attgtgctag ggacgattac 300
gccagcatgg attattgggg ccagggcacc tctgtgacag tgtccagc 348
<210> 190
<211> 336
<212> DNA
<213> 小鼠(Mus musculus)
<400> 190
gacgccttca tgacccagac accactgtcc ctgcctgtga gcctgggcga tcaggcttct 60
atctcctgca gatccagcca gtctctggtg cactccaacg gcaatacata cctgcattgg 120
tatctgcaga agccaggcca gtcccccaag ctgctgatct acaaggtgag caacaggttc 180
tctggcgtgc ctgaccggtt tagcggctct ggctccggca ccgatttcac actgaagatc 240
tccagggtgg aggctgagga cctgggcgtg tacttttgta gccagtctac ccacgtgcca 300
tatacactgg gcggcggcac caagctggag atcaag 336
<210> 191
<211> 357
<212> DNA
<213> 小鼠(Mus musculus)
<400> 191
gaggtgcagc tgcagcagtc tggccccgag ctgaagaagc ctggcgagac cgtgaagatc 60
tcttgcaagg cctccggcta caccttcaca aactatggca tgaattgggt gaagcaggtg 120
ccaggcaagg gcctgaagtg gatgggctgg atcaacacca atacaggcga gcccacatac 180
gccgaggagt tcaagggcag attcgctttt agcctggaga cctctgcccg cacagctttt 240
ctgcagatca acaatctgaa gaacgaggac accgccacat acttctgtac caggttttcc 300
cacctgcggg gccccatgga ttattggggc cagggcgcta gcgtgacagt gtccagc 357
<210> 192
<211> 336
<212> DNA
<213> 小鼠(Mus musculus)
<400> 192
gacgccgtga tgacccagac accactgtcc ctgcccgtga gcctgggcga tcaggcttct 60
atctcctgca gatccagcca gtctctggtg cactccaacg gctacacata tctgcattgg 120
tacctgcaga agcctggcca gtccccaaag ctgctgatct ataaggtgag caataggttc 180
tctggagtgc cagaccggtt tagcggatct ggatccggca ccgatttcac actgaagatc 240
tccaggctgg aggctgagga cctgggcgtg tacttctgta gccagtctac ccacgtgccc 300
cctacatttg gcggcggcac caagctggag atcaag 336
<210> 193
<211> 336
<212> DNA
<213> 小鼠(Mus musculus)
<400> 193
gaagtgatgc tggtggagag cggaggagga ctggtgcagc caggaggcag cctgaagctg 60
tcttgcgccg cttccggctt cacctttagc aactactata tgtcttgggt gagacagaca 120
cccgagaagc gcctggagtg ggtggcttac atctccagcg gaggaggatc cacctactat 180
cctgacagcg tgaagggcag gttcaccatc tctcgggata acgccaagaa tacactgtac 240
ctgcagatgt cttccctgaa gtccgaggac acagctatgt actattgtgc ctggtttgct 300
tattggggcc agggcaccct ggtgacagtg tctgct 336
<210> 194
<211> 336
<212> DNA
<213> 小鼠(Mus musculus)
<400> 194
