TW202305002A - 新型抗-hvegfr2抗體 - Google Patents
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Abstract
本發明在本文中提供了抗-hVEGFR2抗體或其抗原結合片段、編碼該抗-hVEGFR2抗體或其抗原結合片段的分離之多核苷酸、包括該抗-hVEGFR2抗體或其抗原結合片段之醫藥組合物以及其用途。
Description
本發明總體上關於特異性結合人類VEGFR2 (hVEGFR2)之新型抗-hVEGFR2抗體。
血管內皮生長因子受體2 (VEGFR2)為可被血管內皮生長因子(VEGF) (例如VEGF-A、VEGF-C及VEGF-D)刺激之III型酪胺酸激酶。在與VEGF-A結合後,VEGFR2增加其表現且變成二聚體形式。VEGFR2之二聚化誘導VEGFR2之酪胺酸磷酸化,隨後活化參與增殖、遷移、分化、管形成、維持血管完整性及增加內皮細胞血管通透性之下游路徑。VEGFR2之異常高表現及/或活性破壞了血管生成之內穩態且導致各種癌症及/或血管生成疾病。
因此,對於可用於治療對hVEGFR2表現呈陽性的疾病如癌症以及其他血管生成疾病的新型抗-hVEGFR2抗體存在重大需求。
在整個本發明中,冠詞「一(a/an)」及「該(等)」在本文中用於指一個(種)或多於一個(種) (亦即,至少一個(種))該冠詞之語法對象。舉例而言,「一抗體」意指一種抗體或多於一種抗體。
除其他外,本發明提供新型單株抗-hVEGFR2抗體、編碼該抗體之核苷酸序列及其用途。
在一個態樣中,本發明提供了一種抗-hVEGFR抗體或其抗原結合片段,其包括重鏈HCDR1、HCDR2及HCDR3及/或輕鏈LCDR1、LCDR2及LCDR3序列,其中:
HCDR1序列包括
SSWMN(SEQ ID NO: 1)、
DYYMS(SEQ ID NO: 19)、
X
1YGMS
(SEQ ID NO: 41)、
X
4YWIM
(SEQ ID NO: 44),或其至少80%序列同一性的同源序列;
HCDR2序列包括
RIFPGDGDTYYNGKFQV(SEQ ID NO: 2)、
FIRNKANGYTTEYSASVKG(SEQ ID NO: 20)、
SISX
2GGSYTYYADSVX
19G
(SEQ ID NO: 42)、
DIYPGX
5GSTNYNEKFKS
(SEQ ID NO: 45),或其至少80%序列同一性的同源序列;
HCDR3序列包括
FLDTSGRYVDY(SEQ ID NO: 3)、
FDYYGSTYCFDY(SEQ ID NO: 21)、
EX
3DGNYDY
(SEQ ID NO: 43)、
DSNPDY(SEQ ID NO: 46),或其至少80%序列同一性的同源序列;
LCDR1序列包括
KASQDVNTAVA(SEQ ID NO: 4)、
RASQSVSTSSSSFMH(SEQ ID NO: 22)、
RSSKSLLYKDGKTYLN(SEQ ID NO: 28)、
RASESVX
6NSGISFMX
7 (SEQ ID NO: 47),或其至少80%序列同一性的同源序列;
LCDR2序列包括
SASYRYI(SEQ ID NO: 5)、
YASNLES(SEQ ID NO: 23)、
LMSTRAS(SEQ ID NO: 29)、
AASX
8QX
9S
(SEQ ID NO: 48),或其至少80%序列同一性的同源序列;
LCDR3序列包括
QQHYRAPLT(SEQ ID NO: 6)、
QHTWEIPLT(SEQ ID NO: 24)、
QQLVEYPFT(SEQ ID NO: 30)、
QQSKEVPYT(SEQ ID NO: 49),或其至少80%序列同一性的同源序列,
其中X
1為I或M,X
2為V或I,X
3為L或M,X
4為T或S,X
5為T或S,X
6為D或E,X
7為T或H,X
8為T或Y,X
9為G或R且X
19為E或K。
在某些實施例中,HCDR1包括SEQ ID NO: 41之胺基酸序列,HCDR2包括SEQ ID NO: 42之胺基酸序列,HCDR3包括SEQ ID NO: 43之胺基酸序列,LCDR1包括 SEQ ID NO: 28之序列,LCDR2包括SEQ ID NO: 29之序列,且LCDR3包括SEQ ID NO: 30之序列。
在某些實施例中,在本文提供之抗體或其抗原結合片段中,其中
a) HCDR1包括SEQ ID NO: 25之序列,HCDR2包括SEQ ID NO: 26之序列,HCDR3包括SEQ ID NO: 27之序列;LCDR1包括SEQ ID NO: 28之序列,LCDR2包括SEQ ID NO: 29之序列,且LCDR3包括SEQ ID NO: 30之序列;或者
b) HCDR1包括SEQ ID NO: 31之序列,HCDR2包括SEQ ID NO: 32或SEQ ID NO: 37之序列,且HCDR3包括SEQ ID NO: 33之序列,LCDR1包括SEQ ID NO: 28之序列,LCDR2包括SEQ ID NO: 29之序列,且LCDR3包括SEQ ID NO: 30之序列;或者
c) HCDR1包括SEQ ID NO: 34之序列,HCDR2包括SEQ ID NO: 35或SEQ ID NO: 37之序列,且HCDR3包括SEQ ID NO: 36之序列,LCDR1包括SEQ ID NO: 28之序列,LCDR2包括SEQ ID NO: 29之序列,且LCDR3包括SEQ ID NO: 30之序列。
在某些實施例中,在本文提供之抗-hVEGFR抗體或其抗原結合片段中,其中HCDR1包括SEQ ID NO: 44之胺基酸序列,HCDR2包括SEQ ID NO: 45之胺基酸序列,HCDR3包括SEQ ID NO: 46之胺基酸序列,LCDR1包括SEQ ID NO: 47之序列,LCDR2包括SEQ ID NO: 48之序列,且LCDR3包括SEQ ID NO: 49之序列。
在某些實施例中,在本文提供之抗體或其抗原結合片段中,其中
a) HCDR1包括SEQ ID NO: 7之序列,HCDR2包括SEQ ID NO: 8之序列,HCDR3包括SEQ ID NO: 9之序列;LCDR1包括SEQ ID NO: 10之序列,LCDR2包括SEQ ID NO: 11之序列,且LCDR3包括SEQ ID NO: 12之序列;或者
b) HCDR1包括SEQ ID NO: 13之序列,HCDR2包括SEQ ID NO: 14之序列,且HCDR3包括SEQ ID NO: 15之序列,LCDR1包括SEQ ID NO: 16之序列,LCDR2包括SEQ ID NO: 17之序列,且LCDR3包括SEQ ID NO: 18之序列。
在某些實施例中,在本文提供之抗體或其抗原結合片段中,其中
a) HCDR1包括SEQ ID NO: 1之序列,HCDR2包括SEQ ID NO: 2之序列,且HCDR3包括SEQ ID NO: 3之序列,LCDR1包括SEQ ID NO: 4之序列,LCDR2包括SEQ ID NO: 5之序列,且LCDR3包括SEQ ID NO: 6之序列;或者
b) HCDR1包括SEQ ID NO: 19之序列,HCDR2包括SEQ ID NO: 20之序列,且HCDR3包括SEQ ID NO: 21之序列,LCDR1包括SEQ ID NO: 22之序列,LCDR2包括SEQ ID NO: 23之序列,且LCDR3包括SEQ ID NO: 24之序列。
在某些實施例中,本文提供之抗體或其抗原結合片段進一步包括重鏈HFR1、HFR2、HFR3及HFR4中之一或多者,及/或輕鏈LFR1、LFR2、LFR3及LFR4中之一或多者,其中:
HFR1包括
EVQLVESGGGLVKPGGSLX
10LSCAASGFTFS
(SEQ ID NO: 84)或其至少80% (或至少85%、90%、95%)序列同一性的同源序列,
HFR2包括
WVRQX
11PGKRLEWVA
(SEQ ID NO: 85)或其至少80% (或至少90%)序列同一性的同源序列,
HFR3包括
RFTISRDNAKNTLYLQMNSLX
12AEDTAVYYCAR
(SEQ ID NO: 86)或其至少80% (或至少85%、90%、95%)序列同一性的同源序列,
HFR4包括
WGX
13GTTLTVSS
(SEQ ID NO: 87)或其至少80%序列同一性的同源序列,
LFR1包括
DIVITQX
14X
15LSLPVTX
16GESVSISC
(SEQ ID NO: 88)或其至少80% (或至少85%、90%、95%)序列同一性的同源序列,
LFR2包括
WFLQRPGQSPQLLIY(SEQ ID NO: 89)或其至少80% (或至少85%、90%)序列同一性的同源序列,
LFR3包括
GVX
17DRFSGSGSGTDFTLKISRVEAEDVGX
18YYC
(SEQ ID NO: 90)或其至少80% (或至少85%、90%、95%)序列同一性的同源序列,及
LFR4包括
FGSGTKLEIK(SEQ ID NO: 91)或其至少80% (或至少90%)序列同一性的同源序列,
其中X
10為R或K,X
11為A或T,X
12為R或K,X
13為Q或H,X
14為D或T,X
15為E或P,X
16為F或P,X
17為S或P,X
18為V或I。
在某些實施例中,在本文提供之抗體或其抗原結合片段中,其中:
HFR1包括選自由SEQ ID NO: 64、68及72組成之群的序列,
HFR2包括選自由SEQ ID NO: 65、69及73組成之群的序列,
HFR3包括選自由SEQ ID NO: 66、70及74組成之群的序列,
HFR4包括選自由SEQ ID NO: 67、71及75組成之群的序列,
LFR1包括選自由SEQ ID NO: 76及80組成之群的序列,
LFR2包括選自由SEQ ID NO: 77及81組成之群的序列,
LFR3包括選自由SEQ ID NO: 78及82組成之群的序列,及
LFR4包括選自由SEQ ID NO: 79及83組成之群的序列。
在某些實施例中,在本文提供之抗體或其抗原結合片段中,其中重鏈可變區包括選自由以下組成之群的序列:SEQ ID NO: 50、SEQ ID NO: 52、SEQ ID NO: 54、SEQ ID NO: 56、SEQ ID NO: 58、SEQ ID NO: 60、SEQ ID NO: 62、SEQ ID NO: 93、SEQ ID NO: 94、SEQ ID NO: 98,及其具有至少80%序列同一性但仍保留對hVEGFR2之特異性結合親和力的同源序列。
在某些實施例中,在本文提供之抗體或其抗原結合片段中,其中輕鏈可變區包括選自由以下組成之群的序列:SEQ ID NO: 51、SEQ ID NO: 53、SEQ ID NO: 55、SEQ ID NO: 57、SEQ ID NO: 59、SEQ ID NO: 61、SEQ ID NO: 63、SEQ ID NO: 96、SEQ ID NO: 97,及其具有至少80%序列同一性但仍保留對hVEGFR2之特異性結合親和力的同源序列。
在某些實施例中,在本文提供之抗體或其抗原結合片段中,其中:
a)重鏈可變區包括SEQ ID NO: 50之序列及輕鏈可變區包括SEQ ID NO: 51之序列;
b)重鏈可變區包括SEQ ID NO: 52之序列及輕鏈可變區包括SEQ ID NO: 53之序列;
c)重鏈可變區包括SEQ ID NO: 54之序列及輕鏈可變區包括SEQ ID NO: 55之序列;
d)重鏈可變區包括SEQ ID NO: 56之序列及輕鏈可變區包括SEQ ID NO: 57之序列;
e)重鏈可變區包括SEQ ID NO: 58之序列及輕鏈可變區包括SEQ ID NO: 59之序列;
f)重鏈可變區包括SEQ ID NO: 60之序列及輕鏈可變區包括SEQ ID NO: 61之序列;
g)重鏈可變區包括SEQ ID NO: 62之序列及輕鏈可變區包括SEQ ID NO: 63之序列;或者
h)重鏈可變區包括SEQ ID NO: 93或SEQ ID NO: 94或SEQ ID NO: 98之序列及輕鏈可變區包括SEQ ID NO: 96或SEQ ID NO: 97之序列。
在某些實施例中,本文提供之抗體或其抗原結合片段進一步包括一或多個胺基酸殘基取代或修飾,但仍保留對hVEGFR2之特異性結合親和力。
在某些實施例中,取代或修飾中之至少一者在一或多個CDR序列中,及/或在VH或VL序列之一或多個非CDR區中。
在某些實施例中,本文提供之抗體或其抗原結合片段亦包括免疫球蛋白恆定區,視情況人類Ig之恆定區,或視情況人類IgG之恆定區。
在某些實施例中,恆定區包括人類IgG1、IgG2、IgG3或IgG4之恆定區。
在某些實施例中,人類IgG1之恆定區包括SEQ ID NO: 38,或其具有至少80%序列同一性的同源序列。
在某些實施例中,本文提供之抗體或其抗原結合片段為人類化的。
在某些實施例中,本文提供之抗體或其抗原結合片段為雙功能抗體、Fab、Fab'、F(ab')
2、Fd、Fv片段、二硫鍵穩定化Fv片段(dsFv)、(dsFv)
2、雙特異性dsFv (dsFv-dsFv')、二硫鍵穩定化雙功能抗體(ds雙功能抗體)、單鏈抗體分子(scFv)、scFv二聚體(二價雙功能抗體)、多特異性抗體、駱駝化單域抗體、奈米抗體、域抗體或二價域抗體。
在某些實施例中,本文提供之抗體或其抗原結合片段為雙特異性的。
在某些實施例中,本文提供之抗體或其抗原結合片段能夠特異性結合hVEGFR2之第一及第二抗原決定基,或能夠特異性結合hVEGFR2及第二抗原。
在某些實施例中,第二抗原為免疫相關靶標,視情況選自由以下組成之群:PD-L1、PD-L2、PD-1、CLTA-4、TIM-3、LAG3、CD160、2B4、TGF β、VISTA、BTLA、TIGIT、LAIR1、OX40、CD2、CD27、ICAM-1、NKG2C、SLAMF7、NKp80、CD160、B7-H3、LFA-1、1COS、4-1BB、GITR、CD30、CD40、BAFFR、HVEM、CD7、LIGHT、IL-2、IL-15、CD3、CD16及CD83。
在某些實施例中,第二抗原包括腫瘤抗原。
在某些實施例中,腫瘤抗原存在於表現VEGFR2之細胞中。
在某些實施例中,腫瘤抗原包括緊密連接蛋白18.2、CA-125、神經節苷脂G(D2)、G(M2)及G(D3)、CD20、CD52、CD33、Ep-CAM、CEA、鈴蟾肽樣肽、PSA、HER2/neu、表皮生長因子受體(EGFR)、erbB2、erbB3/HER3、erbB4、CD44v6、Ki-67、癌症相關黏蛋白、VEGF、VEGFR (例如VEGFR3)、雌激素受體、Lewis-Y抗原、TGFβ1、IGF-1受體、EGFα、c-Kit受體、轉鐵蛋白受體、IL-2R或CO17-1A。
在某些實施例中,本文提供之抗體或其抗原結合片段與一或多個綴合物部分連接。
在某些實施例中,綴合物部分包括清除調節劑、化學治療劑、毒素、放射性同位素、鑭系元素、發光標記、螢光標記、酶-受質標記、DNA烷化劑、拓樸異構酶抑制劑、微管蛋白結合劑或其他抗癌藥物。
在另一態樣中,本發明亦提供與本文提供之抗體或抗原結合片段競爭結合hVEGFR2之抗體或其抗原結合片段。
在一個態樣中,本發明提供一種醫藥組合物,其包括本文提供之抗體或抗原結合片段,以及一或多種醫藥學上可接受之載劑。
在某些實施例中,本文提供之醫藥組合物進一步包括第二治療劑。
在某些實施例中,第二治療劑包括抗癌療法,視情況地,抗癌療法選自化學治療劑、放射療法、免疫治療劑、抗血管生成劑(例如VEGFR (如VEGFR-1及VEGFR-3)之拮抗劑)、EGFR拮抗劑、PDGFR拮抗劑、IGFR拮抗劑、NGFR拮抗劑、FGFR拮抗劑、靶向治療劑(例如HER2抗體、緊密連接蛋白18.2抗體)、細胞治療劑、基因治療劑、激素治療劑、細胞介素、緩解性治療、治療癌症之手術(例如腫瘤切除術)、一或多種止吐藥、化學療法引起之併發症的治療或癌症患者的膳食補充劑(例如吲哚-3-甲醇)。
在一個態樣中,本發明提供一種分離之多核苷酸,其編碼本文提供之抗體或其抗原結合片段。
在一個態樣中,本發明提供一種載體,其包括本文提供之分離之多核苷酸。
在一個態樣中,本發明提供一種宿主細胞,其包括本文提供之載體。
在一個態樣中,本發明提供一種表現本文提供之抗體或其抗原結合片段的方法,其包括在表現本文提供之載體之條件下培養本文提供之宿主細胞。
在一個態樣中,本發明提供一種在受試者中治療VEGFR2相關疾病或病症、降低VEGFR2相關疾病或病症之嚴重性及/或減緩VEGFR2相關疾病或病症之進展的方法,其包括向受試者投與治療有效量之本文提供之抗體或其抗原結合片段,或本文提供之醫藥組合物。
在某些實施例中,VEGFR2相關疾病或病症為腫瘤或血管生成疾病。
在某些實施例中,腫瘤產生VEGF (例如,VEGF-A)及/或對其微環境中存在之VEGF (例如,VEGF-A)敏感。
在某些實施例中,腫瘤為實體瘤或非實體瘤。
在某些實施例中,實體瘤選自由以下組成之群:乳腺癌、肺癌、大腸直腸癌、胰臟癌、膠質瘤及淋巴瘤、頭頸腫瘤、神經內分泌腫瘤、大腸直腸腫瘤、前列腺腫瘤、乳腺腫瘤、肺腫瘤(如小細胞及非小細胞肺腫瘤)、胰腺腫瘤、甲狀腺腫瘤、卵巢腫瘤、宮頸腫瘤、腎腫瘤、腦腫瘤、肝腫瘤、卡波西肉瘤(Kaposi's sarcoma)、CNS腫瘤、神經母細胞瘤、毛細血管母細胞瘤、腦膜瘤、腦轉移、黑色素瘤、胃腸道及腎癌及肉瘤(例如胃癌)、橫紋肌肉瘤、膠質母細胞瘤(尤為多形性膠質母細胞瘤)、平滑肌肉瘤、鱗狀細胞癌、基底細胞癌及可藉由抑制惡性角化細胞(如人類惡性角化細胞)之生長來治療的皮膚癌。
在某些實施例中,腫瘤選自由以下組成之群:胃癌、非小細胞肺癌如大細胞肺癌。
在某些實施例中,非實體瘤選自由以下組成之群:白血病、多發性骨髓瘤及淋巴瘤,例如急性髓性白血病(AML)、慢性髓性白血病(CML)、急性淋巴球性白血病(ALL)、慢性淋巴球性白血病(CLL)、紅血球白血病或單核細胞白血病、霍奇金及非霍奇金淋巴瘤。
在某些實施例中,血管生成疾病選自由以下組成之群:動脈粥樣硬化、類風濕性關節炎(RA)、新生血管性青光眼、包含增生性糖尿病視網膜病變在內的增生性視網膜病變、黃斑變性、血管瘤、血管纖維瘤、牛皮癬、早產兒視網膜病變(例如,晶狀體後纖維增生)、角膜移植排斥、胰島素依賴型糖尿病、多發性硬化、重症肌無力、克羅恩病(Chron's disease)、自體免疫性腎炎、原發性膽汁性肝硬化、急性胰臟炎、同種異體移植排斥、過敏性發炎、接觸性皮炎及遲發性超敏反應、炎性腸病、感染性休克、骨質疏鬆症、骨關節炎、由神經元發炎引起之認知缺陷、奧斯勒-韋伯症候群(Osler-Weber syndrome)、再狹窄以及真菌、寄生蟲及病毒感染如巨細胞病毒感染。
在某些實施例中,受試者為人類。
在某些實施例中,投與係藉由口服、鼻、靜脈內、皮下、舌下、瘤內或肌肉內投與進行。
在某些實施例中,本文提供之方法進一步包括投與治療有效量之第二治療劑。
在某些實施例中,第二治療劑包括抗癌療法,視情況地,抗癌療法選自化學治療劑、放射療法、免疫治療劑、抗血管生成劑(例如VEGFR (如VEGFR-1、VEGFR-2及VEGFR-3)之拮抗劑)、EGFR拮抗劑、PDGFR拮抗劑、IGFR拮抗劑、NGFR拮抗劑、FGFR拮抗劑、靶向治療劑、細胞治療劑、基因治療劑、激素治療劑、細胞介素、緩解性治療、治療癌症之手術(例如腫瘤切除術)、一或多種止吐藥、化學療法引起之併發症的治療或癌症患者的膳食補充劑(例如吲哚-3-甲醇)。
在一個態樣中,本發明提供一種套組,其包括本文提供之抗體或其抗原結合片段。
在一個態樣中,本發明提供一種偵測樣本中VEGFR2之存在或量的方法,其包括使樣本與本文提供之抗體或其抗原結合片段接觸,且測定樣本中VEGFR2之存在或量。
在一個態樣中,本發明提供本文提供之抗體或其抗原結合片段在製備用於在受試者中治療VEGFR2相關疾病或病症、降低VEGFR2相關疾病或病症之嚴重性及/或減緩VEGFR2相關疾病或病症之進展的藥物中的用途。
在某些實施例中,VEGFR2相關疾病或病症為腫瘤或血管生成疾病。
在某些實施例中,腫瘤產生VEGF (例如,VEGF-A)及/或對其微環境中存在之VEGF (例如,VEGF-A)敏感。
在某些實施例中,腫瘤為實體瘤或非實體瘤。
在某些實施例中,血管生成疾病選自由以下組成之群:動脈粥樣硬化、類風濕性關節炎(RA)、新生血管性青光眼、包含增生性糖尿病視網膜病變在內的增生性視網膜病變、黃斑變性、血管瘤、血管纖維瘤、牛皮癬、早產兒視網膜病變(例如,晶狀體後纖維增生)、角膜移植排斥、胰島素依賴型糖尿病、多發性硬化、重症肌無力、克羅恩病、自體免疫性腎炎、原發性膽汁性肝硬化、急性胰臟炎、同種異體移植排斥、過敏性發炎、接觸性皮炎及遲發性超敏反應、炎性腸病、感染性休克、骨質疏鬆症、骨關節炎、由神經元發炎引起之認知缺陷、奧斯勒-韋伯症候群、再狹窄以及真菌、寄生蟲及病毒感染如巨細胞病毒感染。
以下對本發明之描述僅意欲說明本發明之各種實施例。因此,所論述之具體修改不應被解釋為對本發明範疇之限制。對熟習此項技術者將顯而易見的是,可在不脫離本發明範疇之情況下作出各種等效物、變化及修改,且應理解,此等等效實施例將包含在本文中。本文引用之所有參考文獻,包含出版物、專利及專利申請案,均以全文引用之方式併入本文中。
定義
如本文所用,除非本文另有說明或與上下文明顯矛盾,否則在本發明之上下文中(尤其在申請專利範圍之上下文中)使用之術語「一」、「該(等)」及類似術語將被解釋為涵蓋單數及複數。
如本文所用,術語「抗體」包含與特異性抗原結合之任何免疫球蛋白、單株抗體、多株抗體、多價抗體、二價抗體、單價抗體、多特異性抗體或雙特異性抗體。天然完整抗體包含兩條重(H)鏈及兩條輕(L)鏈。哺乳動物重鏈分為α、δ、ε、γ及μ,每條重鏈由可變區(V
H)及第一、第二及第三恆定區(分別為C
H1、C
H2、C
H3)組成;哺乳動物輕鏈分為λ或κ,而每條輕鏈由可變區(V
L)及恆定區組成。抗體呈「Y」形,其中Y之主幹由藉由二硫鍵結合在一起的兩條重鏈之第二及第三恆定區組成。Y之各臂包含與單條輕鏈之可變區及恆定區結合的單條重鏈之可變區及第一恆定區。輕鏈及重鏈之可變區負責抗原結合。兩條鏈之可變區一般含有三個高度可變之環,稱為互補決定區(CDR) (輕鏈CDR包含LCDR1、LCDR2及LCDR3,重鏈CDR包含HCDR1、HCDR2、HCDR3)。本文揭示之抗體及抗原結合域之CDR邊界可藉由Kabat、IMGT、AbM、Chothia或Al-Lazikani之慣例(Al-Lazikani, B.、Chothia, C.、Lesk, A. M.之《分子生物學雜誌(J. Mol. Biol.)》,273(4), 927 (1997);Chothia, C.等人,《分子生物學雜誌》,12月5日;186(3):651-63 (1985);Chothia, C.及Lesk, A.M.之《分子生物學雜誌》,196,901 (1987);N. R. Whitelegg等人,《蛋白工程(Protein Engineering)》,v13(12), 819-824 (2000);Chothia, C.等人,《自然(Nature)》,12月21日-28日;342(6252):877-83 (1989);Kabat E.A.等人,美國國立衛生研究院(National Institutes of Health),Bethesda, Md. (1991);Marie-Paule Lefranc等人,《發育及比較免疫學(Developmental and Comparative Immunology)》,27: 55-77 (2003);Marie-Paule Lefranc等人,《免疫組學研究(Immunome Research)》,1(3), (2005);Marie-Paule Lefranc,《B細胞之分子生物學(Molecular Biology of B cells)》(第二版),第26章,481-514, (2015))來定義或識別。三個CDR插入於稱為構架區(FR)之側接片段之間,構架區比CDR更高度保守,且形成支撐高變環的支架。重鏈及輕鏈之恆定區不參與抗原結合,但表現出各種效應功能。基於抗體重鏈恆定區之胺基酸序列,將抗體分類。抗體之五種主要類別或同型為IgA、IgD、IgE、IgG及IgM,其特徵在於分別存在α、δ、ε、γ及μ重鏈。將若干主要抗體類別劃分為子類,如IgG1 (γ1重鏈)、IgG2 (γ2重鏈)、IgG3 (γ3重鏈)、IgG4 (γ4重鏈)、IgA1 (α1重鏈)或IgA2 (α2重鏈)。在某些實施例中,本文提供之抗體涵蓋任何其抗原結合片段。
如本文所用,術語「抗原結合片段」係指由包括一或多個CDR之抗體片段,或任何其他與抗原結合但不包括完整之原生抗體結構的抗體部分形成的抗體片段。抗原結合片段之實例包含但不限於雙功能抗體、Fab、Fab'、F(ab')
2、Fd、Fv片段、二硫鍵穩定化Fv片段(dsFv)、(dsFv)
2、雙特異性dsFv (dsFv-dsFv')、二硫鍵穩定化雙功能抗體(ds雙功能抗體)、單鏈抗體分子(scFv)、scFv二聚體(二價雙功能抗體)、多特異性抗體、駱駝化單域抗體、奈米抗體、域抗體及二價域抗體。抗原結合片段能夠與親本抗體所結合的相同抗原結合。在某些實施例中,抗原結合片段可包括來自特定人類抗體之一或多個CDR。
關於抗體之「Fab」係指抗體之單價抗原結合片段,其由單條輕鏈(可變區及恆定區)藉由二硫鍵與單條重鏈之可變區及第一恆定區結合而成。Fab可藉由在接近鉸鏈區的重鏈之間二硫鍵的N端的殘基處木瓜蛋白酶消化抗體來獲得。
「Fab'」係指包含鉸鏈區之一部分的Fab片段,其可藉由胃蛋白酶消化在鉸鏈區重鏈之間的二硫鍵之C末端附近的殘基處的抗體獲得,且因此在鉸鏈區之少量殘基(包含一或多個半胱胺酸)上與Fab不同。
「F(ab')
2」係指Fab'之二聚體,其包括兩條輕鏈及兩條重鏈之一部分。
關於抗體之「Fc」係指由藉由二硫鍵與第二重鏈之第二及第三恆定區結合的第一重鏈之第二及第三恆定區組成的抗體部分。IgG及IgM Fc區含有三個重鏈恆定區(每條鏈中之第二、第三及第四重鏈恆定區)。其可藉由木瓜蛋白酶消化抗體獲得。抗體之Fc部分負責各種效應功能,如ADCC、ADCP及CDC,但不在抗原結合中起作用。
關於抗體之「Fv」係指最小的帶有完整抗原結合位點之抗體片段。Fv片段由結合於單條重鏈之可變區的單條輕鏈之可變區組成。「dsFv」係指二硫鍵穩定化Fv片段,其中在單條輕鏈之可變區與單條重鏈之可變區之間的連接為二硫鍵。
「單鏈Fv抗體」或「scFv」係指由輕鏈可變區及重鏈可變區直接或藉由肽連接子序列相互連接組成的工程化抗體(Huston JS等人,《美國國家科學院院刊》,85:5879(1988))。「scFv二聚體」係指包括具有連接子之兩個重鏈可變區及兩個輕鏈可變區的單鏈。在某些實施例中,「scFv二聚體」為包括與另一個V
H-V
L部分二聚化之V
H-V
L(藉由肽連接子連接)的二價雙功能抗體或二價ScFv (BsFv),使得一個部分之V
H與另一個部分之V
L配位且形成可靶向相同的抗原(或抗原決定基)或不同的抗原(或抗原決定基)的兩個結合位點。在其他實施例中,「scFv二聚體」為雙特異性雙功能抗體,其包含V
H1-V
L2(由肽連接子連接)與V
L1-V
H2(亦由肽連接子連接)結合,使得V
H1與V
L1配位且V
H2與V
L2配位且各配位對具有不同的抗原特異性。
「單鏈Fv-Fc抗體」或「scFv-Fc」係指由連接至抗體Fc區之scFv組成的工程化抗體。
「駱駝化單域抗體」、「重鏈抗體」、「奈米抗體」或「HCAb」係指含有兩個V
H域且不含輕鏈之抗體(Riechmann L.及Muyldermans S.,《免疫方法雜誌(
J Immunol Methods.)》,12月10日;231(1-2):25-38 (1999);Muyldermans S.,《生物技術雜誌(
J Biotechnol.)》,6月;74(4):277-302 (2001);WO94/04678;WO94/25591;美國專利號6,005,079)。重鏈抗體最初由駱駝科(Camelidae) (駱駝、單峰駝及美洲駝)獲得的。儘管沒有輕鏈,但駱駝化抗體具有真正的抗原結合庫(Hamers-Casterman C.等人,《自然》,6月3日;363(6428):446-8 (1993);Nguyen VK.等人,「駱駝科之重鏈抗體;進化創新案例(Heavychain antibodies in Camelidae; a case of evolutionary innovation)」,《免疫遺傳學(Immunogenetics)》,4月;54(1):39-47 (2002);Nguyen VK.等人,《免疫學(
Immunology)》,5月;109(1):93-101 (2003))。重鏈抗體之可變域(VHH域)代表由適應性免疫反應產生的已知最小的抗原結合單位(Koch-Nolte F.等人,《FASEB雜誌(
FASEB J)》,11月;21(13):3490-8. Epub 2007年6月15日(2007))。「雙功能抗體」包含具有兩個抗原結合位點之小抗體片段,其中片段包括單條多肽鏈中與V
L域連接的V
H域(V
H-V
L或V
L-V
H) (參見例如Holliger P.等人,《美國國家科學院院刊》,7月15日;90(14):6444-8 (1993);EP404097;WO93/11161)。因為連接子太短,所以同一條鏈上之兩個域無法配對,因此,迫使域與另一條鏈之互補域配對,從而產生兩個抗原結合位點。抗原結合位點可靶向相同或不同抗原(或抗原決定基)。
「域抗體」係指僅含重鏈之可變區或輕鏈之可變區的抗體片段。在某些實施例中,兩個或更多個V
H域藉由肽連接子共價接合以形成二價或多價域抗體。二價域抗體之兩個V
H域可靶向相同或不同的抗原。
在某些實施例中,「(dsFv)
2」包括三個肽鏈:兩個V
H部分藉由肽連接子連接且藉由二硫橋結合於兩個V
L部分。
在某些實施例中,「雙特異性ds雙功能抗體」包括V
H1-V
L2(由肽連接子連接)與V
L1-V
H2(亦由肽連接子連接)藉由V
H1與V
L1之間的二硫橋結合。
在某些實施例中,「雙特異性dsFv」或「dsFv-dsFv'」包括三個肽鏈:V
H1-V
H2部分,其中重鏈藉由肽連接子(例如,長的可撓性連接子)結合且藉由二硫橋分別與V
L1及V
L2部分配對。各二硫鍵配對的重鏈及輕鏈具有不同的抗原特異性。
如本文所用,術語「人類化」意指抗體或抗原結合片段包括來源於非人類動物之CDR、來源於人類之FR區,及當適用時,來源於人類之恆定區。在某些實施例中,人類化hVEGFR2抗體之可變區構架的胺基酸殘基被替換以進行序列優化。在某些實施例中,人類化hVEGFR2抗體鏈之可變區構架序列與相應的人類可變區構架序列具有至少65%、70%、75%、80%、85%、90%、95%或100%同一性。
如本文所用,術語「嵌合」係指重鏈及/或輕鏈之一部分來源於一個物種,而重鏈及/或輕鏈之其餘部分來源於不同的物種的抗體或抗原結合片段。在一說明性實例中,嵌合抗體可包括來源於人類之恆定區及來源於非人類物種(如小鼠)之可變區。
術語「生殖系序列」係指編碼可變區胺基酸序列或子序列的核酸序列,與所有其他已知的由生殖系免疫球蛋白可變區序列編碼之可變區胺基酸序列相比,該序列與參考可變區胺基酸序列或子序列具有最高的確定胺基酸序列同一性。生殖系序列亦可指與所有其他評估之可變區胺基酸序列相比,與參考可變區胺基酸序列或子序列具有最高胺基酸序列同一性之可變區胺基酸序列或子序列。生殖系序列可為僅構架區、僅互補決定區、構架及互補決定區、可變區段(如上文所定義)或包括可變區之序列或子序列的其他組合。序列同一性可使用本文所述之方法確定,例如,使用BLAST、ALIGN或此項技術中已知的另一種比對算法比對兩個序列。生殖系核酸或胺基酸序列可與參考可變區核酸或胺基酸序列具有至少約90%、91、92%、93%、94%、95%、96%、97%、98%、99%或100%之序列同一性。例如,可藉由可公開獲得的國際ImMunoGeneTics資料庫(IMGT)及V-base確定生殖系序列。
如本文所用,「抗-hVEGFR2抗體」或「抗hVEGFR2抗體」係指能夠以足夠的親和力特異性結合人類VEGFR2例如以提供診斷及/或治療用途的抗體。
如本文所用,術語「親和力」係指免疫球蛋白分子(亦即抗體)或其片段與抗原之間的非共價相互作用之強度。
如本文所用,術語「特異性結合(specific binding/specifically binds)」係指兩個分子之間,如例如抗體與抗原之間的非隨機結合反應。在某些實施例中,本文提供之抗體或抗原結合片段以≤10
-6M (例如,≤5×10
-7M、≤2×10
-7M、≤10
-7M、≤5×10
-8M、≤2×10
-8M、≤10
-8M、≤5×10
-9M、≤4×10
-9M、≤3×10
-9M、≤2×10
-9M或≤10
-9M)之結合親和力(K
D)特異性結合hVEGFR2。本文使用之K
D係指解離速率相對於締合速率之比率(k
off/k
on),其可藉由使用此項技術中已知的任何習知方法來確定,方法包含但不限於表面電漿子共振方法、微尺度熱泳方法、HPLC-MS方法及流動式細胞測量術(如FACS)方法。在某些實施例中,K
D值可藉由使用流式細胞術法適當地確定。可使用各種免疫分析格式來選擇與特定蛋白特異性免疫反應的抗體。例如,固相ELISA免疫分析常規地用於選擇與蛋白特異性免疫反應的抗體(關於可用於確定特異性免疫反應之免疫分析格式及條件的描述,參見例如Harlow及Lane,《使用抗體,實驗室手冊(Using Antibodies, A Laboratory Manual)》,(1998))。通常,特異性或選擇性結合反應將產生至少兩倍於背景信號,更通常係至少10至100倍於背景信號的信號。
關於胺基酸序列(或核酸序列)之「序列同一性百分比(%)」定義為在比對序列且在必要時引入空位以實現最大對應性之後,與參考序列中之胺基酸(或核酸)殘基相同的候選序列中的胺基酸(或核酸)殘基之百分比。可例如使用公開可用的工具如BLASTN、BLASTp (可在美國國家生物技術資訊中心(NCBI)之網站上獲得,亦參見Altschul S.F.等人,《分子生物學雜誌》,215:403-410 (1990);Stephen F.等人,《核酸研究(Nucleic Acids Res.)》,25:3389-3402 (1997))、ClustalW2 (可在可在歐洲生物資訊學研究所網站上獲得,亦參見Higgins D.G.等人,《酶學方法(Methods in Enzymology)》,266:383-402 (1996);Larkin M.A.等人,《生物資訊學(Bioinformatics)》,(Oxford, England), 23(21): 2947-8 (2007)),及ALIGN或Megalign (DNASTAR)軟體來實現用於確定胺基酸(或核酸)序列同一性百分比的比對。熟習此項技術者可使用工具提供之預設參數,或可自定義適於比對之參數,如例如藉由選擇合適算法進行。在某些實施例中,不相同的殘基位置可藉由保守胺基酸取代而不同。「保守胺基酸取代」為其中一個胺基酸殘基被具有化學特性(例如,電荷或疏水性)類似的側鏈(R基團)的另一個胺基酸殘基取代的胺基酸取代。通常,保守胺基酸取代不會實質上改變蛋白之功能特性。在兩個或更多個胺基酸序列因保守取代而彼此不同之情況下,百分比或類似性程度可向上調整以校正取代之保守性質。用於進行此調整之裝置對於熟習此項技術者而言為眾所周知的。參見例如,Pearson (1994),《分子生物學方法(Methods Mol. Biol.)》,24: 307-331,其藉由引用併入本文。
如本文所用,「同源序列(homologue sequence/homologous sequence)」可互換使用且指視情況比對時與其他序列具有至少80% (例如至少85%、88%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%)之序列同一性的多核苷酸序列(或其互補股)或胺基酸序列。
「分離」的物質已藉由人工方式自天然狀態改變。若「分離」的組合物或物質存在於自然界中,則組合物或物質已經自其原始環境改變或自其原始環境移出,或兩種情況均有。例如,天然地存在於活動物體內的多核苷酸或多肽不為「分離」的,但若相同多核苷酸或多肽與其天然狀態的共存材料充分地分離,由此以實質上純的狀態存在,則多核苷酸或多肽為「分離」的。經分離「核酸」或「多核苷酸」可互換使用,且指經分離核酸分子之序列。在某些實施例中,「分離的抗體或其抗原結合片段」係指具有至少60%、70%、75%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%之純度的抗體或抗原結合片段,如藉由電泳方法(如SDS-PAGE、等電聚焦、毛細管電泳)或層析方法(如離子交換層析法或逆相HPLC)所確定的。
如本文所用,「阻斷結合」之能力係指抗體或抗原結合片段將兩個分子(例如VEGR-A及hVEGFR2)之間的結合相互作用抑制至任何可偵測程度的能力。在某些實施例中,阻斷兩個分子(例如VEGR-A及hVEGFR2)之間結合的抗體或抗原結合片段將兩個分子之間的結合相互作用抑制至少50%。在某些實施例中,此抑制可大於60%、大於70%、大於80%或大於90%。
如本文所用,術語「抗體藥物綴合物」係指抗體或其抗原結合片段與另一種藥劑如化學治療劑、毒素、免疫治療劑、成像探針等的連接。該連接可為共價鍵,或非共價相互作用,如藉由靜電力產生之非共價相互作用。可使用此項技術中已知的各種連接子以形成抗體藥物綴合物。此外,抗體藥物綴合物可以融合蛋白之形式提供,該融合蛋白可由編碼綴合物之多核苷酸表現。如本文所用,「融合蛋白」係指藉由連接兩個或更多個基因或基因片段產生之蛋白,該基因或基因片段最初編碼不同的蛋白(包含肽及多肽)。融合基因之轉譯產生具有源自每種原始蛋白之功能特性的單一蛋白。
術語「受試者」包含人類及非人類動物。非人類動物包含所有脊椎動物,例如哺乳動物及非哺乳動物,如非人類靈長類動物、小鼠、大鼠、貓、兔、羊、狗、牛、雞、兩棲動物及爬行動物。除非另有說明,否則術語「患者」或「受試者」在本文中可互換使用。
如本文所用,「效應功能」或「抗體效應功能」係指可歸因於抗體之Fc區與其效應子如C1複合物及Fc受體之結合的生物活性。例示性效應功能包含:由抗體及C1q對C1複合物的相互作用誘導之補體依賴性細胞毒性(CDC);由抗體之Fc區與效應細胞上之Fc受體結合誘導之抗體依賴性細胞介導之細胞毒性(ADCC);及抗體依賴性細胞介導之吞噬作用(ADCP),其中表現FcγR之非特異性細胞毒性細胞識別靶細胞上之結合抗體且隨後引起靶細胞之吞噬作用。效應功能包含在抗原結合之後起作用的功能及獨立於抗原結合起作用的功能。
如本文所用,病症之「治療(treating/treatment)」包含預防或減輕病症,減緩病症之發作或發展速率,降低罹患病症之風險,預防或延遲與病症相關之症狀的發展,減少或結束與病症相關之症狀,產生病症之完全或部分消退,治癒病症或其某一組合。
如本文所用,術語「載體」係指一種媒劑,可將基因元件可操作地插入其中,以實現該基因元件之表現,從而產生由該基因元件編碼之蛋白、RNA或DNA,或複製該基因元件。載體可用於轉型、轉導或轉染宿主細胞,以使其攜帶的基因元件在宿主細胞內表現。載體之實例包含質體;噬菌粒;黏質體;人工染色體,如酵母人工染色體(YAC)、細菌人工染色體(BAC)或P1衍生之人工染色體(PAC);噬菌體,如λ噬菌體或M13噬菌體;及動物病毒。載體可含有多種用於控制表現的元件,包含啟動子序列、轉錄起始序列、強化子序列、可選擇元件及報導基因。另外,載體可含有複製起點。載體亦可包含有助於其進入細胞之材料,包含但不限於病毒粒子、脂質體或蛋白包衣。載體可為表現載體或選殖載體。本發明提供了載體(例如表現載體),其含有本文提供之編碼抗體或其抗原結合片段的核酸序列、至少一個可操作地連接至該核酸序列的啟動子(例如SV40、CMV、EF-1α),及至少一個選擇標記物。
如本文所用,「宿主細胞」係指已將外源多核苷酸及/或載體引入其中的細胞。
可與術語「VEGF受體2」、「含有激酶插入域之受體(KDR)」、「CD309」或「胎肝激酶1 (FLK1)」互換使用的術語「VEGFR2」為VEGF受體(VEGFR)的一種類型,其為III型受體酪胺酸激酶,特徵在於其胺基末端胞外受體配位體結合域中通常具有5或7個免疫球蛋白樣環,以及跨膜區及羧基末端胞內催化域被稱為激酶插入域之可變長度的親水激酶間序列的插入中斷(
Kaipainen 等人,《實驗醫學雜誌 (J. Exp. Med.) 》, 178:2077-88 (1993) ; Terman 等人,《癌基因 (Oncogene) 》, 6:1677-83 (1991))。其他類型之VEGFR包含fins樣酪胺酸激酶受體(fit-1)或VEGFR1,以及VEGFR3 (fit-4) (
Shibuya 等人,《癌基因》,
5:519-24 (1990))。胺基末端胞外受體配位體結合域負責配位體(例如,血管內皮生長因子A (VEGF-A))及域之間的親和力。羧基末端胞內催化域負責啟動參與例如細胞生長之信號傳遞路徑。在例如胚胎發生及腫瘤形成期間,可在內皮細胞上發現VEGFR之表現(Millauer, B.等人,《細胞(Cell)》,72:835-46 (1993);Plate, K.等人,(1993))。VEGFR之表現亦可在非內皮細胞上發現,如腫瘤細胞,尤其係產生VEGF之腫瘤細胞,例如白血病細胞(Fielder等人,《血液(Blood)》,89:1870-5 (1997)及Bellamy等人,《癌症研究(Cancer Res.)》,59728-33 (1999))。本文使用之人類VEGFR2 (hVEGFR2)包括可藉由NCBI資料庫中之登錄號AAI31823.1訪問之胺基酸序列或SEQ ID NO: 39之胺基酸序列(MQSKVLLAVALWLCVETRAASVGLPSVSLDLPRLSIQKDILTIKANTTLQITCRGQRDLDWLWPNNQSGSEQRVEVTECSDGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQDYRSPFIASVSDQHGVVYITENKNKTVVIPCLGSISNLNVSLCARYPEKRFVPDGNRISWDSKKGFTIPSYMISYAGMVFCEAKINDESYQSIMYIVVVVGYRIYDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGITRSDQGLYTCAASSGLMTKKNSTFVRVHEKPFVAFGSGMESLVEATVGERVRIPAKYLGYPPPEIKWYKNGIPLESNHTIKAGHVLTIMEVSERDTGNYTVILTNPISKEKQSHVVSLVVYVPPQIGEKSLISPVDSYQYGTTQTLTCTVYAIPPPHHIHWYWQLEEECANEPSHAVSVTNPYPCEEWRSVEDFQGGNKIEVNKNQFALIEGKNKTVSTLVIQAANVSALYKCEAVNKVGRGERVISFHVTRGPEITLQPDMQPTEQESVSLWCTADRSTFENLTWYKLGPQPLPIHVGELPTPVCKNLDTLWKLNATMFSNSTNDILIMELKNASLQDQGDYVCLAQDRKTKKRHCVVRQLTVLERVAPTITGNLENQTTSIGESIEVSCTASGNPPPQIMWFKDNETLVEDSGIVLKDGNRNLTIRRVRKEDEGLYTCQACSVLGCAKVEAFFIIEGAQEKTNLEIIILVGTAVIAMFFWLLLVIILRTVKRANGGELKTGYLSIVMDPDELPLDEHCERLPYDASKWEFPRDRLKLGKPLGRGAFGQVIEADAFGIDKTATCRTVAVKMLKEGATHSEHRALMSELKILIHIGHHLNVVNLLGACTKPGGPLMVIVEFCKFGNLSTYLRSKRNEFVPYKTKGARFRQGKDYVGAIPVDLKRRLDSITSSQSSASSGFVEEKSLSDVEEEEAPEDLYKDFLTLEHLICYSFQVAKGMEFLASRKCIHRDLAARNILLSEKNVVKICDFGLARDIYKDPDYVRKGDARLPLKWMAPETIFDRVYTIQSDVWSFGVLLWEIFSLGASPYPGVKIDEEFCRRLKEGTRMRAPDYTTPEMYQTMLDCWHGEPSQRPTFSELVEHLGNLLQANAQQDGKDYIVLPISETLSMEEDSGLSLPTSPVSCMEEEEVCDPKFHYDNTAGISQYLQNSKRKSRPVSVKTFEDIPLEEPEVKVIPDDNQTDSGMVLASEELKTLEDRTKLSPSFGGMVPSKSRESVASEGSNQTSGYQSGYHSDDTDTTVYSSEEAELLKLIEIGVQTGSTAQILQPDSGTTLSSPPV)。本文使用之小鼠VEGFR2包括可藉由NCBI資料庫中之登錄號P35918.1訪問之胺基酸序列或SEQ ID NO: 100之胺基酸序列(MESKALLAVALWFCVETRAASVGLPGDFLHPPKLSTQKDILTILANTTLQITCRGQRDLDWLWPNAQRDSEERVLVTECGGGDSIFCKTLTIPRVVGNDTGAYKCSYRDVDIASTVYVYVRDYRSPFIASVSDQHGIVYITENKNKTVVIPCRGSISNLNVSLCARYPEKRFVPDGNRISWDSEIGFTLPSYMISYAGMVFCEAKINDETYQSIMYIVVVVGYRIYDVILSPPHEIELSAGEKLVLNCTARTELNVGLDFTWHSPPSKSHHKKIVNRDVKPFPGTVAKMFLSTLTIESVTKSDQGEYTCVASSGRMIKRNRTFVRVHTKPFIAFGSGMKSLVEATVGSQVRIPVKYLSYPAPDIKWYRNGRPIESNYTMIVGDELTIMEVTERDAGNYTVILTNPISMEKQSHMVSLVVNVPPQIGEKALISPMDSYQYGTMQTLTCTVYANPPLHHIQWYWQLEEACSYRPGQTSPYACKEWRHVEDFQGGNKIEVTKNQYALIEGKNKTVSTLVIQAANVSALYKCEAINKAGRGERVISFHVIRGPEITVQPAAQPTEQESVSLLCTADRNTFENLTWYKLGSQATSVHMGESLTPVCKNLDALWKLNGTMFSNSTNDILIVAFQNASLQDQGDYVCSAQDKKTKKRHCLVKQLIILERMAPMITGNLENQTTTIGETIEVTCPASGNPTPHITWFKDNETLVEDSGIVLRDGNRNLTIRRVRKEDGGLYTCQACNVLGCARAETLFIIEGAQEKTNLEVIILVGTAVIAMFFWLLLVILVRTVKRANEGELKTGYLSIVMDPDELPLDERCERLPYDASKWEFPRDRLKLGKPLGRGAFGQVIEADAFGIDKTATCKTVAVKMLKEGATHSEHRALMSELKILIHIGHHLNVVNLLGACTKPGGPLMVIVEFSKFGNLSTYLRGKRNEFVPYKSKGARFRQGKDYVGELSVDLKRRLDSITSSQSSASSGFVEEKSLSDVEEEEASEELYKDFLTLEHLICYSFQVAKGMEFLASRKCIHRDLAARNILLSEKNVVKICDFGLARDIYKDPDYVRKGDARLPLKWMAPETIFDRVYTIQSDVWSFGVLLWEIFSLGASPYPGVKIDEEFCRRLKEGTRMRAPDYTTPEMYQTMLDCWHEDPNQRPSFSELVEHLGNLLQANAQQDGKDYIVLPMSETLSMEEDSGLSLPTSPVSCMEEEEVCDPKFHYDNTAGISHYLQNSKRKSRPVSVKTFEDIPLEEPEVKVIPDDSQTDSGMVLASEELKTLEDRNKLSPSFGGMMPSKSRESVASEGSNQTSGYQSGYHSDDTDTTVYSSDEAGLLKMVDAAVHADSGTTLQLTSCLNGSGPVPAPPPTPGNHERGAA)。本文使用之恆河猴VEGFR2包括可藉由NCBI資料庫中之登錄號XP_014994176.1訪問之胺基酸序列或SEQ ID NO: 101之胺基酸序列(MASKVLLAVALWLCVETRAASVGLPSVSLDLPRLSIQKDILTIKANTTLQITCRGQRDLDWLWPNNQSGSEQRVEVTECSDGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQDYRSPFIASVSDQHGVVYITENKNKTVVIPCLGSISNLNVSLCARYPEKRFVPDGNRISWDSKKGFTIPSYMISYAGMVFCEAKINDESYQSIMYIVVVVGYRIYDVVLSPSHGVELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKPFVAFGSGMESLVEATVGERVRIPVKYLGYPPPEIKWYKNGIPLESNHTVKVGHVLTIMEVSERDTGNYTVILTNPISKEKQSHVVSLVVYVPPQIGEKSLISPVDSYQYGTTQTLTCTVYAIPPPHHIHWYWQLEEECPNEPSQAVSVTNPYPCEEWRSVEDFQGGNKIEVNKNQFALIEGKNKTVSTLVIQAANVSALYKCEAVNKVGRGERVISFHVTRGPEITLQPDLQPTEQESVSLWCTADKSTFENLTWYKLGPQPLPVHVGELPTPVCKNLDTLWKLNATIFSNSTNDILIMELKNASLQDQGDYVCVAQDRKTKKRHCVVRQLTVLERVAPMITGNLENQTTSIGETIEVSCTASGNPPPQIMWFKDNETLVEDSGIVLKDGNRNLTIRRVRKEDEGLYTCQACSVLGCAKVEAFFIIEGAQEKTNLEIIILVGTAVIAMFFWLLLVIILRTVKRANGGELKTGYLSIVMDPDELPLDEHCERLPYDASKWEFPRDRLKLGKPLGRGAFGQVIEADAFGIDKTATCRTVAVKMLKEGATHSEHRALMSELKILIHIGHHLNVVNLLGACTKPGGPLMVIVEFCKFGNLSTYLRSKRNEFVPYKTKGARFRQGKDYVGAIPVDLKRRLDSITSSQSSASSGFVEEKSLSDVEEEEAPEDLYKDFLTLEHLICYSFQVAKGMEFLASRKCIHRDLAARNILLSEKNVVKICDFGLARDIYKDPDYVRKGDARLPLKWMAPETIFDRVYTIQSDVWSFGVLLWEIFSLGASPYPGVKIDEEFCRRLKEGTRMRAPDYTTPEMYQTMLDCWHGEPSQRPTFSELVEHLGNLLQANAQQDGKDYIVLPISETLSMEEDSGLSLPTSPVSCMEEEEVCDPKFHYDNTAGISQYLQNSKRKSRPVSVKTFEDIPLEEPEVKVIPDDNQTDSGMVLASEELKTLEDRTKLAPSFSGMVSSKSRESVASEGSNQTSGYQSGYHSDDTDTTVYSSEEAELLKLIEIGVQTGSTAQILQPDSGTTLSSPPV)。
如本文所用,「hVEGFR2相關」疾病或病症係指由hVEGFR2表現或活性之增加或減少引起、惡化或以其他方式相關之任何疾病或病症。在一些實施例中,hVEGFR2相關病症為例如癌症或血管生成疾病。
可與術語「血管內皮生長因子A」互換使用的「VEGF-A」係指高度保守之二聚體糖蛋白或其轉錄物剪接變異體,如分別含有206、189、165及121個胺基酸的VEGFA206、VEGFA189、VEGFA165及VEGFA121。VEGF-A為VEGF家族之成員,該家族亦包含其他成員,如VEGF-B、VEGF-C及VEGF-D。
如本文所用,「癌症」係指以惡性細胞生長或腫瘤、異常增殖、浸潤或轉移為特徵的任何醫學病症,且包含實體瘤及非實體癌(例如惡性血液病)如白血病。如本文所用,「實體腫瘤」係指贅生性及/或惡性細胞之實體塊。
如本文所用,「血管生成疾病」係指與血管生成過程中之異常相關之任何醫學病症,血管生成為新血管生長之過程。此類異常包含但不限於過度血管生成、血管生成不足、血管生成不當及破壞性血管生成。以例如過度或破壞性血管生成為特徵的此類醫學病症包含但不限於癌症、糖尿病性視網膜病變、年齡相關性黃斑變性及動脈粥樣硬化、中風及心肌梗塞、類風濕性關節炎。
術語「醫藥學上可接受之」表示指定的載劑、媒劑、稀釋劑、賦形劑及/或鹽通常與構成製劑的其他成分在化學上及/或物理上相容,且與接受者在生理上相容。
本文提及「約」值或參數包含(且描述)針對該值或參數本身的實施例。例如,提及「約X」之描述包含「X」之描述。數字範圍包含定義該範圍的數字。一般而言,術語「約」係指變數之指示值以及在指示值之實驗誤差內(例如,在平均值之95%信賴區間內)或在指示值之10%內(以較大者為凖)的變數之所有值。若在時間段(年、月、週、天等)之上下文中使用術語「約」,則術語「約」係指該時間段加上或減去下一個從屬時間段的一個量(例如約1年意謂11-13個月;約6個月意謂6個月加上或減去1週;約1週意謂6-8天;等等),或在指示值之10%內,以較大者為凖。
抗
-hVEGFR2
抗體
本發明提供抗-hVEGFR2抗體及其抗原結合片段。本文提供之抗-hVEGFR2抗體及抗原結合片段能夠特異性結合hVEGFR2或表現hVEGFR2之細胞。如本文所用,「特異性結合」係指結合親和力(例如K
D)≤10
-6M (例如,≤5×10
-7M、≤2×10
-7M、≤10
-7M、≤5×10
-8M、≤2×10
-8M、≤10
-8M、≤5×10
-9M、≤4×10
-9M、≤3×10
-9M、≤2×10
-9M或≤10
-9M)。
i. 結合親和力
本文提供之抗-hVEGFR2抗體及抗原結合片段之結合親和力可用K
D值表示,K
D值代表抗原與抗原結合分子之間的結合達至平衡時的解離速率與締合速率之比率(k
off/k
on)。低親和力抗體通常緩慢地結合抗原且傾向於容易解離,而高親和力抗體通常更快地結合抗原且傾向於保持更長時間之結合。可使用此項技術中已知的任何合適方法適當地確定抗原結合親和力(例如K
D),包含例如動力學排除分析(KinExA)、Biacore、Fortebio或流式細胞術。
在某些實施例中,根據本發明之「K
D」或「K
D值」在一個實施例中藉由使用抗-hVEGFR2抗體及hVEGFR2進行之Biacore分析量測,如藉由量測抗-hVEGFR2抗體之溶液結合親和力的以下分析所描述的。一般而言,Biacore的工作原理為將恆定量之一種結合伴侶(CBP)與不同濃度的另一種結合伴侶(滴定劑)進行平衡,然後在較短之接觸時間內藉由螢光標記的二抗捕獲一部分游離CBP,接觸時間小於預先形成之CBP-滴定劑複合物解離所需的時間。捕獲之CBP產生的螢光信號與平衡樣本中游離CBP的濃度成正比,且用於在系列量測時生成結合曲線(游離CBP百分比與總滴定劑濃度)。更多詳情可由Schreiber, G.、Fersht, A.R.,《自然結構生物學(Nature Structural Biology)》,1996, 3(5), 427-431獲得。當抗-hVEGFR2抗體以恆定量用作CBP時,則hVEGFR2蛋白可用作滴定劑,反之亦然。在某些實施例中,抗-hVEGFR2抗體或其抗原結合片段的K
D根據本發明實例16所述之方法確定。
在適用之情況下亦可使用適合量測Kd之其他方法,例如,放射性標記之抗原結合分析(參見例如Chen等人(1999),《分子生物學雜誌》293:865-881)。
在某些實施例中,抗-hVEGFR2抗體之結合親和力藉由流式細胞術量測。一般而言,表現hVEGFR2之細胞(例如,HUVEC)與一系列濃度之抗-hVEGFR2抗體一起培育,然後與螢光標記之二抗一起培育,然後分析螢光信號強度。在某些實施例中,抗-hVEGFR2抗體或其抗原結合片段之結合親和力根據本發明實例6中描述之方法確定。
在某些實施例中,本文提供之抗-hVEGFR2抗體及其抗原結合片段以由Biacore分析量測的不超過6 nM、5 nM、4 nM、3 nM、2 nM、1 nM或0.5 nM之K
D值特異性結合hVEGFR2 (或表現hVEGFR2之細胞)。在某些實施例中,本文提供之抗-hVEGFR2抗體及其抗原結合片段以由Biacore分析量測的不超過0.089 nM (或不超過0.001 nM)之K
D值特異性結合hVEGFR2 (或表現hVEGFR2之細胞)。
或者,本文提供之抗-hVEGFR2抗體及抗原結合片段對hVEGFR2之結合親和力亦可用「半最大有效濃度」(EC
50)值表示,其係指其中觀測到其最大作用(例如,結合)的50%之抗體濃度。EC
50值可藉由此項技術中已知的方法,例如夾心分析,如ELISA、西方墨點法、流動式細胞測量分析及其他結合分析來量測。在某些實施例中,本文提供之抗-hVEGFR2抗體及其片段以由ELISA量測的不超過80 ng/ml (或不超過70 ng/ml、65 ng/ml、60 ng/ml、55 ng/ml、50 ng/ml、45 ng/ml、40 ng/ml、35 ng/ml、30 ng/ml、25 ng/ml、20 ng/ml、15 ng/ml、12 ng/ml或10 ng/ml、9 ng/ml或8 ng/ml)之EC50值特異性結合重組hVEGFR2。在某些實施例中,本文提供之抗-hVEGFR2抗體及其片段以由ELISA量測的不超過35 ng/ml、24 ng/ml、15 ng/ml、10 ng/ml、9 ng/ml、8 ng/ml、7 ng/ml或6 ng/ml之EC50值特異性結合重組hVEGFR2。在某些實施例中,本文提供之抗-hVEGFR2抗體及其片段與小鼠VEGFR2交叉反應,藉由ELISA量測的EC50值不超過35 ng/ml。在某些實施例中,本文提供之抗-hVEGFR2抗體及其片段以不超過1121B之EC50值之60%的EC50值結合hVEGFR2,該EC50值由ELISA量測。在此類實施例中,抗-hVEGFR2抗體及其片段包括包括有SEQ ID NO: 31之序列的HCDR1、包括有SEQ ID NO: 32或SEQ ID NO: 37序列的HCDR2、包括有SEQ ID NO: 33之序列的HCDR3、包括有SEQ ID NO: 28之序列的LCDR1、包括有SEQ ID NO: 29之序列的LCDR2及包括有SEQ ID NO: 30之序列的LCDR3。在某些實施例中,本文提供之抗-hVEGFR2抗體及其片段與恆河猴VEGFR2交叉反應,藉由ELISA量測之EC50值不超過30 ng/ml、25 ng/ml、20 ng/ml、15 ng/ml、10 ng/ml或9 ng/ml。
在某些實施例中,本文提供之抗-hVEGFR2抗體及其片段以由流式細胞術量測的不超過160 ng/ml (或不超過150 ng/ml、140 ng/ml、130 ng/ml、120 ng/ml、110 ng/ml、100 ng/ml、90 ng/ml、80 ng/ml、70 ng/ml、65 ng/ml、55 ng/ml、50 ng/ml、45 ng/ml、40 ng/ml、35 ng/ml、30 ng/ml或25 ng/ml)的EC50值特異性結合表現hVEGFR2 (例如,HUVEC)的細胞。
在某些實施例中,本文提供之抗體及其抗原結合片段表現出有效阻斷VEGFR2與VEGF-A結合的競爭性VEGFR2結合特性。本文提供之抗體及其抗原結合片段的阻斷作用可使用例如本發明之實例5中描述之ELISA來量測。在某些實施例中,本文提供之抗體及其抗原結合片段之阻斷作用可以IC50表示,IC50表示在本發明之抗體及其抗原結合片段之存在下VEGFR2與VEGF-A之結合降低50%時的本文提供之抗體及其抗原結合片段之濃度。在某些實施例中,本文提供之抗體及其抗原結合片段之IC50之範圍為0.001 μg/ml至2.5 μg/ml、0.005 μg/ml至0.5 μg/ml、0.05 μg/ml至0.4 μg/ml或0.1 μg/ml至0.2 μg/ml。在某些實施例中,本文提供之抗體及其抗原結合片段以不超過1121B之IC50值之82%的IC50值阻斷VEGF-A誘導之表現hVEGFR2的細胞之增殖,該IC50值藉由細胞活力分析量測。在此類實施例中,本文提供之抗體及其抗原結合片段包括包括有SEQ ID NO: 31之序列的HCDR1、包括有SEQ ID NO: 37之序列的HCDR2以及包括有SEQ ID NO: 33之序列的HCDR3、包括有SEQ ID NO: 28之序列的LCDR1、包括有SEQ ID NO: 29之序列的LCDR2以及包括有SEQ ID NO: 30之序列的LCDR3,較佳在CHO中表現。
抗原決定基
在某些實施例中,本文提供之抗-hVEGFR2抗體或其抗原結合片段結合包括至少一或多個(例如,一個、兩個、三個或更多個)在具有SEQ ID NO: 103之胺基酸序列的hVEGFR2的位置Y137A、R164A、Y165A、V218A、Y221A、R222A、E251A、L252A、N253A、G255A、D257A、K286A、G312A、L313A、M314A、T315A及K316A處的胺基酸殘基的抗原決定基。
如本文所用,術語「抗原決定基」係指抗體所結合之抗原上特定的一組原子或胺基酸。抗原決定基可包含直接接觸抗體之特定胺基酸、糖側鏈、磷醯基或磺醯基。熟習此項技術者將認識到,無需過多實驗即可藉由確定抗體是否與本發明之抗體(例如雜交瘤/嵌合或人類化抗體
002、
003、
006、
018、
042 、 048及
054及本文提供之任何嵌合及其人類化變異體)競爭結合hVEGFR2抗原多肽來確定兩者是否結合相同或重疊或相鄰的抗原決定基。
如本文所用,關於兩種抗原結合蛋白(例如抗體)之術語「競爭結合」係指由競爭性結合分析確定的一種抗原結合蛋白阻斷或減少另一種與抗原(例如人類/小鼠/恆河猴VEGFR2)之結合。競爭性結合分析在此項技術中眾所周知,包含例如直接或間接放射免疫分析(RIA)、直接或間接酶免疫分析(EIA)及夾心競爭分析(參見例如Stahli等人1983, 《酶學方法》9:242-253)。通常,此類分析涉及使用與固體表面結合之純化抗原或帶有抗原之細胞、未標記之測試抗體及標記之參考抗體。競爭性抑制藉由測定在測試抗體存在下結合於固體表面或細胞之標記的量來量測。通常測試抗體過量存在。若兩種抗體競爭結合hVEGFR2,則兩種抗體結合相同或重疊的抗原決定基,或與由另一抗體結合之抗原決定基足夠臨近的相鄰抗原決定基以發生空間位阻。通常,當競爭性抗體過量存在時,它將測試抗體與共同抗原之特異性結合抑制(例如,降低)至少50-55%、55-60%、60-65%、65-70 %、70-75%、75-80%、80-85%、85-90%或更多。
在某些實施例中,抗原決定基或抗體結合的抗原決定基中之胺基酸殘基可藉由突變抗原(亦即hVEGFR2)中之特定殘基來確定。若抗體以相對於其與野生型hVEGFR2之結合顯著降低的水準結合具有突變之胺基酸殘基(例如突變為丙胺酸)的突變hVEGFR2,則此將表明突變殘基直接參與抗體與hVEGFR2抗原之結合,或者當它與抗原結合時與抗體非常接近。此類突變殘基被認為在抗原決定基內,且抗體被認為與包括該殘基之抗原決定基特異性結合。如本文所用,顯著降低之結合水準係指抗體與突變hVEGFR2之間的結合親和力(例如EC50、KD或結合能力)相對於抗體與野生型hVEGFR2之間的結合降低超過10%、20%、30%、40%、50%、60%、70%、80%、90%或更多。此類結合量測可使用此項技術中已知及本文揭示之任何合適方法進行,例如但不限於KinExA分析、ELISA、Biacore、Fortebio及流式細胞術。
在某些實施例中,本文提供之抗-hVEGFR2抗體或其抗原結合片段顯示出由ELISA量測的與突變hVEGFR2之結合降低(例如降低至少30%,降低50%),其中野生型hVEGFR2中之殘基被丙胺酸取代,且殘基選自由以下組成之群:Y137A、R164A、Y165A、V218A、Y221A、R222A、E251A、L252A、N253A、G255A、D257A、K286A、G312A、L313A、M314A、T315A及K316A (相對於SEQ ID NO:103)。
在某些實施例中,本文提供之抗-hVEGFR2抗體或其抗原結合片段結合hVEGFR2上之抗原決定基,其中該抗原決定基包括一或多個選自由以下組成之群的胺基酸殘基:SEQ ID NO: 103之Y137、R164、Y165、V218、Y221、R222、E251、L252、N253、G255、D257、K286、G312、L313、M314、T315及K316。
在某些實施例中,本文提供之抗-hVEGFR2抗體或其抗原結合片段結合包括SEQ ID NO: 103之Y165及/或L313但不包括R222、G255、D257及T315中任一個的抗原決定基。
在某些實施例中,本文提供之抗-hVEGFR2抗體或其抗原結合片段結合包括SEQ ID NO: 103之Y137、V218、Y221、R222、E251、L252、N253、G255、D257、K286、L313、M314、T315、K316或其任何組合的抗原決定基。
在某些實施例中,本文提供之抗-hVEGFR2抗體或其抗原結合片段結合包括SEQ ID NO: 103之R164、Y165、D257或其任何組合的抗原決定基。
在某些實施例中,本文提供之抗-hVEGFR2抗體或其抗原結合片段結合包括SEQ ID NO: 103之Y165、Y221、R222、E251、G255、D257、G312、L313、M314、T315、K316或其任何組合的抗原決定基。
在某些實施例中,本文提供之抗-hVEGFR2抗體或其抗原結合片段結合包括SEQ ID NO: 103之Y165但不包括R222、G255、D257、L313及T315的抗原決定基。
在某些實施例中,本文提供之抗-hVEGFR2抗體或其抗原結合片段結合包括SEQ ID NO: 103之Y165、Y221、R222、E251、N253、G255、D257、G312、L313、M314、T315、K316或其任何組合的抗原決定基。
在某些實施例中,本文提供之抗-hVEGFR2抗體或其抗原結合片段結合包括SEQ ID NO: 103之R164、Y165、D257或其任何組合的抗原決定基。
在某些實施例中,本文提供之抗-hVEGFR2抗體或其抗原結合片段結合包括SEQ ID NO: 103之Y165、Y221、R222、E251、N253、G255、D257、G312、L313、M314、T315、K316或其任何組合的抗原決定基。
抗體序列
在另一態樣中,本發明提供了一種抗-hVEGFR2抗體或其抗原結合片段,其包括重鏈HCDR1、HCDR2及HCDR3及/或輕鏈LCDR1、LCDR2及LCDR3序列,其中
HCDR1序列包括
SSWMN(SEQ ID NO: 1)、
DYYMS(SEQ ID NO: 19)、
X
1YGMS
(SEQ ID NO: 41)、
X
4YWIM
(SEQ ID NO: 44)或其至少80%序列同一性的同源序列;
HCDR2序列包括
RIFPGDGDTYYNGKFQV(SEQ ID NO: 2)、
FIRNKANGYTTEYSASVKG(SEQ ID NO: 20)、
SISX
2GGSYTYYADSVX
19G
(SEQ ID NO: 42)、
DIYPGX
5GSTNYNEKFKS
(SEQ ID NO: 45)或其至少80%序列同一性的同源序列;
HCDR3序列包括
FLDTSGRYVDY(SEQ ID NO: 3)、
FDYYGSTYCFDY(SEQ ID NO: 21)、
EX
3DGNYDY
(SEQ ID NO: 43)、
DSNPDY(SEQ ID NO: 46)或其至少80%序列同一性的同源序列;
LCDR1序列包括
KASQDVNTAVA(SEQ ID NO: 4)、
RASQSVSTSSSSFMH(SEQ ID NO: 22)、
RSSKSLLYKDGKTYLN(SEQ ID NO: 28)、
RASESVX
6NSGISFMX
7 (SEQ ID NO: 47)或其至少80%序列同一性的同源序列;
LCDR2序列包括
SASYRYI(SEQ ID NO: 5)、
YASNLES(SEQ ID NO: 23)、
LMSTRAS(SEQ ID NO: 29)、
AASX
8QX
9S
(SEQ ID NO: 48)或其至少80%序列同一性的同源序列;
LCDR3序列包括
QQHYRAPLT(SEQ ID NO: 6)、
QHTWEIPLT(SEQ ID NO: 24)、
QQLVEYPFT(SEQ ID NO: 30)、
QQSKEVPYT(SEQ ID NO: 49)或其至少80%序列同一性的同源序列,
其中X
1為I或M,X
2為V或I,X
3為L或M,X
4為T或S,X
5為T或S,X
6為D或E,X
7為T或H,X
8為T或Y,X
9為G或R且X
19為E或K。
在一個態樣中,本發明提供了本文提供之抗-hVEGFR2抗體或其抗原結合片段,其中HCDR1包括SEQ ID NO: 41之胺基酸序列,HCDR2包括SEQ ID NO: 42之胺基酸序列,HCDR3包括SEQ ID NO: 43之胺基酸序列,LCDR1包括SEQ ID NO: 28之序列,LCDR2包括SEQ ID NO: 29之序列,且LCDR3包括SEQ ID NO: 30之序列。
在一個態樣中,本發明提供了本文提供之抗-hVEGFR2抗體或其抗原結合片段,其中
a) HCDR1包括SEQ ID NO: 25之序列,HCDR2包括SEQ ID NO: 26之序列,HCDR3包括SEQ ID NO: 27之序列;LCDR1包括SEQ ID NO: 28之序列,LCDR2包括SEQ ID NO: 29之序列,且LCDR3包括SEQ ID NO: 30之序列;或者
b) HCDR1包括SEQ ID NO: 31之序列,HCDR2包括SEQ ID NO: 32或SEQ ID NO: 37之序列,且HCDR3包括SEQ ID NO: 33之序列,LCDR1包括SEQ ID NO: 28之序列,LCDR2包括SEQ ID NO: 29之序列,且LCDR3包括SEQ ID NO: 30之序列;或者
c) HCDR1包括SEQ ID NO: 34之序列,HCDR2包括SEQ ID NO: 35或SEQ ID NO: 37之序列,且HCDR3包括SEQ ID NO: 36之序列,LCDR1包括SEQ ID NO: 28之序列,LCDR2包括SEQ ID NO: 29之序列,且LCDR3包括SEQ ID NO: 30之序列。
在一個態樣中,本發明提供了本文提供之抗-hVEGFR2抗體或其抗原結合片段,其中HCDR1包括SEQ ID NO: 44之胺基酸序列,HCDR2包括SEQ ID NO: 45之胺基酸序列,HCDR3包括SEQ ID NO: 46之胺基酸序列,LCDR1包括SEQ ID NO: 47之序列,LCDR2包括SEQ ID NO: 48之序列,且LCDR3包括SEQ ID NO: 49之序列。
在一個態樣中,本發明提供了本文提供之抗-hVEGFR2抗體或其抗原結合片段,其中
a) HCDR1包括SEQ ID NO: 7之序列,HCDR2包括SEQ ID NO: 8之序列,HCDR3包括SEQ ID NO: 9之序列;LCDR1包括SEQ ID NO: 10之序列,LCDR2包括SEQ ID NO: 11之序列,且LCDR3包括SEQ ID NO: 12之序列;或者
b) HCDR1包括SEQ ID NO: 13之序列,HCDR2包括SEQ ID NO: 14之序列,且HCDR3包括SEQ ID NO: 15之序列,LCDR1包括SEQ ID NO: 16之序列,LCDR2包括SEQ ID NO: 17之序列,且LCDR3包括SEQ ID NO: 18之序列。
在一個態樣中,本發明提供了本文提供之抗-hVEGFR2抗體或其抗原結合片段,其中