gacgccgtgg tgacccagac accactgacc ctgtccgtga caatcggcca gcccgcttct 60
atctcctgca agtccagcca gtccctgctg gacagcgatg gcaagacata cctgaactgg 120
ctgctgcaga ggccaggaca gagccctaag cggctgatct atctggtgtc taagctggac 180
tccggcgtgc ctgatagatt caccggcagc ggctctggca ccgactttac actgaagatc 240
tctcgcgtgg aggccgagga tctgggcgtg tactattgtt ggcagggcac ccacttccca 300
ctgacatttg gcgctggcac caagctggag ctgaag 336
<210> 195
<211> 351
<212> DNA
<213> 小鼠(Mus musculus)
<400> 195
gaggtgcagc tgcagcagtc tgtggccgag ctgatgaagc caggcgcttc cgtgaagatc 60
tactgcaagg ccaccggcta cacattcagc agatattgga tcgagtgggt gaagcagagg 120
ccaggacacg gactggagtg gatcggcgag ttcatccctg gctctgacac cacaaacttc 180
aatgagaagt ttaagggcaa ggccaccttt acagctgaga tctccagcaa caccgcttat 240
atgcagctgt cttccctgac atccgaggac agcgccgtgt acttttgtgc taggggcggc 300
ctgaggcgga tggattattg gggccagggc acctccgtga cagtgagctc t 351
<210> 196
<211> 324
<212> DNA
<213> 小鼠(Mus musculus)
<400> 196
gacatcgtga tgacccagac acccgccatc atgtccgcct ctcctggcga gaaggtgacc 60
atgacatgca gggcctccag ctccgtgtcc agcacctacc tgcactggta tcagcagaag 120
agcggcgctt ctccaaagct gtggatctac accacatcca cactggctag cggagtgcca 180
gctcggttct ccggaagcgg atctggcacc tcctatagcc tgacaatctc ttccgtggag 240
gccgaggacg ccgctaccta ctattgtcag cagttctctg attccacctg gacatttggc 300
ggcggcacaa agctggagat caag 324
<210> 197
<211> 360
<212> DNA
<213> 小鼠(Mus musculus)
<400> 197
gaggtgcagc tgcagcagtc tggagctgag gtggctaggc caggagcttc cgtgaagctg 60
agctgcaccg tgtctggctt caacatcgag gacgattaca tcgagtgggt gaagcagaga 120
ccagagcagg gactggagtg gatcggaagg atcgaccccg ccaacgataa gacaaagtac 180
gctcctaagt ttcaggacaa ggccaccatc acaggcgata cctccagcaa tacagcttat 240
ctgcagctgt cttccctgac ctccgaggac acagccgtgt actattgtac cagacccggc 300
ctgaggcggt actattccat ggattattgg ggccagggca ccagcgtgac agtgagctct 360
<210> 198
<211> 321
<212> DNA
<213> 小鼠(Mus musculus)
<400> 198
aacatcgtgc tgacccagtc ccctaagagc atgtctatgt ccgtgggcga gagggtgaca 60
ctgtcttgca aggcctccga gaacgtggtg tcctacgtga gctggtatca gcagaagccc 120