a) HCDR1包括SEQ ID NO: 1之序列,HCDR2包括SEQ ID NO: 2之序列,且HCDR3包括SEQ ID NO: 3之序列,LCDR1包括SEQ ID NO: 4之序列,LCDR2包括SEQ ID NO: 5之序列,且LCDR3包括SEQ ID NO: 6之序列;或者
b) HCDR1包括SEQ ID NO: 19之序列,HCDR2包括SEQ ID NO: 20之序列,且HCDR3包括SEQ ID NO: 21之序列,LCDR1包括SEQ ID NO: 22之序列,LCDR2包括SEQ ID NO: 23之序列,且LCDR3包括SEQ ID NO: 24之序列。
在某些實施例中,本文提供之抗體包括hVEGFR2抗體
002、
003、
006、
018、
042、
048及
054之一或多個(例如1、2、3、4、5或6個)CDR序列。
如本文所用,關於抗體之「002」或「2」係指具有SEQ ID NO: 50之重鏈可變區及SEQ ID NO: 51之輕鏈可變區的小鼠抗體。
如本文所用,關於抗體之「003」或「3」係指具有SEQ ID NO: 52之重鏈可變區及SEQ ID NO: 53之輕鏈可變區的小鼠抗體。
如本文所用,關於抗體之「006」或「6」係指具有SEQ ID NO: 54之重鏈可變區及SEQ ID NO: 55之輕鏈可變區的小鼠抗體。
如本文所用,關於抗體之「018」或「18」係指具有SEQ ID NO: 56之重鏈可變區及SEQ ID NO: 57之輕鏈可變區的小鼠抗體。
如本文所用,關於抗體之「042」或「42」係指具有SEQ ID NO: 58之重鏈可變區及SEQ ID NO: 59之輕鏈可變區的小鼠抗體。
如本文所用,關於抗體之「048」或「48」係指具有SEQ ID NO: 60之重鏈可變區及SEQ ID NO: 61之輕鏈可變區的小鼠抗體。
如本文所用,關於抗體之「054」或「45」係指具有SEQ ID NO: 62之重鏈可變區及SEQ ID NO: 63之輕鏈可變區的小鼠抗體。
表1顯示了此等hVEGFR2抗體之CDR序列。重鏈及輕鏈可變區序列亦提供於下表2中。
表 1. hVEGFR2 抗體之 CDR 區序列
其中X
1為I或M,X
2為V或I,X
3為L或M,X
4為T或S,X
5為T或S,X
6為D或E,X
7為T或H,X
8為T或Y,X
9為G或R且X
19為E或K。
區域 | CDR1 | CDR2 | CDR3 | |
002 | HCDR | SEQ ID NO: 1 | SEQ ID NO: 2 | SEQ ID NO: 3 |
SSWMN | RIFPGDGDTYYNGKFQV | FLDTSGRYVDY | ||
LCDR | SEQ ID NO: 4 | SEQ ID NO: 5 | SEQ ID NO: 6 | |
KASQDVNTAVA | SASYRYI | QQHYRAPLT | ||
003 | HCDR | SEQ ID NO: 7 | SEQ ID NO: 8 | SEQ ID NO: 9 |
TYWIM | DIYPGTGSTNYNEKFKS | DSNPDY | ||
LCDR | SEQ ID NO: 10 | SEQ ID NO: 11 | SEQ ID NO: 12 | |
RASESVDNSGISFMT | AASTQGS | QQSKEVPYT | ||
006 | HCDR | SEQ ID NO: 13 | SEQ ID NO: 14 | SEQ ID NO: 15 |
SYWIM | DIYPGSGSTNYNEKFKS | DSNPDY | ||
LCDR | SEQ ID NO: 16 | SEQ ID NO: 17 | SEQ ID NO: 18 | |
RASESVENSGISFMH | AASYQRS | QQSKEVPYT | ||
018 | HCDR | SEQ ID NO: 19 | SEQ ID NO: 20 | SEQ ID NO: 21 |
DYYMS | FIRNKANGYTTEYSASVKG | FDYYGSTYCFDY | ||
LCDR | SEQ ID NO: 22 | SEQ ID NO: 23 | SEQ ID NO: 24 | |
RASQSVSTSSSSFMH | YASNLES | QHTWEIPLT | ||
042 | HCDR | SEQ ID NO: 25 | SEQ ID NO: 26 | SEQ ID NO: 27 |
IYGMS | SISVGGSYTYYADSVEG | ELDGNYDY | ||
LCDR | SEQ ID NO: 28 | SEQ ID NO: 29 | SEQ ID NO: 30 | |
RSSKSLLYKDGKTYLN | LMSTRAS | QQLVEYPFT | ||
048 | HCDR | SEQ ID NO: 31 | SEQ ID NO: 32 | SEQ ID NO: 33 |
MYGMS | SISIGGSYTYYADSVEG | EMDGNYDY | ||
SEQ ID NO: 37 | ||||
SISIGGSYTYYADSV KG | ||||
LCDR | SEQ ID NO: 28 | SEQ ID NO: 29 | SEQ ID NO: 30 | |
RSSKSLLYKDGKTYLN | LMSTRAS | QQLVEYPFT | ||
054 | HCDR | SEQ ID NO: 34 | SEQ ID NO: 35 | SEQ ID NO: 36 |
MYGMS | SISIGGSYTYYADSVEG | ELDGNYDY | ||
SEQ ID NO: 37 | ||||
SISIGGSYTYYADSV KG | ||||
LCDR | SEQ ID NO: 28 | SEQ ID NO: 29 | SEQ ID NO: 30 | |
RSSKSLLYKDGKTYLN | LMSTRAS | QQLVEYPFT | ||
042及048及054 | HCDR | SEQ ID NO: 41 | SEQ ID NO: 42 | SEQ ID NO: 43 |
X 1YGMS | SISX 2GGSYTYYADSVX 19G | EX 3DGNYDY | ||
LCDR | SEQ ID NO: 28 | SEQ ID NO: 29 | SEQ ID NO: 30 | |
RSSKSLLYKDGKTYLN | LMSTRAS | QQLVEYPFT | ||
003及006 | HCDR | SEQ ID NO: 44 | SEQ ID NO: 45 | SEQ ID NO: 46 |
X 4YWIM | DIYPGX 5GSTNYNEKFKS | DSNPDY | ||
LCDR | SEQ ID NO: 47 | SEQ ID NO: 48 | SEQ ID NO: 49 | |
RASESVX 6NSGISFMX 7 | AASX 8QX 9S | QQSKEVPYT |
表 2. 小鼠 / 嵌合抗體 VH/VL 之序列
其中CDR區加粗。
VH | VL | |
002 | SEQ ID NO: 50 | SEQ ID NO: 51 |
QVQLQQSGPELVKPGASVKISCKASGYAFS SSWMNWVKQRPGEGLEWIG RIFPGDGDTYYNGKFQVKATLTADKSSSTAYMQLSSLTSEDSAVYFCAI FLDTSGRYVDYWGQGTTLTISS | DIVMTQSHKFMSTSVGDRVSITC KASQDVNTAVAWYQQKPGQSPKLLIY SASYRYIGVPDRFTGSGSGTDFTFTISSVQSEDLTVYYC QQHYRAPLTFGSGTKLELK | |
003 | SEQ ID NO: 52 | SEQ ID NO: 53 |
QVQLQQPGAELVKPGASVKMSCKASGYTFN TYWIMWVKQRPGQGLEWIG DIYPGTGSTNYNEKFKSKVTLTADTSSTTAYMQVSSLTSEDSAVYYCGR DSNPDYWGQGTTLTVSS | DIVLTQSPASLAVSLGQRATISC RASESVDNSGISFMTWFQQKPGQPPKLLIY AASTQGSGVPARFSGSGSGTDFSLNIHPVEEDDTAMYFC QQSKEVPYTFGGGTKLEIK | |
006 | SEQ ID NO: 54 | SEQ ID NO: 55 |
QAQLQQPGAELVKPGTSVKMSCKASGYTFN SYWIMWVKQSPGQGLEWIG DIYPGSGSTNYNEKFKSKVTLTVDTSSSTAYMQVSSLTSEDSAVYYCAR DSNPDYWGQGTTLTVSS | DIVLTQSPASLAVSLGQRATISC RASESVENSGISFMHWFQQKPGQPPKLLIY AASYQRSGVPARFSGSGSGTDFSLNIHPVEEDDIAMYFC QQSKEVPYTFGGGTKLEIK | |
018 | SEQ ID NO: 56 EVKLVESGGGLVQPGGSLSLSCAVSGFTFT DYYMSWVRQPPGKALEWLG FIRNKANGYTTEYSASVKGRFTISRDNSQSILYLQMNALRAEDSATYYCAR FDYYGSTYCFDYWGQGTTLTVSS | SEQ ID NO: 57 DIVLTQSPASLAVSLGQRATISC RASQSVSTSSSSFMHWYQQKPGQPPKLLIK YASNLESGVPARFSGSGSGTDFTLNIHPVEEEDTATYYC QHTWEIPLTFGAGTKLELK |
042 | SEQ ID NO: 58 EVQLVESGGDLVKPGGSLKLSCTASGFSFS IYGMSWVRQTPDKRLEWVA SISVGGSYTYYADSVEGRFTISRENAKNTLYLQMNSLKSEDTALYYCAR ELDGNYDYWGQGTSLTVSS | SEQ ID NO: 59 DIVITQNELSNPVTFGESVSISC RSSKSLLYKDGKTYLNWFLQRPGQSPQLLIY LMSTRASGVSDRFSGSGSGTDFTLEISRVKAEDVGVYYC QQLVEYPFTFGSGTKLEIK |
048 | SEQ ID NO: 60 EVQLVESGGDLVKPGGSLKLSCAASGFTFS MYGMSWVRQTPDKRLEWVA SISIGGSYTYYADSVEGRFTISRENAKNTLFLQMNSLKSEDTALYYCAR EMDGNYDYWGHGTTLTVSS | SEQ ID NO: 61 DVMITQDELSNPVTFGESVSISC RSSKSLLYKDGKTYLNWFLQRPGQSPQLLIY LMSTRASGVSDRFSGSGSGTDFTLEISRVKAEDVGIYYC QQLVEYPFTFGSGTKLEIK |
054 | SEQ ID NO: 62 EVQLVESGGDLVKPGGSLKLSCAASGFTFS MYGMSWVRQTPDKRLEWVA SISIGGSYTYYADSVEGRFIISRENAKNTLFLQMNSLKSEDTALYYCAR ELDGNYDYWGQGTTLTVSS | SEQ ID NO: 63 HIMITQDELSNPVTFGESVSISC RSSKSLLYKDGKTYLNWFLQRPGQSPQLLIY LMSTRASGVSDRFSGSGSGTDFTLEISRVKAEDVGIYYC QQLVEYPFTFGSGTKLEIK |
本文提供之抗-hVEGFR2抗體或其抗原結合片段可為單株抗體、多株抗體、人類化抗體、嵌合抗體、重組抗體、雙特異性抗體、標記抗體、二價抗體或抗獨特型抗體。重組抗體為使用重組方法在活體外而非在動物體內製備的抗體。
已知CDR負責抗原結合,然而,已發現並非所有6個CDR均一定為必不可少的或不可改變的。換句話說,有可能替換或改變或修飾在本文提供之抗-hVEGFR2抗體中之1、2或3個CDR,但仍實質上保留對hVEGFR2之特異性結合親和力。
在某些實施例中,本文提供之抗-hVEGFR2抗體及抗原結合片段包括抗-hVEGFR2抗體
002、
003、
006、
018、
042、
048及
054中一個的重鏈CDR3序列。重鏈CDR3區位於抗原結合位點之中心,且因此被認為與抗原接觸最多,且為抗體與抗原之親和力提供最多的自由能。亦認為至目前為止重鏈CDR3為抗原結合位點中在長度、胺基酸組成及構形方面藉由多種多樣化機制變化最多之CDR (Tonegawa S.,《自然》,302:575-81)。重鏈CDR3的多樣性足以產生大多數的抗體特異性(Xu JL、Davis MM.,《免疫(Immunity)》,13:37-45)以及理想的抗原結合親和力(Schier R等人,《分子生物學雜誌》,263:551-67)。
在一些實施例中,本文提供之抗-hVEGFR2抗體及抗原結合片段包括全部或部分的重鏈可變域及/或全部或部分的輕鏈可變域。在一個實施例中,本文提供之抗-hVEGFR2抗體及抗原結合片段為單域抗體,其由本文提供之全部或部分重鏈可變域組成。此類單域抗體之更多資訊可在此項技術中獲得(參見例如美國專利號6,248,516)。
在某些實施例中,本文提供之抗體及其抗原結合片段包括合適的構架區(FR)序列,只要該抗體及其抗原結合片段能特異性地與hVEGFR2結合。表1中提供之CDR序列獲自小鼠抗體,但其可使用此項技術中已知的合適方法如重組技術移植至任何合適的物種如小鼠、人類、大鼠、兔等的任何合適的FR序列上。
在某些實施例中,本文提供之抗體及其抗原結合片段為人類化的。人類化抗體或抗原結合片段的可取之處在於其對人類之免疫原性降低。人類化抗體在其可變區中為嵌合的,因為非人類CDR序列被移植至人類或實質上人類FR序列。抗體或抗原結合片段之人類化基本上可藉由將非人類(如鼠)CDR基因替換為人類免疫球蛋白基因中相應的人類CDR基因來進行(參見例如,Jones等人(1986),《自然》321:522-525;Riechmann等人(1988),《自然》332:323-327;Verhoeyen等人(1988),《科學(Science)》,239:1534-1536)。
可使用此項技術中已知的方法選擇合適的人類重鏈及輕鏈可變域以實現此目的。在一個說明性之實例中,可使用「最佳匹配」方法,其中篩選非人類(例如嚙齒動物)抗體可變域序列或針對已知的人類可變域生殖系序列資料庫進行BLAST比對,且最接近非人查詢序列的人類序列被識別且用作用於移植非人類CDR序列之人類支架(參見例如,Sims等人(1993),《免疫學雜誌(J. Immunol.)》,151:2296;Chothia等人(1987),《分子生物學雜誌》,196:901)。或者,源自所有人類抗體之共有序列的構架可用於移植非人類CDR (參見例如,Carter等人(1992),《美國國家科學院院刊》,89:4285;Presta等人(1993),《免疫學雜誌》,151:2623)。
在某些實施例中,本文提供之人類化抗體或抗原結合片段由實質上所有人類序列構成,非人類CDR序列除外。在一些實施例中,可變區FR及恆定區若存在則完全或實質上來自人類免疫球蛋白序列。人類FR序列及人類恆定區序列可來源於不同的人類免疫球蛋白基因,例如FR序列來源於一種人類抗體,且恆定區來源於另一人類抗體。在一些實施例中,人類化抗體或抗原結合片段包括人類重/輕鏈FR1-4。
在一些實施例中,來源於人類之FR區可包括與其來源於的人類免疫球蛋白相同之胺基酸序列。在一些實施例中,人類FR的一或多個胺基酸殘基經來自親本非人類抗體之相應殘基取代。在某些實施例中,此可能為合乎需要的,以使人類化抗體或其片段緊密地接近非人類親本抗體結構,以減少或避免免疫原性及/或改善或保留結合活性或結合親和力。
在某些實施例中,本文所提供之人類化抗體或抗原結合片段在各人類FR序列中包括不超過10、9、8、7、6、5、4、3、2或1個胺基酸殘基取代,或者在重鏈或輕鏈可變域的所有FR中包括不超過10、9、8、7、6、5、4、3、2或1個胺基酸殘基取代。在一些實施例中,此類胺基酸殘基之變化可僅存在於重鏈FR區,僅存在於輕鏈FR區,或存在於兩條鏈中。在某些實施例中,一或多個胺基酸殘基突變,例如,回復突變為在衍生CDR序列的非人類親本抗體(例如在小鼠構架區)中發現的相應殘基。合適的突變位置可由技術人員按照此項技術中已知的原則選擇。例如,在以下情況下可選擇突變位置:1)人類生殖系序列構架中之殘基為罕見的(例如在人類可變區序列中少於20%或少於10%);2)該位置緊鄰人類生殖繫鏈主序列中3個CDR中之一或多者,因為它可能與CDR中之殘基相互作用;或3)該位置在3維模型中接近CDR,且因此可與CDR中之胺基酸相互作用的概率大。所選位置之殘基可突變回親本抗體中之相應殘基,或者突變為以下殘基,其既不為人類生殖系序列中之相應殘基亦不為親本抗體中之相應殘基,而係人類序列的典型殘基,亦即在屬於與人類生殖系序列相同的子組的已知人類序列中更頻繁地出現在該位置的殘基(參見美國專利號5,693,762)。
在某些實施例中,本發明之人類化輕鏈及重鏈在人類中實質上沒有免疫原性,且保持與hVEGFR2的親本抗體實質上相同的親和力或甚至更高的親和力。
在某些實施例中,本文提供之人類化抗體及其抗原結合片段包括人類生殖系構架序列VK/2D-40之一或多個輕鏈FR序列,及/或人類生殖系構架序列VH/3-21之一或多個重鏈FR序列,其中有或沒有回復突變。若需要的話,可將回復突變引入人類生殖系構架序列中。在某些實施例中,人類化抗體
054可含有一或多個選自由以下組成之群的回復突變:相對於重鏈構架序列VH/3-21的SEQ ID NO: 92 (EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARELDGNYDYWGQGTTLTVSS) 中之構架序列的R19K、A40T、G44R、S49A、S78T及R87K。人類化抗體
048可含有一或多個選自由以下組成之群的回復突變:相對於重鏈構架序列VH/3-21的SEQ ID NO: 92 (EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARELDGNYDYWGQGTTLTVSS) 中之構架序列的G44R、S49A及S78T。在某些實施例中,人類化抗體
054/048可含有一或多個選自由以下組成之群的回復突變:相對於輕鏈構架序列VK/2D-40的SEQ ID NO: 95(DIVMTQTPLSLPVTPGEPASISCRSSQSLLDSDDGNTYLDWYLQKPGQSPQLLIYTLSYRASGVPDRFSGSGTDFTLKISRVEAEDVGVYYCMQRIEFP) 中之構架序列的M4T、T7D、P8E、P15F、P18S、A19V、Y42F、K45R、P65S及V91I。
在某些實施例中,本文提供之抗-hVEGFR2抗體或其抗原結合片段包括重鏈可變區,其包括選自由SEQ ID NO: 93、SEQ ID NO: 94及SEQ ID NO: 98組成之群的序列,以及其具有至少80% (例如至少85%、90%、95%、96%、97%、98%或99%)序列同一性但仍保留對hVEGFR2,尤其人類hVEGFR2之特異性結合親和力的同源序列。
在某些實施例中,本文提供之抗-hVEGFR2抗體或其抗原結合片段包括輕鏈可變區,其包括選自由SEQ ID NO: 96及SEQ ID NO: 97組成之群的序列,以及其具有至少80% (例如至少85%、90%、95%、96%、97%、98%或99%)序列同一性但仍保留對hVEGFR2,尤其人類hVEGFR2之特異性結合親和力的同源序列。
在某些實施例中,本文提供之抗-hVEGFR2抗體或其抗原結合片段包括:重鏈可變區及輕鏈可變區,該重鏈可變區包括選自由SEQ ID NO: 93、SEQ ID NO: 94及SEQ ID NO: 98組成之群的序列,該輕鏈可變區包括SEQ ID NO: 96或SEQ ID NO: 97之序列。
在某些實施例中,本文提供之抗-hVEGFR2抗體或其抗原結合片段進一步包括重鏈HFR1、HFR2、HFR3及HFR4中之一或多者,及/或輕鏈LFR1、LFR2、LFR3及LFR4中之一或多者,其中:
HFR1包括
EVQLVESGGGLVKPGGSLX
10LSCAASGFTFS
(SEQ ID NO: 84)或其至少80% (或至少85%、90%、95%)序列同一性的同源序列,
HFR2包括
WVRQX
11PGKRLEWVA
(SEQ ID NO: 85)或其至少80% (或至少90%)序列同一性的同源序列,
HFR3序列包括
RFTISRDNAKNTLYLQMNSLX
12AEDTAVYYCAR
(SEQ ID NO: 86)或其至少80% (或至少85%、90%、95%)序列同一性的同源序列,
HFR4包括
WGX
13GTTLTVSS
(SEQ ID NO: 87)或其至少80%序列同一性的同源序列,
LFR1包括
DIVITQX
14X
15LSLPVTX
16GESVSISC
(SEQ ID NO: 88)或其至少80% (或至少85%、90%、95%)序列同一性的同源序列,
LFR2包括
WFLQRPGQSPQLLIY(SEQ ID NO: 89)或其至少80% (或至少85%、90%)序列同一性的同源序列,
LFR3包括
GVX
17DRFSGSGSGTDFTLKISRVEAEDVGX
18YYC
(SEQ ID NO: 90)或其至少80% (或至少85%、90%、95%)序列同一性的同源序列,及
LFR4包括
FGSGTKLEIK(SEQ ID NO: 91)或其至少80% (或至少90%)序列同一性的同源序列,
其中X
10為R或K,X
11為A或T,X
12為R或K,X
13為Q或H,X
14為D或T,X
15為E或P,X
16為F或P,X
17為S或P,X
18為V或I。
在某些實施例中,HFR1包括選自由SEQ ID NO: 64、68及72組成之群的序列,HFR2包括選自由SEQ ID NO: 65、69及73組成之群的序列,HFR3包括選自由SEQ ID NO: 66、70及74組成之群的序列,HFR4包括選自由SEQ ID NO: 67、71及75組成之群的序列,LFR1包括選自由SEQ ID NO: 76及80組成之群的序列,LFR2包括選自由SEQ ID NO: 77及81組成之群的序列,LFR3包括選自由SEQ ID NO: 78及82組成之群的序列,以及LFR4包括選自由SEQ ID NO: 79及83組成之群的序列。
表
3.
人類化
hVEGFR2
抗體
054
及
048
之構架
(FR)
序列
抗體鏈 | FR1 | FR2 | FR3 | FR4 |
Mab54-Hzd-HC-V1 | SEQ ID NO: 64 | SEQ ID NO: 65 | SEQ ID NO: 66 | SEQ ID NO: 67 |
EVQLVESGGGLVKPGGSLKLSCAASGFTFS | WVRQTPGKRLEWVA | RFTISRDNAKNTLYLQMNSLKAEDTAVYYCAR | WGQGTTLTVSS | |
Mab54-HC-V2 | SEQ ID NO: 68 | SEQ ID NO: 69 | SEQ ID NO: 70 | SEQ ID NO: 71 |
EVQLVESGGGLVKPGGSLRLSCAASGFTFS | WVRQAPGKRLEWVA | RFTISRDNAKNTLYLQMNSLRAEDTAVYYCAR | WGQGTTLTVSS | |
Mab48-Hzd-HC-V3 | SEQ ID NO:72 | SEQ ID NO: 73 | SEQ ID NO: 74 | SEQ ID NO: 75 |
EVQLVESGGGLVKPGGSLRLSCAASGFTFS | WVRQAPGKRLEWVA | RFTISRDNAKNTLYLQMNSLRAEDTAVYYCAR | WGHGTTLTVSS | |
Mab54-Hzd-LC-V1 | SEQ ID NO: 76 | SEQ ID NO: 77 | SEQ ID NO: 78 | SEQ ID NO: 79 |
DIVITQDELSLPVTFGESVSISC | WFLQRPGQSPQLLIY | GVSDRFSGSGSGTDFTLKISRVEAEDVGIYYC | FGSGTKLEIK | |
Mab54-Hzd-LC-V2 | SEQ ID NO: 80 | SEQ ID NO: 81 | SEQ ID NO: 82 | SEQ ID NO: 83 |
DIVITQTPLSLPVTPGESVSISC | WFLQRPGQSPQLLIY | GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC | FGSGTKLEIK |
表4及表5說明了人類化054及048抗體之可變區之序列。
表
4.
人類化
054
之序列
抗體鏈 | 序列 |
Mab54-生殖系 | EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARELDGNYDYWGQGTTLTVSS ( SEQ ID NO: 92 ) |
Mab54-Hzd-HC-V1 | EVQLVESGGGLVKPGGSLKLSCAASGFTFSMYGMSWVRQTPGKRLEWVASISIGGSYTYYADSVKGRFTISRDNAKNTLYLQMNSLKAEDTAVYYCARELDGNYDYWGQGTTLTVSS ( SEQ ID NO: 93 ) |
Mab54-HC-V2 | EVQLVESGGGLVKPGGSLRLSCAASGFTFSMYGMSWVRQAPGKRLEWVASISIGGSYTYYADSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCARELDGNYDYWGQGTTLTVSS ( SEQ ID NO: 94 ) |
Mab54 LC生殖系 | DIVMTQTPLSLPVTPGEPASISCRSSQSLLDSDDGNTYLDWYLQKPGQSPQLLIYTLSYRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQRIEFP ( SEQ ID NO: 95 ) |
Mab54-Hzd-LC-V1 | DIVITQDELSLPVTFGESVSISCRSSKSLLYKDGKTYLNWFLQRPGQSPQLLIYLMSTRASGVSDRFSGSGSGTDFTLKISRVEAEDVGIYYCQQLVEYPFTFGSGTKLEIK ( SEQ ID NO: 96) |
Mab54-Hzd-LC-V2 | DIVITQTPLSLPVTPGESVSISCRSSKSLLYKDGKTYLNWFLQRPGQSPQLLIYLMSTRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQLVEYPFTFGSGTKLEIK ( SEQ ID NO: 97 ) |
表
5.
人類化
048
之序列
抗體鏈 | 序列 |
Mab48-Hzd-HC-V3 | EVQLVESGGGLVKPGGSLRLSCAASGFTFSMYGMSWVRQAPGKRLEWVASISIGGSYTYYADSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCAREMDGNYDYWGHGTTLTVSS ( SEQ ID NO: 98 ) |
人類化048之輕鏈可變區與人類化054之輕鏈可變區相同。
本文提供之人類化抗-hVEGFR2抗體保留了與表現hVEGFR2的細胞之特異性結合親和力,且在該態樣中與親本抗體至少相當,或甚至更優。本文提供之人類化抗體亦可保留其與表現VEGFR2之細胞如HUVEC細胞之功能相互作用,因為所有抗體均可抑制VEGF-A誘導之VEGFR2磷酸化、HUVEC增殖及管形成。在某些實施例中,本文提供之抗-hVEGFR2抗體及其片段進一步包括免疫球蛋白恆定區,視情況人類Ig之恆定區,或視情況人類IgG之恆定區。在一些實施例中,免疫球蛋白恆定區包括重鏈及/或輕鏈恆定區。重鏈恆定區包括CH1、鉸鏈及/或CH2-CH3區。在某些實施例中,重鏈恆定區包括Fc區。在某些實施例中,輕鏈恆定區包括Cκ或Cλ。
在某些實施例中,本文提供之抗-hVEGFR2抗體及其片段進一步包括人類IgG1、IgG2、IgG3或IgG4之恆定區。在某些實施例中,本文提供之抗-hVEGFR2抗體及其抗原結合片段包括IgG1同型之恆定區。在某些實施例中,人類IgG1之恆定區包括SEQ ID NO: 38 (ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK)或其具有至少80% (例如至少85%、90%、95%、96%、97%、98%或99%)序列同一性的同源序列。
IgG1同型之恆定區可誘導效應功能,如ADCC或CDC。本文提供之抗-hVEGFR2抗體及其抗原結合片段的效應功能可導致對表現hVEGFR2之細胞之細胞毒性。效應功能可用各種分析評估,如Fc受體結合分析、C1q結合分析及細胞裂解分析,以及上述用於確定ADCC或CDC的任何分析。
抗體變異體
本文提供之抗-hVEGFR2抗體及其抗原結合片段亦涵蓋本文提供之抗體序列的各種類型的變異體。
在某些實施例中,變異體包括表1中提供之1、2或3個CDR序列、一或多個FR序列、本文提供之重鏈或輕鏈可變區序列及/或恆定區(例如Fc區)中之一或多者修飾或取代。此類抗體變異體保留了其親本抗體對hVEGFR2之特異性結合親和力,但具有一或多個由修飾或取代所賦予之理想特性。例如,僅舉幾例,抗體變異體可能具有改善之抗原結合親和力、改善之糖基化模式、減少之糖基化風險、減少之脫胺、減少或增加之效應功能、改善之FcRn受體結合、增加之藥代動力學半衰期、pH敏感性及/或對綴合之兼容性(例如,一或多個引入之半胱胺酸殘基)。
可使用此項技術中已知的方法,例如「丙胺酸掃描誘變」(參見例如Cunningham及Wells (1989),《科學》,244:1081-1085)篩選親本抗體序列,以確定合適的或較佳的殘基進行修飾或取代。簡言之,靶殘基(例如帶電殘基,如Arg、Asp、His、Lys及Glu)可被識別且被中性或帶負電的胺基酸(例如丙胺酸或多丙胺酸)替換,且產生經修飾之抗體且篩選感興趣之特性。若在特定胺基酸位置之取代顯示出感興趣之功能變化,則該位置可被識別為進行修飾或取代的潛在殘基。可藉由用不同類型的殘基(例如半胱胺酸殘基、帶正電的殘基等)替代來進一步評估潛在的殘基。
1. 親和力變異體
親和力變異體保留了親本抗體對hVEGFR2之特異性結合親和力,或者甚至具有比親本抗體更好的hVEGFR2特異性結合親和力。此項技術中已知的各種方法可用於實現此目的。例如,可用噬菌體展示技術產生及表現抗體變異體庫(如Fab或scFv變異體),然後篩選出與hVEGFR2之結合親和力。另一個實例為,可用電腦軟體來虛擬模擬抗體與hVEGFR2之結合,且識別抗體上形成結合界面之胺基酸殘基。此類殘基可避免進行取代以便防止結合親和力之降低,或作為取代的目標以實現較強結合。
在某些實施例中,CDR序列、FR序列或可變區序列中之取代中之至少一者(或全部)包括保守取代。關於胺基酸序列之「保守取代」係指用具有類似生理化學特性之側鏈的不同胺基酸殘基置換胺基酸殘基。例如,可在具有疏水側鏈之胺基酸殘基(如Met、Ala、Val、Leu及Ile)中,在具有中性親水側鏈之殘基(如Cys、Ser、Thr、Asn及Gln)中,在具有酸性側鏈之殘基(如Asp、Glu)中,在具有鹼性側鏈之胺基酸(如His、Lys及Arg)中,或在具有芳族側鏈之殘基(如Trp、Tyr及Phe)中進行保守取代。如此項技術中已知,保守取代通常不會引起蛋白構形結構之顯著變化,且因此可保留蛋白之生物活性。
在某些實施例中,本文所提供之人類化抗體或抗原結合片段包括一或多個CDR序列及/或一或多個FR序列中之一或多者胺基酸殘基取代。在某些實施例中,親和力變異體包括在一或多個CDR序列及/或FR序列中總共不超過10、9、8、7、6、5、4、3、2或1個取代。
在某些實施例中,抗-hVEGFR2抗體及其抗原結合片段包括1、2或3個CDR序列,其與表1中所列的一個(或多個)序列具有至少80% (例如,至少85%、88%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%)序列同一性,且同時將對hVEGFR2之結合親和力保持在類似於或甚至高於其親本抗體之水準。
在某些實施例中,抗-hVEGFR2抗體及其抗原結合片段包括一或多個可變區序列,其與SEQ ID NO: 50-63、93-94及96-98中之一個(或多個)具有至少80% (例如,至少85%、88%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%)之序列同一性,且同時將對hVEGFR2之結合親和力保持在類似於或甚至高於其親本抗體之水準。在一些實施例中,在選自SEQ ID NO: 50-63、93-94及96-98之序列中取代、插入或刪除總計1至10個胺基酸。在一些實施例中,取代、插入或刪除發生在CDR之外的區域(亦即在FR中)。
2. 糖基化變異體
本文提供之抗-hVEGFR2抗體及抗原結合片段亦涵蓋糖基化變異體,可獲得該糖基化變異體以增加或減少抗體或抗原結合片段之糖基化程度。如本文所用,術語「糖基化」係指將聚糖如岩藻糖、木糖、甘露糖或GlcNAc磷酸絲胺酸聚糖連接至蛋白、脂質或其他有機分子上之酶促過程。根據與聚糖相連的碳,糖基化可分為五類,包含:N-連接之糖基化、O-連接之糖基化、磷-糖基化、C-連接之糖基化及糖基磷脂醯肌醇化。
抗體之糖基化通常為N-連接或O-連接的。N-連接係指碳水化合物部分與天冬醯胺殘基(例如三肽序列,如天冬醯胺-X-絲胺酸及天冬醯胺-X-蘇胺酸中之天冬醯胺殘基,其中X為除脯胺酸外的任何胺基酸)的側鏈的連接。O-連接之糖基化係指糖N-乙醯基半乳糖胺、半乳糖或木糖中之一種與羥基胺基酸之連接,最常見地與絲胺酸或蘇胺酸之連接。
在某些實施例中,本文提供之抗體或其抗原結合片段為無岩藻糖基化的。術語「無岩藻糖基化」或「無岩藻糖基化的」係指附著在抗體上之N-聚糖上之核心岩藻糖減少或消失。人類IgG抗體之大多數聚糖被稱為G0、G1及G2,其為複合的雙天線分子,其中核心岩藻糖殘基攜帶零、一或兩個末端半乳糖。
可使用此項技術中已知的方法製備無岩藻糖基化的抗體變異體,該方法例如描述於US 2003/0157108;WO 2000/61739;WO 2001/29246;US 2003/0115614;US 2002/0164328;US 2004/0093621;US 2004/0132140;US 2004/0110704;US 2004/0110282;US 2004/0109865;WO 2003/085119;WO 2003/084570;WO 2005/035586;WO 2005/035778;WO2005/053742;WO2002/031140;Okazaki等人,《分子生物學雜誌》,336:1239-1249 (2004);Yamane-Ohnuki等人,《生物技術與生物工程(Biotech. Bioeng.)》87: 614 (2004)。
在某些實施例中,抗體糖基化變異體可藉由例如移除天然糖基化位點(例如藉由N297A取代)來獲得,使得N-連接糖基化位點的三肽序列或O-連接糖基化位點的絲胺酸或蘇胺酸殘基不再存在於抗體或Fc序列中。或者,在某些實施例中,抗體糖基化變異體可藉由在宿主細胞株中產生抗體獲得,該宿主細胞株在將所選糖基團添加至抗體中成熟核心碳水化合物結構方面存在缺陷。
3. 半胱胺酸工程化變異體
本文提供之抗-hVEGFR2抗體及抗原結合片段亦涵蓋半胱胺酸工程化變異體,其包括一或多個引入的游離半胱胺酸胺基酸殘基。
游離半胱胺酸殘基為並非二硫橋之一部分的半胱胺酸殘基。半胱胺酸工程化變異體可用於藉由例如順丁烯二醯亞胺或鹵乙醯基在工程化半胱胺酸的位點處與例如細胞毒性及/或成像化合物、標記或放射性同位素等綴合。工程化抗體或抗原結合片段以引入游離半胱胺酸殘基之方法為此項技術中已知的,參見例如WO2006/034488。
抗原結合片段
本文亦提供了抗-hVEGFR2抗原結合片段。各種類型之抗原結合片段為此項技術中已知的且可基於本文提供之抗-hVEGFR2抗體開發,包含例如其CDR序列顯示在表1中之例示性抗體,以及其不同變異體(如親和力變異體、糖基化變異體、Fc變異體、半胱胺酸工程化變異體等)。
在某些實施例中,本文提供之抗-hVEGFR2抗原結合片段為雙功能抗體、Fab、Fab'、F(ab')
2、Fd、Fv片段、二硫鍵穩定化Fv片段(dsFv)、(dsFv)
2、雙特異性dsFv (dsFv-dsFv')、二硫鍵穩定化雙功能抗體(ds雙功能抗體)、單鏈抗體分子(scFv)、scFv二聚體(二價雙功能抗體)、多特異性抗體、駱駝化單域抗體、奈米抗體、域抗體或二價域抗體。
各種技術可用於產生此類抗原結合片段。說明性方法包含完整抗體之酶促消化(參見例如,Morimoto等人,《生物化學與生物物理方法雜誌(Journal of Biochemical and Biophysical Methods)》,24:107-117(1992);及Brennan等人,《科學》,229:81 (1985)),藉由宿主細胞如大腸桿菌進行重組表現(例如,對於Fab、Fv及ScFv抗體片段),自如上所討論之噬菌體展示文庫中篩選(例如,對於ScFv),以及將兩個Fab'-SH片段化學偶聯以形成F(ab')
2片段(Carter等人,《生物技術(Bio/Technology)》,10:163-167 (1992))。生產抗體片段之其他技術對熟練的從業者而言將為顯而易見的。
在某些實施例中,抗原結合片段為scFv。scFv之產生描述於例如WO 93/16185;美國專利號5,571,894;及5,587,458。scFv可在胺基或羧基末端與效應蛋白融合以提供融合蛋白(參見例如,《抗體工程化(Antibody Engineering)》,編輯Borrebaeck)。
在某些實施例中,本文提供之抗-hVEGFR2抗體及其抗原結合片段為二價的、四價的、六價的或多價的。如本文所用,術語「價」係指在給定分子中存在指定數量的抗原結合位點。因此,術語「二價」、「四價」及「六價」分別表示在抗原結合分子中存在兩個結合位點、四個結合位點及六個結合位點。任何大於二價之分子被視為多價的,涵蓋例如三價、四價、六價等。
若兩個結合位點均對與相同抗原或相同抗原決定基之結合具有特異性,則二價分子可為單特異性的。在某些實施例中,此提供了比單價對應物更強的與抗原或抗原決定基之結合。類似地,多價分子亦可為單特異性的。在某些實施例中,在二價或多價抗原結合部分中,第一價結合位點及第二價結合位點在結構上相同(亦即具有相同之序列),或在結構上不同(亦即儘管具有相同之特異性但具有不同的序列)。
若兩個結合位點對不同的抗原或抗原決定基具有特異性,則二價亦可為雙特異性的。此亦適用於多價分子。例如,當兩個結合位點對第一抗原(或抗原決定基)為單特異性的,而第三結合位點對第二抗原(或抗原決定基)具有特異性時,則三價分子可為雙特異性的。
雙特異性抗體
在某些實施例中,本文提供之抗體及其抗原結合片段為雙特異性的。如本文所用,術語「雙特異性」涵蓋具有兩種特異性之分子及具有多於兩種特異性之分子,亦即多特異性。在某些實施例中,本文提供之雙特異性抗體及其抗原結合片段能夠特異性結合hVEGFR2之第一及第二抗原決定基,或能夠特異性結合hVEGFR2及第二抗原。在某些實施例中,hVEGFR2之第一抗原決定基及第二抗原決定基彼此不同或不重疊。在某些實施例中,雙特異性抗體及其抗原結合片段可同時與第一抗原決定基及第二抗原決定基結合。
在某些實施例中,雙特異性抗體包括第一結合域及第二結合域,其中第一結合域包括包括有選自由SEQ ID NO: 25、31、34及1組成之群的序列的HCDR1、包括有選自由SEQ ID NO: 26、32、35及2組成之群的序列的HCDR2、包括有選自由SEQ ID NO: 27、33、36及3組成之群的序列的HCDR3、包括有選自由SEQ ID NO: 28及4組成之群的序列的LCDR1、包括有選自由SEQ ID NO: 29及5組成之群的序列的LCDR2及包括有選自由SEQ ID NO: 30及6組成之群的序列的LCDR3;且其中第二結合域包括包括有選自由SEQ ID NO: 7、13及19組成之群的序列的HCDR1、包括有選自由SEQ ID NO: 8、14及20組成之群的序列的HCDR2、包括有選自由SEQ ID NO: 9、15及21組成之群的序列的HCDR3、包括有選自由SEQ ID NO: 10、16及22組成之群的序列的LCDR1、包括有選自由SEQ ID NO: 11、17及23組成之群的序列的LCDR2及包括有選自由SEQ ID NO: 12、18及24組成之群的序列的LCDR3。
在某些實施例中,雙特異性抗體包括第一結合域及第二結合域,
其中第一結合域包括:
a)包括SEQ ID NO: 25之序列的HCDR1、包括SEQ ID NO: 26之序列的HCDR2、包括SEQ ID NO: 27之序列的HCDR3;包括SEQ ID NO: 28之序列的LCDR1、包括SEQ ID NO: 29之序列的LCDR2及包括SEQ ID NO: 30之序列的LCDR3;或
b)包括SEQ ID NO: 31之序列的HCDR1、包括SEQ ID NO: 32或SEQ ID NO: 37之序列的HCDR2、包括SEQ ID NO: 33之序列的HCDR3、包括SEQ ID NO: 28之序列的LCDR1、包括SEQ ID NO: 29之序列的LCDR2及包括SEQ ID NO: 30之序列的LCDR3;或
c)包括SEQ ID NO: 34之序列的HCDR1、包括SEQ ID NO: 35或SEQ ID NO: 37之序列的HCDR2、包括SEQ ID NO: 36之序列的HCDR3、包括SEQ ID NO: 28之序列的LCDR1、包括SEQ ID NO: 29之序列的LCDR2及包括SEQ ID NO: 30之序列的LCDR3;或
d)包括SEQ ID NO: 1之序列的HCDR1、包括SEQ ID NO: 2之序列的HCDR2、包括SEQ ID NO: 3之序列的HCDR3、包括SEQ ID NO: 4之序列的LCDR1、包括SEQ ID NO: 5之序列的LCDR2及包括SEQ ID NO: 6之序列的LCDR3;及
其中第二結合域包括:
e)包括SEQ ID NO: 7之序列的HCDR1、包括SEQ ID NO: 8之序列的HCDR2、包括SEQ ID NO: 9之序列的HCDR3;包括SEQ ID NO: 10之序列的LCDR1、包括SEQ ID NO: 11之序列的LCDR2及包括SEQ ID NO: 12之序列的LCDR3;或
f)包括SEQ ID NO: 13之序列的HCDR1、包括SEQ ID NO: 14之序列的HCDR2、包括SEQ ID NO: 15之序列的HCDR3、包括SEQ ID NO: 16之序列的LCDR1、包括SEQ ID NO: 17之序列的LCDR2及包括SEQ ID NO: 18之序列的LCDR3;或
g)包括SEQ ID NO: 19之序列的HCDR1、包括SEQ ID NO: 20之序列的HCDR2、包括SEQ ID NO: 21之序列的HCDR3、包括SEQ ID NO: 22之序列的LCDR1、包括SEQ ID NO: 23之序列的LCDR2及包括SEQ ID NO: 24之序列的LCDR3。
在某些實施例中,第二抗原不同於hVEGFR2。
在某些實施例中,第二抗原為免疫相關靶標。在一些實施例中,雙特異性抗體及其抗原結合片段特異性結合hVEGFR2及免疫相關靶標,且能夠使免疫細胞靶向表現hVEGFR2之細胞(例如表現hVEGFR2之腫瘤細胞),及/或活化對表現hVEGFR2之靶細胞之hVEGFR2特異性免疫反應。如本文所用,免疫相關靶標涵蓋參與免疫反應、視情況細胞免疫反應的產生或調節的生物分子。免疫相關靶標之實例為免疫檢查點分子,以及細胞溶解性免疫細胞如T細胞或自然殺手(NK)細胞之表面分子。
免疫檢查點分子可介導共刺激信號以增強免疫反應,或者可介導共抑制信號以抑制免疫反應。免疫檢查點分子之實例包含例如PD-L1、PD-L2、PD-1、CLTA-4、TIM-3、LAG3、A2AR、CD160、2B4、TGF β、VISTA、BTLA、TIGIT、LAIR1、OX40、CD2、CD27、CD28、CD30、CD40、CD122、ICAM-1、IDO、NKG2C、SLAMF7、SIGLEC7、NKp80、CD160、B7-H3、LFA-1、1COS、4-1BB、GITR、BAFFR、HVEM、CD7、LIGHT、IL-2、IL-15、CD3、CD16及CD83。
細胞溶解性免疫細胞可由其表面分子觸發以攻擊及介導靶細胞如腫瘤細胞之裂解。在某些實施例中,第二抗原為T細胞表面抗原。T細胞表面抗原之實例包含但不限於選自由CD3、CD2、CD4、CD5、CD6、CD8、CD28、CD40L及/或CD44組成之群的抗原,較佳CD3。在某些實施例中,該第二抗原為CD3之ε鏈。在某些實施例中,該雙特異性抗體與T細胞上之CD3之結合導致該等T細胞增殖及/或活化,此誘導細胞毒性因子之釋放,例如穿孔素及顆粒酶,以及靶細胞之細胞溶解及凋亡。在某些實施例中,第二抗原為NK細胞表面抗原,如CD16 (FcγRIII)或CD56。在某些實施例中,雙特異性抗體與NK細胞上之CD16之結合導致NK細胞脫粒及靶細胞之穿孔素依賴性靶細胞裂解(ADCC)。
在某些實施例中,第二抗原包括腫瘤抗原。如本文所用,「腫瘤抗原」係指腫瘤特異性抗原(例如,腫瘤細胞特有的且通常不在非腫瘤細胞上發現的彼等者)、腫瘤相關抗原(例如在腫瘤及非腫瘤細胞中均發現但在腫瘤細胞中表現不同)及腫瘤新抗原(例如,由於改變蛋白序列或在兩個不相關序列之間產生融合蛋白的體細胞突變而在癌細胞中表現)。
腫瘤抗原之實例包含但不限於EpCAM、HER2/neu、HER3/neu、C250、CEA、MAGE、蛋白多糖、VEGF、EGFR、αVβ3-整合素、HLA、HLA-DR、ASC、CD1、CD2、CD4、CD6、CD7、CD8、CD11、CD13、CD14、CD19、CD20、CD21、CD22、CD23、CD24、CD30、CD33、CD37、CD40、CD41、CD47、CD52、c-erb-2、CALLA、MHCII、CD44v3、CD44v6、p97、神經節苷脂GM1、GM2、GM3、GD1a、GD1b、GD2、GD3、GT1 b、GT3、GQ1、NY-ESO-1、NFX2、SSX2、SSX4、Trp2、gp100 (Pmel 17)、酪胺酸酶、Muc-1、端粒酶、存活素、G250、p53、CA125 MUC、Wue抗原、Lewis Y抗原、HSP-27、HSP-70、HSP-72、HSP-90、Pgp、MCSP、EpHA2及細胞表面靶標GC1 82、GT468或GT512、PD-L1、蟲媒病毒E蛋白抗原決定基、膠質瘤相關抗原、癌胚抗原(CEA)、β-人類絨膜促性腺激素、甲胎蛋白(AFP)、凝集素反應性AFP、甲狀腺球蛋白、RAGE-1、MN-CA IX、人類端粒酶逆轉錄酶、RU1、RU2 (AS)、腸羧基酯酶、mut hsp70-2、M-CSF、前列腺酶、前列腺特異性抗原(PSA)、PAP、NY-ESO-1、LAGE-la、p53、前列腺蛋白(prostein)、PSMA、存活素及端粒酶、前列腺癌腫瘤抗原-1 (PCTA-1)、MAGE、ELF2M、嗜中性白血球彈性蛋白酶、ephrinB2、CD22、胰島素生長因子(IGF)-I、IGF-II、IGF-I受體及間皮素、ART-1/MelanA (MART-1)、酪胺酸酶、TRP-1、TRP-2及腫瘤特異性多系抗原如MAGE-1、MAGE-3、BAGE、GAGE-1、GAGE-2、pi 5;Ras,由染色體易位產生的獨特腫瘤抗原;如BCR-ABL、E2A-PRL、H4-RET、1GH-IGK、MYL-RAR;及病毒抗原,如愛潑斯坦-巴爾(Epstein Barr)病毒抗原EBVA及人類乳頭瘤病毒(HPV)抗原E6及E7;基於蛋白之抗原包含TSP-180、MAGE-4、MAGE-5、MAGE- 6、RAGE、NY-ESO、pl 85erbB2、pl 80erbB-3、c-met、nm-23H l、PSA、TAG-72、CA19-9、CA72-4、CAM 17.1、NuMa、K-ras、β-連環蛋白、CDK4、Mum-1、p15、p16、43-9F、5T4 (791Tgp72)、α-甲胎蛋白、β-HCG、BCA225、BTAA、CA 125、CA 15-3\CA 27.29\BCAA、CA 195、CA 242、CA-50、CAM43、CD68\I、CO-029、FGF-5、G250、Ga733VEpCAM、HTgp-175、M344、MA-50、MG7-Ag、MOV 18、NB/70K、NY-CO-1、RCAS 1、SDCCAG16、TA-90\Mac-2結合蛋白、親環素C相關蛋白、TAAL6、TAG72、TLP及TPS。
本文提供之雙特異性抗體及其抗原結合片段可為此項技術中已知的合適格式。例如,例示性雙特異性格式可為雙特異性雙功能抗體、基於scFv之雙特異性格式、IgG-scFv融合體、雙可變域(DVD)-Ig、四價體瘤、杵-臼、共同輕鏈(例如,帶杵-臼之共同輕鏈等)、BiTE、CrossMab、CrossFab、Duobody、SEEDbody、白胺酸拉鏈、雙作用Fab(DAF)-IgG及Mab
2雙特異性格式(參見例如,Brinkmann等人2017, Mabs,9(2): 182-212)。雙特異性分子可為對稱或不對稱的架構。
本文提供之雙特異性抗體及抗原結合片段可用此項技術中已知的任何合適的方法製備。
在一個實施例中,具有不同抗原特異性之兩個免疫球蛋白重鏈-輕鏈對在宿主細胞中共表現來以重組方式產生雙特異性抗體(參見例如,Milstein及Cuello,《自然》,305: 537 (1983)),然後藉由親和層析法純化。
在另一個實施例中,將編碼兩種特異性之抗體重鏈可變域的序列分別融合至免疫球蛋白恆定域序列,隨後插入一或多個表現載體,該表現載體與輕鏈序列之表現載體共轉染至合適的宿主細胞中以用於雙特異性抗體之重組表現(參見例如,WO 94/04690;Suresh等人,《酶學方法》,121:210 (1986))。類似地,scFv二聚體亦可自宿主細胞重組構築及表現(參見例如,Gruber等人,《免疫學雜誌》,152:5368 (1994))。
在另一種方法中,來自Fos及Jun蛋白之白胺酸拉鏈肽可藉由基因融合與兩種不同抗體之Fab'部分連接。連接的抗體在鉸鏈區被還原為四個半抗體(亦即單體),然後再氧化形成異二聚體(Kostelny等人,《免疫學雜誌》,148(5):1547-1553 (1992))。
兩個抗原結合域亦可綴合或交聯以形成雙特異性抗體或抗原結合片段。例如,一種抗體可與生物素偶聯,而另一種抗體與抗生物素蛋白偶聯,且生物素與抗生物素蛋白之間的強締合將使兩種抗體複合在一起形成雙特異性抗體(參見例如,美國專利號4,676,980;WO 91/00360、WO 92/00373及EP 03089)。對於另一個實例,兩種抗體或抗原結合片段可藉由此項技術中已知的習知方法交聯,例如如美國專利號4,676,980中揭示的。
雙特異性抗原結合片段可由雙特異性抗體產生,例如藉由蛋白水解切割或藉由化學連接產生。例如,可製備抗體之抗原結合片段(例如,Fab')且將其轉化為Fab'-硫醇衍生物,然後與另一種具有不同抗原特異性的轉化的Fab'衍生物混合且反應以形成雙特異性抗原結合片段(參見例如,Brennan等人,《科學》,229: 81 (1985))。
在某些實施例中,本文提供之雙特異性抗體或其抗原結合片段可在界面處工程化,使得可形成杵-臼締合以促進兩個不同抗原結合位點的異二聚化。此可最大化自重組細胞培養物中回收的異二聚體的百分比。如本文所用,「杵-臼」係指兩個多肽(如Fc)之間的相互作用,其中一個多肽由於存在具有龐大側鏈的胺基酸殘基(例如酪胺酸或色胺酸)而具有突起(亦即「杵」),且另一多肽具有腔(亦即「臼」),其中存在小的側鏈胺基酸殘基(例如丙胺酸或蘇胺酸),且突起可定位在腔中以促進兩個多肽相互作用以形成異二聚體或複合物。產生具有杵-臼之多肽的方法在此項技術中為已知的,例如如美國專利號5,731,168所述。
綴合物
在一些實施例中,抗-hVEGFR2抗體及其抗原結合片段與一或多個綴合物部分連接。綴合物為可與抗體或其抗原結合片段連接的部分。預期多種綴合物可與本文提供之抗體或抗原結合片段連接(參見例如,「綴合物疫苗(Conjugate Vaccines)」,《對微生物學及免疫學之貢獻(Contributions to Microbiology and Immunology)》,J. M. Cruse及R. E. Lewis, Jr. (編輯),Carger Press, New York, (1989))。此等綴合物可藉由共價結合、親和力結合、嵌入、配位結合、複合、締合、摻合或添加等方法與抗體或抗原結合片段連接。在某些實施例中,抗體或其抗原結合片段藉由連接子與一或多個綴合物連接。在某些實施例中,連接子為腙連接子、二硫連接子、雙官能連接子、二肽連接子、葡萄糖苷酸連接子、硫醚連接子。
在某些實施例中,本文揭示之抗-hVEGFR2抗體及抗原結合片段可被工程化以含有可用於結合一或多種綴合物之抗原決定基結合部分之外的特定位點。例如,此類位點可包含一或多個反應性胺基酸殘基,如例如半胱胺酸或組胺酸殘基,以促進與綴合物之共價連接。
綴合物可為清除調節劑、治療劑(例如化療劑)、毒素、放射性同位素、可偵測標記(例如鑭系元素、發光標記、螢光標記或酶-受質標記)、藥代動力學修飾部分、DNA-烷化劑、拓樸異構酶抑制劑、微管蛋白結合劑、其他抗癌藥物或純化部分(如磁珠或奈米顆粒)。
可偵測標記之實例可包含螢光標記(例如,螢光素、羅丹明、丹磺醯、藻紅蛋白或德克薩斯紅)、酶-受質標記(例如,辣根過氧化物酶、鹼性磷酸酶、螢光素酶、葡糖澱粉酶、溶菌酶、糖氧化酶或β-D-半乳糖苷酶)、放射性同位素、其他鑭系元素、發光標記、發色部分、地高辛(digoxigenin)、生物素/抗生物素蛋白、DNA分子或用於偵測的金。
放射性同位素之實例可包含
123I、
124I、
125I、
131I、
35S、
3H、
111In、
112In、
14C、
64Cu、
67Cu、
86Y、
88Y、
90Y、
177Lu、
211At、
186Re、
188Re、
153Sm、
212Bi及
32P。放射性同位素標記的抗體可用於受體靶向成像實驗。
在某些實施例中,綴合物可為藥代動力學調節部分,如PEG,其有助於增加抗體之半衰期。其他合適的聚合物包含如羧甲基纖維素、葡聚糖、聚乙烯醇、聚乙烯吡咯啶酮、乙二醇/丙二醇的共聚物等。
在某些實施例中,綴合物可為純化部分,如磁珠或奈米顆粒。
抗體
-
藥物綴合物
在某些實施例中,本發明提供了抗體-藥物綴合物(ADC),其包括與細胞毒劑綴合的任何上述抗-hVEGFR2抗體或抗原結合片段。
ADC可用於局部遞送細胞毒劑,例如用於治療癌症。此允許將細胞毒劑靶向遞送至腫瘤且在其中進行細胞內積聚,其在此等未綴合之細胞毒劑之全身投與可能導致對正常細胞以及尋求消除的腫瘤細胞之毒性水準不可接受之情況下特別有用(Baldwin等人(1986),《柳葉刀(Lancet)》,(1986年3月15日)pp.:603-05;Thorpe (1985),「癌症療法中細胞毒劑之抗體載劑:綜述(Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review)」,《單株抗體'84:生物及臨床應用(Monoclonal Antibodies '84: Biological And Clinical Applications)》,A. Pinchera等人(編輯),pp. 475-506;Syrigos及Epenetos (1999),《抗癌研究(Anticancer Research)》,19:605-614;Niculescu-Duvaz及Springer (1997),《高等藥物遞送綜述(Adv. Drg Del. Rev.)》,26:151-172;美國專利號4,975,278)。
在某些實施例中,細胞毒劑可為對細胞有害或可損害或殺滅細胞之任何藥劑。在某些實施例中,細胞毒劑視情況為毒素、化學治療劑(如DNA烷基化劑、拓樸異構酶抑制劑、微管蛋白結合劑、生長抑制劑或其他抗癌藥物)或放射性同位素。
毒素之實例包含細菌毒素及植物毒素,如例如白喉毒素、外毒素A鏈(來自銅綠假單胞菌(Pseudomonas aeruginosa))、蓖麻毒素、相思豆毒蛋白、莫迪素(modeccin)、α-帚麴黴素、油桐蛋白、石竹素蛋白、洋商陸(Phytolaca americana)蛋白(PARI、PAPII及PAP-S)、苦瓜抑制劑、瀉果素、巴豆素、石鹼花抑制劑、白樹毒素、侷限麴菌素、酚黴素、依諾黴素及單端孢黴烯(參見例如WO93/21232)。此類大分子毒素可使用此項技術中已知的方法與本文提供之抗體或抗原結合片段綴合,例如如Vitetta等人(1987),《科學》,238:1098所述。
細胞毒劑亦可為小分子毒素及化學治療劑,如格爾德黴素(geldanamycin) (Mandler等人(2000),《美國國立癌症研究雜誌(Jour. of the Nat. Cancer Inst.)》,92(19):1573-1581;Mandler等人(2002),《生物綴合物化學(Bioconjugate Chem.)》,13:786-791)、美登素及美登木素(EP 1391213;Liu等人(1996),《美國國家科學院院刊》,93:8618-8623;美國專利號5,208,020)、卡奇黴素(Lode等人(1998),《癌症研究》,58:2928;Hinman等人(1993),《癌症研究》,53:3336-3342)、紫杉醇、細胞鬆弛素B、短桿菌肽D、溴化乙錠、依米汀、絲裂黴素、依託泊苷、替尼泊苷、長春新鹼、長春鹼、長春地辛、秋水仙素、小紅莓、柔紅黴素、二羥基炭疽菌素二酮、米托蒽醌(mitoxantrone)、光神黴素、放線菌素D、1-脫氫睾酮、糖皮質激素、普魯卡因(procaine)、丁卡因(tetracaine)、利多卡因(lidocaine)、普萘洛爾(propranolol)、嘌呤黴素及其類似物、抗代謝物(例如甲胺蝶呤、6-巰基嘌呤、6-硫鳥嘌呤、阿糖胞苷、5-氟尿嘧啶達卡巴嗪)、烷化劑(例如氮芥、噻替派苯丁酸氮芥(thioepa chlorambucil)、美法侖(melphalan)、卡莫司汀(carmustine;BSNU)及洛莫司汀(lomustine;CCNU)、環磷醯胺、白消安、二溴甘露醇、鏈脲佐菌素、絲裂黴素C及順式二氯二胺鉑(II) (DDP)順鉑)、蒽環類(例如柔紅黴素(原道諾黴素)及小紅莓)、抗生素(例如更生黴素(原放線菌素)、博來黴素、光神黴素及安麴黴素(AMC))及抗有絲分裂劑(例如長春新鹼及長春鹼)、卡奇黴素、美登木素、尾海兔素、澳瑞他汀(auristatin) (如MMAE及MMAF (美國專利號5,635,483;5,780,588))、多拉司他汀、單端孢黴烯及CC1065,及其具有細胞毒活性之衍生物。
細胞毒劑亦可為高放射性同位素。實例包含At
211、I
131、I
125、Y
90、Re
186、Sm
153、Bi
212、P
32、Pb
212及Lu之放射性同位素。放射性同位素與抗體綴合之方法為此項技術中已知的,例如,藉由合適的配位體試劑(參見例如,WO94/11026;《免疫學當前方案(Current Protocols in Immunology)》,第1卷及第2卷,Coligen等人編輯,Wiley-Interscience New York, N.Y., Pubs. (1991))。配位體試劑具有能與放射性同位素金屬結合、螯合或以其他方式絡合之螯合配位體,且亦具有與抗體或抗原結合片段中半胱胺酸的硫醇具有反應性的官能基。例示性螯合配位體包含DOTA、DOTP、DOTMA、DTPA及TETA (Macrocyclics, Dallas, Tex.)。
細胞毒劑可藉由此項技術中已知的任何合適的連接子連接至抗體或抗原結合片段,參見例如美國專利號5,208,020、6,441,163或EP專利0 425 235 B1,Chari等人,《癌症研究》,52:127-131 (1992)及US 2005/0169933 A1,其揭示內容藉由引用明確併入本文。
在某些實施例中,連接子在特定生理環境下為可切割的,從而促進細胞毒性藥物在細胞中之釋放。例如,連接子可為酸不穩定連接子、肽酶敏感連接子、光不穩定連接子、二甲基連接子或含二硫鍵的連接子、硫醚連接子及酯酶不穩定連接子(Chari等人,《癌症研究》,52:127-131 (1992);美國專利號5,208,020)。在一些實施例中,連接子可包括胺基酸殘基,如二肽、三肽、四肽或五肽。連接子中之胺基酸殘基可為天然或非天然存在之胺基酸殘基。此類連接子之實例包含:纈胺酸-瓜胺酸(ve或val-cit)、丙胺酸-苯丙胺酸(af或ala-phe)、甘胺酸-纈胺酸-瓜胺酸(gly-yal-cit)、甘胺酸-甘胺酸-甘胺酸(gly-gly-gly)、纈胺酸-瓜胺酸-對胺基苄氧基羰基(「vc-PAB」)。可設計胺基酸連接子組分且在其對特定酶例如腫瘤相關蛋白酶、組織蛋白酶B、C及D或纖溶酶蛋白酶的酶促切割的選擇性方面優化。
在某些實施例中,細胞毒劑可藉由雙官能連接子試劑連接至本文提供之抗體或其抗原結合片段,包含如N-丁二醯亞胺基-3-(2-吡啶基二硫基)丙酸酯(SPDP)、丁二醯亞胺基-4-(N-順丁烯二醯亞胺甲基)環己烷-1-羧酸酯(SMCC)、N-丁二醯亞胺基-4-(2-吡啶基硫基)戊酸酯(SPP)、亞胺基硫雜環戊烷(IT)、亞胺基酯之雙官能衍生物(如二甲基己二亞醯胺HCl)、活性酯(如辛二酸二丁二醯亞胺酯)、醛(如戊二醛)、雙疊氮化合物(如雙(對疊氮基苯甲醯基)己二胺)、雙重氮衍生物(如雙(對重氮苯甲醯基)-乙二胺)、二異氰酸酯(如甲苯2,6-二異氰酸酯)、雙活性氟化合物(如1,5-二氟-2,4-二硝基苯)、BMPS、EMCS、GMBS、HBVS、LC-SMCC、MBS、MPRH、SBAP、SIA、SIAB、SMPB、SMPH、磺基-EMCS、磺基-GMBS、磺基-KMUS、磺基-MBS、磺基-SIAB、磺基-SMCC及磺基-SMPB及SVSG (丁二醯亞胺基-(4-乙烯基碸)苯甲酸酯)。彼等連接子試劑為可商購的(例如,來自Pierce Biotechnology公司, Rockford, Ill., U.S.A,參見《應用手冊及目錄(Applications Handbook and Catalog)》第467頁-第498頁,2003-2004)。
在某些實施例中,在本文提供之ADC中,抗體(或其抗原結合片段)以約1至約20、約1至約6、約2至約6、約3至約6、約2至約5、約2至約4或約3至約4的抗體:藥劑比率與一或多種細胞毒劑綴合。
本文所提供之ADC可藉由此項技術中已知的任何合適的方法製備。在某些實施例中,抗體(或其抗原結合片段)的親核基團首先與雙官能連接子試劑反應,然後與細胞毒劑連接,或反過來,亦即首先使細胞毒劑的親核基團與雙官能連接子反應,然後連接至抗體。
在某些實施例中,細胞毒劑可含有(或修飾為含有)硫醇反應性官能基,其可與本文提供之抗體或抗原結合片段的游離半胱胺酸的半胱胺酸硫醇反應。例示性之硫醇反應性官能基包含例如順丁烯二醯亞胺、碘乙醯胺、吡啶基二硫化物、鹵乙醯基、丁二醯亞胺酯(例如NHS、N-羥基丁二醯亞胺)、異硫氰酸酯、磺醯氯、2,6-二氯三𠯤基、五氟苯基酯或胺基亞磷酸酯(Haugland 2003,《螢光探針及研究化學品之分子探針手冊(Molecular Probes Handbook of Fluorescent Probes and Research Chemicals)》,Molecular Probes公司;Brinkley 1992,《生物綴合物化學》,3:2;Garman 1997,《非放射性標記:一種實用之方法(Non-Radioactive Labelling: A Practical Approach)》,Academic Press, London;Means (1990),《生物綴合物化學》,1:2;Hermanson, G.,《生物綴合物技術(Bioconjugate Techniques)》,(1996) Academic Press, San Diego, pp. 40-55, 643-671)。
細胞毒劑或抗體可與連接試劑反應,隨後綴合形成ADC。例如,細胞毒劑之N-羥基丁二醯亞胺基酯(NHS)可執行、分離、純化及/或表徵,或其可原位形成且與抗體之親核性基團反應。通常,綴合物之羧基形式藉由與以下物質之某些組合反應而活化:碳二亞胺試劑(例如二環己基碳二亞胺;二異丙基碳二亞胺)或脲鎓試劑(例如TsTu(O--(N-丁二醯亞胺基)-N,N,N',N'-四甲基脲鎓四氟硼酸鹽)、HBTU ((O-苯并三唑-1-基)-N,N,N'N'-四甲基脲鎓六氟磷酸鹽)或HATU (O-(7-氮雜苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸鹽));活化劑(如1-羥基苯并三唑(HOBt)及N-羥基丁二醯亞胺)以得到NHS酯。在一些情況下,細胞毒劑及抗體可藉由原位活化及反應連接以一步形成ADC。其他活化及連接試劑包含TBTU (2-(1H-苯并三唑-1-基)-1-1,3,3-四甲基脲鎓六氟磷酸鹽)、TFFH (N,N',N'',N'''-四甲基脲鎓2-氟-六氟磷酸鹽)、PyBOP (苯并三唑-1-基-氧基-參-吡咯啶基-膦鎓六氟磷酸鹽)、EEDQ (2-乙氧基-1-乙氧基羰基-1,2-二氫-喹啉)、DCC (二環己基碳二亞胺);DIPCDI (二異丙基碳二亞胺)、MSNT (1-(均三甲基苯-2-磺醯基)-3-硝基-1H-1,2,4-三唑)及芳基磺醯鹵,例如三異丙基苯磺醯氯。在另一個實例中,抗體或抗原結合片段可與生物素綴合,然後間接綴合至與抗生物素蛋白綴合之第二綴合物。
多核苷酸及重組方法
本發明提供了編碼抗-hVEGFR2抗體及其抗原結合片段的分離之多核苷酸。如本文所用,術語「核酸」或「多核苷酸」係指單股或雙股形式的脫氧核糖核酸(DNA)或核糖核酸(RNA)及其聚合物。除非另有說明,否則特定的多核苷酸序列亦隱含地涵蓋其保守修飾的變異體(例如簡併密碼子取代)、對偶基因、直向同源物、SNP及互補序列以及明確指出的序列。具體而言,簡併密碼子取代可藉由產生其中一或多個選定(或所有)密碼子之第三位被混合鹼基及/或脫氧肌苷殘基取代的序列來實現(參見Batzer等人,《核酸研究》,19:5081 (1991);Ohtsuka等人,《生物化學雜誌(J. Biol. Chem.)》,260:2605-2608 (1985);及Rossolini等人,《分子細胞探針(Mol. Cell. Probes)》,8:91-98 (1994))。
使用習知程序(例如,藉由使用能夠特異性結合編碼抗體重鏈及輕鏈之基因的寡核苷酸探針)容易地分離及定序編碼單株抗體之DNA。編碼DNA亦可藉由合成方法獲得。
本發明提供了包括本文提供之分離之多核苷酸的載體(例如表現載體)。在某些實施例中,本文提供之表現載體包括編碼本文提供之抗體或其抗原結合片段的多核苷酸、可操作地連接至多核苷酸序列之至少一種啟動子(例如SV40、CMV、EF-1α)及至少一種選擇標記物。載體之實例包含但不限於逆轉錄病毒(包含慢病毒)、腺病毒、腺相關病毒、疱疹病毒(例如單純疱疹病毒)、痘病毒、桿狀病毒、乳頭瘤病毒、乳多空病毒(例如SV40)、λ噬菌體及M13噬菌體、質體如pcDNA3.3、pMD18-T、pOptivec、pCMV、pEGFP、pIRES、pQD-Hyg-GSeu、pALTER、pBAD、pcDNA、pCal、pL、pET、pGEMEX、pGEX、pCI、pEGFT、pSV2、pFUSE、pVITRO、pVIVO、pMAL、pMONO、pSELECT、pUNO、pDUO、Psg5L、pBABE、pWPXL、pBI、p15TV-L、pPro18、pTD、pRS10、pLexA、pACT2.2、pCMV-SCRIPT.RTM.、pCDM8、pCDNA1.1/amp、pcDNA3.1、pRc/RSV、PCR 2.1、pEF-1、pFB、pSG5、pXT1、pCDEF3、pSVSPORT、pEF-Bos等。
包括編碼抗體或其抗原結合片段之多核苷酸序列的載體可被引入宿主細胞中進行選殖或基因表現。用於選殖或表現本文載體中之DNA的合適宿主細胞為上述原核生物、酵母或更高等真核生物細胞。用於此目的的合適的原核生物包含真細菌,如革蘭氏陰性或革蘭氏陽性生物體,例如腸桿菌科(
Enterobacteriaceae),如埃希氏桿菌屬(
Escherichia)例如大腸桿菌(
E. coli)、腸桿菌屬(
Enterobacter)、歐文氏菌屬(
Erwinia)、克雷伯氏菌屬(
Klebsiella)、變形桿菌屬(
Proteus)、沙門氏菌屬(
Salmonella)例如鼠傷寒沙門氏菌(
Salmonella typhimurium)、沙雷氏菌屬(
Serratia)例如黏質沙雷氏菌(
Serratia marcescans)及志賀氏菌屬(
Shigella),以及桿菌屬(
Bacilli)如枯草芽孢桿菌(
B. subtilis)及地衣芽孢桿菌(
B. licheniformis)、假單胞菌屬(
Pseudomonas)如銅綠假單胞菌及鏈黴菌屬(
Streptomyces)。
除原核生物外,真核微生物如絲狀真菌或酵母亦為抗-hVEGFR2抗體編碼載體的合適選殖或表現宿主。釀酒酵母或普通麵包酵母為低等真核宿主微生物中最常用的。然而,許多其他屬、種及株在本文中通常為可用的且有用的,如粟酒裂殖酵母(
Schizosaccharomyces pombe);克魯維酵母菌屬(
Kluyveromyces)宿主,如例如乳酸克魯維酵母(
K. lactis)、脆壁克魯維酵母(
K. fragilis) (ATCC 12,424)、保加利亞克魯維酵母(
K. bulgaricus) (ATCC 16,045)、威克克魯維酵母(
K. wickeramii) (ATCC 24,178)、克魯雄酵母(
K. waltii) (ATCC 56,500)、果蠅克魯維酵母(
K. drosophilarum) (ATCC 36,906)、耐熱克魯維酵母(
K. thermotolerans)及馬克斯克魯維酵母(
K. marxianus);耶氏酵母屬(
yarrowia) (EP 402,226);畢赤酵母(
Pichia pastoris) (EP 183,070);念珠菌屬(
Candida);里氏木黴(
Trichoderma reesia) (EP 244,234);粗糙脈孢菌(
Neurospora crassa);許旺酵母屬(
Schwanniomyces),如許旺酵母(
Schwanniomyces occidentalis);及絲狀真菌,如例如,脈孢菌屬(
Neurospora)、青黴菌屬(
Penicillium)、彎頸黴屬(
Tolypocladium)及麴黴屬(
Aspergillus)宿主,如構巢麴黴(
A. nidulans)及黑麴黴(
A. niger)。
用於表現本文提供之糖基化抗體或抗原片段的合適的宿主細胞來源於多細胞生物體,如無脊椎動物細胞,例如植物及昆蟲細胞。已經鑑定出多種桿狀病毒株及變異體以及來自如下宿主的相應容許的昆蟲宿主細胞:草地貪夜蛾(
Spodoptera frugiperda) (毛蟲)、埃及伊蚊(
Aedes aegypti) (蚊子)、白紋伊蚊(
Aedes albopictus) (蚊子)、黑腹果蠅(
Drosophila melanogaster) (果蠅)及家蠶(
Bombyx mori)。用於轉染之多種病毒株為公開可用的,例如苜蓿銀紋夜蛾(
Autographa californica) NPV之L-1變異體及家蠶NPV的Bm-5株,且此類病毒可用作根據本發明之本文的病毒,特別係用於草地貪夜蛾細胞之轉染。棉花、玉米、馬鈴薯、大豆、矮牽牛、番茄及菸草的植物細胞培養物亦可用作宿主。