gagcagagcc ctaagctgct gatctacggc gcttctaata ggtataccgg agtgccagac 180
cggttcatcg gatccggctc cagcaccgat ttcacactga tcatctcttc ctttcagcca 240
gaggacctgg ccgattacca ctgtggccag agctactctt atcccctgac ctttggcgct 300
ggcacaaagc tggagctgaa g 321
圖1為抗CD47嵌合抗體對紅血球凝集的影響;其中,相同列樣品(抗體或對照)種類相同但是濃度不同,相同行樣品濃度相同但是種類不同;由左至右,不同行的樣品濃度依次分別為10000 ng/ml、3333.33 ng/ml、1111.11 ng/ml、370.37 ng/ml、123.46 ng/ml、41.15 ng/ml、13.72 ng/ml、4.57 ng/ml;由上至下,不同列的樣品依次分別為Xi2B2、Xi2H8、Xi3F10、Xi16E5、Xi14A9、Xi16E5-2(Xi16E5的另一個重複)、Hu5F9、IgG4、PBS。
圖2為部分抗CD47人源化抗體對紅血球凝集的影響;其中,相同行抗體種類相同但是濃度不同,相同列抗體濃度相同但是種類不同;由上至下,不同列的抗體濃度依次分別為10000 ng/ml、3333.33 ng/ml、1111.11 ng/ml、370.37 ng/ml、123.46 ng/ml、41.15 ng/ml、13.72 ng/ml、4.57 ng/ml;由左至右,第1-12行的抗體依次分別為hz3F10-1.1、hz3F10-2.1、hz3F10-3.1、hz3F10-4.1、hz3F10-5.1、hz3F10-6.1、hz3F10-1.2、hz3F10-2.2、hz3F10-3.2、hz3F10-4.2、hz3F10-5.2、hz3F10-6.2。
圖3為部分抗CD47人源化抗體對紅血球凝集的影響;其中,相同行抗體種類相同但是濃度不同,相同列抗體濃度相同但是種類不同;由上至下,不同列的抗體濃度依次分別為10000 ng/ml、3333.33 ng/ml、1111.11 ng/ml、370.37 ng/ml、123.46 ng/ml、41.15 ng/ml、13.72 ng/ml、4.57 ng/ml;由左至右,第1-8行的抗體依次分別為hz16E5-1.1、hz16E5-3.1、hz16E5-1.2、hz16E5-3.2、hz16E5-1.3、hz16E5-3.3、hz14A9-2.3、hz14A9-2.4。
圖4為抗CD47抗體對小鼠生存率的影響。
圖5為抗CD47抗體單次給藥後小鼠體重隨時間的變化。
圖6為抗CD47抗體單次給藥後不同時間的小鼠體重變化率。
圖7為抗CD47抗體單次給藥後小鼠RBC隨時間的變化。
圖8為抗CD47抗體單次給藥後不同時間的小鼠RBC變化率。
圖9為抗CD47抗體單次給藥後小鼠HGB含量隨時間的變化。
圖10為抗CD47抗體單次給藥後不同時間的小鼠HGB變化率。
圖11為人急性髓系白血病細胞MOLM-16細胞小鼠模型中,抗CD47抗體給藥後平均腫瘤體積隨時間的變化。
Claims (26)
- 一種結合CD47的分離的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽包含以下互補決定區:重鏈CDR1,其包含與選自SEQ ID NO:1、2、3、4或5的胺基酸序列具有至少80%同一性的胺基酸序列;重鏈CDR2,其包含與選自SEQ ID NO:6、7、8、9或10的胺基酸序列具有至少80%同一性的胺基酸序列;重鏈CDR3,其包含與選自SEQ ID NO:11、12、13、14或15的胺基酸序列具有至少80%同一性的胺基酸序列;輕鏈CDR1,其包含與選自SEQ ID NO:16、17、18、19或20的胺基酸序列具有至少80%同一性的胺基酸序列;輕鏈CDR2,其包含與選自SEQ ID NO:21、22、23、24或25的胺基酸序列具有至少80%同一性的胺基酸序列;和輕鏈CDR3,其包含與選自SEQ ID NO:26、27、28、30或32的胺基酸序列具有至少80%同一性的胺基酸序列。
- 如請求項1所述的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽包含以下互補決定區:重鏈CDR1,其包含選自SEQ ID NO:1、2、3、4或5的胺基酸序列;重鏈CDR2,其包含選自SEQ ID NO:6、7、8、9或10的胺基酸序列;重鏈CDR3,其包含選自SEQ ID NO:11、12、13、14或15的胺基酸序列;輕鏈CDR1,其包含選自SEQ ID NO:16、17、18、19或20的胺基酸序列;輕鏈CDR2,其包含選自SEQ ID NO:21、22、23、24或25的胺基酸序列;和輕鏈CDR3,其包含選自SEQ ID NO:26、27、28、30或32的胺基酸序列。
- 如請求項1或2所述的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽選自由以下各項組成的組:(a)包含重鏈CDR1、重鏈CDR2、重鏈CDR3、輕鏈CDR1、輕鏈CDR2和輕鏈CDR3,所述重鏈CDR1、所述重鏈CDR2和所述重鏈CDR3分別包含與如SEQ ID NOs:1、6和11所示的胺基酸序列具有至少80%同一性的胺基酸序列,所述輕鏈CDR1、所述輕鏈CDR2和所述輕鏈CDR3分別包含與如SEQ ID NOs:16、21和26所示的胺基酸序列具有至少80%同一性的胺基酸序列;(b) 包含重鏈CDR1、重鏈CDR2、重鏈CDR3、輕鏈CDR1、輕鏈CDR2和輕鏈CDR3,所述重鏈CDR1、所述重鏈CDR2和所述重鏈CDR3分別包含與如SEQ ID NOs:2、7和12所示的胺基酸序列具有至少80%同一性的胺基酸序列,所述輕鏈CDR1、所述輕鏈CDR2和所述輕鏈CDR3分別包含與如SEQ ID NOs:17、22和27所示的胺基酸序列具有至少80%同一性的胺基酸序列;(c) 包含重鏈CDR1、重鏈CDR2、重鏈CDR3、輕鏈CDR1、輕鏈CDR2和輕鏈CDR3,所述重鏈CDR1、所述重鏈CDR2和所述重鏈CDR3分別包含與如SEQ ID NOs:3、8和13所示的胺基酸序列具有至少80%同一性的胺基酸序列,所述輕鏈CDR1、所述輕鏈CDR2和所述輕鏈CDR3分別包含與如SEQ ID NOs:18、23和28所示的胺基酸序列具有至少80%同一性的胺基酸序列;(d) 包含重鏈CDR1、重鏈CDR2、重鏈CDR3、輕鏈CDR1、輕鏈CDR2和輕鏈CDR3,所述重鏈CDR1、所述重鏈CDR2和所述重鏈CDR3分別包含與如SEQ ID NOs:4、9和14所示的胺基酸序列具有至少80%同一性的胺基酸序列,所述輕鏈CDR1、所述輕鏈CDR2和所述輕鏈CDR3分別包含與如SEQ ID NOs:19、24和32所示的胺基酸序列具有至少80%同一性的胺基酸序列;以及(e) 包含重鏈CDR1、重鏈CDR2、重鏈CDR3、輕鏈CDR1、輕鏈CDR2和輕鏈CDR3,所述重鏈CDR1、所述重鏈CDR2和所述重鏈CDR3分別包含與如SEQ ID NOs:5、10和15所示的胺基酸序列具有至少80%同一性的胺基酸序列,所述輕鏈CDR1、所述輕鏈CDR2和所述輕鏈CDR3分別包含與如SEQ ID NOs:20、25和30所示的胺基酸序列具有至少80%同一性的胺基酸序列。
- 如請求項1-3中任一項所述的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽包含以下的互補決定區中的一種:(1)包含SEQ ID NO:1的胺基酸序列的重鏈CDR1;包含SEQ ID NO:6的胺基酸序列的重鏈CDR2;包含SEQ ID NO:11的胺基酸序列的重鏈CDR3;包含SEQ ID NO:16的胺基酸序列的輕鏈CDR1;包含SEQ ID NO:21的胺基酸序列的輕鏈CDR2;和包含SEQ ID NO:26的胺基酸序列的輕鏈CDR3;(2)包含SEQ ID NO:2的胺基酸序列的重鏈CDR1;包含SEQ ID NO:7的胺基酸序列的重鏈CDR2;包含SEQ ID NO:12的胺基酸序列的重鏈CDR3;包含SEQ ID NO:17的胺基酸序列的輕鏈CDR1;包含SEQ ID NO:22的胺基酸序列的輕鏈CDR2;和包含SEQ ID NO:27的胺基酸序列的輕鏈CDR3;(3)包含SEQ ID NO:3的胺基酸序列的重鏈CDR1;包含SEQ ID NO:8的胺基酸序列的重鏈CDR2;包含SEQ ID NO:13的胺基酸序列的重鏈CDR3;包含SEQ ID NO:18的胺基酸序列的輕鏈CDR1;包含SEQ ID NO:23的胺基酸序列的輕鏈CDR2;和包含SEQ ID NO:28的胺基酸序列的輕鏈CDR3;(4)包含SEQ ID NO:4的胺基酸序列的重鏈CDR1;包含SEQ ID NO:9的胺基酸序列的重鏈CDR2;包含SEQ ID NO:14的胺基酸序列的重鏈CDR3;包含SEQ ID NO:19的胺基酸序列的輕鏈CDR1;包含SEQ ID NO:24的胺基酸序列的輕鏈CDR2;和包含SEQ ID NO:32的胺基酸序列的輕鏈CDR3;或者(5)包含SEQ ID NO:5的胺基酸序列的重鏈CDR1;包含SEQ ID NO:10的胺基酸序列的重鏈CDR2;包含SEQ ID NO:15的胺基酸序列的重鏈CDR3;包含SEQ ID NO:20的胺基酸序列的輕鏈CDR1;包含SEQ ID NO:25的胺基酸序列的輕鏈CDR2;和包含SEQ ID NO:30的胺基酸序列的輕鏈CDR3。