然而,人們對脊椎動物細胞之興趣最大,脊椎動物細胞之培養繁殖(組織培養)已成為常規程序。有用的哺乳動物宿主細胞株之實例為由SV40轉型的猴腎CV1系(COS-7, ATCC CRL 1651);人類胚胎腎系(次選殖以在懸浮培養物中生長的293或293細胞,Graham等人,《基因病毒雜誌(
J. Gen Virol.)》,36:59 (1977));乳倉鼠腎細胞(BHK, ATCC CCL 10);中國倉鼠卵巢細胞/-DHFR (CHO, Urlaub等人,《美國國家科學院院刊》,77:4216 (1980));小鼠塞特利氏細胞(sertoli cell) (TM4,
Mather,《生殖生物學(
Biol. Reprod.)》,23:243-251 (1980));猴腎細胞(CV1 ATCC CCL 70);非洲綠猴腎細胞(VERO-76, ATCC CRL-1587);人類宮頸癌細胞(HELA, ATCC CCL 2);犬腎細胞(MDCK, ATCC CCL 34);水牛大鼠肝細胞(BRL 3A, ATCC CRL 1442);人類肺細胞(W138, ATCC CCL 75);人類肝細胞(Hep G2, HB 8065);小鼠乳腺腫瘤(MMT 060562, ATCC CCL51);TRI細胞(Mather等人,《紐約科學院年報(
Annals N.Y. Acad. Sci.)》,383:44-68 (1982));MRC5細胞;FS4細胞;及人類肝癌系(Hep G2)。在一些較佳實施例中,宿主細胞為哺乳動物培養細胞株,如CHO、BHK、NS0、293及其衍生物。在一些較佳實施例中,宿主細胞為CHO及其衍生物。
宿主細胞用上述表現或選殖載體轉型以產生抗-hVEGFR2抗體,且在習知營養培養基中培養,該培養基經適當修飾以誘導啟動子、選擇轉型子或擴增編碼所需序列之基因。在另一實施例中,抗體可藉由此項技術中已知的同源重組產生。
用於產生本文提供之抗體或抗原結合片段的宿主細胞可在多種培養基中培養。市售培養基如Ham's F10 (Sigma)、最小必需培養基(MEM) (Sigma)、RPMI-1640 (Sigma)及達爾伯克改良伊格爾培養基(DMEM) (Sigma)適用於培養宿主細胞。此外,描述於Ham等人,《酶學方法》,58:44 (1979),Barnes等人,《分析生物化學(Anal. Biochem.)》,102:255 (1980),美國專利號4,767,704;4,657,866;4,927,762;4,560,655;或5,122,469;WO 90/03430;WO 87/00195;或美國專利RE. 30,985中之任何培養基可用作宿主細胞之培養基。此等培養基中之任一者均可視需要補充激素及/或其他生長因子(如胰島素、轉鐵蛋白或表皮生長因子)、鹽(如氯化鈉、鈣鹽、鎂鹽及磷酸鹽)、緩衝劑(如HEPES)、核苷酸(如腺苷及胸苷)、抗生素(如GENTAMYCIN
TM藥物)、微量元素(定義為通常以微莫耳範圍內之最終濃度存在的無機化合物)及葡萄糖或等效能量源。亦可按照熟習此項技術者已知的適當濃度包含其他必要的補充劑。培養條件(如溫度、pH等)為先前與所選的用於表現的宿主細胞一起使用的彼等條件,且對於一般技術人員而言將為顯而易見的。
當使用重組技術時,抗體可在細胞內、在周質空間中產生,或直接分泌至培養基中。若在細胞內產生抗體,則作為第一步驟,例如藉由離心或超濾移除宿主細胞或裂解片段的微粒碎片。Carter等人,《生物技術》,10:163-167 (1992)描述了一種用於分離分泌至大腸桿菌之周質空間的抗體之程序。簡言之,將細胞糊狀物在乙酸鈉(pH 3.5)、EDTA及苯甲基磺醯氟(PMSF)之存在下經約30分鐘解凍。細胞碎片可藉由離心移除。在抗體分泌至培養基中之情況下,來自此類表現系統之上清液一般首先使用市售的蛋白濃縮過濾器,例如Amicon或Millipore Pellicon超濾裝置進行濃縮。蛋白酶抑制劑如PMSF可包含在任何前述步驟中,以抑制蛋白水解,且可包含抗生素以防止外來污染物的生長。
可使用例如羥基磷灰石層析法、凝膠電泳、透析、DEAE-纖維素離子交換層析法、硫酸銨沈澱、鹽析及親和層析法純化由細胞製備的抗-hVEGFR2抗體及其抗原結合片段,親和層析法為較佳的純化技術。
在某些實施例中,固定在固相上之蛋白A用於進行抗體及其抗原結合片段的免疫親和純化。蛋白A作為親和配位體之適合性取決於抗體中存在的任何免疫球蛋白Fc域的種類及同型。蛋白A可用於純化基於人類γ1、γ2或γ4重鏈之抗體(Lindmark等人,《免疫方法雜誌》,62:1-13 (1983))。建議將蛋白G用於所有小鼠同型及人類γ3 (Guss等人,《EMBO雜誌(EMBO J.)》,5:1567 1575 (1986))。親和配位體所連接之基質最通常為瓊脂糖,但亦可使用其他基質。機械穩定性基質(如受控孔玻璃或聚(苯乙烯二乙烯基)苯)比瓊脂糖具有更快的流速及更短的處理時間。當抗體包括CH3域時,Bakerbond ABX.TM.樹脂(J. T. Baker, Phillipsburg, N.J.)可用於純化。用於蛋白純化之其他技術,如離子交換管柱上分級分離、乙醇沈澱、逆相HPLC、二氧化矽層析、肝素SEPHAROSE
TM上之層析、陰離子或陽離子交換樹脂(如聚天冬胺酸管柱)上之層析、層析聚焦、SDS-PAGE以及硫酸銨沈澱亦為可用的,取決於待回收之抗體。
在任何初步純化步驟之後,可使用pH在約2.5-4.5之溶離緩衝液對包括感興趣之抗體及污染物的混合物進行低pH疏水相互作用層析法,較佳在低鹽濃度(例如,約0-0.25 M鹽)下進行。
醫藥組合物
本發明進一步提供了包括抗-hVEGFR2抗體或其抗原結合片段及一或多種醫藥學上可接受之載劑的醫藥組合物。
用於本文所揭示之醫藥組合物的醫藥學上可接受之載劑可包含例如醫藥學上可接受之液體、凝膠或固體載劑、水性媒劑、非水性媒劑、抗微生物劑、等滲劑、緩衝劑、抗氧化劑、麻醉劑、懸浮/分散劑、掩蔽劑或螯合劑、稀釋劑、佐劑、賦形劑或無毒輔助物質、此項技術中已知的其他組分或其各種組合。
合適的組分可包含例如抗氧化劑、填充劑、黏合劑、崩解劑、緩衝劑、防腐劑、潤滑劑、調味劑、增稠劑、著色劑、乳化劑或穩定劑,如糖及環糊精。合適抗氧化劑可包含例如甲硫胺酸、抗壞血酸、EDTA、硫代硫酸鈉、鉑、過氧化氫酶、檸檬酸、半胱胺酸、硫代甘油、硫代乙醇酸、硫代山梨糖醇、丁基化羥基苯甲醚、丁基化羥基甲苯及/或沒食子酸丙酯。如本文所揭示,在包括如本文所提供之抗體或抗原結合片段及綴合物的組合物中包含一或多種抗氧化劑如甲硫胺酸,降低抗體或抗原結合片段的氧化。此氧化減少將防止或減少結合親和力之損失,由此提高抗體穩定性且使儲存壽命最大化。因此,在某些實施例中,提供了包括一或多種本文揭示之抗體或抗原結合片段及一或多種抗氧化劑如甲硫胺酸的組合物。進一步提供了藉由將抗體或抗原結合片段與一或多種抗氧化劑如甲硫胺酸混合來防止本文提供之抗體或抗原結合片段氧化、延長本文提供之抗體或抗原結合片段之儲存壽命及/或提高本文提供之抗體或抗原結合片段的功效的方法。
為了進一步說明,醫藥學上可接受之載劑可包含例如水性媒劑,如氯化鈉注射液、林格注射液、等滲右旋糖注射液、無菌水注射液或右旋糖及乳酸林格注射液,非水性媒劑,如植物來源之不揮發油、棉籽油、玉米油、芝麻油或花生油,抑細菌或抑真菌濃度之抗微生物劑,等滲劑如氯化鈉或右旋糖,緩衝劑如磷酸鹽或檸檬酸鹽緩衝劑,抗氧化劑如硫酸氫鈉,局部麻醉劑如鹽酸普魯卡因,懸浮劑及分散劑如羧甲基纖維素鈉、羥丙基甲基纖維素或聚乙烯吡咯啶酮,乳化劑如聚山梨醇酯80 (TWEEN-80),掩蔽劑或螯合劑如EDTA (乙二胺四乙酸)或EGTA (乙二醇四乙酸)、乙醇、聚乙二醇、丙二醇、氫氧化鈉、鹽酸、檸檬酸或乳酸。用作載劑之抗微生物劑可添加至多劑量容器中之醫藥組合物中,抗微生物劑包含苯酚或甲酚、汞劑、苯甲醇、氯丁醇、對羥基苯甲酸甲酯及對羥基苯甲酸丙酯、硫柳汞、苯紮氯銨及苄索氯銨。合適的賦形劑可包含例如水、生理鹽水、右旋糖、甘油或乙醇。合適的無毒輔助物質可包含例如潤濕劑或乳化劑、pH緩衝劑、穩定劑、溶解性增強劑或如乙酸鈉、脫水山梨糖醇單月桂酸酯、三乙醇胺油酸酯或環糊精的藥劑。
醫藥組合物可為液體溶液、懸浮液、乳液、丸劑、膠囊、片劑、持續釋放製劑或散劑。口服製劑可包含標準載劑,如藥用級甘露糖醇、乳糖、澱粉、硬脂酸鎂、聚乙烯吡咯啶酮、糖精鈉、纖維素、碳酸鎂等。
在某些實施例中,醫藥組合物被配製成可注射組合物。可注射之醫藥組合物可以任何習知形式製備,如例如液體溶液、懸浮液、乳液或適合產生液體溶液、懸浮液或乳液之固體形式。注射用製劑可包含準備好用於注射之無菌及/或無熱原質溶液;準備好臨在使用之前與溶劑組合的無菌乾燥可溶性產品,如凍乾粉末,包含皮下片劑;準備好用於注射之無菌懸浮液;準備好臨在使用之前與媒劑組合的無菌乾燥不溶性產品;及無菌及/或無熱原質乳液。溶液可為水性或非水性的。
在某些實施例中,單位劑量之非經腸製劑被包裝在安瓿、小瓶或帶針頭之注射器中。所有用於非經腸投與之製劑均應該為無菌且無熱原質的,正如此項技術中所已知及實踐。
在某些實施例中,藉由將本文揭示之抗體或抗原結合片段溶解在合適的溶劑中來製備無菌的凍乾粉末。溶劑可含有提高粉末或由粉末製備的復原溶液的穩定性或其他藥理學組分的賦形劑。可使用的賦形劑包含但不限於水、右旋糖、山梨糖醇、果糖、玉米糖漿、木糖醇、甘油、葡萄糖、蔗糖或其他合適的藥劑。溶劑可含有緩衝劑,如檸檬酸鹽、磷酸鈉或磷酸鉀或熟習此項技術者已知的其他此類緩衝劑,在一個實施例中,pH值約為中性。隨後無菌過濾溶液,接著在熟習此項技術者已知的標準條件下凍乾,得到所需製劑。在一個實施例中,將所得溶液分配至小瓶中以凍乾。各小瓶可含有單劑量或多劑量的抗-hVEGFR2抗體或其抗原結合片段或其組合物。可接受過量填充小瓶,少量超過一劑或一組劑量所需的量(例如,約10%),以促進準確的樣本取出及準確的給藥。凍乾粉末可在適當的條件下儲存,如在約4℃至室溫。
用注射用水重構凍乾粉末提供了用於非經腸投與的製劑。在一個實施例中,為了重構,將無菌及/或無熱原質水或其他合適的液體載劑添加至凍乾粉末中。精確量取決於給定的所選療法,且可憑經驗確定。
使用方法
本發明亦提供了治療方法,其包括:向有此需要的受試者投與治療有效量的本文提供之抗體或抗原結合片段及/或本文提供之醫藥組合物,從而在受試者中治療VEGFR2相關疾病或病症、降低VEGFR2相關疾病或病症之嚴重性及/或減緩VEGFR2相關疾病或病症之進展。
在一些實施例中,VEGFR2相關疾病或病症為腫瘤或血管生成疾病。
腫瘤
在某些實施例中,VEGFR2相關疾病或病症為腫瘤,如實體瘤或非實體瘤。在一些實施例中,腫瘤產生VEGF (例如,VEGF-A)及/或對其微環境中存在的VEGF (例如,VEGF-A)敏感。研究已觀測到實體瘤或非實體瘤如人類白血病中之VEGF產生及VEGFR2表現(Sato, K.等人,《東北實驗醫學雜誌(
Tohoku J. Exp. Med.)》,185: 173-84 (1998);Ishii, Y.,《日本婦科學會雜誌(
Nippon Sanka Fujinka Gakkai Zasshi)》:
4Ί:133-40 (1995);及Ferrer, F. A.等人,《泌尿學(
Urology)》,54:567-72 (1999);Fielder等人,《血液》,89:1870-5 (1997)及Bellamy等人,《癌症研究》,59728- 33 (1999))。不希望受理論束縛,VEGF/hVEGFR2自分泌環在活體內調節腫瘤細胞存活及遷移,且已經進一步證明VEGFR1單株抗體抑制某些實體瘤細胞例如乳腺癌細胞中之自分泌VEGF/VEGFR1環,且抑制VEGF刺激之人類白血病細胞遷移(參見例如,US7498414(B2))。
在某些實施例中,實體瘤選自由以下組成之群:乳腺癌、肺癌、大腸直腸癌、胰臟癌、膠質瘤及淋巴瘤(例如頭頸腫瘤)、大腸直腸腫瘤、前列腺腫瘤、乳腺腫瘤、肺腫瘤(如小細胞及非小細胞肺腫瘤)、胰腺腫瘤、甲狀腺腫瘤、卵巢腫瘤、宮頸腫瘤、腎腫瘤、腦腫瘤及肝腫瘤、卡波西肉瘤、CNS腫瘤、神經母細胞瘤、毛細血管母細胞瘤、腦膜瘤、腦轉移、黑色素瘤、胃腸道及腎癌及肉瘤(例如胃癌)、橫紋肌肉瘤、膠質母細胞瘤(尤為多形性膠質母細胞瘤)、平滑肌肉瘤、鱗狀細胞癌、基底細胞癌及可藉由抑制惡性角化細胞(如人類惡性角化細胞)之生長來治療的皮膚癌。在某些實施例中,實體瘤選自由以下組成之群:胃癌、非小細胞肺癌如大細胞肺癌。
在某些實施例中,非實體瘤選自由以下組成之群:白血病、多發性骨髓瘤及淋巴瘤,例如急性髓性白血病(AML)、慢性髓性白血病(CML)、急性淋巴球性白血病(ALL)、慢性淋巴球性白血病(CLL)、紅血球白血病或單核細胞白血病、霍奇金及非霍奇金淋巴瘤。
血管生成疾病
在某些實施例中,VEGFR2相關疾病或病症為血管生成疾病。血管生成疾病與不受控制之血管生成有關,血管生成可由VEGF例如VEGF-A調節。在傷口癒合過程中,可在胚胎組織、巨噬細胞及增生性表皮角化細胞中發現VEGF之表現(Breier等人,《發育(
Development)》,114:521-32 (1992);Brown等人,《實驗醫學雜誌》,176:1375-9 (1992);及Ferrara等人,《內分泌評論(
Endocr. Rev)》,13:18-32 (1992))。VEGF高表現亦可見於腫瘤,如多形性膠質母細胞瘤、血管母細胞瘤、中樞神經系統腫瘤及AIDS相關卡波西肉瘤;見於動脈粥樣硬化病變、斑塊及炎性細胞(Nakamura, S.等人,《AIDS週刊(AIDS Weekly)》,13 (1) (1992);Plate, K.等人,《自然》,359:845-8 (1992);Plate, K.等人,《癌症研究》,53:5822-7 (1993);及Berkman, R.等人,《臨床研究雜誌(
J. Clin. Invest.)》,91:153-9 (1993))。不希望受理論束縛,與表現VEGF的腫瘤細胞相鄰的內皮細胞通常表現出VEGF受體例如VEGFR2之上調表現。腫瘤釋放VEGF導致刺激相鄰內皮細胞中之血管生成,從而導致增殖、遷移、分化、管形成、維持血管完整性及增加內皮細胞之血管通透性。因此,本發明提供之抗-VEGFR2抗體或其抗原結合片段可治療血管生成疾病中涉及之VEGF/VEGFR2信號傳遞異常。
在一些實施例中,血管生成疾病為動脈粥樣硬化、類風濕性關節炎(RA)、新生血管性青光眼、包含增生性糖尿病視網膜病變在內的增生性視網膜病變、黃斑變性、血管瘤、血管纖維瘤、牛皮癬、早產兒視網膜病變(例如,晶狀體後纖維增生)、角膜移植排斥、胰島素依賴型糖尿病、多發性硬化、重症肌無力、克羅恩病、自體免疫性腎炎、原發性膽汁性肝硬化、急性胰臟炎、同種異體移植排斥、過敏性發炎、接觸性皮炎及遲發性超敏反應、炎性腸病、感染性休克、骨質疏鬆症、骨關節炎、由神經元發炎引起之認知缺陷、奧斯勒-韋伯症候群、再狹窄以及真菌、寄生蟲及病毒感染如巨細胞病毒感染。
在一些實施例中,受試者為人類。
本文提供之抗體或抗原結合片段及/或本文提供之醫藥組合物可藉由口服、鼻、靜脈內、皮下、舌下、瘤內或肌肉內投與來投與。
在一些實施例中,本文提供之方法進一步包括投與治療有效量之第二治療劑,例如抗癌療法,視情況地,該抗癌療法選自化學治療劑、放射療法、免疫治療劑、抗血管生成劑(例如VEGFR (如VEGFR-1、VEGFR-2及VEGFR-3)之拮抗劑)、EGFR拮抗劑、PDGFR拮抗劑、IGFR拮抗劑、NGFR拮抗劑、FGFR拮抗劑、靶向治療劑、細胞治療劑、基因治療劑、激素治療劑、細胞介素、緩解性治療、治療癌症之手術(例如腫瘤切除術)、一或多種止吐藥、化學療法引起之併發症的治療或癌症患者的膳食補充劑(例如吲哚-3-甲醇)。
在一些實施例中,本發明提供了包括任視情況地與可偵測部分綴合的本文提供之抗體或其抗原結合片段的套組。該套組可用於偵測生物樣本中hVEGFR2之存在或量,或可用於本文提供之診斷方法。
在一些實施例中,本發明提供了包括本文提供之抗體或其抗原結合片段及第二治療劑的套組。該套組可用於治療、預防及/或改善VEGFR2相關疾病或病症。
本發明亦提供了偵測樣本中VEGFR2之存在或量的方法,其包括使樣本與本文提供之抗體或其抗原結合片段接觸,且測定樣本中VEGFR2之存在或量。
在一些實施例中,本發明亦提供了本文提供之抗體或其抗原結合片段在製備用於在受試者中治療VEGFR2相關疾病或病症、降低VEGFR2相關疾病或病症之嚴重性及/或減緩VEGFR2相關疾病或病症之進展的藥物中的用途。
實例
實例 1 : VEGFR2 蛋白之製備及表徵
人類 VEGFR2/KDR-His :重組人類VEGFR/KDR蛋白(hVEGFR2-his,登錄號AAI31823.1)在人類293細胞(HEK293)中表現。簡言之,將來自Ala20-Glu764的在C末端具有6×his標籤之人類VEGFR2基因之編碼區用於轉染。使用His-標籤親和管柱純化上清液。使用SDS PAGE凝膠表徵所得純化蛋白。該蛋白購自ACRO Biosystems (Cat#KDR-H5227)。
具有 His 標籤之恆河猴 VEGFR2/KDR :使重組恆河猴VEGFR2/KDR蛋白胞外域Ala20至Glu764 (登錄號XP_014994176.1)在C末端與多組胺酸標籤融合,且在人類293細胞(HEK293)中產生。使用His-標籤親和管柱純化來自HEK293細胞之轉染上清液。使用SDS PAGE凝膠表徵所得純化蛋白。該蛋白購自ACRO Biosystems (Cat#VE2-C52H3)。
上述VEGFR2蛋白用於以下實驗。
實例 2 :抗體產生
1.
抗原綴合及免疫
對於免疫,重組hVEGFR2-his蛋白與各種MabSpace免疫增強肽綴合。簡言之,將2-8倍莫耳過量之肽與磺基-SMCC (4-[N-順丁烯二醯亞胺甲基]環己烷-1-羧酸磺基丁二醯亞胺酯,Peirce#22322)活化的hVEGFR2蛋白混合,且在室溫下培育一小時。停止反應且使用SDS-PAGE凝膠分析及QC綴合的蛋白。
分別使用完全弗氏佐劑(Pierce)將上述綴合的hVEGFR2-his蛋白以1:1的比例乳化,然後皮下及腹膜內免疫C57B/L6小鼠。使用CpG及明礬進行額外的免疫以保持蛋白的天然構形。至少每2週進行一次免疫,且在第1次免疫後自小鼠中取出抗血清以藉由ELISA分析進行抗-hVEGFR2滴度分析。
為了測定血清滴度,由各免疫小鼠製備20 μl小鼠血清。高結合透明聚苯乙烯96孔盤(Nunc)包被有100 µl/孔的1 µg/ml溶液,該溶液由在高pH包被緩衝液(0.16% Na2CO3,0.3% NaHCO3,pH 9.8)中之人類VEGFR2-his組成。將盤在4℃下培育隔夜,然後在自動洗盤機上使用洗滌緩衝液PBS + 0.1% Tween 20 (Sigma)洗滌一次。向各孔中添加200 μl封閉緩衝液(PBS + 1% BSA + 1%山羊血清+ 0.05% Tween 20)且在室溫下培育2小時。然後吸出封閉緩衝液,且將稀釋緩衝液(PBS + 1% BSA + 1%山羊血清+ 0.01% Tween 20)中之100 µl連續稀釋血清轉移至ELISA盤之各孔中,且使其在室溫下培育60 min。然後使用上述方法將盤洗滌3次。然後將100 μl/孔的在稀釋緩衝液中稀釋之HRP綴合山羊抗小鼠Fc抗體溶液(Abcam, Cat#Ab98808)添加至盤之各孔中。之後,使ELISA盤在室溫下培育60 min,用250 μl/孔洗滌緩衝液洗滌盤3次。最後,向各孔中添加100 µl/孔的TMB,且使用0.64 M H
2SO
4終止反應。在Thermo Multiscan FC上在450 nM讀取盤。
2.
融合
融合四天前,每隻小鼠用在PBS中之未綴合的hVEGFR2蛋白腹膜內加強。在融合日,無菌取出脾臟,且將器官加工成單細胞懸浮液。裂解紅血球且用DMEM (Gibco)洗滌脾細胞。將活的、對數期生長的骨髓瘤細胞(SP2/0)與鼠脾細胞以1:4之比例混合。然後在與PEG融合之前將細胞洗滌2次。融合後的細胞用DMEM洗滌且懸浮在補充有10% FBS + HFCS + OPI + 1X HAT的細胞生長培養基中。將每孔200 µl此細胞懸浮液鋪盤於96孔細胞培養盤中,且在37℃加濕的10% CO
2培育箱中培育隔夜。將培養物培育7天,然後將生長培養基自孔中吸出且更換為新鮮的生長培養基。更換培養基2-3天後開始篩選雜交瘤上清液。
3.
由
ELISA
分析進行之抗體篩選
與上述測定血清滴度之方案相同。簡言之,在4℃下包被0.5 μg/ml hVEGFR2-his隔夜。洗滌後,添加100 μl雜交瘤上清液且使其完全結合。然後添加HRP綴合的山羊抗小鼠Fc抗體以偵測結合的VEGFR2抗體。最後,在TMB反應及H
2SO
4終止後,在Thermo Multiscan FC上在450 nM讀取盤。隨後將來自ELISA陽性雜交瘤孔的細胞在細胞培養物中擴增,以進行進一步的表徵研究。
實例 3 :陽性雜交瘤純系之次選殖及小規模抗體生產
1.
陽性雜交瘤純系之次選殖
選擇來自ELISA陽性雜交瘤孔的具有所需結合概況及阻斷活性的細胞,且使用有限稀釋將各細胞鋪盤在96孔盤中。使此等細胞生長7天。一旦達至足夠的細胞質量,就收集來自各孔之上清液且重新篩選抗原結合能力(參見實例2中之篩選)。
自各96孔盤中,識別出具有最高抗原結合活性之純系,且在有限稀釋下進一步擴增至96孔盤中,其中每孔200 μl雜交瘤生長培養基。7天後,對來自96孔盤之細胞進行抗原結合測試。次選殖進行了超過2次。當超過90個孔顯示陽性結合信號時,識別出具有最高抗原結合活性的兩個純系且將其轉移至具有培養基之24孔盤中,且使其再生長2天。一旦24孔盤匯合,就將細胞轉移至6孔盤。培育5天後,將一部分細胞凍結。將剩餘的細胞轉移至燒瓶中且使其擴增。一旦燒瓶匯合,就將一半的細胞凍結(每個純系3個小瓶)以用於額外的備份。使另一半在具有培養基之燒瓶中進一步擴增以用於抗體生產。使用標準方法確定同型。
2.
小規模抗體生產
將雜交瘤細胞接種至滾瓶中且用200-300 ml雜交瘤培養基(Invitrogen)培養14天。如下自雜交瘤細胞培養物中純化VEGFR2單株抗體(mAb)。所有純化過程均在室溫下進行。一種純化方案用於純化各種mAb且使用親和層析法。
將宿主細胞培養液(CCF)離心以移除細胞碎片。然後將CCF上清液過濾、稀釋,然後以管柱(蛋白G高效能(Bio-Rad))的形式加載至蛋白G層析介質上且平衡。
加載後,洗滌蛋白G管柱,直至流穿液的280 nm處的吸光度恢復至基線。然後使用pH 2.5的甘胺酸自管柱中溶離VEGFR2 mAb,且立即藉由每mL溶離體積添加50 μL的1 M Tris Base儲備溶液中和。監測溶離液在280 nm處的吸光度且收集含有蛋白的級分以製備蛋白A池。
純化後,藉由使用10,000 MWCO膜(Pierce Slide-A-Lyzer或透析管)透析在PBS中配製VEGFR2 mAb。配製後,過濾VEGFR2 mAb。
實例 4 :純化之 VEGFR2 抗體之結合分析
與實例2藉由ELISA分析篩選抗體之方案相同。簡言之,包被0.5 µg/ml hVEGFR2-his,且連續稀釋之純化抗體將與包被抗原結合。使用HRP綴合的山羊抗小鼠Fc抗體可偵測各抗體之結合信號。
資料係藉由Graphpad Prism軟體計算及擬合,且抗體之EC50總結在圖1A及圖1B以及表6中。雜交瘤抗體對人類具有相似的親和力。
表 6
實例 5 :評估純化抗體抑制 hVEGF-A 與 hVEGFR2 結合之阻斷活性
在 ELISA 結合中獲得之 VEGFR2 特異性抗體之 EC50 值 (ng/ml) | |
VEGFR2 特異性雜交瘤抗體 | 人類 VEGFR2 |
002 | 16.80 |
003 | 7.69 |
006 | 13.52 |
018 | 12.95 |
042 | 22.44 |
048 | 23.20 |
054 | 8.09 |
高結合透明聚苯乙烯96孔盤用100 μl/孔的1 μg/ml hVEGFR2-his在4℃包被隔夜。洗滌及阻斷後,添加連續稀釋之抗體(10 μg/ml至0.0006 μg/ml)且在室溫下培育1小時。添加0.3 μg/ml hVEGF-A (Acrobiosystem, Cat#VE5-H4210)且在室溫下培育2小時。然後添加100 μl/孔的0.25 μg/ml生物素化兔抗人類VEGF-A (Peprotech, Cat#400-P10Bt)以偵測結合的VEGF-A。然後依次添加100 µl/孔的HRP綴合中性抗生物素蛋白抗體(Pierce, Cat#31001)及TMB溶液。最後,使用0.64 M H
2SO
4終止反應,且在450 nM處讀取盤。1121B為美國專利號:US7498414中揭示之基準抗體(雷莫蘆單抗)。
如圖2所示,002、048、054及1121B具有相似的阻斷活性及相當的IC50,表明前3種抗體亦可藉由阻斷VEGF-A/VEGFR2相互作用來抑制VEGF-A之活性,如1121B。
實例 6 :藉由 FACS 量測的純化 VEGFR2 抗體與 HUVEC 結合之劑量依賴性反應
將對數期HUVEC細胞收集、計數且重懸於FACS緩衝液(5% BSA+PBS)中。將2×10^5個細胞添加至各管中,然後用PBS洗滌一次(1500 rpm,5 min,室溫)。然後將在FACS緩衝液中自雜交瘤上清液中純化之100 μl/管連續稀釋之VEGFR2抗體添加至相應的管中,且在4℃下培育1小時。然後用1 ml PBS洗滌細胞兩次,隨後添加在FACS緩衝液中之100 μl/管的2抗(1:400抗-mIgG (H+L)-PE,Cell signaling#8887)。將細胞在4℃下培育0.5小時,然後用PBS洗滌兩次,隨後對於各樣本將細胞重懸於600 µl PBS中。然後將細胞轉移至FACS管中,且使用流式細胞術(BD Accuri C6)偵測抗體與細胞之結合(見圖3)。
藉由Graphpad Prism軟體計算及擬合陽性結合細胞之百分比。如圖3所示,此等雜交瘤抗體可與HUVEC細胞結合,此即為眾所周知的VEGFR2在細胞表面之表現。
實例 7 :雜交瘤抗體之基因選殖及定序
小鼠抗人類VEGFR2抗體輕鏈及重鏈可變區之序列藉由稱為5' RACE (cDNA末端快速擴增)的聚合酶鏈式反應(PCR)擴增技術獲得。使用Trizol (Invitrogen)分離來自11B8 (002)/21B4 (003)/5G4 (048)/10D11 (054)抗體產生雜交瘤細胞之總RNA,且使用Superscript第一股合成系統(Invitrogen)利用寡核苷酸(DT)12-18引子(Invitrogen)合成cDNA。藉由PCR選殖小鼠IgG基因之可變區,其中MuIgG VH3'-2及MuIg VH5'前導引子用於重鏈可變區,MuIgK VL3'-1及MuIgK VL5'前導引子用於輕鏈可變區(NOVAGEN)。將各抗體之所得條帶選殖於pMD
®18-T選殖載體中,且使用ABI DNA定序儀器(Perkin Elmer)對來自20個純系的DNA進行定序且測定。使用Vector NTI Advance 10軟體(Invitrogen)確定共有序列。
嵌合抗體之產生:在定序分析及確認後,將上述各基因之可變區選殖於重組表現載體pCP-Hck/Hcg1中。簡言之,pCP-Hck/Hcg1載體首先藉由兩步限制酶消化。然後將輕鏈可變區(VL)及重鏈可變區(VH)之基因與消化的載體同源重組。在轉型、菌落PCR及序列確認後,生成嵌合抗體之表現載體。
實例 8 :重組嵌合抗體表現與純化
上述產生之重組嵌合抗體蛋白之表現及純化藉由以下方法進行:用終濃度為0.5 μg/ml之DNA載體及1.0 μg/ml之PEI (聚乙烯亞胺-線性,Polyscience)轉染在含有10% Pluronic F-68之Freestyle 293表現培養基中以1×10
6個細胞/ml培養的HEK293E細胞。DNA與PEI之比例為1:2。與Optimal MEM形成DNA及PEI複合物的時段應為室溫下15分鐘。將轉染細胞在5% CO
2、37℃及125 rpm振盪速度下於燒瓶中培養。在轉染22至26小時後添加1%蛋白腖培養基。在第6天收穫條件培養基且將上清液以3,000 rpm離心30分鐘。然後將澄清的條件培養基加載至預平衡的0.5 ml蛋白A管柱上,用5個管柱體積的1XPBS洗滌,且最後用3 mL pH 3.0 0.1 M甘胺酸-HCL緩衝液溶離結合的IgG。將溶離的抗體蛋白透析至PBS且儲存在-80℃。為了移除內毒素,使純化之蛋白藉由Hitrap DEAE瓊脂糖F.F.管柱進一步加工,且使用尺寸排阻層析法(Superdex 200 5/150 GL, G.E. Healthcare)分析所得抗體以確定純度水準。
實例 9 :純化之抗 -VEGFR2 嵌合抗體與人類
及恆河猴 VEGFR2 蛋白之結合
與實例4相同之方案,不同之處在於使用HRP綴合的山羊抗人類Fc抗體作為二抗。亦對與hVEGFR2-his及恆河猴VEGFR2-his (Acrobiosystems, Cat#VE2-C52H3)之結合進行頭對頭分析。
如圖4A及圖4B所示,4個嵌合抗體可與人類及恆河猴VEGFR2以相似的親和力結合,如1121B,表明在恆河猴中評估安全性問題以進行進一步研究的可能性。
實例 10 :嵌合抗 -VEGFR2 抗體抑制 VEGF-A 與 hVEGFR2 結合之能力的表徵
對於該分析,在添加嵌合抗體及VEGFR2的混合物之前,將0.25 µg/ml VEGF-A包被在ELISA盤上。為了偵測游離的VEGF-A (不與VEGFR2結合),添加1:1000稀釋的小鼠血清(先前用人類VEGFR2免疫的小鼠),且使用HRP綴合的山羊抗小鼠Fc抗體作為二抗。
如圖5所示,3種抗體(042C、048C及054C)對VEGF-A與VEGFR2結合之抑制效果與1121B一樣好,甚至更好。002C顯示出弱得多的中和活性。
實例 11 :選擇純化之嵌合抗體與 HUVEC 結合的基於 FACS 的分析
與實例6的方案相同,不同之處在於使用1:400兔抗-hIgG (H+L)-PE (Cell signaling#8887)作為二抗。如圖6所示,002C及054C與HUVEC細胞結合的EC50與1121B幾乎相同。因此,此等VEGFR2抗體可藉由與在細胞表面表現的人類VEGFR2結合而發揮作用。
實例 12 :藉由競爭分析進行之抗原決定基分箱
與上述ELISA結合分析的方案類似。簡言之,將0.5 μg/ml hVEGFR2-his包被至盤上。同時添加20 µg/ml競爭者抗體及1.25 µg/ml生物素化的其他抗體。培育3小時後,添加中性抗生物素蛋白綴合的HRP以偵測結合的生物素化抗體。若競爭者抗體競爭相同的抗原決定基,則結合的生物素化抗體之信號會降低,但若競爭不同的抗原決定基,則不會產生影響。
如圖7所示,生物素-mA002與002、042、048及054競爭,說明其可能屬於同一抗原決定基組。且後來發現該組具有最佳阻斷活性及與1121B相同的抗原決定基(資料未顯示)。
然後按照上述相同方案添加稀釋的競爭者雜交瘤抗體(002、042、048及054)及較低濃度(100 ng/ml)的嵌合抗體(002C、042C、054C)以進行替換。抗-hIgG Fc-HRP用作偵測抗體。
如圖8A及圖8C所示,隨著雜交瘤抗體濃度之增加,嵌合抗體不能很好地結合或根本不能結合。與圖7A及圖7B相同,雜交瘤002、042、048及054可與嵌合抗體競爭,此可能係由於相同的抗原決定基。
實例 13 :剖析純化嵌合抗體在 HUVEC 細胞中阻斷 VEGF-A 誘導之 pVEGFR2 的活性
表現VEGFR2的細胞如HUVEC細胞將在VEGF-A刺激後上調VEGFR2之表現量。然後增加的VEGFR2可與VEGF-A結合且變成二聚體形式。二聚化將誘導VEGFR2之Tyr磷酸化,隨後活化下游路徑,如MAPK/ERK及PI3K。
簡言之,將HUVEC細胞以1.5×10
5個細胞/孔的密度接種至12孔盤中之含10% FBS之培養基中,且在37℃、5% CO
2培育箱中培育16小時,然後用無血清培養基將細胞饑餓4小時。每孔添加不同的嵌合抗體培育30 min,隨後添加20 ng/ml或40 ng/ml VEGF-A培育15 min。最後,藉由添加100 µl含有完整蛋白酶抑制劑(Roche#04693132001)及磷酸酶抑制劑(Pierce#1862495)的RIPA緩衝液(Thermo Scientific
TM, Cat#89900)製備細胞裂解物,在冰上培育15分鐘且離心以收集上清液。藉由8% SDS-PAGE拆分等量的細胞裂解物。將蛋白轉移至含有冰之罐上的PVDF膜(Millipore),在400 amp下運行150 min。然後將膜與含有5% BSA + TBST之溶液在室溫下培育2小時。然後將膜與含有1% BSA+TBST及兔抗磷酸化VEGFR2 (Tyr1175) mAB (CST, Cat#3770)/小鼠抗-β-肌動蛋白抗體(Abbkine, Cat#A0101502)的溶液在4℃培育隔夜;然後在輕輕旋轉下用TBST洗滌膜3次,每次10 min;然後將膜與在1% BSA+TBST中以1:1000稀釋的HRP綴合的山羊抗兔IgG Fc pAB (Abcam, Cat#Ab97080)/HRP綴合的山羊抗小鼠IgG pAb (Abcam, Cat#ab97040)培育2小時。然後在輕輕旋轉下用TBST洗滌膜3次,每次10 min;最後,將1 ml ECL混合物(Pierce)添加至PVDF膜上以用於信號暴露。
如圖9A、圖9B及圖9C所示,20 ng/ml及40 ng/ml之VEGF-A均能快速誘導VEGFR2磷酸化。且054C、048C、042C及002C以及雷莫蘆單抗可以劑量依賴之方式逆轉此刺激。
實例 14 :人類化抗體之產生及表徵
1.
人類化抗體之產生、表現及純化
小鼠抗體054及048之可變域序列用於識別與鼠構架同源性最高的生殖系序列。電腦建模用於設計具有CDR移植及回復突變的人類化變異體。
Ab-54
用於輕鏈之人類生殖系構架序列VK/2D-40及用於重鏈之VH/3-21分別用於CDR移植。
Mab54 HC之生殖系序列:
Mab54 LC之生殖系序列:
Ab-48
用於輕鏈之人類生殖系構架序列VK/2D-40及用於重鏈之VH/3-21分別用於CDR移植。
Mab48 HC之生殖系序列:
Mab48之生殖系及輕鏈序列與Mab54相同。
因此,人類化Mab54有4種變異體,簡稱為54-H1L1、54-H2L1、54-H1L2、54-H2L2,且人類化Mab48有2種變異體,簡稱為48-H3L1、48-H3L2。事實上,VH/3-21變異體5與VH/3-21變異體2幾乎相同,HCDR3中之一個胺基酸除外。此亦與本專利中顯示的兩種抗體之相似生物活性一致。
合成上述重鏈及輕鏈cDNA,且與Fc區之人類IgG1恆定區融合(本文所述之重鏈殘基編號依據Kabat之EU索引(參見Kabat等人,「免疫感興趣之蛋白(Proteins of Immunological Interest)」,美國衛生與人類服務部(1983)))。合成所選抗體基因之重鏈及輕鏈之可變區且選殖於表現載體中,且使用來自Promega之PureYield™ Plasmid Maxiprep系統製備大規模DNA。根據製造商之方案,使用來自Invitrogen之ExpiFectamine
TM293試劑進行轉染。當細胞活力約為50%時收穫上清液。將蛋白A珠粒及乾淨的上清液於4℃搖動下培育2小時,然後通過管柱。用PBS洗滌管柱內的蛋白A珠粒,且使用100 mM甘胺酸緩衝液(pH 3.0)溶離抗體,將其針對PBS緩衝液(137 mM NaCl, 2.7 mM KCl 10 mM Na
2HPO
4, 2 mM KH
2PO
4, pH 7.4)在4℃下透析隔夜。最後,使用Pierce高容量內毒素移除樹脂(Invitrogen,目錄號:88271)移除內毒素。純化之抗體藉由SDS-PAGE及SEC-HPLC表徵。
2. ELISA
中人類化抗體與
hVEGFR2
及恆河猴
VEGFR2
之結合
與實例9相同之方案。首先測試由293T細胞表現的人類化054及048抗體(參見圖10A及圖10B)。
然後由CHO細胞表現兩種人類化抗體54-H2L1及48-H3L1以用於進一步評估,分別標記為54-H2L1 (CHO)及48-H3L1 (CHO)。維持與恆河猴VEGFR2-his之跨物種結合,此為治療性抗體開發的一個非常重要之特徵(參見圖11A及圖11B)。
3.