- 如請求項1所述的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽包含重鏈可變區和輕鏈可變區,所述重鏈可變區包含與選自SEQ ID NO:33、35、37、39、41、83、85或87的胺基酸序列具有至少80%同一性的胺基酸序列,所述輕鏈可變區包含與選自SEQ ID NO:34、36、38、40、42、84、86或88的胺基酸序列具有至少80%同一性的胺基酸序列。
- 如請求項5所述的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽包含重鏈可變區和輕鏈可變區,所述重鏈可變區包含選自SEQ ID NO:33、35、37、39、41、83、85或87的胺基酸序列,所述輕鏈可變區包含選自SEQ ID NO:34、36、38、40、42、84、86或88的胺基酸序列。
- 如請求項5所述的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽選自由以下各項組成的組:(a)包含重鏈可變區和輕鏈可變區,所述重鏈可變區包含與SEQ ID NO:33的胺基酸序列具有至少80%同一性的胺基酸序列,所述輕鏈可變區包含與SEQ ID NO:34的胺基酸序列具有至少80%同一性的胺基酸序列;(b)包含重鏈可變區和輕鏈可變區,所述重鏈可變區包含與SEQ ID NO:35的胺基酸序列具有至少80%同一性的胺基酸序列,所述輕鏈可變區包含與SEQ ID NO:36的胺基酸序列具有至少80%同一性的胺基酸序列;(c)包含重鏈可變區和輕鏈可變區,所述重鏈可變區包含與SEQ ID NO:37的胺基酸序列具有至少80%同一性的胺基酸序列,所述輕鏈可變區包含與SEQ ID NO:38的胺基酸序列具有至少80%同一性的胺基酸序列;(d)包含重鏈可變區和輕鏈可變區,所述重鏈可變區包含與SEQ ID NO:39的胺基酸序列具有至少80%同一性的胺基酸序列,所述輕鏈可變區包含與SEQ ID NO:40的胺基酸序列具有至少80%同一性的胺基酸序列;(e)包含重鏈可變區和輕鏈可變區,所述重鏈可變區包含與SEQ ID NO:41的胺基酸序列具有至少80%同一性的胺基酸序列,所述輕鏈可變區包含與SEQ ID NO:42的胺基酸序列具有至少80%同一性的胺基酸序列;(f)包含重鏈可變區和輕鏈可變區,所述重鏈可變區包含與SEQ ID NO:83的胺基酸序列具有至少80%同一性的胺基酸序列,所述輕鏈可變區包含與SEQ ID NO:84的胺基酸序列具有至少80%同一性的胺基酸序列;(g)包含重鏈可變區和輕鏈可變區,所述重鏈可變區包含與SEQ ID NO:85的胺基酸序列具有至少80%同一性的胺基酸序列,所述輕鏈可變區包含與SEQ ID NO:86的胺基酸序列具有至少80%同一性的胺基酸序列;以及(h)包含重鏈可變區和輕鏈可變區,所述重鏈可變區包含與SEQ ID NO:87的胺基酸序列具有至少80%同一性的胺基酸序列,所述輕鏈可變區包含與SEQ ID NO:88的胺基酸序列具有至少80%同一性的胺基酸序列。
- 如請求項5-7中任一項所述的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽包含重鏈可變區和輕鏈可變區,其中所述重鏈可變區包含SEQ ID NO:33的胺基酸序列,所述輕鏈可變區包含SEQ ID NO:34的胺基酸序列;所述重鏈可變區包含SEQ ID NO:35的胺基酸序列,所述輕鏈可變區包含SEQ ID NO:36的胺基酸序列;所述重鏈可變區包含SEQ ID NO:37的胺基酸序列,所述輕鏈可變區包含SEQ ID NO:38的胺基酸序列;所述重鏈可變區包含SEQ ID NO:39的胺基酸序列,所述輕鏈可變區包含SEQ ID NO:40的胺基酸序列;所述重鏈可變區包含SEQ ID NO:41的胺基酸序列,所述輕鏈可變區包含SEQ ID NO:42的胺基酸序列;所述重鏈可變區包含SEQ ID NO:83的胺基酸序列,所述輕鏈可變區包含SEQ ID NO:84的胺基酸序列;所述重鏈可變區包含SEQ ID NO:85的胺基酸序列,所述輕鏈可變區包含SEQ ID NO:86的胺基酸序列;所述重鏈可變區包含SEQ ID NO:87的胺基酸序列,所述輕鏈可變區包含SEQ ID NO:88的胺基酸序列;所述重鏈可變區包含SEQ ID NO:81的胺基酸序列,所述輕鏈可變區包含SEQ ID NO:82的胺基酸序列;或者所述重鏈可變區包含SEQ ID NO:79的胺基酸序列,所述輕鏈可變區包含SEQ ID NO:80的胺基酸序列。