人類化
VEGFR2
抗體之結合特異性
簡言之,將1 μg/ml人類VEGFR1 (Sino Biological, cat#10136-H08H)、VEGFR2 (Acrobiosystem, cat#KDR-H5227)及VEGFR3 (Sino Biological, cat#10806-H08H)蛋白在4℃包被隔夜。添加1 µg/ml人類化抗體(在CHO細胞中產生之48-H3L1及54-H2L1,或來自Eli Lilly Germany,批次#20150819之雷莫蘆單抗)以用於結合包被抗原。添加二抗HRP綴合的山羊抗人類Fc抗體用於偵測結合信號。
如圖12所示,VEGFR2抗體48-H3L1、54-H2L1及雷莫蘆單抗僅與VEGFR2結合,而不與VEGFR1或VEGFR3結合,表明此等抗體具有高特異性。
4. ELISA
中
hVEGF-A
與
hVEGFR2
及恆河猴
VEGFR2
之結合的阻斷
與實例10相同之方案。簡言之,將0.25 μg/ml VEGF-A在4℃下包被隔夜。阻斷後,同時添加連續稀釋的54-H2L1、48-H3L1、雷莫蘆單抗及1 µg/ml人類VEGFR2或恆河猴VEGFR2,培育2小時。洗滌後,添加含有多株VEGFR2抗體及HRP綴合的山羊抗小鼠Fc抗體之小鼠血清以用於偵測包被在盤上之游離VEGF-A (參見圖13A及圖13B)。
如圖13A及圖13B所示,兩種人類化抗體可阻斷VEGF-A與人類VEGFR2或恆河猴VEGFR2相互作用。48-H3L1及54-H2L1的中和活性與雷莫蘆單抗相似或者甚至可能更好。
5.
人類化抗體阻斷
VEGF-C
及
VEGF-D
與
VEGFR2
之結合
與實例10類似之方案。簡言之,包被0.5 μg/ml VEGF-A或VEGF-C或VEGF-D,同時添加30 μg/ml VEGFR2抗體及2.5 μg/ml人類VEGFR2,培育2小時。使用與實例10相同之偵測方法,可量測包被在盤上之游離VEGF-A或VEGF-C或VEGF-D (參見圖14A、圖14B及圖14C)。
如圖14A、圖14B及圖14C所示,包含1121B在內的VEGFR2抗體完全阻斷VEGF-A與VEGFR2之結合,但不阻斷VEGF-C或VEGF-D與VEGFR2之結合。雖然觀測到VEGF-C結合略有下降,但窗口太有限以致無法得出結論。
6. FACS
中人類化抗體與
HUVEC
上
hVEGFR2
之結合
與實例11相同之方法。簡言之,收集對數期HUVEC細胞且將其添加至各管中。然後添加在FACS緩衝液中之100 μl/管連續稀釋的人類化抗體,且在4℃下保持1小時。抗體與HUVEC之結合藉由在1抗之後添加的2抗(抗-hIgG(H+L)-PE)的PE信號偵測(參見圖15)。
7. HUVEC
中
hVEGF-A
誘導之
hVEGFR2
磷酸化的阻斷
與實例13相同的方法。簡言之,將HUVEC細胞接種至12孔盤中含有10% FBS之培養基中且培育16小時,然後在沒有血清之情況下饑餓4小時。將稀釋的人類化抗體添加至各孔中,培育30 min,隨後添加40 ng/ml VEGF-A,培育15 min。最後,製備細胞裂解物且藉由實例13中描述之西方墨點法偵測磷酸化-VEGFR2及β-肌動蛋白(參見圖16)。
如圖16所示,人類化54的兩個變異體可降低VEGF-A誘導之磷酸化VEGFR2的量。54-H2L1的抑制作用比54-H1L1強。
實例 15 :純化之人類化抗體抑制 HUVEC 增殖及管形成之能力的評 估
將對數期HUVEC細胞以5×10
3個細胞/孔的密度接種至96孔盤中之含10% FBS之培養基中,且在37℃、5% CO
2培育箱中培育隔夜,然後用50 µl/孔無血清培養基饑餓細胞4小時。以50 μl/孔添加連續稀釋的人類化抗體且培育30 min,隨後添加50 μl/孔的VEGF-A (終濃度:20 ng/ml)且培育72小時。細胞培養結束時,添加20 μl/孔之Cell Titer-Glo
®發光套組,且將上清液轉移至新的白盤上以用於讀取發光信號。
受VEGF家族刺激的HUVEC細胞將被活化且增殖。阻斷VEGFR2及VEGF可逆轉刺激作用。如圖17所示,人類化54及48抗體對增殖之抑制作用可與雷莫蘆單抗相同,呈劑量依賴性方式,表明其阻斷了HUVEC細胞之VEGF/VEGFR2信號路徑。
實例 16 :藉由 Biacore 評 估 選擇小鼠雜交瘤或人類化抗 -VEGFR2 抗體之結合親和力
藉由7-min注射(10 μl/min)新鮮製備之1:1 50 mM N-羥基丁二醯亞胺(NHS): 200 mM 1-乙基-3-(3-二甲基胺基丙基)-碳二亞胺(EDC)在各流動池中激活CM5感測器晶片。然後將在10 mM醋酸鈉緩衝液PH 5.0中濃度為10 μg/ml的抗人類Fc抗體(GE Healthcare)以10 μl/min注射至激活的晶片上(HBS-EP運行緩衝液:10 mM HEPES,150 mM NaCl,3.4 mM EDTA,0.005%界面活性劑P20,pH 7.4)。剩餘的活性偶聯位點藉由以10 μl/min注射1 M乙醇胺7 min封閉。各流動池之固定水準約為9000 RU。藉由抗人類Fc IgG或抗小鼠Fc (GE Healthcare)在FC2中捕獲抗體至200-300 RU。FC1用作參考池。在捕獲抗體後,以不同濃度(2.5 nM、5 nM、10 nM、20 nM、40 nM及80 nM)注射抗原。抗體結合抗原之締合時間為180 s。在Gly pH 1.5中,表面再生條件為120 s,速度為10 μl/min。使用Biacore X100評估軟體2.0版(Biacore)計算自沒有捕獲抗體之信號中減去捕獲抗體之信號。
表 7.與抗原結合之抗體之親和力參數
抗體 | 純系 | Ka(1/Ms) | Kd(1/s) | KD(M) |
mAb002 | 11B8C2C11 | 5.62E+04 | 3.36E-04 | 5.98E-09 |
mAb003 | 21B4G9B4 | 1.26E+05 | 2.95E-05 | 2.35E-10 |
mAb006 | 27E8A9D5 | 1.27E+05 | 1.86E-04 | 1.47E-09 |
mAb018 | 16D9G2E8 | 8.84E+04 | 4.52E-04 | 5.11E-09 |
mAb042 | 8G11G1B2C6 | 8.51E+04 | 4.88E-05 | 5.73E-10 |
mAb054 | 10D11F4D1F6 | 9.18E+04 | 9.12E-05 | 9.93E-10 |
mAb048 | 5G4H2C3D3 | 1.14E+06 | <1.0E-7 | <1.0E-12 |
mAb054 | 10D11F4D1F6 | 9.70E+04 | 1.22E+06 | 1.26E-10 |
mAb054 | 54-H1L1 | 4.51E+04 | 5.15E-05 | 1.14E-09 |
mAb054 | 54-H1L2 | 3.77E+04 | 1.39E-04 | 3.68E-09 |
mAb054 | 54-H2L1 | 5.48E+04 | 1.38E-04 | 2.51E-09 |
mAb054 | 54-H2L2 | 2.97E+04 | 1.28E-04 | 4.30E-09 |
mAb054 | 54-C | 4.60E+04 | 1.13E-04 | 2.45E-09 |
已知人類VEGF-A與VEGFR2-Fc之間的相互作用具有約89 pM之
K
D (doi: 10.1007/s10456-011-9249-6)。
實例 17 :藉由丙胺酸掃描進行的選擇抗 VEGFR2 的抗原決定基作圖
1.
突變人類
VEGFR2
重組蛋白之產生
在活體外合成編碼胞外人類VEGFR2 (胺基酸1-1356)及人類IgG1的Fc片段之cDNA (SEQ ID NO: 103為胺基酸序列)。藉由如下所述之重疊PCR且使用如(表8)中所示的引子(Dr.Oligo BLP-192, Biolytic)擴增在如下所列指定位置具有單個胺基酸變化的人類VEGFR2變異體。所得片段分別在5'及3'末端用Hind III及BamH I的限制酶消化。然後按照製造商之說明,使用Syno組裝混合試劑(Synbio)藉由同源重組方法將PCR產物選殖於pcDNA3.1 (+)載體中。質體為純化之QIAGEN Plasmid Mega Kit (QIAGEN)。
使用上述產生之野生型VEGFR2質體(SEQ ID NO: 103及104)作為模板,用大引子(表8)產生整合序列之兩個片段,且藉由同源重組完成接合。然後將產物選殖於pcDNA3.1 (+)載體中,藉由定序篩選出單個陽性菌落以識別變異體後,證明VEGFR2突變體產生成功。PCR程序及條件如下:
表
8.
變異體突變引子序列
步驟
1
:生成兩個大變異體片段
μl
ddH2O
35
5×S15 PCR
緩衝液
10
10 mM dNTP
1
F
引子
1
R
引子
1
PCR
產物
1
S15
聚合酶
1
----------------------------------------------------------------
50
初始變性
: 98
℃
1 min
變性
: 98
℃
15 s
黏接
: 58
℃
30 s
延伸
: 72
℃
30 s/Kb
最終延伸
: 72
℃
3 min 30
個循環
第
2
步:將兩個部分連接在一起
在冰上建立以下反應
(
同源重組
)
:
Syno
組裝混合物
10 μl
序列產物
1
2 μl
序列產物
2
2 μl
去離子
H
2O
6 μl
------------------------------------------------------------------
總體積
20 μl
其他20個變異體由另一家公司Genewiz (中國蘇州)製備。執行利用Synbio Tech之類似方法來合成VEGFR2變異體。
隨後,將此等突變體及野生型VEGFR2之質體轉染至293T (ATCC® CRL3216)細胞株中。首先,將5×10
6個293T細胞接種至60 mm培養皿中,確保初級比例在60%-80%以用於轉染。然後在400 μl 1×HBS中稀釋10 μg DNA,培育約5 min。向上述混合物中添加10 μl 25 kDa線性PEI轉染試劑(溶於1×HBS,1 mg/ml儲備溶液),確保DNA/PEI比例為1:2.5。然後將混合物逐滴添加至293T培養皿中。大約6-8小時後更換培養基且替換為完整之DMEM。72小時後,分別用0.22 μm過濾器收集細胞培養上清液,然後在-80℃保存備用。
2. ELISA
中
VEGFR2
抗體與
hVEGFR2
突變體之結合
如下所述,使用上清液以藉由ELISA偵測VEGFR2抗體之結合。
2.1
對於小鼠
Ab
:
將0.5 μg/ml抗人類Fc抗體(Abcam)在室溫下包被一小時。將在DMEM中含有各種突變人類VEGFR2-Fc蛋白或500 ng/ml野生型人類VEGFR2-Fc蛋白的160 µl DMEM上清液添加至各孔中,且在室溫下培育1小時。添加0.5 µg/ml的小鼠抗-VEGFR2抗體且在室溫下培育1小時。然後依次添加HRP綴合的山羊抗小鼠IgG Fc抗體及TMB,且使用0.64 M H
2SO
4終止反應。在Thermo Multiscan FC上在450 nM讀取盤。
2.2
對於具有人
類
Fc
之
Ab (
嵌合或人類化抗體
)
:
與
2.1類似之方案,不同之處在於添加嵌合或人類化抗體以結合突變VEGFR2-Fc及HRP綴合的抗hIgG Fc作為二抗。
表9總結了hVEGFR2上之關鍵殘基,該殘基為ELISA分析中針對人類VEGFR2測試各單獨抗體所需的。標記導致結合信號相對於野生型蛋白顯著降低的人類VEGFR2蛋白上之胺基酸殘基突變。
表 9. 各抗體在 hVEGFR2 上之關鍵殘基彙總
實例 18 :大規模生產用於活體內研究之抗 -VEGFR2 抗體
編碼 | 位置 | 突變體 | 02 | 02C | 42 | 42C | 48 | 48C | 54 | 54C | 1121b |
1 | KDR WT | ||||||||||
8 | 133 | H133A | |||||||||
21 | 135 | V135A | |||||||||
9 | 137 | Y137A | ★★ | ||||||||
22 | 164 | R164A | ★ | ★ | |||||||
10 | 165 | Y165A | ★ | ★ | ★ | ★ | ★ | ★ | ★ | ★ | |
23 | 197 | M197A | |||||||||
11 | 215 | I215A | |||||||||
24 | 217 | V217A | |||||||||
12 | 218 | V218A | ★★ | ||||||||
2 | 221 | Y221A | ★★★ | ★★ | ★★★ | ★★ | |||||
15 | 222 | R222A | ★ | ★★★ | ★★★ | ★★★ | ★★ | ||||
3 | 251 | E251A | ★★★ | ★★ | ★★ | ★★ | |||||
13 | 252 | L252A | ★ | ||||||||
25 | 253 | N253A | ★★★ | ★ | ★★ | ||||||
16 | 255 | G255A | ★★★ | ★★ | ★★ | ★★ | ★ | ||||
4 | 257 | D257A | ★★ | ★★★ | ★★★ | ★★★ | ★★ | ★★★ | ★★★ | ||
17 | 259 | N259A | |||||||||
5 | 261 | E261A | |||||||||
14 | 286 | K286A | ★★ | ||||||||
18 | 312 | G312A | ★★ | ★★ | ★★ | ||||||
6 | 313 | L313A | ★★★ | ★★★ | ★★ | ★★★ | ★★ | ★★ | |||
19 | 314 | M314A | ★ | ★★ | ★★ | ★★ | |||||
7 | 315 | T315A | ★★★ | ★★★ | ★★★ | ★★★ | ★★ | ||||
20 | 316 | K316A | ★ | ★★ | ★★ | ★★ |
使用在CHO-K1細胞中之短暫表現產生抗體。使用蛋白-A親和管柱純化產生的抗體,且在脫鹽後,將抗體以5 mg/ml配製入PBS,內毒素水準<3單位/mg。使用SDS-PAGE凝膠及SEC-HPLC表徵所得抗體之純度。
使用
CHO-K1
細胞短暫表現及純化重組抗體
重鏈及輕鏈之可變區選擇的抗體基因被合成且選殖於表現載體中。產生之表現對比用於轉染適合在無血清培養基中生長之CHO-K1細胞。在10 L Applikon生物反應器中生長10天後,收穫培養基且使用超濾器移除細胞及細胞碎片。然後藉由超濾濃縮澄清的上清液且上樣至製備的蛋白A (人類IgG)或G-瓊脂糖(小鼠IgG)管柱上。在用平衡緩衝液在UV監測器之監測下洗滌至基線後,然後用0.1 M檸檬酸,pH 3.5溶離管柱,且立即用1.0 M Tris-HCl緩衝液,pH 8.0中和溶離的抗體,且針對PBS,pH7.2 (Invitrogen)在2-8℃下透析隔夜,其中更換2次緩衝液。純化之抗體藉由0.22 µm無菌注射器過濾器過濾,且在-80℃或更低溫度下以等分試樣儲存。
實例 19 :嵌合抗人 類 VEGFR2 抗體在 HL-60 腫瘤模型中之活體內評估
為了評估VEGFR2候選抗體之抗腫瘤功效,建立了HL-60小鼠模型且評估了對於許多症狀之功效。簡言之,將4-6週的雌性NOD/SCID小鼠隨機分為4組。CTX (150 mpk, i.p.)治療後,在次日靜脈內注射1.5×10^7個細胞/小鼠。且在HL-60細胞注射3天後,用下表(表10)中列出的不同抗體治療小鼠。
表 10. 分組及治療時間表 (n=6)
組 | 劑量 | 治療時間表 |
陰性對照(鹽水) | - | 兩次/週×4 |
1121B | 5 mpk | 兩次/週×4 |
54-C | 5 mpk | 兩次/週×4 |
2-C | 5 mpk | 兩次/週×4 |
如圖18及表11所示,與其他組相比,54-C之存活百分比及狀況最好。54-C治療無動物死亡,陰性對照組及2-C治療組均死亡2隻。正如吾人所知,VEGFR2之活化係藉由與其配位體VEGF-A結合而發生的,VEGF-A藉由自分泌信號傳遞介導HL-60細胞增殖。此可解釋VEGFR2中和抗體54-C及1121B之腫瘤抑制作用。
表 11. 各治療組之症狀及死亡
實例 20 :抗小鼠 VEGFR2 抗體 DC101 之評估
組 | 後肢無力 | 毛髮蓬亂 | 腫頭 | 瘦 | 死亡 |
陰性對照 | 4/4 | 3/4 | 4/4 | 2/4 | 2/6 |
1121B | 4/5 | 4/5 | 4/5 | 0/6 | 1/6 |
54-C | 5/6 | 3/6 | 5/6 | 2/6 | 0/6 |
2-C | 3/4 | 3/4 | 3/4 | 0/4 | 2/6 |
1.
抗小鼠
VEGFR2
抗體
DC101
之活體外評
估
根據下表12所列的其Fab區序列重組及表現抗小鼠VEGFR2抗體DC101。對於DC101之Fc區,將大鼠IgG1 Fc替換為人類IgG1 Fc且命名為嵌合-DC101。然後藉由活體外分析評估嵌合-DC101以確認其生物活性。
表12. DC101之可變鏈序列
表12中加粗序列分別代表VH及VL之信號肽。
VH | VL | |
DC101 | SEQ ID NO: 40 | SEQ ID NO: 99 |
MEFGLSWLFLVAILKGVQCEVQLVETGGGLVQPGNSLKLSCATSGFIFSTTWMNWIRQTPGKRLEWLAQIEDKSNNYFISYSESVKGRFTISRDDSKSSVYLQMNNLKEEDTAIYYCSWKYRSNYYFDYWGQGVMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK | MDMRVPAQLLGLLLLWFPGSRCDIVLTQSPALAVSLEQRATISCKTSQNVDYYGISYLHWYQQKPGQQPKLLIYEGSNLASGIPARFSGSGSGTDFTLTIDPVEADDIVTYYCQQSKDYPYTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC |
進行ELISA結合分析以確認其結合親和力。簡言之,用在包被緩衝液(0.16% Na
2CO
3, 0.3% NaHCO
3)中之500 ng/mL小鼠VEGFR2包被ELISA盤,且在4℃培育隔夜。洗滌兩次後,添加封閉緩衝液(1% BSA、1%山羊血清、0.05% Tween 20,於PBS中)且將盤在室溫下培育2小時。洗滌三次後,將連續稀釋的嵌合-DC101添加至稀釋緩衝液(1% BSA、1%山羊血清、0.01% Tween 20,於PBS中)中,且將盤在室溫下培育3小時。洗滌三次後,添加山羊抗人類HRP (1:5000稀釋),且在室溫下培育盤1小時。最後,洗滌三次後,添加TMB,且在4 min後添加0.16 mol/L硫酸以終止反應。讀取且記錄OD450 nm。
如圖19所示,三批嵌合-DC101具有非常一致之結合曲線及EC
50(約為0.06 μg/mL),此亦與人類化54抗體及48抗體之EC
50非常相似。
進行ELISA阻斷分析以確認其VEGF阻斷活性。簡言之,用在包被緩衝液中之250 ng/mL重組人類VEGF165包被ELISA盤,且在4℃培育隔夜。洗滌兩次後,添加封閉緩衝液,且將盤在室溫下培育2小時。洗滌三次後,在稀釋緩衝液中添加連續稀釋的嵌合-DC101,然後添加1000 ng/mL小鼠VEGFR2。將盤在室溫下培育3小時。洗滌三次後,添加具有小鼠Fc之多株抗小鼠VEGFR2 (1:1000),且在室溫下培育盤1小時。洗滌三次後,添加山羊抗小鼠HRP (1:5000稀釋),且在室溫下培育盤1小時。最後,洗滌三次後,添加TMB,且在4 min後添加0.16 mol/L硫酸以終止反應。讀取且記錄OD450 nm。
如圖20所示,三批嵌合-DC101具有一致的阻斷曲線及IC
50值,與人類化抗人類VEGFR2抗體054及048非常相似。嵌合-DC101顯示出與人類化054及048抗體具有相似之結合親和力及阻斷活性,表明它可用作054及048抗體之替代抗體。
2.
使用
MKN45
胃腫瘤模型在活體內評估抗小鼠
VEGFR2
抗體
DC101
於37℃在空氣中含有5% CO
2的大氣中在補充有10%熱滅活胎牛血清(ExCell Biology)、100 U/ml青黴素及100 ug/ml鏈黴素(Hyclone)的RPMI1640培養基(Thermo Fisher)中將MKN45細胞作為單層培養物在活體外維持。藉由胰蛋白酶-EDTA處理(Hyclone)每週兩次對腫瘤細胞進行常規傳代培養。收穫在指數生長階段中生長的細胞且對其計數以用於腫瘤接種。用與50%基質膠混合的5*10^6個MKN45細胞接種雌性SPF級裸鼠。當腫瘤大小在100 mm^3左右時,選擇荷瘤小鼠且隨機分為5組(n=10)。用30 mg/kg同型對照、3 mg/kg嵌合-DC101、10 mg/kg嵌合-DC101、30 mg/kg嵌合-DC101及5 mg/kg多西他賽(Docetaxel)作為陽性對照治療動物,同型對照及嵌合-DC101每週兩次藉由腹膜內注射投與,持續3週,而多西他賽每週一次藉由靜脈內注射投與,持續3週。每週兩次使用測徑規(INSIZE)在二維上量測腫瘤大小,且使用下式:V=0.5 a*b^2以mm^3表示體積,其中a及b分別為腫瘤之長徑及短徑。使用Prism GraphPad分析結果且表示為平均值±S.E.M.。兩組之間的比較藉由T檢驗進行,且若p為*<0.05及**<0.01,則認為差異顯著。
如表12及圖21所示,與同型對照組相比,3 mg/kg嵌合-DC101顯著抑制MKN45腫瘤生長。隨著劑量之增加,抑瘤率亦有所增加,自54%增加至77%,說明嵌合-DC101以劑量依賴性誘導腫瘤生長抑制。
表 12. 第 22 天嵌合 DC101 對 MKN45 異種移植腫瘤模型之腫瘤生長抑制
治療 (n=10) | 腫瘤大小 (mm^3,平均值±S.E.M.) | TGI (%) | p值與同型對照 |
30 mg/kg同型對照 | 678.65±20.35 | / | / |
3 mg/kg嵌合-DC101 | 242.70±23.42 | 53.76 | 3.8*10^-11 |
10 mg/kg嵌合-DC101 | 206.69±20.18 | 63.96 | 2.7*10^-12 |
30 mg/kg嵌合-DC101 | 109.35±13.11 | 76.85 | 5.8*10^-15 |
5 mg/kg多西他賽 | 190.07±25.21 | 69.98 | 1.2*10^-11 |
3.
使用
H460
肺腫瘤模型在活體內評估抗小鼠
VEGFR2
抗體
DC101
於37℃在空氣中含有5% CO
2的大氣中在補充有10%熱不活化胎牛血清(ExCell Biology)、100 U/ml青黴素及100 ug/ml鏈黴素(Hyclone)的RPMI1640培養基(Thermo Fisher)中將H460細胞作為單層培養物在活體外維持。藉由胰蛋白酶-EDTA處理(Hyclone)每週兩次對腫瘤細胞進行常規傳代培養。收穫在指數生長階段中生長的細胞且對其計數以用於腫瘤接種。用與50%基質膠混合的5*10^6個H460細胞接種雌性SPF級裸鼠。當腫瘤大小在150 mm^3左右時,選擇荷瘤小鼠且隨機分為5組(n=10)。用30 mg/kg同型對照、3 mg/kg嵌合-DC101、10 mg/kg嵌合-DC101、30 mg/kg嵌合-DC101及5 mg/kg多西他賽作為陽性對照治療動物,同型對照及嵌合-DC101每週兩次藉由腹膜內注射投與,持續2週,而多西他賽每5天一次藉由靜脈內注射投與,共3劑。每週兩次使用測徑規(INSIZE)在二維上量測腫瘤大小,且使用下式:V=0.5 a*b^2以mm^3表示體積,其中a及b分別為腫瘤之長徑及短徑。使用Prism GraphPad分析結果且表示為平均值±S.E.M.。兩組之間的比較藉由T檢驗進行,且若p為*<0.05及**<0.01,則認為差異顯著。
如表13及圖22所示,作為最低劑量的3 mg/kg嵌合-DC101似乎不足以抑制H460腫瘤生長。當劑量達至10 mg/kg及30 mg/kg時,H460生長受到顯著影響。劑量依賴性功效明顯,表明它係由嵌合-DC101引起的。
表 13. 在第 15 天嵌合 DC101 在 H460 異種移植腫瘤模型上之腫瘤生長抑制
治療 (n=10) | 腫瘤大小 (mm^3,平均值±S.E.M.) | TGI (%) | p值與同型對照 | |
30 mg/kg同型對照 | 1463.91±118.72 | / | / | |
3 mg/kg嵌合-DC101 | 1212.70±136.42 | 17.16 | 0.1817 | |
10 mg/kg嵌合-DC101 | 845.98±77.85 | 42.21 | 0.0004 | |
30 mg/kg嵌合-DC101 | 541.96±61.33 | 62.98 | 1.9*10 -6 | |
5 mg/kg多西他賽 | 765.28±120.64 | 47.72 | 0.0006 | |
4.
使用
H1975 NSCLC
腫瘤模型在活體內評估抗小鼠
VEGFR2
抗體
DC101
於37℃在空氣中含有5% CO
2的大氣中在補充有10%熱滅活胎牛血清(ExCell Biology)、100 U/ml青黴素及100 ug/ml鏈黴素(Hyclone)的RPMI1640培養基(Thermo Fisher)中將H1975細胞作為單層培養物在活體外維持。藉由胰蛋白酶-EDTA處理(Hyclone)每週兩次對腫瘤細胞進行常規傳代培養。收穫在指數生長階段中生長的細胞且對其計數以用於腫瘤接種。用與50%基質膠混合的5*10^6個H1975細胞接種雌性SPF級裸鼠。當腫瘤大小在100 mm^3左右時,選擇荷瘤小鼠且隨機分為5組(n=10)。用30 mg/kg同型對照、3 mg/kg嵌合-DC101、10 mg/kg嵌合-DC101、30 mg/kg嵌合-DC101及5 mg/kg多西他賽作為陽性對照治療動物,同型對照及嵌合-DC101每週兩次藉由腹膜內注射投與,持續2週,而多西他賽每週一次藉由靜脈內注射投與,持續2週。每週兩次使用測徑規(INSIZE)在二維上量測腫瘤大小,且使用下式:V=0.5 a*b^2以mm^3表示體積,其中a及b分別為腫瘤之長徑及短徑。使用Prism GraphPad分析結果且表示為平均值±S.E.M.。兩組之間的比較藉由T檢驗進行,且若p為*<0.05及**<0.01,則認為差異顯著。
如表14及圖23所示,嵌合-DC101對屬於NSCLC腺癌的H1975異種移植腫瘤模型具有顯著的腫瘤抑制作用。隨著劑量之增加,由3 mg/kg增至30 mg/kg,腫瘤抑制作用越來越顯著,由40%增至80%。劑量依賴性效應表明抑制係由嵌合-DC101引起的。
表 14. 在第 15 天嵌合 DC101 對 H1975 異種移植腫瘤模型之腫瘤生長抑制
治療 (n=10) | 腫瘤大小 (mm^3,平均值±S.E.M.) | TGI (%) | p值與同型對照 |
30 mg/kg同型對照 | 1237.37±54.49 | / | / |
3 mg/kg嵌合-DC101 | 745.90±102.69 | 39.72 | 5.1*10^-3 |
10 mg/kg嵌合-DC101 | 470.00±69.44 | 62.02 | 7.4*10^-8 |
30 mg/kg嵌合-DC101 | 253.72±33.94 | 79.50 | 9.0*10^-12 |
5 mg/kg多西他賽 | 330.54±78.70 | 73.29 | 2.0*10^-8 |
圖1A及圖1B顯示純化之雜交瘤抗體#002、#003、#006、#018、#042、#048及#054與人類VEGFR2 (hVEGFR2)的劑量依賴性結合。
圖2顯示純化之雜交瘤抗體對人類VEGF-A (hVEGF-A)與hVEGFR2結合的劑量依賴性阻斷活性。
圖3顯示雜交瘤抗體與HUVEC細胞之結合。
圖4A及圖4B顯示結合hVEGFR2及恆河猴VEGFR2之嵌合抗體。
圖5顯示嵌合抗體阻斷VEGF-A/VEGFR2相互作用。
圖6顯示嵌合抗體與HUVEC細胞之結合。
圖7A及圖7B顯示藉由競爭分析使用生物素-mAB002之抗原決定基組合。
圖8A、圖8B及圖8C顯示劑量依賴性競爭分析結果。
圖9A、圖9B及圖9C顯示嵌合抗體抑制由VEGF-A誘導之VEGFR2磷酸化。
圖10A及圖10B顯示藉由ELISA得到的在293T細胞中產生的人類化抗體與人類VEGFR2-his之結合。
圖11A及圖11B顯示藉由ELISA得到的在CHO細胞中產生的人類化抗體與人類VEGFR2-his及恆河猴VEGFR2-his之結合。
圖12顯示特異性結合VEGFR2之人類化抗體。
圖13A及圖13B顯示阻斷VEGF-A與人類VEGFR2或恆河猴VEGFR2結合的人類化抗體。
圖14A、圖14B及圖14C顯示阻斷VEGF-A、C或D與VEGFR2結合的人類化抗體。
圖15顯示與HUVEC細胞結合之人類化抗體。
圖16顯示人類化抗體054抑制VEGF-A誘導的VEGFR2磷酸化。
圖17顯示阻斷VEGF-A介導之細胞增殖的人類化抗體。
圖18顯示用基準抗體1121B、嵌合054 (54-C)、嵌合002 (2-C)或鹽水處理的NOD/SCID小鼠上之HL-60移植存活曲線。
圖19顯示嵌合-DC101與小鼠VEGFR2之ELISA結合。
圖20顯示嵌合-DC101阻斷小鼠VEGFR2與人類VEGF165 (VEGF-A之剪接變異體)之結合。
圖21顯示MKN45異種移植腫瘤在裸鼠上之腫瘤生長曲線(平均值±S.E.M.,n=10)。
圖22顯示H460異種移植腫瘤在裸鼠上之腫瘤生長曲線(平均值±S.E.M.,n=10)。
圖23顯示H1975異種移植腫瘤在裸鼠上之腫瘤生長曲線(平均值±S.E.M.,n=10)。
<![CDATA[<110> 中國大陸商蘇州創勝醫藥集團有限公司(SUZHOU TRANSCENTA THERAPEUTICS CO., LTD.)]]> <![CDATA[<120> 新型抗-HVEGFR2抗體]]> <![CDATA[<130> 063694-8009WO02]]> <![CDATA[<140> TW 111113941]]> <![CDATA[<141> 2022-04-13]]> <![CDATA[<150> PCT/CN2021/087278]]> <![CDATA[<151> 2021-04-14]]> <![CDATA[<160> 103 ]]> <![CDATA[<170> PatentIn version 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 1]]> Ser Ser Trp Met Asn 1 5 <![CDATA[<210> 2]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 2]]> Arg Ile Phe Pro Gly Asp Gly Asp Thr Tyr Tyr Asn Gly Lys Phe Gln 1 5 10 15 Val <![CDATA[<210> 3]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 3]]> Phe Leu Asp Thr Ser Gly Arg Tyr Val Asp Tyr 1 5 10 <![CDATA[<210> 4]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 4]]> Lys Ala Ser Gln Asp Val Asn Thr Ala Val Ala 1 5 10 <![CDATA[<210> 5]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 5]]> Ser Ala Ser Tyr Arg Tyr Ile 1 5 <![CDATA[<210> 6]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 6]]> Gln Gln His Tyr Arg Ala Pro Leu Thr 1 5 <![CDATA[<210> 7]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 7]]> Thr Tyr Trp Ile Met 1 5 <![CDATA[<210> 8]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 8]]> Asp Ile Tyr Pro Gly Thr Gly Ser Thr Asn Tyr Asn Glu Lys Phe Lys 1 5 10 15 Ser <![CDATA[<210> 9]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 9]]> Asp Ser Asn Pro Asp Tyr 1 5 <![CDATA[<210> 10]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 10]]> Arg Ala Ser Glu Ser Val Asp Asn Ser Gly Ile Ser Phe Met Thr 1 5 10 15 <![CDATA[<210> 11]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 11]]> Ala Ala Ser Thr Gln Gly Ser 1 5 <![CDATA[<210> 12]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 12]]> Gln Gln Ser Lys Glu Val Pro Tyr Thr 1 5 <![CDATA[<210> 13]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 13]]> Ser Tyr Trp Ile Met 1 5 <![CDATA[<210> 14]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 14]]> Asp Ile Tyr Pro Gly Ser Gly Ser Thr Asn Tyr Asn Glu Lys Phe Lys 1 5 10 15 Ser <![CDATA[<210> 15]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 15]]> Asp Ser Asn Pro Asp Tyr 1 5 <![CDATA[<210> 16]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 16]]> Arg Ala Ser Glu Ser Val Glu Asn Ser Gly Ile Ser Phe Met His 1 5 10 15 <![CDATA[<210> 17]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 17]]> Ala Ala Ser Tyr Gln Arg Ser 1 5 <![CDATA[<210> 18]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 18]]> Gln Gln Ser Lys Glu Val Pro Tyr Thr 1 5 <![CDATA[<210> 19]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 19]]> Asp Tyr Tyr Met Ser 1 5 <![CDATA[<210> 20]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 20]]> Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala Ser 1 5 10 15 Val Lys Gly <![CDATA[<210> 21]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 21]]> Phe Asp Tyr Tyr Gly Ser Thr Tyr Cys Phe Asp Tyr 1 5 10 <![CDATA[<210> 22]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 22]]> Arg Ala Ser Gln Ser Val Ser Thr Ser Ser Ser Ser Phe Met His 1 5 10 15 <![CDATA[<210> 23]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 23]]> Tyr Ala Ser Asn Leu Glu Ser 1 5 <![CDATA[<210> 24]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 24]]> Gln His Thr Trp Glu Ile Pro Leu Thr 1 5 <![CDATA[<210> 25]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 25]]> Ile Tyr Gly Met Ser 1 5 <![CDATA[<210> 26]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 2]]>6 Ser Ile Ser Val Gly Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Glu 1 5 10 15 Gly <![CDATA[<210> 27]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 27]]> Glu Leu Asp Gly Asn Tyr Asp Tyr 1 5 <![CDATA[<210> 28]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 28]]> Arg Ser Ser Lys Ser Leu Leu Tyr Lys Asp Gly Lys Thr Tyr Leu Asn 1 5 10 15 <![CDATA[<210> 29]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 29]]> Leu Met Ser Thr Arg Ala Ser 1 5 <![CDATA[<210> 30]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 30]]> Gln Gln Leu Val Glu Tyr Pro Phe Thr 1 5 <![CDATA[<210> 31]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 31]]> Met Tyr Gly Met Ser 1 5 <![CDATA[<210> 32]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 32]]> Ser Ile Ser Ile Gly Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Glu 1 5 10 15 Gly <![CDATA[<210> 33]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 33]]> Glu Met Asp Gly Asn Tyr Asp Tyr 1 5 <![CDATA[<210> 34]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 34]]> Met Tyr Gly Met Ser 1 5 <![CDATA[<210> 35]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 35]]> Ser Ile Ser Ile Gly Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Glu 1 5 10 15 Gly <![CDATA[<210> 36]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 36]]> Glu Leu Asp Gly Asn Tyr Asp Tyr 1 5 <![CDATA[<210> 37]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 37]]> Ser Ile Ser Ile Gly Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 38]]> <![CDATA[<211> 330]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> ]]> 38 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <![CDATA[<210> 39]]> <![CDATA[<211> 1356]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 39]]> Met Gln Ser Lys Val Leu Leu Ala Val Ala Leu Trp Leu Cys Val Glu 1 5 10 15 Thr Arg Ala Ala Ser Val Gly Leu Pro Ser Val Ser Leu Asp Leu Pro 20 25 30 Arg Leu Ser Ile Gln Lys Asp Ile Leu Thr Ile Lys Ala Asn Thr Thr 35 40 45 Leu Gln Ile Thr Cys Arg Gly Gln Arg Asp Leu Asp Trp Leu Trp Pro 50 55 60 Asn Asn Gln Ser Gly Ser Glu Gln Arg Val Glu Val Thr Glu Cys Ser 65 70 75 80 Asp Gly Leu Phe Cys Lys Thr Leu Thr Ile Pro Lys Val Ile Gly Asn 85 90 95 Asp Thr Gly Ala Tyr Lys Cys Phe Tyr Arg Glu Thr Asp Leu Ala Ser 100 105 110 Val Ile Tyr Val Tyr Val Gln Asp Tyr Arg Ser Pro Phe Ile Ala Ser 115 120 125 Val Ser Asp Gln His Gly Val Val Tyr Ile Thr Glu Asn Lys Asn Lys 130 135 140 Thr Val Val Ile Pro Cys Leu Gly Ser Ile Ser Asn Leu Asn Val Ser 145 150 155 160 Leu Cys Ala Arg Tyr Pro Glu Lys Arg Phe Val Pro Asp Gly Asn Arg 165 170 175 Ile Ser Trp Asp Ser Lys Lys Gly Phe Thr Ile Pro Ser Tyr Met Ile 180 185 190 Ser Tyr Ala Gly Met Val Phe Cys Glu Ala Lys Ile Asn Asp Glu Ser 195 200 205 Tyr Gln Ser Ile Met Tyr Ile Val Val Val Val Gly Tyr Arg Ile Tyr 210 215 220 Asp Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly Glu 225 230 235 240 Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Ile 245 250 255 Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys Leu 260 265 270 Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys Phe 275 280 285 Leu Ser Thr Leu Thr Ile Asp Gly Ile Thr Arg Ser Asp Gln Gly Leu 290 295 300 Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser Thr 305 310 315 320 Phe Val Arg Val His Glu Lys Pro Phe Val Ala Phe Gly Ser Gly Met 325 330 335 Glu Ser Leu Val Glu Ala Thr Val Gly Glu Arg Val Arg Ile Pro Ala 340 345 350 Lys Tyr Leu Gly Tyr Pro Pro Pro Glu Ile Lys Trp Tyr Lys Asn Gly 355 360 365 Ile Pro Leu Glu Ser Asn His Thr Ile Lys Ala Gly His Val Leu Thr 370 375 380 Ile Met Glu Val Ser Glu Arg Asp Thr Gly Asn Tyr Thr Val Ile Leu 385 390 395 400 Thr Asn Pro Ile Ser Lys Glu Lys Gln Ser His Val Val Ser Leu Val 405 410 415 Val Tyr Val Pro Pro Gln Ile Gly Glu Lys Ser Leu Ile Ser Pro Val 420 425 430 Asp Ser Tyr Gln Tyr Gly Thr Thr Gln Thr Leu Thr Cys Thr Val Tyr 435 440 445 Ala Ile Pro Pro Pro His His Ile His Trp Tyr Trp Gln Leu Glu Glu 450 455 460 Glu Cys Ala Asn Glu Pro Ser His Ala Val Ser Val Thr Asn Pro Tyr 465 470 475 480 Pro Cys Glu Glu Trp Arg Ser Val Glu Asp Phe Gln Gly Gly Asn Lys 485 490 495 Ile Glu Val Asn Lys Asn Gln Phe Ala Leu Ile Glu Gly Lys Asn Lys 500 505 510 Thr Val Ser Thr Leu Val Ile Gln Ala Ala Asn Val Ser Ala Leu Tyr 515 520 525 Lys Cys Glu Ala Val Asn Lys Val Gly Arg Gly Glu Arg Val Ile Ser 530 535 540 Phe His Val Thr Arg Gly Pro Glu Ile Thr Leu Gln Pro Asp Met Gln 545 550 555 560 Pro Thr Glu Gln Glu Ser Val Ser Leu Trp Cys Thr Ala Asp Arg Ser 565 570 575 Thr Phe Glu Asn Leu Thr Trp Tyr Lys Leu Gly Pro Gln Pro Leu Pro 580 585 590 Ile His Val Gly Glu Leu Pro Thr Pro Val Cys Lys Asn Leu Asp Thr 595 600 605 Leu Trp Lys Leu Asn Ala Thr Met Phe Ser Asn Ser Thr Asn Asp Ile 610 615 620 Leu Ile Met Glu Leu Lys Asn Ala Ser Leu Gln Asp Gln Gly Asp Tyr 625 630 635 640 Val Cys Leu Ala Gln Asp Arg Lys Thr Lys Lys Arg His Cys Val Val 645 650 655 Arg Gln Leu Thr Val Leu Glu Arg Val Ala Pro Thr Ile Thr Gly Asn 660 665 670 Leu Glu Asn Gln Thr Thr Ser Ile Gly Glu Ser Ile Glu Val Ser Cys 675 680 685 Thr Ala Ser Gly Asn Pro Pro Pro Gln Ile Met Trp Phe Lys Asp Asn 690 695 700 Glu Thr Leu Val Glu Asp Ser Gly Ile Val Leu Lys Asp Gly Asn Arg 705 710 715 720 Asn Leu Thr Ile Arg Arg Val Arg Lys Glu Asp Glu Gly Leu Tyr Thr 725 730 735 Cys Gln Ala Cys Ser Val Leu Gly Cys Ala Lys Val Glu Ala Phe Phe 740 745 750 Ile Ile Glu Gly Ala Gln Glu Lys Thr Asn Leu Glu Ile Ile Ile Leu 755 760 765 Val Gly Thr Ala Val Ile Ala Met Phe Phe Trp Leu Leu Leu Val Ile 770 775 780 Ile Leu Arg Thr Val Lys Arg Ala Asn Gly Gly Glu Leu Lys Thr Gly 785 790 795 800 Tyr Leu Ser Ile Val Met Asp Pro Asp Glu Leu Pro Leu Asp Glu His 805 810 815 Cys Glu Arg Leu Pro Tyr Asp Ala Ser Lys Trp Glu Phe Pro Arg Asp 820 825 830 Arg Leu Lys Leu Gly Lys Pro Leu Gly Arg Gly Ala Phe Gly Gln Val 835 840 845 Ile Glu Ala Asp Ala Phe Gly Ile Asp Lys Thr Ala Thr Cys Arg Thr 850 855 860 Val Ala Val Lys Met Leu Lys Glu Gly Ala Thr His Ser Glu His Arg 865 870 875 880 Ala Leu Met Ser Glu Leu Lys Ile Leu Ile His Ile Gly His His Leu 885 890 895 Asn Val Val Asn Leu Leu Gly Ala Cys Thr Lys Pro Gly Gly Pro Leu 900 905 910 Met Val Ile Val Glu Phe Cys Lys Phe Gly Asn Leu Ser Thr Tyr Leu 915 920 925 Arg Ser Lys Arg Asn Glu Phe Val Pro Tyr Lys Thr Lys Gly Ala Arg 930 935 940 Phe Arg Gln Gly Lys Asp Tyr Val Gly Ala Ile Pro Val Asp Leu Lys 945 950 955 960 Arg Arg Leu Asp Ser Ile Thr Ser Ser Gln Ser Ser Ala Ser Ser Gly 965 970 975 Phe Val Glu Glu Lys Ser Leu Ser Asp Val Glu Glu Glu Glu Ala Pro 980 985 990 Glu Asp Leu Tyr Lys Asp Phe Leu Thr Leu Glu His Leu Ile Cys Tyr 995 1000 1005 Ser Phe Gln Val Ala Lys Gly Met Glu Phe Leu Ala Ser Arg Lys 1010 1015 1020 Cys Ile His Arg Asp Leu Ala Ala Arg Asn Ile Leu Leu Ser Glu 1025 1030 1035 Lys Asn Val Val Lys Ile Cys Asp Phe Gly Leu Ala Arg Asp Ile 1040 1045 1050 Tyr Lys Asp Pro Asp Tyr Val Arg Lys Gly Asp Ala Arg Leu Pro 1055 1060 1065 Leu Lys Trp Met Ala Pro Glu Thr Ile Phe Asp Arg Val Tyr Thr 1070 1075 1080 Ile Gln Ser Asp Val Trp Ser Phe Gly Val Leu Leu Trp Glu Ile 1085 1090 1095 Phe Ser Leu Gly Ala Ser Pro Tyr Pro Gly Val Lys Ile Asp Glu 1100 1105 1110 Glu Phe Cys Arg Arg Leu Lys Glu Gly Thr Arg Met Arg Ala Pro 1115 1120 1125 Asp Tyr Thr Thr Pro Glu Met Tyr Gln Thr Met Leu Asp Cys Trp 1130 1135 1140 His Gly Glu Pro Ser Gln Arg Pro Thr Phe Ser Glu Leu Val Glu 1145 1150 1155 His Leu Gly Asn Leu Leu Gln Ala Asn Ala Gln Gln Asp Gly Lys 1160 1165 1170 Asp Tyr Ile Val Leu Pro Ile Ser Glu Thr Leu Ser Met Glu Glu 1175 1180 1185 Asp Ser Gly Leu Ser Leu Pro Thr Ser Pro Val Ser Cys Met Glu 1190 1195 1200 Glu Glu Glu Val Cys Asp Pro Lys Phe His Tyr Asp Asn Thr Ala 1205 1210 1215 Gly Ile Ser Gln Tyr Leu Gln Asn Ser Lys Arg Lys Ser Arg Pro 1220 1225 1230 Val Ser Val Lys Thr Phe Glu Asp Ile Pro Leu Glu Glu Pro Glu 1235 1240 1245 Val Lys Val Ile Pro Asp Asp Asn Gln Thr Asp Ser Gly Met Val 1250 1255 1260 Leu Ala Ser Glu Glu Leu Lys Thr Leu Glu Asp Arg Thr Lys Leu 1265 1270 1275 Ser Pro Ser Phe Gly Gly Met Val Pro Ser Lys Ser Arg Glu Ser 1280 1285 1290 Val Ala Ser Glu Gly Ser Asn Gln Thr Ser Gly Tyr Gln Ser Gly 1295 1300 1305 Tyr His Ser Asp Asp Thr Asp Thr Thr Val Tyr Ser Ser Glu Glu 1310 1315 1320 Ala Glu Leu Leu Lys Leu Ile Glu Ile Gly Val Gln Thr Gly Ser 1325 1330 1335 Thr Ala Gln Ile Leu Gln Pro Asp Ser Gly Thr Thr Leu Ser Ser 1340 1345 1350 Pro Pro Val 1355 <![CDATA[<210> 40]]> <![CDATA[<211]]>> 470]]> <br/><![CDATA[<212> PRT]]> <br/><![CDATA[<213> 人工序列]]> <br/> <br/><![CDATA[<220>]]> <br/><![CDATA[<223> 合成]]> <br/> <br/><![CDATA[<400> 40]]> <br/> <br/><![CDATA[Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Ala Ile Leu Lys Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Asn Ser Leu Lys Leu Ser Cys Ala Thr Ser Gly Phe Ile Phe 35 40 45 Ser Thr Thr Trp Met Asn Trp Ile Arg Gln Thr Pro Gly Lys Arg Leu 50 55 60 Glu Trp Leu Ala Gln Ile Glu Asp Lys Ser Asn Asn Tyr Phe Ile Ser 65 70 75 80 Tyr Ser Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser 85 90 95 Lys Ser Ser Val Tyr Leu Gln Met Asn Asn Leu Lys Glu Glu Asp Thr 100 105 110 Ala Ile Tyr Tyr Cys Ser Trp Lys Tyr Arg Ser Asn Tyr Tyr Phe Asp 115 120 125 Tyr Trp Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 225 230 235 240 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 245 250 255 Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305 310 315 320 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 325 330 335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 340 345 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 370 375 380 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440 445 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460 Ser Leu Ser Pro Gly Lys 465 470 <![CDATA[<210> 41]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (1)..(1)]]> <![CDATA[<223> I或M]]> <![CDATA[<400> 41]]> Xaa Tyr Gly Met Ser 1 5 <![CDATA[<210> 42]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (4)..(4)]]> <![CDATA[<223> V或I]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (16)..(16)]]> <![CDATA[<223> E或K]]> <![CDATA[<400> 42]]> Ser Ile Ser Xaa Gly Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Xaa 1 5 10 15 Gly <![CDATA[<210> 43]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (2)..(2)]]> <![CDATA[<223> L或M]]> <![CDATA[<400> 43]]> Glu Xaa Asp Gly Asn Tyr Asp Tyr 1 5 <![CDATA[<210> 44]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220]]>>]]> <br/><![CDATA[<221> X]]> <br/><![CDATA[<222> (1)..(1)]]> <br/><![CDATA[<223> T或S]]> <br/> <br/><![CDATA[<400> 44]]> <br/> <br/><![CDATA[Xaa Tyr Trp Ile Met 1 5 <![CDATA[<210> 45]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (6)..(6)]]> <![CDATA[<223> T或S]]> <![CDATA[<400> 45]]> Asp Ile Tyr Pro Gly Xaa Gly Ser Thr Asn Tyr Asn Glu Lys Phe Lys 1 5 10 15 Ser <![CDATA[<210> 46]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 46]]> Asp Ser Asn Pro Asp Tyr 1 5 <![CDATA[<210> 47]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (7)..(7)]]> <![CDATA[<223> D或E]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (15)..(15)]]> <![CDATA[<223> T或H]]> <![CDATA[<400> 47]]> Arg Ala Ser Glu Ser Val Xaa Asn Ser Gly Ile Ser Phe Met Xaa 1 5 10 15 <![CDATA[<210> 48]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (4)..(4)]]> <![CDATA[<223> T或Y]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (6)..(6)]]> <![CDATA[<223> G或R]]> <![CDATA[<400> 48]]> Ala Ala Ser Xaa Gln Xaa Ser 1 5 <![CDATA[<210> 49]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 49]]> Gln Gln Ser Lys Glu Val Pro Tyr Thr 1 5 <![CDATA[<210> 50]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 50]]> Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Ser 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Glu Gly Leu Glu Trp Ile 35 40 45 Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Tyr Tyr Asn Gly Lys Phe 50 55 60 Gln Val Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser 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 Ile Phe Leu Asp Thr Ser Gly Arg Tyr Val Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Leu Thr Ile Ser Ser 115 120 <![CDATA[<210> 51]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 51]]> Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Tyr Arg Tyr Ile Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ser 65 70 75 80 Glu Asp Leu Thr Val Tyr Tyr Cys Gln Gln His Tyr Arg Ala Pro Leu 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu Leu Lys 100 105 <![CDATA[<210> 52]]> <![CDATA[<211> 115]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 52]]> Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Asn Thr Tyr 20 25 30 Trp Ile Met Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Asp Ile Tyr Pro Gly Thr Gly Ser Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Lys Ser Lys Val Thr Leu Thr Ala Asp Thr Ser Ser Thr Thr Ala Tyr 65 70 75 80 Met Gln Val Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Gly Arg Asp Ser Asn Pro Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr 100 105 110 Val Ser Ser 115 <![CDATA[<210> 53]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 53]]> Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Ser 20 25 30 Gly Ile Ser Phe Met Thr Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Ala Ala Ser Thr Gln Gly Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His 65 70 75 80 Pro Val Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys 85 90 95 Glu Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 54]]> <![CDATA[<211> 115]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 54]]> Gln Ala Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Thr 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Asn Ser Tyr 20 25 30 Trp Ile Met Trp Val Lys Gln Ser Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Asp Ile Tyr Pro Gly Ser Gly Ser Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Lys Ser Lys Val Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Val Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Asn Pro Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr 100 105 110 Val Ser Ser 115 <![CDATA[<210> 55]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 55]]> Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Glu Asn Ser 20 25 30 Gly Ile Ser Phe Met His Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Ala Ala Ser Tyr Gln Arg Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His 65 70 75 80 Pro Val Glu Glu Asp Asp Ile Ala Met Tyr Phe Cys Gln Gln Ser Lys 85 90 95 Glu Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 56]]> <![CDATA[<211> 123]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 56]]> Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Ser Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Ala Leu Arg Ala Glu Asp Ser Ala Thr Tyr 85 90 95 Tyr Cys Ala Arg Phe Asp Tyr Tyr Gly Ser Thr Tyr Cys Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser 115 120 <![CDATA[<210> 57]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 57]]> Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Ser 20 25 30 Ser Ser Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 65 70 75 80 Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Thr Trp 85 90 95 Glu Ile Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 <![CDATA[<210> 58]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 58]]> Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Thr Ala Ser Gly Phe Ser Phe Ser Ile Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val 35 40 45 Ala Ser Ile Ser Val Gly Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg Glu Leu Asp Gly Asn Tyr Asp Tyr Trp Gly Gln Gly Thr Ser 100 105 110 Leu Thr Val Ser Ser 115 <![CDATA[<210> 59]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 59]]> Asp Ile Val Ile Thr Gln Asn Glu Leu Ser Asn Pro Val Thr Phe Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu Tyr Lys 20 25 30 Asp Gly Lys Thr Tyr Leu Asn Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Met Ser Thr Arg Ala Ser Gly Val Ser 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Glu Ile 65 70 75 80 Ser Arg Val Lys Ala Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln Leu 85 90 95 Val Glu Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 60]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 60]]> Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Met Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val 35 40 45 Ala Ser Ile Ser Ile Gly Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg Glu Met Asp Gly Asn Tyr Asp Tyr Trp Gly His Gly Thr Thr 100 105 110 Leu Thr Val Ser Ser 115 <![CDATA[<210> 61]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 61]]> Asp Val Met Ile Thr Gln Asp Glu Leu Ser Asn Pro Val Thr Phe Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu Tyr Lys 20 25 30 Asp Gly Lys Thr Tyr Leu Asn Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Met Ser Thr Arg Ala Ser Gly Val Ser 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Glu Ile 65 70 75 80 Ser Arg Val Lys Ala Glu Asp Val Gly Ile Tyr Tyr Cys Gln Gln Leu 85 90 95 Val Glu Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 62]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 62]]> Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Met Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val 35 40 45 Ala Ser Ile Ser Ile Gly Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Ile Ile Ser Arg Glu Asn Ala Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg Glu Leu Asp Gly Asn Tyr Asp Tyr Trp Gly Gln Gly Thr Thr 100 105 110 Leu Thr Val Ser Ser 115 <![CDATA[<210> 63]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 63]]> His Ile Met Ile Thr Gln Asp Glu Leu Ser Asn Pro Val Thr Phe Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu Tyr Lys 20 25 30 Asp Gly Lys Thr Tyr Leu Asn Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Met Ser Thr Arg Ala Ser Gly Val Ser 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Glu Ile 65 70 75 80 Ser Arg Val Lys Ala Glu Asp Val Gly Ile Tyr Tyr Cys Gln Gln Leu 85 90 95 Val Glu Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 64]]> <![CDATA[<211> 30]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 64]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 20 25 30 <![CDATA[<210> 65]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 65]]> Trp Val Arg Gln Thr Pro Gly Lys Arg Leu Glu Trp Val Ala 1 5 10 <![CDATA[<210> 66]]> <![CDATA[<211> 32]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 66]]> Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln 1 5 10 15 Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <![CDATA[<210> 67]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 67]]> Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser 1 5 10 <![CDATA[<210> 68]]> <![CDATA[<211> 30]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 68]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 20 25 30 <![CDATA[<210> 69]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 69]]> Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val Ala 1 5 10 <![CDATA[<210> 70]]> <![CDATA[<211> 32]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 70]]> Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln 1 5 10 15 Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <![CDATA[<210> 71]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 71]]> Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser 1 5 10 <![CDATA[<210> 72]]> <![CDATA[<211> 30]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 72]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 20 25 30 <![CDATA[<210> 73]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 73]]> Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val Ala 1 5 10 <![CDATA[<210> 74]]> <![CDATA[<211> 32]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 74]]> Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln 1 5 10 15 Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <![CDATA[<210> 75]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 75]]> Trp Gly His Gly Thr Thr Leu Thr Val Ser Ser 1 5 10 <![CDATA[<210> 76]]> <![CDATA[<211> 23]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 76]]> Asp Ile Val Ile Thr Gln Asp Glu Leu Ser Leu Pro Val Thr Phe Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys 20 <![CDATA[<210> 77]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 77]]> Trp Phe Leu Gln Arg Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr 1 5 10 15 <![CDATA[<210> 78]]> <![CDATA[<211> 32]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 78]]> Gly Val Ser Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys 20 25 30 <![CDATA[<210> 79]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 79]]> Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 1 5 10 <![CDATA[<210> 80]]> <![CDATA[<211> 23]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 80]]> Asp Ile Val Ile Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys 20 <![CDATA[<210> 81]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 81]]> Trp Phe Leu Gln Arg Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr 1 5 10 15 <![CDATA[<210> 82]]> <![CDATA[<211> 32]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 82]]> Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys 20 25 30 <![CDATA[<210> 83]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 83]]> Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 1 5 10 <![CDATA[<210> 84]]> <![CDATA[<211> 30]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (19)..(19)]]> <![CDATA[<223> R或K]]> <![CDATA[<400> 84]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Xaa Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 20 25 30 <![CDATA[<210> 85]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (5)..(5)]]> <![CDATA[<223> A或T]]> <![CDATA[<400> 85]]> Trp Val Arg Gln Xaa Pro Gly Lys Arg Leu Glu Trp Val Ala 1 5 10 <![CDATA[<210> 86]]> <![CDATA[<211> 32]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (21)..(21)]]> <![CDATA[<223> R或K]]> <![CDATA[<400> 86]]> Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln 1 5 10 15 Met Asn Ser Leu Xaa Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <![CDATA[<210> 8]]>7 <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (3)..(3)]]> <![CDATA[<223> Q或H]]> <![CDATA[<400> 87]]> Trp Gly Xaa Gly Thr Thr Leu Thr Val Ser Ser 1 5 10 <![CDATA[<210> 88]]> <![CDATA[<211> 23]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (7)..(7)]]> <![CDATA[<223> D或T]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (8)..(8)]]> <![CDATA[<223> E或P]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (15)..(15)]]> <![CDATA[<223> F或P]]> <![CDATA[<400> 88]]> Asp Ile Val Ile Thr Gln Xaa Xaa Leu Ser Leu Pro Val Thr Xaa Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys 20 <![CDATA[<210> 89]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 89]]> Trp Phe Leu Gln Arg Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr 1 5 10 15 <![CDATA[<210> 90]]> <![CDATA[<211> 32]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (3)..(3)]]> <![CDATA[<223> S或P]]> <![CDATA[<220>]]> <![CDATA[<221> X]]> <![CDATA[<222> (29)..