- 如請求項1-8中任一項所述的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽包含重鏈和輕鏈,所述重鏈具有與選自SEQ ID NO:89、93、97、101、105、109、113、117、121、125、129、133、137、141、145、149、153、157、161、165、169、173、177、181或185所示的胺基酸序列具有至少80%同一性的胺基酸序列,所述輕鏈具有與選自SEQ ID NO:91、95、99、103、107、111、115、119、123、127、131、135、139、143、147、151、155、159、163、167、171、175、179、183或187所示的胺基酸序列具有至少80%同一性的胺基酸序列。
- 如請求項1-9中任一項所述的抗原結合多肽或其抗原結合部分,其中,所述抗原結合多肽包含根據SEQ ID NO:89的重鏈和根據SEQ ID NO:91的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:93的重鏈和根據SEQ ID NO:95的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:97的重鏈和根據SEQ ID NO:99的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:101的重鏈和根據SEQ ID NO:103的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:105的重鏈和根據SEQ ID NO:107的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:109的重鏈和根據SEQ ID NO:111的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:113的重鏈和根據SEQ ID NO:115的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:117的重鏈和根據SEQ ID NO:119的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:121的重鏈和根據SEQ ID NO:123的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:125的重鏈和根據SEQ ID NO:127的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:129的重鏈和根據SEQ ID NO:131的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:133的重鏈和根據SEQ ID NO:135的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:137的重鏈和根據SEQ ID NO:139的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:141的重鏈和根據SEQ ID NO:143的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:145的重鏈和根據SEQ ID NO:147的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:149的重鏈和根據SEQ ID NO:151的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:153的重鏈和根據SEQ ID NO:155的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:157的重鏈和根據SEQ ID NO:159的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:161的重鏈和根據SEQ ID NO:163的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:165的重鏈和根據SEQ ID