(29)]]> <![CDATA[<223> V或I]]> <![CDATA[<400> ]]> 90 Gly Val Xaa Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Xaa Tyr Tyr Cys 20 25 30 <![CDATA[<210> 91]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 91]]> Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 1 5 10 <![CDATA[<210> 92]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 92]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Leu Asp Gly Asn Tyr Asp Tyr Trp Gly Gln Gly Thr Thr 100 105 110 Leu Thr Val Ser Ser 115 <![CDATA[<210> 93]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 93]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Met Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Thr Pro Gly Lys Arg Leu Glu Trp Val 35 40 45 Ala Ser Ile Ser Ile Gly Gly Ser Tyr Thr Tyr Tyr Ala 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 Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Leu Asp Gly Asn Tyr Asp Tyr Trp Gly Gln Gly Thr Thr 100 105 110 Leu Thr Val Ser Ser 115 <![CDATA[<210> 94]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 94]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Met Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val 35 40 45 Ala Ser Ile Ser Ile Gly Gly Ser Tyr Thr Tyr Tyr Ala 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Leu Asp Gly Asn Tyr Asp Tyr Trp Gly Gln Gly Thr Thr 100 105 110 Leu Thr Val Ser Ser 115 <![CDATA[<210> 95]]> <![CDATA[<211> 101]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 95]]> Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Asp Ser 20 25 30 Asp Asp Gly Asn Thr Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln 35 40 45 Ser Pro Gln Leu Leu Ile Tyr Thr Leu Ser Tyr Arg Ala Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys 65 70 75 80 Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln 85 90 95 Arg Ile Glu Phe Pro 100 <![CDATA[<210> 96]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 96]]> Asp Ile Val Ile Thr Gln Asp Glu Leu Ser Leu Pro Val Thr Phe Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu Tyr Lys 20 25 30 Asp Gly Lys Thr Tyr Leu Asn Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Met Ser Thr Arg Ala Ser Gly Val Ser 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 Val Gly Ile Tyr Tyr Cys Gln Gln Leu 85 90 95 Val Glu Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 97]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 97]]> Asp Ile Val Ile Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu Tyr Lys 20 25 30 Asp Gly Lys Thr Tyr Leu Asn Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Met Ser Thr Arg Ala 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 Val Gly Val Tyr Tyr Cys Gln Gln Leu 85 90 95 Val Glu Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 98]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 98]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Met Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val 35 40 45 Ala Ser Ile Ser Ile Gly Gly Ser Tyr Thr Tyr Tyr Ala 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Met Asp Gly Asn Tyr Asp Tyr Trp Gly His Gly Thr Thr 100 105 110 Leu Thr Val Ser Ser 115 <![CDATA[<210> 99]]> <![CDATA[<211> 239]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 99]]> Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Phe Pro Gly Ser Arg Cys Asp Ile Val Leu Thr Gln Ser Pro Ala Leu 20 25 30 Ala Val Ser Leu Glu Gln Arg Ala Thr Ile Ser Cys Lys Thr Ser Gln 35 40 45 Asn Val Asp Tyr Tyr Gly Ile Ser Tyr Leu His Trp Tyr Gln Gln Lys 50 55 60 Pro Gly Gln Gln Pro Lys Leu Leu Ile Tyr Glu Gly Ser Asn Leu Ala 65 70 75 80 Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 85 90 95 Thr Leu Thr Ile Asp Pro Val Glu Ala Asp Asp Ile Val Thr Tyr Tyr 100 105 110 Cys Gln Gln Ser Lys Asp Tyr Pro Tyr Thr Phe Gly Ala Gly Thr Lys 115 120 125 Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro 130 135 140 Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu 145 150 155 160 Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp 165 170 175 Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp 180 185 190 Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys 195 200 205 Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln 210 215 220 Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <![CDATA[<210> 100]]> <![CDATA[<211> 1367]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 100]]> Met Glu Ser Lys Ala Leu Leu Ala Val Ala Leu Trp Phe Cys Val Glu 1 5 10 15 Thr Arg Ala Ala Ser Val Gly Leu Pro Gly Asp Phe Leu His Pro Pro 20 25 30 Lys Leu Ser Thr Gln Lys Asp Ile Leu Thr Ile Leu Ala Asn Thr Thr 35 40 45 Leu Gln Ile Thr Cys Arg Gly Gln Arg Asp Leu Asp Trp Leu Trp Pro 50 55 60 Asn Ala Gln Arg Asp Ser Glu Glu Arg Val Leu Val Thr Glu Cys Gly 65 70 75 80 Gly Gly Asp Ser Ile Phe Cys Lys Thr Leu Thr Ile Pro Arg Val Val 85 90 95 Gly Asn Asp Thr Gly Ala Tyr Lys Cys Ser Tyr Arg Asp Val Asp Ile 100 105 110 Ala Ser Thr Val Tyr Val Tyr Val Arg Asp Tyr Arg Ser Pro Phe Ile 115 120 125 Ala Ser Val Ser Asp Gln His Gly Ile Val Tyr Ile Thr Glu Asn Lys 130 135 140 Asn Lys Thr Val Val Ile Pro Cys Arg Gly Ser Ile Ser Asn Leu Asn 145 150 155 160 Val Ser Leu Cys Ala Arg Tyr Pro Glu Lys Arg Phe Val Pro Asp Gly 165 170 175 Asn Arg Ile Ser Trp Asp Ser Glu Ile Gly Phe Thr Leu Pro Ser Tyr 180 185 190 Met Ile Ser Tyr Ala Gly Met Val Phe Cys Glu Ala Lys Ile Asn Asp 195 200 205 Glu Thr Tyr Gln Ser Ile Met Tyr Ile Val Val Val Val Gly Tyr Arg 210 215 220 Ile Tyr Asp Val Ile Leu Ser Pro Pro His Glu Ile Glu Leu Ser Ala 225 230 235 240 Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val 245 250 255 Gly Leu Asp Phe Thr Trp His Ser Pro Pro Ser Lys Ser His His Lys 260 265 270 Lys Ile Val Asn Arg Asp Val Lys Pro Phe Pro Gly Thr Val Ala Lys 275 280 285 Met Phe Leu Ser Thr Leu Thr Ile Glu Ser Val Thr Lys Ser Asp Gln 290 295 300 Gly Glu Tyr Thr Cys Val Ala Ser Ser Gly Arg Met Ile Lys Arg Asn 305 310 315 320 Arg Thr Phe Val Arg Val His Thr Lys Pro Phe Ile Ala Phe Gly Ser 325 330 335 Gly Met Lys Ser Leu Val Glu Ala Thr Val Gly Ser Gln Val Arg Ile 340 345 350 Pro Val Lys Tyr Leu Ser Tyr Pro Ala Pro Asp Ile Lys Trp Tyr Arg 355 360 365 Asn Gly Arg Pro Ile Glu Ser Asn Tyr Thr Met Ile Val Gly Asp Glu 370 375 380 Leu Thr Ile Met Glu Val Thr Glu Arg Asp Ala Gly Asn Tyr Thr Val 385 390 395 400 Ile Leu Thr Asn Pro Ile Ser Met Glu Lys Gln Ser His Met Val Ser 405 410 415 Leu Val Val Asn Val Pro Pro Gln Ile Gly Glu Lys Ala Leu Ile Ser 420 425 430 Pro Met Asp Ser Tyr Gln Tyr Gly Thr Met Gln Thr Leu Thr Cys Thr 435 440 445 Val Tyr Ala Asn Pro Pro Leu His His Ile Gln Trp Tyr Trp Gln Leu 450 455 460 Glu Glu Ala Cys Ser Tyr Arg Pro Gly Gln Thr Ser Pro Tyr Ala Cys 465 470 475 480 Lys Glu Trp Arg His Val Glu Asp Phe Gln Gly Gly Asn Lys Ile Glu 485 490 495 Val Thr Lys Asn Gln Tyr Ala Leu Ile Glu Gly Lys Asn Lys Thr Val 500 505 510 Ser Thr Leu Val Ile Gln Ala Ala Asn Val Ser Ala Leu Tyr Lys Cys 515 520 525 Glu Ala Ile Asn Lys Ala Gly Arg Gly Glu Arg Val Ile Ser Phe His 530 535 540 Val Ile Arg Gly Pro Glu Ile Thr Val Gln Pro Ala Ala Gln Pro Thr 545 550 555 560 Glu Gln Glu Ser Val Ser Leu Leu Cys Thr Ala Asp Arg Asn Thr Phe 565 570 575 Glu Asn Leu Thr Trp Tyr Lys Leu Gly Ser Gln Ala Thr Ser Val His 580 585 590 Met Gly Glu Ser Leu Thr Pro Val Cys Lys Asn Leu Asp Ala Leu Trp 595 600 605 Lys Leu Asn Gly Thr Met Phe Ser Asn Ser Thr Asn Asp Ile Leu Ile 610 615 620 Val Ala Phe Gln Asn Ala Ser Leu Gln Asp Gln Gly Asp Tyr Val Cys 625 630 635 640 Ser Ala Gln Asp Lys Lys Thr Lys Lys Arg His Cys Leu Val Lys Gln 645 650 655 Leu Ile Ile Leu Glu Arg Met Ala Pro Met Ile Thr Gly Asn Leu Glu 660 665 670 Asn Gln Thr Thr Thr Ile Gly Glu Thr Ile Glu Val Thr Cys Pro Ala 675 680 685 Ser Gly Asn Pro Thr Pro His Ile Thr Trp Phe Lys Asp Asn Glu Thr 690 695 700 Leu Val Glu Asp Ser Gly Ile Val Leu Arg Asp Gly Asn Arg Asn Leu 705 710 715 720 Thr Ile Arg Arg Val Arg Lys Glu Asp Gly Gly Leu Tyr Thr Cys Gln 725 730 735 Ala Cys Asn Val Leu Gly Cys Ala Arg Ala Glu Thr Leu Phe Ile Ile 740 745 750 Glu Gly Ala Gln Glu Lys Thr Asn Leu Glu Val Ile Ile Leu Val Gly 755 760 765 Thr Ala Val Ile Ala Met Phe Phe Trp Leu Leu Leu Val Ile Leu Val 770 775 780 Arg Thr Val Lys Arg Ala Asn Glu Gly Glu Leu Lys Thr Gly Tyr Leu 785 790 795 800 Ser Ile Val Met Asp Pro Asp Glu Leu Pro Leu Asp Glu Arg Cys Glu 805 810 815 Arg Leu Pro Tyr Asp Ala Ser Lys Trp Glu Phe Pro Arg Asp Arg Leu 820 825 830 Lys Leu Gly Lys Pro Leu Gly Arg Gly Ala Phe Gly Gln Val Ile Glu 835 840 845 Ala Asp Ala Phe Gly Ile Asp Lys Thr Ala Thr Cys Lys Thr Val Ala 850 855 860 Val Lys Met Leu Lys Glu Gly Ala Thr His Ser Glu His Arg Ala Leu 865 870 875 880 Met Ser Glu Leu Lys Ile Leu Ile His Ile Gly His His Leu Asn Val 885 890 895 Val Asn Leu Leu Gly Ala Cys Thr Lys Pro Gly Gly Pro Leu Met Val 900 905 910 Ile Val Glu Phe Ser Lys Phe Gly Asn Leu Ser Thr Tyr Leu Arg Gly 915 920 925 Lys Arg Asn Glu Phe Val Pro Tyr Lys Ser Lys Gly Ala Arg Phe Arg 930 935 940 Gln Gly Lys Asp Tyr Val Gly Glu Leu Ser Val Asp Leu Lys Arg Arg 945 950 955 960 Leu Asp Ser Ile Thr Ser Ser Gln Ser Ser Ala Ser Ser Gly Phe Val 965 970 975 Glu Glu Lys Ser Leu Ser Asp Val Glu Glu Glu Glu Ala Ser Glu Glu 980 985 990 Leu Tyr Lys Asp Phe Leu Thr Leu Glu His Leu Ile Cys Tyr Ser Phe 995 1000 1005 Gln Val Ala Lys Gly Met Glu Phe Leu Ala Ser Arg Lys Cys Ile 1010 1015 1020 His Arg Asp Leu Ala Ala Arg Asn Ile Leu Leu Ser Glu Lys Asn 1025 1030 1035 Val Val Lys Ile Cys Asp Phe Gly Leu Ala Arg Asp Ile Tyr Lys 1040 1045 1050 Asp Pro Asp Tyr Val Arg Lys Gly Asp Ala Arg Leu Pro Leu Lys 1055 1060 1065 Trp Met Ala Pro Glu Thr Ile Phe Asp Arg Val Tyr Thr Ile Gln 1070 1075 1080 Ser Asp Val Trp Ser Phe Gly Val Leu Leu Trp Glu Ile Phe Ser 1085 1090 1095 Leu Gly Ala Ser Pro Tyr Pro Gly Val Lys Ile Asp Glu Glu Phe 1100 1105 1110 Cys Arg Arg Leu Lys Glu Gly Thr Arg Met Arg Ala Pro Asp Tyr 1115 1120 1125 Thr Thr Pro Glu Met Tyr Gln Thr Met Leu Asp Cys Trp His Glu 1130 1135 1140 Asp Pro Asn Gln Arg Pro Ser Phe Ser Glu Leu Val Glu His Leu 1145 1150 1155 Gly Asn Leu Leu Gln Ala Asn Ala Gln Gln Asp Gly Lys Asp Tyr 1160 1165 1170 Ile Val Leu Pro Met Ser Glu Thr Leu Ser Met Glu Glu Asp Ser 1175 1180 1185 Gly Leu Ser Leu Pro Thr Ser Pro Val Ser Cys Met Glu Glu Glu 1190 1195 1200 Glu Val Cys Asp Pro Lys Phe His Tyr Asp Asn Thr Ala Gly Ile 1205 1210 1215 Ser His Tyr Leu Gln Asn Ser Lys Arg Lys Ser Arg Pro Val Ser 1220 1225 1230 Val Lys Thr Phe Glu Asp Ile Pro Leu Glu Glu Pro Glu Val Lys 1235 1240 1245 Val Ile Pro Asp Asp Ser Gln Thr Asp Ser Gly Met Val Leu Ala 1250 1255 1260 Ser Glu Glu Leu Lys Thr Leu Glu Asp Arg Asn Lys Leu Ser Pro 1265 1270 1275 Ser Phe Gly Gly Met Met Pro Ser Lys Ser Arg Glu Ser Val Ala 1280 1285 1290 Ser Glu Gly Ser Asn Gln Thr Ser Gly Tyr Gln Ser Gly Tyr His 1295 1300 1305 Ser Asp Asp Thr Asp Thr Thr Val Tyr Ser Ser Asp Glu Ala Gly 1310 1315 1320 Leu Leu Lys Met Val Asp Ala Ala Val His Ala Asp Ser Gly Thr 1325 1330 1335 Thr Leu Gln Leu Thr Ser Cys Leu Asn Gly Ser Gly Pro Val Pro 1340 1345 1350 Ala Pro Pro Pro Thr Pro Gly Asn His Glu Arg Gly Ala Ala 1355 1360 1365 <![CDATA[<210> 101]]> <![CDATA[<211> 1356]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 101]]> Met Ala Ser Lys Val Leu Leu Ala Val Ala Leu Trp Leu Cys Val Glu 1 5 10 15 Thr Arg Ala Ala Ser Val Gly Leu Pro Ser Val Ser Leu Asp Leu Pro 20 25 30 Arg Leu Ser Ile Gln Lys Asp Ile Leu Thr Ile Lys Ala Asn Thr Thr 35 40 45 Leu Gln Ile Thr Cys Arg Gly Gln Arg Asp Leu Asp Trp Leu Trp Pro 50 55 60 Asn Asn Gln Ser Gly Ser Glu Gln Arg Val Glu Val Thr Glu Cys Ser 65 70 75 80 Asp Gly Leu Phe Cys Lys Thr Leu Thr Ile Pro Lys Val Ile Gly Asn 85 90 95 Asp Thr Gly Ala Tyr Lys Cys Phe Tyr Arg Glu Thr Asp Leu Ala Ser 100 105 110 Val Ile Tyr Val Tyr Val Gln Asp Tyr Arg Ser Pro Phe Ile Ala Ser 115 120 125 Val Ser Asp Gln His Gly Val Val Tyr Ile Thr Glu Asn Lys Asn Lys 130 135 140 Thr Val Val Ile Pro Cys Leu Gly Ser Ile Ser Asn Leu Asn Val Ser 145 150 155 160 Leu Cys Ala Arg Tyr Pro Glu Lys Arg Phe Val Pro Asp Gly Asn Arg 165 170 175 Ile Ser Trp Asp Ser Lys Lys Gly Phe Thr Ile Pro Ser Tyr Met Ile 180 185 190 Ser Tyr Ala Gly Met Val Phe Cys Glu Ala Lys Ile Asn Asp Glu Ser 195 200 205 Tyr Gln Ser Ile Met Tyr Ile Val Val Val Val Gly Tyr Arg Ile Tyr 210 215 220 Asp Val Val Leu Ser Pro Ser His Gly Val Glu Leu Ser Val Gly Glu 225 230 235 240 Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Ile 245 250 255 Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys Leu 260 265 270 Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys Phe 275 280 285 Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp Gln Gly Leu 290 295 300 Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser Thr 305 310 315 320 Phe Val Arg Val His Glu Lys Pro Phe Val Ala Phe Gly Ser Gly Met 325 330 335 Glu Ser Leu Val Glu Ala Thr Val Gly Glu Arg Val Arg Ile Pro Val 340 345 350 Lys Tyr Leu Gly Tyr Pro Pro Pro Glu Ile Lys Trp Tyr Lys Asn Gly 355 360 365 Ile Pro Leu Glu Ser Asn His Thr Val Lys Val Gly His Val Leu Thr 370 375 380 Ile Met Glu Val Ser Glu Arg Asp Thr Gly Asn Tyr Thr Val Ile Leu 385 390 395 400 Thr Asn Pro Ile Ser Lys Glu Lys Gln Ser His Val Val Ser Leu Val 405 410 415 Val Tyr Val Pro Pro Gln Ile Gly Glu Lys Ser Leu Ile Ser Pro Val 420 425 430 Asp Ser Tyr Gln Tyr Gly Thr Thr Gln Thr Leu Thr Cys Thr Val Tyr 435 440 445 Ala Ile Pro Pro Pro His His Ile His Trp Tyr Trp Gln Leu Glu Glu 450 455 460 Glu Cys Pro Asn Glu Pro Ser Gln Ala Val Ser Val Thr Asn Pro Tyr 465 470 475 480 Pro Cys Glu Glu Trp Arg Ser Val Glu Asp Phe Gln Gly Gly Asn Lys 485 490 495 Ile Glu Val Asn Lys Asn Gln Phe Ala Leu Ile Glu Gly Lys Asn Lys 500 505 510 Thr Val Ser Thr Leu Val Ile Gln Ala Ala Asn Val Ser Ala Leu Tyr 515 520 525 Lys Cys Glu Ala Val Asn Lys Val Gly Arg Gly Glu Arg Val Ile Ser 530 535 540 Phe His Val Thr Arg Gly Pro Glu Ile Thr Leu Gln Pro Asp Leu Gln 545 550 555 560 Pro Thr Glu Gln Glu Ser Val Ser Leu Trp Cys Thr Ala Asp Lys Ser 565 570 575 Thr Phe Glu Asn Leu Thr Trp Tyr Lys Leu Gly Pro Gln Pro Leu Pro 580 585 590 Val His Val Gly Glu Leu Pro Thr Pro Val Cys Lys Asn Leu Asp Thr 595 600 605 Leu Trp Lys Leu Asn Ala Thr Ile Phe Ser Asn Ser Thr Asn Asp Ile 610 615 620 Leu Ile Met Glu Leu Lys Asn Ala Ser Leu Gln Asp Gln Gly Asp Tyr 625 630 635 640 Val Cys Val Ala Gln Asp Arg Lys Thr Lys Lys Arg His Cys Val Val 645 650 655 Arg Gln Leu Thr Val Leu Glu Arg Val Ala Pro Met Ile Thr Gly Asn 660 665 670 Leu Glu Asn Gln Thr Thr Ser Ile Gly Glu Thr Ile Glu Val Ser Cys 675 680 685 Thr Ala Ser Gly Asn Pro Pro Pro Gln Ile Met Trp Phe Lys Asp Asn 690 695 700 Glu Thr Leu Val Glu Asp Ser Gly Ile Val Leu Lys Asp Gly Asn Arg 705 710 715 720 Asn Leu Thr Ile Arg Arg Val Arg Lys Glu Asp Glu Gly Leu Tyr Thr 725 730 735 Cys Gln Ala Cys Ser Val Leu Gly Cys Ala Lys Val Glu Ala Phe Phe 740 745 750 Ile Ile Glu Gly Ala Gln Glu Lys Thr Asn Leu Glu Ile Ile Ile Leu 755 760 765 Val Gly Thr Ala Val Ile Ala Met Phe Phe Trp Leu Leu Leu Val Ile 770 775 780 Ile Leu Arg Thr Val Lys Arg Ala Asn Gly Gly Glu Leu Lys Thr Gly 785 790 795 800 Tyr Leu Ser Ile Val Met Asp Pro Asp Glu Leu Pro Leu Asp Glu His 805 810 815 Cys Glu Arg Leu Pro Tyr Asp Ala Ser Lys Trp Glu Phe Pro Arg Asp 820 825 830 Arg Leu Lys Leu Gly Lys Pro Leu Gly Arg Gly Ala Phe Gly Gln Val 835 840 845 Ile Glu Ala Asp Ala Phe Gly Ile Asp Lys Thr Ala Thr Cys Arg Thr 850 855 860 Val Ala Val Lys Met Leu Lys Glu Gly Ala Thr His Ser Glu His Arg 865 870 875 880 Ala Leu Met Ser Glu Leu Lys Ile Leu Ile His Ile Gly His His Leu 885 890 895 Asn Val Val Asn Leu Leu Gly Ala Cys Thr Lys Pro Gly Gly Pro Leu 900 905 910 Met Val Ile Val Glu Phe Cys Lys Phe Gly Asn Leu Ser Thr Tyr Leu 915 920 925 Arg Ser Lys Arg Asn Glu Phe Val Pro Tyr Lys Thr Lys Gly Ala Arg 930 935 940 Phe Arg Gln Gly Lys Asp Tyr Val Gly Ala Ile Pro Val Asp Leu Lys 945 950 955 960 Arg Arg Leu Asp Ser Ile Thr Ser Ser Gln Ser Ser Ala Ser Ser Gly 965 970 975 Phe Val Glu Glu Lys Ser Leu Ser Asp Val Glu Glu Glu Glu Ala Pro 980 985 990 Glu Asp Leu Tyr Lys Asp Phe Leu Thr Leu Glu His Leu Ile Cys Tyr 995 1000 1005 Ser Phe Gln Val Ala Lys Gly Met Glu Phe Leu Ala Ser Arg Lys 1010 1015 1020 Cys Ile His Arg Asp Leu Ala Ala Arg Asn Ile Leu Leu Ser Glu 1025 1030 1035 Lys Asn Val Val Lys Ile Cys Asp Phe Gly Leu Ala Arg Asp Ile 1040 1045 1050 Tyr Lys Asp Pro Asp Tyr Val Arg Lys Gly Asp Ala Arg Leu Pro 1055 1060 1065 Leu Lys Trp Met Ala Pro Glu Thr Ile Phe Asp Arg Val Tyr Thr 1070 1075 1080 Ile Gln Ser Asp Val Trp Ser Phe Gly Val Leu Leu Trp Glu Ile 1085 1090 1095 Phe Ser Leu Gly Ala Ser Pro Tyr Pro Gly Val Lys Ile Asp Glu 1100 1105 1110 Glu Phe Cys Arg Arg Leu Lys Glu Gly Thr Arg Met Arg Ala Pro 1115 1120 1125 Asp Tyr Thr Thr Pro Glu Met Tyr Gln Thr Met Leu Asp Cys Trp 1130 1135 1140 His Gly Glu Pro Ser Gln Arg Pro Thr Phe Ser Glu Leu Val Glu 1145 1150 1155 His Leu Gly Asn Leu Leu Gln Ala Asn Ala Gln Gln Asp Gly Lys 1160 1165 1170 Asp Tyr Ile Val Leu Pro Ile Ser Glu Thr Leu Ser Met Glu Glu 1175 1180 1185 Asp Ser Gly Leu Ser Leu Pro Thr Ser Pro Val Ser Cys Met Glu 1190 1195 1200 Glu Glu Glu Val Cys Asp Pro Lys Phe His Tyr Asp Asn Thr Ala 1205 1210 1215 Gly Ile Ser Gln Tyr Leu Gln Asn Ser Lys Arg Lys Ser Arg Pro 1220 1225 1230 Val Ser Val Lys Thr Phe Glu Asp Ile Pro Leu Glu Glu Pro Glu 1235 1240 1245 Val Lys Val Ile Pro Asp Asp Asn Gln Thr Asp Ser Gly Met Val 1250 1255 1260 Leu Ala Ser Glu Glu Leu Lys Thr Leu Glu Asp Arg Thr Lys Leu 1265 1270 1275 Ala Pro Ser Phe Ser Gly Met Val Ser Ser Lys Ser Arg Glu Ser 1280 1285 1290 Val Ala Ser Glu Gly Ser Asn Gln Thr Ser Gly Tyr Gln Ser Gly 1295 1300 1305 Tyr His Ser Asp Asp Thr Asp Thr Thr Val Tyr Ser Ser Glu Glu 1310 1315 1320 Ala Glu Leu Leu Lys Leu Ile Glu Ile Gly Val Gln Thr Gly Ser 1325 1330 1335 Thr Ala Gln Ile Leu Gln Pro Asp Ser Gly Thr Thr Leu Ser Ser 1340 1345 1350 Pro Pro Val 1355 <![CDATA[<210> 102]]> <![CDATA[<211> 98]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 102]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg <![CDATA[<210> 103]]> <![CDATA[<211> 712]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 103]]> Met Gln Ser Lys Val Leu Leu Ala Val Ala Leu Trp Leu Cys Val Glu 1 5 10 15 Thr Arg Ala Ala Ser Val Gly Leu Pro Ser Val Ser Leu Asp Leu Pro 20 25 30 Arg Leu Ser Ile Gln Lys Asp Ile Leu Thr Ile Lys Ala Asn Thr Thr 35 40 45 Leu Gln Ile Thr Cys Arg Gly Gln Arg Asp Leu Asp Trp Leu Trp Pro 50 55 60 Asn Asn Gln Ser Gly Ser Glu Gln Arg Val Glu Val Thr Glu Cys Ser 65 70 75 80 Asp Gly Leu Phe Cys Lys Thr Leu Thr Ile Pro Lys Val Ile Gly Asn 85 90 95 Asp Thr Gly Ala Tyr Lys Cys Phe Tyr Arg Glu Thr Asp Leu Ala Ser 100 105 110 Val Ile Tyr Val Tyr Val Gln Asp Tyr Arg Ser Pro Phe Ile Ala Ser 115 120 125 Val Ser Asp Gln His Gly Val Val Tyr Ile Thr Glu Asn Lys Asn Lys 130 135 140 Thr Val Val Ile Pro Cys Leu Gly Ser Ile Ser Asn Leu Asn Val Ser 145 150 155 160 Leu Cys Ala Arg Tyr Pro Glu Lys Arg Phe Val Pro Asp Gly Asn Arg 165 170 175 Ile Ser Trp Asp Ser Lys Lys Gly Phe Thr Ile Pro Ser Tyr Met Ile 180 185 190 Ser Tyr Ala Gly Met Val Phe Cys Glu Ala Lys Ile Asn Asp Glu Ser 195 200 205 Tyr Gln Ser Ile Met Tyr Ile Val Val Val Val Gly Tyr Arg Ile Tyr 210 215 220 Asp Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly Glu 225 230 235 240 Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Ile 245 250 255 Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys Leu 260 265 270 Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys Phe 275 280 285 Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp Gln Gly Leu 290 295 300 Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser Thr 305 310 315 320 Phe Val Arg Val His Glu Lys Pro Phe Val Ala Phe Gly Ser Gly Met 325 330 335 Glu Ser Leu Val Glu Ala Thr Val Gly Glu Arg Val Arg Ile Pro Ala 340 345 350 Lys Tyr Leu Gly Tyr Pro Pro Pro Glu Ile Lys Trp Tyr Lys Asn Gly 355 360 365 Ile Pro Leu Glu Ser Asn His Thr Ile Lys Ala Gly His Val Leu Thr 370 375 380 Ile Met Glu Val Ser Glu Arg Asp Thr Gly Asn Tyr Thr Val Ile Leu 385 390 395 400 Thr Asn Pro Ile Ser Lys Glu Lys Gln Ser His Val Val Ser Leu Val 405 410 415 Val Tyr Val Pro Pro Gln Ile Gly Glu Lys Ser Leu Ile Ser Pro Val 420 425 430 Asp Ser Tyr Gln Tyr Gly Thr Thr Gln Thr Leu Thr Cys Thr Val Tyr 435 440 445 Ala Ile Pro Pro Pro His His Ile His Trp Tyr Trp Gln Leu Glu Glu 450 455 460 Glu Cys Ala Asn Glu Pro Ser Gln Ala Val Ser Val Thr Asn Pro Tyr 465 470 475 480 Pro Cys Glu Glu Trp Arg Ser Val Glu Asp Phe Gln Gly Gly Asn Lys 485 490 495 Ile Glu Val Asn Lys Asn Gln Phe Ala Leu Ile Glu Gly Lys Asn Lys 500 505 510 Thr Val Ser Thr Leu Val Ile Gln Ala Ala Asn Val Ser Ala Leu Tyr 515 520 525 Lys Cys Glu Ala Val Asn Lys Val Gly Arg Gly Glu Arg Val Ile Ser 530 535 540 Phe His Val Thr Arg Gly Pro Glu Ile Thr Leu Gln Pro Asp Met Gln 545 550 555 560 Pro Thr Glu Gln Glu Ser Val Ser Leu Trp Cys Thr Ala Asp Arg Ser 565 570 575 Thr Phe Glu Asn Leu Thr Trp Tyr Lys Leu Gly Pro Gln Pro Leu Pro 580 585 590 Ile His Val Gly Glu Leu Pro Thr Pro Val Cys Lys Asn Leu Asp Thr 595 600 605 Leu Trp Lys Leu Asn Ala Thr Met Phe Ser Asn Ser Thr Asn Asp Ile 610 615 620 Leu Ile Met Glu Leu Lys Asn Ala Ser Leu Gln Asp Gln Gly Asp Tyr 625 630 635 640 Val Cys Leu Ala Gln Asp Arg Lys Thr Lys Lys Arg His Cys Val Val 645 650 655 Arg Gln Leu Thr Val Leu Glu Arg Val Ala Pro Thr Ile Thr Gly Asn 660 665 670 Leu Glu Asn Gln Thr Thr Ser Ile Gly Glu Ser Ile Glu Val Ser Cys 675 680 685 Thr Ala Ser Gly Asn Pro Pro Pro Gln Ile Met Trp Phe Lys Asp Asn 690 695 700 Glu Thr Leu Val Glu Asp Ser Glu 705 710
Claims (53)
- 一種抗-hVEGFR抗體或其抗原結合片段,其包括重鏈HCDR1、HCDR2及HCDR3及/或輕鏈LCDR1、LCDR2及LCDR3序列,其中: 該HCDR1序列包括 SSWMN(SEQ ID NO: 1)、 DYYMS(SEQ ID NO: 19)、 X 1YGMS (SEQ ID NO: 41)、 X 4YWIM (SEQ ID NO: 44),或其至少80%序列同一性的同源序列; 該HCDR2序列包括 RIFPGDGDTYYNGKFQV(SEQ ID NO: 2)、 FIRNKANGYTTEYSASVKG(SEQ ID NO: 20)、 SISX 2GGSYTYYADSVX 19G (SEQ ID NO: 42)、 DIYPGX 5GSTNYNEKFKS (SEQ ID NO: 45),或其至少80%序列同一性的同源序列; 該HCDR3序列包括 FLDTSGRYVDY(SEQ ID NO: 3)、 FDYYGSTYCFDY(SEQ ID NO: 21)、 EX 3DGNYDY (SEQ ID NO: 43)、 DSNPDY(SEQ ID NO: 46),或其至少80%序列同一性的同源序列; 該LCDR1序列包括 KASQDVNTAVA(SEQ ID NO: 4)、 RASQSVSTSSSSFMH(SEQ ID NO: 22)、 RSSKSLLYKDGKTYLN(SEQ ID NO: 28)、 RASESVX 6NSGISFMX 7 (SEQ ID NO: 47),或其至少80%序列同一性的同源序列; 該LCDR2序列包括 SASYRYI(SEQ ID NO: 5)、 YASNLES(SEQ ID NO: 23)、 LMSTRAS(SEQ ID NO: 29)、 AASX 8QX 9S (SEQ ID NO: 48),或其至少80%序列同一性的同源序列; 該LCDR3序列包括 QQHYRAPLT(SEQ ID NO: 6)、 QHTWEIPLT(SEQ ID NO: 24)、 QQLVEYPFT(SEQ ID NO: 30)、 QQSKEVPYT(SEQ ID NO: 49),或其至少80%序列同一性的同源序列, 其中X 1為I或M,X 2為V或I,X 3為L或M,X 4為T或S,X 5為T或S,X 6為D或E,X 7為T或H,X 8為T或Y,X 9為G或R且X 19為E或K。
- 如請求項1之抗-hVEGFR抗體或其抗原結合片段,其中該HCDR1包括SEQ ID NO: 41之胺基酸序列,該HCDR2包括SEQ ID NO: 42之胺基酸序列,該HCDR3包括SEQ ID NO: 43之胺基酸序列,該LCDR1包括SEQ ID NO: 28之序列,該LCDR2包括SEQ ID NO: 29之序列,且該LCDR3包括SEQ ID NO: 30之序列。
- 如請求項2之抗體或其抗原結合片段,其中 a)該HCDR1包括SEQ ID NO: 25之序列,HCDR2包括SEQ ID NO: 26之序列,該HCDR3包括SEQ ID NO: 27之序列;該LCDR1包括SEQ ID NO: 28之序列,該LCDR2包括SEQ ID NO: 29之序列,且該LCDR3包括SEQ ID NO: 30之序列;或者 b)該HCDR1包括SEQ ID NO: 31之序列,該HCDR2包括SEQ ID NO: 32或SEQ ID NO: 37之序列,且該HCDR3包括SEQ ID NO: 33之序列,該LCDR1包括SEQ ID NO: 28之序列,該LCDR2包括SEQ ID NO: 29之序列,且該LCDR3包括SEQ ID NO: 30之序列;或者 c)該HCDR1包括SEQ ID NO: 34之序列,該HCDR2包括SEQ ID NO: 35或SEQ ID NO: 37之序列,且該HCDR3包括SEQ ID NO: 36之序列,該LCDR1包括SEQ ID NO: 28之序列,該LCDR2包括SEQ ID NO: 29之序列,且該LCDR3包括SEQ ID NO: 30之序列。
- 如請求項1之抗-hVEGFR抗體或其抗原結合片段,其中該HCDR1包括SEQ ID NO: 44之胺基酸序列,該HCDR2包括SEQ ID NO: 45之胺基酸序列,該HCDR3包括SEQ ID NO: 46之胺基酸序列,該LCDR1包括SEQ ID NO: 47之序列,該LCDR2包括SEQ ID NO: 48之序列,且該LCDR3包括SEQ ID NO: 49之序列。
- 如請求項4之抗體或其抗原結合片段,其中 a)該HCDR1包括SEQ ID NO: 7之序列,HCDR2包括SEQ ID NO: 8之序列,該HCDR3包括SEQ ID NO: 9之序列;該LCDR1包括SEQ ID NO: 10之序列,該LCDR2包括SEQ ID NO: 11之序列,且該LCDR3包括SEQ ID NO: 12之序列;或者 b)該HCDR1包括SEQ ID NO: 13之序列,該HCDR2包括SEQ ID NO: 14之序列,且該HCDR3包括SEQ ID NO: 15之序列,該LCDR1包括SEQ ID NO: 16之序列,該LCDR2包括SEQ ID NO: 17之序列,且該LCDR3包括SEQ ID NO: 18之序列。
- 如請求項1之抗體或其抗原結合片段,其中 a)該HCDR1包括SEQ ID NO: 1之序列,該HCDR2包括SEQ ID NO: 2之序列,且該HCDR3包括SEQ ID NO: 3之序列,該LCDR1包括SEQ ID NO: 4之序列,該LCDR2包括SEQ ID NO: 5之序列,且該LCDR3包括SEQ ID NO: 6之序列;或者 b)該HCDR1包括SEQ ID NO: 19之序列,該HCDR2包括SEQ ID NO: 20之序列,且該HCDR3包括SEQ ID NO: 21之序列,該LCDR1包括SEQ ID NO: 22之序列,該LCDR2包括SEQ ID NO: 23之序列,且該LCDR3包括SEQ ID NO: 24之序列。
- 如前述請求項中任一項之抗體或其抗原結合片段,其進一步包括重鏈HFR1、HFR2、HFR3及HFR4中之一或多者,及/或輕鏈LFR1、LFR2、LFR3及LFR4中之一或多者,其中: 該HFR1包括 EVQLVESGGGLVKPGGSLX 10LSCAASGFTFS (SEQ ID NO: 84)或其至少80% (或至少85%、90%、95%)序列同一性的同源序列, 該HFR2包括 WVRQX 11PGKRLEWVA (SEQ ID NO: 85)或其至少80% (或至少90%)序列同一性的同源序列, 該HFR3包括 RFTISRDNAKNTLYLQMNSLX 12AEDTAVYYCAR (SEQ ID NO: 86)或其至少80% (或至少85%、90%、95%)序列同一性的同源序列, 該HFR4包括 WGX 13GTTLTVSS (SEQ ID NO: 87)或其至少80%序列同一性的同源序列, 該LFR1包括 DIVITQX 14X 15LSLPVTX 16GESVSISC (SEQ ID NO: 88)或其至少80% (或至少85%、90%、95%)序列同一性的同源序列, 該LFR2包括 WFLQRPGQSPQLLIY(SEQ ID NO: 89)或其至少80% (或至少85%、90%)序列同一性的同源序列, 該LFR3包括 GVX 17DRFSGSGSGTDFTLKISRVEAEDVGX 18YYC (SEQ ID NO: 90)或其至少80% (或至少85%、90%、95%)序列同一性的同源序列,及 該LFR4包括 FGSGTKLEIK(SEQ ID NO: 91)或其至少80% (或至少90%)序列同一性的同源序列, 其中X 10為R或K,X 11為A或T,X 12為R或K,X 13為Q或H,X 14為D或T,X 15為E或P,X 16為F或P,X 17為S或P,X 18為V或I。
- 如請求項7之抗體或其抗原結合片段,其中: 該HFR1包括選自由SEQ ID NO: 64、68及72組成之群的序列, 該HFR2包括選自由SEQ ID NO: 65、69及73組成之群的序列, 該HFR3包括選自由SEQ ID NO: 66、70及74組成之群的序列, 該HFR4包括選自由SEQ ID NO: 67、71及75組成之群的序列, 該LFR1包括選自由SEQ ID NO: 76及80組成之群的序列, 該LFR2包括選自由SEQ ID NO: 77及81組成之群的序列, 該LFR3包括選自由SEQ ID NO: 78及82組成之群的序列,及 該LFR4包括選自由SEQ ID NO: 79及83組成之群的序列。
- 如前述請求項中任一項之抗體或其抗原結合片段,其中該重鏈可變區包括選自由以下組成之群的序列:SEQ ID NO: 50、SEQ ID NO: 52、SEQ ID NO: 54、SEQ ID NO: 56、SEQ ID NO: 58、SEQ ID NO: 60、SEQ ID NO: 62、SEQ ID NO: 93、SEQ ID NO: 94、SEQ ID NO: 98,及其具有至少80%序列同一性但仍保留對hVEGFR2之特異性結合親和力的同源序列。
- 如前述請求項中任一項之抗體或其抗原結合片段,其中該輕鏈可變區包括選自由以下組成之群的序列:SEQ ID NO: 51、SEQ ID NO: 53、SEQ ID NO: 55、SEQ ID NO: 57、SEQ ID NO: 59、SEQ ID NO: 61、SEQ ID NO: 63、SEQ ID NO: 96、SEQ ID NO: 97,及其具有至少80%序列同一性但仍保留對hVEGFR2之特異性結合親和力的同源序列。
- 如前述請求項中任一項之抗體或其抗原結合片段,其中: i)該重鏈可變區包括SEQ ID NO: 50之序列及輕鏈可變區包括SEQ ID NO: 51之序列; j)該重鏈可變區包括SEQ ID NO: 52之序列及該輕鏈可變區包括SEQ ID NO: 53之序列; k)該重鏈可變區包括SEQ ID NO: 54之序列及該輕鏈可變區包括SEQ ID NO: 55之序列; l)該重鏈可變區包括SEQ ID NO: 56之序列及該輕鏈可變區包括SEQ ID NO: 57之序列; m)該重鏈可變區包括SEQ ID NO: 58之序列及該輕鏈可變區包括SEQ ID NO: 59之序列; n)該重鏈可變區包括SEQ ID NO: 60之序列及該輕鏈可變區包括SEQ ID NO: 61之序列; o)該重鏈可變區包括SEQ ID NO: 62之序列及該輕鏈可變區包括SEQ ID NO: 63之序列;或者 p)該重鏈可變區包括SEQ ID NO: 93或SEQ ID NO: 94或SEQ ID NO: 98之序列及該輕鏈可變區包括SEQ ID NO: 96或SEQ ID NO: 97之序列。
- 如前述請求項中任一項之抗體或其抗原結合片段,其進一步包括一或多個胺基酸殘基取代或修飾,但仍保留對hVEGFR2之特異性結合親和力。
- 如請求項12之抗體或其抗原結合片段,其中該等取代或修飾中之至少一者在一或多個CDR序列中,及/或在VH或VL序列之一或多個非CDR區中。
- 如前述請求項中任一項之抗體或其抗原結合片段,其亦包括免疫球蛋白恆定區、視情況人類Ig之恆定區、或視情況人類IgG之恆定區。
- 如請求項14之抗體或其抗原結合片段,其中該恆定區包括人類IgG1、IgG2、IgG3或IgG4之恆定區。
- 如請求項15之抗體或其抗原結合片段,其中該人類IgG1之恆定區包括SEQ ID NO: 38,或其具有至少80%序列同一性的同源序列。
- 如前述請求項中任一項之抗體或其抗原結合片段,其為人類化的。
- 如前述請求項中任一項之抗體或其抗原結合片段,其為雙功能抗體、Fab、Fab'、F(ab') 2、Fd、Fv片段、二硫鍵穩定化Fv片段(dsFv)、(dsFv) 2、雙特異性dsFv (dsFv-dsFv')、二硫鍵穩定化雙功能抗體(ds雙功能抗體)、單鏈抗體分子(scFv)、scFv二聚體(二價雙功能抗體)、多特異性抗體、駱駝化單域抗體、奈米抗體、域抗體或二價域抗體。
- 如前述請求項中任一項之抗體或其抗原結合片段,其為雙特異性的。
- 如前述請求項中任一項之抗體或其抗原結合片段,其能夠特異性結合hVEGFR2之第一及第二抗原決定基,或能夠特異性結合hVEGFR2及第二抗原。
- 如請求項20之抗體或其抗原結合片段,其中該第二抗原為免疫相關靶標,視情況選自由以下組成之群:PD-L1、PD-L2、PD-1、CLTA-4、TIM-3、LAG3、CD160、2B4、TGF β、VISTA、BTLA、TIGIT、LAIR1、OX40、CD2、CD27、ICAM-1、NKG2C、SLAMF7、NKp80、CD160、B7-H3、LFA-1、1COS、4-1BB、GITR、CD30、CD40、BAFFR、HVEM、CD7、LIGHT、IL-2、IL-15、CD3、CD16及CD83。
- 如請求項20之抗體或其抗原結合片段,其中該第二抗原包括腫瘤抗原。
- 如請求項22之抗體或其抗原結合片段,其中該腫瘤抗原存在於表現VEGFR2之細胞中。
- 如請求項22之抗體或其抗原結合片段,其中該腫瘤抗原包括緊密連接蛋白18.2、CA-125、神經節苷脂G(D2)、G(M2)及G(D3)、CD20、CD52、CD33、Ep-CAM、CEA、鈴蟾肽樣肽、PSA、HER2/neu、表皮生長因子受體(EGFR)、erbB2、erbB3/HER3、erbB4、CD44v6、Ki-67、癌症相關黏蛋白、VEGF、VEGFR (例如VEGFR3)、雌激素受體、Lewis-Y抗原、TGFβ1、IGF-1受體、EGFα、c-Kit受體、轉鐵蛋白受體、IL-2R或CO17-1A。
- 如前述請求項中任一項之抗體或其抗原結合片段,其與一或多個綴合物部分連接。
- 如請求項25之抗體或其抗原結合片段,其中該綴合物部分包括清除調節劑、化學治療劑、毒素、放射性同位素、鑭系元素、發光標記、螢光標記、酶-受質標記、DNA烷化劑、拓樸異構酶抑制劑、微管蛋白結合劑或其他抗癌藥物。
- 一種抗體或其抗原結合片段,其與如前述請求項中任一項之抗體或其抗原結合片段競爭結合hVEGFR2。
- 一種醫藥組合物,其包括如前述請求項中任一項之抗體或其抗原結合片段、以及一或多種醫藥學上可接受之載劑。
- 如請求項28之醫藥組合物,其進一步包括第二治療劑。
- 如請求項29之醫藥組合物,其中該第二治療劑包括抗癌療法,視情況地,該抗癌療法選自化學治療劑、放射療法、免疫治療劑、抗血管生成劑(例如VEGFR (如VEGFR-1及VEGFR-3)之拮抗劑)、EGFR拮抗劑、PDGFR拮抗劑、IGFR拮抗劑、NGFR拮抗劑、FGFR拮抗劑、靶向治療劑(例如HER2抗體、緊密連接蛋白18.2抗體)、細胞治療劑、基因治療劑、激素治療劑、細胞介素、緩解性治療、治療癌症之手術(例如腫瘤切除術)、一或多種止吐藥、化學療法引起之併發症的治療或癌症患者的膳食補充劑(例如吲哚-3-甲醇)。
- 一種分離之多核苷酸,其編碼如前述請求項之抗體或其抗原結合片段。
- 一種載體,其包括如請求項31之分離之多核苷酸。
- 一種宿主細胞,其包括如請求項32之載體。
- 一種表現如請求項1至27中任一項之抗體或其抗原結合片段的方法,其包括在表現如請求項31之載體之條件下培養如請求項33之宿主細胞。
- 一種在受試者中治療VEGFR2相關疾病或病症、降低VEGFR2相關疾病或病症之嚴重性及/或減緩VEGFR2相關疾病或病症之進展的方法,其包括向該受試者投與治療有效量之如請求項1至26中任一項之抗體或其抗原結合片段、或如請求項28至30中任一項之醫藥組合物。
- 如請求項35之方法,其中該VEGFR2相關疾病或病症為腫瘤或血管生成疾病。
- 如請求項36之方法,其中該腫瘤產生VEGF (例如,VEGF-A)及/或對其微環境中存在之VEGF (例如,VEGF-A)敏感。
- 如請求項36或37之方法,其中該腫瘤為實體瘤或非實體瘤。
- 如請求項38之方法,其中該實體瘤選自由以下組成之群:乳腺癌、肺癌、大腸直腸癌、胰臟癌、膠質瘤及淋巴瘤、頭頸腫瘤、神經內分泌腫瘤、大腸直腸腫瘤、前列腺腫瘤、乳腺腫瘤、肺腫瘤(如小細胞及非小細胞肺腫瘤)、胰腺腫瘤、甲狀腺腫瘤、卵巢腫瘤、肝腫瘤、卡波西肉瘤(Kaposi's sarcoma)、CNS腫瘤、神經母細胞瘤、毛細血管母細胞瘤、腦膜瘤、腦轉移、黑色素瘤、胃腸道及腎癌及肉瘤(例如胃癌)、橫紋肌肉瘤、膠質母細胞瘤(尤為多形性膠質母細胞瘤)、平滑肌肉瘤、鱗狀細胞癌、基底細胞癌及可藉由抑制惡性角化細胞(如人類惡性角化細胞)之生長來治療的皮膚癌。
- 如請求項39之方法,其中該腫瘤選自由以下組成之群:胃癌、非小細胞肺癌如大細胞肺癌。
- 如請求項38之方法,其中該非實體瘤選自由以下組成之群:白血病、多發性骨髓瘤及淋巴瘤,例如急性髓性白血病(AML)、慢性髓性白血病(CML)、急性淋巴球性白血病(ALL)、慢性淋巴球性白血病(CLL)、紅血球白血病或單核細胞白血病、霍奇金及非霍奇金淋巴瘤。
- 如請求項36之方法,其中該血管生成疾病選自由以下組成之群:動脈粥樣硬化、類風濕性關節炎(RA)、新生血管性青光眼、包含增生性糖尿病視網膜病變在內的增生性視網膜病變、黃斑變性、血管瘤、血管纖維瘤、牛皮癬、早產兒視網膜病變(例如,晶狀體後纖維增生)、角膜移植排斥、胰島素依賴型糖尿病、多發性硬化、重症肌無力、克羅恩病(Chron's disease)、自體免疫性腎炎、原發性膽汁性肝硬化、急性胰臟炎、同種異體移植排斥、過敏性發炎、接觸性皮炎及遲發性超敏反應、炎性腸病、感染性休克、骨質疏鬆症、骨關節炎、由神經元發炎引起之認知缺陷、奧斯勒-韋伯症候群(Osler-Weber syndrome)、再狹窄以及真菌、寄生蟲及病毒感染如巨細胞病毒感染。
- 如請求項34至42中任一項之方法,其中該受試者為人類。
- 如請求項34至42中任一項之方法,其中該投與係藉由口服、鼻、靜脈內、皮下、舌下、瘤內或肌肉內投與進行。
- 如請求項34至42中任一項之方法,其進一步包括投與治療有效量之第二治療劑。
- 如請求項45之方法,其中該第二治療劑包括抗癌療法,視情況地,該抗癌療法選自化學治療劑、放射療法、免疫治療劑、抗血管生成劑(例如VEGFR (如VEGFR-1、VEGFR-2及VEGFR-3)之拮抗劑)、EGFR拮抗劑、PDGFR拮抗劑、IGFR拮抗劑、NGFR拮抗劑、FGFR拮抗劑、靶向治療劑、細胞治療劑、基因治療劑、激素治療劑、細胞介素、緩解性治療、治療癌症之手術(例如腫瘤切除術)、一或多種止吐藥、化學療法引起之併發症的治療或癌症患者的膳食補充劑(例如吲哚-3-甲醇)。
- 一種套組,其包括如請求項1至27中任一項之抗體或其抗原結合片段。
- 一種偵測樣本中VEGFR2之存在或量的方法,其包括使該樣本與如請求項1至27中任一項之抗體或其抗原結合片段接觸,且測定該樣本中VEGFR2之存在或量。
- 如請求項1至27中任一項之抗體或其抗原結合片段在製備用於在受試者中治療VEGFR2相關疾病或病症、降低VEGFR2相關疾病或病症之嚴重性及/或減緩VEGFR2相關疾病或病症之進展的藥物中的用途。
- 如請求項49之用途,其中該VEGFR2相關疾病或病症為腫瘤或血管生成疾病。
- 如請求項50之用途,其中該腫瘤產生VEGF (例如,VEGF-A)及/或對其微環境中存在之VEGF (例如,VEGF-A)敏感。
- 如請求項50或51之用途,其中該腫瘤為實體瘤或非實體瘤。
- 如請求項50之用途,其中該血管生成疾病選自由以下組成之群:動脈粥樣硬化、類風濕性關節炎(RA)、新生血管性青光眼、包含增生性糖尿病視網膜病變在內的增生性視網膜病變、黃斑變性、血管瘤、血管纖維瘤、牛皮癬、早產兒視網膜病變(例如,晶狀體後纖維增生)、角膜移植排斥、胰島素依賴型糖尿病、多發性硬化、重症肌無力、克羅恩病、自體免疫性腎炎、原發性膽汁性肝硬化、急性胰臟炎、同種異體移植排斥、過敏性發炎、接觸性皮炎及遲發性超敏反應、炎性腸病、感染性休克、骨質疏鬆症、骨關節炎、由神經元發炎引起之認知缺陷、奧斯勒-韋伯症候群、再狹窄以及真菌、寄生蟲及病毒感染如巨細胞病毒感染。
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