NO:167的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:169的重鏈和根據SEQ ID NO:171的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:173的重鏈和根據SEQ ID NO:175的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:177的重鏈和根據SEQ ID NO:179的輕鏈;所述抗原結合多肽包含根據SEQ ID NO:181的重鏈和根據SEQ ID NO:183的輕鏈;或者所述抗原結合多肽包含根據SEQ ID NO:185的重鏈和根據SEQ ID NO:187的輕鏈。
- 如請求項1-10中任一項所述的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽是嵌合的、人源化的或全人源的。
- 如請求項1-11中任一項所述的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽或其抗原結合部分選自由單株抗體、融合蛋白、多特異性抗體、Fab片段、Fab'片段、F(ab')2 片段、Fd片段、Fv片段、dAb片段、分離的CDR區和scFv組成的組。
- 如請求項1-12中任一項所述的抗原結合多肽或其抗原結合部分,其中,所述抗原結合多肽為IgG1、IgG2、IgG3或IgG4型。
- 如請求項13所述的抗原結合多肽或其抗原結合部分,其中IgG4型抗原結合多肽具有根據EU編號索引的S228P突變。
- 如請求項1-14中任一項所述的抗原結合多肽或其抗原結合部分,其中所述抗原結合多肽或其抗原結合部分展現出下述性質中的一種或多種的組合:(a)以1.89E-08或更小的KD 值與CD47結合;(b)阻斷CD47與SIRPα的結合;(c)促進巨噬細胞介導的對表達CD47細胞的吞噬作用;(d)沒有明顯誘導CD4+T細胞的凋亡;(e)不引起實質性的紅血球減少、貧血或紅血球凝集;和(f)所述抗原結合多肽或其抗原結合部分的熔解溫度T≥62℃,聚集溫度Tagg≥61℃。
- 一種免疫偶聯物,其包含如請求項1-15中任一項所述的抗原結合多肽或其抗原結合部分,以及與所述抗原結合多肽或其抗原結合部分連接或綴合的治療劑。
- 如請求項16所述的免疫偶聯物,其中所述治療劑為細胞毒性藥物、放射性同位素、免疫調節劑或抗體。
- 一種組合物,其包含組分A以及藥學上可接受的載體,其中所述組分A為如請求項1-15中任一項所述的抗原結合多肽或其抗原結合部分或如請求項16或17所述的免疫偶聯物。
- 一種分離的核酸,其編碼如請求項1-15中任一項所述的抗原結合多肽或其抗原結合部分。
- 一種載體,其包含如請求項19所述的分離的核酸。
- 一種宿主細胞,其包含如請求項20所述的載體或在其基因組中整合有請求項19所述的分離的核酸。
- 一種製備如請求項1-15中任一項所述的抗原結合多肽或其抗原結合部分的方法,包括:在適於表達編碼請求項1-15中任一項的抗原結合多肽或其抗原結合部分的核酸的條件下培養請求項21所述的宿主細胞,分離所表達的所述抗原結合多肽或其抗原結合部分。
- 一種組成物用於製備在受試者中減少腫瘤或抑制腫瘤細胞生長的藥物的用途,其中所述用途包括向所述受試者施用治療有效量的如請求項1-15中任一項所述的抗原結合多肽或其抗原結合部分、如請求項16或17所述的免疫偶聯物或請求項18所述的組合物。
- 一種組成物用於製備在有需要的受試者中治療癌症的藥物的用途,其中所述用途包括向所述受試者施用治療有效量的如請求項1-15中任一項所述的抗原結合多肽或其抗原結合部分、如請求項16或17所述的免疫偶聯物或請求項18所述的組合物。
- 如請求項24所述的用途,其中,所述癌症選自由以下組成的組:白血病、淋巴瘤、卵巢癌、乳腺癌、子宮內膜癌、結腸癌、直腸癌、膀胱癌、尿路上皮癌、肺癌、支氣管癌、骨癌、***癌、胰腺癌、胃癌、肝細胞癌、膽囊癌、膽管癌、食道癌、腎細胞癌、甲狀腺癌、頭頸癌、睾丸癌、內分泌腺癌、腎上腺癌、腦下垂體癌、皮膚癌、軟組織癌、血管癌、腦癌、神經癌、眼癌、腦膜癌、口咽癌、下咽部癌、宮頸癌、子宮癌、膠質母細胞瘤、髓母細胞瘤、星形細胞瘤、膠質瘤、腦膜瘤、胃泌素瘤、神經母細胞瘤、黑色素瘤、急性髓系白血病、骨髓增生異常綜合症以及肉瘤。
- 一種組成物用於製備促進受試者巨噬細胞的吞噬作用的藥物的用途,其中所述用途包括向所述受試者施用有效量的如請求項1-15中任一項所述的抗原結合多肽或其抗原結合部分、如請求項16或17所述的免疫偶聯物或請求項18所述的組合物。
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